title: Chemical synthesis, characterisation and biological evaluation of furanic-estradiol derivatives as inhibitors of 17β-hydroxysteroid dehydrogenase type 1.
abstract: 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 17β-hydroxysteroid dehydrogenase type 1 (17β-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 [(14)C]-E1 (100 nM) into [(14)C]-E2 by these compounds was first evaluated with homogenated HEK-293 cells overexpressing 17β-HSD1. The epoxide and butylamide derivatives showed the best inhibitions with 72% and 66%, respectively, at 10 µM. All furanic compounds showed a lower 17β-HSD1 inhibitory potency in intact T47-D 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 [(14)C]-E1 (60 nM) into [(14)C]-E2 transformation at 1 and 10 µM, respectively.
authors.affiliation: Laboratory of Medicinal Chemistry, CHUQ (CHUL)-Research Center, 2705, Laurier Boulevard, Québec (Québec), G1V 4G2, Canada.
authors.forename: Siham
authors.initials: S
authors.lastname: Farhane
authors.forename: Yannick
authors.initials: Y
authors.lastname: Laplante
authors.forename: Donald
authors.initials: D
authors.lastname: Poirier
mesh_terms: D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004958:Estradiol / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D004960:Estradiol Dehydrogenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005663:Furans / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D005663:Furans; D004958:Estradiol; D004960:Estradiol Dehydrogenases; C513331:HSD17B1 protein, human