title: Investigations on estrogen receptor binding. The estrogenic, antiestrogenic, and cytotoxic properties of C2-alkyl-substituted 1,1-bis(4-hydroxyphenyl)-2-phenylethenes.
abstract: C2-Alkyl-substituted 1,1-bis(4-hydroxyphenyl)-2-phenylethenes were synthesized and assayed for estrogen receptor binding in a competition experiment with radiolabeled estradiol ([3H]-E2) using calf uterine cytosol. The relative binding affinity decreased with the length of the side chain R = H (3a: 35.2%) > Me (3b: 32.1%) > Et (3c: 6.20%) approximately CH2CF3 (3d: 5.95%) > n-Pr (3e: 2.09%) > Bu (3f: 0.62%). Agonistic and antagonistic effects were evaluated in the luciferase assay with MCF-7-2a cells stably transfected with the plasmid ERE(wtc)luc. All compounds showed high antiestrogenic activity without significant agonistic potency. The comparison of the IC(50) values for the inhibition of E2 (1 nM) documented the dependence of the antagonistic effects on the kind of the side chain: 3a (IC50 = 150 nM), 3b (IC50 = 30 nM), and 3f (IC50 = 500 nM) were weak antagonists, while 3c (IC50 = 15 nM), 3d (IC50 = 9 nM), and 3e (IC50 = 50 nM) were full antiestrogens and antagonized the effect of E2 completely. The most active compound 3d possessed the same antagonistic potency as 4-hydroxytamoxifen (4OHT: IC50= 7 nM) without bearing a basic side chain. 3d as well as all other 1,1-bis(4-hydroxyphenyl)-2-phenylalkenes were not able to influence the proliferation of hormone dependent MCF-7 cells despite the antagonistic mode of action. In this assay tamoxifen (TAM) and 4OHT reduced the cell growth concentration dependent up to T/C(corr) = 15% and 25%, respectively.
authors.affiliation: Institute of Pharmacy, Free University of Berlin, Königin-Luise Strasse 2+4, D-14195 Berlin, Germany.
authors.forename: Veronika
authors.initials: V
authors.lastname: Lubczyk
authors.forename: Helmut
authors.initials: H
authors.lastname: Bachmann
authors.forename: Ronald
authors.initials: R
authors.lastname: Gust
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001667:Binding, Competitive; D002417:Cattle; D002455:Cell Division / Q000187:drug effects; D003600:Cytosol / Q000378:metabolism; D045166:Estradiol Congeners / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020847:Estrogen Receptor Modulators / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D011869:Radioligand Assay; D011960:Receptors, Estrogen / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013267:Stilbenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014599:Uterus / Q000648:ultrastructure
chemical_list: C469566:1,1-bis(4-hydroxyphenyl)-2-phenyl-4,4,4-trifluorobut-1-ene; D000970:Antineoplastic Agents; D045166:Estradiol Congeners; D020847:Estrogen Receptor Modulators; D011960:Receptors, Estrogen; D013267:Stilbenes; D008156:Luciferases