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.

2-Chloro-, 2-bromo- and 2-azido-1,4,6-androstatriene-3,17-diones were synthesized from 1alpha,2alpha-epoxy-4,6-androstadiene-3,17-dione (2) using HCl, HBr and NaN(3), respectively. Compound 2 was also reacted with NaCN to give 2-cyano-1,4,6-androstatriene-3,17-dione (5) and 2beta-cyano-1alpha-hydroxy-4,6-androstadiene-3,17-dione (6). 6Alpha,7alpha-epoxy-1,4-androstadiene-3,17-dione (8) was reacted with HCl, HBr and NaN(3) to form the corresponding 7beta-chloro-, 7beta-bromo- and 7beta-azido-6alpha-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 6alpha-hydroxy-7beta-substituted analogs were more active than the 2-substituted analogs on both cell lines. Compound 2 showed the highest selective activity against the T47D (IC(50) 7.1 microM) cell line and 5 showed good cytotoxic activity on MDA-MB231 (IC(50) 18.5 microM) cell line, respectively. The 6alpha,7alpha-epoxy analog 8 also showed high cytotoxic activity on both cell lines (IC(50) 17.3 microM on T47D and IC(50) 26.9 microM on MDA-MB231).