title: 7-substituted 1,4,6-androstatriene-3,17-diones as enzyme-activated irreversible inhibitors of aromatase.
abstract: 7-Phenyl-1,4,6-androstatriene-3,17-dione (4), 7-benzyl-1,4,6-androstatriene-3,17-dione (5) and 7-phenethyl-1,4,6-androstatriene-3,17-dione (6) were synthesized and evaluated in vitro in human placental microsomes as enzyme-activated irreversible inhibitors of aromatase. The compounds were synthesized from appropriate 7-substituted 4,6-androstadiene-3,17-diones by reaction with DDQ under neutral conditions. All the compounds produced a first order inactivation of aromatase in the presence of NADPH but not in the absence of NADPH. Substrate 4-androstene-3,17-dione protected the enzyme from inactivation by the inhibitors. Furthermore, cysteine failed to protect aromatase from inactivation by compounds 5 and 6. In contrast, cysteine partially protected aromatase from inactivation by compound 4. Irreversibility studies illustrated the covalent nature of the inactivation by 4, 5 and 6. The above experimental evidence demonstrated that compounds 5 and 6 are effective enzyme-activated irreversible inhibitors of aromatase.
authors.affiliation: College of Pharmacy, Ohio State University, Columbus 43210.
authors.forename: P K
authors.initials: PK
authors.lastname: Li
authors.forename: R W
authors.initials: RW
authors.lastname: Brueggemeier
mesh_terms: D000733:Androstatrienes / Q000037:antagonists & inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D000735:Androstenedione / Q000494:pharmacology; D001141:Aromatase / Q000032:analysis; D047072:Aromatase Inhibitors; D001667:Binding, Competitive; D003545:Cysteine / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D066298:In Vitro Techniques; D007700:Kinetics; D008861:Microsomes / Q000201:enzymology; D009249:NADP / Q000494:pharmacology; D010920:Placenta / Q000201:enzymology
chemical_list: D000733:Androstatrienes; D047072:Aromatase Inhibitors; C065933:7-phenyl-1,4,6-androstatriene-3,17-dione; C065934:7-benzyl-1,4,6-androstatriene-3,17-dione; C065935:7-phenethyl-1,4,6-androstatriene-3,17-dione; D000735:Androstenedione; D009249:NADP; D001141:Aromatase; D003545:Cysteine