Structure based drug design and in vitro metabolism study: Discovery of N-(4-methylthiophenyl)-N,2-dimethyl-cyclopenta[d]pyrimidine as a potent microtubule targeting agent.
Structure based drug design and in vitro metabolism study: Discovery of N-(4-methylthiophenyl)-N,2-dimethyl-cyclopenta[d]pyrimidine as a potent microtubule targeting agent.
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基于结构的药物设计和体外代谢研究：发现 N-(4-甲硫基苯基)-N,2-二甲基-环戊[d]嘧啶作为有效的微管靶向剂。
DOI：
10.1016/j.bmc.2018.04.010
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发表时间：
2018
影响因子：
3.5
通讯作者：
Gangjee,Aleem
中科院分区：
文献类型：
--
作者：
Xiang,Weiguo;Choudhary,Shruti;Hamel,Ernest;Mooberry,SusanL;Gangjee,Aleem
我们报告了一系列的微管蛋白靶向剂，其中一些表现出强大的抗增殖活性。通过改变4′-位的杂原子取代基、4-位氨基部分的碱性和构象限制，设计这些类似物以优化1的抗增殖活性。并合成了活性化合物的潜在代谢产物。一些化合物在MDA-MB-435黑色素瘤细胞中显示出单位数纳摩尔IC 50值的抗增殖作用。特别是，S-甲基类似物3在MDA-MB-435细胞中比1更有效（IC 50 = 4.6 nM）。3与人肝微粒体孵育表明，3的S-甲基部分的主要代谢产物是甲基亚磺酰基，与类似物5相同。在MDA-MB-435细胞中，该代谢物与先导化合物1等效（IC 50 = 7.9 nM）。确定分子建模和静电表面积来解释类似物的活性。大多数有效的化合物克服了多种耐药机制，化合物3成为进一步SAR和临床前开发的先导化合物。
We report a series of tubulin targeting agents, some of which demonstrate potent antiproliferative activities. These analogs were designed to optimize the antiproliferative activity of1by varying the heteroatom substituent at the 4′-position, the basicity of the 4-position amino moiety, and conformational restriction. The potential metabolites of the active compounds were also synthesized. Some compounds demonstrated single digit nanomolar IC50values for antiproliferative effects in MDA-MB-435 melanoma cells. Particularly, theS-methyl analog3was more potent than1in MDA-MB-435 cells (IC50= 4.6 nM). Incubation of3with human liver microsomes showed that the primary metabolite of theS-methyl moiety of3was the methyl sulfinyl group, as in analog5. This metabolite was equipotent with the lead compound1in MDA-MB-435 cells (IC50= 7.9 nM). Molecular modeling and electrostatic surface area were determined to explain the activities of the analogs. Most of the potent compounds overcome multiple mechanisms of drug resistance and compound3emerged as the lead compound for further SAR and preclinical development.