尾-Lactam Estrogen Receptor Antagonists and a Dual-Targeting Estrogen Receptor/Tubulin Ligand

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• 作者：Niamh M. O鈥橞oyle ; Jade K. Pollock ; Miriam Carr ; Andrew J. S. Knox ; Seema M. Nathwani ; Shu Wang ; Laura Caboni ; Daniela M. Zisterer ; Mary J. Meegan
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：November 26, 2014
• 年：2014
• 卷：57
• 期：22
• 页码：9370-9382
• 全文大小：558K
• ISSN：1520-4804

文摘

Twelve novel 尾-lactams were synthesized and their antiproliferative effects and binding affinity for the predominant isoforms of the estrogen receptor (ER), ER伪 and ER尾, were determined. 尾-Lactams 23 and 26 had the strongest binding affinities for ER伪 (IC₅₀ values: 40 and 8 nM, respectively) and ER尾 (IC₅₀ values: 19 and 15 nM). 尾-Lactam 26 was the most potent in antiproliferative assays using MCF-7 breast cancer cells, and further biochemical analysis showed that it caused accumulation of cells in G₂/M phase (mitotic blockade) and depolymerization of tubulin in MCF-7 cells. Compound 26 also induced apoptosis and downregulation of the expression of pro-survival proteins Bcl-2 and Mcl-1. Computational modeling predicted binding preferences for the dual ER/tubulin ligand 26. This series is an important addition to the known pool of ER antagonists and 尾-lactam 26 is the first reported compound that has dual-targeting properties for both the ER and tubulin.