Compounds and methods for treating cancer
The present application relates to compounds comprising an ester, a thioester, or a hydrazide moiety and methods of synthesizing these compounds. The present application also relates to pharmaceutical compositions containing the compounds and methods of treating cell proliferative disorders mediated by the Hedgehog (Hh) signaling pathway, such as cancer, by administering the compounds and pharmaceutical compositions to subjects in need thereof.
1. A compound having formula III:
or a pharmaceutically acceptable salt thereof, wherein:
Z 1 -Z 2 is C(O)—O, O—C(O), C(O)—S, S—C(O), C(O)—NR—NR, or NR—NR—C(O);
each R is independently H or C 1 -C 3 alkyl;
R 31 is H or unsubstituted or substituted C 1 -C 6 alkyl;
n3 is 0, 1, 2, 3, 4, or 5;
each R 32 is independently halogen, cyano, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 1 -C 6 alkoxy, or S(O) m3 -(unsubstituted or substituted C 1 -C 6 alkyl); and
m3 is 0, 1, or 2.
2. The compound of claim 1 , having formula IIIa:
or a pharmaceutically acceptable salt thereof, wherein Z 3 is O, S, or NR—NR.
3. The compound of claim 1 , wherein Z 1 -Z 2 is C(O)—O or O—C(O).
4. The compound of claim 1 , wherein R 31 is methyl, ethyl, or propyl.
5. The compound of claim 4 , wherein R 31 is methyl.
6. The compound of claim 1 , wherein n3 is 0, 1, or 2.
7. The compound of claim 6 , wherein n3 is 2.
8. The compound of claim 1 , wherein at least one R 32 is halogen.
9. The compound of claim 1 , wherein at least one R 32 is methyl substituted with one or more F.
10. The compound of claim 9 , wherein at least one R 32 is CF 3 .
11. The compound of claim 1 , wherein at least one R 32 is cyano.
12. The compound of claim 1 , wherein at least one R 32 is unsubstituted or substituted straight-chain C 1 -C 6 alkoxy or branched C 3 -C 6 alkoxy.
13. The compound of claim 1 , which is:
or a pharmaceutically acceptable salt thereof, wherein Z is O, S, or NH—NH.
14. The compound of claim 13 , which is
or a pharmaceutically acceptable salt thereof.
15. The compound of claim 1 , which is:
or a pharmaceutically acceptable salt thereof, wherein Z is O, S, or NH—NH.
16. The compound of claim 1 , which is:
or a pharmaceutically acceptable salt thereof, wherein Z is O, S, or NH—NH.
17. The compound of claim 1 , which is:
or a pharmaceutically acceptable salt thereof, wherein Z is O, S, or NH—NH.
18. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
19. The pharmaceutical composition of claim 18 , wherein the pharmaceutical composition is a topical composition.
20. A method of modulating the SMO, comprising contacting the SMO with the compound of claim 1 , or a pharmaceutically acceptable salt thereof.
21. A method of treating a disorder mediated by the Hh signaling pathway, comprising administering to a subject in need thereof, a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof.
22. The method of claim 21 , wherein the disorder is a cell proliferative disorder.
23. The method of claim 22 , wherein the cell proliferative disorder is cancer.
24. The method of claim 23 , wherein the cancer is medulloblastoma or basal cell carcinoma.