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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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posted on 2018-12-04, 21:33 authored by Caolin Wang, Shan Xu, Liang Peng, Bingliang Zhang, Hong Zhang, Yingying Hu, Pengwu Zheng, Wufu Zhu

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 EGFRWT with the IC50 value both less than 2 nM. Among the six compounds, 44 exhibited the strongest activity (0.4 nM) and potently inhibited EGFRL858R/T790M (0.1 μM). Excitingly, the most potent compound 14 showed excellent enzyme inhibitory activity with 6.3 nM and 8.4 nM for both EGFRWT and EGFRT790M/L858R. The result of AO single staining and Annexin V/PI staining showed that the compound 14 and 44 could induce remarkable apoptosis of A549 cells. The compound 14 arrested the cell cycle at the S phase and compound 44 arrested the cell cycle at the G0 phase in A549 cells. These preliminary results demonstrate that compound 14 and 44 may be promising lead compound-targeting EGFR.

Funding

This work was supported by The National Natural Science Funds of China [No. 21662014, 81460527], Outstanding Youth Foundation of Jiangxi, Natural Science Foundation of Jiangxi, China [20171BCB23078], Natural Science Foundation of Jiangxi, China [20171ACB21052 & 20171BAB215073].

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