Investigations on Estrogen Receptor Binding. The Estrogenic, Antiestrogenic, and Cytotoxic Properties of C2-Alkyl-Substituted 1,1-Bis(4-hydroxyphenyl)-2-phenylethenes

摘要

C2-Alkyl-substituted 1,1-bis(4-hydroxyphenyl)-2-phenylethenes were synthesized and assayed for estrogen receptor binding in a competition expriment 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%) ≈ CH_2CF_3 (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 (IC_(50) = 150 nM), 3b (IC_(50) = 30 nM), and 3f (IC_(50) = 500 nM) were weak antagonists, while 3c (IC_(50) = 15 nM), 3d (IC_(50) = 9 nM), and 3f (IC_(50) = 500 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: IC_(50) = 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.