Synthesis and biological evaluation of some new A,B-ring modified steroidal d-lactones

Starting from the d-homo lactones of androst-4-en-3-one 3 and 4, prepared from 1 and 2, the new 17a homolactones 5–12, 14 and 15, were synthesized. The 4-hydroxy compounds 9 and 10 were obtained through the reaction of 4α,5α- (5 and 7) and 4β,5β- (6 and 8) epoxides with formic acid. The epoxides 5 and 6 were prepared from compound 3, and epoxides 7 and 8 from compound 4 by oxidation with H2O2 under basic conditions. Compound 1 served as a starting substance for obtaining lactones 11–13. Oxidation of compound 1 with m-chloroperbenzoic acid yielded 11 and 12, but compound 13 gave 14. Compound 15 was obtained from 13 by oxidation with H2O2 under basic conditions. The structures of epoxides 6 and 14 were confirmed by X-ray structural analysis. Cytotoxic activity against three tumor cell lines (human breast adenocarcinoma ER+, MCF-7, human breast adenocarcinoma ER-, MDA-MB-231, and prostate cancer PC3) was evaluated. Compounds 6 and 14 showed strong activity against PC3, the IC50 being 10.6 and 2.2 μM, respectively, whereas compounds 3 and 8 showed strong activity against MDA-MB-231 (IC50 is 9.3 and 3.6 μM, respectively). Aromatase inhibition assay showed that the tested compounds 9, 10, and 14 possess lower activity compared to formestane.