Chemical Synthesis, Characterisation and Biological Evaluation of Furanic-Estradiol Derivatives as Inhibitors of 17β-Hydroxysteroid Dehydrogenase Type 1

Local biosynthesis of estrogens, especially estradiol (E2), is thought to be important for the maintenance and growth of estrogen-sensitive diseases. To control E2 formation, we have investigated a series of epoxide and furanic E2 derivatives as inhibitors of 17 beta-hydroxysteroid dehydrogenase type 1 (17 beta-HSD1), the enzyme responsible for the conversion of estrone (E1) into E2. We report here a strategy to synthesize a series of E2-furanic derivatives from E1. An intermediate epoxide was first obtained and then reduced to give a furanic steroid, which allowed us to introduce a molecular diversity like alcohol, bromide, ester, acid and amide. The inhibition of the transformation of [C-14]-E1 (100 nM) into [C-14]-E2 by these compounds was first evaluated with homogenated HEK-293 cells overexpressing 17 beta-HSD1. The epoxide and butylamide derivatives showed the best inhibitions with 72% and 66%, respectively, at 10 mu M. All furanic compounds showed a lower 17 beta-HSD1 inhibitory potency in intact T-47D breast cancer cells than in homogenated cells, but a great improvement of the inhibitory activity was observed for the epoxide, which gave 62% and 90% of inhibition of the [C-14]-E1 (60 nM) into [14C]-E2 transformation at 1 and 10 mu M, respectively.