Synthesis of 2-and 7-substituted C19 steroids having a 1,4,6-triene or 1,4-diene structure and their cytotoxic effects on T47D and MDA-MB231 breast cancer cells

Abstract

2-Chloro-, 2-bromo-and 2-azido-1,4,6-androstatriene-3,17-diones were synthesized from 1α,2α-epoxy-4,6-androstadiene-3,17-dione (2) using HCl, HBr and NaN3, respectively. Compound 2 was also reacted with NaCN to give 2-cyano-1,4,6-androstatriene-3,17-dione (5) and 2β-cyano-1α-hydroxy- 4,6-androstadiene-3,17-dione (6). 6α,7α-Epoxy-1,4-androstadiene-3, 17-dione (8) was reacted with HCl, HBr and NaN3 to form the corresponding 7β-chloro-, 7β-bromo-and 7β-azido-6α-hydroxy-1,4- androstadiene-3,17-diones. The cytotoxic activity of these compounds towards T47D (estrogen-dependent) and MDA-MB231 (estrogen-independent) breast cancer cell lines was evaluated. The 6α-hydroxy-7β-substituted analogs were more active than the 2-substituted analogs on both cell lines. Compound 2 showed the highest selective activity against the T47D (IC50 7.1 μM) cell line and 5 showed good cytotoxic activity on MDAMB231 (IC50 18.5 μM) cell line, respectively. The 6α,7α-epoxy analog 8 also showed high cytotoxic activity on both cell lines (IC50 17.3 μM on T47D and IC50 26.9 μM on MDAMB231).