Discovery of arylamide-5-anilinoquinazoline-8-nitro derivatives as VEGFR-2 kinase inhibitors: Synthesis, in vitro biological evaluation and molecular docking

Yongqiang Zhao; Feifei Liu; Guojing He; Ke Li; Changcheng Zhu; Wei Yu; Conghai Zhang; Mingjin Xie; Jun Lin; Jihong Zhang; Yi Jin

doi:10.1016/j.bmcl.2019.126711

Discovery of arylamide-5-anilinoquinazoline-8-nitro derivatives as VEGFR-2 kinase inhibitors: Synthesis, in vitro biological evaluation and molecular docking

Bioorg Med Chem Lett. 2019 Dec 1;29(23):126711. doi: 10.1016/j.bmcl.2019.126711. Epub 2019 Oct 19.

Authors

Yongqiang Zhao¹, Feifei Liu², Guojing He¹, Ke Li³, Changcheng Zhu⁴, Wei Yu⁵, Conghai Zhang¹, Mingjin Xie¹, Jun Lin⁶, Jihong Zhang⁷, Yi Jin⁸

Affiliations

¹ Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry Education and Yunnan Province, School of Chemical Science and Technology, Yunnan University, Kunming 650091, PR China.
² Laboratory of Molecular Genetics of Aging and Tumor, Medical School, Kunming University of Science and Technology, Kunming 650500, PR China.
³ Biomedical Department, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming 650118, PR China. Electronic address: likelikelike@126.com.
⁴ Institute of Drug Research and Development, Kunming Pharmaceutical Corporation, Kunming 650100, PR China.
⁵ Pharmaceutical Department, Kunming General Hospital of Chengdu Military Command, Kunming 650118, PR China.
⁶ Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry Education and Yunnan Province, School of Chemical Science and Technology, Yunnan University, Kunming 650091, PR China. Electronic address: linjun@ynu.edu.cn.
⁷ Laboratory of Molecular Genetics of Aging and Tumor, Medical School, Kunming University of Science and Technology, Kunming 650500, PR China. Electronic address: zhjihong2000@126.com.
⁸ Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry Education and Yunnan Province, School of Chemical Science and Technology, Yunnan University, Kunming 650091, PR China. Electronic address: jinyi@ynu.edu.cn.

PMID: 31668972
DOI: 10.1016/j.bmcl.2019.126711

Abstract

Herein, we embarked on a structural optimization campaign aiming at the discovery of novel anticancer agents with our previously reported XL-6f as a lead compound. A library of 23 compounds has been synthesized based on the highly conserved active site of VEGFR-2. Several title compounds exhibited selective inhibitory activities against VEGFR-2, which also displayed selective anti-proliferation potency against HepG2 cell. All synthesized compounds were evaluated for anti-angiogenesis capability. Compound 7o showed the most potent anti-angiogenesis ability, the efficient cytotoxic activities (in vitro against HUVEC and HepG2 cell lines with IC₅₀ values of 0.58 and 0.23 µM, respectively). The molecular docking analysis revealed 7o is a Type-II inhibitor of VEGFR-2 kinase. In general, these results indicated these arylamide-5-anilinoquinazoline-8-nitro derivatives are promising inhibitors of VEGFR-2 for the potential treatment of anti-angiogenesis.

Keywords: Antiangiogenesis; Anticancer agents; Quinazoline; VEGFR-2 kinase inhibitors.

Publication types

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

MeSH terms

Aniline Compounds / pharmacology
Aniline Compounds / therapeutic use*
Humans
Molecular Docking Simulation / methods*
Quinazolines / pharmacology
Quinazolines / therapeutic use*
Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
Vascular Endothelial Growth Factor Receptor-2 / chemical synthesis*

Substances

Aniline Compounds
Quinazolines
anilinoquinazoline
Vascular Endothelial Growth Factor Receptor-2