Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10591459 | Bioorganic & Medicinal Chemistry Letters | 2013 | 6 Pages |
Abstract
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.
Related Topics
Physical Sciences and Engineering
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Organic Chemistry
Authors
Keisuke Maruyama, Masaharu Nakamura, Shusuke Tomoshige, Kazuyuki Sugita, Makoto Makishima, Yuichi Hashimoto, Minoru Ishikawa,