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Design, synthesis and antitumor activity of novel thiophene-pyrimidine derivatives as EGFR inhibitors overcoming T790M and L858R/T790M mutations.
European Journal of Medicinal Chemistry ( IF 6.7 ) Pub Date : 2020-07-06 , DOI: 10.1016/j.ejmech.2020.112511
Zhen Xiao 1 , Zhihui Zhou 1 , Cilong Chu 1 , Qian Zhang 1 , Lingjia Zhou 1 , Zunhua Yang 2 , Xin Li 1 , Liying Yu 1 , Pengwu Zheng 1 , Shan Xu 1 , Wufu Zhu 1
Affiliation  

Five series of novel thiophene-pyrimidine derivatives (9a-h, 10a-f, 11a-f, 12a-f, 13a-f) have been synthesized and tested for their anti-proliferative activity against several cancer cell lines in which EGF is highly expressed. Most of the target compounds showed excellent activity against one or more cancer cell lines. The most promising compound 13a, of which IC50 values on of cell lines A549 and A431 (4.34 ± 0.60 μM and 3.79 ± 0.57 μM) were similar to the lead compound Olmutinib, showed strong activity and selectivity to EGFRT790M and EGFRT790M/L858R. Inhibition data of human normal hepatoma cell line LO2 indicated that most target compounds were less toxic to normal cells and had selective inhibitory effects on cancer cells. In addition, the structure-activity relationship was analyzed and the mechanism of apoptosis induced by the 13a was studied. The results showed that compound 13a induced late apoptosis of A431 cancer cells in a dose-dependent manner.



中文翻译:

新型噻吩-嘧啶衍生物作为克服T790M和L858R / T790M突变的EGFR抑制剂的设计,合成和抗肿瘤活性。

已经合成了五种系列的新型噻吩-嘧啶衍生物(9a-h10a-f11a-f12a-f13a-f),并测试了其对几种癌细胞株的抗增殖活性,其中EGF含量很高。表达。大多数目标化合物对一种或多种癌细胞系均表现出优异的活性。最有前途的化合物13a在细胞系A549和A431上的IC 50值(4.34±0.60μM和3.79±0.57μM)与先导化合物Olmutinib相似,显示出对EGFR T790M和EGFR T790M / L858R的强活性和选择性。人类正常肝癌细胞株LO2的抑制数据表明,大多数目标化合物对正常细胞的毒性较小,并对癌细胞具有选择性抑制作用。此外,分析了结构-活性关系,并研究了13a诱导的细胞凋亡机制。结果表明,化合物13a以剂量依赖性方式诱导A431癌细胞的晚期凋亡。

更新日期:2020-07-14
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