Triaryl-Substituted Schiff Bases Are High-Affinity Subtype-Selective Ligands for the Estrogen Receptor
详细信息 查看全文
- 作者：Zong-Quan Liao ; Chune Dong ; Kathryn E. Carlson ; Sathish Srinivasan ; Jerome C. Nwachukwu ; Robert W. Chesnut ; Abhishek Sharma ; Kendall W. Nettles ; John A. Katzenellenbogen ; Hai-Bing Zhou
- 刊名：Journal of Medicinal Chemistry
- 出版年：2014
- 出版时间：April 24, 2014
- 年：2014
- 卷：57
- 期：8
- 页码：3532-3545
- 全文大小：582K
- 年卷期：v.57,no.8(April 24, 2014)
- ISSN：1520-4804
文摘
We have explored the isoelectronic replacement of the C鈺怌 double bond found at the core of many nonsteroidal estrogen ligands with a simple Schiff base (C鈺怤). Di- and triaryl-substituted imine derivatives were conveniently prepared by the condensation of benzophenones with various anilines without the need for phenolic hydroxy protection. Most of these imines demonstrated high affinity for the estrogen receptors, which, in some cases exceeded that of estradiol. In cell-based assays, these imines profiled as ER伪 agonists but as ER尾 antagonists, showing preferential reliance on the N-terminal activation function (AF1), which is more active in ER伪. X-ray analysis revealed that the triaryl-imines distort the ligand-binding pocket in a new way: by controlling the separation of helices 3 and 11, which appears to alter the C-terminal AF2 surface that binds transcriptional coactivators. This work suggests that C鈺怤 for C鈺怌 substitution might be more widely considered as a general strategy for preparing drug analogues.