Design, synthesis and 3D-QSAR analysis of novel thiopyranopyrimidine derivatives as potential antitumor agents inhibiting A549 and Hela cancer cells
Design, synthesis and 3D-QSAR analysis of novel thiopyranopyrimidine derivatives as potential antitumor agents inhibiting A549 and Hela cancer cells
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新型噻喃并嘧啶衍生物的设计、合成和 3D-QSAR 分析作为抑制 A549 和 Hela 癌细胞的潜在抗肿瘤药物
DOI：
10.1016/j.ejmech.2019.111809
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发表时间：
2020
影响因子：
6.7
通讯作者：
Zheng Pengwu
中科院分区：
文献类型：
--
作者：
Zhao Bingbing;Zhao Chengwu;Hu Xiaohan;Xu Shan;Lan Zhou;Guo Yuping;Yang Zunhua;Zhu Wufu;Zheng Pengwu
设计、合成了4个系列的含丙烯酰胺结构的噻喃嘧啶AZD 9291衍生物，并对其抗A549和Hela细胞增殖活性进行了评价。大多数化合物对A549细胞表现出优异的抗增殖活性。吲哚环上含氟取代的化合物对Hela细胞具有较好的抗增殖活性。其中化合物23 g对EGFRL 858 R/T790 M双突变具有良好的酶抑制活性和选择性。对EGFRL 858 R/T790 M激酶的IC 50值为16 nM。化合物23 g选择性抑制突变形式的EGFR，选择性超过125倍。化合物23 g在低浓度下对A549、Hela和H1975细胞的增殖也有抑制作用，IC 50值分别为0.057 μM、0.104 μM和0.916 μM。为了进一步研究噻喃嘧啶衍生物的QSAR，建立了Hela细胞的CoMFA（q [2] = 0.765，r2= 0.965）和CoMSIA（q [2] = 0.875，r2= 0.956）模型。所建立的三维定量构效关系模型是可靠的，可用于新型选择性EGFR抑制剂的设计和优化。
Four series of thiopyranopyrimidine AZD9291 derivatives containing acrylamide structure were designed, synthesized and evaluated for their antiproliferative activity against A549 and Hela cancer cells. Most of the compounds exhibited excellent antiproliferative activity against A549 cells. Moreover, the compounds with indole ring fluorine substituted exhibited better antiproliferative activity against Hela cells. The most promising compound23gexhibited excellent enzymatic inhibitory activity and selectivity for EGFRL858R/T790Mdouble mutations. The IC50value against EGFRL858R/T790Mkinase was 16 nM. The compound23ginhibits selectively against the mutated form of EGFR, with the selectivity more than 125-fold. Furthermore, compound23galso inhibited A549 cells, Hela cells and H1975 cells proliferation at a low concentration, and the IC50values were 0.057 μM, 0.104 μM and 0.916 μM, respectively. To further investigate the QSARs of thiopyranopyrimidine derivatives, the CoMFA (q [2] = 0.765, r2= 0.965) and CoMSIA (q [2] = 0.875, r2= 0.956) models on Hela cancer cells were established. The generated 3D-QSAR model was validated to be reliable and can be used for further design and optimization of novel and selective EGFR inhibitors.