title: Estrogenic affinity labels: synthesis, irreversible receptor binding, and bioactivity of aziridine-substituted hexestrol derivatives.
abstract: To develop an affinity label for the estrogen receptor that would be an estrogen agonist, rather than antagonist, we prepared several aziridine derivatives of the potent nonsteroidal estrogen hexestrol [3R,4S)-3,4-bis(4-hydroxyphenyl)hexane) bearing an aziridine function on the side chain. Three functional groups link the hexestrol ligand and the aziridine: a carbonyl group (ketone or ester), a thioether, or a methylene chain. The apparent competitive binding affinity of these derivatives for the estrogen receptor ranges from 1.8% to 25% that of estradiol, and most of them bind in a time-dependent, irreversible manner with the receptor, although the rate and efficiency of this binding vary widely, often with relatively small changes in structure. This is consistent with the irreversible attachment requiring a precise alignment of activating and reacting residues in the binding site of the receptor. The estrogenic and antiestrogenic activity of these aziridine derivatives was investigated in MCF-7 human breast cancer cells. Most of the compounds are agonists, with one being an antagonist. The derivative (6R,7S)-1-N-aziridinyl-6,7-bis(4-hydroxyphenyl)-5-nonanone (keto-nonestrol aziridine 3) appears to have the most ideal behavior of the estrogenic affinity labeling agents prepared: It is an agonist, and it binds to receptor irreversibly, efficiently, and quite rapidly.
mesh_terms: D000345:Affinity Labels / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001388:Aziridines / Q000494:pharmacology; D001389:Azirines / Q000494:pharmacology; D001667:Binding, Competitive; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D055598:Chemical Phenomena; D002621:Chemistry; D004965:Estrogen Antagonists / Q000494:pharmacology; D005260:Female; D006589:Hexestrol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism; D006801:Humans; D011960:Receptors, Estrogen / Q000378:metabolism*; D012756:Sheep; D013329:Structure-Activity Relationship; D014599:Uterus / Q000378:metabolism
chemical_list: D000345:Affinity Labels; D001388:Aziridines; D001389:Azirines; D004965:Estrogen Antagonists; D011960:Receptors, Estrogen; D006589:Hexestrol