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【论文发表】Design, synthesis and invitro evaluation of 6-amide-2-aryl benzoxazole/benzimidazole derivatives against tumor cells by inhibiting VEGFR-2 kinase

2019年07月04日 11:15  点击：[]

Design, synthesis and invitro evaluation of 6-amide-2-aryl benzoxazole/benzimidazole derivatives against tumor cells by inhibiting VEGFR-2 kinase

By:Yuan, Xu;Yang, Qingyi;Liu, Tongyan;Li, Ke;Liu, Yuwen;Zhu, Changcheng;Zhang, Zhiyun;Li, Linghua;Zhang, Conghai;Xie, Mingjin; Lin, Jun; Zhang, Jihong; Jin, Yi

European Journal of Medicinal Chemistry

Volume:179

Pages:147-165

DOI:10.1016/j.ejmech.2019.06.054

Published:2019-Jun-20(Epub 2019 Jun 20)

Document Type:Journal Article

Abstract

    Herein, we have carried out a structural optimization campaign to discover the novel anti-tumor agents with our previously screened YQY-26 as the hit compound. A library of thirty-seven 6-amide-2-aryl benzoxazole/benzimidazole derivatives has been designed and synthesized based on the highly conserved active site of VEGFR-2. Several title compounds exhibited selective inhibitory activities against VEGFR-2 than EGFR kinases, which also displayed selective anti-proliferation potency against the HUVEC and HepG2 than the A549 and MDA-MB-231 cancer cell lines. The newly synthesized compounds were evaluated for anti-angiogenesis capability by chick chorioallantoic membrane (CAM) assay. Among them, compounds 9d showed the most potent anti-angiogenesis ability (79% inhibition at 10 nM/eggs), the efficient cytotoxic activities (invitro against the HUVEC and HepG2 cell lines with IC50 values of 1.47 and 2.57 muM, respectively), and excellent VEGFR-2 kinase inhibition (IC50 = 0.051 muM). The molecular docking analysis revealed that compound 9d is a Type II inhibitor of VEGFR-2 kinase. These results indicated that the 6-amide-2-arylbenzoxazole and 6-amide-2-aryl benzimidazole derivatives are promising inhibitors of VEGFR-2 kinase for the potential treatment of anti-angiogenesis.

Keywords

Keyword List:Angiogenesis; Antitumor activity; Benzimidazole; Benzoxazole; VEGFR-2

Author Information

Addresses: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.

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; School of Clinical Medicine, Dehong Vocational College, Mangshi, 678400, China.

Laboratory of Molecular Genetics of Aging and Tumor, Medical School, Kunming University of Science and Technology, Kunming, 650500, PR China.

Biomedical Department, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming, 650118, PR China. Electronic address: likelikelike@126.com.

Institute of Drug Research and Development, Kunming Pharmaceutical Corporation, Kunming, 650100, PR China.

Department of Anorectal, Kunming Municipal Hospital of Traditional Chinese Medicine, Kunming, 650011, PR China.

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.

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.

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.


论文链接：https://doi.org/10.1016/j.ejmech.2019.06.054



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