Murphy C S, Parker C J, McCague R, Jordan V C
Department of Human Oncology, University of Wisconsin Clinical Cancer Center, Madison 53792.
Mol Pharmacol. 1991 Mar;39(3):421-8.
The antiestrogen tamoxifen [(Z)-1(p-beta-dimethylaminoethoxy-phenyl)-1,2-diphenylbut-1-ene] is an effective anticancer agent against estrogen receptor (ER)-positive breast cancer. The alkylaminoethane side chain is essential for antiestrogenic activity, but the potency of the antiestrogen can be increased by para hydroxylation of the phenyl ring on carbon 1 of but-1-ene. This compound, 4-hydroxytamoxifen, is a metabolite of tamoxifen and has a very high binding affinity for ER [J. Endocrinol. 75:305-316 (1977)] because the hydroxyl is located in the equivalent position as the 3-phenolic hydroxyl of 17 beta-estradiol. In this study, we have examined the relationship between the relative positions of the hydroxyl and the alkyl-aminoethane side chain and the pharmacological activity of the ligand. A fixed seven-membered ring derivative of the triphenylethylene was used to prevent isomerization. All compounds were tested, with and without 17 beta-estradiol, for their effects on the growth of estrogen-responsive T47D and MCF-7 human breast cancer cells in vitro. The growth of MDA-MB-231 ER-negative breast cancer cells was not affected by any of the compounds tested, at a concentration (1 microM) that had a profound estrogenic or antiestrogenic action in ER-positive cell lines. The relative binding affinity of the compounds was determined using rat uterine ER and was found to be consistent with the observed potencies in vitro. The compounds found to be antiestrogens in vitro were antiestrogenic against estradiol (0.08 micrograms daily) in the 3-day immature rat uterine weight test. All compounds were partial agonists in vivo. In general, the estrogenic and antiestrogenic results obtained in vivo were consistent with the potency estimates obtained with the breast cancer cells in vitro. The results of this extensive structure-activity relationship study demonstrate that the substitution for 4-hydroxytamoxifen appears to be optimal to produce a potent antiestrogen; all other substitutions produced either estrogenic compounds or less potent antiestrogens. The hydroxyl group appears to be critical to locate the alkyl aminoethoxy side chain in the correct position in the steroid-binding site to block estrogen action. Novel antiestrogens were identified that could have been predicted based upon earlier drug-receptor models for the ER.
抗雌激素他莫昔芬[（Z）-1-（对-β-二甲氨基乙氧基苯基）-1,2-二苯基丁-1-烯]是一种针对雌激素受体（ER）阳性乳腺癌的有效抗癌药物。烷基氨基乙烷侧链对抗雌激素活性至关重要，但通过对丁-1-烯碳1上苯环进行对羟基化可提高抗雌激素的效力。这种化合物4-羟基他莫昔芬是他莫昔芬的一种代谢产物，对ER具有非常高的结合亲和力[《内分泌学杂志》75:305 - 316（1977）]，因为羟基位于与17β-雌二醇的3-酚羟基等效的位置。在本研究中，我们研究了羟基与烷基氨基乙烷侧链的相对位置与配体药理活性之间的关系。使用三苯乙烯的固定七元环衍生物来防止异构化。所有化合物在有和没有17β-雌二醇的情况下，都在体外测试了它们对雌激素反应性T47D和MCF-7人乳腺癌细胞生长的影响。在浓度为1 microM时，MDA-MB-231 ER阴性乳腺癌细胞的生长不受任何测试化合物的影响，而该浓度在ER阳性细胞系中具有显著的雌激素或抗雌激素作用。使用大鼠子宫ER测定化合物的相对结合亲和力，发现其与体外观察到的效力一致。在体外被发现是抗雌激素的化合物在3天的未成熟大鼠子宫重量试验中对雌二醇（每日0.08微克）具有抗雌激素作用。所有化合物在体内都是部分激动剂。一般来说，体内获得的雌激素和抗雌激素结果与体外乳腺癌细胞获得的效力估计一致。这项广泛的构效关系研究结果表明，对4-羟基他莫昔芬进行取代似乎是产生强效抗雌激素的最佳选择；所有其他取代产生的要么是雌激素化合物要么是效力较低的抗雌激素。羟基对于将烷基氨基乙氧基侧链定位在类固醇结合位点的正确位置以阻断雌激素作用似乎至关重要。鉴定出了新型抗雌激素，这些抗雌激素可以根据早期的ER药物受体模型进行预测。
