Heteroaryl-containing isoflavones as aromatase inhibitors
Compounds and methods useful for treating and prevention of cancer, particularly hormone-dependent breast cancer. Provided are compounds of formula I: wherein X is selected from O, N, S, SO, SO 2 , and S(CH 2 ) n , wherein n=1-10; R 1 and R 2 may be the same or different and are selected from H, OH, OCH 3 , OCH 2 CH 3 , OCH 2 C 6 H 5 , NH 2 , NHCH 3 , N(CH 3 ) 2 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , NO 2 , F, Cl, Br, CF 3 , SH, SCH 3 , SCH 2 CH 3 , OCOCH 3 , OCOC(CH 3 ) 3 , OCOCH 2 COOH, and CN; and R 3 is a nitrogen-containing heterocyclic ring. Also provided are method for treating or preventing cancer in a subject by administering a therapeutically effective amount of a heteroaryl-containing isoflavone, or a pharmaceutically acceptable salt or prodrug thereof, to a subject in need of treatment. Also provided is a method for the synthesis of 2-substituted isoflavones by first reacting deoxybenzoins with a phase transfer catalyst to provide a 2-(alkylthio)isoflavone; second deprotecting the 2-(alkylthio)isoflavone; and third applying selective debenzylation to form the final compound.
1. A method for treating breast cancer in a subject, comprising the step of administering to a subject that has been diagnosed with breast cancer a therapeutically effective amount of an isoflavone of formula I
wherein
X is selected from the group consisting of O, NH, S, SO, SO 2 , and S(CH 2 ) n , wherein n=1-10;
R 1 and R 2 can be the same or different and are selected from the group consisting of H, OH, OCH 3 , OCH 2 CH 3 , OCH 2 C 6 H 5 , NH 2 , NHCH 3 , N(CH 3 ) 2 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , NO 2 , F, Cl, Br, CF 3 , SH, SCH 3 , SCH 2 CH 3 , OCOCH 3 , OCOC(CH 3 ) 3 , OCOCH 2 COOH, and CN; and
R 3 is a 5- or 6-membered ring containing 1-3 nitrogen atoms in the ring, the ring being unsubstituted or substituted with a member selected from the group consisting of H, OH, OCH 3 , OCH 2 CH 3 , NH 2 , NHCH 3 , N(CH 3 ) 2 , NO 2 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , F, Cl, Br, CF 3 , SH, SCH 3 , SCH 2 CH 3 , CN and combinations thereof.
2. The method of claim 1 wherein X—R 3 is selected from the group consisting of:
wherein n is 0-3 and R 4 is selected from the group consisting of H, OH, OCH 3 , OCH 2 CH 3 , NH 2 , NHCH 3 , N(CH 3 ) 2 , NO 2 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , F, Cl, Br, CF 3 , SH, SCH 3 , SCH 2 CH 3 , CN and combinations thereof.
3. The method of claim 1 wherein the breast cancer is hormone-dependent breast cancer.
4. A method for the synthesis of a 2-substituted isoflavone, the method comprising the steps of:
(a) reacting a deoxybenzoin with a phase transfer catalyst to provide a 2-(alkylthio)isoflavone;
(b) deprotecting the 2-(alkylthio)isoflavone; and
(c) applying selective debenzylation to form an isoflavone of the following formula I
wherein
X is selected from the group consisting of O, NH, S, SO, SO 2 , and S(CH 2 ) n , wherein n=1-10;
R 1 and R 2 can be the same or different and are selected from the group consisting of H, OH, OCH 3 , OCH 2 CH 3 , OCH 2 C 6 H 5 , NH 2 , NHCH 3 , N(CH 3 ) 2 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , NO 2 , F, Cl, Br, CF 3 , SH, SCH 3 , SCH 2 CH 3 , OCOCH 3 , OCOC(CH 3 ) 3 , OCOCH 2 COOH, and CN; and
R 3 is a 5- or 6-membered ring containing 1-3 nitrogen atoms in the ring, the ring being unsubstituted or substituted with a member selected from the group consisting of H, OH, OCH 3 , OCH 2 CH 3 , NH 2 , NHCH 3 , N(CH 3 ) 2 , NO 2 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , F, Cl, Br, CF 3 , SH, SCH 3 , SCH 2 CH 3 , CN and combinations thereof.
5. The method of claim 1 , wherein R 3 is a 4-pyridyl group.
6. The method of claim 1 , wherein R 2 is a hydroxyl moiety.
7. The method of claim 1 , wherein R 1 is H, R 2 is OCH 2 C 6 H 5 , and R 3 is 4-pyridyl.
8. The method of claim 1 , wherein the ring is selected from the group consisting of unsubstituted or substituted imidazole, triazole, pyrimidine, and pyridine.
9. The method of claim 8 , wherein R 3 is imidazole, triazole, pyrimidine, or pyridine.
10. The method of claim 4 , wherein the ring is selected from the group consisting of unsubstituted or substituted imidazole, triazole, pyrimidine, and pyridine.
11. The method of claim 10 , wherein R 3 is imidazole, triazole, pyrimidine, or pyridine.