Design, synthesis, and biological study of 4-[(2-nitroimidazole-1H-alkyloxyl)aniline]-quinazolines as EGFR inhibitors exerting cytotoxicities both under normoxia and hypoxia
Authors Cheng W, Wang S, Yang Z, Tian X, Hu Y
Received 20 March 2019
Accepted for publication 22 July 2019
Published 28 August 2019 Volume 2019:13 Pages 3079—3089
Checked for plagiarism Yes
Review by Single-blind
Peer reviewer comments 5
Editor who approved publication: Dr Tin Wui Wong
Weiyan Cheng,1,2,* Suhua Wang,1,2,* Zhiheng Yang,1,2 Xin Tian,1,2 Yongzhou Hu3
1Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, People’s Republic of China; 2Henan Key Laboratory of Precision Clinical Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China; 3Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, People’s Republic of China
Correspondence: Xin Tian
Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, 1 Jianshedong Road, Zhengzhou 450052, People’s Republic of China
Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, 388 Yuhangtang Road, Hangzhou 310058, People’s Republic of China
*These authors contributed equally to this work
Purpose: In order to get novel EGFR inhibitors exerting more potency in tumor hypoxia than in normoxia.
Methods: A series of 4-[(2-nitroimidazole-1H-alkyloxyl)aniline]-quinazolines were designed and synthesized, and their in vitro cytotoxicity and EGFR inhibitory activity were evaluated. Molecule docking study was performed for the representative compound.
Results: The structure-activity relationship (SAR) studies revealed that compounds bearing both meta-chloride and para-(2-nitroimidazole-1H-alkyloxy) groups on the aniline displayed potent inhibitory activities both in enzymatic and cellular levels. The most promising compound 16i potently inhibited EGFR with an IC50 value of 0.12 μM. Meanwhile, it manifested more potent cytotoxicity than the positive control lapatinib under tumor normoxia and hypoxia conditions (IC50 values of 1.59 and 1.09 μM against A549 cells, 2.46 and 1.35 μM against HT-29 cells, respectively). The proposed binding model of 16i in complex with EGFR was displayed by the docking results.
Conclusion: This study provides insights for developing hypoxia-activated kinase inhibitors.
Keywords: EGFR inhibitor, hypoxia, tumor, 4-anilinoquinazoline, 2-nitroimidazole
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