title: Desmethylnafoxidine aziridine: an electrophilic affinity label for the estrogen receptor with high efficiency and selectivity.
abstract: Desmethylnafoxidine aziridine (Naf-Az), an affinity label for the estrogen receptor based structurally on the antiestrogen nafoxidine, has been prepared in unlabeled and in high specific activity, tritium-labeled form and has been evaluated for its apparent competitive binding, and time-dependent irreversible, covalent attachment to the estrogen receptor. Naf-Az was synthesized through a key 1,2-diaryl-3,4-dihydronaphthalene intermediate that was prepared from 6-methoxy-1-tetralone by two routes involving alternate strategies for arylation. Conversion of the diaryldihydronaphthalene to Naf-Az through a series of deprotection-activation reactions culminated in ethyleneimine displacement of a methanesulfonate. The tritium-labeled material was prepared by tritium-iodine exchange on an iodinated methanesulfonate precursor, followed by ethyleneimine displacement. Compared to our previously-prepared reagent tamoxifen aziridine (Tam-Az), Naf-Az has a higher apparent competitive binding affinity, and it reacts with the estrogen receptor in cytosol preparations and in intact MCF-7 breast cancer cells rapidly and with at least comparable efficiency and selectivity. SDS-polyacrylamide gel electrophoretic analysis confirms its selective labeling of the Mr 66,000 estrogen receptor. Naf-Az should prove to be useful in studies aimed at characterizing the properties and structure of estrogen receptors.
authors: Department of Chemistry, University of Illinois, Urbana 61801.
authors: D M
authors: DM
authors: Simpson
authors: J F
authors: JF
authors: Elliston
authors: J A
authors: JA
authors: Katzenellenbogen
mesh_terms: D000345:Affinity Labels / Q000138:chemical synthesis*; D000818:Animals; D001388:Aziridines / Q000138:chemical synthesis* / Q000494:pharmacology; D001389:Azirines / Q000138:chemical synthesis*; D001667:Binding, Competitive; D002460:Cell Line; D003600:Cytosol / Q000378:metabolism; D005260:Female; D007202:Indicators and Reagents; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D009256:Nafoxidine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology; D011759:Pyrrolidines / Q000138:chemical synthesis*; D051381:Rats; D011960:Receptors, Estrogen / Q000187:drug effects / Q000378:metabolism*; D014599:Uterus / Q000378:metabolism
chemical_list: D000345:Affinity Labels; D001388:Aziridines; D001389:Azirines; D007202:Indicators and Reagents; D011759:Pyrrolidines; D011960:Receptors, Estrogen; C053702:desmethylnafoxidine aziridine; D009256:Nafoxidine