Synthesis, structural analysis and antiproliferative activity of some novel D-homo lactone androstane derivatives

Abstract

An efficient synthesis of several A,B-modified D-homo lactone androstane derivatives is reported. The synthetic scheme shows the transformation of 17-oxa-D-homoandrost-5-en-16-on-3β-yl acetate 1 into the 5α-hydroxy-17-oxa-D-homoandrostane-6,16-dion-3β-yl acetate (4). After the dehydration of 4, the newly synthesized 6-keto-androst-4-ene-3β-yl acetate derivative 5 was oximinated to give the 6-hydroximino derivative 6, which was converted to A,B-condensed isoxazole derivatives 7 and 8. Compound 4 was also converted (via 6(E)- and 6(Z)-hydroximino derivatives 9 and 10) to the B-seco-cyano derivative 11 under a Beckmann fragmentation, while compound 5 was transformed to the 4β,5β-epoxy derivative 12. Structures were confirmed by IR, ¹H NMR, ¹³C NMR, and HRMS, and for 7 and 8 by X-ray crystallography. All compounds were tested in vitro on six malignant cell lines (MCF-7, MDA-MB-231, PC-3, HeLa, HT-29, K562) and one non-tumor MRC-5 cell line. Significant antiproliferative activity was observed for specific compounds against prostate (PC-3), cervical (HeLa) and colon (HT-29) cancer cells, while no compounds showed antiproliferative activity to non-cancerous control cells (MRC-5). Interestingly, 1–8 displayed selective antiproliferative activity against estrogen-independent (ER−, MDA-MB-231) breast cancer cells over estrogen-dependent (ER+, MCF-7) breast cancer cells.