Design, synthesis, and biological study of 4-[(2-nitroimidazole-1H-alkyloxyl)aniline]-quinazolines as EGFR inhibitors exerting cytotoxicities both under normoxia and hypoxia

• Main Authors: Cheng W, Wang S, Yang Z, Tian X, Hu Y
• Format: Article
• Language: English
• Published: Dove Medical Press 2019-08-01
• Series: Drug Design, Development and Therapy
• Subjects: EGFR inhibitor; hypoxia; tumor; 4-anilinoquinazoline; 2-nitroimidazole
• Online Access: https://www.dovepress.com/design-synthesis-and-biological-study-of-4-2-nitroimidazole-1h-alkylox-peer-reviewed-article-DDDT

Weiyan Cheng,1,2,* Suhua Wang,1,2,* Zhiheng Yang,1,2 Xin Tian,1,2 Yongzhou Hu31Department 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 ChinaCorrespondence: Xin TianDepartment of Pharmacy, The First Affiliated Hospital of Zhengzhou University, 1 Jianshedong Road, Zhengzhou 450052, People’s Republic of ChinaEmail [e-mail] HuZhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, 388 Yuhangtang Road, Hangzhou 310058, People’s Republic of ChinaEmail [e-mail]*These authors contributed equally to this workPurpose: 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