title: Synthesis and biological evaluation of 3-(prop-2-enyl)- and 3-(prop-2-ynyl)pyrrolidine-2,5-dione derivatives as potential aromatase inhibitors.
abstract: 3-(4'-Aminophenyl)pyrrolidine-2,5-dione (WSP3), a known reversible inhibitor of P450 aromatase, was modified using molecular graphics and our model of reversible inhibitor and substrate binding to resemble 10 beta-prop-2-ynylestr-4-ene-3,17-dione (PED), a mechanism-based inactivator of the enzyme. The analogues prepared were 3-substituted 3-(prop-2-enyl) or 3-(prop-2-ynyl) pyrrolidine-2,5-diones and their N-alkyl derivatives. The reported compounds demonstrated no irreversible (time-dependent) inhibition of the human placental P450 aromatase enzyme. However, some reversible activity was seen in several of the 3-(prop-2-ynyl) compounds.
authors.affiliation: Welsh School of Pharmacy, University of Wales, Cardiff, UK.
authors.forename: K J
authors.initials: KJ
authors.lastname: Barrell
authors.forename: W L
authors.initials: WL
authors.lastname: Woo
authors.forename: M
authors.initials: M
authors.lastname: Ahmadi
authors.forename: H J
authors.initials: HJ
authors.lastname: Smith
authors.forename: P J
authors.initials: PJ
authors.lastname: Nicholls
mesh_terms: D000616:Aminoglutethimide / Q000031:analogs & derivatives / Q000138:chemical synthesis*; D000814:Aniline Compounds / Q000737:chemistry*; D047072:Aromatase Inhibitors; D015195:Drug Design; D008958:Models, Molecular; D011759:Pyrrolidines / Q000138:chemical synthesis*; D013388:Succinimides / Q000737:chemistry*
chemical_list: D000814:Aniline Compounds; D047072:Aromatase Inhibitors; D011759:Pyrrolidines; D013388:Succinimides; D000616:Aminoglutethimide; C082712:3-(4'-aminophenyl)pyrrolidine-2,5-dione