FUSED POLYCYCLIC DIMERS

Abstract

Novel fused tricyclic or bicyclic dimers, such as -carboline and quinoline moieties with a central linker, exhibit anti-cancer activities against a variety of human cancer cell lines. The dimer compounds can be used in anti-cancer therapeutic compositions useful in the treatment of human cancers.

Claims

1. A compound having the structure ##STR00025## and the derivatives, isomers, enantiomers, tautomers, esters, complexes, and salts thereof, where R1 and R2 are independently selected from the group consisting of H, C1-C4 alkyl groups, and C1-C4 alkoxy groups, R3 and R4 are independently selected from the group consisting of nothing, H, and C1-C2 alkyl groups, and X is selected from the group consisting of (CH2)3 and C3-C8 geminal alkyl groups having a carbon atom therein with two functional groups bound to said carbon atom, said functional groups independently selected from the group consisting of C1-C3 alkyl groups, C1-C3 alcohols, and metal atoms.

2. The compound of claim 1, where R1 and R2 are each methoxy groups.

3. The compound of claim 1, where R3 and R4 are both nothing.

4. The compound of claim 1, where X is a (CH2)3 group.

5. The compound of claim 1, where X is a C3 geminal alkyl group, with said functional groups bound to said carbon atom both being methyl groups.

6. The compound of claim 1, said compound having the structure ##STR00026##

7. The compound of claim 1, said compound having the structure ##STR00027##

8. The compound of claim 1, said compound being an anti-cancer agent effective against pancreatic, endometrial, breast, lung, ovarian, renal, cervical, lymphoma, and myeloma cancer cells.

9. A therapeutic composition comprising a compound in accordance with claim 1, in combination with one or more of other active agents, preservatives, buffering agents, salts, carriers, excipients, diluents, or other pharmaceutically-acceptable ingredients.

10. A method of treating a human subject comprising the step of administering to the subject a compound in accordance with claim 1.

11. A compound having the structure ##STR00028## and the derivatives, isomers, enantiomers, tautomers, esters, complexes, and salts thereof, where R5 and R6 are independently selected from the group consisting of H, C1-C4 alkyl groups, and C1-C4 alkoxy groups, R7, R8, and R9 are independently selected from the group consisting of H, OH, C1-C4 alkoxy groups, C1-C4 alkyl groups, N2, and CH2N2, and n2 and n3 are independently 1-4, and R10 and R11 are independently selected from the group consisting of nothing, H, and C1-C2 alkyl groups.

12. The compound of claim 11, said compound having the structure ##STR00029##

13. The compound of claim 11, said compound having the structure ##STR00030##

14. The compound of claim 11, said compound having the structure ##STR00031##

15. The compound of claim 11, said compound having the structure ##STR00032##

16. The compound of claim 11, said compound having the structure ##STR00033##

17. The compound of claim 11, said compound being an anti-cancer agent effective against pancreatic, endometrial, breast, lung, ovarian, renal, cervical, lymphoma, and myeloma cancer cells.

18. The compound of claim 11, at least one of said R7, R8, or R9 substituents is selected from the group consisting of N2 and CH2N2.

19. A therapeutic composition comprising a compound in accordance with claim 11, in combination with one or more of other active agents, preservatives, buffering agents, salts, carriers, excipients, diluents, or other pharmaceutically-acceptable ingredients.

20. A method of treating a human subject comprising the step of administering to the subject a compound in accordance with claim 1.

21. A method of treating a human subject comprising the step of administering to the subject a compound in accordance with claim 11.

Description

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0036] The therapeutic agents of the invention are used in therapeutically effective amounts, i.e., amounts that will elicit the biological or medical response of a tissue, system, or subject that is being sought, and in particular to elicit some desired therapeutic effect against a variety of human diseases, and especially cancers; in the case of cancers, the agents operate by preventing and/or inhibiting proliferation and/or survival of cancerous cells, including cancer stem cells, and/or by slowing the progression of cancers. Those skilled in the art recognize that an amount may be considered therapeutically effective even if the condition is not totally eradicated or prevented, but it or its symptoms and/or effects are improved or alleviated partially in the subject. Of course, the appropriate makeup of the agents hereof and dosing regimens using such agents will depend on the particular cancer being treated, the extent of the disease, and other factors related to the patient as determined by those skilled in the art. Hence, the terms therapeutic or treat, as used herein, refer to products or processes in accordance with the invention that are intended to produce a beneficial change in an existing condition (e.g., cancerous tissue, tumor size, metastases, etc.) of a subject, such as by reducing the severity of the clinical symptoms and/or effects of the condition, and/or reducing the duration of the symptoms/effects of a subject.

[0037] Additional ingredients may be included with the chemotherapeutic agents of the invention for administration to the subject. Such additional ingredients include, other active agents, preservatives, buffering agents, salts, carriers, excipients, diluents, or other pharmaceutically-acceptable ingredients. The active agents that could be included in the compositions include antiviral, antibiotic, or other anticancer compounds; the latter could include the compounds described in PCT application serial number PCT/US2015/055968, such as curcumin, harmine, and isovanillin, and metabolites, dimers, derivatives, isomers, enantiomers (both D and L), tautomers, esters, complexes and salts of any of the foregoing.

[0038] The therapeutic agents of the invention give significant and unexpected therapeutic results, particularly in the context of anti-cancer results. In use, a therapeutically effective amount of an agent or composition in accordance with the invention is administered to a subject in need thereof. Such may comprise a single unit dosage or, more usually, periodic (e.g., daily) administration of lower dosages over time.

[0039] The dosages may be administered in any convenient manner, such as by oral, rectal, nasal, ophthalmic, parenteral (including intraperitoneal, gastrointestinal, intrathecal, intravenous, cutaneous (e.g., dermal patch), subcutaneous (e.g., injection or implant), or intramuscular) administrations. The dosage forms of the invention may be in the form of liquids, gels, suspensions, solutions, or solids (e.g., tablets, pills, or capsules). Moreover, therapeutically effective amounts of the agents of the invention may be co-administered with other chemotherapeutic agent(s), where the two products are administered substantially simultaneously or in any sequential manner.

[0040] Levels of dosing using the compositions of the invention are quite variable owing to factors such as the patient's age, patient's physical condition, weight, the type of condition(s) being treated (e.g., specific cancer(s)), and the severity of the conditions. In general, however, regardless of the dosage form or route of administration employed, such as liquid solutions or suspensions, capsules, pills, or tablets, via oral, parenteral, or injection, the compositions should be dosed of from about 5 to 2000 mg per day, and more usually from about 100-800 mg per day. Such dosages may be based on a single administration per day, but more usually multiple administrations per day.

[0041] Additional advantages of the various embodiments of the invention will be apparent to those skilled in the art upon review of the disclosure herein and the working examples below. It will be appreciated that the various embodiments described herein are not necessarily mutually exclusive unless otherwise indicated herein. For example, a feature described or depicted in one embodiment may also be included in other embodiments, but is not necessarily included. Thus, the present invention encompasses a variety of combinations and/or integrations of the specific embodiments described herein.

[0042] As used herein, the phrase and/or, when used in a list of two or more items, means that any one of the listed items can be employed by itself or any combination of two or more of the listed items can be employed. For example, if a composition is described as containing or excluding components A, B, and/or C, the composition can contain or exclude A alone; B alone; C alone; A and B in combination; A and C in combination; B and C in combination; or A, B, and C in combination.

[0043] The present description also uses numerical ranges to quantify certain parameters relating to various embodiments of the invention. It should be understood that when numerical ranges are provided, such ranges are to be construed as providing literal support for claim limitations that only recite the lower value of the range as well as claim limitations that only recite the upper value of the range. For example, a disclosed numerical range of about 10 to about 100 provides literal support for a claim reciting greater than about 10 (with no upper bounds) and a claim reciting less than about 100 (with no lower bounds).

[0044] As used herein, pharmaceutically acceptable salts with reference to the compounds of the present invention mean salts of the compounds which are pharmaceutically acceptable, i.e., salts which are useful in preparing pharmaceutical compositions that are generally safe, non-toxic, and neither biologically nor otherwise undesirable and are acceptable for human pharmaceutical use, and which possess the desired degree of pharmacological activity. Such pharmaceutically acceptable salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, 2-naphthalenesulfonic acid, 3-phenylpropionic acid, 4,4-methylenebis(3-hydroxy-2-ene-1-carboxylic acid), 4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, acetic acid, aliphatic mono- and dicarboxylic acids, aliphatic sulfuric acids, aromatic sulfuric acids, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, carbonic acid, cinnamic acid, citric acid, cyclopentanepropionic acid, ethanesulfonic acid, fumaric acid, glucametacin acid, gluconic acid, glutamic acid, glycolic acid, heptanoic acid, hexanoic acid, hydroxynaphthoic acid, lactic acid, laurylsulfuric acid, maleic acid, malic acid, malonic acid, Mandela acid, methanesulfonic acid, muconic acid, o-(4-hydroxybenzoyl)benzoic acid, oxalic acid, p-chlorobenzenesulfonic acid, phenyl-substituted alkanoic acids, propionic acid, p-toluenesulfonic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, tartaric acid, tertiarybutylacetic acid, trimethylacetic acid, and the like. Pharmaceutically acceptable salts also include base addition salts which may be formed when acidic protons present are capable of reacting with inorganic or organic bases. Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium hydroxide. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like. It should be recognized that the particular anion or cation forming a part of any salt of this invention is not critical, so long as the salt, as a whole, is pharmacologically acceptable. Additional examples of pharmaceutically acceptable salts and their methods of preparation and use are presented in Handbook of Pharmaceutical Salts Properties, and Use, P. H. Stahl & C. G. Wermuth eds., ISBN 978-3-90639-058-1(2008).

[0045] As used herein, the terms alkyl, alkenyl, alkynyl, mean and are intended to cover straight, branched chain, and cyclic groups. Amines means and is intended to cover primary, secondary, and tertiary amines. Sulfur groups means and is intended to cover thiols, sulfides, disulfides, and sulfoxides. Derivative means and is intended to cover compounds, moieties, and/or groups which are substituted with atoms, groups, or side chains which do not materially degrade (e.g., no more than about 20%, preferably no more than about 10%, degradation) of the performance of the compound, moiety, or group as compared with the unsubstituted versions thereof.

[0046] In the development of the present invention, a series of novel and other compounds were prepared and assayed for anti-cancer activity. Set forth below are the syntheses of the specific compounds, followed by the anti-cancer assay results.

Specific Syntheses of Compounds in Accordance with the Invention

[0047] The starting materials, solvents, and reagents were obtained commercially and used directly without purification. The NMR spectra of compounds were recorded on Brker FT-NMR 400 Hz spectrometer in CDCl.sub.3 using tetramethylsilane (TMS) as an internal standard. The values represent chemical shifts reported in parts per million (ppm) and coupling constant (J) values are in Hz. .sup.13C NMR spectra were definitively assigned. ESI-MS and ESI-HRMS were recorded on a Brker MicroTOF instrument. Flash chromatography was conducted by using Silica size (100-200 mesh). Thin layer chromatography was performed on TLC Silica Gel 60 F254 (Merck).

[0048] General Method to Synthesize Compounds 5 and 6

##STR00008##

[0049] A solution of harmaline (200 mg, 1.31 mmoles, 1 eq) and vanillin (100 mg, 0.655 mmoles, 2 eq) in MeOH (5 ml) was prepared and refluxed for 3-4 hrs. The reaction progress was monitored by TLC with 10% MeOH+90% DCM. (ammonia in DCM or 7N ammonia in MeOH). After completion of the reaction, the reaction mixture was filtered, and crude solid was collected. The resulting crude solid was purified using column chromatography to give compound 5 or 6.

4-(1,3-bis(7-methoxy-4,9-dihydro-3H-pyrido[3,4-b]indol-1-yl)propan-2-yl)-2-methoxy-phenol (Compound 5)

[0050] ##STR00009##

[0051] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.86 (s, 1H), 10.70 (s, 1H), 8.72 (d, J=12.3 Hz, 1H), 7.27 (t, J=8.6 Hz, 2H), 6.87 (d, J=1.8 Hz, 1H), 6.83-6.69 (m, 4H), 6.69-6.56 (m, 2H), 3.90-3.81 (m, 1H), 3.82 (s, 1H), 3.84-3.71 (m, 8H), 3.70 (d, J=5.7 Hz, 1H), 3.18 (dd, J=11.8, 4.4 Hz, 5H), 3.07 (dd, J=13.2, 6.1 Hz, 1H), 2.95-2.79 (m, 1H), 2.79-2.66 (m, 1H), 2.65 (s, 2H), 2.66-2.52 (m, 1H), 2.28-2.07 (m, 2H). .sup.13C NMR (101 MHz, CDCl.sub.3) 164.99, 162.53, 146.89, 145.13, 144.90, 130.60, 126.55, 125.61, 122.38, 120.95, 119.12, 116.33, 114.08, 109.49, 93.66, 77.35, 77.03, 76.72, 55.79, 55.64, 41.99, 37.40, 19.92. HRMS (ESI+), m/z [M+H.sup.+] calculated for C.sub.34H.sub.35N.sub.4O.sub.4 563.2674; found 563.2674.

1,1-(2-phenylpropane-1,3-diyl)bis(7-methoxy-4,9-dihydro-3H-pyrido[3,4-b]indole) (Compound 6)

[0052] ##STR00010##

[0053] 1H NMR (400 MHz, Chloroform-d) 12.24 (s, 1H), 11.97 (s, 1H), 7.32 (dd, J=15.2, 8.3 Hz, 4H), 7.06 (dt, J=28.8, 7.4 Hz, 4H), 6.93 (d, J=2.2 Hz, 2H), 6.74 (dd, J=9.0, 2.1 Hz, 2H), 4.58 (t, J=8.5 Hz, 1H), 3.85 (s, 6H), 3.58 (dt, J=21.8, 14.1 Hz, 8H), 2.93-2.84 (m, 4H). .sup.13C NMR (101 MHz, CDCl.sub.3) 156.22, 145.78, 144.78, 136.65, 129.05, 128.98, 128.66, 127.86, 127.54, 126.89, 126.76, 121.67, 119.17, 118.75, 118.55, 118.48, 108.60, 95.11, 55.84, 55.77, 50.64, 40.85, 40.36, 31.95, 29.73, 22.72, 14.15. HRMS (ESI+), m/z [M+H.sup.+] calculated for C.sub.33H.sub.33N.sub.4O.sub.4 517.6578; found 517.2253

[0054] General Method to Synthesize Analogs 10 and 11

##STR00011##

[0055] A solution of 5 or 6 (30 mg, 0.0533 mmoles, 1 equivalent) in dichloromethane (DCM, 1.5 ml) was prepared, and methanol (5 ml) and sodium borohydride (10 mg, 0.266 mmoles, 5 equivalent) were added slowly at 0 C. temperature. (Before addition of sodium borohydride, the reaction mixture was unclear or partially soluble). The reaction mixture was stirred at room temperature for overnight period. The reaction progress was monitored by TLC with 10% MeOH+90% DCM. (ammonia in DCM or 7N ammonia in MeOH). After completion of the reaction, reaction mixture was quenched by addition of 20 ml of water and extracted with DCM (20 ml X2 times). The organic layer was wash with brine, dried over sodium sulphate. The crude oily brown material was purified with column chromatography to give 10 and 11.

4-(1,3-bis(7-methoxy-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)propan-2-yl)-2-methoxyphenol (Analog 10)

[0056] ##STR00012##

[0057] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.86 (s, 1H), 10.70 (s, 1H), 8.72 (d, J=12.3 Hz, 1H), 7.27 (t, J=8.6 Hz, 2H), 6.87 (d, J=1.8 Hz, 1H), 6.83-6.69 (m, 4H), 6.69-6.56 (m, 2H), 3.90-3.81 (m, 1H), 3.82 (s, 1H), 3.84-3.71 (m, 8H), 3.70 (d, J=5.7 Hz, 1H), 3.18 (dd, J=11.8, 4.4 Hz, 5H), 3.07 (dd, J=13.2, 6.1 Hz, 1H), 2.95-2.79 (m, 1H), 2.79-2.66 (m, 1H), 2.65 (s, 2H), 2.66-2.52 (m, 1H), 2.28-2.07 (m, 2H). .sup.13C NMR (101 MHz, Chloroform-d) 155.08, 146.22, 143.76, 135.63, 133.48, 120.74, 118.57, 117.47, 117.37, 114.17, 109.65, 107.70, 107.45, 94.40, 94.15, 54.79, 54.38, 50.23, 40.68, 40.15, 39.07, 28.68, 21.67, 18.13. HRMS (ESI+), m/z [M+H.sup.+] calculated for C.sub.34H.sub.38N.sub.4O.sub.4 567.7058; found 567.6998.

1,1-(2-phenylpropane-1,3-diyl)bis(7-methoxy-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole) (Analog 11)

[0058] ##STR00013##

[0059] 1H NMR (400 MHz, Chloroform-d) 12.21 (s, 2H), 11.97 (s, 2H), 7.33 (dd, J=16.8, 8.3 Hz, 4H), 7.10 (t, J=7.4 Hz, 2H), 7.03 (t, J=7.3 Hz, 1H), 6.93 (d, J=2.2 Hz, 2H), 6.74 (dd, J=9.0, 2.2 Hz, 2H), 4.59 (t, J=8.6 Hz, 1H), 3.85 (s, 6H), 3.58 (dt, J=21.8, 13.4 Hz, 3H), 2.89 (dd, J=10.1, 7.3 Hz, 4H). .sup.13C NMR (101 MHz, CDCl.sub.3) 156.22, 145.78, 144.78, 136.65, 129.05, 128.98, 128.66, 127.86, 127.54, 126.89, 126.76, 121.67, 119.17, 118.75, 118.55, 118.48, 108.60, 95.11, 55.84, 55.77, 50.64, 40.85, 40.36, 31.95, 29.73, 22.72, 14.15. HRMS (ESI+), m/z [M+H.sup.+] calculated for C.sub.33H.sub.37N.sub.4O.sub.4 521.6578; found 521.2253.

[0060] General Method to Synthesize Compounds 13 and 16-18

##STR00014##

[0061] p-Toluenesulfonic acid (PTSOH 0.2eq, 26 mol), 6-methoxy-2-methylquinoline (2 eq, 1.1 mmol) and vanillin (1 eq, 0.53 mmol) were mixed in a pressure tube and then dry Toluene (3 mL) was added. The mixture was stirred at 120 C. in closed pressure tube. The reaction was monitored by TLC. After completion of the reaction, the solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel.

##STR00015##

4-(1,3-di(isoquinolin-1-yl)propan-2-yl)-2-methoxyphenol (Compound 13)

[0062] ##STR00016##

[0063] .sup.1H NMR (400 MHz, Chloroform-d) 8.27 (d, J=5.7 Hz, 2H), 8.02 (d, J=8.5 Hz, 2H), 7.74-7.67 (m, 2H), 7.66-7.54 (m, 1H), 7.59-7.41 (m, 3H), 7.40 (dd, J=15.5, 5.6 Hz, 3H), 7.20 (s, 1H), 6.68 (dd, J=8.1, 2.0 Hz, 1H), 6.51 (d, J=8.1 Hz, 1H), 6.46 (d, J=2.0 Hz, 1H), 4.04 (p, J=7.4 Hz, 1H), 3.74 (dd, J=13.9, 7.3 Hz, 2H), 3.60 (dd, J=13.9, 7.4 Hz, 2H), 3.54 (s, 3H). HRMS (ESI+), m/z [M+H.sup.+] calculated for C.sub.28H.sub.25N.sub.4O.sub.4H 421.5136; found 421.5106.

4-(1,3-di(quinolin-2-yl)propan-2-yl)-2-methoxyphenol (Compound 16)

[0064] ##STR00017##

[0065] .sup.1H NMR (400 MHz, Chloroform-d) 7.94 (dd, J=8.5, 1.1 Hz, 2H), 7.81 (dd, J=8.5, 0.8 Hz, 2H), 7.65-7.53 (m, 4H), 7.37 (ddd, J=8.1, 6.9, 1.2 Hz, 2H), 7.03 (d, J=8.4 Hz, 2H), 6.66-6.57 (m, 2H), 6.55 (d, J=1.7 Hz, 1H), 5.66 (s, 1H), 3.87 (tt, J=8.4, 6.8 Hz, 1H), 3.55 (d, J=2.3 Hz, 1H), 3.54 (s, 2H), 3.36 (dd, J=13.6, 6.8 Hz, 2H), 3.29 (dd, J=13.6, 8.5 Hz, 2H). .sup.13C NMR (101 MHz, Chloroform-d) 160.87, 146.26, 143.94, 135.94, 135.40, 129.32, 128.64, 127.47, 126.69, 125.79, 122.17, 120.33, 114.21, 110.76, 55.73, 45.84, 45.80. HRMS (ESI+), m/z [M+H.sup.+] calculated for C.sub.28H.sub.25N.sub.2O.sub.2 421.1933; found 421.1910.

2,2-(2-phenylpropane-1,3-diyl)diquinoline (Compound 17)

[0066] ##STR00018##

[0067] .sup.1H NMR (400 MHz, Chloroform-d) 8.09-8.02 (m, 1H), 7.86 (dd, J=8.4, 0.8 Hz, 1H), 7.66 (td, J=8.3, 1.2 Hz, 2H), 7.44 (td, J=7.3, 1.2 Hz, 1H), 7.28-7.21 (m, 1H), 7.25-7.14 (m, 1H), 7.18-7.06 (m, 2H), 4.07 (tt, J=8.4, 6.8 Hz, 1H), 3.56-3.37 (m, 2H). .sup.13C NMR (101 MHz, Chloroform-d) 160.76, 147.83, 143.77, 135.76, 129.21, 128.85, 128.28, 127.94, 127.46, 126.69, 126.32, 125.71, 122.11, 46.17, 45.76. HRMS (ESI+), m/z [M+Na.sup.+] calculated for C.sub.27H.sub.23N.sub.2Na 375.1888; found 375.1855.

2,2-(2-phenylpropane-1,3-diyl)bis(6-methoxyquinoline) (Compound 18)

[0068] ##STR00019##

[0069] .sup.1H NMR (400 MHz, Chloroform-d) 7.92 (d, J=9.2 Hz, 1H), 7.72 (dd, J=8.5, 0.7 Hz, 1H), 7.30 (dd, J=9.2, 2.8 Hz, 1H), 7.25-7.16 (m, 1H), 7.19-7.06 (m, 1H), 7.10-6.99 (m, 1H), 6.89 (d, J=2.8 Hz, 1H), 4.05-3.93 (m, 0H), 3.83 (s, 3H), 3.44 (dd, J=13.7, 6.9 Hz, 1H), 3.36 (dd, J=13.7, 8.3 Hz, 1H). .sup.13C NMR (101 MHz, CDCl.sub.3) 158.19, 157.12, 143.98, 143.82, 134.60, 130.19, 128.22, 127.93, 127.50, 126.21, 122.35, 121.72, 105.05, 77.39, 77.08, 76.76, 55.47, 46.32, 45.48. HRMS (ESI+), m/z [M+Na.sup.+] calculated for C.sub.29H.sub.26N.sub.2O.sub.2Na 457.1914; found 457.1886.

[0070] Methods to Synthesize Analogs 7, 8, 9

##STR00020##

[0071] A di-acid (1.4 mmoles, 1 equivalent) and 2-(5-methoxy-1H-indol-3-yl)ethan-1-amine (2.4 mmoles, 2 equivalent) were mixed together and heated at 190 C. for overnight period. After completion of the reaction, the product was diluted with methanol and dichloromethane (4:4 ml), purified with column chromatography to give an amide.

##STR00021##

[0072] A solution of N1,N5-bis(2-(5-methoxy-1H-indol-3-yl)ethyl)glutaramide (1 eq, 0.4 mmol) in Toluene (2 mL) was prepared, and dichloromethane (2 mL) and phosphorous oxychloride (POCl3 1.5 mmole, 0.14 mL) was added. The reaction mixture was heated at reflux temperature for 3-4 hrs. After completion of the reaction, the solvent was distilled off and the reaction mixture was neutralized with 20% NaOH (10 ml). The aqueous solution was then extracted with dichloromethane (2X20 ml dichloromethane), dried with sodium sulfate and then purified with column chromatography to give 1,3-bis(6-methoxy-4,9-dihydro-3H-pyrido[3,4-b]indol-1-yl)propane.

1,3-bis(6-methoxy-4,9-dihydro-3H-pyrido[3,4-b]indol-1-yl)propane (Analog 7)

[0073] ##STR00022##

[0074] .sup.1H NMR (400 MHz, Chloroform-d) 13.12 (s, 1H), 12.29 (s, 1H), 7.43 (d, J=9.2 Hz, 1H), 7.07 (dd, J=9.2, 2.4 Hz, 1H), 6.77 (d, J=2.4 Hz, 1H), 3.86 (td, J=8.7, 3.1 Hz, 2H), 3.78 (s, 3H), 3.29-3.20 (m, 2H), 3.11 (t, J=8.7 Hz, 2H), 2.50 (td, J=16.9, 14.6, 7.5 Hz, 1H). .sup.13C NMR (101 MHz, MeOD) 155.68, 124.81, 113.86, 54.62, 46.95, 42.44, 23.90, 18.71. HRMS (ESI+), m/z [M+H.sup.+] calculated for C.sub.27H.sub.29N.sub.4O.sub.2 441.2279; found 441.2285.

[0075] 1,1-(2,2-dimethylpropane-1,3-diyl)bis(6-methoxy-4,9-dihydro-3H-pyrido[3,4-b]indole) (Analog-8)

##STR00023##

[0076] .sup.1H NMR (400 MHz, Chloroform-d) 11.36 (s, 1H), 7.33 (dd, J=8.8, 1.4 Hz, 2H), 7.01 (d, J=2.3 Hz, 2H), 6.96 (dt, J=8.8, 2.1 Hz, 2H), 4.01 (q, J=8.7, 7.5 Hz, 4H), 3.89 (d, J=1.6 Hz, 6H), 2.92 (td, J=8.3, 1.7 Hz, 4H), 2.69 (d, J=8.0 Hz, 2H), 1.05 (d, J=5.0 Hz, 6H). .sup.13C NMR (101 MHz, Chloroform-d) 160.95, 154.36, 132.23, 130.67, 125.63, 116.19, 115.67, 113.21, 100.42, 55.82, 47.79, 43.71, 35.87, 30.00, 19.47. HRMS (ESI+), m/z [M+H.sup.+] calculated for C.sub.29H.sub.33N.sub.4O.sub.4 469.2610; found 469.2598.

1,4-bis(6-methoxy-4,9-dihydro-3H-pyrido[3,4-b]indol-1-yl)butane (Analog 9)

[0077] ##STR00024##

[0078] .sup.1H NMR (400 MHz, Chloroform-d) 7.50 (d, J=9.2 Hz, 2H), 7.06 (dd, J=9.2, 2.4 Hz, 2H), 6.78 (d, J=2.4 Hz, 2H), 3.89 (t, J=8.5 Hz, 4H), 3.78 (s, 6H), 3.21 (s, 1H), 3.11 (t, J=8.7 Hz, 4H), 2.08 (s, 4H), 1.18 (s, 3H). .sup.13C NMR (101 MHz, Chloroform-d) 122.89, 115.48, 99.28, 55.59, 50.15, 49.94, 49.72, 42.28, 19.63. HRMS (ESI+), m/z [M+H.sup.+] calculated for C.sub.28H.sub.30N.sub.4O.sub.4 455.5789; found 455.5678.

[0079] The following Table sets forth the IC.sub.50 values of harmaline and quinoline analogs against 23 human cancer cell lines. Growth inhibition effects (in vitro cytotoxicity) on pancreatic, endometrial, breast, lung, ovarian, renal, cervical, lymphoma, and myeloma cancer cells were determined by MTT assays and represented by average IC.sub.50 values. In the Table, the results are given in terms of M, and nd=not determined.

TABLE-US-00001 Cell line 5 6 7 8 9 10 11 13 16 17 18 MIA Paca-2 2.87 1.85 4.54 1.22 6.58 2.53 2.25 19.71 24.49 13.33 21.88 ASPC-1 6.75 2.08 7.9 2.07 20.25 4.62 2.4 49.03 94.57 28.67 >100 BxPC-3 2.11 nd 3.21 0.95 10.66 nd nd 20.05 19.52 7.64 25.13 AN3CA 2.5 nd 3.01 1.96 20.66 nd nd 19.5 19.68 9.35 41.83 HEC-1a 5.05 nd 7.02 2.22 20.67 nd nd 39.82 67.68 25.43 37.65 MDA-MB-231 2.52 nd 3.12 1.5 19.39 nd nd 28.19 31.62 14.46 >100 MDA-MB-468 2.76 nd 2.6 1.9 7.09 nd nd 19.58 31.63 25.81 >100 HCC70 2.38 nd 5.13 1.3 11.87 nd nd 37.17 35.18 17.18 >100 H1975 (EGFR mut) 6.12 nd 5.77 2.08 19.06 nd nd 42.2 58.9 30.09 >100 H1650(EGFR mut) 2.78 nd 4.95 1.78 15.1 nd nd 38.14 50.99 24.63 48.5 A2780 5 2.95 2.54 1.38 11.62 6.14 3.4 27.23 29.7 13.34 25.57 A2780CP 3.76 nd 4.12 2.23 17.79 nd nd 25.13 22.26 9 26.61 A498 3.56 nd 5.39 1.71 19.15 nd nd 38.53 81.31 21.93 >100 SiHA 4.88 nd 12.65 2.89 19.74 nd nd 45.21 84.28 23.47 >100 FaDu 3.87 1.58 2.34 0.98 6.82 2.61 2.22 33.61 49.19 18.64 30.33 DoHH-2 1.83 1.98 2.41 2.21 6.48 2.24 2.31 19.52 14.84 6.9 14.29 OCI-LY3 4.54 nd 8.85 2.59 6.99 nd nd 36.73 77.5 23.79 42.24 JIM1 3.17 2.22 6.15 2.59 21.14 2.27 2.42 29.18 35.36 10.99 31.73 KMM-1 3.48 1.91 5.18 1.49 12.16 2.53 2.05 14.81 17 7.99 14.81 KMS-34 4.72 nd 4.41 1.7 15.14 nd nd 11.76 14.81 7.85 17.19 RPMI-8226 3.19 nd 1.97 0.81 5.54 nd nd 17.99 15.24 7.92 17.83 L363 2.69 1.4 2.47 1.21 8.34 2.17 1.92 29.18 29.54 7.99 17.38 MOLP-8 3.37 nd 1.88 0.67 3.68 nd nd 9.71 16.03 6.56 14.97
As is evident from the foregoing, compounds 5-11 and 13-18 demonstrated growth inhibition against human cancer cell lines. For example, compounds 5 and 6 displayed cancer cell growth inhibition at 4-7 M, which are more potent than harmaline and vanillin (25 and 40 M for harmaline and vanillin, respectively). The data also revealed that the hydroxy and methoxy groups present in compounds 5 and 10 are not required for anti-cancer activity, which was confirmed with compounds 6 and 11, which lack these substituents but exhibit cancer cell growth inhibition at similar concentrations (IC.sub.50, 2-4 M). In addition, reduction of the imine on compounds 5 and 6 into the corresponding secondary amines did not significantly affect the IC.sub.50 values. The data derived from the four quinoline-based and isoquinoline-based dimeric compounds 13 and 16-18 demonstrated that these compounds less efficacious as compared to compounds 5-6 and 10-11, indicating that the tricyclic rido[3,4-b]indole ring system is preferred for better anti-cancer activity. Compounds 7 and 8 were found to be the most potent compounds, giving IC.sub.50 values of from 0.6-2 M.

[0080] Compounds 5, 7, and 8 had metabolic half-lives of 76.82.36 minutes, 155.907.43 minutes, and 412.50116.67 minutes, respectively.

[0081] As is evident from a consideration of the dimers of the invention, in preferred forms, the linker is bonded to terminal cyclic groups of the two fused tricyclic moieties; moreover, in many cases, such linker bonding occurs at methyl substituents of the terminal cyclic groups, such as in the case of harmaline