Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Tokyo 113-0032, Japan.
Bioorg Med Chem Lett. 2013 Jul 15;23(14):4031-6. doi: 10.1016/j.bmcl.2013.05.067. Epub 2013 May 30.
Our multi-template approach for drug discovery, focusing on protein targets with similar fold structures, has yielded lead compounds for various targets. We have also shown that a diphenylmethane skeleton can serve as a surrogate for a steroid skeleton. Here, on the basis of those ideas, we hypothesized that the diphenylmethane derivative bisphenol A (BPA) would bind to the ligand-binding domain of estrogen receptors (ERs) in a similar manner to estradiol and act as a steroid surrogate. To test this idea, we synthesized a series of BPA analogs and evaluated their structure-activity relationships, focusing on agonistic/antagonistic activities at ERs and ERα/ERβ subtype selectivity. Among the compounds examined, 18 was found to be a potent ERα-antagonist with high selectivity over ERβ and androgen receptor under our assay conditions. A computational docking study suggested that 18 would bind to the antagonistic conformation of ERα. ERα-selective antagonists, such as 18, are candidate agents for treatment of breast cancer.
我们的多模板药物发现方法专注于具有相似折叠结构的蛋白质靶标，已经为各种靶标生成了先导化合物。我们还表明，二苯甲烷骨架可以作为甾体骨架的替代品。在这里，基于这些想法，我们假设二苯甲烷衍生物双酚 A（BPA）将以类似于雌二醇的方式与雌激素受体（ER）的配体结合域结合，并作为甾体替代品。为了验证这一想法，我们合成了一系列 BPA 类似物，并评估了它们的结构-活性关系，重点关注 ER 激动剂/拮抗剂活性和 ERα/ERβ亚型选择性。在所检查的化合物中，发现化合物 18 在我们的测定条件下是一种有效的 ERα 拮抗剂，对 ERβ 和雄激素受体具有高选择性。计算 docking 研究表明，18 将与 ERα 的拮抗构象结合。ERα 选择性拮抗剂，如 18，是治疗乳腺癌的候选药物。
