title: Design, synthesis and in vitro evaluation of 4-androstene-3,17-dione/adenosine hybrid compounds as bisubstrate inhibitors of type 3 17beta-hydroxysteroid dehydrogenase.
abstract: Steroidogenic enzyme type 3 17beta-hydroxysteroid dehydrogenase (17beta-HSD) is an important therapeutic target for androgen-sensitive diseases. This enzyme selectively reduces the C17 ketone of 4-androstene-3,17-dione (Delta4-dione), thus producing testosterone (T) using NADPH as cofactor. Our group previously synthesized hybrid (estradiol/adenosine) inhibitors that successfully inhibit the biosynthesis of the potent estrogen estradiol by type 1 17beta-HSD. To similarly lower the level of the potent androgen testosterone, inhibitors of type 3 17beta-HSD were designed and synthesized applying the same hybrid (substrate/cofactor) strategy. Two chemical approaches were developed to join the three components of the bisubstrate inhibitor (the substrate Delta4-dione, an alkyl spacer and the cofactor moiety adenosine). An alkylation in the alpha position of steroidal 17-ketone or a cross-metathesis was used as a key step to efficiently join the substrate and the alkyl spacer, whereas an esterification was employed to link the spacer to adenosine. An enzymatic assay in homogenated HEK-293 cells overexpressing type 3 17beta-HSD revealed that the best inhibitors of that series are those bearing an alkyl side-chain spacer of 11 or 12 methylenes: inhibition of 69 and 78% at 1 microM were respectively observed. As expected, these bisubstrate inhibitors were less potent in intact cells than in homogenated cells. However, both enzymatic assays revealed that the strategy of substrate/cofactor dual inhibitors seems to work for type 3 17beta-HSD, although the inhibitors designed have not been optimized yet.
authors.affiliation: Medicinal Chemistry Division, Oncology and Molecular Endocrinology Research Center, CHUQ-Pavillon CHUL, 2705, Laurier Boulevard, Québec, G1V 4G2, Canada.
authors.forename: Marie
authors.initials: M
authors.lastname: Bérubé
authors.forename: Yannick
authors.initials: Y
authors.lastname: Laplante
authors.forename: Donald
authors.initials: D
authors.lastname: Poirier
mesh_terms: D015067:17-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors*; D000241:Adenosine / Q000737:chemistry*; D000735:Androstenedione / Q000737:chemistry*; D002460:Cell Line; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D004791:Enzyme Inhibitors; D000735:Androstenedione; D015067:17-Hydroxysteroid Dehydrogenases; C476565:17beta-hydroxysteroid dehydrogenase type 3; D000241:Adenosine