Meyers M J, Sun J, Carlson K E, Katzenellenbogen B S, Katzenellenbogen J A
Departments of Chemistry, Molecular and Integrative Physiology, and Cell and Structural Biology, University of Illinois, Urbana, Illinois 61801, USA.
J Med Chem. 1999 Jul 1;42(13):2456-68. doi: 10.1021/jm990101b.
We have recently reported that racemic 5,11-cis-diethyl-5,6,11, 12-tetrahydrochrysene-2,8-diol (THC, rac-2b) acts as an agonist on estrogen receptor alpha (ERalpha) and as a complete antagonist on estrogen receptor beta (ERbeta) (Sun et al. Endocrinology 1999, 140, 800-804). To further investigate this novel ER subtype-selective estrogenic activity, we have synthesized a series of cis- and trans-dialkyl THCs. cis-Dimethyl, -diethyl, and -dipropyl THCs 2a-c were prepared in a highly enantio- and diastereoselective manner by the acyloin condensation of enantiomerically pure alpha-alkyl-beta-arylpropionic esters, followed by a Lewis acid-mediated double cyclization under conditions of minimal epimerization. ERalpha and ERbeta binding affinity of both cis and trans isomers of dimethyl, diethyl, and dipropyl THCs was determined in competitive binding assays, and their transcriptional activity was determined in reporter gene assays in mammalian cells. Nearly all THCs examined were found to be affinity-selective for ERbeta. All these THCs are agonists on ERalpha, and THCs with small substituents are agonists on both ERalpha and ERbeta. As substituent size was increased, ERbeta-selective antagonism developed first in the (R,R)-cis enantiomer series and finally in the trans diastereomer and (S,S)-cis enantiomer series. The most potent and selective ligand was identified as (R,R)-cis-diethyl THC 2b, which mimicked the ERbeta-selective antagonist character of racemic cis-diethyl THC 2b. This study illustrates that the antagonist character in THC ligands for ERbeta depends in a progressive way on the size and geometric disposition of substituent groups and suggests that the induction of an antagonist conformation in ERbeta can be achieved with these ligands with less steric perturbation than in ERalpha. Furthermore, antagonists that are selectively effective on ERbeta can have structures that are very different from the typical antiestrogens tamoxifen and raloxifene, which are antagonists on both ERalpha and ERbeta.
我们最近报道，外消旋5,11-顺式-二乙基-5,6,11,12-四氢并四苯-2,8-二醇（THC，rac-2b）作为雌激素受体α（ERα）的激动剂以及雌激素受体β（ERβ）的完全拮抗剂（Sun等人，《内分泌学》1999年，第140卷，800 - 804页）。为了进一步研究这种新型的ER亚型选择性雌激素活性，我们合成了一系列顺式和反式二烷基THC。顺式二甲基、二乙基和二丙基THC 2a - c通过对映体纯的α - 烷基 - β - 芳基丙酸酯的偶姻缩合反应以高度对映选择性和非对映选择性的方式制备，随后在最小差向异构化条件下进行路易斯酸介导的双环化反应。通过竞争性结合试验测定了二甲基、二乙基和二丙基THC的顺式和反式异构体与ERα和ERβ的结合亲和力，并在哺乳动物细胞的报告基因试验中测定了它们的转录活性。几乎所有检测的THC对ERβ都具有亲和力选择性。所有这些THC都是ERα的激动剂，具有小取代基的THC对ERα和ERβ都是激动剂。随着取代基尺寸的增加，ERβ选择性拮抗作用首先在（R,R）-顺式对映体系列中出现，最终在反式非对映体和（S,S）-顺式对映体系列中出现。最有效和选择性最高的配体被鉴定为（R,R）-顺式二乙基THC 2b，它模拟了外消旋顺式二乙基THC 2b的ERβ选择性拮抗剂特性。这项研究表明，THC配体对ERβ的拮抗特性以渐进的方式取决于取代基的大小和几何构型，并表明与ERα相比，用这些配体在ERβ中诱导拮抗剂构象时空间扰动较小。此外，对ERβ有选择性作用的拮抗剂可以具有与典型抗雌激素他莫昔芬和雷洛昔芬非常不同的结构，他莫昔芬和雷洛昔芬对ERα和ERβ都是拮抗剂。
