Synthesis and Anti-Proliferation Activity Evaluation of Novel 2-Chloroquinazoline as Potential EGFR-TK Inhibitors,Chemistry & Biodiversity

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Synthesis and Anti-Proliferation Activity Evaluation of Novel 2-Chloroquinazoline as Potential EGFR-TK Inhibitors
Chemistry & Biodiversity ( IF 2.3 ) Pub Date : 2021-09-12 , DOI: 10.1002/cbdv.202100478
Quan Zheng ₁ , Xuan-Bo Xu ₁ , Hao Jin ₁ , Wen Zhang ₁ , Guo-Wu Rao ₁

Affiliation

A novel series of 2-chloroquinazoline derivatives had been synthesized and their anti-proliferation activities against the four EGFR high-expressing cells A549, NCI-H1975, AGS and HepG2 cell lines were evaluated. The preliminary SAR study of the scaffold of new compounds showed that the compounds with a chlorine substituent on R³ had a better anti-proliferation activity than those substituted by hydrogen atom or vinyl group. Among them, 2-chloro-N-[2-chloro-4-(3-chloro-4-fluoroanilino)quinazolin-6-yl]acetamide (10b) had the best activity, and the corresponding IC₅₀ were 3.68, 10.06, 1.73 and 2.04 μM, respectively. And compound 10b had better or equivalent activity against four cell lines than Gefitinib. The activity of the compound 10b on the EGFR enzyme was subsequently tested. The Wound Healing of A549, AGS and HepG2 cells by this compound showed that the compound can inhibit the migration of cancer cells. Finally, the action channel of the compound 10b was supported by western blotting experiments. It provides useful information for the design of EGFR-TK inhibitors.

中文翻译：

新型 2-氯喹唑啉作为潜在 EGFR-TK 抑制剂的合成和抗增殖活性评价

合成了一系列新的 2-氯喹唑啉衍生物，并评估了它们对四种 EGFR 高表达细胞 A549、NCI-H1975、AGS 和 HepG2 细胞系的抗增殖活性。新化合物支架的初步SAR研究表明，R ³上具有氯取代基的化合物比氢原子或乙烯基取代的化合物具有更好的抗增殖活性。其中，2-氯-N- [2-氯-4-(3-氯-4-氟苯胺)喹唑啉-6-基]乙酰胺(10b)活性最好，相应的IC ₅₀分别为3.68、10.06、分别为 1.73 和 2.04 μM。和化合物10b对四种细胞系的活性优于吉非替尼。随后测试了化合物10b对EGFR酶的活性。该化合物对A549、AGS和HepG2细胞的伤口愈合表明该化合物可以抑制癌细胞的迁移。最后，蛋白质印迹实验支持了化合物10b的作用通道。它为设计 EGFR-TK 抑制剂提供了有用的信息。

更新日期：2021-11-15

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