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 of formula IV:
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;
n4 and p4 are each independently 0, 1, 2, 3, 4, or 5;
m4 and o4 are each independently 0, 1, 2, 3, or 4;
each R 41 , each R 42 , and each R 43 are independently halogen, OH, unsubstituted or substituted C 1 -C 6 alkyl, or unsubstituted or substituted C 1 -C 6 alkoxy;
each R 44 is independently halogen, OH, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 1 -C 6 alkoxy, (CH 2 ) q4 —NH 2 , (CH 2 ) q4 —NH—C 1 -C 6 alkyl, or (CH 2 ) q4 —N(C 1 -C 6 alkyl) 2 ; and
q4 is 0, 1, 2, 3, 4, 5, or 6.
2. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
3. The pharmaceutical composition of claim 2 , wherein the pharmaceutical composition is a topical composition.
4. A method of modulating the SMO, comprising contacting the SMO with a compound of claim 1 .
5. 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 a compound of claim 1 , or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier.
6. The method of claim 5 , wherein the disorder is a cell proliferative disorder.
7. The method of claim 6 , wherein the cell proliferative disorder is cancer.
8. The method of claim 7 , wherein the cancer is medulloblastoma or basal cell carcinoma.
9. The compound of claim 1 , wherein n4 is 0.
10. The compound of claim 1 , wherein m4 is 0.
11. The compound of claim 1 , wherein at least one R 44 is unsubstituted or substituted straight-chain C 1 -C 6 alkyl or branched C 3 -C 6 alkyl.
12. The compound of claim 1 , wherein R 44 is (CH 2 ) q4 —NH 2 , (CH 2 ) q4 —NH—C 1 -C 6 alkyl, or (CH 2 ) q4 —N(C 1 -C 6 alkyl) 2 , wherein the C 1 -C 6 alkyl is methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, or hexyl, each of which is optionally substituted with halogen.
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 1 , which is:
or a pharmaceutically acceptable salt thereof, wherein Z is O, S, or NH-NH.
15. The compound of claim 1 , wherein Z 1 -Z 2 is C(O)—O or O—C(O).
16. The compound of claim 1 , wherein o4 is 0, 1, or 2.
17. The compound of claim 1 , wherein p4 is 0, 1, or 2.
18. The compound of claim 1 , wherein at least one R 44 is halogen or OH.
19. The compound of claim 11 , wherein at least one R 44 is methyl.
20. The compound of claim 12 , wherein at least one R 44 is (CH 2 ) q4 —NH—C 1 -C 6 alkyl.