title: Synthesis, structure elucidation, and biochemical evaluation of 7 alpha- and 7 beta-arylaliphatic-substituted androst-4-ene-3,17-diones as inhibitors of aromatase.
abstract: The inhibition of aromatase, the cytochrome P450 enzyme complex responsible for the conversion of androgens to estrogens, may be useful for the endocrine treatment of breast cancer. Previously, several 7 alpha-thio-substituted androstenediones have been shown to be potent inhibitors of aromatase. Recent research has focused on producing a more metabolically stable aromatase inhibitor by replacing the carbon-sulfur bond at the 7 alpha-position with a carbon-carbon bond. The new inhibitors, 7 alpha-arylaliphatic-substituted androst-4-ene-3,17-diones (2-4), have alkyl chains of varying length between the steroid and the aryl ring at the 7 alpha-position. The desired targets were synthesized via a 1,6-conjugate addition of the appropriate cuprate to 17 beta-(tert-butyldimethylsiloxy)androsta-4,6-dien-3-one (7). The synthesis also resulted in the formation of the 7 beta-substituted diastereomers (10-11 and 13) as minor products. Initial assignments of the 7 alpha-phenethyl and 7 beta-phenethyl diastereomers were made using highfield 1-D and 2-D NMR studies. The assignment of the diastereomers was confirmed using X-ray crystallography. These compounds were all good inhibitors of aromatase in vitro when assayed using microsomes isolated from human placenta. The 7 alpha-substituted androst-4-ene-3,17-diones (2-4) were effective inhibitors with apparent Kis of 13-19 nM. The corresponding 17 beta-hydroxy analogs (8 and 14) and the 7 beta-substituted androstenediones (13 and 16) were less effective inhibitors with apparent Kis of 36-44 nM. Thus, a new series of 7 alpha-arylaliphatic-substituted androst-4-ene-3,17-diones has been synthesized, and the compounds are potent competitive inhibitors of aromatase.
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Ohio State University, Columbus 43210, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: O'Reilly
authors.forename: N
authors.initials: N
authors.lastname: Li
authors.forename: W L
authors.initials: WL
authors.lastname: Duax
authors.forename: R W
authors.initials: RW
authors.lastname: Brueggemeier
mesh_terms: D000735:Androstenedione / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology; D047072:Aromatase Inhibitors; D001667:Binding, Competitive; D018360:Crystallography, X-Ray; D006801:Humans; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D010920:Placenta / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D047072:Aromatase Inhibitors; D000735:Androstenedione