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: [email protected].
  • 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: [email protected].
  • 8. Laboratory of Molecular Genetics of Aging and Tumor, Medical School, Kunming University of Science and Technology, Kunming, 650500, PR China. Electronic address: [email protected].
  • 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: [email protected].
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.