Androsterone 3alpha-ether-3beta-substituted and androsterone 3beta-substituted derivatives as inhibitors of type 3 17beta-hydroxysteroid dehydrogenase: chemical synthesis and structure-activity relationship.
Type 3 17beta-hydroxysteroid dehydrogenase (17beta-HSD) is involved in the biosynthesis of androgen testosterone. To produce potent inhibitors of this key steroidogenic enzyme, we prepared a series of androsterone (ADT) derivatives by adding a variety of substituents at position 3. The 3beta-substituted ADT derivatives proved to be good inhibitors (IC(50) = 57-147 nM) with better inhibitory activities obtained for compounds bearing a propyl, s-butyl, cyclohexylalkyl, or phenylalkyl group. With an IC(50) value of 57 nM, the 3beta-phenylmethyl-ADT was 6-fold more potent than ADT, the lead compound, and 13-fold more potent than 4-androstene-3,17-dione, the natural enzyme substrate used itself as inhibitor. The 3alpha-ether-3beta-substituted ADT derivatives had a lower inhibitory activity compared to the 3beta-substituted ADT analogues except for the 3beta-phenylethyl-3alpha-methl-O-ADT (IC(50) = 73 nM), which proved to be a more potent inhibitor than 3beta-phenylethyl-ADT (IC(50) = 99 nM). The results of our study identified potent type 3 17beta-HSD inhibitors for potential use in the treatment of androgen-sensitive diseases.
Tchédam Ngatcha
Béatrice
B
Medicinal Chemistry Division, Oncology and Molecular Endocrinology Research Center, CHUQ-Pavillon CHUL and Université Laval, 2705 Boulevard Laurier, Québec G1V 4G2, Canada.
Luu-The
Van
V
Labrie
Fernand
F
Poirier
Donald
D
D015067:17-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D000738:Androsterone / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry; D002460:Cell Line; D004987:Ethers / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D013329:Structure-Activity Relationship
D004987:Ethers; D000738:Androsterone; D015067:17-Hydroxysteroid Dehydrogenases; C476565:17beta-hydroxysteroid dehydrogenase type 3