Design, synthesis and biological evaluation of novel 4-anlinoquinazoline derivatives as EGFR inhibitors with the potential to inhibit the gefitinib-resistant nonsmall cell lung cancers
Design, synthesis and biological evaluation of novel 4-anlinoquinazoline derivatives as EGFR inhibitors with the potential to inhibit the gefitinib-resistant nonsmall cell lung cancers
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新型 4-苯氨基喹唑啉衍生物作为 EGFR 抑制剂的设计、合成和生物学评价，具有抑制吉非替尼耐药非小细胞肺癌的潜力
DOI：
10.1080/14756366.2018.1518957
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发表时间：
2019
影响因子：
5.6
通讯作者：
Zhu Wufu
中科院分区：
文献类型：
--
作者：
Wang Caolin;Xu Shan;Peng Liang;Zhang Bingliang;Zhang Hong;Hu Yingying;Zheng Pengwu;Zhu Wufu
设计并合成了一系列含苄叉肼甲酰胺的喹唑啉类EGFR抑制剂。大多数化合物对A549、HepG 2、MCF-7和H1975细胞表现出优异的抗增殖活性。此外，有6个化合物对EGFRWT具有较好的抑制活性，IC 50均小于2 nM。在6种化合物中，44种化合物表现出最强的活性（0.4 nM），并有效地抑制EGFRL 858 R/T790 M（0.1 μM）。令人兴奋的是，最有效的化合物14显示出优异的酶抑制活性，对EGFRWT和EGFRT 790 M/L 858 R均为6.3 nM和8.4 nM。AO单染和Annexin V/PI染色结果显示化合物14和44可诱导A549细胞发生明显的凋亡。化合物14使A549细胞周期阻滞于S期，化合物44使细胞周期阻滞于G 0期。这些初步结果表明化合物14和44可能是靶向EGFR的有希望的先导化合物。
A series of quinazoline derivatives with benzylidene hydrazine carboxamide were designed and synthesised as EGFR inhibitors. Most compounds exhibited exceptional anti-proliferative activity against A549, HepG2, MCF-7 and H1975 cells. Furthermore, six compounds demonstrated excellent inhibition activity against EGFRWTwith the IC50value both less than 2 nM. Among the six compounds,44exhibited the strongest activity (0.4 nM) and potently inhibited EGFRL858R/T790M(0.1 μM). Excitingly, the most potent compound14showed excellent enzyme inhibitory activity with 6.3 nM and 8.4 nM for both EGFRWTand EGFRT790M/L858R. The result of AO single staining and Annexin V/PI staining showed that the compound14and44could induce remarkable apoptosis of A549 cells. The compound14arrested the cell cycle at the S phase and compound44arrested the cell cycle at the G0 phase in A549 cells. These preliminary results demonstrate that compound14and44may be promising lead compound-targeting EGFR.