Zn2Motif-Tethered Short-Chain Fatty Acids as a Novel Class of Histone Deacetylase

• US 20070225373A1
• Filed: 12/01/2004
• Published: 09/27/2007
• Est. Priority Date: 12/02/2003
• Status: Active Grant

• Current Assignee: Ohio State Innovation Foundation (Ohio State University)
• Original Assignee: The Ohio State University Research Foundation
• Inventors: Chen, Ching-Shih, Qiang, Lu
• Granted Patent: US 9,115,090 B2
• Time in Patent Office: Days
• US Class Current: 514/616
• CPC Class Codes: A61K 31/167 having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
• CPC Class Codes: A61K 31/19 Carboxylic acids, e.g. valproic acid salicylic acid A61K31/60
• CPC Class Codes: A61K 31/4402 only substituted in position 2, e.g. pheniramine, bisacodyl
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07B 2200/07 Optical isomers
• CPC Class Codes: C07C 237/22 having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated peptides C07K
• CPC Class Codes: C07C 237/42 having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
• CPC Class Codes: C07C 259/06 having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
• CPC Class Codes: C07C 259/10 having carbon atoms of hydroxamic groups bound to carbon atoms of six-membered aromatic rings
• CPC Class Codes: C07D 213/81 Amides; Imides

Abstract

Zn²⁺-chelating motif-tethered fatty acids as histone deacetylase (HDAC) inhibitors. One hydroxamate-tethered phenylbutyrate compound, N-hydroxy-4-(4-phenylbutyrylamino)-benzamide (HTPB), displayed nM potency in inhibiting HDAC activity. Exposure of several cancer cell lines to HTPB at sub-μM concentrations showed reduced cell proliferation accompanied by histone hyperacetylation and elevated p21^WAF/CIP1 expression, hallmark features associated with intracellular HDAC inhibition.

Claims

1. A histone deacetylase inhibitor having the formula:

wherein;

X is chosen from H and CH₃;

Y is (CH₂)_n wherein n is 0-2;

Z is chosen from (CH₂)_m wherein m is 0-3 and (CH)₂;

A is a hydrocarbyl group;

B is o-aminophenyl or hydroxyl group; and

Q is a halogen, hydrogen, or methyl.

2. The inhibitor according to claim 1, wherein A comprises an aliphatic group.

3. The inhibitor according to claim 2, wherein the aliphatic group is branched.

4. The inhibitor according to claim 1, wherein A comprises an aromatic group.

5. The inhibitor according to claim 4, wherein A comprises a substituted aromatic group.

6. The inhibitor according to claim 1, wherein B is o-aminophenyl.

7. The inhibitor according to claim 1, wherein B is hydroxyl.

8. The inhibitor according to claim 1, wherein n is 0, A comprises an aromatic group, B is hydroxy, and Q is hydrogen.

9. The inhibitor according to claim 1, wherein the inhibitor is chosen from N-(2-Amino-phenyl)-4-[(2-propyl-pentanoylamino)-methyl]-benzamide;

N-Hydroxy-4-[(2-propyl-pentanoylamino)-methyl]-benzamide;

N-(2-Amino-phenyl)-4-(2-propyl-pentanoylamino)-benzamide;

N-Hydroxy-4-(2-propyl-pentanoylamino)-benzamide;

2-Propyl-pentanoic acid {4-[2-amino-phenylcarbamoyl)-methyl]-phenyl}-amide;

2-Propyl-pentanoic acid (4-hydroxycarbamoyl-methyl-phenyl)-amide;

2-Propyl-pentanoic acid {4-[2-amino-phenylcarbamoyl)-ethyl]-phenyl}-amide;

2-Propyl-pentanoic acid [4-(2-hydroxycarbamoyl-ethyl)-phenyl]-amide;

2-Propyl-pentanoic acid {4-2-(2-amino-phenylcarbamoyl)-vinyl]-phenyl}-amide; and

2-Propyl-pentanoic acid [4-(2-hydroxycarbamoyl-vinyl)-phenyl]-amide.

10. The inhibitor according to claim 1, wherein the inhibitor is chosen from N-(2-Amino-phenyl)-4-(butyrylamino-methyl)-benzamide;

N-(2-Amino-phenyl)-4-(phenylacetylamino-methyl)-benzamide;

N-(2-Amino-phenyl)-4-[(4-phenyl-butyrylamino-methyl]-benzamide;

4-(Butyrylamino-methyl)-N-hydroxy-benzamide;

N-hydroxy-4-(phenylacetylamino-methyl)-benzamide;

N-hydroxy-4-[(4-phenyl-butyrylamino)-methyl]-benzamide;

4-Butyrylamino-N-hydroxy-benzamide;

N-hydroxy-4-phenylacetylamino-benzamide;

N-hydroxy-4-(4-phenylbutyrylamino)-benzamide; and

N-[4-(2-Hydroxycarbamoyl-ethyl)-phenyl]-butyramide.

11. The inhibitor according to claim 1, wherein the inhibitor is chosen from N-hydroxy-3-(4-phenylacetylamino-phenyl)-propionamide;

N-[4-(2-Hydroxycarbamoyl-ethyl)-phenyl]-4-phenyl-butyramide;

N-(2-Amino-phenyl)-4-[(2-phenyl-butyrylamino-methyl]-benzamide;

N-(2-Amino-phenyl)-4-[(3-phenyl-butyrylamino-methyl]-benzamide;

N-hydroxy-4-(2-phenylbutyrylamino)-benzamide;

N-hydroxy-4-(3-phenylbutyrylamino)-benzamide;

N-[4-(2-Hydroxycarbamoyl-ethyl)-phenyl]-2-phenyl-butyramide;

N-[4-(2-Hydroxycarbamoyl-ethyl)-phenyl]-3-phenyl-butyramide;

N-hydroxy-4-[(2-phenyl-butyrylamino)-methyl]-benzamide; and

N-hydroxy-4-[(3-phenyl-butyrylamino)-methyl]-benzamide.

12. The inhibitor according to claim 1, wherein the inhibitor is chosen from 4-Benzoylamino-N-hydroxy-benzamide;

4-(4-methyl)-Benzoylamino-N-hydroxy-benzamide;

4-(4-chloro)-Benzoylamino-N-hydroxy-benzamide;

4-(4-bromo)-Benzoylamino-N-hydroxy-benzamide;

4-(4-tert-butyl)-Benzoylamino-N-hydroxy-benzamide;

4-(4-phenyl)-Benzoylamino-N-hydroxy-benzamide;

4-(4-methoxyl)-Benzoylamino-N-hydroxy-benzamide;

4-(4-trifluoromethyl)-Benzoylamino-N-hydroxy-benzamide;

4-(4-nitro)-Benzoylamino-N-hydroxy-benzamide; and

Pyridine-2-carboxylic acid (4-hydroxycarbamoyl-phenyl)-amide.

13. The inhibitor according to claim 1, wherein the inhibitor is chosen from N-hydroxy-4-(2-methyl-2-phenyl-propionylamino)-benzamide;

N-hydroxy-4-(3-methyl-2-phenyl-butyrylamino)-benzamide;

N-hydroxy-4-(3-phenyl-propionylamino)-benzamide;

4-(2,2-Dimethyl-4-phenyl-butyrylamino)-N-hydroxy-benzamide;

N-hydroxy-4-[methyl-(4-phenyl-butyryl)-amino]-benzamide;

N-hydroxy-4-(2-phenyl-propionylamino)-benzamide;

N-hydroxy-4-(2-methoxy-2-phenyl-acetylamino)-benzamide;

4-Diphenylacetylamino-N-hydroxy-benzamide;

N-hydroxy-4-[2-(4-isobutyl-phenyl)-propionylamino]-benzamide; and

N-(2-Amino-phenyl)-4-phenylacetylamino-benzamide.

14. The inhibitor according to claim 1, wherein the inhibitor is chosen from N-(2-Amino-phenyl)-4-(5-phenyl-pentanoylamino)-benzamide;

N-(2-Amino-phenyl)-4-(2-phenyl-butyrylamino)-benzamide;

N-(2-Amino-phenyl)-4-(2,2-dimethyl-4-phenyl-butyrylamino)-benzamide;

N-(2-Amino-phenyl)-4-(3-phenyl-propionylamino)-benzamide;

N-(2-Amino-phenyl)-4-(4-phenyl-butyrylamino)-benzamide;

N-(2-Amino-phenyl)-4-(3-phenyl-butyrylamino)-benzamide;

N-(2-Amino-phenyl)-4-(3-methyl-2-phenyl-butyrylamino)-benzamide;

N-(2-Amino-phenyl)-4-(2-methyl-2-phenyl-propionylamino)-benzamide;

N-(2-Amino-phenyl)-4-[2-(4-isobutyl-phenyl)-propionylamino]-benzamide; and

N-hydroxy-4-[2-(S)-phenylbutyrylamino]-benzamide.

15. The inhibitor according to claim 1, wherein the inhibitor is chosen from N-hydroxy-4-[2-(R)-phenylbutyrylamino]-benzamide;

N-[4-(2-Hydroxycarbamoyl-ethyl)-phenyl]-2-(S)-phenyl-butyramide;

N-[4-(2-Hydroxycarbamoyl-ethyl)-phenyl]-2-(R)-phenyl-butyramide;

N-hydroxy-4-(3-(S)-phenylbutyrylamino)-benzamide;

N-hydroxy-4-(3-(R)-phenylbutyrylamino)-benzamide;

N-hydroxy-4-[3-(S)-phenylbutyrylamino]-benzamide; and

N-hydroxy-4-[3-(R)-phenylbutyrylamino]-benzamide.

16. The inhibitor according to claim 1, wherein the inhibitor is an ester or salt.

17. A pharmaceutical composition comprising the inhibitor according to claim 1, and at least one pharmaceutically acceptable excipient.

18. A method of inhibiting neoplastic cell proliferation in an animal comprising administering a therapeutically effective amount of at least one inhibitor according to claim 1.

19. The method according to claim 18, wherein the animal is a human.

20. The inhibitor according to claim 8, wherein m=0 and X=H.

21. The inhibitor according to claim 20, wherein the compound is:

22. The inhibitor according to claim 20, wherein the compound is:

23. The inhibitor according to claim 20, wherein the compound is:

24. A composition comprising the inhibitor according to claim 21, wherein the composition is enriched in the S-stereoisomer as compared to the R-stereoisomer.

25. The inhibitor according to claim 1, wherein X=H and A is chosen from:

wherein R comprises a branched or unbranched, substituted or unsubstituted, saturated or unsaturated, aliphatic or aromatic group.