Parallel solid-phase synthesis of 3beta-peptido-3alpha-hydroxy-5alpha-androstan-17-one derivatives for inhibition of type 3 17beta-hydroxysteroid dehydrogenase.
Type 3 17beta-hydroxysteroid dehydrogenase (17beta-HSD), a key steroidogenic enzyme, transforms 4-androstene-3,17-dione (Delta(4)-dione) into testosterone. In order to produce potential inhibitors, we performed solid-phase synthesis of model libraries of 3beta-peptido-3alpha-hydroxy-5alpha-androstan-17-ones with 1, 2, or 3 levels of molecular diversity, obtaining good overall yields (23-58%) and a high average purity (86%, without any purification steps) using the Leznoff's acetal linker. The libraries were rapidly synthesized in a parallel format and the generated compounds were tested as inhibitors of type 3 17beta-HSD. Potent inhibitors were identified from these model libraries, especially six members of the level 3 library having at least one phenyl group. One of them, the 3beta-(N-heptanoyl-L-phenylalanine-L-leucine-aminomethyl)-3alpha-hydroxy-5alpha-androstan-17-one (42) inhibited the enzyme with an IC(50) value of 227nM, which is twice as potent as the natural substrate Delta(4)-dione when used itself as an inhibitor. Using the proliferation of androgen-sensitive (AR(+)) Shionogi cells as model of androgenicity, the compound 42 induced only a slight proliferation at 1 microM (less than previously reported type 3 17beta-HSD inhibitors) and, interestingly, no proliferation at 0.1 microM.
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Medicinal Chemistry Division, Oncology and Molecular Endocrinology Research Center, Centre Hospitalier Universitaire de Québec (CHUQ) and Université Laval, 2705 Laurier Blvd, Sainte-Foy, Québec, Canada G1V 4G2.
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D015067:17-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors*; D000731:Androstanes; D000818:Animals; D001671:Biochemistry / Q000379:methods*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D020650:Combinatorial Chemistry Techniques; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D051379:Mice; D011944:Receptors, Androgen / Q000378:metabolism; D013329:Structure-Activity Relationship
C448860:3-(N-heptanoyl-phenylalanine-leucine-aminomethyl)-3-hydroxy-5-androstan-17-one; D000731:Androstanes; D004791:Enzyme Inhibitors; D011944:Receptors, Androgen; D015067:17-Hydroxysteroid Dehydrogenases; C044256:3 (or 17)-beta-hydroxysteroid dehydrogenase