Synthesis of some epoxy and/or N-oxy 17-picolyl and 17-picolinylidene-androst-5-ene derivatives and evaluation of their biological activity

Steroidal epoxy and/or N-oxy 17-picolyl and 17-picolinylidene-androst-5-ene derivatives have been prepared using 3β,17β-dihydroxy-17α-picolyl-androst-5-ene (1), 3β-acetoxy-17-picolinylidene-androst-5-ene (2), and 3β-hydroxy-17-picolinylidene-androst-5-ene (3) as synthetic precursors. The compounds 2 and/or 3 were reacted with m-chloroperoxybenzoic acid (MCPBA). The compounds synthesized from 2 were 17-picolinylidene-N-oxide 4, 5α,6α-epoxy and 5β,6β-epoxy-17-picolinylidene-N-oxide 5 and 6, and 5α,6α:17α,20α- and 5β,6β:17α,20α-diepoxy-N-oxide 7 and 8. Starting from compound 3, a mixture of 5α,6α-epoxy and 5β,6β-epoxy-17-picolinylidene 9 and 10, 5α,6α-epoxy and 5β,6β-epoxy-17-picolinylidene-N-oxide 11 and 12, and 5α,6α:17α,20α- and 5β,6β:17α,20α-diepoxy-N-oxide 13 and 14 were obtained. From compounds 15 and 18, obtained from 1 and 3 by the Oppenauer oxidation, the 4α,5α-epoxy and 4β,5β-epoxy derivatives 16, 17 and 20, 21 were prepared by oxidation with 30% H2O2. Oxidation of 18 with MCPBA yielded only the N-oxide 19. The structures of compounds 15 and 18 were proved by the X-ray analysis. Compounds 1–6, 9, 15, 17, 18, and 21 were tested on activity against the enzyme aromatase. Antitumor 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. Three tested compounds (1, 4, and 19) showed strong activity against PC3, the IC50 values being in the range 0.55–10 μM, whereas compound 17 showed strong activity against MDA-MB-231 (IC50 10.4 μM).