An efficient approach to novel 17-5′-(1′,2′,4′)-oxadiazolyl androstenes via the cyclodehydration of cytotoxic O-steroidacylamidoximes, and an evaluation of their inhibitory action on 17α-hydroxylase/C17,20-lyase

Abstract

Novel 17-exo-oxadiazoles in the androst-5-ene series were efficiently synthesized in a two-step sequence via the corresponding O-acylamidoxime intermediates (obtained from steroidal 17-carboxylic acids and amidoximes in the presence of coupling reagent), which then underwent tetrabutylammonium fluoride-induced cyclocondensation under mild reaction conditions. The synthesized compounds were subjected to in vitro pharmacological studies to investigate their inhibitory effect on rat testicular C17,20-lyase and their antiproliferative action on four malignant human adherent cell lines (HeLa, MCF7, A2780 and A431). One of the oxadiazolyl derivatives proved to exert significant enzyme-inhibitory action (IC50 = 0.60 μM), while some of the isolated O-acylated amidoxime intermediates displayed high cytotoxic activities on all examined cell lines, with IC50 values in the range 0.22–3.94 μM.