title: Evaluation of 6,7-aziridinyl steroids and related compounds as inhibitors of aromatase (P-450arom).
abstract: Inhibitors of human placental aromatase (P-450arom) may be useful in treating estrogen-dependent diseases (e.g., breast cancer). Some 6,7-aziridinyl steroids and related compounds (fused steroidal oxiranes, azidohydrins and an azide) were evaluated as inhibitors of this enzyme. Although the 6,7-aziridines and their N-derivatives are poor inhibitors of the enzyme (IC50 values 3.0-15.0 microM), while 6 beta-azido-7 alpha-acetoxyandrost-4-ene-3,17-dione (10) is a potent inhibitor of the enzyme (IC50 value = 0.4 microM, Ki = 14 nM). The difference in inhibitory potency between 10 and the parent compound, 6 beta-azido-7 alpha-hydroxyandrost-4-ene-3,17-dione (9), (IC50 value = 47 microM, Ki = 294 nM) is striking and unexpected. The inhibitory potency of 10 is comparable to that of formestane (4-hydroxyandrost-4-ene-3,17-dione, 4-OHA, 16) (IC50 value = 0.6 microM, Ki = 9 nM), an inhibitor of aromatase which recently has been approved for clinical use in breast cancer treatment. Our most active inhibitors, 10 and 7 alpha-azido-6 beta-hydroxyandrost-4-ene-3,17-dione (11) (at concentrations of 125 microM each) did not inhibit the rat 17 alpha-hydroxylase/C17,20-lyase (17 alpha-lyase) enzyme.
authors.affiliation: Universität des Saarlandes, Saarbrücken, Germany.
authors.forename: V C
authors.initials: VC
authors.lastname: Njar
authors.forename: G
authors.initials: G
authors.lastname: Grün
authors.forename: R W
authors.initials: RW
authors.lastname: Hartmann
mesh_terms: D000735:Androstenedione / Q000031:analogs & derivatives* / Q000494:pharmacology; D047072:Aromatase Inhibitors; D001388:Aziridines / Q000737:chemistry / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007700:Kinetics; D008861:Microsomes / Q000201:enzymology; D015394:Molecular Structure; D010920:Placenta / Q000201:enzymology; D013250:Steroid Hydroxylases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D047072:Aromatase Inhibitors; D001388:Aziridines; D004791:Enzyme Inhibitors; D000735:Androstenedione; D013250:Steroid Hydroxylases