Compounds for treatment of cancer
Compounds according to formula (I) are disclosed where Q is S, N, or O; X is optional, and can be O═, S═, ═N—NH 2 , ═N—OH, or —OH; Y is optional and can be —N(H)—, O, or C 1 to C 20 hydrocarbon; and R 1 and R 2 are each independently substituted or unsubstituted single-, fused- or multiple-ring aryl or (hetero)cyclic ring systems. Methods of making these compounds, pharmaceutical compositions containing the compounds, and their use, particularly for treating or preventing cancer, are also disclosed.
1. A compound according to formula (I)
wherein,
Q is S;
X is O═, S═, ═N—NH 2 , ═N—OH, or —OH;
Y is optional, and can be C 1 to C 20 hydrocarbon;
R 1 is substituted or unsubstituted furanyl, indolyl, phenyl, biphenyl, triphenyl, diphenylmethane, thiophene-yl, adamantane-yl, or fluorene-yl; wherein said substituents are selected from hydroxyl, an aliphatic straight- or branched-chain C 1 to C 10 hydrocarbon, aryloxy, nitro, cyano, halo, haloalkyl, dihaloalkyl, trihaloalkyl, amino, alkylamino, mesylamino, dialkylamino, arylamino, amido, urea, alkyl-urea, alkylamido, haloalkylamido, arylamido, aryl, C 5 to C 7 cycloalkyl and arylalkyl, and combinations thereof; and
R 2 is substituted or unsubstituted furanyl, indolyl, pyridinyl, phenyl, biphenyl, triphenyl, diphenylmethane, thiophene-yl, adamantane-yl, or fluorene-yl; wherein said substituents are selected from hydroxyl, an aliphatic straight- or branched-chain C 1 to C 10 hydrocarbon, alkoxy, aryloxy, nitro, cyano, halo, haloalkyl, dihaloalkyl, trihaloalkyl, alkylamino, mesylamino, dialkylamino, arylamino, amido, urea, alkyl-urea, alkylamido, haloalkylamido, arylamido, C 5 to C 7 cycloalkyl and arylalkyl, and combinations thereof; or
a pharmaceutically acceptable salt, or prodrug thereof.
2. The compound of claim 1 , wherein formula (I) is
3. The compound of claim 1 , wherein R 1 and R 2 are each a substituted or unsubstituted phenyl.
4. The compound of claim 1 , wherein X is O═.
5. The compound of claim 1 , wherein X is S═.
6. The compound of claim 1 , wherein X is OH.
7. The compound of claim 1 , wherein X is ═N—NH 2 .
8. The compound of claim 1 , wherein X is ═N—OH.
9. The compound of claim 1 , wherein Y is absent, and R 2 is bound directly to —C(X)—.
10. The compound of claim 1 , wherein R 2 is 3,4,5-trimethoxyphenyl.
11. The compound of claim 10 , wherein R 1 is a substituted or unsubstituted phenyl, substituted or unsubstituted thiophene-yl, or substituted or unsubstituted indolyl.
12. The compound of claim 11 , wherein R 1 is phenyl, thiophene-yl, or indolyl substituted with one or more substituents selected from the group of methyl, ethyl, fluoro, bromo, cyano, nitro, trifluoromethyl, and amino.
13. The compound of claim 1 , wherein the compound is selected from the group of:
(3,4,5-trimethoxyphenyl)(2-phenylthiazol-4-yl)methanone;
(2-p-tolylthiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;
(2-(4-fluorophenyl)-thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;
(2-(4-nitrophenyl)-thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;
(2-(4-cyanophenyl)-thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;
(2-(4-(trifluoromethyl)-phenyl)-thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;
(2-(4-bromophenyl)-thiazol-4-yl)-(3,4,5-trimethoxyphenyl)methanone;
(2-(4-ethylphenyl)-thiazol-4-yl)-(3,4,5-trimethoxy-phenyl)methanone;
(2-(4-aminophenyl)-thiazol-4-yl)-(3,4,5-trimethoxy-phenyl)methanone;
(2-(thiophen-2-yl)-thiazol-4-yl)-(3,4,5-trimethoxyphenyl)methanone;
(2-(1H-indol-5-yl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;
(2-(1H-indol-2-yl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;
(2-(1H-indol-1-yl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;
(2-(1H-indol-3-yl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;
(2-(1H-indol-4-yl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone;
(2-(1H-indol-6-yl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone; and
(2-(1H-indol-7-yl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone.
14. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.
15. A method of treating cancer comprising:
administering a compound according to claim 1 to a subject having cancer under conditions effective to treat the cancer.
16. The method of claim 15 , wherein the cancer is selected from the group consisting of prostate cancer, breast cancer, ovarian cancer, skin cancer, lung cancer, colon cancer, leukemia, renal cancer, CNS cancer, and combinations thereof.
17. The method according to claim 15 , wherein said administering is carried out systemically.
18. The method according to claim 15 , wherein said administering is carried out directly to a site where cancer cells are present.
19. The method according to claim 15 , wherein said administering is carried out orally, topically, transdermally, parenterally, subcutaneously, intravenously, intramuscularly, intraperitoneally, by intranasal instillation, by intracavitary or intravesical instillation, intraocularly, intraarterially, intralesionally, or by application to mucous membranes.
20. The method according to claim 15 , wherein the compound is administered at a dosage rate of about 0.01 to about 100 mg/kg·body weight.
21. The method according to claim 15 , wherein said administering is repeated periodically.
22. The method according to claim 15 , wherein said administering is carried out in combination with another cancer therapy.
23. A method of destroying a cancerous cell comprising:
providing a compound according to claim 1 ; and
contacting the cancerous cell with the compound under conditions effective to kill the cancer cell.
24. A method of making a compound according to claim 1 comprising:
reacting intermediate
with either a Grignard reagent containing R 2 or Br—R 2 under conditions effective to form a compound according to formula (I) having a methanone linker group, where R 1 and R 2 are defined as in claim 1 and Q′ is the same as Q.
25. The method according to claim 24 further comprising:
reacting the compound having a methanone linker group with hydroxylamine hydrochloride under conditions effective to form a compound of formula (I) having a methanone oxime linker group.
26. The method according to claim 24 further comprising:
reacting the compound having a methanone linker group with hydrazine under conditions effective to form a compound of formula (I) having a hydrazono linker group.
27. The method according to claim 24 further comprising:
reacting the compound having a methanone linker group with Zn—Hg under acid conditions to form a compound of formula (I) having a methylene linker group.
28. The method according to claim 24 further comprising:
forming the intermediate by dehydrogenation of a precursor
29. A method of making a compound according to claim 1 comprising
reacting intermediate
with a Grignard reagent containing R 2 under conditions effective to form a compound according to formula (I) having a —CH(OH)— linker group, where R 1 and R 2 are defined as in claim 1 and Q′ is the same as Q.
30. The method according to claim 29 further comprising: dehydrogenating the resulting compound of formula (I) to form a thiazole, ring.
31. A method of making a compound according to claim 1 comprising:
reacting an intermediate
with Br—R 2 under conditions effective to form a compound according to formula (I) having an ester or amide linker group, where R 1 and R 2 are defined as in claim 1 and Q′ is the same as Q.
32. The method according to claim 31 further comprising:
dehydrogenating the resulting compound of formula (I) to form a thiazole ring.