APPLICATIONS OF SPERMINE AND DERIVATIVES THEREOF

Abstract

This disclosure relates to a method for treating a disease which can be alleviated by inhibiting PAICS activity. The method includes administering a therapeutically effective amount of spermine or a pharmaceutically acceptable salt or C.sub.1-C.sub.6 amide thereof to a patient in need thereof.

Claims

1. A method for treating a disease which can be alleviated by inhibiting PAICS activity, comprising: administering a therapeutically effective amount of spermine or a pharmaceutically acceptable salt or C.sub.1-C.sub.6 amide thereof to a patient in need thereof

2. The method of claim 1, wherein the method comprises administering spermine to the patient.

3. The method of claim 1, wherein the method comprises administering a pharmaceutically acceptable salt of spermine to the patient.

4. The method of claim 3, wherein the pharmaceutically acceptable salt is prepared from spermine and an acid selected from the group consisting of acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetylamino benzoic acid, butyric acid, (+)-camphoric acid, camphor sulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, hexanoic acid, octanoic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactonic acid, gentisic acid, glucoheptonic acid, D-gluconic acid, glucuronic acid, glutamic acid, a-ketoglutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxyethylsulfonic acid, (+)-L-lactic acid, (+)-DL-lactic acid, lactobionic acid, maleic acid, malic acid, ()-L-malic acid, malonic acid, ()-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxyl-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, L-pyroglutamic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, sulfocyanic acid, p-toluenesulfonic acid, undecylenic acid, pentanoic acid, and acyl-amino acid.

5. The method of claim 1, wherein the disease comprises a tumor with high expression of PAICS.

6. A method for treating or alleviating a disease caused by excessive accumulation of SAICAR, SAICAr or S-Ado, comprising: administering a therapeutically effective amount of spermine or a pharmaceutically acceptable salt or C.sub.1-C.sub.6 amide thereof to a patient in need thereof.

7. The method of claim 6, wherein the method comprises administering spermine to the patient.

8. The method of claim 6, wherein the method comprises administering a pharmaceutically acceptable salt of spermine to the patient.

9. The method of claim 8, wherein the pharmaceutically acceptable salt is prepared from spermine and an acid selected from the group consisting of acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetylamino benzoic acid, butyric acid, (+)-camphoric acid, camphor sulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, hexanoic acid, octanoic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactonic acid, gentisic acid, glucoheptonic acid, D-gluconic acid, glucuronic acid, glutamic acid, a-ketoglutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxyethylsulfonic acid, (+)-L-lactic acid, (+)-DL-lactic acid, lactobionic acid, maleic acid, malic acid, ()-L-malic acid, malonic acid, ()-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxyl-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, L-pyroglutamic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, sulfocyanic acid, p-toluenesulfonic acid, undecylenic acid, pentanoic acid, and acyl-amino acid.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0018] FIG. 1 shows a 3D solid ribbon structure diagram of PAICS; FIG. 2 shows diagrams indicating the interaction of CAIR and SAICAR synthetase in the crystal structure, in which A: PDB access ID 2GQS; B: PDB access ID 2CNQ; and C: PDB access ID 4FE2; and

[0019] FIG. 3 shows the alignment result of different types of SAICAR synthetase protein sequences.

DETAILED DESCRIPTION OF THE EMBODIMENTS

[0020] There are 425 amino acid residues in full length of the human PAICS protein sequence, in which a fragment of 2-260 AA is a SAICAR synthetase domain, and a fragment of 267-425AA is an AIR carboxylase domain, these two domains are linked by a 6-peptide (KSESQC). Furthermore, GLN159-GLN183 a-helix in the SAICAR synthetase domain and ASN395-ASN424 a-helix in the AIR carboxylase domain interact with each other and tightly bind together, as shown in FIG. 1.

[0021] A protein structure data bank (RCSB) collects the crystal structure data of SAICAR synthetases of different origins, which includes Saccharomyces cerevisiae (1A48, 2CNQ, 2CNV, 2CNQ, 1OBD, 1OBG), Pyrococcushorikoshii OT3 (3U54, 3U55), Escherichia coli (2GQR, 2GQS), Methanocaldococcusjannaschii (2YZL, 2Z02), Streptococcus pneumonia (4FGR, 4FE2), Mycobacterium abscessus ATCC 19977/DSM 44196 (3R9R), Thermotoga maritime(1KUT), Clostridium perfringens (3NUA), Ehrlichiachaffeensis (3KRE), Geobacilluskaustophilus (2YWV) as well as PAICS crystal structure data of Homo sapiens (2H31) and Bombyxmori (4JA0). Wherein, there are complexes 2GQS, 2CNQ and 4FE2 which contain the structure of CAIR, and complexes 2CNV, 2CNU and 4FE2 which contain the structure of ASP.

[0022] As shown in FIG. 2, the residues within CAIR 3 in 2CNQ are Arg122, Ser128, ASP215, Arg242 and Arg264; the residues within CAIR 3 in 2GQS are Arg94, Ser100, ASP129, ASP175, Arg199 and Arg215; the residues within CAIR 3 in 4FE2 are Arg93, Ser99, ASP174, Arg199, and Arg214. With reference to the alignment result of the SAICAR protein sequences of different species (FIG. 3), it can be seen that the binding sequences of SAICAR synthetases of different species with CAIR exhibits high-level conservative, and CAIR is primarily fixed by hydrogen bonds.

[0023] On the basis of the above results, the crystal structure conformations in SAICAR synthetases of Saccharormyces cerevisiae (PDB: 2CNQ) and Escherichia coli (PDB: 2GQS) are used as receptor structures for calculating and screening, since there is no conformation which can bind CAIR in human PAICS crystal structure, and no catalytic conformation formed in the catalytic region, and the results obtained by calculation are not reliable. 4661 of small molecule drugs in the DrugBank (http://www.drugbank.ca/downloads#structures) are calculated and screened by using the ligand fit module of Discovery studio. The calculating results show that DB00127 (common name: Spermine) has a Dock Score of 316.723, indicating that the compound spermine can effectively interact with PAICS, influence SAICAR synthesis. Thus, it is expected that this compound can be developed as a drug for treating ADSL deficiency or health-care product for improving the ADSL deficiency.

[0024] Further, it is confirmed by biochemical enzyme activity experiments and cell biology experiments that the inhibition ratio of the compound spermine against SAICAR accumulation can reach 71.1% . By inhibiting the activity of PAICS, the accumulation of toxic compound SAICAR is reduced, which proves that the compound spermine can effectively treat rare disease ADSL deficiency.

[0025] The pharmaceutically acceptable derivatives of the above compound has the same parent core structures as the compound per se, and can produce molecules having the same or similar activity as the original compound through reactions such as hydrolysis and the like in vivo, resulting in the same or similar therapeutic efficacy.

[0026] The pharmaceutically acceptable derivatives of the compound may particularly refer to simple derivatives thereof, and especially refer to one of lower ester, lower ether, lower alkyl substituent, pharmaceutical salt and lower amide thereof, i.e., derivatives obtained by condensation of carboxylic acid, alcohol, amine having 1 to 6, preferably 2 to 6, or 2 to 4 carbon atom(s) with the parent compound.

[0027] The pharmaceutically acceptable pharmaceutical salts of the compound can be synthesized from the parent compound by conventional chemical methods, such as the method described in Pharmaceutical Salts: Properties, Selection and Use, P Heinrich Stahl (Editor), Camille G. Wermuth (Editor), ISBN: 3-90639-026-8, Hardcover, 388 pages, August 2002. In general, such salts can be prepared by reacting free alkali of the compound with an acid in water, organic solvent or a mixed solution of both; generally, a non-aqueous media can be used, such as ethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile.

[0028] Acid addition salts can be prepared with various acids (inorganic acids and organic acids). The examples of the acid addition salts may include salts prepared from an acid which may be selected from a group consisting of acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid (such as L-ascorbic acid), L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetylamino benzoic acid, butyric acid, (+)-camphoric acid, camphor sulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, hexanoic acid, octanoic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactonic acid, gentisic acid, glucoheptonic acid, D-gluconic acid, glucuronic acid (such as D-glucuronic acid), glutamic acid (such as L-glutamic acid), -ketoglutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxyethylsulfonic acid, (+)-L-lactic acid, ()-DL-lactic acid, lactobionic acid, maleic acid, malic acid, ()-L-malic acid, malonic acid, ()-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxyl-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, L-pyroglutamic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, sulfocyanic acid, p-toluenesulfonic acid, undecylenic acid and pentanoic acid, as well as acyl-amino acid and cation exchange resin.

[0029] Combined utilization of the drugs can improve therapeutic effect, and reduce toxic and side effects to a certain extent. Preferably, 2, 3, 4, 5 or more compounds or derivatives thereof can be simultaneously used as the active ingredients for treating ADSL deficiency.