title: Improved synthesis of EM-1745, preparation of its C17-ketone analogue and comparison of their inhibitory potency on 17beta-hydroxysteroid dehydrogenase type 1.
abstract: Endocrine therapies are widely used for the treatment of estrogen-sensitive diseases. 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) is involved in the last step of the biosynthesis of potent estrogen estradiol (E(2)). This enzyme catalyzes the reduction of the C17-ketosteroid estrone (E(1)) into the C17beta-hydroxy steroid E(2) using the cofactor NAD(P)H. The X-ray analysis of E(2)/adenosine bisubstrate inhibitor EM-1745 proven that this compound interacts with both the substrate- and the cofactor-binding sites. However, E(1) is a better substrate of 17beta-HSD1 than E(2). Thus, in order to improve the inhibitory potency of EM-1745, the C17-ketone analogue was prepared. During this work, a new and more efficient method for synthesizing EM-1745 was developed using an esterification and a cross-metathesis as key steps. Contrary to what was expected, the C17-ketone analogue of EM-1745 is a less potent inhibitor (IC(50) = 12 nM) than the C17-alcohol (IC(50) = 4 nM) in homogenated HEK-293 cells overexpressing 17beta-HSD1. Our results contribute to the knowledge of an unexpected observation: the C17-ketone steroidal inhibitors of 17beta-HSD1 are less potent than their corresponding C17-alcohol derivatives.
authors.affiliation: Medicinal Chemistry Division, Oncology and Molecular Endocrinology Laboratory, CHUQ-CHUL Research Center, Québec, G1V 4G2, Canada.
authors.forename: Marie
authors.initials: M
authors.lastname: Bérubé
authors.forename: Donald
authors.initials: D
authors.lastname: Poirier
mesh_terms: D015067:17-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004958:Estradiol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007659:Ketones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000196:embryology; D009682:Magnetic Resonance Spectroscopy; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: C503691:EM-1745; D004791:Enzyme Inhibitors; D007659:Ketones; D004958:Estradiol; D015067:17-Hydroxysteroid Dehydrogenases; C044256:3 (or 17)-beta-hydroxysteroid dehydrogenase