Design, chemical synthesis, and in vitro biological evaluation of simplified estradiol-adenosine hybrids as inhibitors of 17β-hydroxysteroid dehydrogenase type 1

A series of estradiol (E-2) derivatives were designed to interact with both the substrate- and the cofactor-binding sites of 17 beta-hydroxysteroid dehydrogenase type 1 (17 beta-HSD1). These analogues of potent E-2-adenosine hybrid inhibitor EM-1745, where the adenosine moiety was replaced by a more stable benzene derivative, were synthesized from estrone using alkene cross-metathesis and Sonogashira coupling reactions as key steps. In vitro biological evaluation of these steroid derivatives revealed that a spacer of 13 methylenes, between the 16 beta-position of E-2 and the adenosine mimic bearing a carboxylic acid group, gave the best inhibition of 17 beta-HSD1.