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

ABSTRACT: 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 ?M. 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 ?M against A549 cells, 2.46 and 1.35 ?M 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.

SUBMITTER: Cheng W

PROVIDER: S-EPMC6717862 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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

Cheng Weiyan W Wang Suhua S Yang Zhiheng Z Tian Xin X Hu Yongzhou Y

Drug design, development and therapy 20190828

<h4>Purpose</h4>In order to get novel EGFR inhibitors exerting more potency in tumor hypoxia than in normoxia.<h4>Methods</h4>A series of 4-[(2-nitroimidazole-1<i>H</i>-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.<h4>Results</h4>The structure-activity relationship (SAR) studies revealed that compounds bearing both meta-chloride and p ...[more]

PMID: 31695326

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Project description:ObjectiveProinflammatory cytokine interleukin 17 (IL-17) is involved in ventricular remodeling, mainly of the left ventricle. This study was designed to explore the role of IL-17 played in the pathogenesis of right ventricular hypertrophy (RVH), aiming to provide a novel treatment target or diagnostic biomarker options for improving the care of RVH patients.MethodsC57BL/6 mice were maintained in 10% O2 chamber or room air for four weeks. Right ventricular hypertrophy index (RVHI), RV/body weight ratio, pulmonary arteriolar remodeling determined by percent media thickness (%MT), and the cardiomyocyte diameter of RV were evaluated. Mice were treated with exogenous recombinant mouse IL-17 (rmIL-17, 1 μg per dose twice a week) for four weeks. H9c2 cardiomyocytes were cultured and treated with IL-17 (10 ng/mL) and STAT3 inhibitor (10 ng/mL) either under normoxia (21% O2, 5% CO2, 74% N2) or under hypoxia (3% O2, 5% CO2, 92% N2). Cardiomyocyte viability was assessed by Cell counting kit 8 (CCK-8) assay. The mRNA level was detected by RT-PCR, where as the protein expression was measured by Western blot, immunohistochemistry, and immunofluorescent analyses.ResultsIn vivo experiments showed that IL-17 did not affect the pulmonary artery under normoxia, after treatment with rmIL-17, %MT was not changed, while RVHI and the RV/body weight ratio were increased, indicating that IL-17 directly induced right ventricular hypertrophy. In a time-course study, the mice were exposed to hypoxia for 0, 1, 2, 3, 4 weeks, respectively. We found that the expression of IL-17 was gradually upregulated in RV tissue in a time-dependent manner after one week of hypoxia exposure, especially at the third and fourth week. Cardiomyocyte hypertrophy and apoptosis were observed after the exposure of the mice to hypoxia for four weeks, rmIL-17 further aggravated the hypoxia-induced cardiomyocyte hypertrophy and apoptosis. The expression of p-STAT3 in the IL-17-deficient mice was lower than in the wild-type mice. In vitro, IL-17 inhibited cardiomyocyte viability and induced cardiomyocyte apoptosis via STAT3 under both normoxic and hypoxic conditions.ConclusionsThese findings support a role for IL-17 as a mediator in the pathogenesis RVH, which might be considered as a potential novel anti-inflammation therapeutic strategy or diagnostic biomarker for RVH.

Dataset Information

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

Publications

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

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