Novel 5-carboxy-8-HQ based histone demethylase JMJD2A inhibitors: Introduction of an additional carboxyl group at the C-2 position of quinoline
Novel 5-carboxy-8-HQ based histone demethylase JMJD2A inhibitors: Introduction of an additional carboxyl group at the C-2 position of quinoline
复制标题
基于 5-羧基-8-HQ 的新型组蛋白去甲基酶 JMJD2A 抑制剂：在喹啉的 C-2 位引入额外的羧基
DOI：
10.1016/j.ejmech.2015.09.013
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发表时间：
2015-11-13
影响因子：
6.7
通讯作者：
Guo, Xiaoke
中科院分区：
文献类型：
--
作者：
Feng, Taotao;Li, Dongdong;Guo, Xiaoke
通过分析5-羧基-8-羟基喹啉（5-carboxy-8-hydroxyquinoline，5-carboxy-8-HQ）与JMJD 2A的结合方式，设计了一系列JMJD 2A抑制剂。测定合成的化合物对JMJD 2A的抑制活性，然后进行对接模拟以了解结构活性关系。具有强效JMJD 2A抑制活性的化合物显示出对JMJD 2A超过PHD 2的突出选择性。选择了几种有效的化合物来评价它们对肿瘤细胞系的抗增殖活性。其中化合物6p的抗增殖活性最强。基于这些体外生物学数据，选择了七个化合物来确定它们的物理化学性质。化合物6p显示出良好的水溶性和比5-羧基-8-HQ更好的渗透性。我们的数据认识到，化合物6p可以被认为是开发新的Jmjc抑制剂的起点。(C)2015年Elsevier Masson SAS。All rights reserved.
A series of JMJD2A inhibitors had been designed by analyzing the binding mode of 5-carboxy-8-hydroxyquinoline (5-carboxy-8-HQ) with JMJD2A. The inhibitory activity of the synthesized compounds against JMJD2A was determined, followed by docking simulations to understand the structure activity relationships. Compounds with potent JMJD2A inhibitory activity demonstrated outstanding selectivity for JMJD2A over PHD2. Several potent compounds were selected to evaluate their anti-proliferative activity on tumor cell lines. Among them, compound 6p displayed the best anti-proliferative activity. Based on these in vitro biological data, seven compounds were chosen to determine their physicochemical properties. Compound 6p displayed good aqueous solubility and better permeability than 5-carboxy-8-HQ Our data recognized that compound 6p could be considered as a starting point for development of new Jmjc inhibitors. (C) 2015 Elsevier Masson SAS. All rights reserved.