title: Novel 19-(cyclopropylamino)-androst-4-en-3,17-dione: a mechanism-based inhibitor of aromatase.
abstract: The novel 19-(cyclopropylamino)-androst-4-en-3,17-dione (5, CPA), a mechanism-based inhibitor of aromatase has been synthesized from the 10 beta-aldehyde intermediate (2). The key reaction was the trifluoroacetic acid-catalysed condensation of 2 with cyclopropylamine in refluxing toluene to give the 19-cyclopropylimine (3). Enzyme inhibition studies show that CPA is a time-dependent, irreversible inhibitor of human placental microsomal aromatase (Ki = 92 +/- = 2 nM). The inactivation of aromatase by CPA was NADPH-dependent and was protected by the presence of substrate testosterone (20 microns). In addition, the inactivation was not affected by the nucleophile, L-cysteine (0.5 mM), suggesting retention of the inhibitor in the enzyme's active site during the inactivation process.
authors.affiliation: Fachrichtung 12.1 Pharmazeutische Chemie, Universität des Saarlandes, Saarbrücken, Germany.
authors.forename: V C
authors.initials: VC
authors.lastname: Njar
authors.forename: J
authors.initials: J
authors.lastname: Düerkop
authors.forename: R W
authors.initials: RW
authors.lastname: Hartmann
mesh_terms: D000616:Aminoglutethimide / Q000494:pharmacology; D000735:Androstenedione / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D047072:Aromatase Inhibitors; D003521:Cyclopropanes / Q000138:chemical synthesis; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D004795:Enzyme Stability; D004958:Estradiol / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008861:Microsomes / Q000201:enzymology; D015394:Molecular Structure; D009249:NADP / Q000494:pharmacology; D010920:Placenta / Q000201:enzymology; D013256:Steroids / Q000494:pharmacology; D013739:Testosterone / Q000378:metabolism
chemical_list: C104128:19-(cyclopropylamino)androst-4-en-3,17-dione; D047072:Aromatase Inhibitors; D003521:Cyclopropanes; D004791:Enzyme Inhibitors; D013256:Steroids; D000616:Aminoglutethimide; D013739:Testosterone; D000735:Androstenedione; D004958:Estradiol; D009249:NADP