期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 23, 期 14, 页码 4031-4036出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2013.05.067
关键词
Nuclear receptor; Estrogen receptor; Antagonist
资金
- Ministry of Education, Culture, Sports, Science and Technology, Japan
- Japan Society for the Promotion of Science
- Grants-in-Aid for Scientific Research [25670053, 22249006] Funding Source: KAKEN
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 ER alpha/ER beta subtype selectivity. Among the compounds examined, 18 was found to be a potent ER alpha-antagonist with high selectivity over ER beta and androgen receptor under our assay conditions. A computational docking study suggested that 18 would bind to the antagonistic conformation of ER alpha. ER alpha-selective antagonists, such as 18, are candidate agents for treatment of breast cancer. (C) 2013 Elsevier Ltd. All rights reserved.
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