Synthesis and biological evaluation of some A,D-ring modified 16,17-secoandrostane derivatives

Starting from 3 beta-hydroxy-17-oxo-16,17-secoandrost-5-ene-16-nitrile ( 1), the new 16,17-secoandrostane derivatives 2-11 were synthesized. Protection of the 17-oxo function of compound 1 with ethylene glycol yielded compounds 2 and 3. The Oppenauer oxidation of 2 or oxidation with H2O2 in alkaline conditions gave the respective compounds 4 and 10. Epoxidation of compound 4 yielded a mixture of 4 alpha,5 alpha- and 4 beta,5 beta-epoxides 5 and 6 and a mixture of 4 alpha,5 alpha- and 4 beta,5 beta-epoxy-carboxamides 7 and 8. Opening of the oxirane ring of a mixture of compounds 5 and 6 with formic acid afforded the 4-hydroxy derivative 9. Anti-aromatase activity and in vitro cytotoxicity for three tumor cell lines ( human breast adenocarcinoma ER+, MCF-7 as well as human breast adenocarcinoma ER- ,MDA-MB-231, and prostate cancer, PC3) of selected compounds were evaluated. Compounds 2, 4, 9, and 10 showed a strong cytotoxicity for PC3 cells.