title: Discovery of a non-estrogenic irreversible inhibitor of 17β-hydroxysteroid dehydrogenase type 1 from 3-substituted-16β-(m-carbamoylbenzyl)-estradiol derivatives.
abstract: 17β-Hydroxysteroid dehydrogenase type 1 (17β-HSD1) is thought to play a pivotal role in the progression of estrogen-sensitive breast cancer by transforming estrone (E1) into estradiol (E2). We designed three successive series of E2-derivatives at position C3 of the potent inhibitor 16β-(m-carbamoylbenzyl)-E2 to remove its unwanted estrogenic activity. We report the chemical synthesis and characterization of 20 new E2-derivatives, their evaluation as 17β-HSD1 inhibitors, and their proliferative (estrogenic) activity on estrogen-sensitive cells. The structure-activity relationship study provided a new potent and steroidal nonestrogenic inhibitor of 17β-HSD1 named 3-{[(16β,17β)-3-(2-bromoethyl)-17-hydroxyestra-1(10),2,4-trien-16-yl]methyl}benzamide (23b). In fact, this compound inhibited the transformation of E1 into E2 by 17β-HSD1 in T-47D cells (IC50 = 83 nM), did not inhibit 17β-HSD2, 17β-HSD7, 17β-HSD12, and CYP3A4, and did not stimulate the proliferation of estrogen-sensitive MCF-7 cells. We also discussed the results of kinetic and molecular modeling (docking) experiments, suggesting that compound 23b is a competitive and irreversible inhibitor of 17β-HSD1.
authors: Laboratory of Medicinal Chemistry, Oncology and Nephrology Unit, CHU de Québec-Research Center (CHUL, T4-42) and Faculty of Medicine, Laval University , Québec City, Québec G1V 4G2, Canada.
authors: René
authors: R
authors: Maltais
authors: Diana
authors: D
authors: Ayan
authors: Alexandre
authors: A
authors: Trottier
authors: Xavier
authors: X
authors: Barbeau
authors: Patrick
authors: P
authors: Lagüe
authors: Jean-Emmanuel
authors: JE
authors: Bouchard
authors: Donald
authors: D
authors: Poirier
mesh_terms: D015067:17-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors*; D049109:Cell Proliferation / Q000187:drug effects; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D004958:Estradiol / Q000031:analogs & derivatives*; D057809:HEK293 Cells; D006801:Humans; D008958:Models, Molecular; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D004958:Estradiol; D015067:17-Hydroxysteroid Dehydrogenases; C044256:3 (or 17)-beta-hydroxysteroid dehydrogenase