title: Chemical synthesis, characterisation and biological evaluation of lactonic-estradiol derivatives as inhibitors of 17β-hydroxysteroid dehydrogenase type 1.
abstract: To control estradiol (E2) formation, we are interested in synthesizing inhibitors of 17β-hydroxyteroid dehydrogenase type 1 (17β-HSD1). Since the results of docking experiments have shown that E2-lactone derivatives substituted in position 19 or 20 (E-ring) could generate interactions with the active site of the enzyme, we carried out their chemical synthesis. After having prepared the 16β,17β-γ-lactone-E2 in four steps starting from estrone (E1), we introduced the molecular diversity by adding a hydroxymethyl, a methylcarboxylate, a carboxy or an allyl group. The allyl derivative was used as a key intermediate to generate a hydroxyethyl side chain in α or β position. Two lactols were also obtained from two hydroxyalkyl lactones. Enzymatic assays revealed that lactone and lactol derivatives weakly inhibited 17β-HSD1 in homogenized HEK-293 cells overexpressing 17β-HSD1 (34-60% at 1 μM) and in intact T-47D cells expressing 17β-HSD1 (10-40% at 10 μM). This article is part of a Special Issue entitled "Synthesis and biological testing of steroid derivatives as inhibitors".
authors.affiliation: Laboratory of Medicinal Chemistry, CHU de Québec (CHUL) - Research Center and Laval University, Québec (Québec), G1V 4G2, Canada.
authors.forename: Siham
authors.initials: S
authors.lastname: Farhane
authors.forename: Michelle-Audrey
authors.initials: MA
authors.lastname: Fournier
authors.forename: Donald
authors.initials: D
authors.lastname: Poirier
mesh_terms: D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D004958:Estradiol / Q000737:chemistry / Q000494:pharmacology*; D004960:Estradiol Dehydrogenases / Q000037:antagonists & inhibitors*; D057809:HEK293 Cells; D006801:Humans; D006860:Hydrogen Bonding; D007783:Lactones / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry
chemical_list: D004791:Enzyme Inhibitors; D007783:Lactones; D004958:Estradiol; D004960:Estradiol Dehydrogenases; C513331:HSD17B1 protein, human
keywords: 17β-Hydroxysteroid dehydrogenase; Enzyme; Inhibitor; Steroid; Synthesis