TAXANE-LIPID-POLYSACCHARIDE DUAL CONJUGATES, PREPARATION METHODS THEREOF AND USES THEREOF

Abstract

The present invention pertains to a group of taxane-lipid-polysaccharide dual conjugates of the Formula I, a process for the preparation thereof, uses thereof, and pharmaceutical compositions comprising the same. The invention also relates to a series of intermediates for the preparation of taxane-lipid-polysaccharide dual conjugates, a process for their preparation, and their use as drug delivery vehicles.

##STR00001##

Claims

1. A taxane-lipid-polysaccharide dual conjugate depicted by the formula (I): or a pharmaceutically acceptable salt or solvate thereof, ##STR00250## within their structures: the so-called linker unit(s) may be selected from ##STR00251## the polysaccharide is covalently linked to the linker unit(s) through one or more conjugation sites thereof; the linker unit is covalently linked to a taxane compound or a lipid compound unit; the polysaccharide conjugation site refers to a hydroxyl group, a carboxyl group, an amino group, a phosphate group or a sulfonic acid group inherent to the polysaccharide; the molecular molar ratio of the taxane compounds to the lipid compounds unit is an arbitrary ratio, preferably 0.1 to 99.9%, more preferably 0.1 to 60%, and far more preferably the following ratio range: 0.1 to 50, 0.1 to 20, 0.1 to 10, 0.1˜5, 0.1˜1, 1˜50, 1-20, 1˜10 or 1-5, such as 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2 or 0.1, or 9, 8, 7, 6, 5, 4, 3, 2 or 1; the polysaccharide is selected from phyto-polysaccharides, animal polysaccharides, microbial polysaccharides or synthetic polysaccharides and derivatives thereof; the taxane compound is selected from a natural or artificial semi-synthetic compound and a derivative thereof, which contains the core structure of taxane diterpenes; the lipid compound unit is a single molecular lipid compound, or a structural unit composed of a plurality of the same or of different single molecular of lipid compounds; the linker 1-3, the spacer 1-4, and the branching unit are all connected to each other by a covalent bond, and are also covalently bonded to the polysaccharide and the taxane compound; the covalent bond is selected from the group of bonds consisting of an amide bond, an amino-carbamate bond, an aminothiocarbamate bond, an ester bond, an isourea bond, a thiourea bond, a urea bond, a disulfide bond, a carbonate bond, a phosphate ester bond, phosphamide bond, sulfonamide bond, alpha or beta glycosylic bond, a covalent bond containing triazole.

2. The taxane-lipid-polysaccharide dual conjugate according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein the polysaccharide is selected from the group consisting of homopolysaccharides or heteropolysaccharides, in the structure of polysaccharide, the chain may be linear, branched, or cyclic; the glycosylic bond between sugar units of the homopolysaccharide or heteropolysaccharide may be α-type or β-type or α,β-mixed type; the sugar unit of the homopolysaccharide is selected from the group consisting of a tri-carbon sugar, a four-carbon sugar, a five-carbon sugar, a six-carbon sugar, a seven-carbon sugar, and an eight-carbon sugar or a deoxy sugar unit, which are structurally composed of a plurality of single sugar units; the heteropolysaccharide, their saccharide units are composed of a mixture of two or more types of monosaccharide units; the polysaccharides in their structures may be naturally or synthetically modified with one or more substituents which are selected from the group consisting of carboxy acid group, carboxylate group, amino group, sulfonic acid group, sulfonate group, phosphoric acid group, phosphate group, hydroxyethyl group, hydroxypropyl group, methyl group, acyl group; preferably, the polysaccharide is selected from the dextran, hyaluronic acid, hydroxyethyl starch, carboxymethyl cellulose, poly-galactosamine, poly-sialic acid, or polysaccharide of Ganoderma lucidum, lentinan (polysaccharide of Lentinula edodes); wherein the polysaccharide may have a molecular weight ranging from 300 to 3,000,000.

3. The taxane-lipid-polysaccharide dual conjugate according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein the taxane compound is selected from natural taxane compounds and semi-synthetic taxanes, preferably paclitaxel, docetaxel, cabazitaxel and milataxel; the polysaccharide is linked to the taxane by a linker and/or a spacer, optionally linked to 2′-O position, 7-O position, 10-O position of the taxane core structure or the side chain of its altered structure; preferably, 2′-O position of the taxane or the side chain of its altered structure.

4. The taxane-lipid-polysaccharide dual conjugate according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein the single molecular lipid compound is selected from the group consisting of saturated or unsaturated fatty acids and their derivatives thereof, saturated or unsaturated cyclic alkyl acids and their derivatives thereof, aryl or heterocyclic aryl acids and their derivatives thereof, glycerides, glycerol phosphates, sphingolipids, sterols and their derivatives thereof, prenol lipids and their derivatives thereof, glycolipids and their derivatives thereof, lipid-soluble vitamins and their derivatives thereof; these lipid compounds are optionally substituted by one or more substituents which may be the same or different; the substituents are independently selected from the group consisting of C.sub.1-20 hydrocarbyl, C.sub.2-10 alkenyl, C.sub.2-10 alkyne, C.sub.3-15 cycloalkyl, C.sub.5-20 aryl, C.sub.7-20 arylalkyl, heteroaryl, heterocycloalkyl, ester group, keto group, hydroxyl group, phenolic hydroxyl group, C.sub.1-18 alkoxy group, C.sub.3-15 monocyclic or polycyclic alkoxy group, amino group, C.sub.1-10 alkyl group, mono or disubstituted amino group, amide group, sulfonic acid group, sulfonamide group, halogen (fluorine, chlorine, bromine, iodine), trifluoromethyl group; preferably, the saturated or unsaturated fatty acid of the single molecular lipid compound and its derivatives are selected from the group consisting of stearic acid, palmitic acid, octanoic acid, tannic acid, lauric acid, myristic acid, arachidonic acid, behenic acid, lignoceric acid, hexadecanoic acid, myristoleic acid, palmitoleic acid, sapienic acid, oleic acid, Elaidic acid, 11-octadecene acid, linoelaidic acid, alpha-linolenic acid (ALA), gamma-linoleic acid (GLA), arachidonic acid, eicosapentaic acid (EPA), erucic acid, docosahexaenoic acid (DHA), and its corresponding alcohol, amine, azide compound and isocyanate; preferably DHA, EPA, GLA; preferably, the saturated cycloalkyl acid of the single molecular lipid compound is selected from the group consisting of C.sub.3-10 saturated cycloalkyl acids, 3-12 membered saturated heterocycloalkyl acids containing at least one N, O or S hetero atom, wherein C.sub.3-10 The saturated cycloalkyl group is preferably a C.sub.3-10 cycloalkyl group such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group, wherein the saturated 3-12 membered heterocycloalkyl group is preferably selected from the group consisting of tetrahydrofuran, tetrahydrothiophene, azetidine, acridine, tetrahydropyrrole, 1,3-dihydrothiazole, 1,3-dihydrooxazole, piperidine, piperazine, morpholine, thiomorpholine or tetrahydrothiazide; The unsaturated cycloalkyl acid group is selected from the group consisting of C.sub.5-10 cycloalkenyl hydrocarbyl, C.sub.5-10 cycloalkynyl acid, C.sub.5-10 cycloalkenyloxyalkyl acid, C.sub.5-10 cycloalkynyloxyalkyl acid, 5-10 membered heterocycloalkenyl hydrocarbon acid containing at least one N, O or S hetero-atom, a 5-10 membered heterocycloalkenyloxyalkyl acid having at least one N, O or S hetero atom, 5-10 membered heterocyclic alkynyl hydrocarbamic acid which contains at least one N, O or S hetero atom; a 5-10 membered heterocycloalkynyloxyalkyl acid which contains at least one N, O or S hetero atom, wherein the C.sub.5-10 cycloalkenyl group is preferably selected as a cyclopentenyl group, a cyclohexenyl group, cycloheptenyl, or octenyl; C.sub.5-10 cycloalkynyl is preferably selected as a cyclo-octynyl group, the 5-10 membered heterocycloalkynyl group is preferably selected as a cyclo-octynyl group which contains at least one N, O or S hetero atom; and the corresponding alcohol, amine, sulfhydryl, an azide compound and an isocyanate of the aforementioned saturated or unsaturated cycloalkyl acid; More preferably, the saturated or unsaturated cycloalkyl acid is selected from the following structures and derivatives thereof: ##STR00252## preferably, the aryl acid or heterocyclic aryl acid of the single molecular lipid compound and its derivative are selected from an aromatic alkyl group (C.sub.0-8) acid, an aromatic alkenyl group (C.sub.0-8) acid, and one or more aromatic alkyl (C.sub.0-10) acids, two or more aromatic ring fused alkyl(C.sub.0-10) acids, heterocyclic aromatic alkyl groups containing at least one N, O or S hetero atom (C.sub.0-10) Acid, whose structure is as follows: ##STR00253## wherein aryl is selected from: 1) a five-membered heteroaryl, six-membered aryl, six-membered heteroaryl group, preferably phenyl, pyridyl, pyrrolyl, imidazolyl; optionally substituted by the substituents defined above for a single molecular lipid compound; 2) double ring, double fused ring and triple fused ring are selected from: ##STR00254## it is optionally substituted with the substituents defined as above for a single molecular lipid compound; 3) L is selected from a disubstituted saturated linear or branched or cyclic C.sub.0-15 alkylgroup, a disubstituted C.sub.2-10 alkenyl group containing one or more double bonds, and a disubstituted C.sub.2-12 containing one or more triple bonds. An alkyne group, a disubstituted C.sub.3-10 heterocycloalkyl group, a disubstituted C.sub.3-12 heterocycloalkyl group containing one or more double or triple bonds, a keto group; and a disubstituted straight or branched C.sub.0-15 alkylgroup which is optionally substituted with a substituent as defined above for a single molecular lipid compound wherein at least one hetero atom selected from N, O or S; More preferably, the aryl or heterocyclic aryl acid is selected from the following structures and derivatives and isomers thereof: ##STR00255## wherein R is selected from the group consisting of an alkyl group, a cycloalkyl group, an aryl group, an arylalkyl group, and a cycloalkyl group; preferably, the glyceride of the single molecular lipid compound is selected from the group consisting of a saturated or unsaturated fatty acid, a saturated or unsaturated cycloalkyl acid, a monocarboxylic ester or a di-ester, or a tri-ester of an arylcarboxylic acid or a heteroaryl acid with glycerol; more preferably a monoester and a di-ester of an unsaturated fatty acid and glycerol along with derivatives thereof; preferably, the glycerol phosphate of the single molecular lipid compound is selected from the group consisting of cephalin, lecithin, phosphatidylethanolamine, phospholipid serine, phosphatidylinositol; more preferably cephalin, lecithin, phosphatidylethanolamine along with derivatives thereof; preferably, the sphingolipid compound of the single molecular lipid compound is selected from the group consisting of sphingomyelin, ceramide, glycosphingolipid; more preferably sphingomyelin or ceramide and derivatives thereof; preferably, the sterols of the single molecular lipid compound and derivatives thereof are selected from the group consisting of cholesterol and derivatives thereof; 2) free bile acids and conjugated bile acids and their derivatives, such as cholic acid, deoxycholic acid, chenodeoxycholic acid, lithocholic acid, deoxycholic acid, glycocholic acid, taurocholic acid. 3) C.sub.18 sterols and their derivatives such as estrogen. 4) C.sub.19 sterols and their derivatives, including androgens such as testosterone and androstenone; 5) C.sub.21 sterols, including progesterone, glucocorticoids and mineralocorticoids; 6) phytosterols and derivatives thereof such as β-sitosterol, sterol and Brassicasterol; more preferably bile acids, β-sitosterol and derivatives thereof; preferably, the prenol lipids and derivatives thereof of the single molecular lipid compound are selected from the group consisting of isoprene monomers, diploids or/and polyploids and derived alcohols, amines, acids, phospholipids and derivatives thereof; more preferred are isoprene diploids and polyploid-derived alcohols, amines, acids, phospholipids and derivatives thereof; preferably, the glycolipid of the single molecular lipid compound is selected from the group consisting of saturated fatty acids, unsaturated fatty acids, cycloalkyl acids, unsaturated cycloalkyl acids, and arylcarboxylic acids and sugars (including monosaccharides, disaccharides, and trisaccharides), the monoester and the polyester formed thereof; more preferably, a poly-acid ester or amide formed by a saturated fatty acid or an unsaturated fatty acid and a sugar, and derivatives thereof; preferably, the lipid-soluble vitamins and derivatives of the single molecular lipid compound are selected from the group consisting of vitamin A, vitamin D (including vitamins D.sub.1, D.sub.2, D.sub.3, D.sub.4 and D.sub.5), vitamin E (including α, β, γ and δ tocopherol and α, β, γ and δ tocotrienol), vitamin K (including vitamin K.sub.1 and K.sub.2), vitamin P and their derivatives; more preferably vitamin A, vitamin D, vitamin E and their derivatives; preferably, the structural unit consisting of a plurality of the same or of different single molecular lipid compounds comprising two types: a grafted lipid compound unit and a dendritic lipid compound unit: ##STR00256## wherein n is selected from an integer between 0 and 10, preferably an integer between 2 and 5; wherein the lipid compound in the grafted lipid compound unit and/or the dendritic lipid compound unit is selected from the above-mentioned general or preferred definitions for a single molecular lipid compound; more preferably, the structural unit composed of the lipid compound with so called plurality of same or different single molecules is selected from the following structures, derivatives and isomers thereof: ##STR00257## ##STR00258## ##STR00259##

5. The taxane-lipid-polysaccharide dual conjugate according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein the linker-1, 2, 3, which may be the same or each independently different from each other, having the following formula: ##STR00260## the covalently linked units selected from the group consisting of a 1,2,3-triazole fragment, a 1,2,3-triazole fragment with a fused ring with a substituent, a cyclooctyl[d]hydropyridazine fragment, 2-hydrocarbylthiosuccinate lactam fragment, 2-hydrocarbylethylsulfone fragment, amide fragment, disulfide bond fragment, disulfide-substituted aryl moiety, urea bond fragment, substituted 3-(alkylthio)- a 3-phenylacrylonitrile fragment, a substituted cyclooctane[d]hydropyridazine fragment, a substituted 1,2,4-triazolidine-3,5-dione fragment, 1,6a-dihydropyrrolo[3 a 4-triazol-4,6 (5aH,5H)-dione fragment; The so-called substituents being as defined in claim 4 for a substituent of a single molecular lipid compound; the linker-1 and the linker-2 can be the same or different and are independently selected from the following structures: 1) natural amino acids, unnatural amino acids, such as D-amino acids, β-aminopropionic acid, γ-aminobutyric acid or ε-aminocaproic acid, or derivatives thereof, or 2 to 100 oligopeptides composed of these amino acids or a polypeptide fragment; 2) —[X1].sub.0 or 1-[disubstituted hydrocarbyl-1].sub.0 or 1-[X2].sub.0 or 1-[disubstituted aryl].sub.0 or 1-[X3].sub.0 or 1-[disubstituted a structural moiety of a hydrocarbyl-2].sub.0 or 1-[X4].sub.0 or 1-; wherein X1, X2, X3 and X4 can be the same or different and are selected from O, S, NH or NR, CO, CONN, CONHR, S—S, COO, OCOO, SO.sub.2NH, SO.sub.2NR, NHCOO, NRCOO, NHCONH, NRCONH, NR.sub.1CONR.sub.2, OPO.sub.3, OPO.sub.2NH, OPO.sub.2NR, a covalent bond containing a triazole; wherein R, R.sub.1, R.sub.2 are independently selected from the group consisting of an alkyl group, a cycloalkyl group, an aryl group, an arylalkyl group, a cycloalkyl alkyl group; the disubstituted hydrocarbyl-1 fragment and the disubstituted hydrocarbyl-2 fragment are the same or different and are selected from a linear or branched or cyclic (including fused ring or spiro-ring) C.sub.1-20 alkyl group (preferably a C.sub.1-12 alkylgroup), a linear or branched cyclic (including fused ring or spiro-ring) C.sub.1-20 alkylgroup (preferably a C.sub.1-12 alkylgroup) containing at least one heteroatom selected from N, O or S; a linear or branched C.sub.2-15 alkyl group containing one or more double bonds (preferably a C.sub.2-10 alkyl group having a double bond), a linear or branched C.sub.2-10 alkyl group having one or more triple bonds (preferably a C.sub.2-8 alkyl group having a triple bond), a C.sub.3-10 cycloalkyl group containing one or more double bonds (including a fused ring or a spiro ring, preferably a 3-8 membered cycloalkyl group containing a double bond), a cyclic C.sub.2-12 alkyl group containing one or more triple bonds (including fused ring or spiro ring, preferably a 3-8 membered cycloalkyl group containing a triple bond, a 3-10 membered heterocycloalkyl group containing at least one heteroatom selected from N, O or S (including a fused ring or a spiro ring, preferably 3-6 membered heterocycloalkyl group); a heterocycloalkyl group having at least one 3-10 membered heterocycloalkyl group and a hetero atom selected from N, O or S and one or more double bonds (a fused ring or spiro ring, preferably a 3-8 membered heterocycloalkyl group containing a double bond), and a 5-12 membered heterocycloalkyl group containing at least one heteroatom selected from N, O or S and one or more triple bonds (including a fused ring or a spiro ring, preferably a 6-9 membered heterocycloalkyl group containing a triple bond); the disubstituted aryl group is selected from a single aryl group or a fused ring aryl group, a single heteroaryl group or a fused ring heteroaryl group; the disubstituted hydrocarbyl-1 fragment, the disubstituted hydrocarbyl-2 fragment and the disubstituted aryl fragment are optionally substituted by a mono- or poly-substituent as defined in claim 4 for a single molecular lipid compound. 3) polymer fragments such as polyethylene glycol (PEG) having a molecular weight of 100 to 50,000, [CH.sub.2SCH.sub.2].sub.1-10000, [CH.sub.2CH.sub.2OCH.sub.2CH.sub.2].sub.1-10000, polyamide, polylactic acid (PGA), poly(lactic-glycolic acid) copolymer (PLGA); 4) covalently linked (C.sub.3-8) structural fragments consisting of 1-100 saccharide units and derivatives thereof, such as glycerol, mannitol, glucosamine and their derivatives; the linkers are preferably the following structures and derivatives and isomers thereof: ##STR00261## ##STR00262## ##STR00263## ##STR00264## among the structure, the covalently linked unit(s) are selected from the following: ##STR00265## ##STR00266##

6. The taxane-lipid-polysaccharide dual conjugate according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein the spacer group-1, 2, 3, 4 are the same or independently different from each other, and the number is optionally 0 or 1; the spacer is selected from the following structures: 1) a natural amino acid, a non-natural amino acid (such as a D-amino acid, β-aminopropionic acid, γ-aminobutyric acid or ε-aminocaproic acid) or a derivative thereof or a short peptide fragment comprised of 2 to 20 of these amino acids; 2) —[X1].sub.0 or 1-[disubstituted hydrocarbyl-1].sub.0 or 1-[X2].sub.0 or 1-[disubstituted aryl].sub.0 or 1-[X3].sub.0 or 1-[disubstituted a structural moiety of a hydrocarbyl-2].sub.0 or 1-[X4].sub.0 or 1; wherein X1, X2, X3 and X4 are the same or different and are selected from O, S, NH or NR, CO, CONH, CONHR, S—S, COO, OCOO, SO.sub.2NH, SO.sub.2NR, NRCOO, NRCOO, NHCONH, NRCONH, NR.sub.1CONR.sub.2, OPO.sub.3, OPO.sub.2NH, OPO.sub.2NR, a covalent bond containing a triazole; wherein R, R.sub.1, R.sub.2 are independently selected from the group consisting of an alkyl group, a cycloalkyl group, an aryl group, an arylalkyl group, a cycloalkyl alkyl group; the disubstituted hydrocarbyl-1 fragment and the disubstituted hydrocarbyl-2 fragment are the same or different and are selected from a linear or branched or cyclic (including fused ring or spiro-ring) C.sub.1-20 alkylgroup (preferably a C.sub.1-12 alkylgroup), a linear or branched cyclic (including fused ring or spiro-ring) C.sub.1-20 alkyl group (preferably a C.sub.1-12 alkylgroup) containing at least one heteroatom selected from N, O or S; a linear or branched C.sub.2-15 alkyl group containing one or more double bonds (preferably a C.sub.2-10 alkyl group having a double bond), a linear or branched C.sub.2-10 alkyl group having one or more triple bonds (preferably a C.sub.2-8 alkyl group having a triple bond), a C.sub.3-10 cycloalkyl group containing one or more double bonds (including a fused ring or a spiro ring, preferably a 3-8 membered cycloalkyl group containing a double bond), a cyclic C.sub.2-12 alkyl group containing one or more triple bonds (including fused ring or spiro ring, preferably a 3-8 membered cycloalkyl group containing a triple bond, a 3-10 membered heterocycloalkyl group containing at least one heteroatom selected from N, O or S (including a fused ring or a spiro ring, preferably 3-6 membered heterocycloalkyl group); a heterocycloalkyl group having at least one 3-10 membered heterocycloalkyl group and a hetero atom selected from N, O or S and one or more double bonds (a fused ring or spiro ring, preferably a 3-8 membered heterocycloalkyl group containing a double bond), and a 5-12 membered heterocycloalkyl group containing at least one heteroatom selected from N, O or S and one or more triple bonds (including a fused ring or a spiro ring, preferably a 6-9 membered heterocycloalkyl group containing a triple bond); the disubstituted aromatic group is selected from a single aryl or fused ring aryl group, a single heteroaryl group or a fused ring heteroaryl group; the disubstituted hydrocarbyl-1 fragment, the disubstituted hydrocarbyl-2 fragment, and the disubstituted aryl fragment are optionally mono- or poly-substituted, and the substituent is as defined in claim 4 for a single molecular lipid compound. 3) short polymer fragments, such as polyethylene glycol (PEG), polyamide, polylactic acid (PGA), poly(lactic-co-glycolic acid) copolymer (PLGA) having a molecular weight of 100-2000; 4) covalently linked structural fragments consisting of 1-10 sugar units and derivatives thereof such as glycerol, mannitol, glucosamine and their derivatives; preferably, the spacer is selected from the following structures and derivatives and isomers thereof: ##STR00267## ##STR00268## ##STR00269##

7. The taxane-lipid-polysaccharide dual conjugate according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein the branch unit is selected from the group consisting of amino acids (including natural amino acids and unnatural amino acids) and derivatives thereof, saccharide units and derivatives thereof, aryl substituted compounds and derivatives thereof, substituted hydrocarbons and derivatives thereof, triazole containing compound or derivatives of, or compounds with substitution by sulfanes; preferably, the branch units are selected from the following structures and derivatives and isomers thereof: ##STR00270## ##STR00271## ##STR00272## ##STR00273## ##STR00274##

8. The taxane-lipid-polysaccharide dual conjugate according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein the taxane-lipid-polysaccharide dual conjugate is selected from the group consisting of the following compounds, and their derivatives and isomers thereof: ##STR00275## ##STR00276## ##STR00277## ##STR00278## ##STR00279## ##STR00280## ##STR00281## ##STR00282## ##STR00283## ##STR00284## ##STR00285## ##STR00286## ##STR00287## ##STR00288## ##STR00289## ##STR00290## ##STR00291## ##STR00292## ##STR00293## ##STR00294## ##STR00295## ##STR00296## ##STR00297## ##STR00298## ##STR00299## ##STR00300## ##STR00301## ##STR00302##

9. A functionalized taxane derivative of the formula II, or a pharmaceutically acceptable salt, solvate or isomer thereof, ##STR00303## wherein the taxane compound, is selected from a natural or artificial semi-synthetic compound and a derivative thereof, which contains the core structure of taxane diterpenes, preferably paclitaxel, docetaxel, cabazitaxel and milataxel; the polysaccharide is linked to the taxane by a linker and/or a spacer, optionally linked to 2′-O position, 7-O position, 10-O position of the taxane core structure or the side chain of its altered structure; preferably, 2′-O position of the taxane or the side chain of its altered structure; wherein spacer-1, spacer-2 and linker-1 can be the same or different and are independently selected from the following structures: 1) natural amino acids, unnatural amino acids, such as D-amino acids, β-aminopropionic acid, γ-aminobutyric acid or ε-aminocaproic acid, or derivatives thereof, or 2 to 100 oligopeptides composed of these amino acids or a polypeptide fragment 2) —[X1].sub.0 or 1-[disubstituted hydrocarbyl-1].sub.0 or 1-[X2].sub.0 or 1-[disubstituted aryl].sub.0 or 1-[X3].sub.0 or 1-[disubstituted a structural moiety of a hydrocarbyl-2].sub.0 or 1-[X4].sub.0 or 1-; wherein X1, X2, X3 and X4 can be the same or different and are selected from O, S, NH or NR, CO, CONN, CONHR, S—S, COO, OCOO, SO.sub.2NH, SO.sub.2NR, NHCOO, NRCOO, NHCONH, NRCONH, NR.sub.1CONR.sub.2, OPO.sub.3, OPO.sub.2NH, OPO.sub.2NR, a covalent bond containing a triazole; wherein R, R.sub.1, R.sub.2 are independently selected from the group consisting of an alkyl group, a cycloalkyl group, an aryl group, an arylalkyl group, a cycloalkyl alkyl group; the disubstituted hydrocarbyl-1 fragment and the disubstituted hydrocarbyl-2 fragment are the same or different and are selected from a linear or branched or cyclic (including fused ring or spiro-ring) C.sub.1-20 alkyl group (preferably a C.sub.1-12 alkylgroup), a linear or branched cyclic (including fused ring or spiro-ring) C.sub.1-20 alkylgroup (preferably a C.sub.1-12 alkylgroup) containing at least one heteroatom selected from N, O or S; a linear or branched C.sub.2-15 alkyl group containing one or more double bonds (preferably a C.sub.2-10 alkyl group having a double bond), a linear or branched C.sub.2-10 alkyl group having one or more triple bonds (preferably a C.sub.2-8 alkyl group having a triple bond), a C.sub.3-10 cycloalkyl group containing one or more double bonds (including a fused ring or a spiro ring, preferably a 3-8 membered cycloalkyl group containing a double bond), a cyclic C.sub.2-12 alkyl group containing one or more triple bonds (including fused ring or spiro ring, preferably a 3-8 membered cycloalkyl group containing a triple bond, a 3-10 membered heterocycloalkyl group containing at least one heteroatom selected from N, O or S (including a fused ring or a spiro ring, preferably 3-6 membered heterocycloalkyl group); a heterocycloalkyl group having at least one 3-10 membered heterocycloalkyl group and a hetero atom selected from N, O or S and one or more double bonds (a fused ring or spiro ring, preferably a 3-8 membered heterocycloalkyl group containing a double bond), and a 5-12 membered heterocycloalkyl group containing at least one heteroatom selected from N, O or S and one or more triple bonds (including a fused ring or a spiro ring, preferably a 6-9 membered heterocycloalkyl group containing a triple bond); the disubstituted aryl group is selected from a single aryl group or a fused ring aryl group, a single heteroaryl group or a fused ring heteroaryl group; the disubstituted hydrocarbyl-1 fragment, the disubstituted hydrocarbyl-2 fragment and the disubstituted aryl fragment are optionally substituted by a mono- or poly-substituent as defined in claim 4 for a single molecular lipid compound, 3) polymer fragments such as polyethylene glycol (PEG) having a molecular weight of 100 to 50,000, [CH.sub.2SCH.sub.2].sub.1-10000, [CH.sub.2CH.sub.2OCH.sub.2CH.sub.2].sub.1-10000, polyamide, polylactic acid (PGA), poly(lactic-glycolic acid) copolymer (PLGA); 4) covalently linked (C.sub.3-8) structural fragments consisting of 1-100 saccharide units and derivatives thereof, such as glycerol, mannitol, glucosamine and their derivatives; the covalent bond of the taxane compound linking to spacer-1 is selected from the group consisting of an urethane bond, an amino thiocarboxylate bond, an ester bond, a carbonate bond, a phosphate bond, an alpha or beta glycosylic bond; the number of spacers is optionally 0 or 1; the functional group is selected from the group consisting of: 1) amino (—NH.sub.2), substituted amino (—NHR), carboxyl (—COOH), azide (—N.sub.3), sulfhydryl (—SH), sulfonic acid (—SO.sub.3H), sulfonylamino (—SO.sub.2NH—, —SO.sub.2NHR), phosphate group (—PO.sub.3H), phosphate ester group (—PO.sub.3R), phosphoramide group (—PO.sub.3NH—, —PO.sub.3NR—), isothiocyano group, iso-oxycyano group, phenolic hydroxyl group; among them, the substituent R group is selected from an alkyl group, a cycloalkyl group, an aromatic alkyl group, an arylalkyl group, or a cycloalkyl alkyl group; 2) an alkynyl compound capable of coupling with an azide compound, a monocyclic derivative containing an acetylenic bond, a fused ring derivative containing an acetylenic bond, any of above compound is selected from aryl cyclooctyne (ALO), thiocyclooctyne, cyclooctyne (OCT), Biarylazacyclooctynone (BARAC), Dibenzoazacyclooctyne (DIBAC), Bicyclononyne (BCN), Dibenzocyclooctyne (DIBO), Difluorocyclooctyne (DIFO), Monofluororinated cyclooctyne (MOFO), Dimethoxy azacyclooctyne (DIMAC), Nonfluoroocyclooctyne (NOFO), (thioOCT)), Tetramethoxy dibenzocyclooctyne (TMDIBO); 3) maleimide group, substituted propynyl nitrile group, halogen (chlorine, bromine, or iodine) substituted acetamide group, acryl group, substituted vinyl sulfone group, 2-pyridine disulfide group, which is capable of coupling with sulfhydryl group, a 3-nitro-2-pyridinedithio group, a group reactive with a bi-sulfhydryl group; 4) a substituted tetrazine group capable of undergoing a coupling reaction, a monocyclic group having a trans olefinic bond; 5) phenolic compounds and derivatives thereof, and substituted derivatives of 4-phenyl-3H-1,2,4-triazoline-3,5 (4H)-dione (PTAD); preferably, the functional group is selected from the group consisting of amino, carboxyl, azido, sulfhydryl, phenolic hydroxyl, alkynyl, maleimide, cycloheptynyl, tetrazinyl; preferably, the functionalized taxane is selected from the group consisting of the following compounds and the derivatives and isomers thereof: ##STR00304## ##STR00305## ##STR00306## ##STR00307## ##STR00308## ##STR00309##

10. A functionalized polysaccharide derivative of compound shown by formula III or a pharmaceutically acceptable salt or solvate thereof, including isomers thereof, ##STR00310## wherein the so-called polysaccharide is selected from the group consisting of homopolysaccharides or heteropolysaccharides, in the structure of polysaccharide, the chain may be linear, branched, or cyclic; the glycosylic bond between sugar units of the homopolysaccharide or heteropolysaccharide may be α-type or β-type or α,β-mixed type; the sugar unit of the homopolysaccharide is selected from the group consisting of a tri-carbon sugar, a four-carbon sugar, a five-carbon sugar, a six-carbon sugar, a seven-carbon sugar, and an eight-carbon sugar or a deoxy sugar unit, which are structurally composed of a plurality of single sugar units; the heteropolysaccharide, their saccharide units are composed of a mixture of two or more types of monosaccharide units; the polysaccharides in their structures may be naturally or synthetically modified with one or more substituents which are selected from the group consisting of carboxy acid group, carboxylate group, amino group, sulfonic acid group, sulfonate group, phosphoric acid group, phosphate group, hydroxyethyl group, hydroxypropyl group, methyl group, acyl group; preferably, the polysaccharide is selected from the dextran, hyaluronic acid, hydroxyethyl starch, carboxymethyl cellulose, poly-galactosamine, poly-sialic acid, or polysaccharide of Ganoderma lucidum, lentinan (polysaccharide of Lentinula edodes); wherein spacer-1, spacer-2 and linker-1 can be the same or different and are independently selected from the following structures: 1) natural amino acids, unnatural amino acids, such as D-amino acids, β-aminopropionic acid, γ-aminobutyric acid or ε-aminocaproic acid, or derivatives thereof, or 2 to 100 oligopeptides composed of these amino acids or a polypeptide fragment 2) —[X1].sub.0 or 1-[disubstituted hydrocarbyl-1].sub.0 or 1-[X2].sub.0 or 1-[disubstituted aryl].sub.0 or 1-[X3].sub.0 or 1-[disubstituted a structural moiety of a hydrocarbyl-2].sub.0 or 1-[X4].sub.0 or 1-; wherein X1, X2, X3 and X4 can be the same or different and are selected from O, S, NH or NR, CO, CONN, CONHR, S—S, COO, OCOO, SO.sub.2NH, SO.sub.2NR, NHCOO, NRCOO, NHCONH, NRCONH, NR.sub.1CONR.sub.2, OPO.sub.3N OPO.sub.2NH, OPO.sub.2NR, a covalent bond containing a triazole; wherein R, R.sub.1, R.sub.2 are independently selected from the group consisting of an alkyl group, a cycloalkyl group, an aryl group, an arylalkyl group, a cycloalkyl alkyl group; the disubstituted hydrocarbyl-1 fragment and the disubstituted hydrocarbyl-2 fragment are the same or different and are selected from a linear or branched or cyclic (including fused ring or spiro-ring) C.sub.1-20 alkyl group (preferably a C.sub.1-12 alkylgroup), a linear or branched cyclic (including fused ring or spiro-ring) C.sub.1-20 alkylgroup (preferably a C.sub.1-12 alkylgroup) containing at least one heteroatom selected from N, O or S; a linear or branched C.sub.2-15 alkyl group containing one or more double bonds (preferably a C.sub.2-10 alkyl group having a double bond), a linear or branched C.sub.2-10 alkyl group having one or more triple bonds (preferably a C.sub.2-8 alkyl group having a triple bond), a C.sub.3-10 cycloalkyl group containing one or more double bonds (including a fused ring or a spiro ring, preferably a 3-8 membered cycloalkyl group containing a double bond), a cyclic C.sub.2-12 alkyl group containing one or more triple bonds (including fused ring or spiro ring, preferably a 3-8 membered cycloalkyl group containing a triple bond, a 3-10 membered heterocycloalkyl group containing at least one heteroatom selected from N, O or S (including a fused ring or a spiro ring, preferably 3-6 membered heterocycloalkyl group); a heterocycloalkyl group having at least one 3-10 membered heterocycloalkyl group and a hetero atom selected from N, O or S and one or more double bonds (a fused ring or spiro ring, preferably a 3-8 membered heterocycloalkyl group containing a double bond), and a 5-12 membered heterocycloalkyl group containing at least one heteroatom selected from N, O or S and one or more triple bonds (including a fused ring or a spiro ring, preferably a 6-9 membered heterocycloalkyl group containing a triple bond); the disubstituted aryl group is selected from a single aryl group or a fused ring aryl group, a single heteroaryl group or a fused ring heteroaryl group; the disubstituted hydrocarbyl-1 fragment, the disubstituted hydrocarbyl-2 fragment and the disubstituted aryl fragment are optionally substituted by a mono- or poly-substituent as defined in claim 4 for a single molecular lipid compound. 3) polymer fragments such as polyethylene glycol (PEG) having a molecular weight of 100 to 50,000, [CH.sub.2SCH.sub.2].sub.1-10000, [CH.sub.2CH.sub.2OCH.sub.2CH.sub.2].sub.1-10000, polyamide, polylactic acid (PGA), poly(lactic-glycolic acid) copolymer (PLGA); 4) covalently linked (C.sub.3-8) structural fragments consisting of 1-100 saccharide units and derivatives thereof, such as glycerol, mannitol, glucosamine and their derivatives; the covalent bond of the polysaccharide linking to spacer-1 is selected from the group consisting of an amide bond, a carbamate bond, an urethane bond, an aminothiocarbamate bond, an ester bond, an isourea bond, a thiourea bond, an urea bond, a disulfide a bond, a carbonate bond, a phosphate bond, a phosphate ester bond, a sulfonamide bond, an alpha or beta glycosylic bond, a triazole-containing covalent bond; the number of spacers optionally being 0 or 1; the functional group is selected from the group consisting of 1) amino (—NH.sub.2), substituted amino (—NHR), carboxyl (—COOH), azide (—N.sub.3), sulfhydryl (—SH), sulfonic acid (—SO.sub.3H), sulfonylamino (—SO.sub.2NH—, —SO.sub.2NHR), phosphate group (—PO.sub.3H), phosphate ester group (—PO.sub.3R), phosphoramide group (—PO.sub.3NH—, —PO.sub.3NR—), isothiocyano group, iso-oxycyano group, phenolic hydroxyl group; among them, the substituent R group is selected from an alkyl group, a cycloalkyl group, an aromatic alkyl group, an arylalkyl group, or a cycloalkyl alkyl group; 2) an alkynyl compound capable of coupling with an azide compound, a monocyclic derivative containing an acetylenic bond, a fused ring derivative containing an acetylenic bond, any of above compound is selected from aryl cyclooctyne (ALO), thiocyclooctyne, cyclooctyne (OCT), Biarylazacyclooctynone (BARAC), Dibenzoazacyclooctyne (DIBAC), Bicyclononyne (BCN), Dibenzocyclooctyne (DIBO), Difluorocyclooctyne (DIFO), Monofluororinated cyclooctyne (MOFO), Dimethoxy azacyclooctyne (DIMAC), Nonfluoroocyclooctyne (NOFO), (thioOCT)), Tetramethoxy dibenzocyclooctyne (TMDIBO); 3) maleimide group, substituted propynyl nitrile group, halogen (chlorine, bromine, or iodine) substituted acetamide group, acryl group, substituted vinyl sulfone group, 2-pyridine disulfide group, which is capable of coupling with sulfhydryl group, a 3-nitro-2-pyridinedithio group, a group reactive with a bi-sulfhydryl group; 4) a substituted tetrazine group capable of undergoing a coupling reaction, a monocyclic group having a trans olefinic bond; 5) phenolic compounds and derivatives thereof, and substituted derivatives of 4-phenyl-3H-1,2,4-triazoline-3,5 (4H)-dione (PTAD); preferably, the derivative of functionalized polysaccharide is selected from the following structure of compound and its derivatives and isomers thereof: ##STR00311## ##STR00312## ##STR00313## ##STR00314## ##STR00315##

11. A bifunctional or multifunctional polysaccharide derivative of compounds shown by formula IV or a pharmaceutically acceptable salt or solvate thereof; ##STR00316## wherein the polysaccharide is selected from the group consisting of homopolysaccharides or heteropolysaccharides, in the structure of polysaccharide, the chain may be linear, branched, or cyclic; the glycosylic bond between sugar units of the homopolysaccharide or heteropolysaccharide may be α-type or β-type or α,β-mixed type; the sugar unit of the homopolysaccharide is selected from the group consisting of a tri-carbon sugar, a four-carbon sugar, a five-carbon sugar, a six-carbon sugar, a seven-carbon sugar, and an eight-carbon sugar or a deoxy sugar unit, which are structurally composed of a plurality of single sugar units; the heteropolysaccharide, their saccharide units are composed of a mixture of two or more types of monosaccharide units; the polysaccharides in their structures may be naturally or synthetically modified with one or more substituents which are selected from the group consisting of carboxy acid group, carboxylate group, amino group, sulfonic acid group, sulfonate group, phosphoric acid group, phosphate group, hydroxyethyl group, hydroxypropyl group, methyl group, acyl group; preferably, the polysaccharide is selected from the dextran, hyaluronic acid, hydroxyethyl starch, carboxymethyl cellulose, poly-galactosamine, poly-sialic acid, or polysaccharide of Ganoderma lucidum, lentinan (polysaccharide of Lentinula edodes); wherein the linker unit is the same or different and are independently selected from the following structures: 1) natural amino acids, unnatural amino acids, such as D-amino acids, β-aminopropionic acid, γ-aminobutyric acid or ε-aminocaproic acid, or derivatives thereof, or 2 to 100 oligopeptides composed of these amino acids or a polypeptide fragment 2) —[X1].sub.0 or 1-[disubstituted hydrocarbyl-1].sub.0 or 1-[X2].sub.0 or 1-[disubstituted aryl].sub.0 or 1-[X3].sub.0 or 1-[disubstituted a structural moiety of a hydrocarbyl-2].sub.0 or 1-[X4].sub.0 or 1-; wherein X1, X2, X3 and X4 can be the same or different and are selected from O, S, NH or NR, CO, CONN, CONHR, S—S, COO, OCOO, SO.sub.2NH, SO.sub.2NR, NHCOO, NRCOO, NHCONH, NRCONH, NR.sub.1CONR.sub.2, OPO.sub.3N OPO.sub.2NH, OPO.sub.2NR, a covalent bond containing a triazole; wherein R, R.sub.1, R.sub.2 are independently selected from the group consisting of an alkyl group, a cycloalkyl group, an aryl group, an arylalkyl group, a cycloalkyl alkyl group; the disubstituted hydrocarbyl-1 fragment and the disubstituted hydrocarbyl-2 fragment are the same or different and are selected from a linear or branched or cyclic (including fused ring or spiro-ring) C.sub.1-20 alkyl group (preferably a C.sub.1-12 alkylgroup), a linear or branched cyclic (including fused ring or spiro-ring) C.sub.1-20 alkylgroup (preferably a C.sub.1-12 alkylgroup) containing at least one heteroatom selected from N, O or S; a linear or branched C.sub.2-15 alkyl group containing one or more double bonds (preferably a C.sub.2-10 alkyl group having a double bond), a linear or branched C.sub.2-10 alkyl group having one or more triple bonds (preferably a C.sub.2-8 alkyl group having a triple bond), a C.sub.3-10 cycloalkyl group containing one or more double bonds (including a fused ring or a spiro ring, preferably a 3-8 membered cycloalkyl group containing a double bond), a cyclic C.sub.2-12 alkyl group containing one or more triple bonds (including fused ring or spiro ring, preferably a 3-8 membered cycloalkyl group containing a triple bond, a 3-10 membered heterocycloalkyl group containing at least one heteroatom selected from N, O or S (including a fused ring or a spiro ring, preferably 3-6 membered heterocycloalkyl group); a heterocycloalkyl group having at least one 3-10 membered heterocycloalkyl group and a hetero atom selected from N, O or S and one or more double bonds (a fused ring or spiro ring, preferably a 3-8 membered heterocycloalkyl group containing a double bond), and a 5-12 membered heterocycloalkyl group containing at least one heteroatom selected from N, O or S and one or more triple bonds (including a fused ring or a spiro ring, preferably a 6-9 membered heterocycloalkyl group containing a triple bond); the disubstituted aryl group is selected from a single aryl group or a fused ring aryl group, a single heteroaryl group or a fused ring heteroaryl group; the disubstituted hydrocarbyl-1 fragment, the disubstituted hydrocarbyl-2 fragment and the disubstituted aryl fragment are optionally substituted by a mono- or poly-substituent as defined in claim 4 for a single molecular lipid compound. 3) polymer fragments such as polyethylene glycol (PEG) having a molecular weight of 100 to 50,000, [CH.sub.2SCH.sub.2].sub.1-10000, [CH.sub.2CH.sub.2OCH.sub.2CH.sub.2].sub.1-10000, polyamide, polylactic acid (PGA), poly(lactic-glycolic acid) copolymer (PLGA); 4) covalently linked (C.sub.3-8) structural fragments consisting of 1-100 saccharide units and derivatives thereof, such as glycerol, mannitol, glucosamine and their derivatives; the covalent bond connecting the polysaccharide to the linker unit is selected from the group consisting of an amide bond, a carbamate bond, a urethane bond, an amino-thiocarbamate bond, an ester bond, an iso-urea bond, a thiourea bond, a urea bond, a disulfide bond, a carbonate bond, a phosphate bond, a phosphoric acid amide bond, a sulfonamide bond, an alpha or beta glycosylic bond, a covalent bond containing a triazole moiety; wherein the functional groups-1 and -2 are selected from the group consisting of: 1) amino (—NH.sub.2), substituted amino (—NHR), carboxyl (—COOH), azide (—N.sub.3), sulfhydryl (—SH), sulfonic acid (—SO.sub.3H), sulfonylamino (—SO.sub.2NH—, —SO.sub.2NHR), phosphate group (—PO.sub.3H), phosphate ester group (—PO.sub.3R), phosphoramide group (—PO.sub.3NH—, —PO.sub.3NR—), isothiocyano group, iso-oxycyano group, phenolic hydroxyl group; among them, the substituent R group is selected from an alkyl group, a cycloalkyl group, an aromatic alkyl group, an arylalkyl group, or a cycloalkyl alkyl group; 2) an alkynyl compound capable of coupling with an azide compound, a monocyclic derivative containing an acetylenic bond, a fused ring derivative containing an acetylenic bond, any of above compound is selected from aryl cyclooctyne (ALO), thiocyclooctyne, cyclooctyne (OCT), Biarylazacyclooctynone (BARAC), Dibenzoazacyclooctyne (DIBAC), Bicyclononyne (BCN), Dibenzocyclooctyne (DIBO), Difluorocyclooctyne (DIFO), Monofluororinated cyclooctyne (MOFO), Dimethoxy azacyclooctyne (DIMAC), Nonfluoroocyclooctyne (NOFO), (thioOCT)), Tetramethoxy dibenzocyclooctyne (TMDIBO); 3) maleimide group, substituted propynyl nitrile group, halogen (chlorine, bromine, or iodine) substituted acetamide group, acryl group, substituted vinyl sulfone group, 2-pyridine disulfide group, which is capable of coupling with sulfhydryl group, a 3-nitro-2-pyridinedithio group, a group reactive with a bi-sulfhydryl group; 4) a substituted tetrazine group capable of undergoing a coupling reaction, a monocyclic group having a trans olefinic bond; 5) phenolic compounds and derivatives thereof, and substituted derivatives of 4-phenyl-3H-1,2,4-triazoline-3,5 (4H)-dione (PTAD); preferably, the difunctional or multifunctional polysaccharide derivative is selected from the following structures and derivatives and isomers thereof. ##STR00317## ##STR00318## ##STR00319## ##STR00320##

12. A conjugate of a polysaccharide with a taxane compound as shown by formula V or a pharmaceutically acceptable salt or solvate thereof. ##STR00321## wherein the polysaccharide is selected from the group consisting of homopolysaccharides or heteropolysaccharides, in the structure of polysaccharide, the chain may be linear, branched, or cyclic; the glycosylic bond between sugar units of the homopolysaccharide or heteropolysaccharide may be α-type or β-type or α,β-mixed type; the sugar unit of the homopolysaccharide is selected from the group consisting of a tri-carbon sugar, a four-carbon sugar, a five-carbon sugar, a six-carbon sugar, a seven-carbon sugar, and an eight-carbon sugar or a deoxy sugar unit, which are structurally composed of a plurality of single sugar units; the heteropolysaccharide, their saccharide units are composed of a mixture of two or more types of monosaccharide units; the polysaccharides in their structures may be naturally or synthetically modified with one or more substituents which are selected from the group consisting of carboxy acid group, carboxylate group, amino group, sulfonic acid group, sulfonate group, phosphoric acid group, phosphate group, hydroxyethyl group, hydroxypropyl group, methyl group, acyl group; preferably, the polysaccharide is selected from the dextran, hyaluronic acid, hydroxyethyl starch, carboxymethyl cellulose, poly-galactosamine, poly-sialic acid, or polysaccharide of Ganoderma lucidum, lentinan (polysaccharide of Lentinula edodes); wherein taxane compound is selected from a natural or artificial semi-synthetic compound and a derivative thereof, which contains the core structure of taxane diterpenes, preferably paclitaxel, docetaxel, cabazitaxel and milataxel; the polysaccharide is linked to the taxane by a linker and/or a spacer, optionally linked to 2′-O position, 7-O position, 10-O position of the taxane core structure or the side chain of its altered structure; preferably, 2′-O position of the taxane or the side chain of its altered structure; wherein spacer-1, -2, and linker-1 can be the same or different and are independently selected from the following structures: 1) natural amino acids, unnatural amino acids, such as D-amino acids, β-aminopropionic acid, γ-aminobutyric acid or ε-aminocaproic acid, or derivatives thereof, or 2 to 100 oligopeptides composed of these amino acids or a polypeptide fragment 2) —[X1].sub.0 or 1-[disubstituted hydrocarbyl-1].sub.0 or 1-[X2].sub.0 or 1-[disubstituted aryl].sub.0 or 1-[X3].sub.0 or 1-[disubstituted a structural moiety of a hydrocarbyl-2].sub.0 or 1-[X4].sub.0 or 1-; wherein X1, X2, X3 and X4 can be the same or different and are selected from O, S, NH or NR, CO, CONN, CONHR, S—S, COO, OCOO, SO.sub.2NH, SO.sub.2NR, NHCOO, NRCOO, NHCONH, NRCONH, NR.sub.1CONR.sub.2, OPO.sub.3, OPO.sub.2NH, OPO.sub.2NR, a covalent bond containing a triazole; wherein R, R.sub.1, R.sub.2 are independently selected from the group consisting of an alkyl group, a cycloalkyl group, an aryl group, an arylalkyl group, a cycloalkyl alkyl group; the disubstituted hydrocarbyl-1 fragment and the disubstituted hydrocarbyl-2 fragment are the same or different and are selected from a linear or branched or cyclic (including fused ring or spiro-ring) C.sub.1-20 alkyl group (preferably a C.sub.1-12 alkylgroup), a linear or branched cyclic (including fused ring or spiro-ring) C.sub.1-20 alkylgroup (preferably a C.sub.1-12 alkylgroup) containing at least one heteroatom selected from N, O or S; a linear or branched C.sub.2-15 alkyl group containing one or more double bonds (preferably a C.sub.2-10 alkyl group having a double bond), a linear or branched C.sub.2-10 alkyl group having one or more triple bonds (preferably a C.sub.2-8 alkyl group having a triple bond), a C.sub.3-10 cycloalkyl group containing one or more double bonds (including a fused ring or a spiro ring, preferably a 3-8 membered cycloalkyl group containing a double bond), a cyclic C.sub.2-12 alkyl group containing one or more triple bonds (including fused ring or spiro ring, preferably a 3-8 membered cycloalkyl group containing a triple bond, a 3-10 membered heterocycloalkyl group containing at least one heteroatom selected from N, O or S (including a fused ring or a spiro ring, preferably 3-6 membered heterocycloalkyl group); a heterocycloalkyl group having at least one 3-10 membered heterocycloalkyl group and a hetero atom selected from N, O or S and one or more double bonds (a fused ring or spiro ring, preferably a 3-8 membered heterocycloalkyl group containing a double bond), and a 5-12 membered heterocycloalkyl group containing at least one heteroatom selected from N, O or S and one or more triple bonds (including a fused ring or a spiro ring, preferably a 6-9 membered heterocycloalkyl group containing a triple bond); the disubstituted aryl group is selected from a single aryl group or a fused ring aryl group, a single heteroaryl group or a fused ring heteroaryl group; the disubstituted hydrocarbyl-1 fragment, the disubstituted hydrocarbyl-2 fragment and the disubstituted aryl fragment are optionally substituted by a mono- or poly-substituent as defined in claim 4 for a single molecular lipid compound. 3) polymer fragments such as polyethylene glycol (PEG) having a molecular weight of 100 to 50,000, [CH.sub.2SCH.sub.2].sub.1-10000, [CH.sub.2CH.sub.2OCH.sub.2CH.sub.2].sub.1-10000, polyamide, polylactic acid (PGA), poly(lactic-glycolic acid) copolymer (PLGA); 4) covalently linked (C.sub.3-8) structural fragments consisting of 1-100 saccharide units and derivatives thereof, such as glycerol, mannitol, glucosamine and their derivatives; the number of spacers optionally being 0 or 1; preferably, the conjugate of polysaccharide and taxane compound is selected from the following structures, and the derivatives and isomers thereof: ##STR00322## ##STR00323## ##STR00324## ##STR00325## ##STR00326## ##STR00327## ##STR00328## ##STR00329## ##STR00330## ##STR00331## ##STR00332## ##STR00333## ##STR00334## ##STR00335## ##STR00336## ##STR00337##

13. A conjugate of polysaccharide and a lipid as showed by the formula VI or a pharmaceutically acceptable salt or solvate thereof, ##STR00338## wherein the polysaccharide is selected from the group consisting of homopolysaccharides or heteropolysaccharides, in the structure of polysaccharide, the chain may be linear, branched, or cyclic; the glycosylic bond between sugar units of the homopolysaccharide or heteropolysaccharide may be α-type or β-type or α,β-mixed type; the sugar unit of the homopolysaccharide is selected from the group consisting of a tri-carbon sugar, a four-carbon sugar, a five-carbon sugar, a six-carbon sugar, a seven-carbon sugar, and an eight-carbon sugar or a deoxy sugar unit, which are structurally composed of a plurality of single sugar units; the heteropolysaccharide, their saccharide units are composed of a mixture of two or more types of monosaccharide units; the polysaccharides in their structures may be naturally or synthetically modified with one or more substituents which are selected from the group consisting of carboxy acid group, carboxylate group, amino group, sulfonic acid group, sulfonate group, phosphoric acid group, phosphate group, hydroxyethyl group, hydroxypropyl group, methyl group, acyl group; preferably, the polysaccharide is selected from the dextran, hyaluronic acid, hydroxyethyl starch, carboxymethyl cellulose, poly-galactosamine, poly-sialic acid, or polysaccharide of Ganoderma lucidum, lentinan (polysaccharide of Lentinula edodes); wherein spacer-1, -2, and linker-1 can be the same or different and are independently selected from the following structures: 1) natural amino acids, unnatural amino acids, such as D-amino acids, β-aminopropionic acid, γ-aminobutyric acid or ε-aminocaproic acid, or derivatives thereof, or 2 to 100 oligopeptides composed of these amino acids or a polypeptide fragment 2) —[X1].sub.0 or 1-[disubstituted hydrocarbyl-1].sub.0 or 1-[X2].sub.0 or 1-[disubstituted aryl].sub.0 or 1-[X3].sub.0 or 1-[disubstituted a structural moiety of a hydrocarbyl-2].sub.0 or 1-[X4].sub.0 or 1-; wherein X1, X2, X3 and X4 can be the same or different and are selected from O, S, NH or NR, CO, CONN, CONHR, S—S, COO, OCOO, SO.sub.2NH, SO.sub.2NR, NHCOO, NRCOO, NHCONH, NRCONH, NR.sub.1CONR.sub.2, OPO.sub.3, OPO.sub.2NH, OPO.sub.2NR, a covalent bond containing a triazole; wherein R, R.sub.1, R.sub.2 are independently selected from the group consisting of an alkyl group, a cycloalkyl group, an aryl group, an arylalkyl group, a cycloalkyl alkyl group; the disubstituted hydrocarbyl-1 fragment and the disubstituted hydrocarbyl-2 fragment are the same or different and are selected from a linear or branched or cyclic (including fused ring or spiro-ring) C.sub.1-20 alkyl group (preferably a C.sub.1-12 alkylgroup), a linear or branched cyclic (including fused ring or spiro-ring) C.sub.1-20 alkylgroup (preferably a C.sub.1-12 alkylgroup) containing at least one heteroatom selected from N, O or S; a linear or branched C.sub.2-15 alkyl group containing one or more double bonds (preferably a C.sub.2-10 alkyl group having a double bond), a linear or branched C.sub.2-10 alkyl group having one or more triple bonds (preferably a C.sub.2-8 alkyl group having a triple bond), a C.sub.3-10 cycloalkyl group containing one or more double bonds (including a fused ring or a spiro ring, preferably a 3-8 membered cycloalkyl group containing a double bond), a cyclic C.sub.2-12 alkyl group containing one or more triple bonds (including fused ring or spiro ring, preferably a 3-8 membered cycloalkyl group containing a triple bond, a 3-10 membered heterocycloalkyl group containing at least one heteroatom selected from N, O or S (including a fused ring or a spiro ring, preferably 3-6 membered heterocycloalkyl group); a heterocycloalkyl group having at least one 3-10 membered heterocycloalkyl group and a hetero atom selected from N, O or S and one or more double bonds (a fused ring or spiro ring, preferably a 3-8 membered heterocycloalkyl group containing a double bond), and a 5-12 membered heterocycloalkyl group containing at least one heteroatom selected from N, O or S and one or more triple bonds (including a fused ring or a spiro ring, preferably a 6-9 membered heterocycloalkyl group containing a triple bond); the disubstituted aryl group is selected from a single aryl group or a fused ring aryl group, a single heteroaryl group or a fused ring heteroaryl group; the disubstituted hydrocarbyl-1 fragment, the disubstituted hydrocarbyl-2 fragment and the disubstituted aryl fragment are optionally substituted by a mono- or poly-substituent as defined in claim 4 for a single molecular lipid compound. 3) polymer fragments such as polyethylene glycol (PEG) having a molecular weight of 100 to 50,000, [CH.sub.2SCH.sub.2].sub.1-10000, [CH.sub.2CH.sub.2OCH.sub.2CH.sub.2].sub.1-10000, polyamide, polylactic acid (PGA), poly(lactic-glycolic acid) copolymer (PLGA); 4) covalently linked (C.sub.3-8) structural fragments consisting of 1-100 saccharide units and derivatives thereof, such as glycerol, mannitol, glucosamine and their derivatives; Wherein a lipid compound unit is selected from the single molecular lipid compound or the structural unit consisting of a plurality of the same or of different single molecular lipid compounds; the single molecular lipid compound is selected from saturated or unsaturated fatty acids and their derivatives thereof, saturated or unsaturated cyclic alkyl acids and their derivatives thereof, aryl or heterocyclic aryl acids and their derivatives thereof, glycerides, glycerol phosphates, sphingolipids, sterols and their derivatives thereof, prenol lipids and their derivatives thereof, glycolipids and their derivatives thereof, lipid-soluble vitamins and their derivatives thereof; these lipid compounds are optionally substituted by one or more substituents which may be the same or different the substituents are independently selected from the group consisting of C.sub.1-20 hydrocarbyl, C.sub.2-10 alkenyl, C.sub.2-10 alkyne, C.sub.3-15 cycloalkyl, C.sub.5-20 aryl, C.sub.7-20 arylalkyl, heteroaryl, heterocycloalkyl, ester group, keto group, hydroxyl group, phenolic hydroxyl group, C.sub.1-18 alkoxy group, C.sub.3-15 monocyclic or polycyclic alkoxy group, amino group, C.sub.1-10 alkyl group, mono or disubstituted amino group, amide group, sulfonic acid group, sulfonamide group, halogen (fluorine, chlorine, bromine, iodine), trifluoromethyl group; the structural unit consisting of a plurality of the same or of different single molecular lipid compounds is selected form a grafted lipid compound unit or a dendritic lipid compound unit: ##STR00339## wherein n is selected from an integer between 0 and 10, preferably an integer between 2 and 5; wherein the lipid compound in the grafted lipid compound unit and/or the dendritic lipid compound unit is selected from the above-mentioned general or preferred definitions for a single molecular lipid compound; more preferably, the structural unit composed of the lipid compound with so called plurality of same or different single molecules is selected from the following structures, derivatives and isomers thereof: The number of spacers being optionally 0 or 1; preferably, the conjugate of polysaccharide and lipid is selected from the following structures, and the derivatives and isomers thereof: ##STR00340## ##STR00341## ##STR00342## ##STR00343## ##STR00344## ##STR00345## ##STR00346##

14. A conjugate of a functionalized polysaccharide and lipid compound as shown by formula VII, or a pharmaceutically acceptable salt or solvate thereof, ##STR00347## wherein the polysaccharide is selected from the group consisting of homopolysaccharides or heteropolysaccharides, in the structure of polysaccharide, the chain may be linear, branched, or cyclic; the glycosylic bond between sugar units of the homopolysaccharide or heteropolysaccharide may be α-type or β-type or α,β-mixed type; the sugar unit of the homopolysaccharide is selected from the group consisting of a tri-carbon sugar, a four-carbon sugar, a five-carbon sugar, a six-carbon sugar, a seven-carbon sugar, and an eight-carbon sugar or a deoxy sugar unit, which are structurally composed of a plurality of single sugar units; the heteropolysaccharide, their saccharide units are composed of a mixture of two or more types of monosaccharide units; the polysaccharides in their structures may be naturally or synthetically modified with one or more substituents which are selected from the group consisting of carboxy acid group, carboxylate group, amino group, sulfonic acid group, sulfonate group, phosphoric acid group, phosphate group, hydroxyethyl group, hydroxypropyl group, methyl group, acyl group; preferably, the polysaccharide is selected from the dextran, hyaluronic acid, hydroxyethyl starch, carboxymethyl cellulose, poly-galactosamine, poly-sialic acid, or polysaccharide of Ganoderma lucidum, lentinan (polysaccharide of Lentinula edodes); wherein linker unit can be the same or different and are independently selected from the following structures: 1) natural amino acids, unnatural amino acids, such as D-amino acids, β-aminopropionic acid, γ-aminobutyric acid or ε-aminocaproic acid, or derivatives thereof, or 2 to 100 oligopeptides composed of these amino acids or a polypeptide fragment 2) —[X1].sub.0 or 1-[disubstituted hydrocarbyl-1].sub.0 or 1-[X2].sub.0 or 1-[disubstituted aryl].sub.0 or 1-[X3].sub.0 or 1-[disubstituted a structural moiety of a hydrocarbyl-2].sub.0 or 1-[X4].sub.0 or 1-; wherein X1, X2, X3 and X4 can be the same or different and are selected from O, S, NH or NR, CO, CONH, CONHR, S—S, COO, OCOO, SO.sub.2NH, SO.sub.2NR, NHCOO, NRCOO, NHCONH, NRCONH, NR.sub.1CONR.sub.2, OPO.sub.3, OPO.sub.2NH, OPO.sub.2NR, a covalent bond containing a triazole; wherein R, R.sub.1, R.sub.2 are independently selected from the group consisting of an alkyl group, a cycloalkyl group, an aryl group, an arylalkyl group, a cycloalkyl alkyl group; the disubstituted hydrocarbyl-1 fragment and the disubstituted hydrocarbyl-2 fragment are the same or different and are selected from a linear or branched or cyclic (including fused ring or spiro-ring) C.sub.1-20 alkyl group (preferably a C.sub.1-12 alkylgroup), a linear or branched cyclic (including fused ring or spiro-ring) C.sub.1-20 alkylgroup (preferably a C.sub.1-12 alkylgroup) containing at least one heteroatom selected from N, O or S; a linear or branched C.sub.2-15 alkyl group containing one or more double bonds (preferably a C.sub.2-10 alkyl group having a double bond), a linear or branched C.sub.2-10 alkyl group having one or more triple bonds (preferably a C.sub.2-8 alkyl group having a triple bond), a C.sub.3-10 cycloalkyl group containing one or more double bonds (including a fused ring or a spiro ring, preferably a 3-8 membered cycloalkyl group containing a double bond), a cyclic C.sub.2-12 alkyl group containing one or more triple bonds (including fused ring or spiro ring, preferably a 3-8 membered cycloalkyl group containing a triple bond, a 3-10 membered heterocycloalkyl group containing at least one heteroatom selected from N, O or S (including a fused ring or a spiro ring, preferably 3-6 membered heterocycloalkyl group); a heterocycloalkyl group having at least one 3-10 membered heterocycloalkyl group and a hetero atom selected from N, O or S and one or more double bonds (a fused ring or spiro ring, preferably a 3-8 membered heterocycloalkyl group containing a double bond), and a 5-12 membered heterocycloalkyl group containing at least one heteroatom selected from N, O or S and one or more triple bonds (including a fused ring or a spiro ring, preferably a 6-9 membered heterocycloalkyl group containing a triple bond); the disubstituted aryl group is selected from a single aryl group or a fused ring aryl group, a single heteroaryl group or a fused ring heteroaryl group; the disubstituted hydrocarbyl-1 fragment, the disubstituted hydrocarbyl-2 fragment and the disubstituted aryl fragment are optionally substituted by a mono- or poly-substituent as defined in claim 4 for a single molecular lipid compound. 3) polymer fragments such as polyethylene glycol (PEG) having a molecular weight of 100 to 50,000, [CH.sub.2SCH.sub.2].sub.1-10000, [CH.sub.2CH.sub.2OCH.sub.2CH.sub.2].sub.1-10000, polyamide, polylactic acid (PGA), poly(lactic-glycolic acid) copolymer (PLGA); 4) covalently linked (C.sub.3-8) structural fragments consisting of 1-100 saccharide units and derivatives thereof, such as glycerol, mannitol, glucosamine and their derivatives; wherein the lipid unit is selected from the single molecular lipid compound or the structural unit consisting of a plurality of the same or of different single molecular lipid compounds; the single molecular lipid compound is selected from saturated or unsaturated fatty acids and their derivatives thereof, saturated or unsaturated cyclic alkyl acids and their derivatives thereof, aryl or heterocyclic aryl acids and their derivatives thereof, glycerides, glycerol phosphates, sphingolipids, sterols and their derivatives thereof, prenol lipids and their derivatives thereof, glycolipids and their derivatives thereof, lipid-soluble vitamins and their derivatives thereof; these lipid compounds are optionally substituted by one or more substituents which may be the same or different the substituents are independently selected from the group consisting of C.sub.1-20 hydrocarbyl, C.sub.2-10 alkenyl, C.sub.2-10 alkyne, C.sub.3-15 cycloalkyl, C.sub.5-20 aryl, C.sub.7-20 arylalkyl, heteroaryl, heterocycloalkyl, ester group, keto group, hydroxyl group, phenolic hydroxyl group, C1-18 alkoxy group, C.sub.3-15 monocyclic or polycyclic alkoxy group, amino group, C.sub.1-10 alkyl group, mono or disubstituted amino group, amide group, sulfonic acid group, sulfonamide group, halogen (fluorine, chlorine, bromine, iodine), trifluoromethyl group; the structural unit consisting of a plurality of the same or of different single molecular lipid compounds is selected form a grafted lipid compound unit or a dendritic lipid compound unit: ##STR00348## wherein n is selected from an integer between 0 and 10, preferably an integer between 2 and 5; wherein the lipid compound in the grafted lipid compound unit and/or the dendritic lipid compound unit is selected from the above-mentioned general or preferred definitions for a single molecular lipid compound; more preferably, the structural unit composed of the lipid compound with so called plurality of same or different single molecules is selected from the following structures, derivatives and isomers thereof: wherein the functional group is selected from the group consisting of 1) amino (—NH.sub.2), substituted amino (—NHR), carboxyl (—COOH), azide (—N.sub.3), sulfhydryl (—SH), sulfonic acid (—SO.sub.3H), sulfonylamino (—SO.sub.2NH—, —SO.sub.2NHR), phosphate group (—PO.sub.3H), phosphate ester group (—PO.sub.3R), phosphoramide group (—PO.sub.3NH—, —PO.sub.3NR—), isothiocyano group, iso-oxycyano group, phenolic hydroxyl group; among them, the substituent R group is selected from an alkyl group, a cycloalkyl group, an aromatic alkyl group, an arylalkyl group, or a cycloalkyl alkyl group; 2) an alkynyl compound capable of coupling with an azide compound, a monocyclic derivative containing an acetylenic bond, a fused ring derivative containing an acetylenic bond, any of above compound is selected from aryl cyclooctyne (ALO), thiocyclooctyne, cyclooctyne (OCT), Biarylazacyclooctynone (BARAC), Dibenzoazacyclooctyne (DIBAC), Bicyclononyne (BCN), Dibenzocyclooctyne (DIBO), Difluorocyclooctyne (DIFO), Monofluororinated cyclooctyne (MOFO), Dimethoxy azacyclooctyne (DIMAC), Nonfluoroocyclooctyne (NOFO), (thioOCT)), Tetramethoxy dibenzocyclooctyne (TMDIBO); 3) maleimide group, substituted propynyl nitrile group, halogen (chlorine, bromine, or iodine) substituted acetamide group, acryl group, substituted vinyl sulfone group, 2-pyridine disulfide group, which is capable of coupling with sulfhydryl group, a 3-nitro-2-pyridinedithio group, a group reactive with a bi-sulfhydryl group; 4) a substituted tetrazine group capable of undergoing a coupling reaction, a monocyclic group having a trans olefinic bond; 5) phenolic compounds and derivatives thereof, and substituted derivatives of 4-phenyl-3H-1,2,4-triazoline-3,5 (4H)-dione (PTAD); preferably, the conjugate of functionalized polysaccharide to lipid compound unit is selected from the following structures and derivatives and isomers thereof: ##STR00349## ##STR00350## ##STR00351##

15. A conjugate of the functionalized taxane to lipid as showed by formula VIII, or a pharmaceutically acceptable salt or solvate thereof, ##STR00352## wherein the taxane compound is selected from natural taxane compounds and semi-synthetic taxanes, preferably paclitaxel, docetaxel, cabazitaxel and milataxel; the polysaccharide is linked to the taxane by a linker and/or a spacer, optionally linked to 2′-O position, 7-O position, 10-O position of the taxane core structure or the side chain of its altered structure; preferably, 2′-O position of the taxane or the side chain of its altered structure; where the spacer-1, -2, -3, and linker-1, -2, -3 can be the same or different and are independently selected from the following structures: 1) natural amino acids, unnatural amino acids, such as D-amino acids, β-aminopropionic acid, γ-aminobutyric acid or ε-aminocaproic acid, or derivatives thereof, or 2 to 100 oligopeptides composed of these amino acids or a polypeptide fragment 2) —[X1].sub.0 or 1-[disubstituted hydrocarbyl-1].sub.0 or 1-[X.sup.2].sub.0 or 1-[disubstituted aryl].sub.0 or 1-[X3].sub.0 or 1-[disubstituted a structural moiety of a hydrocarbyl-2].sub.0 or 1-[X4].sub.0 or 1-; wherein X1, X2, X3 and X4 can be the same or different and are selected from O, S, NH or NR, CO, CONN, CONHR, S—S, COO, OCOO, SO.sub.2NH, SO.sub.2NR, NHCOO, NRCOO, NHCONH, NRCONH, NR.sub.1CONR.sub.2, OPO.sub.3, OPO.sub.2NH, OPO.sub.2NR, a covalent bond containing a triazole; wherein R, R.sub.1, R.sub.2 are independently selected from the group consisting of an alkyl group, a cycloalkyl group, an aryl group, an arylalkyl group, a cycloalkyl alkyl group; the disubstituted hydrocarbyl-1 fragment and the disubstituted hydrocarbyl-2 fragment are the same or different and are selected from a linear or branched or cyclic (including fused ring or spiro-ring) C.sub.1-20 alkyl group (preferably a C.sub.1-12 alkylgroup), a linear or branched cyclic (including fused ring or spiro-ring) C.sub.1-20 alkylgroup (preferably a C.sub.1-12 alkylgroup) containing at least one heteroatom selected from N, O or S; a linear or branched C.sub.2-15 alkyl group containing one or more double bonds (preferably a C2-10 alkyl group having a double bond), a linear or branched C2-10 alkyl group having one or more triple bonds (preferably a C.sub.2-8 alkyl group having a triple bond), a C.sub.3-10 cycloalkyl group containing one or more double bonds (including a fused ring or a spiro ring, preferably a 3-8 membered cycloalkyl group containing a double bond), a cyclic C.sub.2-12 alkyl group containing one or more triple bonds (including fused ring or spiro ring, preferably a 3-8 membered cycloalkyl group containing a triple bond, a 3-10 membered heterocycloalkyl group containing at least one heteroatom selected from N, O or S (including a fused ring or a spiro ring, preferably 3-6 membered heterocycloalkyl group); a heterocycloalkyl group having at least one 3-10 membered heterocycloalkyl group and a hetero atom selected from N, O or S and one or more double bonds (a fused ring or spiro ring, preferably a 3-8 membered heterocycloalkyl group containing a double bond), and a 5-12 membered heterocycloalkyl group containing at least one heteroatom selected from N, O or S and one or more triple bonds (including a fused ring or a spiro ring, preferably a 6-9 membered heterocycloalkyl group containing a triple bond); the disubstituted aryl group is selected from a single aryl group or a fused ring aryl group, a single heteroaryl group or a fused ring heteroaryl group; the disubstituted hydrocarbyl-1 fragment, the disubstituted hydrocarbyl-2 fragment and the disubstituted aryl fragment are optionally substituted by a mono- or poly-substituent as defined in claim 4 for a single molecular lipid compound. 3) polymer fragments such as polyethylene glycol (PEG) having a molecular weight of 100 to 50,000, [CH.sub.2SCH.sub.2].sub.1-10000, [CH.sub.2CH.sub.2OCH.sub.2CH.sub.2].sub.1-10000, polyamide, polylactic acid (PGA), poly(lactic-glycolic acid) copolymer (PLGA); 4) covalently linked (C.sub.3-8) structural fragments consisting of 1-100 saccharide units and derivatives thereof, such as glycerol, mannitol, glucosamine and their derivatives; wherein the branch unit is selected from the group consisting of amino acids (including natural amino acids and unnatural amino acids) and derivatives thereof, saccharide units and derivatives thereof, aryl substituted compounds and derivatives thereof, substituted hydrocarbons and derivatives thereof, triazole containing compound or derivatives of, or compounds with substitution by sulfanes; wherein lipid unit is selected from the single molecular lipid compound or the structural unit consisting of a plurality of the same or of different single molecular lipid compounds; the single molecular lipid compound is selected from saturated or unsaturated fatty acids and their derivatives thereof, saturated or unsaturated cyclic alkyl acids and their derivatives thereof, aryl or heterocyclic aryl acids and their derivatives thereof, glycerides, glycerol phosphates, sphingolipids, sterols and their derivatives thereof, prenol lipids and their derivatives thereof, glycolipids and their derivatives thereof, lipid-soluble vitamins and their derivatives thereof; these lipid compounds are optionally substituted by one or more substituents which may be the same or different the substituents are independently selected from the group consisting of C.sub.1-20 hydrocarbyl, C.sub.2-10 alkenyl, C.sub.2-10 alkyne, C.sub.3-15 cycloalkyl, C.sub.5-20 aryl, C.sub.7-20 arylalkyl, heteroaryl, heterocycloalkyl, ester group, keto group, hydroxyl group, phenolic hydroxyl group, C1-18 alkoxy group, C.sub.3-15 monocyclic or polycyclic alkoxy group, amino group, C.sub.1-10 alkyl group, mono or disubstituted amino group, amide group, sulfonic acid group, sulfonamide group, halogen (fluorine, chlorine, bromine, iodine), trifluoromethyl group; the structural unit consisting of a plurality of the same or of different single molecular lipid compounds is selected form a grafted lipid compound unit or a dendritic lipid compound unit: ##STR00353## wherein n is selected from an integer between 0 and 10, preferably an integer between 2 and 5; wherein the lipid compound in the grafted lipid compound unit and/or the dendritic lipid compound unit is selected from the above-mentioned general or preferred definitions for a single molecular lipid compound; more preferably, the structural unit composed of the lipid compound with so called plurality of same or different single molecules is selected from the following structures, derivatives and isomers thereof: the number of spacers is optionally 0 or 1; wherein the functional group is selected from the group consisting of 1) amino (—NH.sub.2), substituted amino (—NHR), carboxyl (—COOH), azide (—N.sub.3), sulfhydryl (—SH), sulfonic acid (—SO.sub.3H), sulfonylamino (—SO.sub.2NH—, —SO.sub.2NHR), phosphate group (—PO.sub.3H), phosphate ester group (—PO.sub.3R), phosphoramide group (—PO.sub.3NH—, —PO.sub.3NR—), isothiocyano group, iso-oxycyano group, phenolic hydroxyl group; among them, the substituent R group is selected from an alkyl group, a cycloalkyl group, an aromatic alkyl group, an arylalkyl group, or a cycloalkyl alkyl group; 2) an alkynyl compound capable of coupling with an azide compound, a monocyclic derivative containing an acetylenic bond, a fused ring derivative containing an acetylenic bond, any of above compound is selected from aryl cyclooctyne (ALO), thiocyclooctyne, cyclooctyne (OCT), Biarylazacyclooctynone (BARAC), Dibenzoazacyclooctyne (DIBAC), Bicyclononyne (BCN), Dibenzocyclooctyne (DIBO), Difluorocyclooctyne (DIFO), Monofluororinated cyclooctyne (MOFO), Dimethoxy azacyclooctyne (DIMAC), Nonfluoroocyclooctyne (NOFO), (thioOCT)), Tetramethoxy dibenzocyclooctyne (TMDIBO); 3) maleimide group, substituted propynyl nitrile group, halogen (chlorine, bromine, or iodine) substituted acetamide group, acryl group, substituted vinyl sulfone group, 2-pyridine disulfide group, which is capable of coupling with sulfhydryl group, a 3-nitro-2-pyridinedithio group, a group reactive with a bi-sulfhydryl group; 4) a substituted tetrazine group capable of undergoing a coupling reaction, a monocyclic group having a trans olefinic bond; 5) phenolic compounds and derivatives thereof, and substituted derivatives of 4-phenyl-3H-1,2,4-triazoline-3,5 (4H)-dione (PTAD); preferably, the conjugate of the functionalized taxane to lipid is selected from the following structures and the derivatives and isomers thereof: ##STR00354##

16. A preparation process of the taxane-lipid-polysaccharide dual conjugate as showed by formula (I) according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, ##STR00355## the preparation process includes the following steps: the polysaccharide and the functionalized fatty or aromatic isocyanate are separately dissolved in anhydrous or aqueous DMSO or DMF. Then the above solutions are mixed to react in the presence of a base, optionally in the presence of a coupling agent, to form a functionalized polysaccharide (Formula III); wherein the preparation reaction temperature is from 5 to 100° C., preferably from 0° C. to 30° C.; the base is selected from the group consisting of organic bases such as tertiary amines (triethylamine, trimethylamine, diisopropyl-Ethylamine) or dimethylaminopyridine (DMAP), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), or an inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, or potassium bicarbonate; the coupling agent is selected from the group consisting of carbodiimides (DCC, EDC, DIPC) or N,N′-carbonyldiimidazole; the functional groups are defined as the group consisting of: 1) amino (—NH.sub.2), substituted amino (—NHR), carboxyl (—COOH), azide (—N.sub.3), sulfhydryl (—SH), sulfonic acid (—SO.sub.3H), sulfonylamino (—SO.sub.2NH—, —SO.sub.2NHR), phosphate group (—PO.sub.3H), phosphate ester group (—PO.sub.3R), phosphoramide group (—PO.sub.3NH—, —PO.sub.3NR—), isothiocyano group, iso-oxycyano group, phenolic hydroxyl group; among them, the substituent R group is selected from an alkyl group, a cycloalkyl group, an aromatic alkyl group, an arylalkyl group, or a cycloalkyl alkyl group; 2) an alkynyl compound capable of coupling with an azide compound, a monocyclic derivative containing an acetylenic bond, a fused ring derivative containing an acetylenic bond, any of above compound is selected from aryl cyclooctyne (ALO), thiocyclooctyne, cyclooctyne (OCT), Biarylazacyclooctynone (BARAC), Dibenzoazacyclooctyne (DIBAC), Bicyclononyne (BCN), Dibenzocyclooctyne (DIBO), Difluorocyclooctyne (DIFO), Monofluororinated cyclooctyne (MOFO), Dimethoxy azacyclooctyne (DIMAC), Nonfluoroocyclooctyne (NOFO), (thioOCT)), Tetramethoxy dibenzocyclooctyne (TMDIBO); 3) maleimide group, substituted propynyl nitrile group, halogen (chlorine, bromine, or iodine) substituted acetamide group, acryl group, substituted vinyl sulfone group, 2-pyridine disulfide group, which is capable of coupling with sulfhydryl group, a 3-nitro-2-pyridinedithio group, a group reactive with a bi-sulfhydryl group; 4) a substituted tetrazine group capable of undergoing a coupling reaction, a monocyclic group having a trans olefinic bond; 5) phenolic compounds and derivatives thereof, and substituted derivatives of 4-phenyl-3H-1,2,4-triazoline-3,5 (4H)-dione (PTAD); the lipid compound is reacted with the compound having the functional group and a linker unit and/or spacer, optionally in the presence of a base and/or a coupling agent, to form a functionalized lipid compound, wherein the reaction solvent is selected from anhydrous or aqueous conventional solvents such as DMSO, DMF, dioxane, tetrahydrofuran, dichloromethane, chloroform, methanol or ethanol, preferably DMSO or DMF; the preparation reaction temperature, base, coupling agent are the same or similar to the preparation of the functionalized polysaccharide as defined or described above; the functional group is defined by the aforementioned types of functional groups; the linker and spacers can be the same or different and are independently selected from the following structures: 1) natural amino acids, unnatural amino acids, such as D-amino acids, β-aminopropionic acid, γ-aminobutyric acid or ε-aminocaproic acid, or derivatives thereof, or 2 to 100 oligopeptides composed of these amino acids or a polypeptide fragment 2) —[X1].sub.0 or 1-[disubstituted hydrocarbyl-1].sub.0 or 1-[X2].sub.0 or 1-[disubstituted aryl].sub.0 or 1-[X3].sub.0 or 1-[disubstituted a structural moiety of a hydrocarbyl-2].sub.0 or 1-[X4].sub.0 or 1-; wherein X1, X2, X3 and X4 can be the same or different and are selected from O, S, NH or NR, CO, CONN, CONHR, S—S, COO, OCOO, SO.sub.2NH, SO.sub.2NR, NHCOO, NRCOO, NHCONH, NRCONH, NR.sub.1CONR.sub.2, OPO.sub.3, OPO.sub.2NH, OPO.sub.2NR, a covalent bond containing a triazole; wherein R, R.sub.1, R.sub.2 are independently selected from the group consisting of an alkyl group, a cycloalkyl group, an aryl group, an arylalkyl group, a cycloalkyl alkyl group; the disubstituted hydrocarbyl-1 fragment and the disubstituted hydrocarbyl-2 fragment are the same or different and are selected from a linear or branched or cyclic (including fused ring or spiro-ring) C.sub.1-20 alkyl group (preferably a C.sub.1-12 alkylgroup), a linear or branched cyclic (including fused ring or spiro-ring) C.sub.1-20 alkylgroup (preferably a C.sub.1-12 alkylgroup) containing at least one heteroatom selected from N, O or S; a linear or branched C.sub.2-15 alkyl group containing one or more double bonds (preferably a C.sub.2-10 alkyl group having a double bond), a linear or branched C.sub.2-10 alkyl group having one or more triple bonds (preferably a C.sub.2-8 alkyl group having a triple bond), a C.sub.3-10 cycloalkyl group containing one or more double bonds (including a fused ring or a spiro ring, preferably a 3-8 membered cycloalkyl group containing a double bond), a cyclic C.sub.2-12 alkyl group containing one or more triple bonds (including fused ring or spiro ring, preferably a 3-8 membered cycloalkyl group containing a triple bond, a 3-10 membered heterocycloalkyl group containing at least one heteroatom selected from N, O or S (including a fused ring or a spiro ring, preferably 3-6 membered heterocycloalkyl group); a heterocycloalkyl group having at least one 3-10 membered heterocycloalkyl group and a hetero atom selected from N, O or S and one or more double bonds (a fused ring or spiro ring, preferably a 3-8 membered heterocycloalkyl group containing a double bond), and a 5-12 membered heterocycloalkyl group containing at least one heteroatom selected from N, O or S and one or more triple bonds (including a fused ring or a spiro ring, preferably a 6-9 membered heterocycloalkyl group containing a triple bond); the disubstituted aryl group is selected from a single aryl group or a fused ring aryl group, a single heteroaryl group or a fused ring heteroaryl group; the disubstituted hydrocarbyl-1 fragment, the disubstituted hydrocarbyl-2 fragment and the disubstituted aryl fragment are optionally substituted by a mono- or poly-substituent as defined in claim 4 for a single molecular lipid compound. 3) polymer fragments such as polyethylene glycol (PEG) having a molecular weight of 100 to 50,000, [CH.sub.2SCH.sub.2].sub.1-10000, [CH.sub.2CH.sub.2OCH.sub.2CH.sub.2].sub.1-10000, polyamide, polylactic acid (PGA), poly(lactic-glycolic acid) copolymer (PLGA); 4) covalently linked (C.sub.3-8) structural fragments consisting of 1-100 saccharide units and derivatives thereof, such as glycerol, mannitol, glucosamine and their derivatives; in the presence of a base and/or a coupling reagent, the linker and/or spacer which contains functional group is covalently linked to a side chain position of the taxane compound, preferably at the 2′-O position of the side chain to form a functionalized taxane compound (according to Formula II) by employing the combination strategy of spot selective synthetic approach with selectively protecting/deprotecting the hydroxyl group of the taxane compound, wherein the solvent used for the preparation, The reaction temperature, base, and coupling agent are as defined or like the above for the preparation of the functionalized lipid compound; the functional group is defined as the aforementioned types of functional groups; and the linkers and spacers are also defined as the aforementioned types of structures respectively; the functionalized taxanes and functionalized lipids are covalently coupled to the functionalized polysaccharides through the reaction in the presence of a coupling reagent or an optional catalyst, respectively, to form Taxane-lipid-polysaccharide dual conjugate (showed by Formula I) containing variable proportions of taxanes and lipids in conjugate, wherein the ratios of the functionalized polysaccharide, the functionalized taxane compound, the functionalized lipid compound is set as a molar ratio, optionally from about 10:5:0.1 to 10:0.1:5; the preparation reaction temperature is −10° C. to −50° C., preferably 5° C.-30° C.; the coupling reagent is selected from carbodiimides (DCC, EDC, DIPC) or N,N′-carbonyldiimidazole; the preparation solvent is anhydrous or aqueous conventional solvent such iso-oxycyano group, phenolic hydroxyl group; among them, the substituent R group is selected from an alkyl group, a cycloalkyl group, an aromatic alkyl group, an arylalkyl group, or a cycloalkyl alkyl group; 2) an alkynyl compound capable of coupling with an azide compound, a monocyclic derivative containing an acetylenic bond, a fused ring derivative containing an acetylenic bond, any of above compound is selected from aryl cyclooctyne (ALO), thiocyclooctyne, cyclooctyne (OCT), Biarylazacyclooctynone (BARAC), Dibenzoazacyclooctyne (DIBAC), Bicyclononyne (BCN), Dibenzocyclooctyne (DIBO), Difluorocyclooctyne (DIFO), Monofluororinated cyclooctyne (MOFO), Dimethoxy azacyclooctyne (DIMAC), Nonfluoroocyclooctyne (NOFO), (thioOCT)), Tetramethoxy dibenzocyclooctyne (TMDIBO); 3) maleimide group, substituted propynyl nitrile group, halogen (chlorine, bromine, or iodine) substituted acetamide group, acryl group, substituted vinyl sulfone group, 2-pyridine disulfide group, which is capable of coupling with sulfhydryl group, a 3-nitro-2-pyridinedithio group, a group reactive with a bi-sulfhydryl group; 4) a substituted tetrazine group capable of undergoing a coupling reaction, a monocyclic group having a trans olefinic bond; 5) phenolic compounds and derivatives thereof, and substituted derivatives of 4-phenyl-3H-1,2,4-triazoline-3,5 (4H)-dione (PTAD); a lipid compound is derivatized by a coupling reaction to have at least two same or different functional groups, in the presence of optionally a base and/or a coupling agent, to form a bifunctional or multifunctional lipid compound; the reaction temperature, reagent, base, coupling reagent, and functional group are defined as in the above descriptions in the preparation of the functionalized lipid compound; a functionalized group of a bifunctional or multifunctional lipid compound is coupled with a functionalized polysaccharide under the reaction in presence of a coupling agent or an optional catalyst, therefore to form a functionalized lipid polysaccharide conjugate in which itself still has a free functional group (as formula VII); or a functionalized polysaccharide is converted into a polysaccharide lipid conjugate (as formula VI), which is further converted into functionalized polysaccharide-lipid conjugate (as Formula VII); The reaction temperature, reagents, catalysts, coupling agents and functional groups are defined as in the above description in the final as DMSO, DMF, dioxane, tetrahydrofuran, methanol or ethanol, preferably DMSO or DMF; the catalyst is selected from the group consisting of a click chemistry copper salt catalyst, such as a cuprous halide (Cuprous chloride, cuprous iodide), a vitamin C sodium salt, or a cuprous salt or ligand containing I valent copper salt produced from gallic acid and cupric sulfate salt. When coupling is carried out without using a catalyst, the coupling reaction is selected from a copper-free click chemistry reaction and an addition reaction with maleic acid lactam and mercaptan.

17. A process for preparing a taxane-lipid-polysaccharide dual conjugate or a pharmaceutically acceptable salt or solvate thereof according to the formula (I) from claim 1, ##STR00356## wherein the preparation includes the following steps: the polysaccharide is reacted with a functional group-containing fatty or aromatic isocyanate in the presence of a base, optionally in the presence of a coupling reagent, to form a functionalized polysaccharide (Formula III); the reaction temperature is −10° C. to −50° C., preferably 5° C. to 30° C.; the coupling reagent is selected from carbodiimides (DCC, EDC, DIPC) or N,N-carbonyldiimidazole; the preparation solvent is anhydrous or aqueous conventional solvent such as DMSO, DMF, dioxane, tetrahydrofuran, methanol or ethanol, preferably DMSO or DMF; the base is selected from the group consisting of organic bases such as tertiary amines (triethylamine, trimethylamine, diisopropyl-Ethylamine) or dimethylaminopyridine (DMAP), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), or an inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, or potassium bicarbonate; and functional group of the functional poysaccharides are defined as the group consisting of: 1) amino (—NH.sub.2), substituted amino (—NHR), carboxyl (—COOH), azide (—N.sub.3), sulfhydryl (—SH), sulfonic acid (—SO.sub.3H), sulfonylamino (—SO.sub.2NH—, —SO.sub.2NHR), phosphate group (—PO.sub.3H), phosphate ester group (—PO.sub.3R), phosphoramide group (—PO.sub.3NH—, —PO.sub.3NR—), isothiocyano group, step of the preparation for a taxane-lipid-polysaccharide dual conjugate; in the presence of a base and/or a coupling reagent, the linker and/or spacer which contains functional group is covalently linked to a side chain position of the taxane compound, preferably at the 2′-O position of the side chain to form a functionalized taxane compound (according to Formula II) by employing the combination strategy of spot selective synthetic approach with selectively protecting/deprotecting the hydroxyl group of the taxane compound. As stated, reaction temperature, reagent, base, a coupling agent, a linker arm, a spacer, and a functional group are defined as the aforementioned types of functional groups for the preparation of a functionalized taxane compound; the functionalized taxane compound or drug is covalently coupled to the functionalized polysaccharides lipid conjugate with certain ratio through the reaction in presence of a coupling reagent or an optional catalyst, respectively, to form taxane-lipid-polysaccharide dual conjugate (showed by Formula I) containing variable proportions of taxanes and lipids in conjugate, wherein the molar ratio of the functionalized taxane compound, the functionalized polysaccharide lipid conjugate is optionally about 1:99˜90:10, for example as 1:99˜80:20, 1:99˜70:30, 1:99˜60:40, preferably as 1:99˜50:50; the catalyst is selected from the group consisting of a click chemistry copper salt catalyst, such as a cuprous halide (Cuprous chloride, cuprous iodide), a vitamin C sodium salt, or a cuprous salt or ligand containing I valent copper salt produced from gallic acid and cupric sulfate salt. When coupling is carried out without using a catalyst, the coupling reaction is selected from a copper-free click chemistry reaction and an addition reaction with maleic acid lactam and mercaptan.

18. A process for the preparation of a taxane-lipid-polysaccharide dual conjugate or a pharmaceutically acceptable salt or solvate thereof, which are shown in formula (I) according to claim 1, ##STR00357## the preparation includes the following steps: the polysaccharide is reacted with a functional group-containing fatty or aromatic isocyanate in the presence of a base, optionally in the presence of a coupling reagent, to form a functionalized polysaccharide (Formula III); the reaction temperature is −10° C. to −50° C., preferably 5° C.-30° C.; the coupling reagent is selected from carbodiimides (DCC, EDC, DIPC) or N,N-carbonyldiimidazole; the preparation solvent is anhydrous or aqueous conventional solvent such as DMSO, DMF, dioxane, tetrahydrofuran, methanol or ethanol, preferably DMSO or DMF; the base is selected from the group consisting of organic bases such as tertiary amines (triethylamine, trimethylamine, diisopropyl-Ethylamine) or dimethylaminopyridine (DMAP), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), or an inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, or potassium bicarbonate; the functional group for the preparation of the functionalized polysaccharide is defined as the group consisting of: 1) amino (—NH.sub.2), substituted amino (—NHR), carboxyl (—COOH), azide (—N.sub.3), sulfhydryl (—SH), sulfonic acid (—SO.sub.3H), sulfonylamino (—SO.sub.2NH—, —SO.sub.2NHR), phosphate group (—PO.sub.3H), phosphate ester group (—PO.sub.3R), phosphoramide group (—PO.sub.3NH—, —PO.sub.3NR—), isothiocyano group, iso-oxycyano group, phenolic hydroxyl group; among them, the substituent R group is selected from an alkyl group, a cycloalkyl group, an aromatic alkyl group, an arylalkyl group, or a cycloalkyl alkyl group; 2) an alkynyl compound capable of coupling with an azide compound, a monocyclic derivative containing an acetylenic bond, a fused ring derivative containing an acetylenic bond, any of above compound is selected from aryl cyclooctyne (ALO), thiocyclooctyne, cyclooctyne (OCT), Biarylazacyclooctynone (BARAC), Dibenzoazacyclooctyne (DIBAC), Bicyclononyne (BCN), Dibenzocyclooctyne (MO), Difluorocyclooctyne (DIFO), Monofluororinated cyclooctyne (MOFO), Dimethoxy azacyclooctyne (DIMAC), Nonfluoroocyclooctyne (NOFO), (thioOCT)), Tetramethoxy dibenzocyclooctyne (TMDIBO); 3) maleimide group, substituted propynyl nitrile group, halogen (chlorine, bromine, or iodine) substituted acetamide group, acryl group, substituted vinyl sulfone group, 2-pyridine disulfide group, which is capable of coupling with sulfhydryl group, a 3-nitro-2-pyridinedithio group, a group reactive with a bi-sulfhydryl group; 4) a substituted tetrazine group capable of undergoing a coupling reaction, a monocyclic group having a trans olefinic bond; 5) phenolic compounds and derivatives thereof, and substituted derivatives of 4-phenyl-3H-1,2,4-triazoline-3,5 (4H)-dione (PTAD); a lipid compound is derivatized by a coupling reaction to have at least two identical or different functional groups, in the presence of optionally a base and/or a coupling agent, to form a bifunctional or multifunctional lipid compound; The reaction temperature, the reagent, the base, the coupling reagent and the functional group are defined as the same as in the preparation of the above functionalized polysacharides; in the presence of a base and/or a coupling reagent, the linker and/or spacer which contains functional group is covalently linked to a side chain position of the taxane compound, preferably at the 2′-O position of the side chain to form a functionalized taxane compound (according to Formula II) by employing the combination strategy of spot selective synthetic approach with selectively protecting/deprotecting the hydroxyl group of the taxane compound. The reaction temperature, reagent, base, a coupling reagent, a spacer, and functional group are defined as the same as in the preparation of the above functional poysaccharides; the one functional group of dual-functionalized lipid compound is covalently coupled to the functionalized taxane compound with certain ratios through the reaction in presence of a coupling reagent or an optional catalyst, respectively, to form the functionalized taxane-lipid conjugate (showed by Formula VIII) which still contains free functional group. The reaction temperature, reagent, catalyst, coupling agent and functional group are defined as the same as in the preparation of the above functional poysaccharides; the functionalized polysaccharides is covalently coupled to free functional group of the functionalized taxane compound lipid conjugate in presence of a coupling reagent or an optional catalyst, respectively, to form taxane-lipid-polysaccharide dual conjugate (showed by Formula I), wherein the molar ratio of the functionalized taxane compound-lipid conjugate and the functionalized polysaccharides is optionally about 1:99˜90:10, for example as 1:99˜80:20, 1:99˜70:30, 1:99˜60:40, preferably as 1:99˜50:50; the catalyst is selected from the group consisting of a click chemistry copper salt catalyst, such as a cuprous halide (Cuprous chloride, cuprous iodide), a vitamin C sodium salt, or a cuprous salt or ligand containing I valent copper salt produced from gallic acid and cupric sulfate salt. When coupling is carried out without using a catalyst, the coupling reaction is selected from a copper-free click chemistry reaction and an addition reaction with maleic acid lactam and mercaptan.

19. A pharmaceutical composition comprising one or more (in any ratio) compounds of formula I, formula II, formula V, or formula VIII, or the pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable commonly used pharmaceutical excipient or adjuvant, wherein the taxane-containing pharmaceutical composition usually contains 0.1-60% of taxanes by weight.

20. The pharmaceutical composition of claim 19, which further comprises a compound or more compounds as defined by formula III, formula IV, formula VI, and formula VII; the pharmaceutical composition may comprise any one or more compounds defined by Formula I, Formula II, Formula V, and Formula VIII; it also may comprise any one or more compounds defined by Formula III, Formula IV, Formula VI, and Formula VII.

21. A pharmaceutical composition comprising a poorly water-soluble drug, a pharmaceutically acceptable commonly used pharmaceutical excipient or adjuvant, and a carrier material, wherein the carrier material is selected from the group consisting of compounds or conjugates as defined by Formula I, II, III, IV, V, VI, VII, VIII, it may also comprise a pharmaceutically acceptable salt thereof or a solvate thereof; wherein the poorly water-soluble drug is selected from the group consisting of paclitaxel, docetaxel, cabazitaxel, Vinblastine, vincristine, lipitor, artemisinin, dihydroartemisinin, indomethacin, capecitabine, oxaliplatin, gefitinib, doxorubicin, irinotecan, gemcitabine, pemetrexed, temozolomide, imatinib, vinorelbine, letrozole, teniposide, etoposide, podophyllotoxin, camptothecin, 10-hydroxycamptothecin, 9-hydroxyl-Camptothecin, 7-ethyl-10-hydroxycamptothecin, SN-38, topotecan, irinotecan, vindesine, vinflunine, vinpocetine, desmethylcantharidin, silybin, propofol, florfenicol, mitiglinide, sirolimus, buprofen, nitrendipine, nicardipine, nimodipine, grid Zitt, cisapride, nifedipine, felodipine, glibenclamide, acyclovir, oleanolic acid, breviscapine, ferulic acid, paracetamol, palmitoyl Benikedine, vitamin A, vitamin D, tamoxifen, noviben, valproic acid, tacrolimus, cyclosporine A, amphotericin B, ketoconazole, domperidone, sulpiride, fenofibine, bezafibrate, azithromycin, itraconazole, miconazole, propofol, brimonidine, latanoprost, silybin, curcumin, Adriamycin, erythromycin, roxithromycin, Fuximin, cisapride, cyclosporin, diclofenac, felodipine, ibuprofen, nicardipine, nifedipine, terfenadine, theophylline, ketoprofen, furosemide, spironolactone, dipyrimidine Damo, piroxicam, mefenamic acid, trichlorothiazide, guanolol, saturated or unsaturated fatty acids (such as stearic acid, palmitic acid, oleic acid, linoleic acid, DHA, etc.) or combinations thereof.

22. The pharmaceutical composition according claim 20, which is in the form of a pharmaceutical formulation selected from a liquid dosage form or a solid dosage form; a liquid dosage form is selected from the group consisting of a true solution, a colloidal form, a microparticulate form, a nanoparticle form, a suspension form, an eye drop form; the solid dosage form is selected from the group consisting of an implant, a tablet, a capsule, a dropping pill, an aerosol, a pill, a powder, an emulsion, a granule, a suppository, and a lyophilized powder; the pharmaceutical formulation may also be selected from ordinary formulations, sustained release formulations, controlled release formulations, targeted formulations or various nanoparticle drug delivery systems.

23. A compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof or a solvate thereof, a compound of formula II or a pharmaceutically acceptable salt thereof or a solvate thereof, a compound of formula V or a pharmaceutically acceptable salt thereof or a solvate thereof, or a compound of formula VIII or a pharmaceutically acceptable salt thereof, is for the preparation of an antitumor drug, wherein the tumor is selected from the group consisting of lung cancer, breast cancer, oral cancer, liver cancer, intestinal cancer, gastric cancer, blood cancer, bladder cancer, pancreatic cancer, uterine cancer, and skin cancer.

Description

DESCRIPTION OF THE DRAWINGS

[0284] The present invention is also described by the following exemplary figures. The attached figures show:

[0285] Figure A shows the percentage of paclitaxel released from dual conjugate 298 incubated in rat plasma.

[0286] Figure B shows the body weight change of xenograft mice (%) of dual conjugate 307 group, DTX control group and saline control group.

DETAILED DESCRIPTION

[0287] In the following, the present invention will be further described in the embodiments. It should be noted that the following embodiments are not intended to limit the protection scope of the present invention, and any improvement made on the basis of the present invention does not violate the spirit of the present invention.

SYNTHESIS EXAMPLES

[0288] Each abbreviation in the following synthesis examples has the meaning commonly understood by those skilled in the art.

Part 1. Preparation of Functionalized Taxanes

Synthetic Scheme 1

[0289] ##STR00129## ##STR00130## ##STR00131##

Sample 1: Preparation of Compound 1

[0290] To a 1000 mL round-bottom flask charged with 86.0 g (100.6 mmol) of paclitaxel and 23.8 g (350.21 mmol) of imidazole, 300 mL of anhydrous dimethylformamide (DMF) was added, followed by addition of 52.7 g (350.21 mmol) of tert-butyldimethylchloride, and the reaction mixture was stirred at room temperature for 12 h. Upon completion of the reaction, the mixture was partitioned between ethyl acetate (800 mL) and brine (800 mL). The organic phase was further washed with brine (600 mL×2), dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with ethyl acetate in petroleum (10-70%) to provide 91.9 g of compound 1. Yield: 95%.

[0291] .sup.1H NMR (500 MHz, CDCl.sub.3, ppm): δ 8.13 (d, J=7.2 Hz, 2H), 7.75 (d, J=7.2 Hz, 2H), 7.63 (t, J=7.2 Hz, 2H), 7.52 (m, 3H), 7.40 (m, 4H), 7.32 (m, 3H), 7.07 (d, J=9.0 Hz, 1H), 6.28 (m, 2H), 5.75 (d, J=9.0 Hz, 1H), 5.72 (d, J=9.0 Hz, 1H), 4.98 (d, J=9.0 Hz, 1H), 4.68 (s, 1H), 4.47 (brs, 1H), 4.36 (d, J=9.0 Hz, 1H), 4.21 (d, J=9.0 Hz, 1H), 3.86 (d, J=7.2 Hz, 1H), 2.57 (m, 4H), 2.52 (s, 1H), 2.43 (m, 1H), 2.23 (s, 3H), 2.16 (m, 1H), 1.87 (s, 3H), 1.83 (m, 1H), 1.71 (s, 3H), 1.25 (s, 3H), 1.15 (s, 3H), 0.81 (s, 9H), −0.03 (s, 3H), −0.26 (s, 3H); ESI-MS (m/z): calcd for C.sub.53H.sub.65N.sub.3O.sub.14Si [M+H].sup.+: 968.4; found: 968.3.

Sample 2: Preparation of Compound 2

[0292] In a 500 mL round-bottom flask, 30.0 g (31.02 mmol) of compound 1 was dissolved in 150 mL of anhydrous THF under nitrogen protection and cooled down to −70° C.; 34.2 mL (1.0M) of lithium bis(trimethylsilyl)amide (LHMDS) in THF was then added and stirred for 1 h. To the above solution, 5.86 g (34.2 mmol) of benzyl chloroformate was dropwise added and stirred at −70° C. for 1 h, and then the reaction mixture was allowed to warm up to room temperature and quenched with 5.0 mL of acetic acid. After removal of volatiles, the residue was partitioned between ethyl acetate (500 mL) and brine (500 mL), the organic phase was further washed with brine twice (500 mL×2), dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with ethyl acetate in petroleum (10-60%) to provide 30.7 g of compound 2. Yield: 89%.

[0293] .sup.1H NMR (500 MHz, CDCl.sub.3, ppm): δ 8.13 (d, J=7.8 Hz, 2H), 7.77 (d, J=7.8 Hz, 2H), 7.62 (t, J=7.8 Hz, 1H), 7.54 (m, 3H), 7.31-7.45 (m, 12H), 7.10 (d, J=7.8 Hz, 1H), 6.45 (s, 1H), 6.29 (t, J=8.4 Hz, 1H), 5.76 (d, J=7.8 Hz, 1H), 5.72 (d, J=7.8 Hz, 1H), 5.57 (t, J=7.8 Hz, 1H), 5.27 (d, J=12.0 Hz, 1H), 5.20 (d, J=12.0 Hz, 1H), 5.00 (d, J=9.0 Hz, 1H), 4.69 (s, 1H), 4.36 (d, J=7.8 Hz, 1H), 4.22 (d, J=8.4 Hz, 1H), 4.13 (d, J=6.6 Hz, 1H), 4.00 (d, J=6.6 Hz, 1H), 2.57 (m, 1H), 2.56 (s, 3H), 2.43 (m, 1H), 2.19 (s, 3H), 2.18 (m, 1H), 2.04 (s, 3H), 1.98 (s, 3H), 1.97 (t, J=12.0 Hz, 1H), 1.83 (s, 3H), 1.24 (s, 3H), 1.19 (s, 3H), 0.82 (s, 9H), −0.01 (s, 3H), −0.28 (s, 3H); ESI-MS (m/z): calcd for C.sub.61H.sub.72NO.sub.16Si [M+H].sup.+: 1102.4; found: 1102.5.

Sample 3: Preparation of Compound 3

[0294] In a 250 mL round-bottom flask, 25.0 g (21.78 mmol) of compound 2 was dissolved in anhydrous THF (100 mL), and 43.6 mL of tetrabutylammonium fluoride (TBAF, 1.0M) in THF was added and stirred for 5 h at room temperature. Upon completion of the reaction, the resulting reaction mixture was concentrated and purified on a silica gel column and eluted with ethyl acetate in petroleum (10-70%) to provide 19.1 g of compound 3. Yield: 88%.

[0295] .sup.1H NMR (500 MHz, CDCl.sub.3, ppm): δ 8.12 (d, J=7.8 Hz, 2H), 7.77 (d, J=7.8 Hz, 2H), 7.62 (t, J=7.8 Hz, 1H), 7.51 (m, 5H), 7.42 (m, 6H), 7.35 (m, 4H), 7.13 (d, J=7.8 Hz, 1H), 6.41 (s, 1H), 6.21 (t, J=8.4 Hz, 1H), 5.82 (t, J=8.4 Hz, 1H), 5.70 (d, J=6.6 Hz, 1H), 5.51 (m, 1H), 5.26 (d, 1H, J=12.0 Hz, 1H), 5.19 (d, J=12.0 Hz, 1H), 4.96 (d, J=9.0 Hz, 1H), 4.83 (s, 1H), 4.32 (d, J=8.4 Hz, 1H), 4.20 (d, J=8.4 Hz, 1H), 3.95 (d, J=9.6 Hz, 1H), 2.61 (m, 1H), 2.39 (s, 3H), 2.34 (m, 1H), 2.20 (s, 3H), 2.05 (s, 3H), 1.98 (t, J=12.0 Hz, 1H), 1.89 (s, 3H), 1.82 (s, 3H), 1.23 (s, 3H), 1.19 (s, 3H); ESI-MS (m/z): calcd for C.sub.55H.sub.58NO.sub.16 [M+H].sup.+: 988.4; found: 988.5.

Sample 4: Preparation of Compound 4

[0296] To a 250 mL round-bottom flask charged with 3.41 g (15.18 mmol) of benzyl diglycolic acid monoester and 2.90 g (15.18 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), 100 mL of anhydrous chloroform was added and stirred at room temperature for 30 min. To the above solution, 10.0 g (10.11 mmol) of compound 3 and 1.85 g (15.18 mmol) of 4-dimethylaminopyridine (DMAP) were added and stirred for 12 h. Upon completion of the reaction, the reaction mixture was washed with brine three times (150 mL×3), dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with ethyl acetate in petroleum (10-60%) to provide 10.3 g of compound 4. Yield: 86%.

[0297] .sup.1H NMR (500 MHz, CDCl.sub.3, ppm): δ 8.15 (d, J=7.8 Hz, 2H), 7.79 (d, J=7.8 Hz, 2H), 7.63 (t, J=7.8 Hz, 1H), 7.53 (m, 3H), 7.38-7.44 (m, 14H), 7.11 (d, J=7.8 Hz, 1H), 6.44 (s, 1H), 6.28 (t, J=9.6 Hz, 1H), 6.06 (d, J=9.6 Hz, 1H), 5.26 (m, 1H), 5.19 (m, 2H), 5.09 (m, 2H), 4.98 (d, J=9.6 Hz, 1H), 4.36 (m, 3H), 4.21 (s, 2H), 3.98 (d, J=6.0 Hz, 1H), 2.61 (m, 1H), 2.49 (s, 3H), 2.41 (m, 2H), 2.29 (m, 1H), 2.19 (s, 3H), 2.06 (s, 3H), 1.98 (t, J=12.0 Hz, 1H), 1.82 (s, 3H), 1.24 (s, 3H), 1.19 (s, 3H); ESI-MS (m/z): calcd for C.sub.66H.sub.68NO.sub.20 [M+H].sup.+: 1194.3; found: 1194.5.

Sample 5: Preparation of Compound 5

[0298] In a 250 mL hydrogenation glass bottle, 7.0 g (5.86 mmol) of compound 4 was dissolved in 80 mL of methanol, and was treated with 500 mg of 10% Pd—C under hydrogen gas of 1.2 atm for 12 h. Solid material was filtered off, and the filtrate was concentrated and purified on a RP-C18 column and eluted with methanol in water (5-80%) to give 4.62 g of compound 5. Yield: 81%.

[0299] .sup.1H NMR (500 MHz, CD.sub.3OD, ppm): δ 8.15 (d, J=7.2 Hz, 2H), 7.82 (d, J=7.2 Hz, 2H), 7.68 (t, J=7.2 Hz, 1H), 7.60 (d, J=7.2 Hz, 2H), 7.41-7.51 (m, 9H), 7.30 (t, J=7.2 Hz, 1H), 6.46 (s, 1H), 6.11 (m, 1H), 5.91 (d, J=6.6 Hz, 1H), 5.67 (d, J=6.6 Hz, 1H), 5.61 (d, J=6.6 Hz, 1H), 5.02 (d, J=9.6 Hz, 2H), 4.44 (m, 2H), 4.62 (m, 5H), 3.84 (d, J=6.6 Hz, 1H), 2.51 (m, 1H), 2.47 (s, 3H), 2.28 (m, 1H), 2.18 (s, 3H), 1.98 (m, 3H), 1.92 (m, 1H), 1.82 (t, J=12.0 Hz, 1H), 1.67 (s, 3H), 1.16 (s, 3H), 1.15 (s, 3H); ESI-MS (m/z): calcd for C.sub.51H.sub.56NO.sub.18 [M+H].sup.+: 970.3; found: 970.3.

Sample 6: Preparation of Compound 6

[0300] In a 100 mL round-bottom flask, 3.0 g (3.09 mmol) of compound 5 and 1.41 g (3.71 mmol) of benzotriazole-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU) and 502 mg (3.71 mmol) of 1-hydroxybenzotriazole (HOBt) were dissolved in 15.0 mL of dry DMF, and followed by addition of 309 mg (3.71 mmol) 4-pentyn-1-amine and 0.85 mL (6.18 mmol) of triethylamine, and stirred at room temperature for 3 h. Upon completion of the reaction, the reaction mixture was partitioned between ethyl acetate (300 mL) and brine (300 mL). The organic phase was further washed with brine twice (300 mL×2), dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with methanol in chloroform (1-10%) to provide 2.43 g of compound 6. Yield: 76%.

[0301] .sup.1H NMR (500 MHz, DMSO-d.sub.6, ppm): δ 8.11 (d, J=7.2 Hz, 2H), 7.63 (d, J=7.2 Hz, 2H), 7.53 (t, J=7.2 Hz, 1H), 7.20-7.45 (m, 10H), 6.76 (m, 2H), 6.21 (s, 1H), 6.18 (t, J=9.0 Hz, 1H), 5.96 (d, J=6.0 Hz, 1H), 5.87 (d, J=7.2 Hz, 1H), 5.50 (s, 1H), 5.43 (t, J=9.0 Hz, 1H), 4.87 (d, J=12.0 Hz, 1H), 4.37 (t, J=7.2 Hz, 1H), 4.22 (m, 1H), 4.12 (m, 1H), 4.05 (dd, J=12.0, 7.2 Hz, 1H), 3.90 (m, 2H), 3.71 (d, J=7.2 Hz, 1H), 3.27 (dd, J=12.0, 7.2 Hz, 2H), 2.47 (m, 1H), 2.37 (s, 3H), 2.29 (m, 1H), 2.06 (s, 3H), 1.93 (m, 3H), 1.85 (m, 3H), 1.81 (t, J=12.0 Hz, 1H), 1.70 (m, 3H), 1.63 (s, 3H), 1.17 (s, 3H), 1.06 (s, 3H); ESI-MS (m/z): calcd for C.sub.56H.sub.63N.sub.2O.sub.17 [M+H].sup.+: 1035.4; found: 1035.5.

Sample 7: Preparation of Compound 7

[0302] To a 10 mL round-bottom flask charged with 300 mg (0.29 mmol) of compound 6 and 60 mg (0.38 mmol) of 6-azido-hexanoic acid, 5.0 mL of DMSO was added. 100 uL of copper sulfate (1.0M) in water and 100 uL of sodium ascorbate (1.0M) in water were mixed together and added to the above solution. After stirring for 2 days at room temperature, the reaction mixture was partitioned between ethyl acetate (50 mL) and brine (50 mL). The organic phase was further washed with brine twice (50 mL×2), dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with methanol in chloroform (1-10%) to give 275 mg of compound 7. Yield: 87%.

[0303] .sup.1H NMR (500 MHz, DMSO-d.sub.6, ppm): δ 8.11 (d, J=7.2 Hz, 2H), 7.50-7.78 (m, 6H), 7.25-7.45 (m, 9H), 6.43 (s, 1H), 6.03 (t, J=7.8 Hz, 1H), 5.86 (d, J=6.0 Hz, 1H), 5.60 (d, J=7.2 Hz, 1H), 5.58 (d, J=7.2 Hz, 1H), 5.23 (d, J=9.0 Hz, 1H), 4.94 (d, J=9.0 Hz, 1H), 4.63 (s, 1H), 4.46 (s, 1H), 4.35 (m, 4H), 4.18 (m, 2H), 4.13 (s, 2H), 4.02 (m, 3H), 3.77 (d, J=7.2 Hz, 1H), 3.22 (t, J=7.2 Hz, 2H), 2.67 (t, J=7.2 Hz, 2H), 2.43 (m, 2H), 2.37 (s, 3H), 2.25 (m, 3H), 2.16 (m, 1H), 2.15 (s, 3H), 1.97 (s, 3H), 1.81 (m, 3H), 1.73 (t, J=12.0 Hz, 1H), 1.61 (s, 3H), 1.58 (m, 4H), 1.26 (m, 2H), 1.12 (s, 3H), 1.07 (s, 3H); ESI-MS (m/z): calcd for C.sub.62H.sub.74N.sub.5O.sub.19 [M+H].sup.+: 1092.5; found: 1092.7.

Synthetic Scheme 2

[0304] ##STR00132##

Sample 8: Preparation of Compound 8

[0305] To a 250 mL round-bottom flask charged with 30.0 g (30.98 mmol) of compound 1, 120 mL of anhydrous chloroform was added under nitrogen protection and cooled down to 0° C., and followed by 22.71 g (185.9 mmol) of DMAP and 22.71 g (185.9 mmol) of allyl chloroformate. Upon completion of addition, the cooled batch was removed, and the reaction mixture was stirred at room temperature for 12 h. After removal of volatiles, the residue was purified on a silica gel column and eluted with ethyl acetate in petroleum (5-60%) to provide 31.5 g of compound 8. Yield: 96%.

[0306] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 8.12 (d, J=7.2 Hz, 2H), 7.76 (d, J=7.2 Hz, 2H), 7.60 (t, J=7.2 Hz, 2H), 7.51 (m, 3H), 7.42 (m, 4H), 7.33 (m, 3H), 7.15 (d, J=9.0 Hz, 1H), 6.37 (s, 1H), 6.25 (t, J=9.0 Hz, 1H), 5.97 (m, 1H), 5.75 (d, J=9.0 Hz, 1H), 5.71 (d, J=7.2 Hz, 1H), 5.38 (dd, J=10.2, 7.8 Hz, 1H), 5.31 (d, J=15.6 Hz, 1H), 5.23 (d, J=15.6 Hz, 1H), 4.98 (d, J=9.6 Hz, 1H), 4.75 (m, 1H), 4.69 (s, 1H), 4.63 (m, 1H), 4.35 (d, J=9.0 Hz, 1H), 4.20 (d, J=9.0 Hz, 1H), 3.97 (d, J=6.6 Hz, 1H), 2.61 (m, 1H), 2.57 (s, 3H), 2.43 (dd, J=15.0, 9.0 Hz, 1H), 2.21 (dd, J=15.0, 9.0 Hz, 1H), 2.17 (s, 3H), 2.03 (s, 3H), 1.97 (m, 1H), 1.81 (s, 3H), 1.26 (s, 3H), 1.16 (s, 3H), 0.83 (s, 9H), −0.03 (s, 3H), −0.27 (s, 3H); ESI-MS (m/z): calcd for C.sub.57H.sub.70NO.sub.16Si [M+H].sup.+: 1052.4; found: 1052.5.

Sample 9: Preparation of Compound 9

[0307] In a 100 mL round-bottom flask, 16.0 g (15.21 mmol) of compound 8 was dissolved in anhydrous THF (50 mL), and 30.5 mL of tetrabutylammonium fluoride (TBAF, 1.0M) in THF was added and stirred for 2 h at room temperature. Upon completion of the reaction, the resulting reaction mixture was concentrated and purified on a silica gel column and eluted with ethyl acetate in petroleum (10-60%) to provide 12.1 g of compound 9. Yield: 85%.

[0308] .sup.1H NMR (500 MHz, CDCl.sub.3, ppm): δ 8.12 (d, J=7.2 Hz, 2H), 7.75 (d, J=7.2 Hz, 2H), 7.60 (t, J=7.2 Hz, 2H), 7.30-7.51 (m, 10H), 7.11 (d, J=9.0 Hz, 1H), 6.37 (s, 1H), 6.17 (t, J=9.0 Hz, 1H), 5.96 (m, 1H), 5.83 (d, J=9.0 Hz, 1H), 5.67 (d, J=7.2 Hz, 1H), 5.43 (m, 1H), 5.32 (d, J=12.0 Hz, 1H), 5.21 (d, J=12.0 Hz, 1H), 4.93 (d, J=9.0 Hz, 1H), 4.77 (s, 1H), 4.70 (m, 1H), 4.63 (m, 1H), 4.31 (d, J=8.4 Hz, 1H), 4.16 (d, J=8.4 Hz, 1H), 4.08 (dd, J=15.0, 7.2 Hz, 1H), 3.90 (d, J=7.2 Hz, 1H), 2.61 (m, 1H), 2.37 (s, 3H), 2.35 (m, 1H), 2.13 (m, 4H), 1.97 (t, J=12.0 Hz, 1H), 1.84 (s, 3H), 1.81 (m, 1H), 1.80 (s, 3H), 1.19 (s, 3H), 1.15 (s, 3H); ESI-MS (m/z): calcd for C.sub.51H.sub.56NO.sub.16 [M+H].sup.+: 938.3; found: 938.6.

Sample 10: Preparation of Compound 10

[0309] In a 500 mL round bottom flask, 20.0 g (111.1 mmol) of anhydrous glucose and 32.0 g (114.8 mmol) of triphenylchloromethane were combined in 160 mL of anhydrous pyridine, heated to 50° C., and stirred for 12 h; then 50 mL of acetic anhydride was added and stirred for another 8 h. Upon completion of the reaction, the reaction mixture was poured into ice water upon which a white precipitate formed; the resulting precipitate was filtered, dried under high vacuum, redissolved in anhydrous ether (200 mL), and cooled down to 0° C.; 35.7 g (333.3 mmol) of benzylamine was added to the above ether solution and stirred overnight. The final reaction mixture was washed with water (100 mL×2), dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted ethyl acetate in petroleum (10-70%) to give 37.8 g of compound 10. Yield: 62%.

[0310] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 7.20-7.60 (m, 15H), 5.51 (d, J=3.6 Hz, 1H), 5.46 (t, J=10.0 Hz, 1H), 5.21 (t, J=10.0 Hz, 1H), 4.95 (dd, J=3.6, 10.0 Hz, 1H), 4.17 (m, 1H), 3.27 (d, J=10.0 Hz, 1H), 3.11 (m, 1H), 2.08 (s, 3H), 2.00 (s, 3H), 1.74 (s, 3H); ESI-MS (m/z): calcd for C.sub.31H.sub.33O.sub.9 [M+H].sup.+: 549.2; found: 549.3.

Sample 11: Preparation of Compound 11

[0311] To a 250 mL round-bottom flask charged with 20.0 g (36.42 mmol) of compound 10, 100 mL of anhydrous chloroform was added, followed by addition of 4.38 mL (185.9 mmol) of trichloroacetonitrile and 0.5 mL (3.65 mmol) of 1,8-diazabicyclo(5,4,0)undec-7-ene under the protection of nitrogen, and stirred at room temperature overnight. After removal of volatiles and the residue was purified by flash chromatography on silica gel (ethyl acetate:petroleum/10-70%) to provide an intermediate as an oil; The intermediate was dissolved in 120 mL of anhydrous chloroform and cooled down to −70° C. under nitrogen protection, and then 5.9 mL (40.06 mmol) of trimethylsilyl trifluoromethanesulfonate was added and stirred for 2 h, and followed by addition of 6.13 g (72.85 mmol) of 4-pentyn-1-ol. After stirring for another 5 h, the reaction was stopped by slowly adding 5.9 mL of triethylamine. The reaction mixture was filtered, and the filtrate was concentrated and purified on a silica gel column and eluted ethyl acetate in petroleum (10-70%) to give 12.5 g of compound 11. Yield: 56%.

[0312] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 7.27-7.60 (m, 15H), 5.31 (d, J=3.6 Hz, 1H), 5.05 (t, J=10.0 Hz, 1H),), 4.53 (d, J=10.0 Hz, 1H), 4.17 (m, 1H), 4.05 (m, 1H), 3.78 (m, 1H), 3.57 (m, 1H), 3.27 (d, J=10.0 Hz, 1H), 3.11 (m, 1H), 2.31 (t, J=7.0 Hz, 2H), 2.08 (s, 3H), 1.95 (s, 1H), 2.00 (s, 3H), 1.74 (s, 3H), 1.67 (m, 2H); ESI-MS (m/z): calcd for C.sub.31H.sub.33O.sub.9 [M+H].sup.+: 615.2; found: 615.3.

Sample 12: Preparation of Compound 12

[0313] In a 250 mL round-bottom flask, 10.0 g (16.25 mmol) of compound 11 was dissolved 100 mL of dichloromethane, and followed by addition of 7.89 g (48.75 mmol) of ferric chloride, and stirred at room temperature overnight. Upon completion of the reaction, the reaction mixture was washed with distilled water (100 mL×3), dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted ethyl acetate in petroleum (10-80%) to give 4.52 g of compound 12. Yield: 75%.

[0314] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 5.18 (d, J=3.6 Hz, 1H), 4.97 (t, J=10.0 Hz, 1H), 4.90 (d, J=10.0 Hz, 1H), 4.49 (m, 1H), 3.91 (m, 1H), 3.78 (m, 1H), 3.50-3.70 (m, 4H), 2.21 (t, J=7.0 Hz, 2H), 1.93-2.10 (m, 10H), 1.70 (m, 2H); ESI-MS (m/z): calcd for C.sub.17H.sub.25O.sub.9 [M+H].sup.+: 373.1; found: 373.2.

Sample 13: Preparation of Compound 13

[0315] In a 250 mL round-bottom flask, 3.6 g (9.65 mmol) of compound 12 was dissolved in 50 mL of anhydrous dichloromethane, followed by addition of 3.36 g (28.95 mmol) of diglycolic acid anhydride and 3.0 mL of triethylamine, and stirred at room temperature overnight. After removal of volatiles, the residue was partitioned between ethyl acetate (100 mL) and saturated citric acid (100 mL); the aqueous phase was extracted with ethyl acetate (60 mL×2), and the organic phases were pooled, dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with methanol in chloroform (0-10%) to give 3.39 g of compound 13. Yield: 72%.

[0316] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 5.21 (d, J=3.6 Hz, 1H), 5.09 (t, J=10.0 Hz, 1H), 4.93 (d, J=10.0 Hz, 1H), 4.50 (d, J=10.0 Hz, 1H), 4.41 (d, J=10.0 Hz, 1H), 4.27 (m, 5H), 4.12 (m, 1H), 3.92 (m, 1H), 3.72 (m, 1H), 3.60 (m, 1H), 2.20 (t, J=7.0 Hz, 2H), 1.92-2.07 (m, 10H), 1.70-1.75 (m, 2H); ESI-MS (m/z): calcd for C.sub.21H.sub.29O.sub.13 [M+H].sup.+: 489.1; found: 489.2.

Sample 14: Preparation of Compound 14

[0317] To a 250 mL round-bottom flask charged with 2.5 g (5.12 mmol) of compound 13 and 978 mg (5.12 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), 30 mL of anhydrous dichloromethane was added, and stirred at room temperature for 30 min; and then 2.39 g (2.56 mmol) of compound 3 and 629 mg (5.12 mmol) of DMAP were added. The reaction was continuously stirred for 12 h. After removal of volatiles, the residue was partitioned between ethyl acetate (100 mL) and brine (100 mL); the aqueous phase was extracted with ethyl acetate (60 mL×2), and the organic phases were pooled, dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with ethyl acetate in petroleum (10-80%) to provide 3.09 g of compound 14. Yield: 86%.

[0318] .sup.1H NMR (500 MHz, CDCl.sub.3, ppm): δ 8.15 (d, J=7.2 Hz, 2H), 7.73 (d, J=7.2 Hz, 2H), 7.60 (t, J=7.2 Hz, 1H), 7.15-7.51 (m, 10H), 6.97 (d, J=9.0 Hz, 1H), 6.31 (m, 2H), 6.05 (m, 1H), 5.71 (d, J=9.0 Hz, 1H), 5.62 (d, J=7.2 Hz, 1H), 5.46 (m, 1H), 4.90-5.36 (m, 6H), 4.00-4.60 (m, 14H), 3.95 (d, J=7.2 Hz, 1H), 3.82 (m, 1H), 3.60 (m, 1H), 2.58 (m, 1H), 2.37 (s, 3H), 2.33 (m, 1H), 2.20 (m, 6H), 1.92-2.05 (m, 11H), 1.84 (s, 3H), 1.82 (m, 4H), 1.70-1.81 (m, 5H), 1.20 (s, 3H), 1.15 (s, 3H); ESI-MS (m/z): calcd for C.sub.72H.sub.82NO.sub.28 [M+H].sup.+: 1408.5; found: 1408.7.

Sample 15: Preparation of Compound 15

[0319] To a 250 mL round-bottom flask charged with 2.0 g (1.42 mmol) of compound 14, 165 mg (0.142 mmol) of tetrakis(triphenylphosphine)palladium(O), and 266 mg (1.70 mmol) of 1,3-dimethylbarbituric acid under nitrogen protection, 20.0 mL of anhydrous THF was added and the reaction mixture was stirred at room temperature for 5 h. After removal of volatiles and the residue was purified on a silica gel column and eluted with methanol in chloroform (0-8%) to give 1.57 g of compound 15. Yield: 83%.

[0320] .sup.1H NMR (500 MHz, CDCl.sub.3, ppm): δ 8.13 (d, J=7.2 Hz, 2H), 7.74 (d, J=7.2 Hz, 2H), 7.58 (t, J=7.2 Hz, 1H), 7.15-7.51 (m, 10H), 6.95 (d, J=9.0 Hz, 1H), 6.30 (m, 2H), 6.03 (m, 1H), 5.72 (d, J=9.0 Hz, 1H), 5.60 (d, J=7.2 Hz, 1H), 4.90-5.36 (m, 3H), 4.00-4.60 (m, 14H), 3.96 (d, J=7.2 Hz, 1H), 3.81 (m, 1H), 3.61 (m, 1H), 2.61 (m, 1H), 2.36 (s, 3H), 2.35 (m, 1H), 2.21 (m, 6H), 1.92-2.05 (m, 11H), 1.85 (s, 3H), 1.81 (m, 4H), 1.70-1.80 (m, 5H), 1.21 (s, 3H), 1.15 (s, 3H); ESI-MS (m/z): calcd for C.sub.68H.sub.78NO.sub.26 [M+H].sup.+: 1324.4; found: 1324.3.

Sample 16: Preparation of Compound 16

[0321] To a 25 mL round-bottom flask charged with 500 mg (0.38 mmol) of compound 15 and 108 mg (0.76 mmol) of 6-azido-hexanoic acid, 5.0 mL of DMSO was added. 100 uL of copper sulfate (1.0M) in water and 100 uL of sodium ascorbate (1.0M) in water were mixed together and added to the above solution. After stirring for 2 days at room temperature, the reaction mixture was partitioned between ethyl acetate (50 mL) and brine (50 mL), the organic phase was further washed with brine twice (50 mL×2), dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with methanol in chloroform (1-10%) to provide 496 mg of compound 16. Yield: 91%.

[0322] .sup.1H NMR (500 MHz, CD.sub.3OD, ppm): δ 8.15 (d, J=7.2 Hz, 2H), 7.73 (d, J=7.2 Hz, 2H), 7.60 (t, J=7.2 Hz, 1H), 7.15-7.51 (m, 11H), 6.97 (d, J=9.0 Hz, 1H), 6.32 (m, 2H), 6.03 (m, 1H), 5.73 (d, J=9.0 Hz, 1H), 5.62 (d, J=7.2 Hz, 1H), 4.90-5.36 (m, 3H), 4.00-4.60 (m, 14H), 3.96 (d, J=7.2 Hz, 1H), 3.81 (m, 1H), 3.61 (m, 3H), 2.721 (m, 2H), 2.53 (m, 1H), 2.33-2.37 (m, 4H), 2.21 (m, 6H), 1.92-2.05 (m, 11H), 1.85 (s, 3H), 1.81 (m, 4H), 1.70-1.80 (m, 7H), 1.42 (m, 2H), 1.25 (m, 4H), 1.22 (s, 3H), 1.13 (s, 3H); ESI-MS (m/z): calcd for C.sub.74H.sub.91N.sub.4O.sub.27 [M+H].sup.+: 1467.6; found: 1467.9.

Synthetic Scheme 3

[0323] ##STR00133## ##STR00134##

Sample 17: Preparation of Compound 17

[0324] In a 250 mL round-bottom flask, 5.0 g (18.09 mmol) of 3-amniopropanoyl dibenzocyclooctyne amide was dissolved in 100 mL of anhydrous chloroform, followed by addition of 5.0 mL of triethylamine and 5.35 g (19.91 mmol) of Boc-glycine N-hydroxyl succinimide ester, and stirred at room temperature overnight. The reaction mixture was washed with brine twice (100 mL×2), dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with acetone in chloroform (0-50%) to give 6.73 g of compound 17. Yield: 85%.

[0325] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 7.73 (m, 1H), 7.13-7.16 (m, 7H), 6.50 (s, 1H), 5.10 (d, J=15.0 Hz, 1H), 3.80 (m, 2H), 3.68 (d, J=15.0 Hz, 1H), 2.57 (m, 1H), 2.05 (m, 1H), 1.46 (s, 9H); ESI-MS (m/z): calcd for C.sub.25H.sub.28N.sub.3O.sub.4 [M+H].sup.+: 434.2; found: 434.3.

Sample 18: Preparation of Compound 18

[0326] To a 100 mL round-bottom flask charged with 6.0 g (12.82 mmol) of compound 17, 30 mL of dichloromethane and 10.0 mL of trifluoracetic acid were successively added at 0° C., and stirred overnight. After removal of volatiles, the residue was purified on a reverse phase C-18 column and eluted with acetonitrile in water (5-70%) to provide 1.62 g of compound 18. Yield: 38%.

[0327] .sup.1H NMR (300 MHz, CD.sub.3OD, ppm): δ 7.68 (m, 1H), 7.13-7.16 (m, 7H), 5.13 (d, J=15.0 Hz, 1H), 3.86 (m, 2H), 3.73 (d, J=15.0 Hz, 1H), 3.33 (m, 2H), 2.52 (m, 1H), 2.07 (m, 1H); ESI-MS (m/z): calcd for C.sub.20H.sub.20N.sub.3O.sub.2 [M+H].sup.+: 334.1; found: 334.1.

Sample 19: Preparation of Compound 19

[0328] To a 100 mL round-bottom flask charged with 1.7 g (3.62 mmol) of compound 18, 20 mL of chloroform, 5.0 mL of triethylamine, and 905 mg (9.05 mmol) of diglycolic acid anhydride were successively added at 0° C., and stirred overnight. After removal of volatiles, the residue was partitioned between chloroform (20 mL) and aqueous HCl (1.0N, 20 mL); the organic phase was evaporated, and the residue was purified on a reverse phase C-18 column and eluted with acetonitrile in water (10-80%) to provide 1.52 g of compound 19. Yield: 96%.

[0329] .sup.1H NMR (300 MHz, DMSO-d.sub.6, ppm): δ 7.70-7.93 (m, 3H), 7.29-7.61 (m, 4H), 5.34 (d, J=15.0 Hz, 1H), 4.02 (m, 2H), 3.65 (d, J=15.0 Hz, 1H), 3.23 (m, 2H), 2.25-2.52 (m, 6H); ESI-MS (m/z): calcd for C.sub.24H.sub.24N.sub.3O.sub.5 [M+H].sup.+: 434.1; found: 434.2.

Sample 20: Preparation of Compound 20

[0330] To a 100 mL round-bottom flask charged with 1.0 g (2.31 mmol) of compound 19 and 440 mg (2.31 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), 30 mL of anhydrous dichloromethane was added, and stirred at room temperature for 30 min; and then 1.11 g (1.16 mmol) of compound 9 and 282 mg (2.31 mmol) of DMAP were added. The reaction was continuously stirred for 12 h. After removal of volatiles, the residue was partitioned between ethyl acetate (50 mL) and brine (50 mL); the aqueous phase was extracted with ethyl acetate (30 mL×2), and the organic phases were pooled, dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with methanol in dichloromethane (0-10%) to provide 1.31 g of compound 20. Yield: 83%.

[0331] .sup.1H NMR (500 MHz, CDCl.sub.3, ppm): δ 8.11 (d, J=7.2 Hz, 2H), 7.17-7.77 (m, 23H), 6.37 (s, 1H), 6.20 (t, J=9.0 Hz, 1H), 5.95 (m, 1H), 5.82 (d, J=9.0 Hz, 1H), 5.68 (d, J=7.2 Hz, 1H), 5.46 (m, 1H), 5.35 (d, J=12.0 Hz, 1H), 5.26 (m, 2H), 4.97 (d, J=9.0 Hz, 1H), 4.72 (m, 1H), 4.41 (m, 2H), 4.29 (m, 1H), 4.21 (m, 1H), 4.02 (m, 2H), 3.52-3.76 (m, 5H), 3.21 (m, 2H), 2.75 (m, 4H), 2.57 (m, 2H), 2.42 (s, 3H), 2.33 (m, 1H), 2.15 (m, 3H), 1.98 (m, 2H), 1.86 (s, 3H), 1.82 (m, 1H), 1.80 (s, 3H), 1.19 (s, 3H), 1.17 (s, 3H); ESI-MS (m/z): calcd for C.sub.75H.sub.77N.sub.4O.sub.20 [M+H].sup.+: 1353.5; found: 1353.3.

Sample 21: Preparation of Compound 21

[0332] To a 25 mL round-bottom flask charged with 900 mg (0.663 mmol) of compound 20, 60 mg (0.051 mmol) of tetrakis(triphenylphosphine)palladium(O), and 115 mg (0.769 mmol) of 1,3-dimethylbarbituric acid under nitrogen protection, 10.0 mL of anhydrous THF was added; the reaction mixture was stirred at room temperature for 2 h. After removal of volatiles and the residue was purified on a silica gel column and eluted with methanol in chloroform (0-10%) to give 691 mg of compound 21. Yield: 82%.

[0333] .sup.1H NMR (500 MHz, CDCl.sub.3, ppm): δ 8.12 (d, J=7.2 Hz, 2H), 7.17-7.77 (m, 23H), 6.52 (m, 2H), 6.20 (t, J=9.0 Hz, 1H), 5.99 (m, 1H), 5.75 (d, J=9.0 Hz, 1H), 5.68 (d, J=7.2 Hz, 1H), 5.21 (m, 2H), 4.99 (d, J=9.0 Hz, 1H), 4.72 (m, 1H), 4.41 (m, 2H), 4.29 (m, 1H), 4.21 (m, 1H), 4.01 (m, 2H), 3.52-3.76 (m, 5H), 3.20 (m, 2H), 2.73 (m, 4H), 2.55 (m, 2H), 2.42 (s, 3H), 2.33 (m, 1H), 2.15 (m, 3H), 1.98 (m, 2H), 1.87 (s, 3H), 1.83 (m, 1H), 1.81 (s, 3H), 1.19 (s, 3H), 1.18 (s, 3H); ESI-MS (m/z): calcd for C.sub.71H.sub.73N.sub.4O.sub.18 [M+H].sup.+: 1269.5; found: 1269.6.

Sample 22: Preparation of Compound 22

[0334] To a 25 mL round-bottom flask charged with 250 mg (0.196 mmol) of compound 21 and 46 mg (0.196 mmol) of 6-azido-hexanoic acid, 5.0 mL of methanol was added. 100 uL of copper sulfate (1.0M) in water and 100 uL of sodium ascorbate (1.0M) in water were mixed together, and then added to the above solution. After stirring overnight at room temperature, the reaction mixture was concentrated, and purified on a reverse phase column and eluted with acetonitrile in water (1-10%) to provide 201 mg of compound 22a and 22b. Yield: 72%.

[0335] .sup.1H NMR (500 MHz, CDCl.sub.3, ppm): δ 8.11 (d, J=7.2 Hz, 2H), 7.17-7.77 (m, 24H), 6.51 (m, 2H), 6.22 (t, J=9.0 Hz, 1H), 5.97 (m, 1H), 5.73 (d, J=9.0 Hz, 1H), 5.67 (d, J=7.2 Hz, 1H), 5.20 (m, 2H), 4.97 (d, J=9.0 Hz, 1H), 4.72 (m, 1H), 4.42 (m, 2H), 4.27 (m, 1H), 4.22 (m, 1H), 4.03 (m, 2H), 3.52-3.76 (m, 5H), 3.23 (m, 4H), 2.73 (m, 4H), 2.53 (m, 4H), 2.42 (s, 3H), 2.33 (m, 1H), 2.15 (m, 3H), 1.98 (m, 2H), 1.87 (s, 3H), 1.83 (m, 1H), 1.75-1.81 (m, 5H), 1.45 (m, 2H), 1.29 (m, 2H), 1.17 (s, 3H), 1.13 (s, 3H); ESI-MS (m/z): calcd for C.sub.77H.sub.84N.sub.7O.sub.20 [M+H].sup.+: 1426.5; found: 1426.7.

Synthetic Scheme 4

[0336] ##STR00135## ##STR00136##

Sample 23: Preparation of Compound 23

[0337] To a 250 mL round bottom flask charged with 3.0 g (39.97 mmol) of glycine and 5.0 mL (36.17 mmol) of triethylamine in 15.0 mL of DMF, 5.57 g (26.64 mmol) of 4-alkynoic acid N-hydroxysuccinimide ester in dry DMF was dropwise added, and stirred at room temperature overnight. After removal of volatiles, the residue was acidified with concentrated HCl solution, and extracted with ethyl acetate twice (250 mL×2); the organic phases were pooled, dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a reverse phase C-18 column and eluted with acetonitrile in water (10-70%) to provide 3.38 g of compound 23. Yield: 75%.

[0338] .sup.1H NMR (300 MHz, D.sub.2O, ppm): δ 3.95 (s, 2H), 2.43 (t, J=7.2 Hz, 2H), 2.33 (t, J=3.0 Hz, 1H), 2.23 (m, 2H), 1.79 (m, 2H); ESI-MS (m/z): calcd for C.sub.8H.sub.12NO.sub.3 [M+H].sup.+: 170.1; found: 170.1.

Sample 24: Preparation of Compound 24

[0339] To a 100 mL round-bottom flask charged with 2.5 g (14.78 mmol) of compound 23, 3.39 g 75 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), and 2.40 g (17.75 mmol) of 1-hydroxybenzotriazole (HOBt) in 100 mL of anhydrous DMF, 2.73 g (22.17 mmol) of 4-aminobenzyl alcohol, and 3.0 mL of triethylamine were added; and stirred at room temperature for 3 h. Upon completion of the reaction, the reaction mixture was partitioned between ethyl acetate (300 mL) and brine (300 mL), and the organic phase was further washed with brine twice (300 mL×2), dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with methanol in chloroform (1-10%) to provide 3.48 g of compound 24. Yield: 86%.

[0340] .sup.1H NMR (300 MHz, DMSO-d.sub.6, ppm): δ 9.81 (s, 1H), 8.08 (s, 1H), 7.42 (d, J=7.8 Hz, 2H), 7.13 (d, J=7.8 Hz, 2H), 4.99 (brs, 1H), 4.31 (s, 2H), 3.74 (s 2H), 1.96-2.15 (m, 5H), 1.57 (t, J=7.2 Hz, 2H); ESI-MS (m/z): calcd for C.sub.15H.sub.19N.sub.2O.sub.3 [M+H].sup.+: 275.1; found: 275.1.

Sample 25: Preparation of Compound 25

[0341] To a 250 mL round-bottom flask charged with 2.3 g (8.39 mmol) of compound 24, 20 mL of chloroform, 5.0 mL of triethylamine, and 2.92 g (25.17 mmol) of diglycolic acid anhydride were successively added and stirred at room temperature overnight. After removal of volatiles, the residue was partitioned between ethylacetate (150 mL) and saturated citric acid (150 mL); the aqueous phase was further extracted with ethyl acetate (100 mL×2), and the organic phases were combined together, dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with methanol in chloroform (0-15%) to provide 2.52 g of compound 25. Yield: 77%.

[0342] .sup.1H NMR (500 MHz, DMSO-d.sub.6, ppm): δ 10.0 (s, 1H), 8.12 (s, 1H), 7.42 (d, J=7.8 Hz, 2H), 7.19 (d, J=7.8 Hz, 2H), 4.99 (s, 2H), 4.11 (s, 2H), 3.92 (s, 2H), 3.75 (s, 2H), 2.05-2.15 (m, 5H), 1.57 (t, J=7.2 Hz, 2H); ESI-MS (m/z): calcd for C.sub.19H.sub.23N.sub.2O.sub.7 [M+H].sup.+: 391.1; found: 391.1.

Sample 26: Preparation of Compound 26

[0343] To a 100 mL round-bottom flask charged with 1.5 g (3.85 mmol) of compound 25 and 736 mg (3.85 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), 50 mL of anhydrous dichloromethane were added, and stirred at room temperature for 30 min; and then 1.8 g (1.93 mmol) of compound 9 and 470 mg (3.85 mmol) of DMAP were added. The reaction was continuously stirred for another 12 h. After removal of volatiles, the residue was partitioned between ethyl acetate (100 mL) and brine (100 mL); the aqueous phase was extracted with ethyl acetate (50 mL×3), and the organic phases were pooled, dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with methanol in dichloromethane (0-10%) to provide 2.33 g of compound 26. Yield: 92%.

[0344] .sup.1H NMR (500 MHz, CDCl.sub.3, ppm): δ 8.85 (s, 1H), 8.03 (d, J=7.2 Hz, 2H), 7.62 (t, J=7.2 Hz, 1H), 749 (t, J=7.2 Hz, 1H), 7.30-7.42 (m, 6H), 7.20-7.30 (m, 7H), 7.13 (m, 1H), 7.10 (m, 2H), 6.57 (s, 1H), 6.27 (s, 1H), 6.15 (t, J=9.0 Hz, 1H), 5.92 (m, 1H), 5.85 (m, 1H), 5.60 (d, J=7.2 Hz, 1H), 5.52 (d, J=7.2 Hz, 1H), 5.41 (m, 1H), 5.29 (m, 1H), 5.11 (m, 1H), 4.92 (m, 2H), 4.61 (m, 1H), 4.53 (m, 1H), 4.22 (m, 2H), 4.10 (m, 4H), 4.03 (dd, J=14.7, 8.4 Hz, 1H), 3.83 (d, J=7.0 Hz, 1H), 2.52 (m, 2H), 2.39 (s, 5H), 2.28 (m, 3H), 2.07-2.14 (m, 4H), 1.94 (s, 3H), 1.84 (m, 5H), 1.75 (m, 2H), 1.72 (s, 3H), 1.67 (m, 4H), 1.10 (s, 3H), 1.06 (s, 3H); ESI-MS (m/z): calcd for C.sub.19H.sub.23N.sub.2O.sub.7 [M+H].sup.+: 1310.4; found: 1310.5.

Sample 27: Preparation of Compound 27

[0345] To a 100 mL round-bottom flask charged with 1.30 g (1.00 mmol) of compound 26, 116 mg (0.10 mmol) of tetrakis(triphenylphosphine)palladium(O), and 188 mg (1.20 mmol) of 1,3-dimethylbarbituric acid under nitrogen protection, 20.0 mL of anhydrous THF was added, and stirred at room temperature for 2 h. After removal of volatiles, and the residue was purified on a silica gel column and eluted with methanol in chloroform (2-10%) to give 1.11 g of compound 27. Yield: 91%.

[0346] .sup.1H NMR (500 MHz, CDCl.sub.3, ppm): δ 8.95 (s, 1H), 8.05 (d, J=7.2 Hz, 2H), 7.62 (t, J=7.2 Hz, 1H), 7.49 (t, J=7.2 Hz, 1H), 7.30-7.42 (m, 6H), 7.20-7.30 (m, 7H), 7.13 (m, 1H), 7.10 (m, 2H), 6.78 (s, 1H), 6.27 (s, 1H), 6.18 (t, J=9.0 Hz, 1H), 5.93 (m, 1H), 5.58 (d, J=7.2 Hz, 1H), 5.49 (d, J=7.2 Hz, 1H), 4.97 (m, 2H), 4.87 (m, 1H), 4.34 (m, 1H), 4.25 (m, 3H), 4.15 (m, 4H), 4.03 (dd, J=14.7, 8.4 Hz, 1H), 3.89 (m, 2H), 3.73 (d, J=7.0 Hz, 1H), 2.52 (m, 2H), 2.36 (s, 5H), 2.28 (m, 3H), 2.02-2.18 (m, 8H), 1.94 (s, 3H), 1.84 (m, 2H), 1.82 (s, 3H), 1.75 (m, 5H), 1.58 (s, 3H), 1.12 (s, 3H), 1.04 (s, 3H); ESI-MS (m/z): calcd for C.sub.66H.sub.72N.sub.3O.sub.2 [M+H].sup.+: 1266.4; found: 1226.5.

Sample 28: Preparation of Compound 28

[0347] To a 25 mL round-bottom flask charged with 300 mg (0.25 mmol) of compound 27 and 72 mg (0.50 mmol) of 6-azido-hexanoic acid, 5.0 mL of DMSO was added. 150 uL of copper sulfate (1.0M) in water and 150 uL of sodium ascorbate (1.0M) in water were mixed together, and then added to the above solution. After stirring overnight at room temperature for 2 days, the reaction mixture was partitioned between ethyl acetate (50 mL) and brine (50 mL); the organic phase was washed with ethyl acetate (30 mL×2), dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with methanol in chloroform (1-10%) to provide 328 mg of compound 28. Yield: 95%.

[0348] .sup.1H NMR (500 MHz, CD.sub.3OD, ppm): δ 8.02 (d, J=7.2 Hz, 2H), 7.70 (t, J=7.2 Hz, 1H), 7.67 (s, 1H), 7.55 (t, J=7.2 Hz, 1H), 7.47 (m, 4H), 7.39 (m, 3H), 7.31 (m, 5H), 7.15 (m, 3H), 6.38 (s, 1H), 5.99 (t, J=9.0 Hz, 1H), 5.78 (d, J=7.2 Hz, 1H), 5.54 (d, J=7.2 Hz, 1H), 5.48 (d, J=7.2 Hz, 1H), 5.38 (s, 2H), 4.98 (m, 2H), 4.89 (m, 1H), 4.25 (m, 6H), 4.10 (m, 4H), 3.90 (s, 2H), 3.73 (d, J=7.0 Hz, 1H), 3.41 (d, J=7.0 Hz, 1H), 2.65 (t, J=7.0 Hz, 2H), 2.38 (m, 1H), 2.32 (s, 3H), 2.23 (t, J=7.0 Hz, 2H), 2.10 (m, 1H), 2.05 (s, 3H), 1.83-1.89 (m, 7H), 1.82 (s, 3H), 1.81 (m, 2H), 1.53 (s, 3H), 1.41 (m, 2H), 1.27 (m, 2H), 1.19 (m, 2H), 1.03 (s, 3H), 1.02 (s, 3H); ESI-MS (m/z): calcd for C.sub.72H.sub.85N.sub.6O.sub.21 [M+H].sup.+: 1369.5; found: 1369.3.

Synthetic Scheme 5

[0349] ##STR00137## ##STR00138##

Sample 29: Preparation of Compound 29

[0350] Compound 29 was prepared by standard Fmoc solid-phase peptide synthesis method. 20.0 g of pre-loaded Fmoc-L-Lys(Boc)-Trityl resin (substitution: 0.51 mmol/g) was swollen in DMF for 30 min, drained, and followed by initial Fmoc deprotection (20% piperidine in DMF) twice. After DMF wash twice, sequential coupling of the remaining residues began: elongating amino acid sequence involved adding the appropriate Fmoc amino acid (5-fold excess) precombined with HBTU (5-fold excess) and HOBt (5-fold excess) in DMF to the resin; After mixing for 5 min, diisopropyl ethylamine (DIPEA, 5-fold excess) was added and allowed to react for 45 min; After DMF washing the previous piperidine deprotection conditions were used; These steps were repeated for each added amino acid. Finally, the crude desired product was cleaved from the resin with the cocktail (dichloromethane:acetic acid, trifluoroethanol/8:1:1); after filtering off solid resin, the filtrate was concentrated and purified on a reverse phase column and eluted with acetonitrile in water to provide 3.67 g of compound 29. Yield: 72%.

[0351] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 7.20-7.50 (m, 5H), 6.71 (brs, 1H), 5.98 (brs, 1H), 4.72 (m, 1H), 4.51 (m, 1H), 2.98-3.25 (m, 4H), 2.35 (t, J=7.2 Hz, 2H), 2.16 (m, 2H), 1.98 (t, J=3.0 Hz, 1H), 1.89 (m, 2H), 1.35-1.52 (m, 13H); ESI-MS (m/z): calcd for C.sub.26H.sub.38N.sub.3O.sub.6 [M+H].sup.+: 488.2; found: 488.3.

Sample 30: Preparation of Compound 30

[0352] To a 100 mL round-bottom flask charged with 3.3 g (6.76 mmol) of compound 29 and 1.94 g (10.51 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) in 50 mL of anhydrous chloroformate, 3.0 mL of absolute ethanol and 1.25 g (10.51 mmol) of DMAP were added and stirred at room temperature overnight. After removal of volatiles, the residue was partitioned between ethyl acetate (100 mL) and brine (100 mL); the aqueous phase was extracted with ethyl acetate (50 mL×2), and the organic phases were pooled, dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with ethyl acetate in petroleum (10-70%) to give 3.02 g of compound 30. Yield: 86%.

[0353] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 7.20-7.50 (m, 5H), 4.76 (m, 1H), 4.51 (m, 1H), 4.22 (q, J=7.2 Hz, 2H), 2.98-3.25 (m, 4H), 2.35 (t, J=7.2 Hz, 2H), 2.16 (m, 2H), 1.97 (t, J=3.0 Hz, 1H), 1.83 (m, 2H), 1.35-1.52 (m, 13H), 1.25 (t, J=7.2 Hz, 3H); ESI-MS (m/z): calcd for C.sub.28H.sub.42N.sub.3O.sub.6 [M+H].sup.+: 516.3; found: 516.3.

Sample 31: Preparation of Compound 31

[0354] To a 100 mL round-bottom flask charged with 3.50 g (6.78 mmol) of compound 30, 20 mL of hydrochloride ethanol solution (4.0N) was added, and stirred at room temperature overnight. After removal of volatiles, the residue was purified on a reverse phase C-18 column and eluted with acetonitrile in water (10-80%) to provide 2.85 g of compound 31. Yield: 93%.

[0355] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 7.10-7.30 (m, 5H), 4.66 (m, 1H), 4.31 (m, 1H), 4.12 (q, J=7.2 Hz, 2H), 3.11 (m, 1H), 2.89-3.05 (m, 3H), 2.21 (t, J=7.2 Hz, 2H), 2.12 (m, 2H), 1.95 (t, J=3.0 Hz, 1H), 1.79 (m, 2H), 1.50-1.70 (m, 6H), 1.35 (m, 2H), 1.25 (t, J=7.2 Hz, 3H); ESI-MS (m/z): calcd for C.sub.23H.sub.34N.sub.3O.sub.4 [M+H].sup.+: 416.2; found: 416.2.

Sample 32: Preparation of Compound 32

[0356] In a 100 mL round-bottom flask, 1.5 g (1.54 mmol) of compound 5 and 0.72 g (1.86 mmol) of benzotriazole-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU) and 251 mg (1.86 mmol) of 1-hydroxybenzotriazole (HOBt) were dissolved in 10.0 mL of dry DMF followed by addition of 835 mg (1.85 mmol) compound 31 and 0.43 mL (3.14 mmol) of triethylamine, and stirred at room temperature for 3 h. Upon completion, the reaction mixture was partitioned between ethyl acetate (150 mL) and brine (150 mL), the organic phase was further washed with brine twice (100 mL×2), dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with methanol in chloroform (1-10%) to provide 1.51 g of compound 32. Yield: 71%.

[0357] .sup.1H NMR (500 MHz, CDCl.sub.3, ppm): δ 8.12 (d, J=7.2 Hz, 2H), 7.65 (d, J=7.2 Hz, 2H), 7.10-7.50 (m, 16H), 6.76 (m, 2H), 6.20 (s, 1H), 6.17 (t, J=9.0 Hz, 1H), 5.86 (d, J=7.2 Hz, 1H), 5.45 (t, J=9.0 Hz, 1H), 4.86 (m 1H), 4.67 (m, 1H), 4.35 (m, 2H), 4.25 (m, 1H), 4.08 (m, 3H), 3.92 (m, 2H), 3.68 (m, 1H), 2.90-3.20 (m, 4H), 2.45 (m, 1H), 2.37 (s, 3H), 2.00-2.30 (m, 8H), 1.95 (m, 4H), 1.85 (m, 3H), 1.79 (m, 3H), 1.50-1.70 (m, 12H), 1.35 (m, 2H), 1.25 (t, J=7.2 Hz, 3H), 1.19 (s, 3H), 1.07 (s, 3H); ESI-MS (m/z): calcd for C.sub.74H.sub.87N.sub.4O.sub.21 [M+H].sup.+: 1376.5; found: 1367.5.

Sample 33: Preparation of Compound 33

[0358] To a 10 mL round-bottom flask charged with 200 mg (0.15 mmol) of compound 32 and 45 mg (0.31 mmol) of 6-azido-hexan-1-ol, 5.0 mL of DMSO was added. 100 uL of copper sulfate (1.0M) in water and 200 uL of sodium ascorbate (1.0M) in water were mixed together, and then added to the above solution. After stirring overnight at room temperature for 2 days, the reaction mixture was partitioned between ethyl acetate (50 mL) and brine (50 mL); the organic phase was washed with ethyl acetate (50 mL×2), dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with methanol in chloroform (1-10%) to provide 185 mg of compound 33. Yield: 82%.

[0359] .sup.1H NMR (500 MHz, CDCl.sub.3, ppm): δ 8.13 (d, J=7.2 Hz, 2H), 7.65 (d, J=7.2 Hz, 2H), 7.10-7.50 (m, 17H), 6.75 (m, 2H), 6.21 (s, 1H), 6.19 (t, J=9.0 Hz, 1H), 5.88 (d, J=7.2 Hz, 1H), 5.43 (t, J=9.0 Hz, 1H), 4.85 (m 1H), 4.66 (m, 1H), 4.35 (m, 2H), 4.25 (m, 1H), 4.10 (m, 3H), 3.92 (m, 2H), 3.59 (m, 2H), 3.27 (m, 2H), 2.90-3.23 (m, 4H), 2.47 (m, 1H), 2.35 (s, 3H), 2.00-2.30 (m, 7H), 1.93 (m, 4H), 1.83 (m, 3H), 1.76 (m, 3H), 1.50-1.70 (m, 13H), 1.35 (m, 4H), 1.29 (m, 4H), 1.25 (t, J=7.2 Hz, 3H), 1.15 (s, 3H), 1.05 (s, 3H); ESI-MS (m/z): calcd for C.sub.80H.sub.100N.sub.7O.sub.22 [M+H].sup.+: 1510.7; found: 1510.9.

Synthetic Scheme 6

[0360] ##STR00139## ##STR00140## ##STR00141##

Sample 34: Preparation of Compound 34

[0361] To a 500 mL round-bottom flask charged with 50.0 g (60.8 mmol) of docetaxel and 32.6 g (216.3 mmol) of imidazole, 150 mL of anhydrous dimethylformamide (DMF) was added, and followed by addition of 14.3 g (216.3 mmol) of tert-butyldimethylchloride. The reaction mixture was stirred at room temperature for 12 h. Upon completion of the reaction, the reaction mixture was partitioned between ethyl acetate (500 mL) and brine (500 mL). The organic phase was further washed with brine (500 mL×2), dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with ethyl acetate in petroleum (10-70%) to provide 53.6 g of compound 34. Yield: 95%.

[0362] .sup.1H NMR (500 MHz, DMSO-d.sub.6, ppm): δ 7.97 (d, J=7.2 Hz, 2H), 7.73 (t, J=7.2 Hz, 1H), 7.61 (t, J=7.2 Hz, 2H), 7.57 (d, J=9.0 Hz, 1H), 7.35 (m, 4H), 7.17 (brs, 1H), 5.78 (t, J=9.0 Hz, 1H), 5.37 (d, J=7.2 Hz, 1H), 5.07 (s, 1H), 5.01 (d, J=7.2 Hz, 1H), 4.97 (s, 1H), 4.92 (m, 2H), 4.41 (m, 2H), 4.07 (m, 3H), 3.62 (d, J=6.6 Hz, 1H), 2.31 (s, 3H), 2.25 (m, 1H), 1.85 (m, 1H), 1.67 (m, 1H), 1.63 (m, 3H), 1.53 (m, 4H), 1.37 (s, 9H), 0.97 (s, 3H), 0.83 (s, 12H), 0.08 (s, 3H), 0.03 (s, 3H); ESI-MS (m/z): calcd for C.sub.49H.sub.68NO.sub.14Si [M+H].sup.+: 922.1; found: 922.3.

Sample 35: Preparation of Compound 35

[0363] To a 500 mL round-bottom flask charged with 20.0 g (21.71 mmol) of compound 34, 120 mL of absolute THF was added under nitrogen protection and cooled down to −70° C., followed by addition of 54.9 mL of lithium bis(trimethylsilyl)amide THF solution (1.0M) and stirred for 1 h, and then 54.9 g (45.9 mmol) of allyl chloroformate was added to the above solution. After stirring for another 1 h, the cooled batch was removed and the reaction mixture allowed to warm up to room temperature, and the reaction was stopped by addition of 15.0 mL of acetic acid. After removal of volatiles, the residue was partitioned between ethyl acetate (500 mL) and brine (500 mL). The organic phase was further washed with brine (500 mL×2), dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with ethyl acetate in petroleum (5-50%) to provide 21.56 g of compound 35. Yield: 91%.

[0364] .sup.1H NMR (500 MHz, DMSO-d.sub.6, ppm): δ 7.98 (d, J=7.2 Hz, 2H), 7.83 (t, J=7.2 Hz, 1H), 7.63 (m, 3H), 7.38 (m, 4H), 7.15 (t, J=7.2 Hz, 1H), 6.01 (s, 1H), 5.95 (m, 2H), 5.77 (t, J=9.0 Hz, 1H), 5.41 (d, J=7.2 Hz, 1H), 5.23-5.37 (m, 5H), 5.02 (d, J=8.4 Hz, 1H), 4.91 (t, J=8.4 Hz, 1H), 4.77 (s, 1H), 4.63 (m, 2H), 4.57 (m, 2H), 4.41 (d, J=7.8 Hz, 1H), 4.07 (s, 2H), 3.69 (d, J=7.2 Hz, 1H), 2.45 (m, 3H), 2.35 (s, 3H), 1.85 (m, 1H), 1.77 (t, J=12.0 Hz, 1H), 1.75 (s, 3H), 1.66 (s, 3H), 1.61 (m, 1H), 1.37 (s, 9H), 0.97 (s, 3H), 0.91 (s, 9H), 0.12 (s, 3H), 0.05 (s, 3H); ESI-MS (m/z): calcd for: C.sub.57H.sub.75NO.sub.18Si [M+H].sup.+: 1090.4; found: 1090.5.

Sample 36: Preparation of Compound 36

[0365] In a 250 mL round-bottom flask, 21.5 g (22.95 mmol) of compound 35 was dissolved 50.0 mL of tetrabutylammonium fluoride solution (TBAF, 1.0M) was added and stirred for 3 h at room temperature. Upon completion of the reaction, the reaction mixture was concentrated and purified on a silica gel column and eluted with ethyl acetate in petroleum (10-70%) to provide 21.5 g of compound 36. Yield: 96%.

[0366] .sup.1H NMR (500 MHz, DMSO-d.sub.6, ppm): δ 7.97 (d, J=7.2 Hz, 2H), 7.73 (t, J=7.2 Hz, 1H), 7.61 (d, J=7.2 Hz, 2H), 7.47 (d, J=9.0 Hz, 1H), 7.35 (t, J=7.8 Hz, 1H), 7.30 (d, J=7.2 Hz, 2H), 7.22 (t, J=7.2 Hz, 1H), 6.09 (s, 1H), 5.87-5.98 (m, 3H), 5.47 (d, J=7.2 Hz, 1H), 5.21-5.38 (m, 5H), 4.97 (d, J=9.0 Hz, 1H), 4.92 (t, J=9.0 Hz, 1H), 4.81 (s, 1H), 4.61 (m, 2H), 4.59 (d, J=6.0 Hz, 2H), 4.37 (d, J=6.0 Hz, 1H), 4.07 (m, 2H), 3.67 (d, J=7.2 Hz, 1H), 2.45 (m, 1H), 2.25 (s, 3H), 1.95 (m, 1H), 1.83 (m, 1H), 1.81 (s, 3H), 1.75 (t, J=12.0 Hz, 1H), 1.67 (s, 3H), 1.36 (s, 9H), 1.05 (s, 3H), 0.97 (s, 3H); ESI-MS (m/z): calcd for: C.sub.51H.sub.62NO.sub.18 [M+H].sup.+: 976.4; found: 976.5.

Sample 37: Preparation of Compound 37

[0367] To a 250 mL round-bottom flask charged with 12.0 g (12.30 mmol) of compound 36, 4.27 g (36.84 mmol) of diglycolic acid anhydride, and 4.50 g (38.84 mmol) of 4-dimethylaminopyridine (DMAP), 70.0 mL of anhydrous dichloromethane was added and stirred at room temperature for 12 h. After removal of volatiles, the residue was partitioned between ethyl acetate (200 mL) and 10% citric acid solution (200 mL); the aqueous phase was extracted with ethyl acetate (150 mL×2), and the organic phases were pooled, dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with methanol in chloroform (0-10%) to give 11.1 g of compound 37. Yield: 83%.

[0368] .sup.1H NMR (500 MHz, CDCl.sub.3, ppm): δ 8.12 (d, J=7.8 Hz, 2H), 7.63 (t, J=7.8 Hz, 1H), 7.52 (t, J=7.8 Hz, 2H), 7.33 (m, 5H), 6.20 (s, 2H), 6.01 (m, 2H), 5.65 (s, 1H), 5.21-5.51 (m, 6H), 4.97 (d, J=7.2 Hz, 1H), 4.69 (m, 6H), 4.31 (m, 1H), 4.15 (m, 2H), 4.12 (m, 2H), 3.90 (m, 4H), 2.63 (m, 1H), 2.49 (s, 3H), 2.33 (m, 1H), 2.11 (m, 1H), 1.98 (s, 3H), 1.82 (s, 3H), 1.28 (s, 9H), 1.18 (s, 3H), 1.16 (s, 3H); ESI-MS (m/z): calcd for: C.sub.55H.sub.66NO.sub.22 [M+H].sup.+: 1092.4; found: 1092.5.

Sample 38: Preparation of Compound 38

[0369] In a 250 mL round-bottom flask, 25.0 g (22.91 mmol) of compound 37 was dissolved in 100 mL of methanol, and bubbled with hydrogen gas in the presence of 1.2 g of 10% Pd—C for 6 h. Solid material was filtered off, and the filtrate was concentrated and purified on a reverse phase C-18 column and eluted with acetonitrile in water (10-80%) to give 17.55 g of compound 38. Yield: 83%.

[0370] .sup.1H NMR (500 MHz, CD.sub.3OD, ppm): δ 8.11 (d, J=7.8 Hz, 2H), 7.63 (t, J=7.8 Hz, 1H), 7.55 (t, J=7.8 Hz, 2H), 7.38 (m, 4H), 7.21 (m, 1H), 6.07 (s, 2H), 5.61 (t, J=7.2 Hz, 1H), 5.30 (t, J=9.0 Hz, 1H), 5.27 (s, 1H), 4.97 (d, J=9.0 Hz, 1H), 4.86 (m, 2H), 4.55 (m, 2H), 4.28 (m, 2H), 4.15 (m, 1H), 4.14 (s, 2H), 3.86 (s, 2H), 3.83 (m, 2H), 2.45 (m, 1H), 2.36 (s, 3H), 1.98 (m, 1H), 1.86 (s, 3H), 1.78 (t, J=12.1 Hz, 1H), 1.46 (s, 3H), 1.38 (s, 9H), 1.14 (s, 3H), 1.09 (s, 3H); ESI-MS (m/z): calcd for: C.sub.47H.sub.58NO.sub.18 [M+H].sup.+: 924.3; found: 924.4.

Sample 39: Preparation of Compound 39

[0371] In a 100 mL round-bottom flask, 2.0 g (1.08 mmol) of compound 38 and 608 mg (1.60 mmol) of benzotriazole-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU) and 216 mg (1.60 mmol) of 1-hydroxybenzotriazole (HOBt) were dissolved in 7.0 mL of dry DMF, and followed by addition of 208 mg (3.71 mmol) 4-pentyn-1-amine and 0.30 mL (2.16 mmol) of triethylamine, and stirred at room temperature for 5 h. Upon completion of the reaction, the reaction mixture was partitioned between ethyl acetate (80 mL) and brine (80 mL), the organic phase was further washed with brine twice (60 mL×2), dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with methanol in chloroform (1-10%) to provide 1.52 g of compound 39. Yield: 77%.

[0372] .sup.1H NMR (300 MHz, CDCl.sub.3+CD.sub.3OD, ppm): δ 8.11 (d, J=7.2 Hz, 2H), 7.20-7.85 (m, 8H), 6.15 (s, 2H), 5.89 (m, 2H), 5.59 (d, J=7.2 Hz, 1H), 5.42 (m, 2H), 5.12-5.29 (m, 6H), 4.87 (d, J=9.8 Hz, 1H), 4.56 (m, 3H), 4.33 (s, 2H), 4.23 (m, 3H), 4.08 (d, J=8.4 Hz, 1H), 3.85 (d, J=7.2 Hz, 1H), 3.64 (s, 1H), 3.23 (m, 2H), 2.54 (m, 1H), 2.43 (m, 4H), 2.23 (m, 1H), 2.13 (m, 3H), 1.95 (s, 1H), 1.92 (s, 3H), 1.69 (m, 2H), 1.59 (m, 2H), 1.25 (s, 9H), 1.16 (s, 3H), 1.08 (s, 3H); ESI-MS (m/z): calcd for: C.sub.52H.sub.65N.sub.2O.sub.17 [M+H].sup.+: 989.4; found: 989.6.

Sample 40: Preparation of Compound 40

[0373] To a 25 mL round-bottom flask charged with 300 mg (0.303 mmol) of compound 39 and 76 mg (0.607 mmol) of 6-azido-hexan-1-ol, 5.0 mL of DMSO was added. 100 uL of copper sulfate (1.0M) in water and 200 uL of sodium ascorbate (1.0M) in water were mixed together, and then added to the above solution. After stirring overnight at room temperature for 2 days, the reaction mixture was partitioned between ethyl acetate (50 mL) and brine (50 mL); the organic phase was washed with brine (50 mL×2), dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with methanol in chloroform (1-10%) to provide 296 mg of compound 40. Yield: 86%.

[0374] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 8.12 (d, J=7.2 Hz, 2H), 7.20-7.85 (m, 9H), 6.13 (s, 2H), 5.87 (m, 2H), 5.57 (d, J=7.2 Hz, 1H), 5.40 (m, 2H), 5.12-5.29 (m, 6H), 4.85 (d, J=9.8 Hz, 1H), 4.52 (m, 3H), 4.29 (s, 2H), 4.21 (m, 3H), 4.05 (d, J=8.4 Hz, 1H), 3.83 (d, J=7.2 Hz, 1H), 3.57 (m, 3H), 3.21 (m, 4H), 2.52 (m, 1H), 2.41 (m, 4H), 2.19 (m, 1H), 2.11 (m, 3H), 1.93 (s, 1H), 1.89 (s, 3H), 1.50-1.80 (m, 8H), 1.26-1.45 (m, 4H), 1.26 (s, 9H), 1.15 (s, 3H), 1.06 (s, 3H); ESI-MS (m/z): calcd for: C.sub.58H.sub.78N.sub.5O.sub.18 [M+H].sup.+: 1132.5; found: 1132.8.

Synthetic Scheme 7

[0375] ##STR00142##

Sample 41: Preparation of Compound 41

[0376] To a 250 mL round-bottom flask charged with 5.0 g (28.71 mmol) of diglycolic acid anhydride allyl monoester, 2.90 g (15.18 mmol) of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC), and 4.65 g (34.50 mmol) of 1-hydroxybenzotriazole (HOBt), 30.0 mL of dry DMF was added and stirred for 30 min, followed by 4-aminobenzyl alcohol and 5.0 mL of triethylamine, and stirred at room temperature for another 6 h. Upon completion, the reaction mixture was partitioned between ethyl acetate (200 mL) and brine (200 mL), the organic phase was further washed with brine twice (100 mL×2), dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with methanol in chloroform (1-10%) to provide 3.92 g of compound 41. Yield: 54%.

[0377] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 8.25 (s, 1H), 7.53 (d, J=7.8 Hz, 2H), 7.21 (d, J=7.8 Hz, 2H), 5.86 (m, 1H), 5.25 (d, J=16.8 Hz, 1H), 5.21 (d, J=9.8 Hz, 1H), 4.62 (d, J=7.0 Hz, 2H), 4.55 (s, 2H), 4.17 (s, 1H), 4.11 (s, 2H); ESI-MS (m/z): calcd for: C.sub.14H.sub.18NO.sub.5 [M+H].sup.+: 280.1; found: 280.1.

Sample 42: Preparation of Compound 42

[0378] In a 250 mL round-bottom flask, 2.0 g (7.16 mmol) of compound 41 was dissolved in anhydrous chloroform and cooled down to 0° C. under argon protection, and 600 uL (5.02 mmol) of diphosgene and 5.0 mL (28.3 mmol) of N,N-diisopropyl ethylamine were successively added and stirred for 1 h. After removal of volatiles, the residue was redissoved in 50.0 mL of anhydrous chloroform under argon protection; 4.0 g (4.10 mmol) of compound 36 and 5.0 mL (28.3 mmol) of N,N-diisopropylethylamine were added to the above solution, and stirred at room temperature for 12 h. After removal of volatiles, the residue was partitioned between ethyl acetate (50 mL) and brine (50 mL), the organic phase was further washed with brine twice (100 mL×2), dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with ethyl acetate in petroleum (20-80%) to provide 2.32 g of compound 42. Yield: 58%.

[0379] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 8.85 (s, 1H), 8.09 (d, J=7.2 Hz, 2H), 7.20-7.85 (m, 12H), 6.14 (s, 1H), 5.82 (m, 3H), 5.61 (d, J=7.0 Hz, 1H), 5.41 (m, 1H), 5.10-5.35 (m, 6H), 5.01 (m, 2H), 4.85 (d, J=9.0 Hz, 1H), 4.60 (d, J=7.0 Hz, 1H), 4.52 (m, 4H), 4.26 (d, J=8.4 Hz, 1H), 4.21 (s, 2H), 4.08 (s, 2H), 4.05 (m, 1H), 2.57 (m, 1H), 2.36 (s, 3H), 2.27 (m, 1H), 2.13 (m, 1H), 1.97 (s, 3H), 1.91 (t, J=12.6 Hz, 1H), 1.67 (s, 3H), 1.25 (s, 9H), 1.19 (s, 3H), 1.16 (s, 3H); ESI-MS (m/z): calcd for: C.sub.66H.sub.77N.sub.2O.sub.24 [M+H].sup.+: 1281.4; found: 1281.5.

Sample 43: Preparation of Compound 43

[0380] In a 100 mL round-bottom flask, 1.0 g (0.78 mmol) of compound 42 was dissolved in 20 mL of methanol, and bubbled with hydrogen gas in the presence of 300 mg of 10% Pd—C at room temperature for 5 h. Solid material was filtered off, and the filtrate was concentrated and purified on a reverse phase C-18 column and eluted with methanol in water (20-80%) to give 537 mg of compound 43. Yield: 69%.

[0381] .sup.1H NMR (300 MHz, CD.sub.3OD, ppm): δ 8.11 (d, J=7.2 Hz, 2H), 7.10-7.85 (m, 9H), 5.98 (t, J=6.0 Hz, 1H), 5.53 (d, J=7.0 Hz, 1H), 5.18 (m, 2H), 5.13 (d, J=6.0 Hz, 1H), 5.04 (m, 2H), 4.90 (d, J=9.8 Hz, 1H), 4.15 (m, 1H), 4.07 (s, 2H), 4.03 (s, 2H), 3.95 (s, 2H), 3.73 (d, J=7.0 Hz, 1H), 2.37 (m, 1H), 2.32 (s, 3H), 2.07 (m, 1H), 1.85 (m, 1H), 1.97 (s, 3H), 1.57 (s, 3H), 1.31 (s, 9H), 1.05 (s, 3H), 1.03 (s, 3H); ESI-MS (m/z): calcd for: C.sub.55H.sub.65N.sub.2O.sub.20 [M+H].sup.+: 1073.4; found: 1073.5.

Synthetic Scheme 8

[0382] ##STR00143##

Sample 44: Preparation of Compound 44

[0383] To a 500 mL round-bottom flask charged with 60 g (308.9 mmol) of polyethylene glycol (PEG.sub.4), 150 ml of anhydrous chloroform and 47 mL (339.8) of triethyl amine were added and cooled down to 0° C., followed by slow addition of 64.78 g (339.8 mmol) of 4-toluenesulfonyl chloride in anhydrous chloroform and stirred for 12 h. Upon completion of the reaction, the reaction mixture was washed with brine twice (200 mL×2), dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with acetone in chloroform (0-30%) to provide 47.3 g of compound 44. Yield: 43%.

[0384] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 7.81 (d, J=7.2 Hz, 2H), 7.41 (d, J=7.2 Hz, 2H), 4.21 (d, J=7.0 Hz, 2H), 3.50-3.80 (m, 14H), 2.48 (s, 3H); ESI-MS (m/z): calcd for: C.sub.15H.sub.25O.sub.7S [M+H].sup.+: 349.1; found: 349.1.

Sample 45: Preparation of Compound 45

[0385] To a 500 mL round-bottom flask charged with 30.0 g (86.11 mmol) of compound 44, 100 ml of anhydrous DMF and 16.8 g (258.3 mmol) of sodium azide were added and heated to 90° C., and stirred for 12 h. Upon completion of the reaction, the reaction mixture was evaporated under reduced vacuum, and the residue was partitioned between chloroform (500 mL) and brine (500 mL), the organic phase was further washed with brine twice (500 mL×2), dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with acetone in chloroform (0-30%) to provide 13.1 g of compound 45. Yield: 76%.

[0386] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 3.67 (d, J=7.0 Hz, 2H), 3.50-3.75 (m, 10H), 3.28 (d, J=7.2 Hz, 2H); ESI-MS (m/z): calcd for: C.sub.8H.sub.18N.sub.3O.sub.4 [M+H].sup.+: 220.1; found: 220.1.

Sample 46: Preparation of Compound 46

[0387] In a 250 mL round-bottom flask, 25.0 g (114.0 mmol) of compound 45 was dissolved in 100 mL of methanol, and bubbled with hydrogen gas in the presence of 3.0 g of 10% Pd—C at room temperature for 6 h. Solid material was filtered off, and the filtrate was concentrated and purified on a reverse phase C-18 column and eluted with acetonitrile in water (10-50%) to provide 19.1 g of compound 46. Yield: 86%.

[0388] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 3.67 (m, 4H), 3.65 (m, 8H), 3.53 (d, J=7.0 Hz, 2H), 3.02 (brs, 2H), 2.80 (t, J=7.0 Hz, 2H); ESI-MS (m/z): calcd for: C.sub.8H.sub.20NO.sub.4 [M+H].sup.+: 194.1; found: 194.1.

Sample 47: Preparation of Compound 47

[0389] To a 500 mL round-bottom flask charged with 20.0 g (103.5 mmol) of compound 46 and 17.1 g (203.5 mmol) of sodium bicarbonate in 150 ml of methanol-water (7:3) 44.2 g (203.5 mmol) of ditert-butyl decarbonate in anhydrous THF was added and stirred at room temperature overnight. Upon completion of the reaction, the reaction mixture was concentrated and extracted with chloroform three times (300 mL×3); the organic phases were combined together, dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with acetone in chloroform (0-20%) to provide 17.6 g of compound 47. Yield: 58%.

[0390] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 3.67 (d, J=7.0 Hz, 2H), 3.65 (m, 8H), 3.57 (d, J=7.0 Hz, 2H), 3.26 (t, J=7.2 Hz, 2H), 1.47 (s, 9H); ESI-MS (m/z): calcd for: C.sub.13H.sub.28NO.sub.6 [M+H].sup.+: 294.1; found: 294.1.

Sample 48: Preparation of Compound 48

[0391] To a 500 mL round-bottom flask charged with 12.0 g (40.96 mmol) of compound 47, 150 ml of anhydrous DMF and 61.35 mL (1.0M) of potassium tert-butoxide in THF were added under nitrogen protection, cooled down to 0° C., and followed by slow addition of 7.30 g (61.35 mmol) of propargyl bromide; Upon completion of addition, the cooled bath was removed. After stirring at room temperature for 12 h, After removal of volatiles, the residue was partitioned between chloroform (300 mL) and brine (300 mL); the organic phase was washed with brine twice (200 mL×2), dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with ethyl acetate in chloroform (0-70%) to provide 11.2 g of compound 48. Yield: 76%.

[0392] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 4.20 (s, 2H), 4.00 (t, J=7.0 Hz, 2H), 3.60-3.73 (m, 14H), 2.42 (s, 1H), 1.47 (s, 9H); ESI-MS (m/z): calcd for: C.sub.16H.sub.30NO.sub.6 [M+H].sup.+: 332.1; found: 332.1.

Sample 49: Preparation of Compound 49

[0393] In a 250 mL round-bottom flask, 8.2 g (24.73 mmol) of compound 48 was dissolved in 70 mL of hydrochloride (4.0N) at 0° C., and stirred overnight. The reaction mixture was washed with chloroform twice (70 mL×2); the aqueous phase was basified with sodium hydroxide (2.0N) to pH=11.0, concentrated, and extracted with chloroform three times (50 mL×3); The organic phases were combined together, dried over anhydrous MgSO.sub.4, filtered, and evaporated to dryness to provide 4.75 g of compound 49. Yield: 83%.

[0394] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 4.21 (s, 2H), 3.65 (m, 14H), 3.51 (t, J=7.0 Hz, 2H), 2.87 (t, J=7.0 Hz, 2H), 2.43 (s, 1H); ESI-MS (m/z): calcd for: C.sub.11H.sub.22NO.sub.4 [M+H].sup.+: 232.1; found: 232.1.

Sample 50: Preparation of Compound 50

[0395] In a 100 mL round-bottom flask, 3.0 g (3.25 mmol) of compound 38 and 1.48 g (3.89 mmol) of benzotriazole-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU) and 526 mg (3.89 mmol) of 1-hydroxybenzotriazole (HOBt) were dissolved in 15.0 mL of dry DMF, followed by addition of 899 mg (3.89 mmol) compound 49 and 900 uL (6.50 mmol) of triethylamine, and stirred at room temperature for 5 h. Upon completion of the reaction, the reaction mixture was partitioned between ethyl acetate (80 mL) and brine (80 mL), the organic phase was further washed with brine twice (60 mL×2), dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with methanol in chloroform (1-10%) to provide 2.66 g of compound 50. Yield: 71%.

[0396] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 8.13 (d, J=7.2 Hz, 2H), 7.20-7.85 (m, 10H), 6.13 (s, 2H), 5.68 (t, J=7.2 Hz, 1H), 5.29 (m, 3H), 4.96 (d, J=9.0 Hz, 1H), 4.83 (m, 2H), 4.55 (m, 2H), 4.10-4.30 (m, 7H), 3.85 (s, 2H), 3.81 (m, 2H), 3.50-3.75 (m, 14H), 2.46 (m, 1H), 2.35 (m, 3H), 2.03 (s, 3H), 1.97 (m, 1H), 1.60-1.85 (m, 4H), 1.39 (s, 9H), 1.17 (s, 3H), 1.13 (s, 3H); ESI-MS (m/z): calcd for: C.sub.58H.sub.77N.sub.2O.sub.21 [M+H].sup.+: 1137.5; found: 1137.6.

Synthetic Scheme 9

[0397] ##STR00144## ##STR00145##

Sample 51: Preparation of Compound 51

[0398] To a 500 mL round-bottom flask charged with 21.1 g (159.7 mmol) of Gly-Gly and 26.9 g (320.0 g) of sodium carbonate in 150 mL of distilled water, 17.0 g (81.3 mmol) of 5-pentynoic acid N-hydroxy-succinimide ester in THF was dropwise added and stirred at room temperature for 5 h; and then was acidified with hydrochloride solution (2.0N) to pH=1.0. After removal of volatiles, the residue was purified on a reverse phase column and eluted with acetonitrile in water (0-30%) to provide 10.1 g of compound 51. Yield: 66%.

[0399] .sup.1H NMR (300 MHz, DMSO-d.sub.6, ppm): δ 3.75 (d, J=6.0 Hz, 2H), 3.65 (d, J=6.0 Hz, 2H), 2.76 (t, J=3.0 Hz, 1H), 2.25 (t, J=7.2 Hz, 2H), 2.19 (m, 2H), 1.65 (m, 2H); ESI-MS (m/z): calcd for: C.sub.10H.sub.15N.sub.2O.sub.4[M+H].sup.+: 227.1; found: 227.1.

Sample 52: Preparation of Compound 52

[0400] To a 500 mL round-bottom flask charged with 10.0 g (44.0 mmol) of compound 51, 6.1 g (52.9 mmol) of N-hydroxy-succinimide, and 9.3 g (48.7 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), 60.0 mL of dry DMF was added and stirred at room temperature for 12 h. The above solution was drop wise added to the solution of 10.9 g (44.7 mmol) of N.sub.6-Boc-L-Lysine and 12.3 mL (88.0 mmol) of triethyl amine in dry DMF, and the reaction mixture was further stirred at room temperature overnight. After removal of volatiles, and the residue was partitioned between ethyl acetate (300 mL) and 30% citric acid solution (300 ml); the aqueous phase was further extracted with ethyl acetate (200 mL×2), and the organic phases were combined together, dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with methanol in chloroform (0-25%) to provide 13.0 g of compound 52. Yield: 55%.

[0401] .sup.1H NMR (300 MHz, DMSO-d.sub.6, ppm): δ 8.15 (t, J=7.2 Hz, 1H), 8.09 (t, J=7.2 Hz, 1H), 8.03 (d, J=7.2 Hz, 1H), 6.76 (t, J=7.2 Hz, 1H), 4.13 (m, 1H), 3.76 (d, J=7.2 Hz, 1H), 3.68 (d, J=7.2 Hz, 1H), 2.87 (m, 2H), 2.72 (t, J=3.0 Hz, 1H), 2.23 (t, J=7.2 Hz, 2H), 2.08 (m, 2H), 1.66 (m, 3H), 1.54 (m, 1H), 1.36 (m, 11H), 1.25 (m, 1H); ESI-MS (m/z): calcd for: C.sub.21H.sub.35N.sub.4O.sub.7 [M+H].sup.+: 455.3; found: 455.3.

Sample 53: Preparation of Compound 53

[0402] To a 250 mL round-bottom flask charged with 13.0 g (28.63 mmol) of compound 52 and 10.6 g (55.48 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), 150 mL of anhydrous dichloromethane was added, and stirred at room temperature for 30 min; and then 2.0 mL of absolute ethanol and 6.8 g (55.7 mmol) of DMAP were added. The reaction was continuously stirred overnight. After removal of volatiles, the residue was partitioned between ethyl acetate (200 mL) and brine (200 mL); the aqueous phase was extracted with ethyl acetate (200 mL×2), and the organic phases were pooled, dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with methanol in dichloromethane (0-15%) to provide 10.2 g of compound 53. Yield: 74%.

[0403] .sup.1H NMR (300 MHz, DMSO-d.sub.6, ppm): δ 8.16 (t, J=7.2 Hz, 1H), 8.07 (d, J=7.2 Hz, 1H), 8.02 (t, J=7.2 Hz, 1H), 6.73 (t, J=7.2 Hz, 1H), 4.12 (m, 1H), 4.08 (q, J=7.2 Hz, 2H), 3.73 (d, J=7.2 Hz, 1H), 3.60 (d, J=7.2 Hz, 1H), 2.81 (m, 2H), 2.72 (t, J=3.0 Hz, 1H), 2.20 (t, J=7.2 Hz, 2H), 1.95 (m, 2H), 1.63 (m, 3H), 1.52 (m, 1H), 1.36 (m, 11H), 1.23 (m, 1H); ESI-MS (m/z): calcd for C.sub.23H.sub.39N.sub.4O.sub.7 [M+H].sup.+: 483.3; found: 483.4.

Sample 54: Preparation of Compound 54

[0404] In a 250 mL round-bottom flask, 10.2 g (21.15 mmol) of compound 53 was dissolved in 100 mL of hydrochloride ethanol solution (4.0N) at 0° C., and stirred overnight. The reaction mixture was evaporated to dryness to provide 8.8 g of compound 54, which was directly used in next step without purification. Yield: 100%.

[0405] .sup.1H NMR (300 MHz, CD.sub.3OD, ppm): δ 4.36 (m, 1H), 4.12 (q, J=7.2 Hz, 2H), 3.81 (s, 1H), 3.78 (s, 2H), 2.81 (t, J=7.2 Hz, 2H), 2.32 (t, J=7.2 Hz, 2H), 2.11 (m, 3H), 1.60-1.82 (m, 4H), 1.56 (m, 2H), 1.32 (m, 2H), 1.13 (t, J=7.2 Hz, 2H); ESI-MS (m/z): calcd for C.sub.18H.sub.31N.sub.4O.sub.5 [M+H].sup.+: 383.2; found: 383.3.

Sample 55: Preparation of Compound 55

[0406] To a 250 mL round-bottom flask charged with 8.8 g (22.96 mmol) of compound 54 and 14.8 mL (107.0 mmol) of triethyl amine in 100 mL of anhydrous DMF, 12.3 g (106.0 mmol) of diglycolic acid anhydride was added and stirred at room temperature overnight. After removal of volatiles, the residue was acidified with hydrochloride solution (2.0N) to pH=1.0, concentrated, and purified on a reverse phase column C-18 eluted with acetonitrile in water (5-60%) to provide 4.0 g of compound 55. Yield: 37%.

[0407] .sup.1H NMR (300 MHz, D.sub.2O, ppm): δ 4.31 (m, 1H), 4.21 (s, 2H), 4.13 (q, J=7.2 Hz, 2H), 4.06 (s, 2H), 3.90 (s, 2H), 3.88 (s, 2H), 3.18 (t, J=7.2 Hz, 2H), 2.37 (t, J=7.2 Hz, 2H), 2.35 (t, J=3.0 Hz, 2H), 2.15 (m, 2H), 1.60-1.85 (m, 4H), 1.45 (m, 2H), 1.31 (m, 2H), 1.15 (t, J=7.2 Hz, 3H); ESI-MS (m/z): calcd for C.sub.22H.sub.35N.sub.4O.sub.9 [M+H].sup.+: 499.2; found: 499.3.

Sample 56: Preparation of Compound 56

[0408] To a 100 mL round-bottom flask charged with 1.27 g (2.56 mmol) of compound 55 and 813 mg (4.26 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), 15 mL of dry DMF was added, and stirred at room temperature for 30 min; and then 2.0 g (2.13 mmol) of compound 9 and 520 mg (4.26 mmol) of DMAP were added. The reaction was continuously stirred for 24 h. Upon completion of the reaction, the reaction mixture was partitioned between ethyl acetate (100 mL) and brine (100 mL); the aqueous phase was further extracted with ethyl acetate (50 mL×2), and the organic phases were pooled, dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with methanol in chloroform (0-10%) to provide 2.15 g of compound 56. Yield: 71%.

[0409] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 8.12 (d, J=7.2 Hz, 2H), 8.09 (t, J=7.2 Hz, 1H), 7.20-7.80 (m, 16H), 6.39 (s, 1H), 6.10 (m, 1H), 5.97 (m, 1H), 5.62 (m, 2H), 5.51 (m, 1H), 4.97 (d, J=9.7 Hz, 1H), 4.63 (m, 2H), 4.39 (m, 3H), 4.00-4.25 (m, 6H), 3.96 (s, 2H), 3.70-3.97 (m, 5H), 3.23 (t, J=7.2 Hz, 2H), 2.45 (m, 1H), 2.43 (m, 1H), 2.41 (m, 4H), 2.36 (s, 3H), 2.25 (m, 4H), 2.17 (m, 1H), 1.95-2.05 (m, 6H), 1.83 (s, 3H), 1.60-1.85 (m, 4H), 1.45 (m, 2H), 1.31 (m, 2H), 1.17 (t, J=7.2 Hz, 3H), 1.15 (s, 3H), 1.12 (s, 3H); ESI-MS (m/z): calcd for C.sub.73H.sub.88N.sub.5O.sub.24 [M+H].sup.+: 1418.6; found: 1418.7.

Sample 57: Preparation of Compound 57

[0410] To a 100 mL round-bottom flask charged with 1.23 g (2.56 mmol) of compound 55 and 783 mg (4.10 mmol) of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC), 15 mL of dry DMF was added, and stirred at room temperature for 30 min; and then 2.0 g (2.05 mmol) of compound 36 and 500 mg (4.10 mmol) of DMAP were added. The reaction was continuously stirred for 24 h. Upon completion of the reaction, the reaction mixture was partitioned between ethyl acetate (100 mL) and brine (100 mL); the aqueous phase was extracted with ethyl acetate (50 mL×2), and the organic phases were pooled, dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with methanol in chloroform (0-10%) to provide 2.06 g of compound 57. Yield: 69%.

[0411] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 8.13 (d, J=7.2 Hz, 2H), 7.20-7.85 (m, 10H), 6.15 (s, 1H), 5.98 (m, 2H), 5.65 (t, J=7.2 Hz, 1H), 5.43 (m, 2H), 5.25 (s, 1H), 4.97 (d, J=9.6 Hz, 1H), 4.63 (m, 4H), 4.37 (m, 6H), 4.15 (m, 4H), 4.01 (s, 2H), 3.70-4.00 (m, 5H), 3.21 (t, J=7.2 Hz, 2H), 2.46 (m, 1H), 2.00-2.35 (m, 9H), 1.96 (m, 1H), 1.60-1.80 (m, 9H), 1.37 (s, 9H), 1.23 (t, J=7.2 Hz, 3H), 1.16 (s 3H), 1.13 (s, 3H); ESI-MS (m/z): calcd for C.sub.73H.sub.93N.sub.5O.sub.26 [M+H].sup.+: 1455.6; found: 1455.7.

Sample 58: Preparation of Compound 58

[0412] To a 50 mL round-bottom flask charged with 639 mg (1.28 mmol) of compound 55 and 410 mg (2.15 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), 15 mL of dry DMF was added, and stirred at room temperature for 30 min; and then 900 mg (1.07 mmol) of cabazitaxel and 263 mg (2.15 mmol) of DMAP were added. The reaction was continuously stirred for 24 h. Upon completion of the reaction, the reaction mixture was partitioned between ethyl acetate (100 mL) and brine (100 mL); the aqueous phase was extracted with ethyl acetate (50 mL×2), and the organic phases were pooled, dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with methanol in chloroform (0-10%) to provide 1.17 g of compound 58. Yield: 75%.

[0413] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 8.10 (d, J=7.8 Hz, 2H), 7.20-7.80 (m, 10H), 6.23 (m, 1H), 5.62 (t, J=7.2 Hz, 1H), 5.50 (m, 1H), 5.42 (m, 2H), 5.01 (d, J=9.6 Hz, 1H), 4.80 (s, 1H), 4.53 (m, 1H), 4.10-4.40 (m, 5H), 4.17 (s, 2H), 3.80-4.05 (m, 6H), 3.48 (m, 3H), 3.28 (m, 4H), 2.47 (m, 1H), 2.30-2.40 (m, 4H), 2.07 (s, 3H), 2.05 (m, 2H), 1.96 (m, 1H), 1.65-1.80 (m, 9H), 1.37 (s, 9H), 1.25 (t, J=7.2 Hz, 3H), 1.18 (s 3H), 1.16 (s, 3H); ESI-MS (m/z): calcd for C.sub.67H.sub.90N.sub.5O.sub.22 [M+H].sup.+: 1455.6; found: 1455.8.

Sample 59: Preparation of Compound 59

[0414] To a 50 mL round-bottom flask charged with 1.5 g (1.06 mmol) of compound 56, 73 mg (0.063 mmol) of tetrakis(triphenylphosphine)palladium(O), and 198 mg (1.27 mmol) of 1,3-dimethylbarbituric acid under nitrogen protection, 20.0 mL of anhydrous THF was added and the reaction mixture was stirred at room temperature for 5 h. After removal of volatiles and the residue was purified on a silica gel column and eluted with methanol in chloroform (0-15%) to give 1.17 g of compound 59. Yield: 79%.

[0415] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 8.10 (d, J=7.2 Hz, 2H), 7.20-7.85 (m, 14H), 6.38 (s, 1H), 6.10 (m, 1H), 5.93 (m, 1H), 5.63 (m, 2H), 4.97 (d, J=9.7 Hz, 1H), 4.38 (m, 3H), 4.00-4.25 (m, 6H), 3.96 (s, 2H), 3.82 (s, 2H), 3.75 (m, 3H), 3.65 (m, 1H), 3.17 (t, J=7.2 Hz, 2H), 2.45 (m, 1H), 2.42 (m, 1H), 2.37 (s, 3H), 2.35 (m, 4H), 2.17 (m, 1H), 2.15 (m, 2H), 2.13 (m, 2H), 1.99 (m, 2H), 1.84 (s, 3H), 1.60-1.80 (m, 4H), 1.45 (m, 2H), 1.31 (m, 2H), 1.18 (t, J=7.2 Hz, 3H), 1.12 (s, 3H), 1.10 (s, 3H); ESI-MS (m/z): calcd for C.sub.69H.sub.84N.sub.5O.sub.22 [M+H].sup.+: 1334.5; found: 1334.7.

Sample 60: Preparation of Compound 60

[0416] To a 50 mL round-bottom flask charged with 1.7 g (1.17 mmol) of compound 57, 135 mg (0.117 mmol) of tetrakis(triphenylphosphine)palladium(O), and 401 mg (2.57 mmol) of 1,3-dimethylbarbituric acid under nitrogen protection, 20.0 mL of anhydrous THF was added and the reaction mixture was stirred at room temperature for 5 h. After removal of volatiles and the residue was purified on a silica gel column and eluted with methanol in chloroform (0-15%) to give 1.29 g of compound 60. Yield: 85%.

[0417] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 8.12 (d, J=7.8 Hz, 2H), 7.20-7.85 (m, 10H), 6.13 (m, 1H), 5.68 (t, J=7.2 Hz, 1H), 5.43 (m, 2H), 5.26 (s, 1H), 4.97 (d, J=9.6 Hz, 1H), 4.48 (m, 1H), 4.38 (m, 5H), 4.17 (s, 2H), 4.12 (q, J=7.2 Hz, 2H), 4.01 (s, 2H), 3.70-4.00 (m, 5H), 3.59 (s, 1H), 3.18 (t, J=7.2 Hz, 2H), 2.46 (m, 1H), 2.37 (t, J=7.2 Hz, 2H), 2.35 (m, 2H), 2.06 (s, 3H), 2.05 (m, 2H), 1.95 (m, 1H), 1.60-1.80 (m, 9H), 1.38 (s, 9H), 1.20 (t, J=7.2 Hz, 3H), 1.18 (s 3H), 1.15 (s, 3H); ESI-MS (m/z): calcd for C.sub.65H.sub.86N.sub.5O.sub.22 [M+H].sup.+: 1288.6; found: 1288.9.

Sample 61: Preparation of Compound 61

[0418] To a 25 mL round-bottom flask charged with 200 mg (0.15 mmol) of compound 59 and 42 mg (0.30 mmol) of 6-azido-hexanoic acid, 5.0 mL of DMSO was added. 100 uL of copper sulfate (1.0M) in water and 100 uL of sodium ascorbate (1.0M) in water were mixed together and added to the above solution. After stirring for 2 days at room temperature, the reaction mixture was partitioned between ethyl acetate (50 mL) and brine (50 mL), the organic phase was further washed with brine twice (30 mL×2), dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with methanol in chloroform (1-15%) to provide 166 mg of compound 61. Yield: 76%.

[0419] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 8.12 (d, J=7.2 Hz, 2H), 7.20-7.85 (m, 15H), 6.36 (s, 1H), 6.11 (m, 1H), 5.92 (m, 1H), 5.65 (m, 2H), 4.96 (d, J=9.7 Hz, 1H), 4.37 (m, 3H), 4.00-4.25 (m, 6H), 3.97 (s, 2H), 3.81 (s, 2H), 3.77 (m, 3H), 3.50-3.80 (m, 8H), 3.18 (t, J=7.2 Hz, 2H), 2.46 (m, 1H), 2.41 (m, 1H), 2.38 (s, 3H), 2.36 (m, 4H), 2.16 (m, 1H), 2.15 (m, 2H), 2.13 (m, 2H), 1.99 (m, 2H), 1.83 (s, 3H), 1.60-1.80 (m, 6H), 1.48 (m, 4H), 1.31 (m, 6H), 1.19 (t, J=7.2 Hz, 3H), 1.13 (s, 3H), 1.09 (s, 3H); ESI-MS (m/z): calcd for C.sub.75H.sub.96N.sub.8O.sub.23 [M+H].sup.+: 1459.7; found: 1459.9.

Sample 62: Preparation of Compound 62

[0420] To a 25 mL round-bottom flask charged with 200 mg (0.155 mmol) of compound 60 and 45 mg (0.31 mmol) of 6-azido-hexanoic acid, 5.0 mL of DMSO was added. 100 uL of copper sulfate (1.0M) in water and 100 uL of sodium ascorbate (1.0M) in water were mixed together and added to the above solution. After stirring for 2 days at room temperature, the reaction mixture was partitioned between ethyl acetate (50 mL) and brine (50 mL), the organic phase was further washed with brine twice (30 mL×2), dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a reverse phase C-18 column and eluted with methanol in chloroform (10-70%) to provide 195 mg of compound 62. Yield: 89%.

[0421] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 8.11 (d, J=7.8 Hz, 2H), 7.20-7.85 (m, 11H), 6.15 (m, 1H), 5.69 (t, J=7.2 Hz, 1H), 5.42 (m, 2H), 5.28 (s, 1H), 4.96 (d, J=9.5 Hz, 1H), 4.41 (m, 5H), 4.18 (s, 2H), 4.15 (q, J=7.2 Hz, 2H), 4.02 (s, 2H), 3.70-4.00 (m, 5H), 3.50-3.85 (m, 5H), 3.18 (t, J=7.2 Hz, 2H), 2.45 (m, 1H), 2.36 (t, J=7.2 Hz, 2H), 2.33 (m, 2H), 2.05 (s, 3H), 2.04 (m, 2H), 1.97 (m, 1H), 1.60-1.80 (m, 11H), 1.45 (m, 2H), 1.38 (s, 9H), 1.20-1.30 (m, 5H), 1.18 (s 3H), 1.15 (s, 3H); ESI-MS (m/z): calcd for: C.sub.71H.sub.98N.sub.8O.sub.23 [M+H].sup.+: 1430.7; found: 1430.8.

Sample 63: Preparation of Compound 63

[0422] To a 25 mL round-bottom flask charged with 200 mg (0.137 mmol) of compound 58 and 39 mg (0.275 mmol) of 6-azido-hexanoic acid, 5.0 mL of DMSO was added. 100 uL of copper sulfate (1.0M) in water and 100 uL of sodium ascorbate (1.0M) in water were mixed together and added to the above solution. After stirring for 2 days at room temperature, the reaction mixture was partitioned between ethyl acetate (50 mL) and brine (50 mL), the organic phase was further washed with brine twice (30 mL×2), dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with methanol in chloroform (1-15%) to provide 186 mg of compound 63. Yield: 93%.

[0423] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 8.09 (d, J=7.8 Hz, 2H), 7.20-7.80 (m, 11H), 6.23 (m, 1H), 5.63 (t, J=7.2 Hz, 1H), 5.48 (m, 1H), 5.45 (m, 2H), 4.97 (d, J=9.6 Hz, 1H), 4.81 (s, 1H), 4.52 (m, 1H), 4.10-4.40 (m, 5H), 4.17 (s, 2H), 3.70-4.05 (m, 8H), 3.51 (m, 5H), 3.26 (m, 4H), 2.45 (m, 1H), 2.30-2.40 (m, 4H), 2.06 (s, 3H), 2.05 (m, 2H), 1.96 (m, 1H), 1.65-1.80 (m, 11H), 1.47 (m, 2H), 1.37 (s, 9H), 1.29 (m, 4H), 1.25 (t, J=7.2 Hz, 3H), 1.18 (s 3H), 1.16 (s, 3H); ESI-MS (m/z): calcd for: C.sub.73H.sub.103N.sub.8O.sub.23 [M+H].sup.+: 1459.7; found: 1460.0.

Synthetic Scheme 10

[0424] ##STR00146## ##STR00147## ##STR00148##

Sample 64: Preparation of Compound 64

[0425] In a 250 mL round-bottom flask, 3.38 g (6.0 mmol) of Nα-Boc-Nε-ivDde-L-lysine, 1.73 g (9.0 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), and 1.1 g (9.0 mmol) of DMAP were combined in 20 mL of anhydrous DCM and stirred at room temperature for 30 min; and then 5.0 mL of absolute ethanol was added and continued stirring overnight. After removal of volatiles, the residue was partitioned between ethyl acetate (50 mL) and brine (50 mL), the organic phase was further washed with brine twice (30 mL×2), dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with ethyl acetate in petroleum (10-70%) to provide 2.95 g of compound 64. Yield: 83%.

[0426] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 5.09 (s, 1H), 4.27 (m, 1H), 4.18 (q, J=7.0 Hz, 2H), 3.41 (m, 2H), 2.96 (m, 2H), 2.46 (s, 4H), 2.16 (m, 2H), 1.96 (m, 1H), 1.79 (m, 2H), 1.63 (m, 3H), 1.51 (m, 1H), 1.43 (s, 9H), 1.25 (t, J=7.0 Hz, 3H), 1.03 (s, 6H), 0.98 (s, J=7.0 Hz, 6H); ESI-MS (m/z): calcd for C.sub.26H.sub.45N.sub.2O.sub.6 [M+H].sup.+: 481.3; found: 481.3.

Sample 65: Preparation of Compound 65

[0427] To a 250 mL round-bottom flask charged with 3.0 g (5.08 mmol) of compound 64, 50 mL of hydrochloride ethanol solution (4.0N) was added and stirred at room temperature overnight. After removal of volatiles, the residue was purified on a reverse phase C-18 column and eluted with acetonitrile in water (10-70%) to provide 1.43 g of compound 65. Yield: 57%.

[0428] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 8.89 (s, 3H), 4.26 (q, J=7.0 Hz, 2H), 4.10 (m, 1H), 3.51 (m, 2H), 2.97 (m, 2H), 2.35 (s, 4H), 2.16 (m, 2H), 1.97 (m, 1H), 1.78 (m, 2H), 1.56 (m, 2H), 1.23 (t, J=7.0 Hz, 3H), 1.03 (s, 6H), 0.98 (s, J=7.0 Hz, 6H); ESI-MS (m/z): calcd for C.sub.21H.sub.37N.sub.2O.sub.4 [M+H].sup.+: 381.2; found: 381.2.

Sample 66: Preparation of Compound 66

[0429] To a 100 mL round-bottom flask charged with 710 mg (3.06 mmol) of Boc-Gly-Gly-OH, 584 mg (3.06 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), and 413 mg (3.06 mmol) of 1-hydroxybenzotriazole (HOBt), 6.0 mL of dry DMF was added and stirred for 30 min, and followed by addition of 1.0 g (2.02 mmol) of compound 66 and 0.56 mL of triethylamine and stirred at room temperature for another 3 h. Upon completion of the reaction, the reaction mixture was partitioned between ethyl acetate (50 mL) and brine (50 mL), the organic phase was further washed with brine twice (30 mL×2), dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with methanol in chloroform (1-10%) to provide 1.12 g of compound 66. Yield: 62%.

[0430] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 7.51 (d, J=5.0 Hz, 1H), 7.02 (d, J=5.0 Hz, 1H), 5.47 (d, J=5.0 Hz, 1H), 4.53 (m, 1H), 4.17 (q, J=7.0 Hz, 2H), 3.82 (d, J=6.0 Hz, 2H), 3.81 (d, J=6.0 Hz, 2H), 3.42 (m, 2H), 2.97 (m, 2H), 2.34 (s, 4H), 1.93 (m, 1H), 1.72 (m, 4H), 1.63 (m, 2H), 1.42 (s, 9H), 1.21 (t, J=7.0 Hz, 3H), 1.03 (s, 6H), 0.96 (s, J=7.0 Hz, 6H); ESI-MS (m/z): calcd for C.sub.30H.sub.51N.sub.4O.sub.8 [M+H].sup.+: 595.4; found: 595.5.

Sample 67: Preparation of Compound 67

[0431] To a stirred solution of 1.40 g (2.35 mmol) of compound 66 in 50 mL of methanol, 154 uL (23.50 mmol) of hydrazine hydrate was added and stirred at room temperature overnight. Upon completion of the reaction, the white solid was filtered off, and the filtrate was concentrated, and purified on a reverse phase C-18 column and eluted with acetonitrile in water (10-80%) to provide 796 mg of compound 67. Yield: 87%.

[0432] .sup.1H NMR (300 MHz, DMSO-d.sub.6, ppm): δ 8.39 (s, 1H), 8.06 (s, 1H), 7.08 (s, 1H), 4.27 (m, 1H), 4.12 (q, J=7.0 Hz, 2H), 3.78 (d, J=6.0 Hz, 2H), 3.65 (d, J=6.0 Hz, 2H), 2.75 (d, J=7.0 Hz, 2H), 1.68 (m, 1H), 1.51 (m, 4H), 1.47 (s, 9H), 1.38 (m, 1H); ESI-MS (m/z): calcd for C.sub.17H.sub.33N.sub.4O.sub.6 [M+H].sup.+: 389.2; found: 389.2.

Sample 68: Preparation of Compound 68

[0433] To a 100 mL round-bottom flask charged with 1.8 g (4.63 mmol) of compound 67 and 1.61 g (13.90 mmol) of diglycolic acid anhydride, 10 mL of anhydrous DMF and 1.92 mL (13.90 mmol) of triethylamine were successively added and stirred at room temperature overnight. After removal of volatiles, the residue was acidified to pH=1.0 with 2.0N hydrochloride solution; the aqueous solution was further concentrated, and purified on a reverse phase C-18 column and eluted with acetonitrile in water (5-70%) to provide 1.92 g of compound 68. Yield: 82%.

[0434] .sup.1H NMR (300 MHz, D.sub.2O, ppm): δ 4.36 (m, 1H), 4.27 (s, 2H), 4.15 (q, J=7.0 Hz, 2H), 4.17 (s, 2H), 4.01 (s, 2H), 3.87 (s, 2H), 3.23 (d, J=7.0 Hz, 2H), 1.86 (m, 1H), 1.75 (m, 1H), 1.56 (m, 2H), 1.43 (s, 9H), 1.35 (m, 2H); ESI-MS (m/z): calcd for C.sub.21H.sub.37N.sub.4O.sub.10 [M+H].sup.+: 505.2; found. 505.2.

Sample 69: Preparation of Compound 69

[0435] To a 250 mL round-bottom flask charged with 2.0 g (3.67 mmol) of compound 68, 50 mL of hydrochloride ethanol solution (4.0N) was added and stirred at room temperature overnight. After removal of volatiles, the residue was purified on a reverse phase C-18 column and eluted with acetonitrile in water (10-70%) to provide 848 mg of compound 69. Yield: 57%.

[0436] .sup.1H NMR (300 MHz, D.sub.2O, ppm): δ 4.39 (m, 1H), 4.28 (s, 2H), 4.23 (q, J=7.0 Hz, 2H), 4.20 (s, 2H), 4.04 (s, 2H), 3.90 (s, 2H), 3.26 (d, J=7.0 Hz, 2H), 1.92 (m, 2H), 1.89 (m, 1H), 1.56 (m, 2H), 1.39 (s, 2H), 1.25 (t, J=7.0 Hz, 3H); ESI-MS (m/z): calcd for C.sub.16H.sub.29N.sub.4O.sub.8 [M+H].sup.+: 405.2; found: 405.2.

Sample 70: Preparation of Compound 70

[0437] To a 50 mL round-bottom flask charged with 603 mg (1.50 mmol) of compound 69 in 3.0 mL of anhydrous DMF, 829 uL (6.0 mmol) of triethylamine, and 502 mg (1.08 mmol) of 2-(cyclohept-2-yn-1-yloxy)acetic acid-(N-hydroxysuccinyl lactam) ester were successively added and stirred at room temperature overnight. After removal of volatiles, the residue was acidified to pH=1.0 with 2.0N hydrochloride solution; the aqueous solution was further concentrated, and purified on a reverse phase C-18 column and eluted with acetonitrile in water (10-70%) to provide 621 mg of compound 70. Yield: 72%.

[0438] .sup.1H NMR (300 MHz, D.sub.2O, ppm): δ 4.00-4.50 (m, 12H), 3.88 (d, J=6.0 Hz, 2H), 3.25 (t, J=7.0 Hz, 2H); 2.00-2.30 (m, 4H), 1.70-2.00 (m, 5H), 1.55 (m, 5H), 1.25-1.55 (m, 3H), 1.23 (t, J=7.0 Hz, 3H); ESI-MS (m/z): calcd for C.sub.26H.sub.41N.sub.4O.sub.10 [M+H].sup.+: 569.3; found: 569.3.

Sample 71: Preparation of Compound 71

[0439] To a 50 mL round-bottom flask charged with 333 mg (0.587 mmol) of compound 70 and 153 mg (0.789 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), 3.0 mL of dry DMF was added and stirred at room temperature for 30 min; and then 500 mg (0.533 mmol) of compound 9 and 98 mg (0.798 mmol) of DMAP were added. The reaction was continuously stirred for 24 h. Upon completion of the reaction, the reaction mixture was partitioned between ethyl acetate (50 mL) and brine (50 mL); the aqueous phase was extracted with ethyl acetate (30 mL×2), and the organic phases were pooled, dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with methanol in chloroform (0-12%) to provide 657 mg of compound 71. Yield: 82%.

[0440] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 8.11 (d, J=7.2 Hz, 2H), 7.00-7.80 (m, 15H), 6.35 (s, 1H), 6.17 (t, J=9.0 Hz, 1H), 5.93 (m, 2H), 5.85 (d, J=9.0 Hz, 1H), 5.65 (d, J=7.2 Hz, 1H), 5.23 (m, 2H), 4.97 (d, J=9.0 Hz, 1H), 4.81 (m, 3H), 4.00-4.50 (m, 14H), 3.75-4.00 (m, 4H), 3.25 (t, J=7.0 Hz, 2H), 2.51 (m, 1H), 2.37 (s, 3H), 2.00-2.35 (m, 9H), 1.70-2.00 (m, 13H), 1.25-1.55 (m, 3H), 1.25 (t, J=7.0 Hz, 3H), 1.25 (s, 3H), 1.16 (s, 3H), 1.13 (s, 3H); ESI-MS (m/z): calcd for C.sub.77H.sub.94N.sub.5O.sub.25 [M+H].sup.+: 1488.6; found: 1488.8.

Sample 72: Preparation of Compound 72

[0441] To a 50 mL round-bottom flask charged with 192 mg (0.338 mmol) of compound 70 and 90 mg (0.462 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), 3.0 mL of dry DMF was added and stirred at room temperature for 30 min; and then 300 mg (0.308 mmol) of compound 6 and 58 mg (0.462 mmol) of DMAP were added. The reaction mixture was continuously stirred for 24 h. Upon completion of the reaction, the reaction mixture was partitioned between ethyl acetate (50 mL) and brine (50 mL); the aqueous phase was extracted with ethyl acetate (30 mL×2), and the organic phases were pooled, dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with methanol in chloroform (0-12%) to provide 399 mg of compound 72. Yield: 85%.

[0442] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 8.10 (d, J=7.2 Hz, 2H), 7.20-7.80 (m, 10H), 6.15 (s, 1H), 5.91 (m, 1H), 5.63 (s, 1H), 5.25-5.50 (m, 5H), 4.98 (d, J=9.8 Hz, 1H), 4.00-4.80 (m, 19H), 3.50-4.00 (m, 6H), 3.26 (t, J=7.2 Hz, 2H), 2.45 (m, 1H), 2.00-2.35 (m, 9H), 1.98 (m, 1H), 1.50-1.90 (m, 12H), 1.37 (s, 9H), 1.25 (m, 3H), 1.22 (t, J=7.2 Hz, 3H), 1.16 (s, 3H), 1.11 (s, 3H); ESI-MS (m/z): calcd for C.sub.77H.sub.100N.sub.5O.sub.27 [M+H].sup.+: 1526.7; found: 1526.9.

Sample 73: Preparation of Compound 73

[0443] To a 50 mL round-bottom flask charged with 600 mg (0.402 mmol) of compound 71, 39 mg (0.033 mmol) of tetrakis(triphenylphosphine)palladium(O), and 75 mg (0.483 mmol) of 1,3-dimethylbarbituric acid under nitrogen protection, 20.0 mL of anhydrous THF was added; the reaction mixture was stirred at room temperature for 5 h. After removal of volatiles, the residue was purified on a silica gel column and eluted with methanol in chloroform (0-8%) to give 451 mg of compound 73. Yield: 80%.

[0444] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 8.12 (d, J=7.2 Hz, 2H), 7.00-7.80 (m, 15H), 6.32 (s, 1H), 6.18 (t, J=9.0 Hz, 1H), 5.96 (m, 1H), 5.82 (d, J=9.0 Hz, 1H), 5.68 (d, J=7.2 Hz, 1H), 4.99 (d, J=9.0 Hz, 1H), 4.78 (s, 1H), 4.00-4.50 (m, 14H), 3.75-4.00 (m, 4H), 3.23 (t, J=7.0 Hz, 2H), 2.56 (m, 1H), 2.35 (s, 3H), 2.00-2.35 (m, 9H), 1.70-2.00 (m, 13H), 1.25-1.55 (m, 3H), 1.23 (t, J=7.0 Hz, 3H), 1.20 (s, 3H), 1.17 (s, 3H), 1.15 (s, 3H); ESI-MS (m/z): calcd for C.sub.73H.sub.90N.sub.5O.sub.23 [M+H].sup.+: 1404.6; found: 1404.5.

Sample 74: Preparation of Compound 74

[0445] To a 50 mL round-bottom flask charged with 450 mg (0.294 mmol) of compound 72, 41 mg (0.035 mmol) of tetrakis(triphenylphosphine)palladium(O), and 105 mg (0.672 mmol) of 1,3-dimethylbarbituric acid under nitrogen protection, 20.0 mL of anhydrous THF was added; the reaction mixture was stirred at room temperature for 5 h. After removal of the volatiles, the residue was purified on a silica gel column and eluted with methanol in chloroform (0-8%) to give 291 mg of compound 74. Yield: 73%.

[0446] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 8.13 (d, J=7.2 Hz, 2H), 7.20-7.80 (m, 10H), 6.18 (s, 1H), 5.65 (s, 1H), 5.25-5.50 (m, 3H), 4.98 (d, J=9.8 Hz, 1H), 4.00-4.60 (m, 17H), 3.50-4.00 (m, 6H), 3.25 (t, J=7.2 Hz, 2H), 2.47 (m, 1H), 2.00-2.35 (m, 9H), 1.97 (m, 1H), 1.50-1.90 (m, 12H), 1.39 (s, 9H), 1.27 (m, 3H), 1.23 (t, J=7.2 Hz, 3H), 1.15 (s, 3H), 1.12 (s, 3H); ESI-MS (m/z): calcd for C.sub.69H.sub.92N.sub.5O.sub.23 [M+H].sup.+: 1358.6; found: 1358.7.

Sample 75: Preparation of Compound 75a (75b)

[0447] In a 25 mL round-bottom flask, 100 mg (0.071 mmol) of compound 73 and 20 mg (0.142 mmol) of 6-azidohexan-1-ol were combined in 1.0 mL of methanol and stirred at room temperature overnight, and directly and purified on a reverse phase C-18 column and eluted with acetonitrile in water (10-70%) to provide 101 mg of compounds 75a (75b). Yield: 91%.

[0448] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 8.10 (d, J=7.2 Hz, 2H), 7.00-7.80 (m, 15H), 6.35 (s, 1H), 6.17 (t, J=9.0 Hz, 1H), 5.95 (m, 1H), 5.83 (d, J=9.0 Hz, 1H), 5.66 (d, J=7.2 Hz, 1H), 4.95 (d, J=9.0 Hz, 1H), 4.76 (s, 1H), 4.00-4.50 (m, 14H), 3.50-4.00 (m, 8H), 3.25 (t, J=7.0 Hz, 2H), 2.56 (m, 1H), 2.35 (s, 3H), 2.00-2.35 (m, 9H), 1.70-2.00 (m, 15H), 1.25-1.55 (m, 9H), 1.23 (t, J=7.0 Hz, 3H), 1.21 (s, 3H), 1.13 (s, 3H), 1.10 (s, 3H); ESI-MS (m/z): calcd for C.sub.79H.sub.103N.sub.8O.sub.24 [M+H].sup.+: 1547.7; found: 1547.6.

Sample 76: Preparation of Compound 76a (76b)

[0449] In a 25 mL round-bottom flask, 100 mg (0.073 mmol) of compound 73 and 21 mg (0.147 mmol) of 6-azidohexan-1-ol were combined in 1.0 mL of methanol and stirred at room temperature overnight, and directly and purified on a reverse phase C-18 column and eluted with acetonitrile in water (10-70%) to provide 92 mg of compounds 76a (76b). Yield: 84%.

[0450] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 8.12 (d, J=7.2 Hz, 2H), 7.20-7.80 (m, 10H), 6.15 (s, 1H), 5.67 (s, 1H), 5.25-5.50 (m, 3H), 4.95 (d, J=9.8 Hz, 1H), 4.00-4.60 (m, 17H), 3.50-4.00 (m, 10H), 3.23 (t, J=7.2 Hz, 2H), 2.45 (m, 1H), 2.00-2.35 (m, 9H), 1.95 (m, 1H), 1.50-1.90 (m, 16H), 1.38 (s, 9H), 1.28 (m, 7H), 1.25 (t, J=7.2 Hz, 3H), 1.13 (s, 3H), 1.10 (s, 3H); ESI-MS (m/z): calcd for C.sub.75H.sub.105N.sub.8O.sub.24 [M+H].sup.+:1501.7; found: 1501.8.

Synthetic Scheme 11

[0451] ##STR00149##

Sample 77: Preparation of Compound 77

[0452] To a 250 mL round-bottom flask charged with 10.0 g (40.62 mmol) of N.sub.6-Boc-L-lysine and 6.28 g (81.24 mmol) of sodium carbonate, 70 mL of DMF and 30 mL of distilled water were added, followed by 9.3 g (36.56 mmol) of 6-azido-hexanoic acid-(N-hydroxysuccinyl lactam) ester, and stirred at room temperature overnight. Upon completion of the reaction, the reaction mixture was acidified with hydrochloride solution (2.0N) to pH=1.0, and extracted with ethyl acetate three times (300 mL×3); the organic phases were combined together, dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with methanol in chloroform (2-10%) to provide 8.91 g of compound 77. Yield: 57%.

[0453] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 6.21 (s, 1H), 4.55 (m, 1H), 3.23 (t, J=7.2 Hz, 2H), 2.25 (t, J=7.2 Hz, 2H), 1.82 (m, 2H), 1.52-1.75 (m, 4H), 1.45 (m, 2H), 1.42 (s, 9H), 1.26-1.41 (m, 4H); ESI-MS (m/z): calcd for C.sub.17H.sub.32N.sub.5O.sub.5 [M+H].sup.+: 386.2; found: 386.2.

Sample 78: Preparation of Compound 78

[0454] To a 100 mL round-bottom flask charged with 8.0 g (20.76 mmol) of compound 77 and 5.95 g (31.15 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), 100 mL of anhydrous dichloromethane was added and stirred at room temperature for 30 min; and then 6.0 mL of absolute ethanol and 38.27 g (31.15 mmol) of DMAP were added. The reaction mixture was continuously stirred overnight. Upon completion of the reaction, the reaction mixture was washed with brine (100 mL×2), dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with ethyl acetate in petroleum (10-80%) to provide 6.26 g of compound 78. Yield: 73%.

[0455] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 6.11 (s, 1H), 4.52 (m, 1H), 4.12 (q, J=7.2 Hz, 2H), 3.25 (t, J=7.2 Hz, 2H), 2.24 (t, J=7.2 Hz, 2H), 1.83 (m, 2H), 1.52-1.75 (m, 4H), 1.45 (m, 2H), 1.42 (s, 9H), 1.26-1.41 (m, 4H), 1.25 (t, J=7.2 Hz, 3H); ESI-MS (m/z): calcd for C.sub.19H.sub.36N.sub.5O.sub.5 [M+H].sup.+: 414.2; found: 414.3.

Sample 79: Preparation of Compound 79

[0456] In a 250 mL round-bottom flask, 5.0 g (12.09 mmol) of compound 78 was dissolved in 50 mL of hydrochloride ethanol solution (4.0N) at room temperature, and stirred overnight. The reaction mixture was concentrated, and purified on a reverse phase C-18 column and eluted with acetonitrile in water (10-70%) to provide 3.85 g of compounds 79. Yield: 91%.

[0457] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 6.21 (s, 1H), 4.57 (m, 1H), 4.18 (q, J=7.2 Hz, 2H), 3.25 (t, J=7.2 Hz, 2H), 2.69 (s, 3H), 2.28 (t, J=7.2 Hz, 2H), 1.82 (m, 2H), 1.52-1.75 (m, 4H), 1.45 (m, 2H), 1.26-1.41 (m, 4H), 1.25 (t, J=7.2 Hz, 3H); ESI-MS (m/z): calcd for C.sub.14H.sub.28N.sub.5O.sub.3 [M+H].sup.+: 314.2; found: 314.2.

Sample 80: Preparation of Compound 80

[0458] In a 100 mL round-bottom flask, 2.0 g (2.06 mmol) of compound 5 and 1.17 g (3.09 mmol) of benzotriazole-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU) and 418 mg (3.09 mmol) of 1-hydroxybenzotriazole (HOBt) were dissolved in 10.0 mL of dry DMF, followed by addition of 1.07 mg (3.09 mmol) of compound 79 and 0.57 mL (4.12 mmol) of triethylamine, and stirred at room temperature for 3 h. Upon completion of the reaction, the reaction mixture was partitioned between ethyl acetate (200 mL) and brine (200 mL), the organic phase was further washed with brine twice (200 mL×2), dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with methanol in chloroform (2-10%) to provide 1.79 g of compound 80. Yield: 67%.

[0459] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 8.11 (d, J=7.2 Hz, 2H), 7.20-7.80 (m, 13H), 7.10 (d, J=7.0 Hz, 1H), 6.23 (s, 1H), 6.21 (m, 2H), 5.79 (m, 1H), 5.68 (d, J=9.6 Hz, 1H), 4.96 (d, J=9.6 Hz, 1H), 4.79 (m, 1H), 4.57 (m, 1H), 4.00-4.50 (m, 9H), 3.81 (m, 1H), 3.25 (m, 4H), 2.56 (m, 1H), 2.47 (m, 1H), 2.38 (s, 3H), 2.30-2.37 (m, 6H), 2.23 (s, 3H), 1.82 (m, 2H), 1.79 (m, 4H), 1.68 (s, 3H), 1.57 (m, 7H), 1.23-1.46 (m, 6H), 1.22 (s, 3H), 1.21 (t, J=7.2 Hz, 3H), 1.15 (s, 3H); ESI-MS (m/z): calcd for C.sub.65H.sub.EN.sub.6O.sub.20 [M+H].sup.+: 1265.6; found: 1265.7.

Part 2. Preparation of Functionalized Polysaccharides

Synthetic Scheme 12

[0460] ##STR00150##

Sample 81: Preparation of Compound 81

[0461] In a 250 mL round bottom flask, 5.46 g (65.12 mmol) of sodium bicarbonate and 105 mg (0.66 mmol) of copper sulfate were dissolved in 90 mL of water-methanol (2:1), followed by addition of 8.0 g (32.56 mmol) N.sub.6-Boc-L-lysine and stirred for 20 min. To the above solution 6.85 g (39.07 mmol) of trifluoromethanesulfonic azide in THF was dropwise added and stirred at room temperature overnight. Upon completion of the reaction, the reaction mixture was concentrated, acidified with hydrochloride solution (2.0N) to pH=1.0, and extracted with ethyl acetate three times (50 mL×3); the organic phases were combined together, dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with acetone in chloroform (5-30%) to provide 4.97 g of compound 81. Yield: 56%.

[0462] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 3.92 (m, 1H), 3.12 (t, J=7.2 Hz, 2H), 1.87 (m, 2H), 1.81 (m, 2H), 1.55 (m, 2H), 1.45 (s, 9H); ESI-MS (m/z): calcd for C.sub.11H.sub.21N.sub.4O.sub.4 [M+H].sup.+: 273.1; found: 273.1.

Sample 82: Preparation of Compound 82

[0463] To a 250 mL round-bottom flask charged with 4.0 g (14.71 mmol) of compound 81 and 4.20 g (22.04 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), 50 mL of anhydrous dichloromethane was added, and stirred at room temperature for 30 min; and then 3.0 mL of absolute ethanol and 2.69 g (22.04 mmol) of DMAP were added. The reaction was continuously stirred overnight. Upon completion of the reaction, the reaction mixture was washed with brine (50 mL×2), dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with ethyl acetate in petroleum (5-60%) to provide 3.67 g of compound 82. Yield: 83%.

[0464] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 4.24 (q, J=7.2 Hz, 2H), 3.81 (m, 1H), 3.11 (t, J=7.2 Hz, 2H), 1.83 (m, 2H), 1.77 (m, 2H), 1.52 (m, 2H), 1.46 (m, 2H), 1.46 (s, 9H), 1.31 (t, J=7.2 Hz, 3H); ESI-MS (m/z): calcd for C.sub.13H.sub.25N.sub.4O.sub.4 [M+H].sup.+: 301.2; found: 301.2.

Sample 83: Preparation of Compound 83

[0465] In a 250 mL round-bottom flask, 4.5 g (14.98 mmol) of compound 82 was dissolved in 50 mL of hydrochloride ethanol solution (4.0N), and stirred overnight. The reaction mixture was concentrated, and purified on a reverse phase C-18 column and eluted with acetonitrile in water (10-70%) to provide 3.35 g of compounds 83. Yield: 95%.

[0466] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 4.27 (q, J=7.2 Hz, 2H), 3.92 (m, 1H), 3.02 (s, 3H), 1.85 (m, 4H), 1.52 (m, 2H), 1.27 (t, J=7.2 Hz, 3H); ESI-MS (m/z): calcd for C.sub.8H.sub.17N.sub.4O.sub.2 [M+H].sup.+: 201.1; found: 201.1.

Sample 84: Preparation of Compound 84

[0467] In a 250 mL round bottom flask, 2.5 g (8.23 mmol) of diphosgene was dissolved in 60.0 mL of dichloromethane and cooled to 0° C., followed by addition of 60 mL of saturated sodium carbonate solution and 2.0 g (8.23 mmol) of compound 83 in dichloromethane and stirred for 3 h. Upon completion of the reaction, the organic phase was separated, dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with ethyl acetate in petroleum (5-60%) to provide 1.07 g of compound 84. Yield: 85%.

[0468] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 4.27 (q, J=7.2 Hz, 2H), 3.91 (m, 1H), 3.35 (t, J=7.2 Hz, 2H), 1.85 (m, 2H), 1.65 (m, 2H), 1.52 (m, 2H), 1.31 (t, J=7.2 Hz, 3H); ESI-MS (m/z): calcd for C.sub.9H.sub.15N.sub.4O.sub.3 [M+H].sup.+: 227.1; found: 227.1.

Sample 85: Preparation of Functionalized Dextran 85

[0469] In a 100 mL round bottom flask, 20.0 mL of anhydrous DMSO was added and heated to 60° C., followed by addition of 2.0 g of dextran (average molecular weight 100,000) and stirred until completely dissolved. After the solution was cooled down to 38° C., 200 mg (0.88 mmol) of compound 84 and 107 mg (0.88 mmol) of 4-dimethylaminopyridine (DMAP) were added and stirred for 12 hours. Upon completion of the reaction, the reaction mixture was precipitated in methanol, dialyzed against distilled water, and lyophilized to provide 1.52 g of functionalized dextran 85. Yield: 76%.

[0470] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH); minor signals: 1.50-1.90 (m, CH2), 1.23 (t, CH.sub.3).

Sample 86: Preparation of Functionalized Dextran 86

[0471] In a 100 mL round bottom flask, 20.0 mL of anhydrous DMSO was added and heated to 60° C., followed by addition of 2.0 g of hydroxyethyl starch (average molecular weight 100,000) and stirred until completely dissolved. After the solution was cooled down to 38° C., 200 mg (0.88 mmol) of compound 84 and 107 mg (0.88 mmol) of 4-dimethylaminopyridine (DMAP) were added and stirred for 12 hours, Upon completion of the reaction, the reaction mixture was precipitated in methanol, dialyzed against distilled water, and lyophilized to provide 1.41 g of functionalized dextran 86. Yield: 70%.

[0472] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.20 (m, CHOH, CH.sub.2OH, CH.sub.2O); minor signals: 1.50-1.90 (m, CH.sub.2), 1.24 (t, CH.sub.3).

Synthetic Scheme 13

[0473] ##STR00151##

Sample 87: Preparation of Compound 87

[0474] In a 500 mL round bottom flask, 8.20 g (97.56 mmol) of sodium bicarbonate and 156 mg (0.98 mmol) of copper sulfate were dissolved in 300 mL of water-methanol (2:1), followed by addition of 12.0 g (48.78 mmol) of Boc-L-lysine and stirred for 30 min. To the above solution 10.3 g (58.53 mmol) of trifluoromethanesulfonic azide in THF was dropwise added and stirred at room temperature overnight. Upon completion of the reaction, the reaction mixture was concentrated, acidified with hydrochloride solution (2.0N) to pH=1.0, and extracted with ethyl acetate three times (100 mL×3); the organic phases were combined together, dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with acetone in chloroform (5-30%) to provide 5.18 g of compound 87. Yield: 39%.

[0475] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 5.07 (d, J=6.0 Hz, 1H), 4.32 (m, 1H), 3.28 (t, J=7.2 Hz, 2H), 1.87 (m, 1H), 1.72 (m, 1H), 1.61 (m, 3H), 1.47 (m, 1H), 1.44 (s, 9H); ESI-MS (m/z): calcd for C.sub.11H.sub.21N.sub.4O.sub.4 [M+H].sup.+: 273.1; found: 273.1.

Sample 88: Preparation of Compound 88

[0476] A 250 mL round-bottom flask charged with 5.0 g (18.38 mmol) of compound 87 and 5.27 g (27.57 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), 50 mL of anhydrous dichloromethane was added, and stirred at room temperature for 30 min; and then 3.0 mL of absolute ethanol and 3.36 g (27.57 mmol) of DMAP were added. The reaction was continuously stirred overnight. Upon completion of reaction, the reaction mixture was washed with brine (50 mL×2), dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with ethyl acetate in petroleum (5-60%) to provide 3.79 g of compound 88. Yield: 76%.

[0477] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 5.05 (d, J=6.0 Hz, 1H), 4.28 (m, 1H), 4.19 (q, J=7.2 Hz, 2H), 3.26 (t, J=7.2 Hz, 2H), 1.82 (m, 1H), 1.75 (m, 1H), 1.61 (m, 3H), 1.47 (m, 1H), 1.45 (s, 9H), 1.23 (t, J=7.2 Hz, 3H); ESI-MS (m/z): calcd for C.sub.13H.sub.25N.sub.4O.sub.4 [M+H].sup.+: 301.2; found: 301.2.

Sample 89: Preparation of Compound 89

[0478] In a 250 mL round-bottom flask, 3.5 g (11.65 mmol) of compound 88 was dissolved in 30 mL of hydrochloride ethanol solution (4.0N), and stirred overnight. The reaction mixture was concentrated, and purified on a reverse phase C-18 column and eluted with acetonitrile in water (10-70%) to provide 2.61 g of compounds 89. Yield: 95%.

[0479] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 4.26 (q, J=7.2 Hz, 2H), 3.98 (s, 1H), 3.27 (t, J=7.2 Hz, 2H), 1.95 (m, 2H), 1.63 (m, 2H), 1.52 (m, 2H), 1.27 (t, J=7.2 Hz, 3H); ESI-MS (m/z): calcd for C.sub.8H.sub.17N.sub.4O.sub.2 [M+H].sup.+: 201.1; found: 201.1.

Sample 90: Preparation of Compound 90

[0480] In a 250 mL round bottom flask, 3.13 g (10.56 mmol) of diphosgene was dissolved in 60.0 mL of dichloromethane and cooled to 0° C., followed by addition of 60 mL of saturated sodium carbonate solution and 2.50 g (10.56 mmol) of compound 89 in dichloromethane and stirred for 3 h. Upon completion of reaction, the organic phase was separated, dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with ethyl acetate in petroleum (5-60%) to provide 1.72 g of compound 90. Yield: 72%.

[0481] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 4.27 (q, J=7.2H), 4.02 (m, 1H), 3.29 (t, J=7.2 Hz), 1.85 (m, 2H), 1.62 (m, 2H), 1.51 (m, 2H), 1.25 (t, J=7.2 Hz, 3H); ESI-MS (m/z): calcd for C.sub.9H.sub.15N.sub.4O.sub.3 [M+H].sup.+: 227.1; found: 227.1.

Sample 91: Preparation of Functionalized Dextran 91

[0482] In a 500 mL round bottom flask, 200 mL of anhydrous DMSO was added and heated to 60° C., followed by addition of 20.0 g of dextran (average molecular weight ˜150,000) and stirred until completely dissolved. After the solution was cooled down to 38° C., 1.0 g (4.42 mmol) of compound 90 and 539 mg (0.88 mmol) of 4-dimethylaminopyridine (DMPP) were added and stirred for 12 hours. Upon completion of the reaction, the reaction mixture was precipitated in methanol, dialyzed against distilled water, and lyophilized to provide 16.3 g of functionalized dextran 91. Yield: 81%.

[0483] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH); minor signals: 1.50-1.90 (m, CH2), 1.24 (t, CH.sub.3).

Sample 92: Preparation of Functionalized Hydroxyethyl Starch 92

[0484] In a 100 mL round bottom flask, 20 mL of anhydrous DMSO was added and heated to 60° C., followed by addition of 2.0 g of hydroxyethyl starch (average molecular weight ˜60,000) and stirred until completely dissolved. After the solution was cooled down to 38° C., 200 mg (0.88 mmol) of compound 90 and 107 mg (0.88 mmol) of 4-dimethylaminopyridine (DMAP) were added and stirred for 12 hours. Upon completion of the reaction, the reaction mixture was precipitated in methanol, dialyzed against distilled water, and lyophilized to provide 1.06 g of functionalized hydroxyethyl starch 92. Yield: 51%.

[0485] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.20 (m, CHOH, CH.sub.2OH, CH.sub.2O); minor signals: 1.50-1.90 (m, CH.sub.2), 1.23 (t, CH.sub.3).

Synthetic Scheme 14

[0486] ##STR00152##

Sample 93: Preparation of Compound 93

[0487] In a 250 mL round bottom flask, 12.0 g (48.78 mmol) of compound Boc-L-lysine and 8.20 g (97.56 mmol) of sodium bicarbonate were dissolved in 200.0 mL of methanol-water (2:1), followed by addition of 13.6 g (53.46 mmol) of 6-azido-n-hexanoic acid-(N-hydroxysuccinyl lactam) ester and stirred overnight. Upon completion of the reaction, the reaction mixture was neutralized with 2.0N HCl to pH=1.0, extracted with ethyl acetate (100 mL×3); the organic phases were combined, dried over MgSO.sub.4, concentrated, and purified on a reverse phase C-18 column and eluted with acetonitrile in water (10-80%) to provide 11.9 g of compound 93. Yield: 63%.

[0488] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 6.69 (s, 1H), 5.28 (s, 1H), 4.28 (m, 1H), 3.28 (m, 4H), 2.23 (t, J=7.2 Hz, 2H), 1.81 (m, 1H), 1.69 (m, 2H), 1.63 (m, 3H), 1.53 (m, 2H), 1.42 (s, 9H), 1.38 (m, 4H); ESI-MS (m/z): calcd for C.sub.17H.sub.32N.sub.5O.sub.5 [M+H].sup.+: 386.2; found: 386.2.

Sample 94: Preparation of Compound 94

[0489] To a 250 mL round-bottom flask charged with 10.0 g (25.95 mmol) of compound 93 and 7.43 g (38.93 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), 100 mL of anhydrous dichloromethane was added and stirred at room temperature for 30 min; and then 5.0 mL of absolute ethanol and 4.75 g (38.93 mmol) of DMAP were added. The reaction was continuously stirred overnight. Upon completion of the reaction, the reaction mixture was washed with brine (80 mL×2), dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with ethyl acetate in petroleum ether (10-70%) to provide 3.79 g of compound 94. Yield: 75%.

[0490] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 5.19 (s, 1H), 4.25 (q, J=7.2 Hz, 2H), 4.15 (m, 1H), 3.23 (m, 4H), 2.17 (t, J=7.2 Hz, 2H), 1.81 (m, 1H), 1.69 (m, 2H), 1.63 (m, 3H), 1.53 (m, 2H), 1.42 (s, 9H), 1.38 (m, 4H), 1.23 (t, J=7.2 Hz, 3H); ESI-MS (m/z): calcd for C.sub.19H.sub.36N.sub.5O.sub.5 [M+H].sup.+: 414.2; found: 414.3.

Sample 95: Preparation of Compound 95

[0491] To a 250 mL round-bottom flask charged with 7.0 g (16.93 mmol) of compound 94, 50 mL of hydrochloride ethanol solution (4.0N) was added and stirred at room temperature overnight. After removal of volatiles, the residue was purified on a reverse phase C-18 column and eluted with acetonitrile in water (10-70%) to provide 5.46 g of compound 95. Yield: 92%.

[0492] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 7.16 (s, 1H), 4.24 (q, J=7.2 Hz, 2H), 3.97 (m, 1H), 3.24 (m, 4H), 2.25 (t, J=7.2 Hz, 2H), 1.98 (m, 2H), 1.56 (m, 6H), 1.48 (m, 2H), 1.36 (m, 2 h), 1.26 (t, J=7.2 Hz, 3H); ESI-MS (m/z): calcd for C.sub.14H.sub.28N.sub.5O.sub.3 [M+H].sup.+: 314.2; found: 314.2.

Sample 96: Preparation of Compound 96

[0493] In a 250 mL round bottom flask, 2.54 g (8.57 mmol) of diphosgene was dissolved in 50.0 mL of dichloromethane and cooled to 0° C., followed by addition of 50 mL of saturated sodium carbonate solution and 3.0 g (8.57 mmol) of compound 89 in dichloromethane and stirred for 3 h. Upon completion of the reaction, the organic phase was separated, dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with ethyl acetate in petroleum (5-60%) to provide 1.89 g of compound 96. Yield: 65%.

[0494] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 7.13 (s, 1H), 4.29 (q, J=7.2 Hz, 2H), 4.11 (m, 1H), 3.27 (m, 4H), 2.25 (t, J=7.2 Hz, 2H), 1.87 (m, 2H), 1.63 (m, 2H), 1.56 (m, 4H), 1.46 (m, 2H), 1.35 (m, 2 h), 1.28 (t, J=7.2 Hz, 3H); ESI-MS (m/z): calcd for C.sub.15H.sub.26N.sub.5O.sub.4 [M+H].sup.+: 340.2; found: 340.2.

Sample 97: Preparation of Compound 97

[0495] In a 100 mL round bottom flask, 20 mL of anhydrous DMSO was added and heated to 60° C., followed by addition of 2.0 g of dextran (average molecular weight ˜150,000) and stirred until completely dissolved. After the solution was cooled down to 38° C., 250 mg (0.73 mmol) of compound 96 and 89 mg. (0.73 mmol) of 4-dimethylaminopyridine (DMAP) were added and stirred for 12 hours. Upon completion of the reaction, the reaction mixture was precipitated in methanol, dialyzed against distilled water, and lyophilized to provide 1.72 g of functionalized dextran 97. Yield: 86%.

[0496] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH); minor signals: 1.35-1.90 (m, CH.sub.2), 1.23 (t, CH.sub.3).

Sample 98: Preparation of Functionalized Polysaccharide 98

[0497] In a 500 mL round bottom flask, 5.0 mL of anhydrous DMSO was added and heated to 60° C., followed by addition of 500 mg of Ganoderma lucidun polysaccharide (average molecular weight ˜50.000) and stirred until completely dissolved. After the solution was cooled down to 38° C., 100 mg (0.29 mmol) of compound 96 and 35 mg (0.29 mmol) of 4-dimethylaminopyridine (DMAP) were added and stirred for 12 hours, Upon completion of the reaction, the reaction mixture was precipitated in methanol, dialyzed against distilled water, and lyophilized to provide 436 mg of functionalized polysaccharide 98. Yield: 87%.

[0498] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH); minor signals: 1.35-1.90 (m, CH.sub.2), 1.25 (t, CH.sub.3).

Sample 99: Preparation of Functionalized Hydroxyethyl Starch 99

[0499] In a 100 mL round bottom flask, 20 mL of anhydrous DMSO was added and heated to 60° C., followed by addition of 2.0 g of hydroxyethyl starch (average molecular weight ˜5,000) and stirred until completely dissolved. After the solution was cooled down to 38° C., 260 mg (0.76 mmol) of compound 96 and 93 mg (0.76 mmol) of 4-dimethylaminopyridine (DMAP) were added and stirred for 12 hours. Upon completion of the reaction, the reaction mixture was precipitated in methanol, dialyzed against distilled water, and lyophilized to provide 1.86 g of functionalized hydroxyethyl starch 99. Yield: 93%.

[0500] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.20 (m, CHOH, CH.sub.2OH, CH.sub.2O); minor signals: 1.35-1.90 (m, CH.sub.2), 1.24 (t, CH.sub.3).

Synthetic Scheme 15

[0501] ##STR00153##

Sample 100: Preparation of Compound 100

[0502] In a 250 mL round bottom flask, 2.54 g (8.57 mmol) of diphosgene was dissolved in 50.0 mL of dichloromethane and cooled to 0° C., followed by addition of 50 mL of saturated sodium carbonate solution and 3.0 g (8.57 mmol) of compound 79 in dichloromethane and stirred for 6 h. Upon completion of the reaction, the organic phase was separated, dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with ethyl acetate in petroleum (5-60%) to provide 1.83 g of compound 100. Yield: 63%.

[0503] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 6.22 (s, 1H), 4.56 (m, 1H), 4.21 (q, J=7.2 Hz, 2H), 3.25-3.40 (m, 4H), 2.25 (t, J=7.2 Hz, 2H), 1.82 (m, 2H), 1.52-1.75 (m, 6H), 1.45 (m, 2H), 1.26-1.44 (m, 4H), 1.25 (t, J=7.2 Hz, 3H); ESI-MS: calcd for C.sub.15H.sub.26N.sub.5O.sub.4 [M+H].sup.+: 340.2; found: 340.2.

Sample 101: Preparation of Functionalized Dextran 101

[0504] In a 100 mL round bottom flask. 20.0 mL of anhydrous DMSO was added and heated to 60° C. followed by addition of 3.0 g of dextran (average molecular weight ˜200,000) and stirred until completely dissolved, After the solution was cooled down to 38° C., 270 mg (0.76 mmol) of compound 100 and 93 mg (0.76 mmol) of 4-dimethylaminopyridine (DMAP) were added and stirred for 12 hours. Upon completion of the reaction, the reaction mixture was precipitated in methanol, dialyzed against distilled water, and lyophilized to provide 2.75 g of functionalized dextran 101. Yield: 92%.

[0505] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH); minor signals: 1.35-1.90 (m, CH.sub.2), 1.23 (t, CH.sub.3).

Synthetic Scheme 16

[0506] ##STR00154##

Sample 102: Preparation of Compound 102

[0507] In a 250 mL round bottom flask, 1.65 g (5.53 mmol) of diphosgene was dissolved in 30.0 mL of dichloromethane and cooled to 0° C., followed by addition of 30 mL of saturated sodium carbonate solution and 2.5 g (5.53 mmol) of compound 31 in dichloromethane and stirred for 6 h. Upon completion of the reaction, the organic phase was separated, dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with ethyl acetate in petroleum (5-50%) to provide 1.76 g of compound 102. Yield: 72%.

[0508] .sup.1H NMR (500 MHz, CDCl.sub.3, ppm): δ 7.10-7.35 (m, 5H), 4.71 (m, 1H), 4.46 (m, 1H), 4.15 (q, J=7.2 Hz, 2H), 3.25 (t, J=7.2 Hz, 2H), 3.11 (m, 1H), 2.98 (m, 1H), 2.31 (t, J=7.2 Hz, 2H), 2.05 (m, 2H), 1.96 (t, J=3.0 Hz, 1H), 1.81 (m, 2H), 1.50-1.70 (m, 6H), 1.35 (m, 2H), 1.25 (t, J=7.2 Hz, 3H); ESI-MS: calcd for C.sub.24H.sub.32N.sub.3O.sub.5 [M+H].sup.+: 442.2; found: 442.3.

Sample 103: Preparation of Compound 103

[0509] In a 100 mL round bottom flask, 20.0 mL of anhydrous DMSO was added and heated to 60° C., followed by addition of 3.0 g of dextran (average molecular weight 150,000) and stirred until completely dissolved. After the solution was cooled down to 38° C., 270 mg (0.76 mmol) of compound 102 and 93 mg (0.76 mmol) of 4-dimethylaminopyridine (DMAP) were added and stirred for 12 hours. Upon completion of the reaction, the reaction mixture was precipitated in methanol, dialyzed against distilled water, and lyophilized to provide 2.75 g of functionalized dextran 103. Yield: 92%.

[0510] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH); minor signals: 7.10-8.50 (m, CONH, ArH), 1.23 (t, CH.sub.3).

Synthetic Scheme 17

[0511] ##STR00155## ##STR00156##

Sample 104: preparation of compound 104

[0512] To a 250 mL round-bottom flask charged with 8.99 g (57.31 mmol) of 6-azidohexanoic acid, 11.0 g (57.31 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), and 7.75 g (57.31 mmol) of 1-hydroxybenzotriazole (HOBt), 50.0 mL of dry DMF was added and stirred for 30 min, followed by addition of 10.0 g (47.79 mmol) of L-tyrosine methyl ester and 13.0 mL (95.60 mmol) of triethylamine and stirred at room temperature for another 5 h. Upon completion of the reaction, the reaction mixture was partitioned between ethyl acetate (200 mL) and brine (200 mL), the organic phase was further washed with brine twice (100 mL×2), dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with ethyl acetate in petroleum ether (20-80%) to provide 15.92 g of compound 104. Yield: 95%.

[0513] .sup.1H NMR (500 MHz, CDCl.sub.3, ppm): δ 6.95 (d, J=7.0 Hz, 2H), 6.71 (d, J=7.0 Hz, 2H), 6.05 (d, J=7.0 Hz, 2H), 4.86 (m, 1H), 4.21 (q, J=7.2 Hz, 2H), 3.24 (t, J=7.2 Hz, 2H), 3.05 (m, 1H), 2.99 (m, 1H), 2.19 (t, J=7.2 Hz, 2H), 1.53 (m, 4H), 1.34 (m, 2H), 1.25 (t, J=7.2 Hz, 2H); ESI-MS: calcd for C.sub.17H.sub.25N.sub.4O.sub.4 [M+H].sup.+: 349.2; found: 349.2.

Sample 105: Preparation of Compound 105

[0514] In a 250 mL round bottom flask, 7.0 g (30.17 mmol) of Boc-2-bromoethylamine and 6.76 g (20.11 mmol) of compound 104 were dissolved in 30.0 mL of anhydrous dimethylformamide, followed by addition of 9.83 g (30.17 mmol) of cesium carbonate, heated at 50° C. overnight. Upon completion of the reaction, the reaction mixture was partitioned between ethyl acetate (150 mL) and brine (150 mL); the organic phase was further washed with brine (60 mL×2), dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with ethyl acetate in petroleum ether (10-70%) to give 7.61 g of compound 105. Yield: 77%.

[0515] .sup.1H NMR (500 MHz, CDCl.sub.3, ppm): δ 7.01 (d, J=7.0 Hz, 2H), 6.79 (d, J=7.0 Hz, 2H), 5.89 (d, J=7.0 Hz, 2H), 4.81 (m, 1H), 4.19 (q, J=7.2 Hz, 2H), 3.97 (t, J=7.2 Hz, 2H), 3.50 (t, J=7.2 Hz, 2H), 3.23 (t, J=7.2 Hz, 2H), 3.02 (m, 1H), 2.99 (m, 1H), 2.17 (t, J=7.2 Hz, 2H), 1.62 (m, 4H), 1.45 (s, 9H), 1.36 (m, 2H), 1.24 (t, J=7.2 Hz, 2H); ESI-MS: calcd for C.sub.24H.sub.38N.sub.5O.sub.6 [M+H].sup.+: 492.3; found: 492.3.

Sample 106: Preparation of Compound 106

[0516] To a 200 mL round-bottom flask charged with 7.0 g (16.93 mmol) of compound 105, 50 mL of hydrochloride ethanol solution (4.0N) was added and stirred at room temperature overnight. After removal of volatiles, the residue was purified on a reverse phase C-18 column and eluted with acetonitrile in water (10-70%) to provide 5.85 g of compound 106. Yield: 96%.

[0517] .sup.1H NMR (500 MHz, CDCl.sub.3, ppm): δ 6.99 (d, J=7.0 Hz, 2H), 6.72 (d, J=7.0 Hz, 2H), 5.92 (d, J=7.0 Hz, 2H), 4.82 (m, 1H), 4.19 (q, J=7.2 Hz, 2H), 3.94 (t, J=7.2 Hz, 2H), 3.23 (t, J=7.2 Hz, 2H), 2.99-3.06 (m, 4H), 2.18 (t, J=7.2 Hz, 2H), 1.63 (m, 4H), 1.34 (m, 2H), 1.23 (t, J=7.2 Hz, 2H); ESI-MS: calcd for C.sub.19H.sub.30N.sub.5O.sub.4 [M+H].sup.+: 392.2; found: 392.3.

Sample 107: Preparation of Compound 107

[0518] In a 250 mL round bottom flask, 3.50 g (5.53 mmol) of diphosgene was dissolved in 30.0 mL of dichloromethane and cooled to 0° C., followed by addition of 50 mL of saturated sodium carbonate solution and 5.0 g (11.68 mmol) of compound 106 in dichloromethane and stirred for 5 h. Upon completion of the reaction, the organic phase was separated, dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with ethyl acetate in chloroform (5-70%) to provide 3.31 g of compound 107. Yield: 68%.

[0519] .sup.1H NMR (500 MHz, CDCl.sub.3, ppm): δ 7.01 (d, J=7.0 Hz, 2H), 6.82 (d, J=7.0 Hz, 2H), 5.92 (d, J=7.0 Hz, 2H), 4.81 (m, 1H), 4.16 (q, J=7.2 Hz, 2H), 4.07 (t, J=7.2 Hz, 2H), 3.62 (t, J=7.2 Hz, 2H), 3.04 (m, 1H), 2.99 (m, 1H), 2.18 (t, J=7.2 Hz, 2H), 1.63 (m, 4H), 1.35 (m, 2H), 1.26 (t, J=7.2 Hz, 2H); ESI-MS: calcd for C.sub.20H.sub.28N.sub.5O.sub.5 [M+H].sup.+: 418.2; found: 418.3.

Sample 108: Preparation of Functionalized Dextran 108

[0520] In a 100 mL round bottom flask, 20 mL of anhydrous DMSO was added and heated to 60° C., followed by addition of 3.0 g of dextran (average molecular weight ˜150,000) and stirred until completely dissolved. After the solution was cooled down to 38° C., 300 mg (0.72 mmol) of compound 107 and 87 mg (0.72 mmol) of 4-dimethylaminopyridine (DMPP) were added and stirred for 12 hours. Upon completion of the reaction, the reaction mixture was precipitated in methanol, dialyzed against distilled water, and lyophilized to provide 2.51 g of functionalized dextran 108, Yield: 83%.

[0521] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH); minor signals: 6.75-7.20 (m, ArH), 1.23 (t, CH.sub.3).

Sample 109: Preparation of Functionalized Dextran 109

[0522] To a 250 mL round-bottom flask charged with 500 mg of hyaluronic acid (average molecular weight ˜10,000), 10.0 mL of anhydrous DMSO was added and heated at 60° C. completely dissolved, and then cooled down to room temperature. To the above solution, 35 mg (0.18 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), and 25 mg (0.18 mmol) of 1-hydroxybenzotriazole (HOBt), and 50 mg (0.12 mmol) of compound 106 were added and stirred at room temperature for 2 days. Upon completion of the reaction, the reaction mixture was precipitated in methanol, dialyzed against distilled water, and lyophilized to provide 312 mg of functionalized dextran 109. Yield: 62%.

[0523] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH); minor signals: 6.75-7.20 (m, ArH), 2.05 (s, CH.sub.3CO), 1.23 (t, CH.sub.3).

Synthetic Scheme 18

[0524] ##STR00157##

Sample 110: Preparation of Compound 110

[0525] In a well ventilation hood, 60.0 g (202.13 mmol) of diphosgene was dissolved in 300 mL of dichloromethane in a 1000 mL round bottom flask and cooled to 0° C., followed by addition of 300 mL of saturated sodium carbonate solution and 36.0 g (202.13 mmol) of 6-azido-hexylamine hydrochloride in dichloromethane and stirred for 3 h. Upon completion of the reaction, the organic phase was separated, dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified by fractional distillation to provide 10.5 g of compound 110. Yield: 31%.

[0526] .sup.1H NMR (500 MHz, CDCl.sub.3, ppm): δ 3.20-3.45 (m, 4H), 1.35-1.85 (m, 8H); ESI-MS: calcd for C.sub.7H.sub.12N.sub.4O [M+H].sup.+: 168.1; found: 168.1.

Sample 111: Preparation of Functionalized Dextran 111

[0527] In a 100 mL round bottom flask, 20.0 mL of anhydrous DMSO was added and heated to 60° C., followed by addition of 3.0 g of dextran (average molecular weight ˜100,000) and stirred until completely dissolved. After the solution was cooled down to 38° C., 600 mg (3.57 mmol) of compound 110 and 436 mg (3.57 mmol) of 4-dimethylaminopyridine (DMAP) were added and stirred for 12 hours. Upon completion of the reaction, the reaction mixture was precipitated in methanol, dialyzed against distilled water, and lyophilized to provide 2.89 g of functionalized dextran 111, Yield: 96%.

[0528] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH); minor signals: 1.35-1.90 (m, CH.sub.2).

Synthetic Scheme 19

[0529] ##STR00158##

Sample 112: Preparation of Compound 112

[0530] In a 250 mL round bottom flask, 4.95 g (16.68 mmol) of diphosgene was dissolved in 50.0 mL of dichloromethane and cooled to 0° C., followed by addition of 70 mL of saturated sodium carbonate solution and 6.0 g (16.68 mmol) of azido-tetra-ethylene glycol amine in dichloromethane and stirred for 5 h. Upon completion of the reaction, the organic phase was separated, dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with acetone in chloroform (10-70%) to provide 3.16 g of compound 112. Yield: 57%.

[0531] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 3.61 (m, 20H), 3.31 (m, 4H); ESI-MS: calcd for C.sub.13H.sub.25N.sub.4O.sub.6 [M+H].sup.+: 333.1; found: 333.1.

Sample 113: Preparation of Functionalized Hydroxyethyl Starch 113

[0532] In a 100 mL round bottom flask, 20 mL of anhydrous DMSO was added and heated to 60° C., followed by addition of 2.0 g of hydroxyethyl starch (average molecular weight ˜5,000) and stirred until completely dissolved. After the solution was cooled down to 38° C., 600 mg (1.81 mmol) of compound 112 and 220 mg (1.81 mmol) of 4-dimethylaminopyridine (DMAP) were added and stirred for 24 hours. Upon completion of the reaction, the reaction mixture was precipitated in methanol, dialyzed against distilled water, and lyophilized to provide 1.32 g of functionalized hydroxyethyl starch 113. Yield: 66%.

[0533] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.20-4.20 (m, CHOH, CH.sub.2OH, CH.sub.2O, CH.sub.2N).

Synthetic Scheme 20

[0534] ##STR00159##

Sample 114: Preparation of Compound 114

[0535] In a 25 mL, round bottom flask, 20.0 g (94.7 mmol) of 6-(N-maleimide) hexanoic acid was suspended in 78 mL (284.1 mmol) of sulfonyl chloride and heated at 50° C. for 3 hours. After removal of volatiles, the residue was dissolved in 250 mil, of chloroform and cooled to 0° C., then 12.3 g (189.4 mmol) sodium azide in water (200 mL) and 2.16 g (9.46 mmol) of phenyltrimethylammonium fluoride were added and stirred for 2 hours. The organic phase was washed with 5% sodium bicarbonate (250 mL×2), dried over anhydrous MgSO.sub.4 and filtered, and the filtrate was refluxed until there were no bubbles, and the solvent was evaporated, and the residue was purified by fractional distillation under vacuum to provide 7.92 g of compound 114. Yield: 41%.

[0536] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 6.73 (s, 2H), 3.53 (t, J=7.0 Hz, 2H), 3.31 (t, J=7.0 Hz, 2H), 1.50-1.70 (m, 4H), 1.30-1.45 (m, 2H); ESI-MS: calcd for C.sub.10H.sub.13N.sub.2O.sub.3 [M+H].sup.+: 209.1; found: 209.1.

Sample 115: Preparation of Functionalized Dextran 115

[0537] In a 100 mL round bottom flask, 20.0 mL of anhydrous DMSO was added and heated to 60° C., followed by addition of 3.0 g of dextran (average molecular weight 150,000) and stirred until completely dissolved. After the solution was cooled down to room temperature, 210 mg (1.0 mmol) of compound 114 and 122 mg (1.0 mmol) of 4-dimethylaminopyridine (DMAP) were added and stirred for 36 hours. Upon completion of the reaction, the reaction mixture was precipitated in methanol, dialyzed against distilled water, and lyophilized to provide 2.11 g of functionalized dextran 115. Yield: 70%.

[0538] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH); minor signals: 7.05 (s, CH), 1.30-1.70 (m, CH.sub.2).

Sample 116: Preparation of Functionalized Dextran 116

[0539] In a 100 mL round bottom flask, 20.0 mL of anhydrous DMSO was added and heated to 60° C., followed by addition of 3.0 g of dextran (average molecular weight ˜150,000) and stirred until completely dissolved. After the solution was cooled down to room temperature, 100 mg (0.48 mmol) of compound 114, 211 mg (0.48 mmol) of compound 102, and 117 mg (1.0 mmol) of 4-dimethylaminopyridine (DMAP) were added and stirred for 36 hours. Upon completion of the reaction, the reaction mixture was precipitated in methanol, dialyzed against distilled water, and lyophilized to provide 2.32 g of functionalized dextran 116. Yield: 77%.

[0540] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH); minor signals: 7.00-8.50 (m, CONH, ArH, CH), 1.23 (t, CH.sub.3).

Synthetic Scheme 21

[0541] ##STR00160##

Sample 117: Preparation of Compound 117

[0542] In a 250 mL round bottom flask, 2.67 g (8.98 mmol) of diphosgene was dissolved in 30.0 mL of dichloromethane and cooled to 0° C., followed by addition of 30 mL of saturated sodium carbonate solution and 2.0 g (8.98 mmol) of 2-(pyridyldithio)ethyl amine hydrochloride in dichloromethane and stirred for 5 h. Upon completion of the reaction, the organic phase was separated, dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with ethyl acetate in chloroform (5-60%) to provide 1.39 g of compound 117. Yield: 73%.

[0543] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 8.52 (m, 1H), 7.68 (m, 2H), 7.15 (m, 1H), 3.60 (t, J=7.0 Hz, 2H), 2.97 (t, J=7.0 Hz, 2H); ESI-MS: calcd for C.sub.10H.sub.13N.sub.2O.sub.3 [M+H].sup.+: 213.0; found: 213.0.

Sample 118: Preparation of Functionalized Dextran 118

[0544] In a 100 mL round bottom flask, 20.0 mL of anhydrous DMSO was added and heated to 60° C. followed by addition of 2.0 g of dextran (average molecular weight ˜50,000) and stirred until completely dissolved. After the solution was cooled down to room temperature, 160 mg (0.75 mmol) of compound 117 and 92 mg (0.72 mmol) of 4-dimethylaminopyridine (DMAP) were added and stirred for 36 hours, Upon completion of the reaction, the reaction mixture was precipitated in methanol, dialyzed against distilled water, and lyophilized to provide 1.32 g of functionalized dextran 118. Yield: 66%.

[0545] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH); minor signals: 7.20-8.50 (m, ArH).

Synthetic Scheme 22

[0546] ##STR00161##

Sample 119: Preparation of Compound 119

[0547] In a 100 mL round bottom flask, 250 mg (0.842 mmol) of diphosgene was dissolved in 10.0 mL of dichloromethane and cooled to 0° C., followed by addition of 10 mL of saturated sodium carbonate solution and 200 mg (0.842 mmol) of 3-(4-aminophenyl)-4-methyl-1,2,4,5-tetrazole hydrochloride in dichloromethane and stirred for 3 h. Upon completion of the reaction, the organic phase was separated, dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with ethyl acetate in petroleum ether (5-60%) to provide 151 mg of compound 119. Yield: 79%.

[0548] .sup.1H NMR (500 MHz, CDCl.sub.3, ppm): δ 8.60 (d, J=7.0 Hz, 2H), 7.51 (d, J=7.0 Hz, 2H), 4.65 (s, 2H), 3.10 (s, 3H); ESI-MS: calcd for C.sub.11H.sub.10N.sub.5O [M+H].sup.+: 228.1; found: 228.1.

Sample 120: Preparation of Compound 120

[0549] In a 50 mL round bottom flask. 6.0 mL of anhydrous DMSO was added and heated to 60° C., followed by addition of 1.0 g of dextran (average molecular weight ˜100,000) and stirred until completely dissolved. After the solution was cooled down to room temperature, 80 mg (0.35 mmol) of compound 119 and 86 mg (0.70 mmol) of 4-dimethylaminopyridine (DMAP) were added and stirred for 36 hours. Upon completion of the reaction, the reaction mixture was precipitated in methanol, dialyzed against distilled water, and lyophilized to provide 0.78 g of functionalized dextran 120, Yield: 78%.

[0550] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH); minor signals: 7.30-8.60 (m, ArH)∘

Synthetic Scheme 23

[0551] ##STR00162##

Sample 121: Preparation of Compound 121

[0552] In a 250 mL round bottom flask, 2.69 g (9.05 mmol) of diphosgene was dissolved in 50.0 mL of dichloromethane and cooled to 0° C., followed by addition of 50 mL of saturated sodium carbonate solution and 2.5 g (9.05 mmol) of 3-aminopropionyl-diphenylazetidine (DECO) in dichloromethane and stirred for 5 h. Upon completion of the reaction, the organic phase was separated, dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with ethyl acetate in chloroform (5-60%) to provide 2.36 g of compound 121. Yield: 86%.

[0553] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 7.75 (m, 1H), 7.23-7.50 (m, 7H), 5.11 (d, J=15.0 Hz, 1H), 3.72 (d, J=15.0 Hz, 1H), 3.27 (m, 2H), 2.53 (m, 1H), 2.05 (m, 1H); ESI-MS: calcd for C.sub.19H.sub.15N.sub.2O.sub.2 [M+H].sup.+: 303.1; found: 303.1.

Sample 122: Preparation of Functionalized Hydroxyethyl Starch 122

[0554] In a 100 mL round bottom flask, 200 mL of anhydrous DMSO was added and heated to 60° C., followed by addition of 2.0 g of hydroxyethyl starch (average molecular weight ˜100,000) and stirred until completely dissolved. After the solution was cooled down to room temperature, 200 mg (0.66 mmol) of compound 121 and 81 mg (1.81 mmol) of 4-dimethylaminopyridine (DMAP) were added and stirred for 24 hours. Upon completion of the reaction, the reaction mixture was precipitated in methanol, dialyzed against distilled water, and lyophilized to provide 1.62 g of functionalized hydroxyethyl starch 122. Yield: 81%.

[0555] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.20 (m, CHOH, CH.sub.2OH); minor signals: 7.20-7.90 (m, ArH).

Synthetic Scheme 24

[0556] ##STR00163##

Sample 123: Preparation of Functionalized Dextran 123

[0557] To a stirred solution of 10.0 g of dextran (average molecular weight ˜100,000), 10% sodium hydroxide aqueous solution was added, and flowed by 1.5 g (10.8 mmol) of bromoacetic acid in tert-butanol (50 mL), and then heated to 60° C., stirred for 3 hours, After cooling, the reaction mixture was poured into 100 mL of acetone to precipitate, and the supernatant was decanted. The precipitate was further washed with methanol three times, and then dissolved in 100 mL of distilled water, adjusted to pH=2.0 with 5% hydrochloric acid, dialyzed against distilled water, and lyophilized to give 8.6 g of functionalized dextran 123. Yield: 86%.

[0558] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.20 (m, CHOH, CH.sub.2OH).

Sample 124: Preparation of Functionalized Dextran 124

[0559] To a 100 mL round-bottom flask charged with 2.0 g of functionalized dextran 123, 20.0 mL of anhydrous DMSO was added and heated at 60° C. till completely dissolved, and then cooled down to room temperature. To the above solution, 398 mg (2.08 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), and 281 mg (2.08 mmol) of 1-hydroxybenzotriazole (HOBt), and 430 uL (3.12 mmol) of triethylamine were added and stirred for 1 hour, and then 350 mg (1.04 mmol) of compound 89 was added and stirred at room temperature for 2 days. Upon completion of the reaction, the reaction mixture was precipitated in methanol, dialyzed against distilled water, and lyophilized to provide 1.52 g of functionalized dextran 124. Yield: 71%.

[0560] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.20 (m, CHOH, CH.sub.2OH, CH.sub.2O); minor signals: 1.45-1.90 (m, CH.sub.2), 1.23 (t, CH.sub.3).

Sample 125: Preparation of Functionalized Dextran 125

[0561] To a 100 mL round-bottom flask charged with 2.0 g of functionalized dextran 123, 20.0 mL of anhydrous DMSO was added and heated at 60° C. till completely dissolved, and then cooled down to room temperature. To the above solution, 398 mg (2.08 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), and 281 mg (2.08 mmol) of 1-hydroxybenzotriazole (HOBt), and 430 uL (3.12 mmol) of triethylamine were added and stirred for 1 hour, and then 429 mg (1.00 mmol) of compound 106 was added and stirred at room temperature for 2 days. Upon completion of the reaction, the reaction mixture was precipitated in methanol, dialyzed against distilled water, and lyophilized to provide 1.77 g of functionalized dextran 125. Yield: 88%.

[0562] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH); minor signals: 6.75-7.20 (m, ArH), 1.23 (t, CH.sub.3).

Sample 126: Preparation of Functionalized Dextran 126

[0563] To a 100 mL round-bottom flask charged with 2.0 g of functionalized dextran 123, 20.0 mL of anhydrous DMSO was added and heated at 60° C. till completely dissolved, and then cooled down to room temperature. To the above solution, 398 mg (2.08 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), and 281 mg (2.08 mmol) of 1-hydroxybenzotriazole (HOBt), and 430 uL (3.12 mmol) of triethylamine were added and stirred for 1 hour, and then 179 mg (1.00 mmol) of 6-azido-hexanylamine was added and stirred at room temperature for 2 days. Upon completion of the reaction, the reaction mixture was precipitated in methanol, dialyzed against distilled water, and lyophilized to provide 1.65 g of functionalized dextran 126. Yield: 73%.

[0564] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.20 (m, CHOH, CH.sub.2OH, CH.sub.2O); minor signals: 1.35-1.80 (m, CH.sub.2).

Synthetic Scheme 25

[0565] ##STR00164##

Sample 127: Preparation of Functionalized Cellulose 127

[0566] 10.0 g of sodium carboxymethylcellulose (average molecular weight ˜90,000) was dissolved in 100 mL of distilled water, adjusted to pH=2.0 with 5% hydrochloric acid, dialyzed against distilled water three times, and lyophilized to obtain 7.2 g of carboxymethylcellulose. In a. 100 mL round bottom flask, 1.0 g of carboxymethyl cellulose was suspended in 20 mL of DMSO solution containing 10% tetrabutylammonium fluoride, heated at 60° C., stirred for 30 minutes, and then cooled down to room temperature. To the above solution, 192 mg (1.00 mmol) N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride (EDC), 136 mg (1.00 mmol) 1-hydroxybenzotriazole (HOBt) and 300 uL (2.17 mmol) of triethylamine were added and stirred for 1 hour, and then 120 mg (0.50 mmol) of compound 89 was added and stirred for 48 hours. Upon completion of the reaction, the reaction mixture was precipitated in methanol, dialyzed against distilled water, and lyophilized to give 0.53 g of functionalized cellulose 127. Yield: 53%.

[0567] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.20 (m, CHOH, CH.sub.2OH, CH.sub.2O); minor signals: 1.40-1.90 (m, CH.sub.2), 1.23 (t, CH.sub.3).

Synthetic Scheme 26

[0568] ##STR00165##

Sample 128: Preparation of Compound 128

[0569] In a 250 mL round bottom flask, 5.50 g (18.54 mmol) of diphosgene was dissolved in 100.0 mL of dichloromethane and cooled to 0° C., followed by addition of 100 mL of saturated sodium carbonate solution and 4.0 g (18.54 mmol) of L-alanine benzyl ester hydrochloride in dichloromethane and stirred for 5 h. Upon completion of the reaction, the organic phase was separated, dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with ethyl acetate in petroleum ether (5-60%) to provide 2.51 g of compound 128. Yield: 66%.

[0570] .sup.1H NMR (500 MHz, CDCl.sub.3, ppm): δ 7.38 (m, 5H), 5.23 (s, 2H), 4.12 (m, 1H), 1.50 (d, J=7.2 Hz, 3H); ESI-MS: calcd for C.sub.11H.sub.12NO.sub.3 [M+H].sup.+: 206.1, found: 206.1.

Sample 129: Preparation of Compound 129

[0571] In a 250 mL round bottom flask, 120 mL of anhydrous DMSO was added and heated to 60° C., and followed by addition of 20.0 g of dextran (average molecular weight ˜100,000) and stirred until completely dissolved, After the solution was cooled down to room temperature, 2.0 g (9.73 mmol) of compound 128 and 1.18 g (9.73 mmol) of 4-dimethylaminopyridine (DMAP) were added and stirred for 24 hours. Upon completion of the reaction, the reaction mixture was precipitated in methanol, dialyzed against distilled water, and lyophilized to provide 17.9 g of functionalized dextran 129. Yield: 89%.

[0572] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH); minor signals: 7.20-7.50 (m, ArH), 1.26 (d, CH.sub.3).

Sample 130: Preparation of Functionalized Dextran 130

[0573] In a 300 mL hydrogenation flask, 10.0 g of functionalized dextran 129 was dissolved in 100 mL of methanol-water (9:1 and followed by addition of 700 mg of Pd—C and shaken for 12 hours under 1.2 atmospheres of hydrogen gas. Upon completion of the reaction, solid material was filtered off, washed with ethyl acetate three times (60 mL×3), and the aqueous phase was lyophilized to give 8.73 g of functionalized dextran 130. Yield: 87%.

[0574] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH); minor signals: 1.23 (d, CH.sub.3).

Sample 131: Preparation of Functionalized Dextran 131

[0575] To a 100 mL round-bottom flask charged with 2.0 g of functionalized dextran 130, 20.0 mL of anhydrous DMSO was added and heated at 60° C. till completely dissolved, and then cooled down to room temperature. To the above solution, 383 mg (2.00 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), 271 mg (2.00 mmol) of 1-hydroxybenzotriazole (HOBt), and 500 uL (3.61 mmol) of triethylamine were added and stirred for 1 hour, and then 238 mg (1.00 mmol) of compound 89 was added and stirred at room temperature for 2 days. Upon completion of the reaction, the reaction mixture was precipitated in methanol, dialyzed against distilled water, and lyophilized to provide 1.56 g of functionalized dextran 131. Yield: 78%.

[0576] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH); minor signals: 1.45-1.90 (m, CH.sub.2), 1.23 (m, CH.sub.3).

Sample 132: Preparation of Functionalized Dextran 132

[0577] To a 100 mL round-bottom flask charged with 2.0 g of functionalized dextran 130, 20.0 mL of anhydrous DMSO was added and heated at 60° C. till completely dissolved, and then cooled down to room temperature. To the above solution, 383 mg (2.00 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), 271 mg (2.00 mmol) of 1-hydroxybenzotriazole (HOBt), and 500 uL (3.61 mmol) of triethylamine were added and stirred for 1 hour, and then 83 mg (1.00 mmol) of 4-pentyn-1-amine was added and stirred at room temperature for 2 days. Upon completion of the reaction, the reaction mixture was precipitated in methanol, dialyzed against distilled water, and lyophilized to provide 1.23 g of functionalized dextran 132. Yield: 61%.

[0578] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH); minor signals: 1.70-2.00 (m, CH.sub.2, CH), 1.23 (d, CH.sub.3).

Sample 133: Preparation of Functionalized Dextran 133

[0579] To a 100 mL round-bottom flask charged with 3.0 g of functionalized dextran 130, 30.0 mL of anhydrous DMSO was added and heated at 60° C. till completely dissolved, and then cooled down to room temperature. To the above solution, 573 mg (3.00 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), 367 mg (2.00 mmol) of 1-hydroxybenzotriazole (HOBt), and 700 uL (5.06 mmol) of triethylamine were added and stirred for 1 hour, and then 642 mg (1.50 mmol) of compound 106 was added and stirred at room temperature for 2 days. Upon completion of the reaction, the reaction mixture was precipitated in methanol, dialyzed against distilled water, and lyophilized to provide 2.35 g of functionalized dextran 133. Yield: 78%.

[0580] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH); minor signals: 6.75-7.20 (m, ArH), 1.25 (m, CH.sub.3).

Synthetic Scheme 27

[0581] ##STR00166##

Sample 134: Preparation of Compound 134

[0582] In a 500 mL round bottom flask, 9.16 g (27.51 mmol) of diphosgene was dissolved in 150 mL of dichloromethane and cooled to 0° C., followed by addition of 100 mL of saturated sodium carbonate solution and 10.0 g (27.51 mmol) of L-glutamic acid dibenzyl ester hydrochloride in dichloromethane and stirred overnight. Upon completion of the reaction, the organic phase was separated, dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with ethyl acetate in chloroform (5-60%) to provide 8.32 g of compound 134. Yield: 85%.

[0583] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 7.35 (m, 10H), 5.15 (s, 2H), 5.10 (s, 2H), 4.19 (m, 1H), 2.50 (m, 2H), 2.06 (m, 1H), 2.02 (m, 1H); ESI-MS: calcd for C.sub.20H.sub.20NO.sub.5 [M+H].sup.+: 354.1; found: 354.2.

Sample 135: Preparation of Functionalized Dextran 135

[0584] In a 250 mL round bottom flask, 50.0 mL of anhydrous DMSO was added and heated to 60° C., followed by addition of 5.0 g of dextran (average molecular weight ˜100,000) and stirred until completely dissolved. After the solution was cooled down to room temperature, 708 mg (2.00 mmol) of compound 134 and 245 mg (2.00 mmol) of 4-dimethylaminopyridine (DMAP) were added and stirred for 24 hours. Upon completion of the reaction, the reaction mixture was precipitated in methanol, dialyzed against distilled water, and lyophilized to provide 3.95 g of functionalized hydroxyethyl starch 135, Yield: 79%.

[0585] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.20 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH); minor signals: 7.20-7.50 (m, ArH).

Sample 136: Preparation of Functionalized Dextran 136

[0586] In a 200 mL hydrogenation flask, 3.6 g of functionalized dextran 135 was dissolved in 60 mL of methanol-water (9:1), followed by addition of 300 mg of Pd—C and shaken for 12 hours with 1.2 atmospheres of hydrogen. Upon completion of the reaction, solid material was filtered off, washed with ethyl acetate three times (30 mL×3), and the aqueous phase was lyophilized to give 2.755 g of functionalized dextran 136, Yield: 76%.

[0587] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.20 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH); minor signals: 2.00-2.50 (m, CH.sub.2).

Sample 137: Preparation of Functionalized Dextran 137

[0588] To a 100 mL round-bottom flask charged with 2.0 g of functionalized dextran 136, 20.0 mL of anhydrous DMSO was added and heated at 60° C. till completely dissolved, and then cooled down to room temperature. To the above solution, 955 mg (5.00 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), 610 mg (5.00 mmol) of 1-hydroxybenzotriazole (HOBt), and 830 uL (3.61 mmol) of triethylamine were added and stirred for 1 hour, and then 445 mg (2.50 mmol) of compound 106 was added and stirred at room temperature for 2 days. Upon completion of the reaction, the reaction mixture was precipitated in methanol, dialyzed against distilled water, and lyophilized to provide 1.53 g of functionalized dextran 137 Yield: 76%.

[0589] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.20 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH); minor signals: 1.35-1.85 (m, CH.sub.2).

Synthetic Scheme 28

[0590] ##STR00167##

Sample 138: Preparation of Functionalized Dextran 138

[0591] In a 250 mL round bottom flask, 5.0 g of dextran (average molecular weight ˜7,000)) was dissolved in 50 mL of distilled water, then 2.0 g of cyanogen bromide was added, and pH was adjusted to 10 with sodium bicarbonate. To the above solution, 2.0 g of δ-amino-hexanoic acid was added and stirred at room temperature for 48 hours. Upon completion of the reaction, the reaction mixture was adjusted to pH=2.0 with 1.0N hydrochloric acid, filtered, dialyzed against distilled water, and lyophilized to give 3.23 g of functionalized dextran 138. Yield: 65%.

[0592] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH); minor signals: 1.45-2.30 (m, CH.sub.2).

Sample 139: Preparation of Functionalized Dextran 139

[0593] To a 100 mL round-bottom flask charged with 2.6 g of functionalized dextran 138, 26.0 mL of anhydrous DMSO was added and heated at 60° C. till completely dissolved, and then cooled down to room temperature. To the above solution, 402 mg (2.10 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), 256 mg (2.10 mmol) of 1-hydroxybenzotriazole (HOBt), and 600 uL (4.35 mmol) of triethylamine were added and stirred for 1 hour, and then 250 mg (1.05 mmol) of compound 89 was added and stirred at room temperature for 2 days. Upon completion of the reaction, the reaction mixture was precipitated in methanol, dialyzed against distilled water, and lyophilized to provide 1.23 g of functionalized dextran 139. Yield: 47%.

[0594] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH); minor signals: 1.45-2.30 (m, CH.sub.2), 1.23 (t, CH.sub.3).

Synthetic Scheme 29

[0595] ##STR00168##

[0596] In a 250 mL round-bottom flask, 5.0 g (23.78 mmol) trifluoracetic anhydride and 1.0 g (8.91 mmol) 5-hexynoic acid were combined together, heated to 40° C., and stirred for 1 hour, and then cooled to room temperature, To the stirred mixture 0.3 g of 85% phosphoric add and 1.0 g of chitosan (Mr˜5000) were added, heated to 50° C., and stirred for 24 hours. Upon completion of reaction, the reaction mixture was cooled down to room temperature and precipitated with ether. The precipitate was filtered and washed 5 times with ether. The solid powder was collected, dialyzed against distilled water, and lyophilized to provide 1.12 g of functionalized dextran 140. Yield: 100%.

[0597] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH); minor signals: 1.45-2.35 (m, CH.sub.2, CH).

Synthetic Scheme 29-1

[0598] ##STR00169##

Sample 140-1: Preparation of Functionalized Dextran 140-1

[0599] In a 100 mL round bottom flask, 20.0 mL of anhydrous DMSO was added and heated to 60° C. followed by addition of 3.0 g of dextran (average molecular weight ˜100,000) and stirred until completely dissolved. After the solution was cooled down to room temperature, 678 mg (3.0 mmol) of compound 90, 205 mg (1.0 mmol) of compound 128, and 489 mg (4.0 mmol) of 4-dimethylaminopyridine (DMAP) were added and stirred for 24 hours. Upon completion of the reaction, the reaction mixture is precipitated in methanol, and the precipitate is dissolved in 20 mL of 1.0N sodium hydroxide solution, stirred for 6 hours, and then acidified to pH=3.0 with 1.0N hydrochloric acid, finally the reaction solution is concentrated, dialyzed against distilled water, and lyophilized to provide 2.76 g of functionalized dextran 140-1. Yield: 92%.

[0600] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH); minor signals: 1.00-1.75 (m, CH.sub.2, CH.sub.3).

Synthetic Scheme 30

[0601] ##STR00170##

Sample 141: Preparation of Functionalized Dextran 141

[0602] To a 100 mL round-bottom flask charged with 3.0 g of dextran (average molecular weight ˜100,000), 30.0 mL of anhydrous DMSO was added and heated at 60° C. till completely dissolved, and then cooled down to room temperature. To the above solution, 300 mg (1.91 mmol) of 6-azidohexanoic acid, 730 mg (3.82 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), and 466 mg (3.82 mmol) of 4-dimethylaminopyridine (DMAP) were added and stirred at room temperature for 2 days. Upon completion of the reaction, the reaction mixture was precipitated in methanol, dialyzed against distilled water, and lyophilized to provide 2.12 g of functionalized dextran 141. Yield: 70%.

[0603] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH); minor signals: 1.35-2.35 (m, CH.sub.2).

Synthetic Scheme 31

[0604] ##STR00171##

Sample 142: Preparation of Functionalized Dextran 142

[0605] In a 500 mL hydrogenation flask, 20.0 g of functionalized dextran 91 was dissolved in 150 mL of distilled water and shaken under 1.5 atmospheres of hydrogen gas in the presence of 1.0 g of 10% Pd—C. After shaking for 12 hours, the solid PD-C was filtered off, and filtrate was precipitated in methanol, dialyzed against distilled water, and lyophilized to provide 17.3 g of functionalized dextran 142. Yield: 86%.

[0606] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH); minor signals: 1.45-2.20 (m, CH.sub.2), 1.25 (t, CH.sub.3).

Sample 143: Preparation of Functionalized Dextran 143

[0607] To a 100 mL round-bottom flask charged with 3.0 g of functionalized dextran 142, 30.0 mL of anhydrous DMSO was added and stirred till completely dissolved. To the above solution, 113 mg (0.5 mmol) of 3-(2-Pyridyldithio)propionic acid, 91 mg (0.5 mmol) of 2-(cyclooct-2-ynyloxy)acetic acid 383 mg (2.0 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), 271 mg (2.00 mmol) of 1-hydroxybenzotriazole (HOBt), and 415 uL (3.00 mmol) of triethylamine were added and stirred at room temperature for 2 days. Upon completion of the reaction, the reaction mixture was precipitated in methanol, dialyzed against distilled water, and lyophilized to provide 2.33 g of functionalized dextran 143, Yield: 77%.

[0608] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH); minor signals: 7.20-8.60 (m, CONH, ArH), 1.35-2.00 (m, CH.sub.2), 1.22 (t, CH.sub.3).

Synthetic Scheme 32

[0609] ##STR00172##

Sample 144: Preparation of Compound 144

[0610] In a 250 mL round bottom flask, 10.0 g (40.62 mmol) of Nε-Boc-lysine and 6.28 g (81.24 mmol) of NaHCO.sub.3 were dissolved in 100.0 mL of methanol-water (2:1), followed by slow addition of 7.6 g (36.56 mmol) of 5-hexynoic acid-(N-hydroxysuccinyl lactam) ester and stirred overnight. Upon completion of the reaction, the reaction mixture was acidified to pH=1.0 with 2.0N HO, extracted with ethyl acetate three times (300 mL×3), and the organic phases were pooled, dried over MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with methanol in chloroform (2-10%) to give 6.35 g of compound 144, Yield: 51%.

[0611] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 6.81 (s, 1H), 4.55 (m, 1H), 3.12 (t, J=7.2 Hz, 2H), 2.38 (t, J=7.2 Hz, 2H), 2.38 (m, 2H), 1.97 (t, J=2.1 Hz, 1H), 1.75 (m, 4H), 1.35-1.50 (m, 9H); ESI-MS (m/z): calcd for C.sub.17H.sub.29N.sub.2O.sub.5 [M+H].sup.+: 341.2; found: 341.2.

Sample 145: Preparation of Compound 145

[0612] To a 250 mL round-bottom flask charged with 6.0 g (18.21 mmol) of compound 144, 50 mL of hydrochloride ethanol solution (4.0N) was added and stirred at room temperature overnight. After removal of volatiles, the residue was purified on a reverse phase C-18 column and eluted with acetonitrile in water (10-70%) to provide 3.35 g of compound 145. Yield: 92%.

[0613] .sup.1H NMR (300 MHz, D.sub.2O, ppm): δ 4.27 (m, 1H), 3.87 (t, J=7.2 Hz, 2H), 2.35 (t, J=7.2 Hz, 2H), 2.25 (t, J=2.1 Hz, 1H), 2.35 (m, 2H), 1.75 (m, 4H), 1.63 (m, 2H), 1.32 (m, 2H); ESI-MS (m/z): calcd for C.sub.12H.sub.21N.sub.2O.sub.3 [M+H].sup.+: 241.1; found: 241.2.

Sample 146: Preparation of Compound 146

[0614] In a 250 mL round bottom flask, 3.2 g (40.62 mmol) of compound 145 and 1.93 g (23.02 mmol) of NaHCO.sub.3 were dissolved in 60.0 mL of methanol-water (2:1), followed by slow addition of 3.91 g (12.66 mmol) of 6-(N-hydroxysuccinyl lactam) hexanoic acid (N-hydroxysuccinimide) ester, and stirred overnight. Upon completion of the reaction, the reaction mixture was acidified to pH=1.0 with 2.0N HCl, extracted with ethyl acetate three times (300 mL×3), and the organic phases were pooled, dried over MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with methanol in chloroform (2-10%) to give 2.35 g of compound 146. Yield: 47%.

[0615] .sup.1H NMR (300 MHz, CD.sub.3OD, ppm): δ 6.82 (s, 2H), 4.36 (m, 1H), 3.45 (t, J=7.2 Hz, 2H), 3.17 (t, J=7.2 Hz, 2H), 2.35 (t, J=7.2 Hz, 2H), 2.25 (t, J=7.2 Hz, 2H), 2.12 (m, 1H), 1.98 (t, J=2.0 Hz, 1H), 1.75 (m, 4H), 1.62 (m, 2H), 1.52 (m, 6H), 1.31 (m, 2H); ESI-MS (m/z): calcd for C.sub.22H.sub.32N.sub.3O.sub.6 [M+H].sup.+: 434.2; found: 434.3.

Sample 147: Preparation of Functionalized Dextran 147

[0616] To a 100 mL round-bottom flask charged with 2.0 g of functionalized dextran 142, 30.0 mL of anhydrous DMSO was added and stirred till completely dissolved. To the above solution, 210 mg (0.48 mmol) of compound 146, 139 mg (0.73 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), 98 mg (0.73 mmol) of 1-hydroxybenzotriazole (HOBt), and 138 uL (1.00 mmol) of triethylamine were added and stirred at room temperature for 2 days. Upon completion of the reaction, the reaction mixture was precipitated in methanol, dialyzed against distilled water, and lyophilized to provide 1.83 g of functionalized dextran 147. Yield: 81%.

[0617] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH); minor signals: 7.00-8.60 (m, CONH, CH), 1.35-2.35 (m, CH.sub.2), 1.23 (t, CH.sub.3).

Synthetic Scheme 33

[0618] ##STR00173##

Sample 148: Preparation of Compound 148

[0619] In a 250 mL round bottom flask, 4.34 g (24.24 mmol) of 3-azidopropanyl methylsulfonate and 5.0 g (16.16 mmol) of L-tyrosine ethyl ester were dissolved in 30.0 mL of anhydrous dimethylformamide, followed by addition of 10.53 g (32.32 mmol) of cesium carbonate, and heated at 50° C. overnight. Upon completion of the reaction, the reaction mixture was partitioned between ethyl acetate (150 mL) and brine (150 mL). The organic phase was further washed with brine (60 mL×2), dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with ethyl acetate in petroleum ether (10-70%) to to gave 4.31 g of compound 148. Yield: 68%.

[0620] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 7.06 (d, J=7.3 Hz, 2H), 6.82 (d, J=7.3 Hz, 2H), 4.98 (s, 1H), 4.51 (m, 1H), 4.19 (m, 2H), 4.07 (t, J=7.2 Hz, 2H), 3.52 (t, J=7.2 Hz, 2H), 3.03 (m, 2H), 2.05 (m, 2H), 1.43 (s, 9H), 1.25 (t, J=7.2 Hz, 2H); ESI-MS (m/z): calcd for C.sub.19H.sub.29N.sub.4O.sub.5 [M+H].sup.+: 393.2; found: 393.3.

Sample 149: Preparation of Compound 149

[0621] To a 200 mL round-bottom flask charged with 3.8 g (9.69 mmol) of compound 148, 30 mL of hydrochloride ethanol solution (3.0N) was added and stirred at room temperature overnight. After removal of volatiles, the residue was purified on a reverse phase C-18 column and eluted with acetonitrile in water (10-70%) to provide 2.41 g of compound 149. Yield: 85%.

[0622] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 8.74 (s, 3H), 7.24 (d, J=7.2 Hz, 2H), 6.83 (d, J=7.2 Hz, 2H), 4.33 (s, 1H), 4.17 (m, 2H), 4.13 (t, J=7.2 Hz, 2H), 3.50 (t, J=7.2 Hz, 2H), 3.42 (m, 2H), 2.03 (m, 2H), 1.19 (t, J=7.2 Hz, 3H); ESI-MS (m/z): calcd for C.sub.14H.sub.21N.sub.4O.sub.3 [M+H].sup.+: 293.2; found: 293.2.

Sample 150: Preparation of Compound 150

[0623] In a 250 mL round bottom flask, 1.49 g (7.52 mmol) of diphosgene was dissolved in 30.0 mL of dichloromethane and cooled to 0° C., followed by addition of 50 mL of saturated sodium carbonate solution and 2.2 g (7.52 mmol) of compound 149 in dichloromethane, and stirred for 5 h. Upon completion of the reaction, the organic phase was separated, dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with ethyl acetate in petroleum ether (10-80%) to provide 1.27 g of compound 150. Yield: 53%.

[0624] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 7.13 (d, J=7.2 Hz, 2H), 6.87 (d, J=7.2 Hz, 2H), 4.25 (m, 2H), 4.21 (m, 2H), 4.01 (t, J=7.2 Hz, 2H), 3.53 (m, 1H), 3.51 (m, 1H), 2.05 (m, 2H), 1.31 (t, J=7.2 Hz, 3H); ESI-MS (m/z): calcd for C.sub.15H.sub.19N.sub.4O.sub.4 [M+H].sup.+: 319.1; found: 319.3.

Sample 151: Preparation of Functionalized Dextran 151

[0625] In a 100 mL round bottom flask, 20.0 mL of anhydrous DMSO was added and heated to 60° C., and followed by addition of 3.0 g of dextran (average molecular weight ˜100,000) and stirred until completely dissolved. After the solution was cooled down to 38° C., 200 mg (0.63 mmol) of compound 150 and 77 mg (0.63 mmol) of 4-dimethylaminopyridine (DMAP) were added and stirred for 12 hours. Upon completion of the reaction, the reaction mixture was precipitated in methanol, dialyzed against distilled water, and lyophilized to provide 2.78 g of functionalized dextran 151. Yield: 92%.

[0626] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.20 (m, CHOH, CH.sub.2OH, CH.sub.2O); minor signals: 6.70-7.30 (m, ArH), 1.96 (m, CH.sub.2), 1.23 (t, CH.sub.3).

Part 3. Preparation of Lipid-Polysaccharide Conjugates

Synthetic Scheme 34

[0627] ##STR00174##

Sample 152: Preparation of Compound 152

[0628] To a 250 mL round-bottom flask charged with 3.0 g (8.82 mmol) of compound 144, 2.53 g (13.23 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and 50 mL of anhydrous dichloromethane were added and stirred at room temperature for 30 min; and then 2.0 mL of absolute ethanol and 1.62 g (13.23 mmol) of DMAP were added. The reaction was continuously stirred overnight. The reaction mixture was washed with brine twice (50 mL×2), dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with ethyl acetate in petroleum ether (10-80%) to provide 2.63 g of compound 152. Yield: 81%.

[0629] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 4.51 (m, 1H), 4.15 (q, J=7.2 Hz, 2H), 3.17 (t, J=7.2 Hz, 2H), 2.35 (q, J=7.2 Hz, 2H), 2.21 (m, 2H), 1.95 (t, J=2.1 Hz, 1H), 1.83 (m, 3H), 1.61 (m, 1H), 1.39 (m, 2H), 1.37 (s, 9H), 1.25 (m, 2H), 1.23 (t, J=7.2 Hz, 3H); ESI-MS (m/z): calcd for C.sub.19H.sub.33N.sub.2O.sub.5 [M+H].sup.+: 369.2; found: 369.2.

Sample 153: Preparation of Compound 153

[0630] To a 100 mL round-bottom flask charged with 2.5 g (6.79 mmol) of compound 152, 30 mL of hydrochloride ethanol solution (4.0N) was added, and stirred at room temperature overnight. After removal of volatiles, the residue was purified on a reverse phase C-18 column and eluted with acetonitrile in water (10-70%) to provide 1.75 g of compound 153. Yield: 96%.

[0631] .sup.1H NMR (300 MHz, DMSO-d.sub.6, ppm): δ 4.11 (m, 3H), 2.70 (m, 2H), 2.25 (t, J=7.2 Hz, 2H), 2.15 (m, 2H), 2.05 (s, 1H), 1.50-1.75 (m, 6H), 1.31 (m, 2H), 1.17 (t, J=7.2 Hz, 3H); ESI-MS (m/z): calcd for C.sub.14H.sub.25N.sub.2O.sub.3 [M+H].sup.+: 269.2; found: 269.2.

Sample 154: Preparation of Compound 154

[0632] To a 250 mL round bottom flask charged with 2.03 g (6.16 mmol) of docosahexaenoic acid (DHA), 1.18 g (6.16 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and 832 mg (6.16 mmol) 1-hydroxybenzotriazole (HOBt), 15.0 mL of anhydrous dimethylformamide were added, and flowed by 1.5 g (5.60 mmol) of compound 153 and 1.5 mL (11.2 mmol) triethylamine, and stirred for 5 hours. Upon completion of the reaction, the reaction mixture was partitioned from ethyl acetate (100 mL) and brine (100 mL). The organic phase was further washed with brine twice (100 mL×2), dried over MgSO.sub.4, concentrated, and purified on a silica gel column and eluted with ethyl acetate in petroleum ether to give 2.69 g of compound 154. Yield: 83%.

[0633] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 5.25-5.00 (m, 12H), 4.51 (m, 1H), 4.21 (t, J=7.2 Hz, 2H), 3.23 (t, J=7.2 Hz, 2H), 2.76 (m, 10H), 2.30-2.50 (m, 4H), 2.23 (t, J=7.2 Hz, 2H), 2.25 (m, 2H), 2.16 (t, J=7.2 Hz, 2H), 2.03 (m, 3H), 1.73 (m, 2H), 1.55 (m, 2H), 1.35 (m, 2H), 1.23 (t, J=7.2 Hz, 3H), 0.95 (t, J=7.2 Hz, 3H); ESI-MS: calcd for C.sub.36H.sub.55N.sub.2O.sub.4 [M+H].sup.+: 579.4; found: 579.6.

Sample 155: Preparation of Compound 155

[0634] In a 100 mL round bottom flask, 1.0 g (1.73 mmol) of compound 154 and 339 mg (2.59 mmol) of 2-(2-azidoethoxy)ethanol were dissolved in 10 mL of acetonitrile, and followed by addition of 32 mg (0.17 mmol) of CuI and 50 uL (0.35 mmol) of triethylamine were stirred at room temperature overnight. After removal of volatiles, the residue was purified on a silica gel column and eluted with methanol in chloroform (0-10%) to provide 1.05 g of compound 155. Yield: 85%.

[0635] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 7.61 (s, 1H), 5.25-5.00 (m, 12H), 4.52 (m, 1H), 4.16 (t, J=7.2 Hz, 2H), 3.83 (t, J=7.2 Hz, 2H), 3.71 (m, 2H), 3.57 (t, J=7.2 Hz, 2H), 3.25 (m, 4H), 2.73 (m, 10H), 2.35-2.50 (m, 4H), 2.23 (t, J=7.2 Hz, 2H), 2.12 (t, J=7.2 Hz, 2H), 2.05 (m, 5H), 1.72 (m, 2H), 1.53 (m, 2H), 1.35 (m, 2H), 1.23 (t, J=7.2 Hz, 3H), 0.93 (t, J=7.2 Hz, 3H); ESI-MS: calcd for C.sub.40H.sub.64N.sub.5O.sub.6 [M+H].sup.+: 710.4; found: 710.6.

Sample 156: Preparation of Conjugate 156

[0636] In a 25 mL round bottom flask, 500 mg of functionalized polysaccharide 111 and 80 mg (0.11 mmol) of compound 154 were dissolved in 3.0 mL of DMSO, and followed by addition of copper sulfate solution (30 uL×1.0 M), THPTA (30 uL×1.0 M), and sodium (60 uL×1.0 M), and stirred at room temperature for 2 days. Upon completion of the reaction, the reaction mixture was precipitated in methanol, filtered, and washed three times with methanol. The precipitate was then dissolved in 2.0 mL of distilled water, dialyzed against distilled water, and lyophilized to provide 462 mg of conjugate 156. Yield: 93%.

[0637] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH); minor signals: 7.20-8.50 (m, ArHCONH), 5.32 (m, CH), 1.24 (t, CH.sub.3), 1.01 (t, CH.sub.3).

Synthetic Scheme 35

[0638] ##STR00175##

Sample 157: Preparation of Compound 157

[0639] In a 250 mL round bottom flask, 9.0 g (36.55 mmol) of compound Boc-L-lysine and 6.25 g (73.11 mmol) of sodium bicarbonate were dissolved in 200 mL of methanol-water (2:1), followed by addition of 12.8 g (32.90 mmol) of gamma-linoleic acid-(N-hydroxysuccinyl lactam) ester and stirred overnight. Upon completion of the reaction, the reaction mixture was acidified with 2.0N HCl to pH=1.0, extracted with ethyl acetate (100 mL×3); the organic phases were combined together, dried over MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with methanol in chloroform (0-12%) to provide 11.7 g of compound 157. Yield: 67%.

[0640] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 6.07 (s, 1H), 5.35 (m, 6H), 4.51 (m, 1H), 3.21 (t, J=7.2 Hz, 2H), 2.76 (m, 4H), 2.25 (t, J=7.2 Hz, 2H), 2.17 (m, 4H), 1.82 (m, 2H), 1.51-1.75 (m, 4H), 1.42 (s, 9H), 1.25-1.41 (m, 13H); ESI-MS (m/z): ESI-MS: calcd for C.sub.29H.sub.51N.sub.2O.sub.5 [M+H].sup.+: 507.3; found: 507.4.

Sample 158: Preparation of Compound 158

[0641] To a 250 mL round-bottom flask charged with 10.0 g (19.75 mmol) of compound 157 and 5.66 g (29.62 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), 100 mL of anhydrous dichloromethane were added and stirred at room temperature for 30 min; and then 3.0 mL of absolute ethanol and 3.62 g (29.62 mmol) of DMAP were added. The reaction was continuously stirred overnight. Upon completion of the reaction, the reaction mixture was washed with brine (100 mL×2), dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with ethyl acetate in petroleum ether (10-80%) to provide 8.55 g of compound 158. Yield: 75%.

[0642] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 6.12 (s, 1H), 5.48 (m, 6H), 4.53 (m, 1H), 4.12 (q, J=7.2 Hz, 2H), 3.21 (t, J=7.2 Hz, 2H), 2.76 (m, 4H), 2.25 (t, J=7.2 Hz, 2H), 2.17 (m, 4H), 1.82 (m, 2H), 1.51-1.75 (m, 4H), 1.42 (s, 9H), 1.25-1.41 (m, 13H), 0.96 (t, J=7.2 Hz, 3H); ESI-MS (m/z): calcd for C.sub.31H.sub.55N.sub.2O.sub.5 [M+H].sup.+: 535.4; found: 535.5.

Sample 159: Preparation of Compound 159

[0643] To a 250 mL round-bottom flask charged with 8.5 g (15.90 mmol) of compound 158, 100 mL of hydrochloride ethanol solution (4.0N) was added and stirred at room temperature overnight. After removal of volatiles, the residue was purified on a reverse phase C-18 column and eluted with acetonitrile in water (10-70%) to provide 7.17 g of compound 159. Yield: 96%.

[0644] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 8.18 (brs, 3H), 5.37 (m, 6H), 4.52 (m, 1H), 4.18 (q, J=7.2 Hz, 2H), 3.05 (t, J=7.2 Hz, 2H), 2.79 (m, 4H), 2.42 (t, J=7.2 Hz, 2H), 2.09 (m, 4H), 1.45-1.95 (m, 6H), 1.25-1.43 (m, 13H), 0.97 (t, J=7.2 Hz, 3H); ESI-MS (m/z): calcd for C.sub.26H.sub.47N.sub.2O.sub.3 [M+H].sup.+: 435.3; found: 435.3.

Sample 160: Preparation of Compound 160

[0645] In a 250 mL round bottom flask, 1.71 g (5.75 mmol) of diphosgene was dissolved in 30.0 mL of dichloromethane and cooled to 0° C., followed by addition of 30 mL of saturated sodium carbonate solution and 2.7 g (5.75 mmol) of compound 159 in dichloromethane, and stirred for 3 h. Upon completion of the reaction, the organic phase was separated, dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with ethyl acetate in petroleum (5-60%) to provide 1.88 g of compound 160. Yield: 71%.

[0646] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 6.21 (m, 1H), 5.36 (m, 6H), 4.54 (m, 1H), 4.23 (q, J=7.2 Hz, 2H), 3.20 (t, J=7.2 Hz, 2H), 2.80 (m, 4H), 2.23 (t, J=7.2 Hz, 2H), 2.05 (m, 4H), 1.45-1.95 (m, 6H), 1.25-1.43 (m, 13H), 0.97 (t, J=7.2 Hz, 3H); ESI-MS (m/z): calcd for C.sub.27H.sub.45N.sub.2O.sub.4 [M+H].sup.+: 461.3; found: 461.3.

Sample 161: Preparation of Conjugate 161

[0647] In a 100 mL round bottom flask, 20 mL of anhydrous DMSO was added and heated to 60° C., followed by addition of 2.0 g of dextran (average molecular weight ˜150,000) and stirred until completely dissolved. After the solution was cooled down to 38° C., 300 mg (0.65 mmol) of compound 160 and 79 mg (0.65 mmol) of 4-dimethylaminopyridine (DMAP) were added and stirred for 12 hours. Upon completion of the reaction, the reaction mixture was precipitated in methanol, dialyzed against distilled water, and lyophilized to provide 1.63 g of functionalized dextran 161. Yield: 86%.

[0648] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH); minor signals: 5.33 (m, CH), 1.23 (t, CH.sub.3), 0.82 (t, CH.sub.3).

Synthetic Scheme 36

[0649] ##STR00176##

Sample 162: Preparation of Compound 162

[0650] In a 250 mL round bottom flask, 10.1 g (33.7 mmol) of retinoic acid was dissolved in 50.0 mL of anhydrous dimethylformamide, followed by addition of 15.4 g (40.5 mmol) of 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU), and stirred for 30 minutes. To the above solution, 10.0 g (33.7 mmol) of Boc-L-lysine methyl ester hydrochloride and 5.6 mL triethylamine (40.5 mmol) were added and stirred for 3 hours. Upon completion of the reaction, the reaction mixture was partitioned from ethyl acetate (150 mL) and brine (150 mL). The organic phase was further washed with brine twice (100 mL×2), and dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with ethyl acetate in petroleum ether to give 15.1 g of compound 162. Yield: 83%.

[0651] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 5.70-7.00 (m, 6H), 4.25 (m, 1H), 3.68 (s, 3H), 3.25 (t, J=7.2 Hz, 2H), 2.35 (s, 3H), 2.02 (m, 5H), 1.76 (m, 2H), 1.72 (s, 3H), 1.63 (s, 3H), 1.36-1.62 (m, 4H), 1.45 (m, 11H), 1.25-1.40 (m, 2H), 1.03 (s, 3H), 1.01 (s, 3H); ESI-MS (m/z): calcd for C.sub.32H.sub.51N.sub.2O.sub.5 [M+H].sup.+: 543.3; found: 543.5.

Sample 163: Preparation of Compound 163

[0652] In a 250 mL round bottom flask, 10.0 g (18.30 mmol) of compound 162 was dissolved in 50 mL of formic acid (70%) in dichloromethane, stirred overnight. After removal of volatiles, the residue was purified on a silica gel column and eluted with methanol in chloroform (3-20%) to give 2.56 g of compound 163. Yield: 25%.

[0653] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 5.70-7.00 (m, 6H), 3.97 (m, 1H), 3.67 (s, 3H), 3.27 (t, J=7.2 Hz, 2H), 2.37 (s, 3H), 2.05 (m, 5H), 1.77 (m, 2H), 1.71 (s, 3H), 1.65 (s, 3H), 1.36-1.62 (m, 4H), 1.45 (m, 2H), 1.25-1.40 (m, 2H), 1.04 (s, 3H), 1.02 (s, 3H); ESI-MS (m/z): calcd for C.sub.27H.sub.43N.sub.2O.sub.3 [M+H].sup.+: 443.3; found: 443.3.

Sample 164: Preparation of Compound 164

[0654] In a 250 mL round bottom flask, 1.0 g (3.38 mmol) of diphosgene was dissolved in 30.0 mL of dichloromethane and cooled to 0° C., followed by addition of 30 mL of saturated sodium carbonate solution and 2.7 g (3.38 mmol) of compound 163 in dichloromethane and stirred for 5 h. Upon completion of the reaction, the organic phase was separated, dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with ethyl acetate in petroleum (5-60%) to provide 1.88 g of compound 164. Yield: 50%.

[0655] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 5.70-7.00 (m, 6H), 4.10 (m, 1H), 3.66 (s, 3H), 3.25 (t, J=7.2 Hz, 2H), 2.35 (s, 3H), 2.03 (m, 5H), 1.75 (m, 2H), 1.70 (s, 3H), 1.63 (s, 3H), 1.36-1.62 (m, 4H), 1.45 (m, 2H), 1.25-1.40 (m, 2H), 1.05 (s, 3H), 1.02 (s, 3H); ESI-MS (m/z): calcd for C.sub.28H.sub.41N.sub.2O.sub.4 [M+H].sup.+: 469.3; found: 469.4.

Sample 165: Preparation of Conjugate 165

[0656] In a 100 mL round bottom flask, 20 mL of anhydrous DMSO was added and heated to 60° C., followed by addition of 2.0 g of dextran (average molecular weight ˜150,000) and stirred until completely dissolved. After the solution was cooled down to 38° C., 250 mg (0.53 mmol) of compound 164 and 65 mg (0.53 mmol) of 4-dimethylaminopyridine (DMAP) were added and stirred for 24 hours. Upon completion of the reaction, the reaction mixture was precipitated in methanol, dialyzed against distilled water, and lyophilized to provide 1.75 g of conjugate 165. Yield: 87%.

[0657] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH); minor signals: 6.50-7.00 (m, CH), 1.02 (m, CH.sub.3).

Synthetic Scheme 37

[0658] ##STR00177## ##STR00178##

Sample 166: Preparation of Compound 166

[0659] To a 250 mL round-bottom flask charged with 2.0 g (6.09 mmol) of docosahexaenoic (DHA), 1.39 g (7.31 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), and 987 mg (7.31 mmol) of 1-hydroxybenzotriazole (HOBt), 30.0 mL of dry DMF were added and stirred for 30 min, followed by addition of 1.41 g (6.09 mmol) of L-tyrosine methyl ester and 1.78 mL (12.78 mmol) of triethylamine, and stirred at room temperature for another 5 h. Upon completion of the reaction, the reaction mixture was partitioned between ethyl acetate (100 mL) and brine (100 mL), the organic phase was further washed with brine twice (100 mL×2), dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with ethyl acetate in petroleum ether (20-80%) to provide 2.72 g of compound 166. Yield: 95%.

[0660] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 6.98 (d, J=7.8 Hz, 2H), 6.77 (d, J=7.8 Hz, 2H), 5.37 (m, 12H), 4.87 (m, 1H), 3.73 (s, 3H), 3.06 (m, 2H), 2.85 (m, 10H), 2.37 (m, 2H), 2.25 (m, 2H), 2.05 (m, 2H), 0.97 (t, J=7.2H, 3H); ESI-MS (m/z): calcd for C.sub.32H.sub.44NO.sub.4 [M+H].sup.+: 506.3; found: 506.4.

Sample 167: Preparation of Compound 167

[0661] In a 250 mL round bottom flask, 1.33, (5.95 mmol) of Boc-2-bromoethylamine and 2.5 g (4.95 mmol) of compound 166 were dissolved in 15.0 mL of anhydrous dimethylformamide, and followed by addition of 3.22 g (9.9 mmol) of cesium carbonate, and heated at 50° C. overnight. Upon completion of the reaction, the reaction mixture was partitioned between ethyl acetate (100 mL) and brine (100 mL). The organic phase was further washed with brine (60 mL×2), dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with ethyl acetate in petroleum ether (10-60%) to give 2.3 g of compound 167. Yield: 71%.

[0662] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 6.97 (d, J=7.8 Hz, 2H), 6.75 (d, J=7.8 Hz, 2H), 5.35 (m, 12H), 4.83 (m, 1H), 3.99 (t, J=7.2 Hz, 2H), 3.75 (s, 3H), 3.51 (t, J=7.2 Hz, 2H), 3.07 (m, 2H), 2.83 (m, 10H), 2.35 (m, 2H), 2.27 (m, 2H), 2.03 (m, 2H), 1.45 (s, 3H), 0.97 (t, J=7.2H, 3H); ESI-MS (m/z): calcd for C.sub.39H.sub.56N.sub.2O.sub.6 [M+H].sup.+: 649.4; found: 649.6.

Sample 168: Preparation of Compound 168

[0663] To a 200 mL round-bottom flask charged with 2.0 g (3.09 mmol) of compound 167, 30 mL of hydrochloride ethanol solution (4.0N) was added, and stirred at room temperature overnight. After removal of volatiles, the residue was purified on a reverse phase C-18 column and eluted with acetonitrile in water (10-70%) to provide 1.64 g of compound 168. Yield: 91%.

[0664] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 6.98 (d, J=7.8 Hz, 2H), 6.78 (d, J=7.8 Hz, 2H), 5.33 (m, 12H), 4.81 (m, 1H), 4.10 (t, J=7.2 Hz, 2H), 3.71 (s, 3H), 3.25 (t, J=7.2 Hz, 2H), 3.06 (m, 2H), 2.87 (m, 10H), 2.36 (m, 2H), 2.24 (m, 2H), 2.07 (m, 2H), 0.96 (t, J=7.2H, 3H); ESI-MS (m/z): calcd for C.sub.34H.sub.49N.sub.2O.sub.4 [M+H].sup.+: 549.3; found: 549.3.

Sample 169: Preparation of Compound 169

[0665] In a 250 mL round bottom flask, 703 mg (2.37 mmol) of diphosgene was dissolved in 20.0 mL of dichloromethane and cooled to 0° C., followed by addition of 20 mL of saturated sodium carbonate solution and 1.3 g (2.37 mmol) of compound 168 in dichloromethane, and stirred for 5 h. Upon completion of the reaction, the organic phase was separated, dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with ethyl acetate in chloroform (5-50%) to provide 982 mg of compound 169. Yield: 72%.

[0666] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 7.02 (d, J=7.8 Hz, 2H), 6.79 (d, J=7.8 Hz, 2H), 5.35 (m, 12H), 4.85 (m, 1H), 4.06 (t, J=7.2 Hz, 2H), 3.72 (s, 3H), 3.62 (t, J=7.2 Hz, 2H), 3.05 (m, 2H), 2.83 (m, 10H), 2.35 (m, 2H), 2.25 (m, 2H), 2.06 (m, 2H), 0.97 (t, J=7.2H, 3H); ESI-MS (m/z): calcd for C.sub.35H.sub.47N.sub.2O.sub.5 [M+H].sup.+: 575.3; found: 575.5.

Sample 170: Preparation of Conjugate 170

[0667] In a 100 mL round bottom flask. 20.0 mL of anhydrous DMSO was added and heated to 60° C., followed by addition of 2.0 g of dextran (average molecular weight ˜100,000) and stirred until completely dissolved. After the solution was cooled down to room temperature, 360 mg (0.62 mmol) of compound 169 and 77 mg (0.63 mmol) of 4-dimethylaminopyridine (DMAP) were added and stirred for 24 hours. Upon completion of the reaction, the reaction mixture was precipitated in methanol, dialyzed against distilled water, and lyophilized to provide 1.68 g of conjugate 170. Yield: 84%.

[0668] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH); minor signals: 6.75-7.20 (m, ArH), 5.32 (m, CH), 1.01 (t, CH.sub.3).

Sample 170: Preparation of Conjugate 171

[0669] In a 100 mL round bottom flask, 20.0 mL of anhydrous DMSO was added and heated to 60° C., and followed by addition of 2.0 g of hydroxyethyl starch (average molecular weight ˜100,000) and stirred until completely dissolved. After the solution was cooled down to room temperature, 250 mg (0.43 mmol) of compound 169 and 52 mg (0.63 mmol) of 4-dimethylaminopyridine (DMAP) were added and stirred for 24 hours. Upon completion of the reaction, the reaction mixture was precipitated in methanol, dialyzed against distilled water, and lyophilized to provide 1.72 g of conjugate 171. Yield: 86%.

[0670] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.20 (m, CHOH, CH.sub.2OH, CH.sub.2O); minor signals: 6.75-7.20 (m, ArH), 5.33 (m, CH), 1.02 (t, CH.sub.3).

Synthetic Scheme 38

[0671] ##STR00179## ##STR00180##

Sample 172: Preparation of Compound 172

[0672] Under the protection of nitrogen, 10.0 g (23.20 mmol) of alpha-tocopherol was dissolved in 100 mL of anhydrous tetrahydrofuran and cooled to −10° C., and then potassium t-butoxide solution (1.0 M×35.0 mL) was added and stirred for 30 minutes. To the above solution, 2.8 mL (30.16 mmol) of methyl bromoacetate was added and stirred overnight. After warming up to room temperature, the reaction mixture was evaporated and the residue was partitioned between ethyl acetate (200 mL) and brine (200 mL); the organic phase was further washed with brine (100 mL×2), dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with ethyl acetate in petroleum ether (0-20%) to give 10.3 g of compound 172. Yield: 88%.

[0673] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 4.30 (s, 2H), 3.84 (s, 3H), 2.59 (t, J=7.0 Hz, 2H), 2.07-2.25 (m, 9H), 1.82 (m, 2H), 1.00-1.70 (m, 24H), 0.85 (m, 12H); ESI-MS (m/z): calcd for C.sub.32H.sub.55O.sub.4 [M+H]: 503.4; found: 503.5.

Sample 173: Preparation of Compound 173

[0674] In a 250 mL round bottom flask charged with 6.0 g (11.94 mmol) of compound 172 and 1.53 g (38.25 mmol) of sodium hydroxide, 30 mL of dimethylformamide-water (7:3) was added and stirred at room temperature for 2 days. After the completion of the reaction, the mixture was acidified with 2.0N HCl to pH=1.0, and extracted with ethyl acetate (100 mL×3); the organic phases were pooled, dried over MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with ethyl acetate in petroleum ether (0-50%) to give 4.32 g of compound 173. Yield: 74%.

[0675] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 4.37 (s, 2H), 2.52 (t, J=7.0 Hz, 2H), 2.07-2.25 (m, 9H), 1.82 (m, 2H), 1.00-1.70 (m, 24H), 0.85 (m, 12H); ESI-MS (m/z): calcd for C.sub.31H.sub.53O.sub.4 [M+H]: 489.3; found: 489.3.

Sample 174: Preparation of Compound 174

[0676] In a 250 mL round bottom flask, 6.5 g (13.31 mmol) of compound 173, 3.82 g (19.96 mmol) of N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride (EDC) and 2.30 g (19.96 mmol) of N-hydroxysuccinic acid lactam (NHS) were dissolved in 100 mL of chloroform and stirred at room temperature overnight. After the completion of the reaction, the reaction mixture was washed with brine, dried over MgSO.sub.4, filtered, and evaporated to dryness to provide 7.63 g of compound 174. Yield: 98%.

[0677] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 4.33 (s, 2H), 2.75 (m, 4H), 2.53 (t, J=7.0 Hz, 2H), 2.07-2.25 (m, 9H), 1.82 (m, 2H), 1.00-1.70 (m, 24H), 0.85 (m, 12H); ESI-MS (m/z): calcd for C.sub.35H.sub.56NO.sub.6 [M+H]: 586.4, found: 586.5.

Sample 175: Preparation of Compound 175

[0678] In a 250 mL round bottom flask, 2.78 g (11.27 mmol) of compound N.sub.ε-Boc-L-lysine and 3.74 g (45.54 mmol) of sodium bicarbonate were dissolved in 100.0 mL of methanol-water (2:1), followed by addition of 6.0 g (10.25 mmol) of compound 174, and stirred overnight. Upon completion of the reaction, the reaction mixture was acidified with 2.0N HCl to pH=1.0, and extracted with ethyl acetate (100 mL×3); the organic phases were combined together, dried over MgSO.sub.4, concentrated, and purified on a silica gel eluted with methanol in chloroform (0-10%) to provide 5.21 g of compound 175. Yield: 71%.

[0679] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 4.57 (m, 1H), 4.23 (s, 2H), 3.27 (t, J=7.0 Hz, 2H), 2.52 (t, J=7.0 Hz, 2H), 2.07-2.25 (m, 9H), 1.82 (m, 2H), 1.00-1.70 (m, 39H), 0.83 (m, 12H); ESI-MS (m/z): calcd for C.sub.42H.sub.73N.sub.2O.sub.7 [M+H]: 717.5; found: 717.7.

Sample 176: Preparation of Compound 176

[0680] To a 250 mL round-bottom flask charged with 5.0 g (6.98 mmol) of compound 175 and 2.0 g (38.93 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), 100 mL of anhydrous dichloromethane were added and stirred at room temperature for 30 min; and then 2.0 mL of absolute ethanol and 1.28 g (10.47 mmol) of DMAP were added. The reaction mixture was continuously stirred overnight. Upon completion of the reaction, the reaction mixture was washed with brine (100 mL×2), dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with methanol in chloroform (0-10%) to provide 4.31 g of compound 176. Yield: 83%.

[0681] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 4.58 (m, 1H), 4.33 (s, 2H), 4.21 (q, J=7.0 Hz, 2H), 3.19 (t, J=7.0 Hz, 2H), 2.52 (t, J=7.0 Hz, 2H), 2.07-2.25 (m, 9H), 1.82 (m, 2H), 1.00-1.70 (m, 42H), 0.83 (m, 12H); ESI-MS (m/z): calcd for C.sub.44H.sub.77N.sub.2O.sub.7 [M+H].sup.+: 745.5; found: 745.6.

Sample 177: Preparation of Compound 177

[0682] To a 250 mL round-bottom flask charged with 5.0 g (6.72 mmol) of compound 176, 50 mL of hydrochloride ethanol solution (4.0N) was added and stirred at room temperature overnight. After removal of volatiles, the residue was purified on a silica gel column and eluted with methanol in chloroform (0-12%) to provide 4.53 g of compound 177. Yield: 99%.

[0683] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 4.70 (m, 1H), 4.11-4.30 (m, 4H), 3.16 (t, J=7.0 Hz, 2H), 2.52 (t, J=7.0 Hz, 2H), 2.07-2.25 (m, 9H), 1.82 (m, 2H), 1.00-1.70 (m, 33H), 0.85 (m, 12H); ESI-MS (m/z): calcd for C.sub.39H.sub.69N.sub.2O.sub.5 [M+H]: 645.5; found: 645.7.

Sample 178: Preparation of Compound 178

[0684] In a 250 mL round bottom flask, 1.31 g (4.40 mmol) of diphosgene was dissolved in 30.0 mL of dichloromethane and cooled to 0° C., followed by addition of 30 mL of saturated sodium carbonate solution and 3.0 g (4.40 mmol) of compound 177 in dichloromethane, and stirred for 5 h.

[0685] Upon completion of the reaction, the organic phase was separated, dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with ethyl acetate in chloroform (5-60%) to provide 1.83 g of compound 178. Yield: 62%.

[0686] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 4.64 (m, 1H), 4.11-4.30 (m, 4H), 3.23 (t, J=7.0 Hz, 2H), 2.52 (t, J=7.0 Hz, 2H), 2.07-2.25 (m, 9H), 1.82 (m, 2H), 1.00-1.70 (m, 33H), 0.83 (m, 12H); ESI-MS (m/z): calcd for C.sub.40H.sub.67N.sub.2O.sub.6 [M+H].sup.+: 671.5; found: 671.6.

Sample 179: Preparation of Conjugate 179

[0687] In a 100 mL round bottom flask, 20 mL of anhydrous DMSO was added and heated to 60° C., and followed by addition of 2.0 g of dextran (average molecular weight 100,000) and stirred until completely dissolved. After the solution was cooled down to room temperature, 450 mg (0.67 mmol) of compound 178 and 82 mg (0.67 mmol) of 4-dimethylaminopyridine (DMAP) were added and stirred for 24 hours. Upon completion of the reaction, the reaction mixture was precipitated in methanol, dialyzed against distilled water, and lyophilized to provide 1.87 g of conjugate 179. Yield: 93%.

[0688] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH); minor signals: 2.00-2.30 (m, CH.sub.3), 0.83 (m, CH.sub.3).

Synthetic Scheme 39

[0689] ##STR00181##

Sample 180: Preparation of Compound 180

[0690] In a 250 mL round bottom flask, 20.0 g (71.32 mmol) of linoleic acid was dissolved in 15.5 mL (213.96 mmol) of sulfonyl chloride, and heated to 50° C. for 5 hours. After removal of then volatiles, 100 mL of anhydrous tetrahydrofuran and 23.2 g (356.6 mmol) of sodium azide were added, and the mixture was refluxed for 3 hours, filtered, and filtrate was subjected to fractional distillation to give 10.5 g of compound 180. Yield: 51%.

[0691] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 5.33 (m, 4H), 3.21 (t, J=7.0 Hz, 2H), 2.75 (m, 2H), 2.03 (m, 4H), 1.25-1.70 (m, 16H), 0.85 (t, J=7.0 Hz, 3H); ESI-MS (m/z): calcd for C.sub.18H.sub.32NO [M+H].sup.+: 278.2; found: 278.2.

Sample 181: Preparation of Conjugate 181

[0692] In a 100 mL round bottom flask, 20 mL of anhydrous DMSO was added and heated to 60° C., and followed by addition of 3.0 g of hydroxyethyl starch (average molecular weight ˜10,000) and stirred until completely dissolved. After the solution was cooled down to room temperature, 500 mg (1.81 mmol) of compound 180 and 122 mg (1.81 mmol) of 4-dimethylaminopyridine (DMAP) were added and stirred for 24 hours. Upon completion of the reaction, the reaction mixture was precipitated in methanol, dialyzed against distilled water, and lyophilized to provide 2.21 g of conjugate 181. Yield: 73%.

[0693] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH); minor signals: 5.31 (m, CH), 1.25-2.20 (m, CH.sub.2), 0.81 (t, CH.sub.3).

Synthetic Scheme 40

[0694] ##STR00182##

Sample 182: Preparation of Compound 182

[0695] In a 250 mL round bottom flask, 1.6 g (13.21 mmol) of cysteine and 2.22 g (26.42 mmol) of NaHCO.sub.3 were dissolved in 100.0 mL of methanol-water (2:1), followed by slow addition of 5.06 g (11.89 mmol) of docosahexaenoic acid N-hydroxysuccinimide ester in dry THF, and stirred overnight. Upon completion of the reaction, the reaction mixture was acidified with 2.0N HCl to pH=1.0 and extracted with ethyl acetate three times (100 mL×3); the organic phases were pooled, dried over MgSO.sub.4, concentrated, and purified on a silica gel column and eluted with methanol in chloroform (0-12%) to give 2.87 g of compound 182. Yield: 56%.

[0696] .sup.1H NMR (300 MHz, DMSO-d.sub.6, ppm): δ 8.02 (d, J=6.0 Hz, 1H), 5.39 (m, 12H), 4.43 (m, 1H), 2.60-2.80 (m, 14H), 2.32-2.52 (m, 4H), 2.15 (t, J=7.0 Hz, 2H), 0.91 (t, J=7.0 Hz, 3H); ESI-MS (m/z): calcd for C.sub.25H.sub.38NO.sub.3S [M+H].sup.+: 432.3; found: 432.5.

Sample 183: Preparation of Conjugate 183

[0697] In a 100 mL round bottom flask, 2.0 g of functionalized dextran 115 was dissolved in 20.0 mL of anhydrous DMSO, followed by addition of 380 mg (0.89 mmol) of compound 182 in methanol, and stirred for 24 hours. The reaction mixture was precipitated in methanol, dialyzed against distilled water, and lyophilized to provide 1.83 g of conjugate 183. Yield: 91%.

[0698] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH); minor signals: 5.35 (m, CH), 1.01 (t, CH.sub.3).

Synthetic Scheme 41

[0699] ##STR00183##

Sample 184: Preparation of Compound 184

[0700] To a 250 mL round-bottom flask charged with 2.0 g (6.09 mmol) of docosahexaenoic (DHA), 1.39 g (7.31 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), and 987 mg (7.31 mmol) of 1-hydroxybenzotriazole (HOBt), 30.0 mL of dry DMF were added and stirred for 30 min, followed by addition of 706 mg (3.03 mmol) of L-tyrosine methyl ester hydrochloride, and 1.78 mL (12.18 mmol) of triethylamine, and stirred at room temperature for another 5 h. Upon completion of the reaction, the reaction mixture was partitioned between ethyl acetate (100 mL) and brine (100 mL), and the organic phase was further washed with brine twice (100 mL×2), dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with ethyl acetate in petroleum ether (20-80%) to provide 1.73 g of compound 184. Yield: 73%.

[0701] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 5.35-5.45 (m, 24H), 4.42 (m, 1H), 3.65 (s, 3H), 3.21 (t, J=7.2 Hz, 2H), 2.50-3.00 (m, 20H), 2.10-2.40 (m, 8H), 2.01 (m, 4H), 1.75 (m, 2H), 1.47 (m, 2H), 1.32 (m, 2H), 0.92 (t, J=7.0 Hz, 6H); ESI-MS (m/z): calcd for C.sub.51H.sub.77N.sub.2O.sub.4 [M+H].sup.+: 781.6; found: 781.7.

Sample 185: Preparation of Compound 185

[0702] In a 100 mL round bottom flask, 1.5 g (1.92 mmol) of compound 180 and 307 mg (7.69 mmol) of sodium hydroxide were dissolved in 30 of dimethylformamide-water (7:3), and stirred at room temperature 2 day. After the completion of the reaction, the mixture was acidified with 2.0 N HCl, and extracted with ethyl acetate three times (100 mL×3); the organic phases were pooled, dried over MgSO.sub.4, concentrated, and purified on a silica gel column and eluted with methanol in chloroform (0-10%) to give 1.13 g of compound 185. Yield: 77%.

[0703] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 5.35-5.45 (m, 24H), 4.51 (m, 1H), 3.25 (t, J=7.2 Hz, 2H), 2.50-3.00 (m, 20H), 2.10-2.40 (m, 8H), 2.01 (m, 4H), 1.77 (m, 2H6), 1.49 (m, 2H), 1.32 (m, 2H), 0.94 (t, J=7.0 Hz, 6H); ESI-MS (m/z): calcd for C.sub.50H.sub.75N.sub.2O.sub.4 [M+H].sup.+: 767.6; found: 767.9.

Sample 186: Preparation of Conjugate 186

[0704] In a 100 mL round-bottom flask, 3.0 g of functionalized dextran 142 was dissolved in 20.0 mL of anhydrous DMSO, and followed by addition of 131 mg (0.68 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), 92 mg (0.68 mmol) of 1-hydroxybenzotriazole (HOBt), and 200 uL (1.36 mmol) of triethylamine were added and stirred for 48 hours. Upon completion of the reaction, the reaction mixture was precipitated in methanol, dialyzed against distilled water, and lyophilized to provide 2.31 g of conjugate 186. Yield: 77%.

[0705] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH); minor signals: 7.20-8.50 (m, CONH), 5.32 (m, CH), 1.01 (m, CH.sub.3).

Synthetic Scheme 42

[0706] ##STR00184##

Sample 187: Preparation of Compound 187

[0707] In a 250 mL round bottom flask, 4.55 g (20.32 mmol) of Boc-2-bromoethylamine and 5.0 g (16.93 mmol) of Boc-L-tyrosine methyl ester were dissolved in 15.0 mL of anhydrous dimethylformamide, and followed by addition of 11.0 g (9.9 mmol) of cesium carbonate, and heated at 50° C. and stirred overnight. Upon completion of the reaction, the reaction mixture was partitioned between ethyl acetate (200 mL) and brine (200 mL). The organic phase was further washed with brine twice (100 mL×2), dried over anhydrous MgSO.sub.4., filtered, concentrated, and purified on a silica gel column and eluted with ethyl acetate in petroleum ether (20-80%) to give 4.82 g of compound 187, Yield: 65%.

[0708] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 7.03 (d, J=7.8 Hz, 2H), 6.81 (d, J=7.8 Hz, 2H), 5.01 (d, J=6.0 Hz, 1H), 4.51 (m, 1H), 3.95 (t, J=7.2 Hz, 2H), 3.70 (s, 3H), 3.52 (m, 2H), 3.08 (m, 2H), 1.44 (s, 9H), 1.42 (s, 9H); ESI-MS (m/z): calcd for C.sub.22H.sub.35N.sub.2O.sub.7 [M+H].sup.+: 439.2; found: 439.1.

Sample 188: Preparation of Compound 188

[0709] To a 250 mL round-bottom flask charged with 4.5 g (10.27 mmol) of compound 187, 50 mL of hydrochloride ethanol solution (4.0N) was added and stirred at room temperature overnight. After removal of volatiles, the residue was purified on a reverse phase C-18 column and eluted with acetonitrile in water (5-50%) to provide 3.01 g of compound 188. Yield: 95%.

[0710] .sup.1H NMR (300 MHz, D.sub.2O, ppm): δ 7.28 (d, J=7.8 Hz, 2H), 7.06 (d, J=7.8 Hz, 2H), 4.42 (m, 1H), 4.31 (t, J=7.2 Hz, 2H), 3.85 (s, 3H), 3.43 (m, 2H), 3.28 (m, 2H); ESI-MS (m/z): calcd for C.sub.12H.sub.19N.sub.2O.sub.3 [M+H].sup.+: 239.1; found: 239.1.

Sample 189: Preparation of Compound 189

[0711] To a 250 mL round-bottom flask charged with 2.0 g (6.09 mmol) of docosahexaenoic (DHA), 1.39 g (7.31 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), and 987 mg (7.31 mmol) of 1-hydroxybenzotriazole (HOBt), 30.0 mL of dry DMF was added and stirred for 30 min, and followed by addition of 942 mg (3.03 mmol) of compound 188 and 1.78 mL (12.18 mmol) of triethylamine and stirred at room temperature for another 6 hours. Upon completion of the reaction, the reaction mixture was partitioned between ethyl acetate (100 mL) and brine (100 mL), the organic phase was further washed with brine twice (100 mL×2), dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with ethyl acetate in petroleum ether (10-70%) to provide 1.69 g of compound 189. Yield: 65%.

[0712] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 7.00 (d, J=7.8 Hz, 2H), 6.80 (d, J=7.8 Hz, 2H), 5.92 (m, 2H), 5.35-5.45 (m, 24H), 4.82 (m, 1H), 3.99 (t, J=7.2 Hz, 2H), 3.71 (s, 3H), 3.64 (m, 2H), 3.10 (m, 2H), 2.70-2.90 (m, 20H), 2.41 (m, 4H), 2.23 (m, 4H), 2.06 (m, 4H), 0.96 (t, J=7.2 Hz, 6H); ESI-MS (m/z): calcd for C.sub.56H.sub.79N.sub.2O.sub.5 [M+H].sup.+: 859.6; found: 859.8.

Sample 190: Preparation of Compound 190

[0713] In a 100 mL round bottom flask, 1.6 g (1.86 mmol) of compound 189 and 298 mg (7.56 mmol) of sodium hydroxide were dissolved in 30 mL of dimethylformamide-water (7:3), and stirred at room temperature 2 day. After the completion of the reaction, the mixture was acidified with 2.0 N Eta and extracted with ethyl acetate three times (100 mL×3) the organic phases were pooled dried over MgSO.sub.4, concentrated, and purified on a silica gel column and eluted with methanol in chloroform (0-10%) to give 1.27 g of compound 190. Yield: 81%.

[0714] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 7.07 (d, J=7.8 Hz, 2H), 6.78 (d, J=7.8 Hz, 2H), 6.15 (m, 2H), 5.30-5.45 (m, 24H), 4.82 (m, 1H), 3.97 (t, J=7.2 Hz, 2H), 3.63 (m, 2H), 3.13 (m, 2H), 2.70-2.90 (m, 20H), 2.39 (m, 4H), 2.25 (m, 4H), 2.02 (m, 4H), 0.95 (t, J=7.2 Hz, 6H); ESI-MS (m/z): calcd for C.sub.55H.sub.77N.sub.2O.sub.5 [M+H].sup.+: 845.6; found: 845.7.

Sample 191: Preparation of Conjugate 191

[0715] In a 100 mL round-bottom flask, 3.6 g of functionalized dextran 142 was dissolved in 20.0 mL of anhydrous DMSO, and followed by addition of 450 mg (0.53 mmol) of compound 190, 153 mg (0.79 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), 106 mg (0.79 mmol) of 1-hydroxybenzotriazole (HOBt), and 200 uL (1.36 mmol) of triethylamine and stirred for 48 hours. Upon completion of the reaction, the reaction mixture was precipitated in methanol, dialyzed against distilled water, and lyophilized to provide 2.98 g of conjugate 191. Yield: 82%.

[0716] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH); minor signals: 7.25-8.50 (m, CONH), 6.75-7.20 (m, ArH), 5.32 (m, CH), 0.99 (m, CH.sub.3).

Synthetic Scheme 43

[0717] ##STR00185##

Sample 192: Preparation of Compound 192

[0718] In a 500 mL round bottom flask, 9.30 g (55.71 mmol) of methyl 3-bromopropionate and 20.0 g (46.43 mmol) of alpha-tocopherol were dissolved in 50.0 mL of anhydrous dimethylformamide, and followed by addition of 30.3 g (92.86 mmol) of cesium carbonate, heated at 50° C. and stirred for 12 hours. Upon completion of the reaction, the reaction mixture was partitioned between ethyl acetate (200 mL) and brine (200 mL). The organic phase was further washed with brine twice (100 mL×2), dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with ethyl acetate in petroleum ether (20-80%) to give 14.6 g of compound 192. Yield: 61%.

[0719] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 3.95 (t, J=7.0 Hz, 2H), 3.68 (s, 3H), 2.79 (t, J=7.0 Hz, 2H), 2.59 (t, J=7.0 Hz, 2H), 2.07-2.25 (m, 9H), 1.82 (m, 2H), 1.00-1.70 (m, 24H), 0.85 (m, 12H); ESI-MS: calcd for C.sub.33H.sub.57O.sub.4 [M+H].sup.+: 517.4; found: 517.6.

Sample 193: Preparation of Compound 193

[0720] In a 250 mL round bottom flask, 12.0 g (23.23 mmol) of compound 192 and 3.72 g (92.95 mmol) of sodium hydroxide were dissolved in 80 mL of dimethylformamide-water (7:3), and stirred at room temperature 2 day. Ater the completion of the reaction, the mixture was acidified with 2.0 N HCl to pH=1.0 and extracted with ethyl acetate three times (100 mL×3); the organic phases were pooled, dried over MgSO.sub.4, concentrated, and purified on a silica gel column and eluted with ethyl acetate in petroleum ether (0-50%) to give 10.1 g of compound 193. Yield: 86%.

[0721] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 3.98 (t, J=7.0 Hz, 2H), 2.83 (t, J=7.0 Hz, 2H), 2.59 (t, J=7.0 Hz, 2H), 2.07-2.25 (m, 9H), 1.82 (m, 2H), 1.00-1.70 (m, 24H), 0.85 (m, 12H); ESI-MS: calcd for C.sub.32H.sub.55O.sub.4 [M+H].sup.+: 503.4; found: 503.3.

Sample 194: Preparation of Compound 194

[0722] To a 250 mL round-bottom flask charged with 9.5 g (18.91 mmol) of compound 193, 5.42 g (28.36 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), and 3.83 g (28.36 mmol) of 1-hydroxybenzotriazole (HOBt), 50.0 mL of dry DMF was added and stirred for 30 min, followed by addition of 4.41 g (18.91 mmol) of L-lysine methyl ester hydrochloride and 5.2 mL (37.82 mmol) of triethylamine and stirred at room temperature for another 6 hours. Upon completion of the reaction, the reaction mixture was partitioned between ethyl acetate (200 mL) and brine (200 mL), the organic phase was further washed with brine twice (100 mL×2), dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with ethyl acetate in petroleum ether (10-70%) to provide 12.6 g of compound 194. Yield: 59%.

[0723] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 4.77 (m, 1H), 3.70-4.10 (m, 7H), 3.41 (t, J=7.0 Hz, 2H), 2.70-2.90 (m, 4H), 2.55 (m, 4H), 2.07-2.25 (m, 18H), 1.00-1.83 (m, 56H), 0.85 (m, 24H); ESI-MS: calcd for C.sub.71H.sub.121N.sub.2O.sub.8 [M+H].sup.+: 1129.9; found: 1130.1.

Sample 195: Preparation of Compound 195

[0724] In a 250 mL round bottom flask, 11.0 g (9.74 mmol) of compound 194 and 1.56 g (38.98 mmol) of sodium hydroxide were dissolved in 100 mL of dimethylformamide-water (7:3), and stirred at room temperature 2 day. After the completion of the reaction, the mixture was acidified with 2.0 N HCl to pH=1.0 and extracted with ethyl acetate three times (150 mL×3); the organic phases were pooled, dried over MgSO.sub.4, concentrated, and purified on a silica gel column and eluted with methanol in chloroform (0-10%) to give 8.79 g of compound 195. Yield: 81%.

[0725] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 4.73 (m, 1H), 3.70-4.10 (m, 4H), 3.42 (t, J=7.0 Hz, 2H), 2.70-2.90 (m, 4H), 2.55 (m, 4H), 2.07-2.25 (m, 18H), 1.00-1.83 (m, 56H), 0.85 (m, 24H); ESI-MS: calcd for C.sub.70H.sub.119N.sub.2O.sub.8 [M+H].sup.+: 1115.9; found: 1115.8.

Sample 196: Preparation of Conjugate

[0726] In a 100 mL round-bottom flask, 3.0 g of functionalized dextran 142 was dissolved in 20.0 mL of anhydrous DMSO, and followed by addition of 500 mg (0.53 mmol) of compound 195, 129 mg (0.68 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), 92 mg (0.68 mmol) of 1-hydroxybenzotriazole (HOBt), and 139 uL (1.00 mmol) of triethylamine were added and stirred for 48 hours. Upon completion of the reaction, the reaction mixture was precipitated in methanol, dialyzed against distilled water, and lyophilized to provide 2.16 g of conjugate 1%. Yield: 72%.

[0727] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH); minor signals: 7.25-8.50 (m, CONH), 2.00 (m, CH.sub.3), 0.82 (m, CH.sub.3).

Synthetic Scheme 44

[0728] ##STR00186##

Sample 197: Preparation of Compound 197

[0729] Fmoc-L-Lys(ivDde)-OH was bonded to 3.0 g of trityl chloride resin (substitution: 0.61 mmol/g) and loaded onto a peptide synthesizer using standard protocols for Fmoc solid-phase peptide synthesis: Fmoc protecting group was deprotected with 20% piperidine in DMF, and ivdde protecting group deported with 5% hydrazine in DMF; 5 equivalents of protected amino acid or docosahexaenoic acid (DHA), 5 equivalents of coupling agent: DIPC and hydroxybenzotriazole (HOBt) and 5 equivalent diisopropylethylamine (DIPEA) were used in coupling steps. After completion of the synthesis, the peptide derivative was cleaved from the resin using the cocktail: a dichloromethane/trifluoroethanol/acetic acid (8:1:1) and purified through a silica gel column and eluted with methanol in chloroform to give 1.21 g of compound 197. Yield: 55%.

[0730] .sup.1H NMR (300 MHz, CDCl3, ppm): δ 5.35-5.50 (m, 24H), 4.51 (m, 2H), 3.23 (m, 4H), 2.70-2.85 (m, 20H), 2.25-2.50 (m, 8H), 2.17 (m, 4H), 1.75 (m, 4H), 1.56 (m, 4H), 1.31 (m, 4H), 0.96 (t, J=7.2 Hz, 9H); ESI-MS: calcd for C.sub.78H.sub.118N.sub.4O.sub.6 [M+2H].sup.+:1206.9; found: 1207.3.

Sample 198: Preparation of Conjugate 198

[0731] In a 100 mL round-bottom flask, 2.0 g of functionalized dextran 142 was dissolved in 30.0 mL of anhydrous DMSO, and followed by addition of 200 mg (0.17 mmol) of compound 197, 48 mg (0.25 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), 33 mg (0.25 mmol) of 1-hydroxybenzotriazole (HOBt), and 69 uL (0.5 mmol) of triethylamine were added and stirred for 48 hours. Upon completion of the reaction, the reaction mixture was precipitated in methanol, dialyzed against distilled water, and lyophilized to provide 1.73 g of conjugate 198. Yield: 87%.

[0732] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH); minor signals: 7.25-8.50 (m, CONH), 5.33 (m, CH), 1.02 (m, CH.sub.3).

Part 4. Preparation of Functionalized Lipid-Polysaccharide Conjugates

Synthetic Scheme 45

[0733] ##STR00187##

Sample 199: Preparation of Compound 199

[0734] To a 250 mL round-bottom flask charged with 10.0 g (35.55 mmol) of Boc-L-tyrosine methyl ester, 8.15 g (42.66 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), and 5.76 g (42.66 mmol) of 1-hydroxybenzotriazole (HOBt), 50.0 mL of dry DMF was added and stirred for 30 min, followed by addition of 6.37 mg (35.66 mmol) of 6-azido-hexanylamine hydrochloride and 9.8 mL (71.1 mmol) of triethylamine and stirred at room temperature overnight. Upon completion of the reaction, the reaction mixture was partitioned between ethyl acetate (200 mL) and brine (200 mL), the organic phase was further washed with brine twice (100 mL×2), dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with ethyl acetate in petroleum ether (10-70%) to provide 11.9 g of compound 199. Yield: 83%.

[0735] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 6.99 (d, J=7.8 Hz, 2H), 6.67 (d, J=7.8 Hz, 2H), 4.15 (m, 1H), 3.25 (t, J=7.2 Hz, 2H), 3.19 (m, 2H), 3.09 (m, 1H), 2.97 (m, 1H), 1.59 (m, 2H), 1.35 (s, 9H), 1.33 (m, 4H), 1.17 (m, 2H); ESI-MS: calcd for C.sub.20H.sub.32N.sub.5O.sub.4 [M+H].sup.+: 406.2; found: 406.3.

Sample 200: Preparation of Compound 200

[0736] The preparation of compound 200 was similar to that of compound 199.

[0737] .sup.1H NMR (300 MHz, Acetone-d.sub.6, ppm): δ 7.05 (d, J=7.8 Hz, 2H), 6.72 (d, J=7.8 Hz, 2H), 4.25 (m, 1H), 3.25-3.70 (m, 10H), 2.95 (m, 1H), 2.87 (m, 1H), 1.33 (s, 9H); ESI-MS: calcd for C.sub.20H.sub.32N.sub.5O.sub.6 [M+H].sup.+: 438.2; found: 438.3.

Sample 201: Preparation of Compound 201

[0738] In a 250 mL round bottom flask, 10.0 g (20.32 mmol) of compound 199 and 7.93 g (29.58 mmol) 2-(3-bromopropyl)isoindoline-1,3-dione were dissolved in 60.0 mL of anhydrous dimethylformamide, followed by addition of 16.1 g (49.3 mmol) of cesium carbonate, and heated at 50° C. and stirred overnight. Upon completion of the reaction, the reaction mixture was partitioned between ethyl acetate (200 mL) and brine (200 mL). The organic phase was further washed with brine twice (100 mL×2), dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with ethyl acetate in petroleum ether (20-80%) to give 9.2 g of compound 201. Yield: 65%.

[0739] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 7.78 (d, J=7.8 Hz, 2H), 7.65 (d, J=7.8 Hz, 2H), 7.00 (d, J=7.8 Hz, 2H), 6.67 (d, J=7.8 Hz, 2H), 4.13 (m, 1H), 3.95 (t, J=7.2 Hz, 2H), 3.83 (t, J=7.2 Hz, 2H), 3.25 (t, J=7.2 Hz, 2H), 3.18 (m, 2H), 2.98 (m, 1H), 2.85 (m, 1H), 2.12 (m, 2H), 1.50 (m, 2H), 1.37 (s, 9H), 1.35 (m, 4H), 1.19 (m, 2H); ESI-MS: calcd for C.sub.31H.sub.41N.sub.6O.sub.6 [M+H].sup.+: 593.3; found: 593.3.

Sample 202: Preparation of Compound 202

[0740] The preparation of compound 202 is similar to that of compound 201.

[0741] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 7.84 (m, 2H), 7.73 (m, 2H), 7.05 (d, J=7.8 Hz, 2H), 6.70 (d, J=7.8 Hz, 2H), 4.25 (m, 1H), 3.96 (t, J=7.2 Hz, 2H), 3.88 (t, J=7.2 Hz, 2H), 3.25-3.70 (m, 10H), 2.96 (m, 2H), 2.20 (m, 2H), 1.43 (s, 9H); ESI-MS: calcd for C.sub.31H.sub.41N.sub.6O.sub.8 [M+H].sup.+: 625.3; found: 625.3.

Sample 203: Preparation of Compound 203

[0742] In a 250 mL round bottom flask, 9.0 g (15.17 mmol) of compound 201 was dissolved in 100 mL of ethanol, followed by addition of 1.0 mL of anhydrous hydrazine. Upon completion of the reaction, the white precipitate was filtered off, and the filtrate was concentrated and purified on a reversed phase C-18 column and eluted with acetonitrile in water (10-70%) to provide 5.68 g of compound 203. Yield: 81%.

[0743] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 7.01 (d, J=7.8 Hz, 2H), 6.72 (d, J=7.8 Hz, 2H), 4.15 (m, 1H), 3.96 (t, J=7.2 Hz, 2H), 3.26 (t, J=7.2 Hz, 2H), 3.18 (m, 2H), 2.97 (m, 1H), 2.87 (m, 1H), 2.67 (m, 2H), 1.96 (m, 2H), 1.53 (m, 2H), 1.35 (m, 4H), 1.19 (m, 2H); ESI-MS: calcd for C.sub.23H.sub.39N.sub.6O.sub.4 [M+H].sup.+: 463.3; found: 463.5.

Sample 204: Preparation of Compound 204

[0744] The preparation of compound 204 was similar to that of 203.

[0745] .sup.1H NMR (300 MHz, CD.sub.3OD, ppm): δ 7.13 (d, J=7.8 Hz, 2H), 6.85 (d, J=7.8 Hz, 2H), 4.25 (m, 1H), 4.02 (t, J=7.2 Hz, 2H), 3.25-3.70 (m, 10H), 2.96 (m, 1H), 2.86 (d, J=7.8 Hz, 2H), 2.76 (m, 1H), 1.92 (m, 2H), 1.38 (s, 9H); ESI-MS: calcd for C.sub.23H.sub.39N.sub.6O.sub.6 [M+H].sup.+: 495.3; found: 495.3.

Sample 205: Preparation of Compound 205

[0746] In a 250 mL round bottom flask, 3.56 g (10.82 mmol) of docosahexaenoic acid (DHA) and (12.98 mmol) of 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) were combined in 50.0 mL of anhydrous dimethylformamide, followed by addition of 5.0 g (10.82 mmol) of compound 203 and 1.8 mL triethylamine (12.98 mmol) and stirred overnight. Upon completion of the reaction, the reaction mixture was partitioned from ethyl acetate (100 mL) and brine (100 mL); the organic phase was further washed with brine twice (50 mL×2), and dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with ethyl acetate in petroleum ether (10-80%) to give 6.6 g of compound 205. Yield: 79%.

[0747] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 7.05 (d, J=7.8 Hz, 2H), 6.75 (d, J=7.8 Hz, 2H), 5.35-5.50 (m, 12H), 4.15 (m, 1H), 3.95 (t, J=7.2 Hz, 2H), 3.37 (t, J=7.2 Hz, 2H), 3.21 (t, J=7.2 Hz, 2H), 3.18 (m, 2H), 2.95 (m, 2H), 2.89 (m, 10H), 2.35 (m, 2H), 2.17 (m, 2H), 2.12 (m, 2H), 1.98 (m, 2H), 1.51 (m, 2H), 1.37 (s, 9H), 1.34 (m, 4H), 1.18 (m, 2H), 0.95 (t, J=7.2 Hz, 3H); ESI-MS: calcd for C.sub.45H.sub.69N.sub.6O.sub.5 [M+H].sup.+: 773.5; found: 773.7.

Sample 206: Preparation of Compound 206

[0748] The preparation of compound 206 was similar to that of compound 205.

[0749] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 7.11 (d, J=7.8 Hz, 2H), 6.80 (d, J=7.8 Hz, 2H), 5.35-5.50 (m, 12H), 4.25 (m, 1H), 3.98 (t, J=7.2 Hz, 2H), 3.25-3.70 (m, 10H), 2.96 (m, 3H), 2.87 (m, 10H), 2.40 (m, 2H), 2.25 (d, J=7.2 Hz, 2H), 2.06 (m, 2H), 1.96 (m, 2H), 1.40 (s, 9H), 0.95 (t, J=7.2 Hz, 3H); ESI-MS: calcd for C.sub.45H.sub.69N.sub.6O.sub.7 [M+H].sup.+: 805.5, found: 805.6.

Sample 207: Preparation of Compound 207

[0750] To a 250 mL round-bottom flask charged with 5.0 g (6.48 mmol) of compound 205, 50 mL of hydrochloride ethanol solution (4.0N) was added, and stirred at room temperature overnight. After removal of volatiles, the residue was purified on a reverse phase column and eluted with acetonitrile in water (10-80%) to provide 3.7 g of compound 207. Yield: 85%.

[0751] .sup.1H NMR (300 MHz, CD.sub.3OD, ppm): δ 7.07 (d, J=7.8 Hz, 2H), 6.82 (d, J=7.8 Hz, 2H), 5.28 (m, 12H), 3.89 (t, J=7.2 Hz, 2H), 3.81 (m, 1H), 3.21 (m, 4H), 2.97 (m, 2H), 2.76 (m, 10H), 2.30 (m, 2H), 2.12 (t, J=7.2 Hz, 2H), 1.98 (m, 2H), 1.86 (m, 2H), 1.45 (m, 2H), 1.25 (m, 4H), 1.16 (m, 2H), 0.88 (t, J=7.2 Hz, 2H); ESI-MS: calcd for C.sub.40H.sub.61N.sub.6O.sub.3 [M+H].sup.+: 673.5; found: 673.5.

Sample 208: Preparation of Compound 208

[0752] The preparation of compound 208 is similar to that of compound 207.

[0753] .sup.1H NMR (300 MHz, DMSO-d.sub.6, ppm): δ 8.51 (s, 1H), 8.25 (m, 2H), 7.85 (s, 1H), 7.16 (d, J=7.8 Hz, 2H), 6.82 (d, J=7.8 Hz, 2H), 5.35-5.50 (m, 12H), 4.01 (m, 1H), 3.98 (t, J=7.2 Hz, 2H), 3.15-3.70 (m, 10H), 2.97 (m, 3H), 2.86 (m, 1H), 2.25 (m, 2H), 2.13 (m, 2H), 1.81 (m, 2H), 0.89 (t, J=7.2 Hz, 2H); ESI-MS: calcd for C.sub.40H.sub.61N.sub.6O.sub.5 [M+H].sup.+: 705.5; found: 705.7.

Sample 209: Preparation of Conjugate 209

[0754] In a 100 mL round-bottom flask, 2.5 g of functionalized dextran 130 was dissolved in 30.0 mL of anhydrous DMSO, followed by addition of 300 mg (0.45 mmol) of compound 206, 129 mg (0.68 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), 92 mg (0.68 mmol) of 1-hydroxybenzotriazole (HOBt), and 139 uL (1.0 mmol) of triethylamine, and stirred at room temperature for 48 hours. Upon completion of the reaction, the reaction mixture was precipitated in methanol, dialyzed against distilled water, and lyophilized to provide 1.93 g of conjugate 209. Yield: 77%.

[0755] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH); minor signals: 6.75-7.20 (m, ArH), 5.32 (CH), 1.23 (d, CH.sub.3), 1.01 (t, CH.sub.3).

Sample 210: Preparation of Conjugate 210

[0756] In a 100 mL round-bottom flask, 3.0 g of functionalized dextran 130 was dissolved in 30.0 mL of anhydrous DMSO, followed by addition of 500 mg (0.71 mmol) of compound 207, 203 mg (1.06 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), 143 mg (1.06 mmol) of 1-hydroxybenzotriazole (HOBt), and 276 uL (2.0 mmol) of triethylamine, and stirred for 48 hours. Upon completion of the reaction, the reaction mixture was precipitated in methanol, dialyzed against distilled water, and lyophilized to provide 2.23 g of conjugate 210. Yield: 73%.

[0757] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH); minor signals: 6.75-7.20 (m, ArH), 5.33 (CH), 1.22 (d, CH.sub.3), 0.99 (t, CH.sub.3).

Synthetic Scheme 46

[0758] ##STR00188##

Sample 211: Preparation of Conjugate 211

[0759] In a 100 mL round-bottom flask, 500 mg of hyaluronic acid (average molecular weight 10,000) was dissolved in 10.0 mL of anhydrous DMSO at 60° C. and cooled down to room temperature, followed by addition of 60 mg (0.09 mmol) of compound 207, 26 mg (0.14 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), 19 mg (O. 14 mmol) of 1-hydroxybenzotriazole (HOBt), and 200 uL of triethylamine, and stirred for 48 hours. Upon completion of the reaction, the reaction mixture was precipitated in methanol, dialyzed against distilled water, and lyophilized to provide 353 mg of conjugate 211. Yield: 71%.

[0760] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH); minor signals: 7.20-8.70 (m, CONH), 6.75-7.20 (m, ArH), 5.35 (m, CH), 2.06 (s, CH.sub.3CO), 0.99 (t, CH.sub.3).

Synthetic Scheme 47

[0761] ##STR00189##

Sample 212: Preparation of Compound 212

[0762] To a 250 mL round bottom flask charged with 500 mg (0.59 mmol) of compound 190, 136 mg (0.71 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and 96 mg (0.71 mmol) 1-hydroxybenzotriazole (1-10130, 6.0 mL of anhydrous dimethylformamide was added, flowed by 227 mg (0.65 mmol) of compound 79 and 235 uL (1.70 mmol) triethylamine and stirred for 12 hours, Upon completion of the reaction, the reaction mixture was partitioned from ethyl acetate (60 mL) and brine (60 mL), and the organic phase was further washed with brine mice (30 mL×2), dried over MgSO.sub.4, concentrated, and purified on a silica gel column and eluted with methanol in chloroform to give 572 mg of compound 212. Yield: 85%.

[0763] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 7.01 (d, J=7.8 Hz, 2H), 6.75 (d, J=7.8 Hz, 2H), 5.30-5.50 (m, 24H), 4.83 (m, 1H), 4.45 (m, 1H), 4.21 (q, J=7.2 Hz, 2H), 3.95 (t, J=7.2 Hz, 2H), 3.65 (m, 2H), 3.10-3.30 (m, 4H), 2.70-2.90 (m, 20H), 2.39 (m, 4H), 2.25 (m, 6H), 2.02 (m, 4H), 1.82 (m, 2H), 1.50-1.75 (m, 4H), 1.46 (m, 2H), 1.26-1.43 (m, 4H), 1.25 (t, J=7.2 Hz, 3H), 0.95 (t, J=7.2 Hz, 6H); ESI-MS: calcd for C.sub.69H.sub.102N.sub.7O.sub.7 [M+H].sup.+: 1140.7; found: 1141.1.

Sample 213: Preparation of Compound 213

[0764] In a 50 mL round bottom flask, 500 mg (0.43 mmol) of compound 212 and 88 mg (2.20 mmol) of sodium hydroxide were dissolved in 10 mL of dimethylformamide-water (7:3), and stirred at room temperature for 2 days. Upon the completion of the reaction, the mixture was acidified with 2.0 N HCl to pH=1.0, and extracted with ethyl acetate three times (20 mL×3); the organic phases were pooled, dried over MgSO.sub.4, concentrated, and purified on a silica gel column and eluted with methanol in chloroform (0-10%) to give 435 mg of compound 213. Yield: 91%.

[0765] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 7.03 (d, J=7.8 Hz, 2H), 6.77 (d, J=7.8 Hz, 2H), 5.30-5.50 (m, 24H), 4.85 (m, 1H), 4.52 (m, 1H), 3.97 (t, J=7.2 Hz, 2H), 3.63 (m, 2H), 3.10-3.30 (m, 4H), 2.70-2.90 (m, 20H), 2.37 (m, 4H), 2.25 (m, 6H), 2.03 (m, 4H), 1.83 (m, 2H), 1.50-1.75 (m, 4H), 1.46 (m, 2H), 1.26-1.43 (m, 4H), 0.97 (t, J=7.2 Hz, 6H); ESI-MS: calcd for C.sub.67H.sub.98N.sub.7O.sub.7 [M+H].sup.+: 1112.7; found: 1112.9.

Sample 214: Preparation of Conjugate 214

[0766] In a 100 mL round-bottom flask, 2.0 g of functionalized dextran 142 was dissolved in 10.0 mL of anhydrous DMSO at 60° C. and cooled down to room temperature, followed by addition of 200 mg (0.18 mmol) of compound 213, 69 mg (0.36 mmol) of 1-ethyl-3-(3 ethylaminopropyl)carbodiimide (EDC), 49 mg (0.36 mmol) of 1-hydroxybenzotriazole (HOBt), and 50 uL (0.36 mmol) of triethylamine and stirred for 48 hours. Upon completion of the reaction, the reaction mixture was precipitated in methanol, dialyzed against distilled water, and lyophilized to provide 1.51 g of conjugate 214. Yield: 76%.

[0767] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH); minor signals: 7.20-8.70 (m, CONH), 6.75-7.20 (m, ArH), 5.33 (m, CH), 1.02 (m, CH.sub.3).

Synthetic Scheme 48

[0768] ##STR00190##

Sample 215: Preparation of Compound 215

[0769] Fmoc-Gly-OH was covalently attached to 10.0 g of trityl chloride resin (substitution: 0.39 mmol/g) and loaded on to a peptide synthesizer using standard protocols for Fmoc solid-phase peptide synthesis: Fmoc protecting group was deprotected with 20% piperidine in DMF, and ivdde protecting group deprotected with 5% hydrazine in DMF; 5 equivalents of protected amino acid or 6-azidohexanioc acid, 5 equivalents of coupling agent: DIPC and hydroxybenzotriazole (HOBt) and 5 equivalent diisopropylethyl amine (DIPEA), were used in coupling steps. After completion of the synthesis, the peptide derivative was cleaved from the resin using the cocktail: dichloromethane/trifluoroethanol/acetic acid (8:1:1), and purified on a reverse phase column and eluted with acetonitrile in water (10-80%) to give 1.32 g of compound 215. Yield: 31%.

[0770] .sup.1H NMR (300 MHz, DMSO-D.sub.6, ppm): δ 7.00-7.50 (m, 5H), 5.35-5.50 (m, 24H), 4.47 (m, 2H), 4.11 (m, 2H), 3.10-3.30 (m, 6H), 2.75 (m, 20H), 2.15-2.40 (m, 14H), 1.00-2.00 (m, 18H), 0.97 (t, J=7.2 Hz, 6H); ESI-MS: calcd for C.sub.64H.sub.99N.sub.8O.sub.7 [M+H].sup.+: 1091.7; found: 1091.9.

Sample 216: Preparation of Conjugate 216

[0771] In a 100 mL round-bottom flask, 2.0 g of functionalized dextran 142 was dissolved in 30.0 mL of anhydrous DMSO, followed by addition of 200 mg (0.18 mmol) of compound 215, 52 mg (0.28 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), 38 mg (0.28 mmol) of 1-hydroxybenzotriazole (HOBt), and 69 uL (0.5 mmol) of triethylamine and stirred for 48 hours. Upon completion of the reaction, the reaction mixture was precipitated in methanol, dialyzed against distilled water, and lyophilized to provide 1.67 g of conjugate 216. Yield: 83%.

[0772] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH); minor signals: 7.20-8.70 (m, CONH), 5.32 (m, CH), 1.01 (m, CH.sub.3).

Synthetic Scheme 49

[0773] ##STR00191##

Sample 217: Preparation of Compound 217

[0774] Fmoc-Gly-01-1 was covalently attached to 5.0 g of trityl chloride resin (substitution: 0.39 mmol/g) and loaded on to a peptide synthesizer using standard protocols for Fmoc solid-phase peptide synthesis: Fmoc protecting group was deprotected with 20% piperidine in DMF, and ivdde protecting group deprotected with 5% hydrazine in DMF; 5 equivalents of protected amino acid or gamma-linolenic acid (GLA), 5 equivalents of coupling agent: DIPC, hydroxybenzotriazole (HOBO, and 5 equivalent diisopropylethylamine (DIPEA) were used in coupling steps. After completion of the synthesis, the peptide derivative was cleaved from the resin using the cocktail dichloromethane/trifluoroethanol/acetic acid (8:1:1), and repeatedly crystalized in chloroform-methanol to give 669 mg of compound 217. Yield: 23%.

[0775] .sup.1H NMR (600 MHz, DMSO-d.sub.6, ppm): δ 7.00-7.50 (m, 9H), 5.35-5.50 (m, 18H), 4.43-4.55 (m, 3H), 3.90-4.20 (m, 6H), 3.10-3.30 (m, 8H), 2.78 (m, 12H), 2.37 (m, 12H), 2.15 (m, 8H), 1.00-2.00 (m, 54H), 0.97 (m, 9H); TOF-MS: calcd for C.sub.84H.sub.142N.sub.12O.sub.11 [M+2H].sup.+:1495.1; found: 1495.6.

Sample 218: Preparation of Conjugate 218

[0776] In a 100 mL round-bottom flask, 1.6 g of functionalized dextran 142 was dissolved in 30.0 mL of anhydrous DMSO, followed by addition of 160 mg (0.11 mmol) of compound 217, 31 mg (0.16 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), 22 mg (0.16 mmol) of 1-hydroxybenzotriazole (HOBt), and 69 uL (0.5 mmol) of triethylamine were added and stirred for 48 hours. Upon completion of the reaction, the reaction mixture was precipitated in methanol, dialyzed against distilled water, and lyophilized to provide 1.12 g of conjugate 218, Yield: 70%.

[0777] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH); minor signals: 7.20-8.70 (m, CONH), 5.32 (m, CH), 0.81 (m, CH.sub.3).

Synthetic Scheme 50

[0778] ##STR00192##

Sample 219: Preparation of Compound 219

[0779] Fmoc-Gly-OH was covalently attached to 5.0 g of trityl chloride: resin (substitution: 0.39 mmol/g) and loaded on to a peptide synthesizer using standard protocols for Fmoc solid-phase peptide synthesis: Fmoc protecting group was deprotected with 20% piperidine in DMF, and ivdde protecting group deprotected with 5% hydrazine in DMF; 5 equivalents of protected amino acid or 5-hexynoic acid and 5 equivalents of stearic acid, 5 equivalents of coupling agent: DIPC and hydroxybenzotriazole (HOBt) and 5 equivalent diisopropylethylamine (DIPEA), were used in coupling steps. After completion of the synthesis, the peptide derivative was cleaved from the resin using the cocktail: dichloromethane/trifluoroethanol/acetic acid (8:1:1), and repeatedly crystalized in chloroform-methanol to give 743 mg of compound 219. Yield: 26%.

[0780] .sup.1H NMR (600 MHz, DMSO-d.sub.6, ppm): δ 7.00-7.50 (m, 9H), 4.43-4.55 (m, 3H), 3.90-4.20 (m, 6H), 3.10-3.30 (m, 6H), 2.15 (m, 8H), 1.00-2.00 (m, 54H), 0.97 (m, 9H); TOF-MS: calcd for C.sub.84H.sub.157N.sub.9O.sub.11 [M+2H].sup.+:1468.2; found: 1468.5.

Sample 220: Preparation of Conjugate 220

[0781] In a 100 mL round-bottom flask, 2.0 g of functionalized dextran 142 was dissolved in 30.0 mL of anhydrous DMSO, followed by addition of 200 mg (0.13 mmol) of compound 219, 39 mg (0.20 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), 27 mg (0.20 mmol) of 1-hydroxybenzotriazole (HOBt), and 69 uL (0.5 mmol) of triethylamine were added and stirred for 48 hours. Upon completion of the reaction, the reaction mixture was precipitated in methanol, dialyzed against distilled water, and lyophilized to provide 1.53 g of conjugate 220. Yield: 76%.

[0782] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH); minor signals: 7.20-8.70 (m, CONH), 0.83 (m, CH.sub.3).

Synthetic Scheme 51

[0783] ##STR00193##

Sample 221: Preparation of Conjugate 221

[0784] In a 100 mL round-bottom flask, 2.0 g of functionalized dextran 142 was dissolved in 30.0 mL of anhydrous DMSO, followed by addition of 91 mg (0.3 mmol) of retinoic acid, 47 mg (0.3 mmol) of 6-azidohexanoic acid, 380 mg (1.0 mmol) of 2-(7-aza-1H-Benzotriazole-1-yl)-1,1,3,3-Tetramethyluronium hexafluorophosphate (HATU), and 138 uL (1.0 mmol) of triethylamine were added and stirred for 48 hours. Upon completion of the reaction, the reaction mixture was precipitated in methanol, dialyzed against distilled water, and lyophilized to provide 1.62 g of conjugate 221. Yield. 81%.

[0785] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH); minor signals: 7.10-8.70 (m, CONH), 6.50-7.00 (m, CH), 1.25 (m, CH.sub.3), 1.02 (m, CH.sub.3).

Synthetic Scheme 52

[0786] ##STR00194##

Sample 222: Preparation of Conjugate 222

[0787] In a 25 mL round bottom flask, 1.0 g of functionalized polysaccharide 116 was dissolved in 6.0 mL of DMSO-phosphate buffer solution (7:3, pH=8.0), then 86 mg (0.20 mmol) of compound 182 was added and stirred for 12 hours. Upon completion of the reaction, the reaction mixture was precipitated in methanol, dialyzed against distilled water, and lyophilized to provide 732 mg of conjugate 222. Yield: 73%.

[0788] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH); minor signals: 7.10-8.70 (m, CONH, ArH), 5.35 (m, CH), 1.23 (t, CH.sub.3), 1.01 (m, CH.sub.3).

Synthetic Scheme 53

[0789] ##STR00195##

Sample 223: Preparation of Conjugate 223

[0790] In a 25 mL round bottom flask, 1.5 g of functionalized polysaccharide 143 was dissolved 7.0 mL of DMSO, then 129 mg (0.30 mmol) of compound 182 was added, and stirred for 12 hours. Upon completion of the reaction, the reaction mixture was precipitated in methanol, dialyzed against distilled water, and lyophilized to provide 1.21 g of conjugate 223, Yield: 81%.

[0791] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH); minor signals: 7.20-8.50 (m, CONH), 5.35 (m, CH), 1.23 (m, CH.sub.3), 1.00 (m, CH.sub.3).

Synthetic Scheme 54

[0792] ##STR00196##

Sample 224: Preparation of Conjugate 224

[0793] The preparation of conjugate 224 is similar to that of conjugate 223.

[0794] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH); minor signals: 7.10-8.60 (m, CONH), 5.32 (m, CH), 1.25 (t, CH.sub.3), 0.99 (t, CH.sub.3).

Synthetic Scheme 55

[0795] ##STR00197##

Sample 225: Preparation of Conjugate 225

[0796] In a 100 mL round-bottom flask, 3.0 g of functionalized dextran 123 was dissolved in 30.0 mL of anhydrous DMSO, followed by addition of 71 mg (0.3 mmol) of compound 89 and 141 mg 0.3 mmol) of compound 159, 191 mg (1.0 mmol) of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC), 135 mg (1.0 mmol) of 1-hydroxybenzotriazole (HOBt), and 138 uL (1.0 mmol) of triethylamine were added and stirred for 48 hours. Upon completion of the reaction, the reaction mixture was precipitated in methanol, dialyzed against distilled water, and lyophilized to provide 2.21 g of conjugate 225. Yield: 73%.

[0797] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH); minor signals: 7.20-8.50 (m, CONH), 5.35 (m, CH), 1.24 (m, CH.sub.3), 0.83 (t, CH.sub.3).

Synthetic Scheme 56

[0798] ##STR00198##

Sample 226: Preparation of Conjugate 226

[0799] The preparation of conjugate 226 is similar to that of conjugate 225.

[0800] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH); minor signals: 7.20-8.60 (m, CONH), 6.75-7.10 (m, ArH), 5.32 (m, CH), 1.23 (t, CH.sub.3), 1.01 (t, CH.sub.3).

Synthetic Scheme 57

[0801] ##STR00199##

Sample 227: Preparation of Conjugate 227

[0802] The preparation of conjugate 227 is similar to that of conjugate 225.

[0803] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH); minor signals: 7.20-8.60 (m, CONH), 6.75-7.10 (m, ArH), 5.33 (m, CH), 1.01 (t, CH.sub.3).

Synthetic Scheme 58

[0804] ##STR00200##

Sample 228: Preparation of Conjugate 228

[0805] The preparation of conjugate 228 is similar to that of conjugate 225.

[0806] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH); minor signals: 7.20-8.60 (m, CONH), 2.00 (m, CH.sub.3), 0.83 (m, CH.sub.3).

Part. 5. Preparation of Taxane-Polysaccharide Conjugates

Synthetic Scheme 59

[0807] ##STR00201##

Sample 229: Preparation of Conjugate 229

[0808] In a 25 mL round bottom flask, 300 mg of functionalized dextran 91 and 36 mg (0.025 mmol) of compound 58 were dissolved in 2.0 mL of DMSO, followed by addition of copper sulfate solution (30 uL×1.0 M), THPTA (Tris (3-hydroxypropyl triazolylmethyl) amine, 30 uL×1.0 M) and sodium ascorbate solution (30 uL×1.0 M) were stirred at room temperature for 2 days. Upon completion of the reaction, the reaction mixture was precipitated with methanol, filtered, and washed with methanol three times. The precipitate was then dissolved in 2.0 mL of distilled water, dialyzed against distilled water, and lyophilized to offer 203 mg of conjugate 229. By comparing its UV absorption with that of of compound 63 at wavelength of 280 nm, 7% (w/w) cabazitaxel content was determined in conjugate 229.

[0809] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH); minor signals: 7.10-8.45 (m, CONH, ArH), 1.35 (s, OC(CH.sub.3).sub.3), 1.23 (m, CH.sub.3), 1.01 (m, CH.sub.3).

Sample 230: Preparation of Conjugate 230

[0810] The preparation of conjugate 230 is similar to that of conjugate 229.

[0811] By comparing its UV absorption with that of of compound 61 at wavelength of 280 nm, 10% (w/w) paclitaxel content was determined in conjugate 230.

[0812] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH); minor signals: 7.10-8.50 (m, CONH, ArH), 1.23 (m, CH.sub.3), 0.99 (m, CH.sub.3).

Sample 231: Preparation of Conjugate 231

[0813] The preparation of conjugate 231 is similar to that of conjugate 229.

[0814] By comparing its UV absorption with that of of compound 62 at wavelength of 280 nm, 9% (w/w) docetaxel content was determined in conjugate 231.

[0815] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH); minor signals: 7.10-8.50 (m, CONH, ArH), 1.35 (s, OC(CH.sub.3).sub.3), 1.23 (m, CH.sub.3), 1.00 (m, CH.sub.3).

Synthetic Scheme 60

[0816] ##STR00202##

Sample 232: Preparation of Conjugate 232

[0817] The preparation of conjugate 232 is similar to that of conjugate 229.

[0818] By comparing its UV absorption with that of of compound 62 at wavelength of 0 nm, 8% (w/w) docetaxel content was determined in conjugate 232.

[0819] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH); minor signals: 7.10-8.50 (m, CONH, ArH), 1.34 (s, OC(CH.sub.3).sub.3), 1.24 (m, CH.sub.3), 1.01 (m, CH.sub.3).

Synthetic Scheme 61

[0820] ##STR00203##

Sample 233: Preparation of Conjugate 233

[0821] The preparation of conjugate 233 is similar to that of conjugate 229.

[0822] By comparing its UV absorption with that of of compound 7 and functionalized dextran 103 at wavelength of 280 nm, 6% (w/w) paclitaxel content was determined in conjugate 233.

[0823] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH); minor signals: 7.10-8.50 (m, CONH, ArH), 1.23 (m, CH.sub.3), 0.99 (m, CH.sub.3).

Synthetic Scheme 62

[0824] ##STR00204##

Sample 234: Preparation of Conjugate 234

[0825] The preparation of conjugate 234 is similar to that of conjugate 229.

[0826] By comparing its UV absorption with that of of compound 7 and functionalized dextran 108 at wavelength of 280 nm, 11% (w/w) paclitaxel content was determined in conjugate 234.

[0827] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH); minor signals: 6.80-8.50 (m, CONH, ArH), 1.24 (m, CH.sub.3), 1.02 (m, CH.sub.3).

Synthetic Scheme 63

[0828] ##STR00205##

Sample 235: Preparation of Conjugate 235

[0829] The preparation of conjugate 231 is similar to that of conjugate 235.

[0830] By comparing its UV absorption with that of of compound 62 and functionalized hyaluronic acid 109 at wavelength of 280 nm, 11% (w/w) docetaxel content was determined in conjugate 235.

[0831] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH); minor signals: 6.75-8.45 (m, CONH, ArH), 2.05 (s, CH.sub.3CO), 1.35 (s, OC(CH.sub.3).sub.3), 1.23 (m, CH.sub.3), 1.01 (m, CH.sub.3).

Sample 236: Preparation of Conjugate 236

[0832] The preparation of conjugate 236 is similar to that of conjugate 229.

[0833] By comparing its UV absorption with that of of compound 40 and functionalized hyaluronic acid 109 at wavelength of 280 nm, 9% (w/w) docetaxel content was determined in conjugate 236.

[0834] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH); minor signals: 6.75-8.45 (m, CONH, ArH), 2.06 (s, CH.sub.3CO), 1.34 (s, OC(CH.sub.3).sub.3), 1.24 (m, CH.sub.3), 1.00 (m, CH.sub.3).

Sample 237: Preparation of Conjugate 237

[0835] In a 25 mL round bottom flask, 500 mg of functionalized hyaluronic acid 109 and 100 mg (0.07 mmol) of compound 74 were dissolved in 5.0 mL of DMSO, and stirred at room temperature for 3 days. Upon completion of the reaction, the reaction mixture was precipitated with methanol, filtered, and washed with methanol three times. The precipitate was then dissolved in 2.0 mL of distilled water, dialyzed against distilled water, and lyophilized to give 321 mg of conjugate 237, By comparing its UV absorption with that of of compound 76a (76b) at wavelength of 280 nm, 6% (w/w) docetaxel content was determined in conjugate 237.

[0836] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH); minor signals: 6.75-8.50 (m, CONH, ArH), 2.04 (s, CH.sub.3CO), 1.35 (s, OC(CH.sub.3).sub.3), 1.22 (m, CH.sub.3), 0.99 (m, CH.sub.3).

Synthetic Scheme 64

[0837] ##STR00206##

Sample 238: Preparation of Conjugate 238

[0838] The preparation of conjugate 238 is similar to that of conjugate 229.

[0839] By comparing its UV absorption with that of of compound 61 at wavelength of 280 nm, 5% (w/w) paclitaxel content was determined in conjugate 238.

[0840] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH); minor signals: 7.10-8.50 (m, CONH, ArH), 1.23 (m, CH.sub.3), 0.99 (m, CH.sub.3).

Sample 239: Preparation of Conjugate 239

[0841] The preparation of conjugate 239 is similar to that of conjugate 229.

[0842] By comparing its UV absorption with that of of compound 62 at wavelength of 280 nm, 12% (w/w) docetaxel content was determined in conjugate 239.

[0843] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH); minor signals: 7.10-8.50 (m, CONH, ArH), 1.34 (s, OC(CH.sub.3).sub.3), 1.24 (m, CH.sub.3), 1.01 (m, CH.sub.3).

Synthetic Scheme 65

[0844] ##STR00207##

Sample 240: Preparation of Conjugate 240

[0845] The preparation of conjugate 240 is similar to that of conjugate 237.

[0846] By comparing its UV absorption with that of of compound 75a (75b) at wavelength of 280 nm, 12% (w/w) paclitaxel content was determined in conjugate 240.

[0847] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH); minor signals: 7.10-8.50 (m, CONH, ArH), 1.24 (m, CH.sub.3), 0.99 (m, CH.sub.3).

Sample 241: Preparation of Conjugate 241

[0848] The preparation of conjugate 241 is similar to that of conjugate 237.

[0849] By comparing its UV absorption with that of of compound 76a (76b) at wavelength of 280 nm, 11% (w/w) docetaxel content was determined in conjugate 241.

[0850] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH); minor signals: 7.10-8.50 (m, CONH, ArH), 1.34 (s, OC(CH.sub.3).sub.3), 1.23 (m, CH.sub.3), 1.00 (m, CH.sub.3).

Synthetic Scheme 66

[0851] ##STR00208##

Sample 242: Preparation of Conjugate 242

[0852] The preparation of conjugate 242 is similar to that of conjugate 229.

[0853] By comparing its UV absorption with that of of compound 61 and functionalized dextran 125 at wavelength of 280 nm, 9% (w/tip-) paclitaxel content was determined in conjugate 242.

[0854] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.20 (m, CHOH, CH.sub.2OH, CH.sub.2O); minor signals: 6.75-8.50 (m, CONH, ArH), 1.24 (m, CH.sub.3), 0.99 (m, CH.sub.3).

Sample 243: Preparation of Conjugate 243

[0855] The preparation of conjugate 243 is similar to that of conjugate 229.

[0856] By comparing its UV absorption with that of of compound 62 and functionalized dextran 125 at wavelength of 280 nm, 12% (w/w) docetaxel content was determined in conjugate 243.

[0857] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.20 (m, CHOH, CH.sub.2OH, CH.sub.2O); minor signals: 6.75-8.50 (m, CONH, ArH), 1.34 (s, OC(CH.sub.3).sub.3), 1.25 (m, CH.sub.3), 1.01 (m, CH.sub.3).

Synthetic Scheme 67

[0858] ##STR00209##

Sample 244: Preparation of Conjugate 244

[0859] The preparation of conjugate 244 is similar to that of conjugate 237.

[0860] By comparing its UV absorption with that of of compound 75a (75b) and functionalized dextran 125 at wavelength of 280 nm, 11% (w/w) paclitaxel content was determined in conjugate 244.

[0861] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.20 (m, CHOH, CH.sub.2OH, CH.sub.2O); minor signals: 6.75-8.50 (m, CONH, ArH), 1.23 (m, CH.sub.3), 0.98 (m, CH.sub.3).

Sample 245: Preparation of Conjugate 245

[0862] The preparation of conjugate 245 is similar to that of conjugate 237.

[0863] By comparing its UV absorption with that of of compound 76a (76b) and functionalized dextran 125 at wavelength of 280 nm, 9% (w/w) docetaxel content was determined in conjugate 245.

[0864] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.20 (m, CHOH, CH.sub.2OH, CH.sub.2O); minor signals: 6.75-8.50 (m, CONH, ArH), 1.35 (s, OC(CH.sub.3).sub.3), 1.24 (m, CH.sub.3), 1.00 (m, CH.sub.3).

Synthetic Scheme 68

[0865] ##STR00210##

Sample 246: Preparation of Conjugate 246

[0866] The preparation of conjugate 246 is similar to that of conjugate 229.

[0867] By comparing its UV absorption with that of of compound 16 at wavelength of 280 n, 7% (w/w) paclitaxel content was determined in conjugate 246.

[0868] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH, CH.sub.2O); minor signals: 7.10-8.50 (m, CONH, ArH), 1.95-2.30 (m, CH.sub.3CO), 1.23 (t, CH.sub.3), 0.99 (m, CH.sub.3).

Synthetic Scheme 69

[0869] ##STR00211##

Sample 247: Preparation of Conjugate 247

[0870] The preparation of conjugate 247 is similar to that of conjugate 229.

[0871] By comparing its UV absorption with that of of compound 7 and functionalized dextran 132 at wavelength of 280 nm, 7% (w/w) paclitaxel content was determined in conjugate 247.

[0872] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH); minor signals: 7.10-8.50 (m, CONH, ArH), 1.23-1.26 (m, CH.sub.3), 0.98 (m, CH.sub.3).

Synthetic Scheme 70

[0873] ##STR00212##

Sample 248: Preparation of Conjugate 248

[0874] The preparation of conjugate 248 is similar to that of conjugate 229.

[0875] By comparing its UV absorption with that of of compound 61 at wavelength of 280 nm, 17% (w/w) paclitaxel content was determined in conjugate 248.

[0876] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH); minor signals: 7.10-8.50 (m, CONH, ArH), 1.24 (m, CH.sub.3), 1.01 (m, CH.sub.3).

Synthetic Scheme 71

[0877] ##STR00213##

Sample 249: Preparation of Conjugate 249

[0878] The preparation of conjugate 249 is similar to that of conjugate 229.

[0879] By comparing its UV absorption with that of of compound 40 at wavelength of 280 nm, 6% (w/w) paclitaxel content was determined in conjugate 249.

[0880] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.20 (m, CHOH, CH.sub.2OH, CH.sub.2O); minor signals: 7.10-8.50 (m, CONH, ArH), 1.34 (s, OC(CH.sub.3).sub.3), 1.23 (t, CH.sub.3), 1.01 (m, CH.sub.3).

Synthetic Scheme 72

[0881] ##STR00214##

Sample 250: Preparation of Conjugate 250

[0882] The preparation of conjugate 250 is similar to that of conjugate 237.

[0883] By comparing its UV absorption with that of of compound 22a (22b) at wavelength of 280 nm, 9% (w/w) paclitaxel content was determined in conjugate 250.

[0884] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH); minor signals: 7.10-8.50 (m, CONH, ArH), 1.23 (t, CH.sub.3), 0.99 (m, CH.sub.3).

Synthetic Scheme 73

[0885] ##STR00215##

Sample 251: Preparation of Conjugate 251

[0886] The preparation of conjugate 251 is similar to that of conjugate 229.

[0887] By comparing its UV absorption with that of of compound 28 at wavelength of 280 nm, 12% (w/w) paclitaxel content was determined in conjugate 251.

[0888] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.20 (m, CHOH, CH.sub.2OH, CH.sub.2O); minor signals: 6.75-8.50 (m, CONH, ArH), 1.23 (t, CH.sub.3), 0.99 (m, CH.sub.3).

Part 6. Preparation of Functionalized Lipid-Taxane Conjugates

Synthetic Scheme 74

[0889] ##STR00216## ##STR00217## ##STR00218##

Sample 252: Preparation of Compound 252

[0890] To a 1000 mL round-bottom flask charged with 62.0 g (143.2 mmol) of Fmoc L-lysine ethyl ester, 70 mL (716 mmol) of diisopropyl ethylamine, 500 mL of anhydrous ethanol was added and cooled down to 0° C. and stirred for 30 mins, followed by addition of 48.0 g (171.8 mmol) of triphenyl methyl chloride and stirred overnight. Upon completion of the reaction, the reaction mixture was evaporated and the residue was partitioned between ethyl acetate (600 mL) and brine (600 mL), the organic phase was further washed with brine twice (600 mL×2), dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with ethyl acetate in petroleum ether (10-70%) to provide 57.0 g of compound 252. Yield: 62%.

[0891] .sup.1H NMR (400 MHz, DMSO-d.sub.6, ppm): δ 7.83 (d, J=6.8 Hz, 1H), 7.72 (d, J=6.8 Hz, 1H), 7.45 (m, 6H), 7.26 (m, 6H), 7.21 (m, 3H), 4.32 (d, J=7.2 Hz, 2H), 4.21 (m, 1H), 4.17 (m, 2H), 1.95 (m, 2H), 1.61 (m, 2H), 1.47 (m, 2H), 1.26 (m, 2H), 1.13 (t, J=7.2 Hz, 3H); ESI-MS (m/z): calcd for C.sub.42H.sub.43N.sub.2O.sub.4 [M+H].sup.+: 639.3; found: 639.4.

Sample 253: Preparation of Compound 253

[0892] To a 1000 mL round-bottom flask was loaded with 57.0 g (89.3 mmol) of compound 252 in 500 mL of dichloromethane, 38.0 g (446.5 mmol) of piperidine was added and stirred at room temperature for 2 hours. Upon completion of the reaction, the reaction mixture was evaporated, and the residue was purified on a silica gel column and eluted with ethyl acetate in petroleum ether (10-70%) to provide 33.0 g of compound 253. Yield: 89%.

[0893] .sup.1H NMR (400 MHz, DMSO-d.sub.6, ppm): δ 7.47 (m, 6H), 7.32 (m, 6H), 7.21 (m, 3H), 4.17 (m, 2H), 3.25 (m, 1H), 1.89 (m, 2H), 1.25-1.50 (m, 6H), 1.14 (t, J=7.2 Hz, 3H); ESI-MS (m/z): calcd for C.sub.27H.sub.33N.sub.2O.sub.2 [M+H].sup.+: 417.2; found: 417.3.

Sample 254: Preparation of Compound 254

[0894] In a 500 mL round-bottom flask, 25.2 g (94.4 mmol) of Cbz-Gly-Gly-OH, 19.6 g (102.2 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), 13.5 g (102.2 mmol) of 1-hydroxybenzotriazole (HOBt) was dissolved in 150 mL of dry DMF, and followed by addition of 33 g (79.1 mmol) of compound 253 and 14 mL (102 mmol) of triethylamine and stirred at room temperature overnight. Upon completion of the reaction, the reaction mixture was partitioned between ethyl acetate (600 mL) and brine (600 mL), the organic phase was further washed with brine twice (600 mL×2), dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with methanol in chloroform (0-10%) to provide 34.0 g of compound 254. Yield: 65%.

[0895] .sup.1H NMR (400 MHz, DMSO-d.sub.6, ppm): δ 8.23 (d, J=6.8 Hz, 1H), 8.21 (t, J=6.8 Hz, 1H), 7.49 (t, J=6.8 Hz, 1H), 7.21-7.48 (m, 20H), 4.19 (m, 1H), 4.08 (m, 2H), 3.75 (t, J=7.2 Hz, 2H), 3.62 (t, J=7.2 Hz, 2H), 1.95 (m, 2H), 1.25-1.68 (m, 6H), 1.15 (t, J=7.2 Hz, 3H); ESI-MS (m/z): calcd for C.sub.39H.sub.45N.sub.4O.sub.6 [M+H].sup.+: 665.3; found: 665.4.

Sample 255: Preparation of Compound 255

[0896] In a 500 mL round-bottom flask, 34 g (51.1 mmol) of compound 254 was dissolved in 250 mL of ethanol, and bubbled with hydrogen gas in the presence of 3.4 g of 10% Pd—C for 4 hours. Upon completion of the reaction, Pd-carbon was filtered off, and the filtrate was concentrated and purified on a reverse phase C-18 column and eluted with acetonitrile in water (10-80%) to give 6.2 g of compound 255. Yield: 23%.

[0897] .sup.1H NMR (400 MHz, DMSO-d.sub.6, ppm): δ 8.24 (d, J=6.8 Hz, 1H), 8.22 (t, J=6.8 Hz, 1H), 7.20-7.50 (m, 15H), 4.20 (m, 1H), 4.07 (m, 2H), 3.76 (s, 2H), 3.09 (s, 2H), 1.95 (m, 2H), 1.25-1.70 (m, 2H), 1.14 (t, J=7.2 Hz, 3H); ESI-MS (m/z): calcd for C.sub.31H.sub.39N.sub.4O.sub.6 [M+H].sup.+: 531.3; found: 531.3.

Sample 256: Preparation of Compound 256

[0898] In a 500 mL round-bottom flask, 12.6 g (51.2 mmol) of N.sub.6-Boc-L-lysine and 9.5 g (113 mmol) of sodium bicarbonate were dissolved in 100 mL of distilled water, followed by addition of 10.0 g (51.2 mmol) of 4-alkynoic acid-(N-hydroxysuccinyl lactam) ester in tetrahydrofuran, and stirred at room temperature overnight. After removal of volatiles, the residue was acidified with 2.0N hydrochloride solution to pH=1.0, and extracted with dichloromethane three times (200 mL×3); the organic phases were pooled, dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with methanol in chloroform (0-10%) to provide 14.0 g of compound 256. Yield: 83%.

[0899] .sup.1H NMR (400 MHz, DMSO-d.sub.6, ppm): δ 8.01 (d, J=7.2 Hz, 1H), 6.71 (d, J=7.2 Hz, 1H), 4.21 (m, 1H), 2.93 (m, 2H), 2.82 (s, 1H), 2.75 (m, 4H), 1.71 (m, 1H), 1.51 (m, 1H), 1.27 (s, 9H), 1.23-1.25 (m, 4H); ESI-MS (m/z): calcd for C.sub.16H.sub.27N.sub.2O.sub.5 [M+H].sup.+: 327.2; found: 327.3.

Sample 257: Preparation of Compound 257

[0900] To a 500 mL round-bottom flask was loaded with 14.0 g (42.9 mmol) of compound 252, 12 g (86.6 mmol) potassium carbonate, 200 mL of acetonitrile, 15 g (105.6 mmol) of methyl iodide was added, and heated at 40° C. and stirred overnight. After removal of volatiles, the residue was partitioned between ethyl acetate (200 mL) and brine (200 mL), the organic phase was further washed with brine twice (200 mL×2), dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with ethyl acetate in petroleum ether (20-90%) to provide 10.6 g of compound 257. Yield: 72%.

[0901] .sup.1H NMR (400 MHz, DMSO-d.sub.6, ppm): δ 8.25 (d, J=6.8 Hz, 1H), 8.75 (t, J=6.8 Hz, 1H), 4.25 (m, 1H), 3.63 (s, 3H), 2.83 (m, 2H), 2.75 (s, 1H), 2.35 (m, 2H), 1.72 (m, 1H), 1.53 (m, 1H), 1.27 (s, 9H), 1.20-1.25 (m, 4H); ESI-MS (m/z): calcd for C.sub.17H.sub.29N.sub.2O.sub.5 [M+H].sup.+: 341.2; found: 341.1.

Sample 258: Preparation of Compound 258

[0902] To a 250 mL round-bottom flask charged with 10.6 g (31.1 mmol) of compound 257, 50 mL of hydrochloride ethanol solution (3.0N) was added and stirred at room temperature overnight. After removal of volatiles, the residue was purified on a reverse phase C-18 column and eluted with acetonitrile in water (10-70%) to provide 8.6 g of compound 258. Yield: 99%.

[0903] .sup.1H NMR (400 MHz, DMSO-d.sub.6, ppm): δ 8.05 (d, J=6.8 Hz, 1H), 8.01 (brs, 3H), 4.23 (m, 1H), 3.53 (s, 3H), 2.71 (m, 3H), 2.35 (m, 4H), 1.50-1.72 (m, 4H), 1.27 (m, 2H); ESI-MS (m/z): calcd for C.sub.12H.sub.21N.sub.2O.sub.3 [M+H].sup.+: 241.1; found: 241.1.

Sample 259: Preparation of Compound 259

[0904] To a 250 mL round-bottom flask charged with 4.0 g (12.2 mmol) of docosahexaenoic acid (DHA), 3.0 g (15.6 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), 2.2 g (16.2 mmol) of 1-hydroxybenzotriazole (HOBt) in 30 mL of dry DMF, 3.4 g (12.2 mmol) of compound 258 and 3.5 mL (24.5 mmol) of triethylamine were added and stirred at room temperature overnight. Upon completion of the reaction, the reaction mixture was partitioned between ethyl acetate (200 mL) and brine (200 mL), the organic phase was further washed with brine twice (100 mL×2), dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with methanol in chloroform (0-10%) to provide 4.8 g of compound 259. Yield: 72%.

[0905] .sup.1H NMR (400 MHz, CD.sub.3OD, ppm): δ 5.41 (m, 12H), 4.41 (m, 1H), 3.75 (s, 3H), 2.89 (m, 10H), 2.49 (m, 4H), 2.46 (m, 2H), 2.27 (t, J=3.0 Hz, 1H), 2.25 (t, J=7.2 Hz, 2H), 2.10 (m, 2H), 1.81 (m, 2H), 1.72 (m, 2H), 1.53 (m, 2H), 1.47 (m, 2H), 1.02 (t, J=7.2 Hz, 3H); ESI-MS (m/z): calcd for C.sub.34H.sub.51N.sub.2O.sub.4 [M+H].sup.+: 551.3; found: 551.4.

Sample 260: Preparation of Compound 260

[0906] To a 250 mL round bottom flask charged with 4.8 g (8.72 mmol) of compound 259 in 50 mL of dimethylformamide-water (7:3), 1.05 g (26.2 mmol) of sodium hydroxide was added, and stirred at room temperature for 1 day. Upon completion of the reaction, the mixture was acidified with 2.0N HCl to pH=1.0, and extracted with ethyl acetate (100 mL×3); the organic phases were pooled, dried over MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with methanol in dichloromethane (0-10%) to give 4.5 g of compound 260. Yield: 96%.

[0907] .sup.1H NMR (400 MHz, DMSO-d.sub.6, ppm): δ 8.21 (d, J=6.8 Hz, 1H), 7.80 (t, J=6.8 Hz, 1H), 5.31 (m, 12H), 4.21 (m, 1H), 3.01 (m, 2H), 2.81 (m, 10H), 2.21-2.70 (m, 6H), 2.05 (m, 4H), 1.71 (m, 1H), 1.57 (m, 1H), 1.25-1.45 (m, 4H), 0.92 (t, J=7.2 Hz, 3H); ESI-MS (m/z): calcd for C.sub.33H.sub.49N.sub.2O.sub.4 [M+H].sup.+: 537.4; found: 537.4.

Sample 261: Preparation of Compound 261

[0908] To a 250 mL round-bottom flask charged with 4.5 g (8.39 mmol) of compound 260, 2.0 g (10.4 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), 1.4 g (10.4 mmol) of 1-hydroxybenzotriazole (HOBt) in 30 mL of dry DMF, 5.0 g (9.42 mmol) of compound 255 and 3.5 mL (24.5 mmol) of triethylamine were added and stirred at room temperature overnight. Upon completion of the reaction, the reaction mixture was partitioned between ethyl acetate (200 mL) and brine (200 mL), the organic phase was further washed with brine twice (100 mL×2), dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with methanol in chloroform (0-10%) to provide 5.5 g of compound 261. Yield: 63%.

[0909] .sup.1H NMR (400 MHz, CD.sub.3OD, ppm): 6; 7.20-7.50 (m, 15H), 5.38 (m, 12H), 4.37 (m, 1H), 4.17 (m, 3H), 3.89 (t, J=7.2 Hz, 2H), 3.81 (t, J=7.2 Hz, 2H), 3.16 (t, J=7.2 Hz, 2H), 2.86 (m, 10H), 2.49 (m, 4H), 2.45 (m, 2H), 2.27 (t, J=2.9 Hz, 1H), 2.25 (t, J=7.2 Hz, 2H), 2.10 (m, 4H), 1.60-1.75 (m, 4H), 1.25-1.55 (m, 8H), 1.22 (t, J=7.2 Hz, 2H), 0.97 (t, J=7.2 Hz, 2H); ESI-MS (m/z): calcd for C.sub.64H.sub.85N.sub.6O.sub.7 [M+H].sup.+: 1049.6; found: 1049.7.

Sample 262: Preparation of Compound 262

[0910] To a 250 mL round-bottom flask charged with 5.5 g (5.25 mmol) of compound 261 in 50 mL of dichloromethane, 5.0 mL of trifluoroacetic acid was added, and stirred at 0° C. for 1 hour. After removal of volatiles, the residue was purified on a reverse phase C-18 column and eluted with acetonitrile in water (10-80%) to provide 4.8 g of compound 262. Yield: 98%.

[0911] .sup.1H NMR (400 MHz, CD.sub.3OD, ppm): 6; 5.37 (m, 12H), 4.45 (m, 1H), 4.21 (m, 1H), 3.89 (d, J=7.2 Hz, 2H), 3.85 (d, J=7.2 Hz, 2H), 3.18 (t, J=7.2 Hz, 2H), 2.94 (t, J=7.2 Hz, 2H), 2.88 (m, 10H), 2.51 (m, 4H), 2.47 (m, 2H), 2.27 (t, J=3.0 Hz, 1H), 2.23 (t, J=7.2 Hz, 2H), 2.06 (m, 2H), 1.55-1.90 (m, 6H), 1.27-1.55 (m, 6H), 1.26 (t, J=7.2 Hz, 2H), 0.97 (t, J=7.2 Hz, 2H); ESI-MS (m/z): calcd for C.sub.45H.sub.71N.sub.6O.sub.7 [M+H].sup.+: 807.5; found: 807.5.

Sample 263: Preparation of Compound 263

[0912] To a 250 mL round-bottom flask charged with 4.8 g (5.95 mmol) of compound 262 in 50 mL of anhydrous acetonitrile, 2.0 g (17.9 mmol) of DMAP and 1.45 g (11.9 mmol) of diglycolic acid anhydride were added and stirred at room temperature overnight. After removal of volatiles, the residue was partitioned between ethyl acetate (200 mL) and 3.0N hydrochloride (200 mL), and the aqueous solution was further with 3.0N hydrochloride twice (100 mL×2), dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with methanol in chloroform (0-30%) to provide 3.26 g of compound 263. Yield: 59%.

[0913] .sup.1H NMR (400 MHz, DMSO-d.sub.6, ppm): δ 9.61 (s, 1H), 9.05 (s, 1H), 8.22 (m, 2H), 8.51 (d, J=6.8 Hz, 1H), 8.22 (m, 2H), 7.76 (t, J=7.2 Hz, 2H), 5.37 (m, 12H), 4.21 (m, 1H), 4.19 (m, 1H), 3.91 (s, 2H), 3.85 (d, J=6.8 Hz, 2H), 3.81 (s, 2H), 3.76 (t, J=6.8 Hz, 2H), 3.19 (m, 2H), 3.17 (m, 2H), 2.81 (m, 10H), 2.75 (m, 4H), 2.25 (m, 2H), 2.01-2.30 (m, 6H), 1.55-1.75 (m, 3H), 1.20-1.55 (m, 9H), 1.18 (t, J=7.2 Hz, 2H), 0.92 (t, J=7.2 Hz, 2H); ESI-MS (m/z): calcd for C.sub.45H.sub.71N.sub.6O.sub.7 [M+H].sup.+: 923.5; found: 923.6.

Sample 264: Preparation of Compound 264

[0914] To a 100 mL round-bottom flask charged with 300 mg (0.325 mmol) of compound 263 and 125 mg (0.65 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) in 5.0 mL of dry DMF, 708 mg (0.65 mmol) of compound 36 and 79 mg (0.65 mmol) of DMAP were added, and the reaction mixture was stirred at room temperature for 24 hours. Upon completion of the reaction, the reaction mixture was partitioned between ethyl acetate (100 mL) and brine (100 mL); the aqueous phase was extracted with ethyl acetate (50 mL×2), and the organic phases were pooled, dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with methanol in chloroform (0-10%) to provide 237 mg of compound 264. Yield: 39%.

[0915] .sup.1H NMR (500 MHz, CDCl.sub.3, ppm): δ 8.02 (d, J=7.2 Hz, 2H), 6.80-7.85 (m, 12H), 6.12 (s, 1H), 5.93 (m, 4H), 5.61 (t, J=7.2 Hz, 1H), 5.15-5.50 (m, 17H), 4.92 (m, 1H), 4.40-4.70 (m, 5H), 3.70-4.30 (m, 14H), 3.25 (m, 4H), 2.91 (m, 10H), 2.10-2.60 (m, 13H), 1.85-2.05 (m, 10H), 1.60-2.05 (m, 19H), 1.00-1.55 (m, 30H), 0.89 (t, J=7.2 Hz, 3H); ESI-MS (m/z): calcd for C.sub.100H.sub.134N.sub.7O.sub.28 [M+H].sup.+: 1880.9; found: 1882.3.

Sample 265: Preparation of Compound 265

[0916] The preparation of compound 265 is similar to that of compound 264.

[0917] .sup.1H NMR (500 MHz, CDCl3, ppm): δ 8.05 (d, J=7.2 Hz, 2H), 6.80-7.85 (m, 15H), 6.15 (s, 1H), 5.95 (m, 2H), 5.65 (t, J=7.2 Hz, 1H), 5.15-5.50 (m, 15H), 4.96 (m, 1H), 4.40-4.70 (m, 3H), 3.70-4.30 (m, 14H), 3.25 (m, 4H), 2.93 (m, 10H), 2.10-2.60 (m, 16H), 1.85-2.05 (m, 10H), 1.60-2.05 (m, 19H), 1.00-1.55 (m, 21H), 0.91 (t, J=7.2 Hz, 3H); ESI-MS (m/z): calcd for C.sub.100H.sub.128N.sub.7O.sub.26 [M+H].sup.+: 1843.9; found: 1844.5.

Sample 266: Preparation of Compound 266

[0918] To a 50 mL round-bottom flask charged with 200 mg (0.11 mmol) of compound 264, and 39 mg (0.25 mmol) of 1,3-dimethylbarbituric acid in 10.0 mL of anhydrous THF, 39 mg (0.011 mmol) of tetrakis(triphenylphosphine)palladium(O) was added under nitrogen protection; the reaction mixture was stirred at room temperature for 5 h. After removal of volatiles and the residue was purified on a silica gel column and eluted with methanol in chloroform (0-15%) to give 133 mg of compound 266. Yield: 71%.

[0919] .sup.1H NMR (500 MHz, CDCl.sub.3, ppm): δ 8.03 (d, J=7.2 Hz, 2H), 6.90-7.60 (m, 12H), 6.12 (s, 1H), 5.98 (m, 2H), 5.61 (t, J=7.2 Hz, 1H), 5.20-5.45 (m, 13H), 4.91 (m, 1H), 4.46 (m, 2H), 3.70-4.30 (m, 16H), 3.23 (m, 4H), 2.87 (m, 10H), 2.10-2.60 (m, 13H), 1.60-2.05 (m, 19H), 1.00-1.55 (m, 30H), 1.00 (t, J=7.2 Hz, 3H), 0.91 (m, 3H); ESI-MS (m/z): calcd for C.sub.92H.sub.126N.sub.7O.sub.24 [M+H].sup.+: 1712.9; found: 1714.5.

Sample 267: Preparation of Compound 267

[0920] The preparation of compound 267 is similar to that of compound 266.

[0921] .sup.1H NMR (500 MHz, CDCl3, ppm): δ 8.03 (d, J=7.2 Hz, 2H), 6.80-7.85 (m, 15H), 6.15 (s, 1H), 5.95 (m, 1H), 5.63 (t, J=7.2 Hz, 1H), 5.15-5.50 (m, 13H), 4.96 (m, 1H), 4.30 (m, 3H), 3.70-4.20 (m, 14H), 3.26 (m, 4H), 2.91 (m, 10H), 2.10-2.60 (m, 16H), 1.85-2.05 (m, 10H), 1.60-2.05 (m, 19H), 1.00-1.55 (m, 21H), 0.90 (t, J=7.2 Hz, 3H); ESI-MS (m/z): calcd for C.sub.96H.sub.124N.sub.7O.sub.24 [M+H].sup.+: 1758.9; found: 1759.6.

Synthetic Scheme 75

[0922] ##STR00219## ##STR00220##

Sample 268: Preparation of Compound 268

[0923] To a 500 mL round-bottom flask charged with 30 g (64.0 mmol) of Nε-Boc-Na-Fmoc-L-lysine, 13.5 g (70.4 mmol) of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC), 9.5 g (70.4 mmol) of 1-hydroxybenzotriazole (HOBt) in 100 mL of dry DMF, 5.1 g (64.0 mmol) of 4-alkyn-1-amine was added and stirred at room temperature overnight. Upon completion of reaction, the reaction mixture was partitioned between ethyl acetate (200 mL) and brine (200 mL), the organic phase was further washed with brine twice (200 mL×2), dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with methanol in chloroform (0-10%) to provide 22.2 g of compound 268. Yield: 65%.

[0924] .sup.1H NMR (300 MHz, DMSO-d.sub.6, ppm): δ 7.89 (d, J=7.3 Hz, 3H), 7.76 (q, J=2.5 Hz, 2H), 7.42 (t, J=7.2 Hz, 3H), 7.33 (t, J=7.6 Hz, 2H), 6.78 (m, 1H), 4.22 (m, 3H), 3.91 (m, 1H), 3.12 (m, 2H), 2.89 (d, J=6.4 Hz, 2H), 2.77 (t, J=2.8 Hz, 1H), 2.15 (m, 2H), 1.57 (m, 4H), 1.36 (s, 9H), 1.21 (m, 4H); ESI-MS (m/z): calcd for C.sub.31H.sub.40N.sub.3O.sub.5 [M+H].sup.+: 534.3; found: 534.5.

Sample 269: Preparation of Compound 269

[0925] To a 500 mL round-bottom flask charged with 20 g (37.5 mmol) of compound 268 in 200 mL of methanol-water (9:1), 3.6 g (150.0 mmol) of lithium hydroxide were added and stirred at room temperature overnight. Upon completion of the reaction, the reaction mixture was extracted with dichloromethane three times (200 mL×3), the organic phases were pooled, dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with methanol in chloroform (0-10%) to provide 7.2 g of compound 269. Yield: 61%.

[0926] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 7.49 (s, 1H), 4.62 (s, 1H), 3.36 (q, J=6.8 Hz, 2H), 3.13 (t, J=7.0 Hz, 2H), 2.23 (m, 2H), 1.99 (t, J=2.4 Hz, 1H), 1.70-1.85 (m, 5H), 1.25-1.60 (m, 13H); ESI-MS (m/z): calcd for C.sub.16H.sub.30N.sub.3O.sub.3 [M+H].sup.+: 312.2; found: 312.3.

Sample 270: Preparation of Compound 270

[0927] To a 250 mL round-bottom flask charged with 6.33 g (19.3 mmol) of docosahexaenoic acid (DHA), 4.43 g (23.1 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), 3.12 g (4.43 mmol) of 1-hydroxybenzotriazole (HOBt) in 50 mL of dry DMF, 3.4 g (12.2 mmol) of compound 269 and 4.0 mL (28.95 mmol) of triethylamine were added and stirred at room temperature overnight. Upon completion of the reaction, the reaction mixture was partitioned between ethyl acetate (150 mL) and brine (150 mL), the organic phase was further washed with brine twice (100 mL×2), dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with methanol in chloroform (0-10%) to provide 10.3 g of compound 270. Yield: 86%.

[0928] .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): δ 6.32 (d, J=7.6 Hz, 1H), 5.35 (m, 12H), 4.67 (m, 1H), 4.38 (m, 3H), 3.37 (m, 2H), 3.23 (m, 2H), 2.89 (m, 10H), 2.379-2.433 (m, 2H), 2.25 (m, 4H), 2.076 (m, 1H), 1.99 (t, J=2.8 Hz, 1H), 1.70-1.87 (m, 6H), 1.30-1.70 (m, 14H), 0.97 (t, J=7.2 Hz, 3H). ESI-MS (m/z): calcd for C.sub.38H.sub.60N.sub.3O.sub.4 [M+H].sup.+: 622.4; found: 622.6.

Sample 271: Preparation of Compound 271

[0929] To a 250 mL round-bottom flask charged with 10.0 g (16.1 mmol) of compound 270, 50 mL of hydrochloride ethanol solution (3.0N) was added and stirred at room temperature overnight. After removal of volatiles, the residue was purified on a reverse phase C-18 column and eluted with acetonitrile in water (10-80%) to provide 7.47 g of compound 271. Yield: 89%.

[0930] .sup.1H NMR (300 MHz, DMSO-d.sub.6, ppm): δ 7.95 (m, 5H), 5.35 (m, 12H), 4.17 (m, 1H), 3.12 (m, 2H), 2.60-2.93 (m, 12H), 2.00-2.40 (m, 8H), 1.20-1.70 (m, 9H), 0.91 (t, J=7.2 Hz, 3H); ESI-MS (m/z): calcd for C.sub.33H.sub.52N.sub.3O.sub.2 [M+H].sup.+: 522.4; found: 522.7.

Sample 272: Preparation of Compound 272

[0931] To a 500 mL round-bottom flask charged with 7.76 g (26.82 mmol) of Boc-Gly-Gly-Gly, 6.69 g (34.88 mmol) of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC), 4.72 g (34.88 mmol) of 1-hydroxybenzotriazole (HOBt) in 100 mL of dry DMF, 15.0 g (26.82 mmol) of compound 271 and 9.6 mL (53.64 mmol) of triethylamine were added and stirred at room temperature overnight. Upon completion of the reaction, the reaction mixture was partitioned between ethyl acetate (200 mL) and brine (200 mL), the organic phase was further washed with brine twice (150 mL×2), dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with methanol in chloroform (0-15%) to provide 15.9 g of compound 272. Yield: 75%.

[0932] .sup.1H NMR (300 MHz, CDCl.sub.3+CD.sub.3OD, ppm): δ; 5.35 (m, 12H), 4.23 (m, 1H), 3.75-4.10 (m, 6H), 3.31 (m, 2H), 3.23 (m, 2H), 2.89 (m, 10H), 2.20-2.45 (m, 6H), 2.15 (m, 4H), 1.98 (s, 1H), 1.71 (m, 3H), 1.20-1.60 (m, 16H), 0.97 (t, J=7.6 Hz, 3H); ESI-MS (m/z): calcd for C.sub.44H.sub.69N.sub.6O.sub.7 [M+H].sup.+: 793.5; found: 793.8.

Sample 273: Preparation of Compound 273

[0933] To a 250 mL round-bottom flask charged with 9.0 g (11.35 mmol) of compound 272, 60 mL of hydrochloride ethanol solution (3.0N) was added and stirred at room temperature overnight. After removal of volatiles, the residue was purified on a reverse phase C-18 column and eluted with acetonitrile in water (10-80%) to provide 7.86 g of compound 273. Yield: 71%.

[0934] .sup.1H NMR (300 MHz, CD.sub.3OD, ppm): δ 5.37 (m, 12H), 4.25 (m, 1H), 4.03 (s, 2H), 3.85 (s, 2H), 3.80 (s, 2H), 3.22 (m, 4H), 2.85 (m, 10H), 2.00-2.50 (m, 9H), 1.76 (m, 4H), 1.63 (m, 2H), 1.47 (m, 2H), 0.98 (t, J=7.2 Hz, 3H); ESI-MS (m/z): calcd for C.sub.39H.sub.61N.sub.6O.sub.5 [M+H].sup.+: 693.5; found: 693.7.

Sample 274: Preparation of Compound 274

[0935] To a 250 mL round-bottom flask charged with 5.0 g (7.22 mmol) of compound 273 in 50 mL of anhydrous DMF, 3.5 mL (25.0 mmol) of triethylamine and 2.43 g (21.66 mmol) of diglycolic acid anhydride were added and stirred at room temperature overnight. After removal of volatiles, the residue was partitioned between ethyl acetate (200 mL) and 3.0N hydrochloride (200 mL), and the aqueous solution was further with 3.0N hydrochloride twice (100 mL×2), dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with methanol in chloroform (0-30%) to provide 3.05 g of compound 274. Yield: 52%.

[0936] .sup.1H NMR (300 MHz, DMSO-d.sub.6, ppm): δ 7.50-8.20 (m, 6H), 5.33 (m, 12H), 4.00-4.20 (m, 5H), 3.50-4.00 (m, 6H), 3.32 (m, 4H), 2.82 (m, 10H), 2.00-2.45 (m, 8H), 1.10-1.70 (m, 8H), 0.93 (t, J=7.2 Hz, 3H); ESI-MS (m/z): calcd for C.sub.43H.sub.65N.sub.6O.sub.9 [M+H].sup.+: 809.5; found: 809.9.

Sample 275: Preparation of Compound 275

[0937] To a 100 mL round-bottom flask charged with 100 mg (0.13 mmol) of compound 274 and 60 mg (0.13 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) in 5.0 mL of dry DMF, 263 mg (0.31 mmol) of paclitaxel and 38 mg (0.31 mmol) of DMAP were added, and the reaction mixture was stirred at room temperature for 24 hours. Upon completion of the reaction, the reaction mixture was partitioned between ethyl acetate (100 mL) and brine (100 mL); the aqueous phase was extracted with ethyl acetate (50 mL×2), and the organic phases were pooled, dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a reverse phase C-18 column and eluted with acetonitrile in water (30-100%) to provide 112 mg of compound 275. Yield: 53%.

[0938] .sup.1H NMR (500 MHz, CDCl.sub.3+CD.sub.3OD, ppm): δ 8.12 (d, J=7.2 Hz, 2H), 7.00-8.00 (m, 14H), 6.21 (s, 1H), 6.14 (m, 1H), 5.93 (m, 1H), 5.63 (d, J=9.6 Hz, 1H), 5.51 (d, J=7.1 Hz, 1H), 5.35 (m, 12H), 4.98 (d, J=9.6 Hz), 4.00-5.00 (m, 5H), 3.50-4.00 (m, 8H), 3.20-3.40 (m, 4H), 2.83 (m, 10H), 2.00-2.50 (m, 17H), 1.00-2.00 (m, 22H), 0.93 (t, J=7.2 Hz, 3H); ESI-MS (m/z): calcd for C.sub.90H.sub.114N.sub.7O.sub.22 [M+H].sup.+: 1644.8; found: 1645.1.

Synthetic Scheme 76

[0939] ##STR00221## ##STR00222##

Sample 276: Preparation of Compound 276

[0940] To a 1000 mL round-bottom flask charged with 30.0 g (121.9 mmol) of N.sub.6-Boc-L-lysine and 33 mL (143 mmol) of triethylamine in 100 mL of DMF, 44.2 g (121.9 mmol) of Cbz-Gly-Gly N-hydroxy-succinimide ester in DMF was dropwise added and stirred at room temperature overnight; After removal of volatiles, the residue was partitioned between ethyl acetate (300 mL) and 3N HCl solution (300 mL); and the organic phases were further washed with 3N HCl solution twice (150 mL×2), dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with methanol in chloroform (0-20%) to provide 33.8 g of compound 276. Yield: 56%.

[0941] .sup.1H NMR (300 MHz, DMSO-d.sub.6, ppm): δ 8.12 (s, 1H), 7.75 (s, 1H), 7.36 (t, J=5.2 Hz, 1H), 7.32 (m, 5H), 7.02 (d, J=7.6 Hz, 1H), 5.04 (s, 2H), 3.83 (m, 1H), 3.67 (m, 4H), 3.05 (m, 2H), 1.50-1.70 (m, 2H), 1.20-1.40 (m, 13H); ESI-MS (m/z): calcd for C.sub.23H.sub.35N.sub.4O.sub.8 [M+H].sup.+: 495.3; found: 495.5.

Sample 277: Preparation of Compound 277

[0942] To a 250 mL round-bottom flask charged with 25.0 g (50.6 mmol) of compound 276 and 14.6 g (75.9 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) in 300 mL of anhydrous dichloromethane, 10.0 mL of absolute ethanol and 9.3 g (75.9 mmol) of DMAP were added, and stirred at room temperature overnight. After removal of volatiles, the residue was partitioned between ethyl acetate (200 mL) and brine (200 mL), and the organic phase was washed with brine (100 mL×2), dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with methanol in dichloromethane (0-10%) to provide 19.1 g of compound 277. Yield: 72%.

[0943] .sup.1H NMR (300 MHz, DMSO-d.sub.6, ppm): δ 8.12 (t, J=5.2 Hz, 1H), 7.75 (t, J=5.2 Hz, 1H), 7.51 (t, J=5.2 Hz, 1H), 7.37 (m, 5H), 7.17 (d, J=7.6 Hz, 1H), 5.04 (s, 2H), 4.10 (m, 2H), 3.88 (m, 1H), 3.68 (m, 4H), 3.07 (m, 2H), 1.50-1.70 (m, 2H), 1.20-1.40 (m, 13H), 1.14 (t, J=7.2 Hz, 3H); ESI-MS (m/z): calcd for C.sub.25H.sub.39N.sub.4O.sub.8 [M+H].sup.+: 523.3; found: 523.6.

Sample 278: Preparation of Compound 278

[0944] In a 500 mL round-bottom flask, 26.0 g (49.8 mmol) of compound 277 was dissolved in 250 mL of anhydrous ethanol, followed by addition of 3.0 g of Pd—C and bubbled with hydrogen gas for 5 hours. Upon completion of the reaction, Pd—C was filtered off, and the filtrate was concentrated, purified on a reverse phase C-18 column and eluted with acetonitrile in water (10-70%) to provide 15.7 g of compound 278. Yield: 81%.

[0945] .sup.1H NMR (300 MHz, DMSO-d.sub.6, ppm): δ 8.10 (s, 1H), 7.86 (t, J=5.2 Hz, 1H), 7.19 (t, J=5.2 Hz, 1H), 4.11 (m, 2H), 4.05 (s, 2H), 3.88 (m, 1H), 3.69 (m, 4H), 3.05 (m, 2H), 1.50-1.70 (m, 2H), 1.20-1.40 (m, 13H), 1.16 (t, J=7.2 Hz, 3H); ESI-MS (m/z): calcd for C.sub.17H.sub.33N.sub.4O.sub.6 [M+H].sup.+: 389.2; found: 389.3.

Sample 279: Preparation of Compound 279

[0946] To a 500 mL round-bottom flask charged with 10.0 g (5.95 mmol) of compound 278 in 50 mL of anhydrous acetonitrile, 11.0 mL (77.26 mmol) of triethylamine and 8.67 g (77.26 mmol) of diglycolic acid anhydride were added and stirred at room temperature overnight. After removal of volatiles, the residue was partitioned between ethyl acetate (200 mL) and 3.0N hydrochloride (200 mL), and the organic phase was further with 3.0N hydrochloride twice (100 mL×2), dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a reverse phase C-18 column and eluted with acetonitrile in water (5-70%) to provide 8.05 g of compound 279. Yield: 62%.

[0947] .sup.1H NMR (300 MHz, D.sub.2O, ppm): δ 4.24 (m, 3H), 4.21 (s, 2H), 4.04 (m, 1H), 3.98 (s, 2H), 3.81 (s, 1H), 3.16 (m, 2H), 1.85 (m, 1H), 1.75 (m, 1H), 1.45 (m, 2H), 1.28 (m, 11H), 1.17 (t, J=7.2 Hz, 3H); ESI-MS (m/z): calcd for C.sub.21H.sub.37N.sub.4O.sub.10 [M+H].sup.+: 505.2; found: 505.3.

Sample 280: Preparation of Compound 280

[0948] In a 500 mL round-bottom flask, 17.0 g (33.71 mmol) of compound 279 was dissolved in 100 mL of 30% trifluoroacetic acid in dichloromethane and stirred overnight. After removal of volatiles, the residue was purified on a reverse phase C-18 column and eluted with acetonitrile in water (5-60%) to provide 11.7 g of compound 280. Yield: 86%.

[0949] .sup.1H NMR (300 MHz, DMSO-d.sub.6, ppm): δ 8.45 (s, 3H), 8.21 (t, J=5.2 Hz, 1H), 8.10 (t, J=5.2 Hz, 1H), 7.77 (t, J=5.2 Hz, 1H), 4.25 (m, 2H), 4.19 (s, 2H), 4.05 (s, 2H), 4.02 (m, 1H), 3.78 (d, J=5.2 Hz, 2H), 3.65 (d, J=5.2 Hz, 2H), 3.06 (m, 2H), 1.78 (m, 2H), 1.43 (m, 4H), 1.21 (t, J=7.2 Hz, 3H); ESI-MS (m/z): calcd for C.sub.16H.sub.29N.sub.4O.sub.8 [M+H].sup.+: 405.2; found: 405.3.

Sample 281: Preparation of Compound 281

[0950] To a 1000 mL round-bottom flask charged with 25.0 g (101.5 mmol) of N.sub.6-Boc-lysine and 28.1 mL (203 mmol) of triethylamine in 100 mL of DMF, 43.2 g (101.5 mmol) of docosahexaenoic acid (DHA) N-hydroxy-succinimide ester in DMF was dropwise added and stirred at room temperature overnight; After removal of volatiles, the residue was partitioned between ethyl acetate (300 mL) and 3.0N HCl solution (300 mL); and the organic phase was further washed with 3.0N HCl solution twice (150 mL×2), dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with methanol in chloroform (0-10%) to provide 27.7 g of compound 281. Yield: 49%.

[0951] .sup.1H NMR (300 MHz, DMSO-d.sub.6, ppm): δ 7.80 (t, J=5.2 Hz, 1H), 6.32 (d, J=7.6 Hz, 1H), 5.32 (m, 12H), 4.05 (m, 1H), 3.05 (m, 2H), 2.85 (m, 10H), 2.25 (m, 2H), 2.10 (m, 4H), 1.40-1.70 (m, 4H), 1.37 (s, 9H), 1.32 (m, 2H), 0.97 (t, J=7.2 Hz, 3H); ESI-MS (m/z): calcd for C.sub.33H.sub.53N.sub.2O.sub.5 [M+H].sup.+: 557.4; found: 557.7.

Sample 282: Preparation of Compound 282

[0952] To a 500 mL round-bottom flask charged with 15.0 g (26.94 mmol) of compound 281, 100 mL of hydrochloride tetrahydrofurane solution (3.0N) was added and stirred at room temperature overnight. After removal of volatiles, the residue was purified on a reverse phase C-18 column and eluted with acetonitrile in water (10-80%) to provide 8.01 g of compound 282. Yield: 65%.

[0953] .sup.1H NMR (300 MHz, DMSO-d.sub.6, ppm): δ 8.29 (s, 3H), 7.82 (t, J=5.2 Hz, 1H), 5.35 (m, 12H), 3.87 (m, 1H), 3.03 (m, 2H), 2.83 (m, 10H), 2.27 (m, 2H), 2.10 (m, 4H), 1.79 (m, 2H), 1.37 (m, 4H), 0.92 (t, J=7.2 Hz, 3H); ESI-MS (m/z): calcd for C.sub.28H.sub.45N.sub.2O.sub.3 [M+H].sup.+: 457.3; found: 457.5.

Sample 283: Preparation of Compound 283

[0954] To a 250 mL round-bottom flask charged with 7.0 g (14.16 mmol) of compound 282 and 4.9 mL (35.4 mmol) of triethylamine in 35 mL of DMF, 4.18 g (15.0 mmol) of 2-(cyclooct-2-ynyloxy)acetic acid N-hydroxy-succinimide ester in DMF was dropwise added and stirred at room temperature overnight; After removal of volatiles, the residue was partitioned between ethyl acetate (300 mL) and 3N HCl solution (300 mL); and the organic phase was further washed with 3.0N HCl solution twice (150 mL×2), dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with methanol in chloroform (0-10%) to provide 3.7 g of compound 283. Yield: 43%.

[0955] .sup.1H NMR (300 MHz, DMSO-d.sub.6, ppm): δ 7.92 (t, J=5.2 Hz, 1H), 7.57 (s, 1H), 5.36 (m, 12H), 4.30 (m, 2H), 4.06 (m, 2H), 3.88 (m, 1H), 3.03 (m, 2H), 2.87 (m, 10H), 2.15 (m, 2H), 2.05 (m, 4H), 1.45-2.00 (m, 10H), 1.27 (m, 4H), 1.22 (m, 3H), 0.95 (t, J=7.2 Hz, 3H); ESI-MS (m/z): calcd for C.sub.38H.sub.57N.sub.2O.sub.5 [M+H].sup.+: 621.4; found: 621.5.

Sample 284: Preparation of Compound 284

[0956] To a 250 mL round-bottom flask charged with 3.0 g (4.83 mmol) of compound 283, 1.2 g (6.28 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), and 723 mg (6.28 mmol) N-hydroxy-succinimide ester, 15.0 mL of anhydrous DMF was added and stirred at room temperature for 5 hours. To a stirred solution of compound 280 and 1.8 mL (12.56 mmol) of triethylamine in DMF, the above reaction mixture was dropwise added, and the final reaction mixture was stirred at room temperature overnight. After removal of volatiles, the residue the residue was partitioned between ethyl acetate (100 mL) and 3.0N HCl solution (100 mL); and the organic phases were further washed with 3.0N HCl solution twice (100 mL×2), dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a silica gel column and eluted with methanol in chloroform (0-30%) to provide 1.61 g of compound 284. Yield: 33%.

[0957] .sup.1H NMR (300 MHz, CD.sub.3OD, ppm): δ 5.39 (m, 12H), 4.33 (m, 1H), 4.31 (m, 2H), 4.24 (s, 2H), 4.17 (m, 2H), 4.06 (m, 4H), 3.86 (s, 2H), 3.21 (m, 4H), 2.87 (m, 10H), 2.00-2.45 (m, 7H), 1.60-2.00 (m, 10H), 1.35-1.60 (m, 9H), 1.25 (t, J=7.2 Hz, 3H), 0.98 (t, J=7.2 Hz, 3H); ESI-MS (m/z): calcd for C.sub.54H.sub.83N.sub.6O.sub.12 [M+H].sup.+: 1007.6; found: 1008.0.

Sample 285: Preparation of Compound 285

[0958] To a 100 mL round-bottom flask charged with 150 mg (0.15 mmol) of compound 284 and 71 mg (0.37 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) in 5.0 mL of dry DMF, 316 mg (0.37 mmol) of paclitaxel, and 45 mg (0.37 mmol) of DMAP were added, and the reaction mixture was stirred at room temperature for 24 hours. Upon completion of the reaction, the reaction mixture was partitioned between ethyl acetate (50 mL) and brine (50 mL); the aqueous phase was extracted with ethyl acetate (50 mL×2), and the organic phases were pooled, dried over anhydrous MgSO.sub.4, filtered, concentrated, and purified on a reverse phase C-18 column and eluted with methanol in water (30-100%) to provide 86 mg of compound 285. Yield: 31%.

[0959] .sup.1H NMR (500 MHz, CDCl.sub.3+CD.sub.3OD, ppm): δ 8.07 (d, J=7.2 Hz, 2H), 7.00-8.00 (m, 14H), 6.26 (s, 1H), 6.07 (m, 1H), 5.61 (m, 1H), 5.49 (d, J=7.1 Hz, 1H), 5.33 (m, 12H), 4.92 (d, J=9.6 Hz, 1H), 4.00-4.60 (m, 15H), 3.50-4.00 (m, 4H), 3.19 (m, 4H), 2.78 (m, 10H), 2.00-2.50 (m, 17H), 1.50-2.00 (m, 15H), 1.10-1.50 (m, 12H), 0.70-1.00 (m, 9H); ESI-MS (m/z): calcd for C.sub.101H.sub.132N.sub.7O.sub.25 [M+H].sup.+: 1842.9; found: 1843.2.

Part 7. Preparative of Taxane-Lipid-Polysaccharide Drual Conjugates

Synthetic Scheme 77

[0960] ##STR00223##

Sample 286: Preparation of Dual Conjugate 286

[0961] In a 25 mL round bottom flask, 600 mg of functionalized dextran 111, 120 mg (0.08 mmol) of compound 59 and 46 mg (0.08 mmol) of compound 154 were dissolved in 2.0 mL of DMSO, and followed by addition of copper sulfate solution (100 uL×1.0 M), THPTA (Tris (3-hydroxypropyltriazolylmethyl) amine, 100 uL×1.0 M) and sodium ascorbate solution (30 uL×1.0 M), and were stirred at room temperature for 2 days. Upon completion of the reaction, the reaction mixture was precipitated with methanol, filtered, and washed with methanol three times. The precipitate was then dissolved in 2.0 mL of distilled water, dialyzed against distilled water, and lyophilized to offer 379 mg of conjugate 286. By comparing its UV absorption with that of of compound 61 and compound 151 at wavelength of 280 nm, 11% (w/w) paclitaxel content was determined in conjugate 286.

[0962] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.20 (m, CHOH, CH.sub.2OH, CH.sub.2O); minor signals: 7.10-8.50 (m, CONH, ArH), 5.32 (m, CH), 1.23 (m, CH.sub.3), 1.00 (m, CH.sub.3).

Synthetic Scheme 78

[0963] ##STR00224##

Sample 287: Preparation of Dual Conjugate 287

[0964] The preparation of conjugate 287 is similar to that of conjugate 286.

[0965] By comparing its UV absorption with that of of compound 61 and compound 155 at wavelength of 280 nm, 6% (w/w) paclitaxel content was determined in conjugate 287.

[0966] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.20 (m, CHOH, CH.sub.2OH, CH.sub.2O); minor signals: 7.10-8.50 (m, CONH, ArH), 5.32 (m, CH), 1.23 (m, CH.sub.3), 0.99 (m, CH.sub.3).

Synthetic Scheme 79

[0967] ##STR00225##

Sample 288: Preparation of Dual Conjugate 288

[0968] The preparation of conjugate 288 is similar to that of conjugate 286.

[0969] By comparing its UV absorption with that of of compound 62 and compound 154 at wavelength of 280 nm, 9% (w/w) docetaxel content was determined in conjugate 288.

[0970] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.20 (m, CHOH, CH.sub.2OH, CH.sub.2O); minor signals: 7.10-8.50 (m, CONH, ArH), 5.32 (m, CH), 1.23 (m, CH.sub.3), 1.00 (m, CH.sub.3).

Synthetic Scheme 80

[0971] ##STR00226##

Sample 289: Preparation of Dual Conjugate 289

[0972] The preparation of conjugate 289 is similar to that of conjugate 286.

[0973] By comparing its UV absorption with that of of compound 61 and compound 209 at wavelength of 280 nm, 6% (w/w) paclitaxel content was determined in conjugate 289.

[0974] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.20 (m, CHOH, CH.sub.2OH, CH.sub.2O); minor signals: 6.75-8.50 (m, CONH, ArH), 5.32 (m, CH), 1.23 (m, CH.sub.3), 0.99 (m, CH.sub.3).

Synthetic Scheme 81

[0975] ##STR00227##

Sample 290: Preparation of Dual Conjugate 290

[0976] In a 25 mL round bottom flask, 300 mg of conjugate 211 and 50 mg (0.07 mmol) of compound 74 were dissolved in 5.0 mL of DMSO, and stirred at room temperature for 3 days. Upon completion of the reaction, the reaction mixture was precipitated with methanol, filtered, and washed with methanol three times. The precipitate was then dissolved in 3.0 mL of distilled water, dialyzed against distilled water, and lyophilized to give 2.71 mg of conjugate 290. By comparing its UV absorption with that of of compound 76a (76b) and functionalized hyaluronic acid 211 at wavelength of 280 nm, 9% (w/w) docetaxel content was determined in conjugate 290.

[0977] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.20 (m, CHOH, CH.sub.2OH, CH.sub.2O); minor signals: 7.10-8.50 (m, CONH, ArH), 5.32 (m, CH), 2.03 (m, CH.sub.3CO), 1.35 (s, OC(CH.sub.3).sub.3), 1.23 (m, CH.sub.3), 1.00 (m, CH.sub.3).

Synthetic Scheme 82

[0978] ##STR00228##

Sample 291: Preparation of Dual Conjugate 291

[0979] The preparation of conjugate 291 is similar to that of conjugate 286.

[0980] By comparing its UV absorption with that of of compound 61 and conjugate 214 at wavelength of 280 nm, 7% (w/w) paclitaxel content was determined in conjugate 291.

[0981] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.20 (m, CHOH, CH.sub.2OH, CH.sub.2O); minor signals: 7.00-8.50 (m, CONH, ArH), 5.32 (m, CH), 2.03 (m, CH.sub.3CO), 1.35 (s, OC(CH.sub.3).sub.3), 1.23 (m, CH.sub.3), 1.00 (m, CH.sub.3).

Synthetic Scheme 83

[0982] ##STR00229##

Sample 292: Preparation of Dual Conjugate 292

[0983] The preparation of conjugate 292 is similar to that of conjugate 286.

[0984] By comparing its UV absorption with that of of compound 62 and conjugate 214 at wavelength of 280 nm, 11% (w/w) docetaxel content was determined in conjugate 292.

[0985] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH, CH.sub.2O); minor signals: 7.10-8.50 (m, CONH, ArH), 5.32 (m, CH), 1.33 (s, OC(CH.sub.3).sub.3), 1.22 (m, CH.sub.3), 0.99 (m, CH.sub.3).

Synthetic scheme 84

##STR00230##

Sample 293: Preparation of Dual Conjugate 293

[0986] The preparation of conjugate 293 is similar to that of conjugate 286.

[0987] By comparing its UV absorption with that of of compound 7 and conjugate 216 at wavelength of 280 nm, (w/w) paclitaxel content was determined in conjugate 293. .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH, CH.sub.2O); minor signals: 7.10-8.50 (m, CONH, ArH), 5.35 (m, CH), 0.99 (m, CH.sub.3).

Synthetic Scheme 85

[0988] ##STR00231##

Sample 294: Preparation of Dual Conjugate 294

[0989] The preparation of conjugate 294 is similar to that of conjugate 286.

[0990] By comparing its UV absorption with that of of compound 40 and conjugate 218 at wavelength of 280 nm, 5% (w/w) docetaxel content was determined in conjugate 294.

[0991] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH, CH.sub.2O); minor signals: 7.10-8.50 (m, CONH, ArH), 5.33 (m, CH), 1.34 (s, OC(CH.sub.3).sub.3), 1.00 (m, CH.sub.3), 0.83 (m, CH.sub.3).

Synthetic Scheme 86

[0992] ##STR00232##

Sample 295: Preparation of Dual Conjugate 295

[0993] The preparation of conjugate 295 is similar to that of conjugate 286.

[0994] By comparing its UV absorption with that of of compound 63 and conjugate 221 at wavelength of 280 nm, 6% (w/w) carbazitaxel content was determined in conjugate 295.

[0995] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH, CH.sub.2O); minor signals: 7.10-8.50 (m, CONH, ArH), 6.25 (m, CH), 1.34 (s, OC(CH.sub.3).sub.3), 1.00 (m, CH.sub.3).

Synthetic Scheme 87

[0996] ##STR00233##

Sample 296: Preparation of Dual Conjugate 296

[0997] The preparation of conjugate 296 is similar to that of conjugate 286.

[0998] By comparing its UV absorption with that of of compound 7 and conjugate 224 at wavelength of 280 nm, 7% (w/w) paclitaxel content was determined in conjugate 296.

[0999] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH, CH.sub.2O); minor signals: 7.10-8.50 (m, CONH, ArH), 5.35 (m, CH), 1.25 (m, CH.sub.3), 1.00 (m, CH.sub.3).

Synthetic Scheme 88

[1000] ##STR00234##

Sample 297: Preparation of Dual Conjugate 297

[1001] The preparation of conjugate 297 is similar to that of conjugate 286.

[1002] By comparing its UV absorption with that of of compound 40 and conjugate 225 at wavelength of 280 nm, 10% (w/w) docetaxel content was determined in conjugate 297.

[1003] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH, CH.sub.2O); minor signals: 7.10-8.50 (m, CONH, ArH), 5.35 (m, CH), 1.35 (s, OC(CH.sub.3).sub.3), 1.00 (m, CH.sub.3), 0.83 (t, CH.sub.3).

Synthetic Scheme 89

[1004] ##STR00235##

Sample 298: Preparation of Dual Conjugate 298

[1005] The preparation of conjugate 298 is similar to that of conjugate 286.

[1006] By comparing its UV absorption with that of of compound 61 and conjugate 225 at wavelength of 280 nm, 9% (w/w) paclitaxel content was determined in conjugate 298.

[1007] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH, CH.sub.2O); minor signals: 7.10-8.50 (m, CONH, ArH), 5.33 (m, CH), 1.23 (m, CH.sub.3), 1.00 (m, CH.sub.3), 0.85 (t, CH.sub.3).

Synthetic Scheme 90

[1008] ##STR00236##

Sample 299: Preparation of Dual Conjugate 299

[1009] The preparation of conjugate 299 is similar to that of conjugate 290.

[1010] By comparing its UV absorption with that of of compound 75a (75b) and conjugate 214 at wavelength of 280 nm, 7% (w/w) paclitaxel content was determined in conjugate 299.

[1011] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH, CH.sub.2O); minor signals: 7.00-8.60 (m, CONH, ArH), 5.32 (m, CH), 1.23 (m, CH.sub.3), 1.00 (m, CH.sub.3).

Synthetic Scheme 91

[1012] ##STR00237##

Sample 300: Preparation of Dual Conjugate 300

[1013] The preparation of conjugate 300 is similar to that of conjugate 286.

[1014] By comparing its UV absorption with that of of compounds 61 and functionalized dextran 140 at wavelength of 280 nm, 13% (w/w) paclitaxel content was determined in conjugate 300.

[1015] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.00 (m, CHOH, CH.sub.2OH, CH.sub.2O); minor signals: 6.70-8.50 (m, CONH, ArH), 5.33 (m, CH), 0.90-1.23 (m, CH.sub.3).

Synthetic Scheme 92

[1016] ##STR00238##

Sample 301: Preparation of Dual Conjugate 301

[1017] The preparation of conjugate 301 is similar to that of conjugate 286.

[1018] By comparing its UV absorption with that of of compounds 40 and functionalized dextran 209 at wavelength of 280 nm, 11% (w/w) docetaxel content was determined in conjugate 301.

[1019] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.20 (m, CHOH, CH.sub.2OH, CH.sub.2O); minor signals: 6.50-8.50 (m, CONH, ArH), 5.33 (m, CH), 0.90-1.23 (m, CH.sub.3).

Synthetic Scheme 93

[1020] ##STR00239##

Sample 302: Preparation of Dual Conjugate 302

[1021] The preparation of conjugate 302 is similar to that of conjugate 286.

[1022] By comparing its UV absorption with that of of compound 62 and functionalized dextran 140 at wavelength of 280 nm, 12% (w/w) docetaxel content was determined in conjugate 302.

[1023] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.20 (m, CHOH, CH.sub.2OH, CH.sub.2O); minor signals: 6.50-8.50 (m, CONH, ArH), 5.33 (m, CH), 0.90-1.23 (m, CH.sub.3).

Synthetic Scheme 94

[1024] ##STR00240##

Sample 303: Preparation of Dual Conjugate 303

[1025] The preparation of conjugate 303 is similar to that of conjugate 290.

[1026] By comparing its UV absorption with that of of compound 75a (75b) and conjugate 227 at wavelength of 280 nm, 9% (w/w) paclitaxel content was determined in conjugate 303.

[1027] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.20 (m, CHOH, CH.sub.2OH, CH.sub.2O); minor signals: 7.00-8.60 (m, CONH, ArH), 5.33 (m, CH), 0.99 (m, CH.sub.3).

Synthetic Scheme 95

[1028] ##STR00241##

Sample 304: Preparation of Dual Conjugate 304

[1029] The preparation of conjugate 304 is similar to that of conjugate 290.

[1030] By comparing its UV absorption with that of of compound 76a (76b and conjugate 227 at wavelength of 280 nm, 11% (w/w) docetaxel content was determined in conjugate 304.

[1031] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.20 (m, CHOH, CH.sub.2OH, CH.sub.2O); minor signals: 6.50-8.50 (m, CONH, ArH), 5.33 (m, CH), 1.22 (m, CH.sub.3), 1.01 (m, CH.sub.3). 0.83 (m, CH.sub.3). 7.00-8.60 (m, CONH, ArH), 5.33 (m, CH), 1.34 (s, OC(CH.sub.3).sub.3), 1.00 (m, CH.sub.3).

Synthetic Scheme 96

[1032] ##STR00242##

Sample 305: Preparation of Dual Conjugate 305

[1033] The preparation of conjugate 305 is similar to that of conjugate 286.

[1034] By comparing its UV absorption with that of of compound 61 and conjugate 228 at wavelength of 280 nm, 9% (w/w) paclitaxel content was determined in conjugate 305, .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.20 (m, CHOH, CH.sub.2OH, CH.sub.2O); minor signals: 6.50-8.50 (m, CONH, ArH), 5.33 (m, CH), 1.22 (m, CH.sub.3), 1.01 (m, CH.sub.3). 0.83 (m, CH.sub.3).

Synthetic Scheme 97

[1035] ##STR00243##

Sample 306: Preparation of Dual Conjugate 306

[1036] The preparation of conjugate 306 is similar to that of conjugate 286.

[1037] By comparing its UV absorption with that of of compound 61 and conjugate 85 at wavelength of 280 nm, 7% (w/w) paclitaxel content was determined in conjugate 306.

[1038] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.20 (m, CHOH, CH.sub.2OH, CH.sub.2O); minor signals: 7.00-8.50 (m, CONH, ArH), 5.33 (m, CH), 0.90-1.23 (m, CH.sub.3).

Synthetic Scheme 98

[1039] ##STR00244##

Sample 307: Preparation of Dual Conjugate 307

[1040] The preparation of conjugate 307 is similar to that of conjugate 286.

[1041] By comparing its UV absorption with that of of compound 62 and conjugate 91 at wavelength of 280 nm, 9% w/w) docetaxel content was determined in conjugate 307.

[1042] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.20 (m, CHOH, CH.sub.2OH, CH.sub.2O); minor signals: 7.00-8.50 (m, CONH, ArH), 5.33 (m, CH), 0.90-1.23 (m, CH.sub.3).

Synthetic Scheme 99

[1043] ##STR00245##

Sample 308: Preparation of Dual Conjugate 308

[1044] The preparation of conjugate 308 is similar to that of conjugate 286.

[1045] By comparing its UV absorption with that of of compound 61 and conjugate 91 at wavelength of 280 nm, 7% (w/w) paclitaxel content was determined in conjugate 308.

[1046] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.20 (m, CHOH, CH.sub.2OH, CH.sub.2O); minor signals: 7.00-8.50 (m, CONH, ArH), 5.33 (m, CH), 0.90-1.23 (m, CH.sub.3).

Synthetic Scheme 100

[1047] ##STR00246##

Sample 309: Preparation of Dual Conjugate 309

[1048] The preparation of conjugate 309 is similar to that of conjugate 286.

[1049] By comparing its UV absorption with that of of functionalized dextran 151 and conjugate 266 at wavelength of 280 nm, 7% (kw) docetaxel content was determined in conjugate 309, .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.20 (m, CHOH, CH.sub.2OH, CH.sub.2O); minor signals: 6.70-8.50 (m, CONH, ArH), 5.33 (m, CH), 0.90-1.23 (m, CH.sub.3).

Synthetic Scheme 101

[1050] ##STR00247##

Sample 310: Preparation of Dual Conjugate 310

[1051] The preparation of conjugate 310 is similar to that of conjugate 286.

[1052] By comparing its UV absorption with that of of compound 62 and conjugate 108 at wavelength of 280 nm. 6% (w/w) docetaxel content was determined in conjugate 310.

[1053] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.20 (m, CHOH, CH.sub.2OH, CH.sub.2O); minor signals: 6.70-8.50 (m, CONH, ArH), 5.33 (m, CH), 0.90-1.23 (m, CH.sub.3).

Synthetic Scheme 102

[1054] ##STR00248##

Sample 311: Preparation of Dual Conjugate 311

[1055] The preparation of conjugate 311 is similar to that of conjugate 290.

[1056] By comparing its UV absorption with that of of compound 75475b) and conjugate 91 at wavelength of 280 nm. 8% (w/w) paclitaxel content was determined in conjugate 311.

[1057] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.20 (m, CHOH, CH.sub.2OH, CH.sub.2O); minor signals: 7.00-8.50 (m, CONH, ArH), 5.33 (m, CH), 0.90-1.23 (m, CH.sub.3).

Synthetic Scheme 103

[1058] ##STR00249##

Sample 312: Preparation of Dual Conjugate 312

[1059] The preparation of conjugate 312 is similar to that of conjugate 286.

[1060] By comparing its UV absorption with that of of compound 61 and conjugate 151 at wavelength of 280 nm, 9% (w w) paclitaxel content was determined in conjugate 312.

[1061] .sup.1H NMR (selected characteristic signals, 500 MHz, DMSO-d.sub.6, ppm): major signals: 4.50-5.00 (m, CHOH, CHOH, CH.sub.2OH), 3.30-4.20 (m, CHOH, CH.sub.2OH, CH.sub.2O); minor signals: 6.70-8.50 (m, CONH, ArH), 5.33 (m, CH), 0.90-1.23 (m, CH.sub.3).

Enhanced Solubility Test for Poorly Water-Soluble Compounds

[1062] In a 5.0 mL glass vial, 300 mg of conjugate 196 was dissolved in 3.0 mL of distilled water and followed by addition of a solution of 1.0 mg of docetaxel in 100 μL of tetrahydrofuran, sonicated for 1 minute, and the resulting mixture was lyophilized to obtain white powder. The powder was then added to a glass vial with 2.0 mL of distilled water and sonicated for 1 minute to obtain a translucent misty solution. No precipitation was observed at the bottom of the bottle, and no floating powder was observed on the liquid surface, as a result the enhanced docetaxel solubility is 0.5 mg/mL in water. In contrast, 1.0 mg of docetaxel was weighed into a 5.0 mL glass vial, then 2.0 ml of distilled water was added to the glass vial, the vial was sonicated for 1 minute, and the undissolved powder floated over water surface was clearly observed.

[1063] The literature reports that the solubility of docetaxel in water is 0.00127 mg/mL https://www.drugbank.ca/drugs/DB01248).

[1064] In a 5.0 mL glass vial, 300 mg of conjugate 198 was dissolved in 3.0 mL of distilled water and followed by addition of a solution of 1.0 mg of stearic acid in 100 μL of tetrahydrofuran, sonicated for 1 minute, and the resulting mixture was lyophilized to obtain white powder. The powder was then added to a glass vial with 2.0 mL of distilled water and sonicated for 1 minute to obtain a translucent misty solution. No precipitation was observed at the bottom of the bottle, and no floating powder was observed on the liquid surface, as a result the enhanced stearic acid solubility is 0.5 mg/mL in water. In contrast, 1.0 mg of stearic acid was weighed into a 5.0 mL glass vial, then 2.0 ml of distilled water was added to the glass vial, the vial was sonicated for 1 minute, and the undissolved powder floated over water surface was clearly observed.

[1065] The literature reports that the solubility of stearic acid in water is 0.000597 mg/mL https://www.drugbank.ca/drugs/DB03193).

[1066] In a 5.0 mL glass vial, 250 mg of conjugate 291 was dissolved in 3.0 mL of distilled water and followed by addition of a solution of 1.0 mg of paclitaxel in 100 μL of tetrahydrofuran, sonicated for 1 minute, and the resulting mixture was lyophilized to obtain white powder. The powder was then added to a glass vial with 2.0 mL of distilled water and sonicated for 1 minute to obtain a milk-like solution. No precipitation was observed at the bottom of the bottle, and no floating powder was observed on the liquid surface, as a result the enhanced paclitaxel solubility is 0.5 mg/mL in water. In contrast, 1.0 mg of paclitaxel was weighed into a 5.0 mL glass vial, then 2.0 ml of distilled water was added to the glass vial, the vial was sonicated for 1 minute, and the undissolved powder floated over water surface was clearly observed.

[1067] The literature reports that the solubility of paclitaxel in water is 0.00556 mg/mL https://www.drugbank.ca/drugs/DB01229).

[1068] In summary, theses four types of substances: polysaccharide-lipid conjugates, functionalized polysaccharide-lipid conjugates, polysaccharide-taxane conjugates, and taxane-polysaccharide-lipid dual conjugates, contain a hydrophilic component and a lipophilic component, and enhance solubility of poorly water-soluble compounds.

In Vitro Antitumor Activity Assay

[1069] In order to determine if the activity of the prepared intermediates and prepared conjugates, we evaluated their antitumor activities by using MTT assay.

[1070] All cell lines were maintained in a humidified atmosphere containing 5% CO2 at 37° C. in different media supplemented with 10% FBS, 100 U/ml penicillin, and 100 μg/ml streptomycin. MCF-7, NCI-H460 or OVCAR-3 tumor cells were seeded into a 96-well cell culture plate and incubated overnight. The 96-well culture plate was taken out from the incubator, and the conjugates or mixture of different compounds or polysaccharides were added into it. The concentration of each compound or conjugate were set to 500 nM, 200 nM, 100 nM, 50 nM, 25 nM, 12.5 nM, 6 nM, 3 nM and 1 nM. Three wells were set at each concentration. Blank control contained tumor cells in normal medium without any sample. After treatment for 72 h, 20 μL of 3-(4, 5-dimethylthiazole-2)-2,5-diphenyltetrazolium bromide (MTT) were added to each well and incubated for 4 hours at 37° C. After the removal of the supernatant, MTT formazan was dissolved in 150 μl dimethyl sulfoxide (DMSO) and monitored using a microplate reader at a wavelength of 570 nM. The half-inhibitory concentration (IC.sub.50 value) of each compound or conjugate was calculated. The growth inhibition rate (%) of each drug concentration group=(1−average OD value of the experimental well/average OD value of the control well)×100%; MTT assay were repeated for 3 times and the average IC.sub.50 value was repeated for each sample.

TABLE-US-00001 TABLE 1 The antitumor activity of some samples (IC.sub.50 value: nM) Substance MCF-7 NCI-H460 Cabazitaxel  8.3 ± 0.5  7.1 ± 0.3 Docetaxel  9.5 ± 0.2  6.7 ± 0.6 Paclitaxel 21.9 ± 1.1 17.9 ± 1.3 Conjugate 165 >500 >500 Conjugate 179 >500 >500 Conjugate 191 >500 >500 Conjugate 218 >500 >500 Conjugate 229 39.1 ± 3.7 27.3 ± 5.2 Conjugate 230 56.5 ± 2.5 67.5 ± 3.3 Conjugate 231 45.6 ± 5.1 33.9 ± 4.7 Conjugate 232 36.7 ± 3.2 54.6 ± 7.1 Conjugate 236 58.9 ± 2.1 36.3 ± 5.3 Conjugate 237 47.3 ± 4.9 65.5 ± 3.6 Conjugate 239 39.7 ± 5.6 45.3 ± 5.2 Conjugate 243 53.8 ± 7.2 37.3 ± 3.5 Conjugate 244 67.6 ± 6.5 41.5 ± 6.3 Conjugate 245 48.2 ± 3.9 31.3 ± 5.7 Conjugate 249 128.6 ± 9.5  97.3 ± 8.6 Dual conjugate 286 32.3 ± 4.5 42.5 ± 5.6 Dual conjugate 287 41.7 ± 6.3 30.9 ± 6.3 Dual conjugate 288 27.7 ± 5.1 38.4 ± 6.3 Dual conjugate 289 36.2 ± 7.3 25.9 ± 3.8 Dual conjugate 290 39.1 ± 5.2 45.6 ± 4.7 Dual conjugate 291 32.6 ± 6.3 23.6 ± 3.9 Dual conjugate 292 15.3 ± 4.7 21.8 ± 3.2 Dual conjugate 293 47.3 ± 7.1 53.9 ± 6.2 Dual conjugate 294 33.3 ± 5.6 29.3 ± 5.5 Dual conjugate 295 43.9 ± 3.7 33.6 ± 5.6 Dual conjugate 296 33.2 ± 4.5 41.9 ± 5.2 Dual conjugate 297 25.6 ± 3.6 15.9 ± 3.2 Dual conjugate 298 38.6 ± 6.1 26.9 ± 3.5 Dual conjugate 299 32.1 ± 5.4 29.1 ± 3.8 Dual conjugate 300 35.7 ± 4.5 28.7 ± 4.6 Dual conjugate 301 31.5 ± 5.3 23.6 ± 7.2 Dual conjugate 302 27.7 ± 3.9 15.3 ± 5.6 Dual conjugate 303 36.8 ± 5.7 29.9 ± 4.5 Dual conjugate 304 21.3 ± 2.6 17.7 ± 3.1 Dual conjugate 305 37.8 ± 3.3 31.9 ± 5.6 IC.sub.50 values of conjugates were calculated in terms of taxane molar equivalents.

[1071] In summary, 1) both the taxane-polysaccharide conjugates and the taxane-lipid-polysaccharide dual conjugates well keep their antitumor activities; 2) introduction of lipid compounds, particularly unsaturated fatty acids, can enhance the antitumor activities of the taxane-lipid-polysaccharide dual conjugates.

TABLE-US-00002 TABLE 2 The antitumor activity of some compounds (IC.sub.50 value: nM) Substance Molar ratio of OVCAR-3 or mixture taxane to lipid (drug resistance) Paclitaxel Paclitaxel:DHA/1:0 57.6 ± 6.3 Paclitaxel + DHA Paclitaxel:DHA/1:1 45.6 ± 5.1 Paclitaxel + Paclitaxel:DHA/1:2 51.6 ± 3.9 Conjugate191 Dual conjugate 291 + Paclitaxel:DHA/1:4 39.2 ± 4.3 Conjugate191 IC.sub.50 values of conjugates were calculated in terms of taxane molar equivalents.

[1072] In summary, unsaturated fatty acids can enhance the antitumor activity of taxanes in both free form and conjugated form.

[1073] In Vitro Drug Release Test

[1074] In order to confirm if free taxane drug or its derivatives can be effectively released from the polysaccharide-taxane-lipid dual conjugates, in vitro plasma drug release tests were performed. LC-MS analysis technology was used to quantify free taxane drug.

[1075] Normally, the retention time (RT) and molecular weight of standard sample of paclitaxel, docetaxel, or cabazitaxel were acquired by the optimized test condition of LC-MS, and then polysaccharide-taxane-lipid dual conjugate was added in the incubation solution with rat plasma. At the same time, standard taxane drug was separately added into rat plasma incubation solution as compared to the control sample. At different time points during drug release incubation test, a certain volume of incubation solution was sampled, processed, and subjected to LC-MS analysis. For an example, to test free paclitaxel release from conjugate 298, the experiments were simultaneously carried out in two incubation solution consisting of tested substance, rat plasma, PBS; one incubated with standard taxane drug and another incubated with conjugate 298. The drug release test procedure was performed as following details: 200 uL of the measured substance (100 uM standard taxane drug or conjugate 298 containing with equivalent taxane drug in PBS buffer, pH 7.4), 200 uL of rat plasma, and 600 uL of PBS buffer (pH=7.4) were added to make a final solution of 1.0 mL of the reaction mixture. Prior to incubation, 100 uL of the reaction mixture was transferred into 1.5 ml Eppendorf vial, and two volumes of cold 90% acetonitrile was added to precipitate proteins, then sample was centrifuged at 15,000 rpm for 15 min, the supernatant was subjected to LC-MS analysis as 0 min time point, the free paclitaxel reaction mixture was processed the same way and used as a standard for calculating the relative release drug concentration. Subsequently, the remaining 900 uL of the reaction mixture was incubated at 37° C. with shaking moderately at 500 rpm, and 100 uL of the incubation solution mixture was taken at different time points at 0.5, 1, 3, 5, 12, and 20 hours, and processed as the same procedure as above mentioned; The supernatant was obtained and subjected to LC-MS analysis, the amounts of released paclitaxel in the conjugate at the time points were calculated;

[1076] The results of dual conjugate 298 drug release experiments are as follows:

TABLE-US-00003 TABLE 3 The percentage of paclitaxel released from conjugate 298 at different time points determined by LC-MS analysis Incubation (hrs) 0 0.5 1 3 5 12 20 Paclitaxel 100% 87% 77% 77% 67% 58% 58% Dual conjugate 298  0% 16% 25% 32% 48% 74% 99%

[1077] In conclusion, the in vitro drug release test of dual conjugate 298 showed: 1) the paclitaxel can be released effectively from dual conjugate 298; 2) up to 20 hrs incubation in rat plasma, the paclitaxel can be almost fully released from conjugate 298 (see Figure A).

[1078] In Vivo Safety Assay

[1079] BALB/c (nu/nu) mice (20±2 g, 4-6 weeks old) were housed under pathogen-free conditions. Cancer cells such MCF-7 and NCI-H460 5.0×10.sup.6, suspended in 100 μl PBS, were subcutaneously inoculated into the lower right rank of the nude mice. When the tumor size reached 100-150 mm.sup.3, the mice were divided randomly into different groups (n=6 in each group). The control group received the solvent only. The treatment groups received docexal (8.0 mg/kg), or dual conjugate 307 (average molecular weight: 11K Dalton, an equimolar dose of docetaxol, 8.0 mg/kg) intravenously through mice tails once a week. The mice were treated for 4 weeks. After the administration, the mice are raised normally. The tumor volume and mouse body weight were measured on every 3 days.

[1080] During the whole experiment period, there was no death of nude mice, and their diet and activities were normal. The mice in the dual conjugate 307 group and the docetaxel group showed similar tumor inhibition rates. However, the weight loss rate of dual conjugate 307 group was significantly lower than that of the docetaxel group (see Figure B), which confirmed that the dual conjugate is highly safe and well tolerated; it also indicates that the dual conjugate conjugate can bring high survival rate and has a long survival time.

[1081] On the other hand, the studies showed that as the molecular weight of polysaccharides increases (for example, average molecular weight is above 25 k Dalton), it is expected that the tumor targeting of these dual conjugates will be further improved, and the dual conjugates in the present invention may exhibit their in vivo enhanced anti-tumor effects and safety than their original drugs.