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

Eur J Med Chem. 2019 Oct 1:179:147-165. doi: 10.1016/j.ejmech.2019.06.054.

Xu Yuan ¹, Qingyi Yang ², Tongyan Liu ³, Ke Li ⁴, Yuwen Liu ¹, Changcheng Zhu ⁵, Zhiyun Zhang ⁶, Linghua Li ⁶, Conghai Zhang ¹, Mingjin Xie ¹, Jun Lin ⁷, Jihong Zhang ⁸, Yi Jin ⁹

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 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.
3 Laboratory of Molecular Genetics of Aging and Tumor, Medical School, Kunming University of Science and Technology, Kunming, 650500, PR China.
4 Biomedical Department, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming, 650118, PR China. Electronic address: likelikelike@126.com.
5 Institute of Drug Research and Development, Kunming Pharmaceutical Corporation, Kunming, 650100, PR China.
6 Department of Anorectal, Kunming Municipal Hospital of Traditional Chinese Medicine, Kunming, 650011, PR China.
7 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.
8 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.
9 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: 31252306 DOI: 10.1016/j.ejmech.2019.06.054

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 (in vitro against the HUVEC and HepG2 cell lines with IC₅₀ values of 1.47 and 2.57 μM, respectively), and excellent VEGFR-2 kinase inhibition (IC₅₀ = 0.051 μM). 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

Angiogenesis; Antitumor activity; Benzimidazole; Benzoxazole; VEGFR-2.

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