Zn 2+ -chelating motif-tethered fatty acids as histone deacetylase (HDAC) inhibitors. Compounds performed well in in vitro and in vivo tests.
1. A method of treating a cancer in an animal comprising:
administering to an animal having cancer a therapeutically effective amount of a compound having the formula:
wherein:
X is chosen from H and CH 3 ;
Y is (CH 2 )n wherein n is 0-2;
Z is chosen from (CH 2 ) m wherein m is 0-3 and (CH) 2 ;
A is an aliphatic group having from 5 to 14 carbons;
B is o-aminophenyl or hydroxyl group; and
Q is a halogen, hydrogen, or methyl; and
wherein the cancer is selected from a group consisting of prostate cancer, lung cancer, acute leukemia, multiple myeloma, breast carcinoma, and melanoma.
2. The method according to claim 1 , wherein the aliphatic group is branched.
3. A method of treating a cancer in an animal comprising:
administering to an animal having cancer a therapeutically effective amount of a compound having the formula:
wherein:
X is chosen from H and CH 3 ;
Y is (CH 2 )n wherein n is 0-2;
Z is chosen from (CH 2 ) m wherein m is 0-3 and (CH) 2 ;
A is an aliphatic group having from 5 to 14 carbons;
B is a hydroxyl group; and
Q is a halogen, hydrogen, or methyl; and
wherein the cancer is selected from a group consisting of prostate cancer, lung cancer, acute leukemia, multiple myeloma, breast carcinoma, and melanoma.
4. A method of treating a cancer in an animal comprising administering to an animal having cancer a therapeutically effective amount of a compound 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 7 hydroxy-4-(2-phenyl-propionylamino)-benzamide; N-hydroxy-4-(2-methoxy-2-phenyl-acetylamino)-benzamide; 4-Diphenylacetylamino-N-hydroxy-benzamide; and N-hydroxy-4-[2-(4-isobutyl-phenyl)-propionylamino]-benzamide, wherein the cancer is selected from a group consisting of prostate cancer, lung cancer, acute leukemia, multiple myeloma, breast carcinoma, and melanoma.
5. A method of treating a cancer in an animal comprising:
administering to an animal having cancer a therapeutically effective amount of a compound having the formula:
wherein:
X is chosen from H and CH 3 ;
Y is (CH 2 )n wherein n is 0-2;
Z is chosen from (CH 2 ) m wherein m is 0-3 and (CH) 2 ;
A is an α- or β- branched aromatic fatty group having from 8 to 14 carbons;
B is hydroxyl, and Q is hydrogen; and
wherein the cancer is selected from a group consisting of prostate cancer, lung cancer, acute leukemia, multiple myeloma, breast carcinoma, and melanoma.
6. A method of treating a cancer in an animal comprising administering to an animal having cancer a therapeutically effective amount of the compound:
or a pharmaceutically acceptable salt thereof, wherein the cancer is selected from a group consisting of prostate cancer, lung cancer, acute leukemia, multiple myeloma, breast carcinoma, and melanoma.
7. The method of claim 1 , wherein the animal is a human.
8. A method of inhibiting cancerous cell proliferation in an animal comprising:
administering a therapeutically effective amount of a compound having the formula:
wherein:
X is chosen from H and CH 3 ;
Y is (CH 2 )n wherein n is 0-2;
Z is chosen from (CH 2 ) m wherein m is 0-3 and (CH) 2 ;
A is an aliphatic group having from 5 to 14 carbons;
B is o-aminophenyl or hydroxyl group; and
Q is a halogen, hydrogen, or methyl, and
wherein the cancerous cell is selected from a group consisting of prostate cancer, lung cancer, acute leukemia, multiple myeloma, breast carcinoma, and melanoma.
9. The method according to claim 8 , wherein the aliphatic group is branched.
10. The method according to claim 8 , wherein B is hydroxyl.
11. A method of inhibiting cancerous cell proliferation in an animal comprising administering a therapeutically effective amount of a compound 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; and N-hydroxy-4-[2-(4-isobutyl-phenyl)-propionylamino]-benzamide, wherein the cancer is selected from a group consisting of prostate cancer, lung cancer, acute leukemia, multiple myeloma, breast carcinoma, and melanoma.
12. A method of inhibiting cancerous cell proliferation in an animal comprising:
administering a therapeutically effective amount of a compound having the formula:
wherein:
X is chosen from H and CH 3 ;
Y is (CH 2 )n wherein n is 0-2;
Z is chosen from (CH 2 ) m wherein m is 0-3 and (CH) 2 ;
A is an α-branched aromatic fatty group having from 8 to 14 carbons;
B is hydroxyl, and Q is hydrogen; and
wherein the cancerous cell is selected from a group consisting of prostate cancer, lung cancer, acute leukemia, multiple myeloma, breast carcinoma, and melanoma.
13. The method according to claim 12 , wherein m=0 and X═H.
14. A method of inhibiting cancerous cell proliferation in an animal comprising administering a therapeutically effective amount of the compound:
or a pharmaceutically acceptable salt thereof, wherein the cancerous cell is selected from a group consisting of prostate cancer, lung cancer, acute leukemia, multiple myeloma, breast carcinoma, and melanoma.
15. The method of claim 8 , wherein the animal is a human.
16. A method of inducing apoptosis in cancerous cells comprising:
administering a therapeutically effective amount of a compound having the formula:
wherein:
X is chosen from H and CH 3 ;
Y is (CH 2 )n wherein n is 0-2;
Z is chosen from (CH 2 ) m wherein m is 0-3 and (CH) 2 ;
A is an aliphatic group having from 5 to 14 carbons;
B is o-aminophenyl or hydroxyl group; and
Q is a halogen, hydrogen, or methyl; and
wherein the cancerous cell is selected from a group consisting of prostate cancer, lung cancer, acute leukemia, multiple myeloma, breast carcinoma, and melanoma.
17. The method according to claim 16 , wherein the aliphatic group is branched.
18. The method according to claim 16 , wherein B is hydroxyl.
19. A method of inducing apoptosis in cancerous cells comprising administering a therapeutically effective amount of a compound 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; and N-hydroxy-4[2-(4-isobutyl-phenyl)-propionylamino]-benzamide, wherein the cancer is selected from a group consisting of prostate cancer, lung cancer, acute leukemia, multiple myeloma, breast carcinoma, and melanoma.
20. A method of inducing apoptosis in cancerous cells comprising:
administering a therapeutically effective amount of a compound having the formula:
wherein:
X is chosen from H and CH 3 ;
Y is (CH 2 )n wherein n is 0-2;
Z is chosen from. (CH 2 ) m wherein m is 0-3 and (CH) 2 ;
A is an α-branched aromatic fatty group having from 8 to 14 carbons;
B is hydroxyl, and Q is hydrogen; and
wherein the cancerous cell is selected from a group consisting of prostate cancer, lung cancer, acute leukemia, multiple myeloma, breast carcinoma, and melanoma.
21. The method according to claim 20 , wherein m=0 and X═H.
22. A method of inducing apoptosis in cancerous cells comprising administering a therapeutically effective amount of the compound:
or a pharmaceutically acceptable salt thereof, wherein the cancerous cell is selected from a group consisting of prostate cancer, lung cancer, acute leukemia, multiple myeloma, breast carcinoma, and melanoma.
23. The method of claim 16 , wherein the animal is a human.
24. A method of inhibiting the activity of histone deacetylases within a cancerous cell comprising:
administering a therapeutically effective amount of at least one histone deacetylase inhibitor having the formula:
wherein:
X is chosen from H and CH 3 ;
Y is (CH 2 )n wherein n is 0-2;
Z is chosen from (CH 2 ) m wherein m is 0-3 and (CH) 2 ;
A is an aliphatic group having from 5 to 14 carbons;
B is o-aminophenyl or hydroxyl group; and
Q is a halogen, hydrogen, or methyl; and
wherein the cancerous cell is selected from a group consisting of prostate cancer, lung cancer, acute leukemia, multiple myeloma, bladder carcinoma, renal carcinoma, breast carcinoma, colorectal carcinoma, neuroblastoma, and melanoma.
25. The method according to claim 24 , wherein the aliphatic group is branched.
26. The method according to claim 24 , wherein B is hydroxyl.
27. A method of inhibiting the activity of histone deacetylases within a cancerous cell comprising administering a therapeutically effective amount of at least one histone deacetylase inhibitor 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; and N-hydroxy-4-[2-(4-isobutyl-phenyl)-propionylamino]-benzamide, wherein the cancer is selected from a group consisting of prostate cancer, lung cancer, acute leukemia, multiple myeloma, breast carcinoma, and melanoma.
28. A method of inhibiting the activity of histone deacetylases within a cancerous cell comprising:
administering a therapeutically effective amount of at least one histone deacetylase inhibitor having the formula:
wherein:
X is chosen from H and CH 3 ;
Y is (CH 2 )n wherein n is 0-2;
Z is chosen from (CH 2 ) m wherein m is 0-3 and (CH) 2 ;
A is an α-branched aromatic fatty group having from 8 to 14 carbons;
B is hydroxyl, and Q is hydrogen; and
wherein the cancerous cell is selected from a group consisting of prostate cancer, lung cancer, acute leukemia, multiple myeloma, bladder carcinoma, renal carcinoma, breast carcinoma, colorectal carcinoma, neuroblastoma, and melanoma.
29. The method according to claim 28 , wherein m=0 and X═H.
30. A method of inhibiting the activity of histone deacetylases within a cancerous cell comprising administering a therapeutically effective amount of the compound:
or a pharmaceutically acceptable salt thereof, wherein the cancerous cell is selected from a group consisting of prostate cancer, lung cancer, acute leukemia, multiple myeloma, bladder carcinoma, renal carcinoma, breast carcinoma, colorectal carcinoma, neuroblastoma, and melanoma.
31. The method of claim 24 , wherein the animal is a human.
32. The method according to claim 5 , wherein A is selected from the group consisting of
33. The method according to claim 12 , wherein A is selected from the group consisting of
34. The method according to claim 20 , wherein A is selected from the group consisting of
35. The method according to claim 28 , wherein A is selected from the group consisting of
36. A method of treating a cancer in an animal comprising:
administering to an animal having cancer a therapeutically effective amount of a compound having the formula:
wherein:
X is chosen from H and CH 3 ;
Y is (CH 2 )n wherein n is 0-2;
Z is chosen from (CH 2 ) m wherein m is 0-3;
A is an aralkyl, or alkaryl group having from 8 to 14 carbons;
B is hydroxyl, and Q is hydrogen; and
wherein the cancer is selected from a group consisting of prostate cancer, lung cancer, acute leukemia, multiple myeloma, breast carcinoma, and melanoma.
37. The method according to claim 36 , wherein m=0 and X═H.
38. The method according to claim 36 , wherein the animal is human.