Development of Steroidal Spiro-Heterocycles Through One-Step Cyclocondensation, Their Evaluation as Antiproliferative Agents

Abstract

New conformationally-restricted steroids were synthesized by incorporating a spiranic heterocyclic motif at the C-17 position, using trans-androsterone, trans-dehydroandrosterone, and estrone as starting materials. A cyclocondensation process with o-disubstituted aromatic bis-nucleophiles enabled the modification of the structure. In silico calculations were employed to predict the diastereoselectivity and the assignment of the new chiral center stereochemistry. Spiranic derivatives were evaluated in vitro for antiproliferative activity against six human tumor cell lines, with benzoxazolines showing the highest activity. Derivatives of estrone exhibited greater potency than those of androsterone, being up to 50-fold more active than abiraterone, a steroidal anticancer drug. Live cell imaging of the lead compound combining estrone and a benzimidazoline residue revealed apoptotic events such as membrane blebbing, nuclear condensation, and cell shrinkage, suggesting potential utility for therapeutic applications.