Design, synthesis and biological evaluation of 6-(nitroimidazole-1H-alkyloxyl)-4-anilinoquinazolines as efficient EGFR inhibitors exerting cytotoxic effects both under normoxia and hypoxia

Weiyan Cheng; Shijun Zhu; Xiaodong Ma; Ni Qiu; Peng Peng; Rong Sheng; Yongzhou Hu

doi:10.1016/j.ejmech.2014.11.010

Design, synthesis and biological evaluation of 6-(nitroimidazole-1H-alkyloxyl)-4-anilinoquinazolines as efficient EGFR inhibitors exerting cytotoxic effects both under normoxia and hypoxia

Eur J Med Chem. 2015 Jan 7:89:826-34. doi: 10.1016/j.ejmech.2014.11.010. Epub 2014 Nov 6.

Authors

Weiyan Cheng¹, Shijun Zhu¹, Xiaodong Ma¹, Ni Qiu¹, Peng Peng¹, Rong Sheng², Yongzhou Hu³

Affiliations

¹ Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
² Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China. Electronic address: shengr@zju.edu.cn.
³ Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China. Electronic address: huyz@zju.edu.cn.

PMID: 25462282
DOI: 10.1016/j.ejmech.2014.11.010

Abstract

A series of novel 6-(nitroimidazole-1H-alkyloxyl)-4-anilinoquinazoline derivatives (15a-15r) were designed, synthesized and evaluated as efficient EGFR inhibitors through introduction of hypoxia activated nitroimidazole moiety into the quinazoline scaffold of EGFR inhibitors. The majority of these newly synthesized compounds exhibited comparable EGFR inhibitory activities to gefitinib and moderate to excellent anti-proliferative activities against HT-29 cells under normoxia and hypoxia. The most promising compound 15c displayed the IC50 value of 0.47 nM against EGFR kinase and excellent cytotoxic effect against HT-29 cells under normoxia and hypoxia with the IC50 values of 2.21 μM and 1.62 μM, respectively. The mimic reductive activation study revealed that compound 15c exerted reductive activation properties under hypoxia, which were consistent with the in vitro metabolic study, wherein 15c was easily reductive activated under hypoxia and much more stable under normoxia. All these results suggested that 15c was a potential cancer therapeutic agent both under normoxia and hypoxia and was worth of further development.

Keywords: 4-Anilinoquinazoline; EGFR inhibitor; Hypoxia; Nitroimidazole; Normoxia.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Death / drug effects
Cell Hypoxia / drug effects*
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Design*
ErbB Receptors / antagonists & inhibitors*
ErbB Receptors / metabolism
HT29 Cells
Humans
Imidazoles / chemical synthesis
Imidazoles / chemistry
Imidazoles / pharmacology*
Molecular Docking Simulation
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Quinazolines / chemical synthesis
Quinazolines / chemistry
Quinazolines / pharmacology*
Structure-Activity Relationship

Substances

Imidazoles
N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(4-(2-nitro-1H-imidazol-1-yl)butoxy)quinazolin-4-amine
Protein Kinase Inhibitors
Quinazolines
ErbB Receptors