title: Synthesis and evaluation of 4-substituted-4-androstene-3,17-dione derivatives as aromatase inhibitors.
abstract: The synthesis and biological evaluation of 4-amino-, 4-alkoxy-, 4-aryloxy-, 4-alkyl- and 4-aryl-4-androstenedione derivatives as inhibitors of estrogen synthetase (aromatase) are described. Inhibitory activity of synthesized compounds was assessed using a human placental microsomal preparation as the enzyme source and [1 beta-3H] androstenedione as substrate. Synthesized compounds exhibiting aromatase inhibitory activity were evaluated further under initial velocity conditions to determine apparent Ki values. Several compounds were effective competitive inhibitors and have apparent Ki values ranging from 38 to 1290 nM, with the apparent Km for androstenedione being 47 nM. Alkylation or arylation of 4-N, S, or O-substituted steroids results in compounds that are effective competitive inhibitors that are devoid of time-dependent inactivation and that the free pair of electrons on N, S, or O is not an essential requirement for 4-substituted androstenedione derivatives to be effective aromatase inhibitors. The results obtained from this investigation are consistent with our previous studies which show that aromatase has a hydrophobic pocket in the active site around the C-4 alpha region of androstenedione.
authors.affiliation: Department of Medicinal Chemistry, University of Minnesota, Minneapolis 55455, USA.
authors.forename: Y J
authors.initials: YJ
authors.lastname: Abul-Hajj
authors.forename: X P
authors.initials: XP
authors.lastname: Liu
authors.forename: M
authors.initials: M
authors.lastname: Hedge
mesh_terms: D000735:Androstenedione / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D047072:Aromatase Inhibitors; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D047072:Aromatase Inhibitors; D004791:Enzyme Inhibitors; D000735:Androstenedione