title: 3Beta-alkyl-androsterones as inhibitors of type 3 17beta-hydroxysteroid dehydrogenase: inhibitory potency in intact cells, selectivity towards isoforms 1, 2, 5 and 7, binding affinity for steroid receptors, and proliferative/antiproliferative activities on AR+ and ER+ cell lines.
abstract: Type 3 17beta-hydroxysteroid dehydrogenase (17beta-HSD) is involved in the biosynthesis of the potent androgen testosterone (T), which plays an important role in androgen-sensitive diseases. In an attempt to design compounds to lower the level of T, we designed androsterone (ADT) derivatives substituted at the position 3beta as inhibitors of type 3 17beta-HSD, and then selected the eight most potent ones (compounds 1-8) for additional studies. In an intact cell assay, they inhibited efficiently the conversion of natural substrate 4-androstene-3,17-dione into T, although they were less active in intact cells (IC50 approximately 1 microM) than in homogenated cells (IC50=57-100 nM). A study of the inhibitory potency with four other 17beta-HSDs revealed they were selective, since they do not inhibit reductive types 1, 5 and 7, nor oxidative type 2. Interestingly, they did not show any binding affinity for steroid receptors (androgen, estrogen, glucocorticoid and progestin). Only two inhibitors, 3beta-phenyl-ADT (5) and 3beta-phenylmethyl-ADT (6) showed some proliferative activities on an AR+ cell line and on an ER+ cell line, but their effects were not mediated through the androgen or estrogen receptors. This study identified selective inhibitors of type 3 17beta-HSD acting through a mixed-type inhibition, and devoid of non-suitable androgenic and estrogenic proliferative activities. The more potent inhibitors were 3beta-hexyl-ADT (2), 3beta-cyclohexylethyl-ADT (4) and 3beta-phenylethyl-ADT (7).
authors.affiliation: Oncology and Molecular Endocrinology Research Center, CHUL Research Center and Université Laval, CHUQ-Pavillon CHUL, 2705 Boulevard Laurier, Qué, Canada G1V 4G2.
authors.forename: Béatrice Tchédam
authors.initials: BT
authors.lastname: Ngatcha
authors.forename: Yannick
authors.initials: Y
authors.lastname: Laplante
authors.forename: Fernand
authors.initials: F
authors.lastname: Labrie
authors.forename: Van
authors.initials: V
authors.lastname: Luu-The
authors.forename: Donald
authors.initials: D
authors.lastname: Poirier
mesh_terms: D015067:17-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors*; D000738:Androsterone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D011987:Receptors, Steroid / Q000187:drug effects
chemical_list: C510580:3-cyclohexylethylandrosterone; C510579:3-hexylandrosterone; C510581:3-phenylethylandrosterone; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D011987:Receptors, Steroid; D000738:Androsterone; D015067:17-Hydroxysteroid Dehydrogenases; C476565:17beta-hydroxysteroid dehydrogenase type 3