ZFIN ID: ZDB-PUB-160313-7
Quinoxalinone (Part II). Discovery of (Z)-3-(2-(pyridin-4-yl)vinyl)quinoxalinone derivates as potent VEGFR-2 kinase inhibitors
Shi, L., Zhou, J., Wu, J., Cao, J., Shen, Y., Zhou, H., Li, X.
Date: 2016
Source: Bioorganic & Medicinal Chemistry   24(8): 1840-52 (Journal)
Registered Authors: Zhou, Jianfeng
Keywords: Activity evaluation, Antiangiogenesis, Pyridyl motif, Quinoxalinone derivates, VEGFR-2 inhibitor
MeSH Terms:
  • Angiogenesis Inhibitors/chemical synthesis
  • Angiogenesis Inhibitors/chemistry
  • Angiogenesis Inhibitors/pharmacology*
  • Animals
  • Cell Line, Tumor
  • Cell Proliferation/drug effects
  • Dose-Response Relationship, Drug
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Neovascularization, Physiologic/drug effects
  • Protein Kinase Inhibitors/chemical synthesis
  • Protein Kinase Inhibitors/chemistry
  • Protein Kinase Inhibitors/pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Structure-Activity Relationship
  • Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors*
  • Vascular Endothelial Growth Factor Receptor-2/metabolism
  • Zebrafish
PubMed: 26968648 Full text @ Bioorg. Med. Chem.
Inhibition of VEGFR-2 kinase has been highlighted as one of the well-defined strategies to suppress tumor growth via blockade of angiogenesis. Guided by the principles of bioisosteric replacement and pharmacophoric fragment migration, a series of novel quinoxalinone derivates were designed, synthesized and evaluated for their VEGFR-2 inhibitory potencies. Among them, compounds 7c, 8b, 8c, 8e and 10b displayed antiangiogenic abilities via the in vitro tube formation assay (cellular level) and ex vivo rat aortic ring assay (tissue level) at a low concentration (0.1μM). By means of in vivo zebrafish embryo model, two (Z)-3-(2-(pyridin-4-yl)vinyl)quinoxalinone derivates 8c and 8e showed significant antiangiogenesis effects, suggesting they have potentials to be developed into antiangiogenesis agents via further structural optimization. Moreover, these two compounds also demonstrated potent inhibition toward VEGFR-2 and B-raf kinases in a low concentration (1μM). A possible interpretation of our evaluation result has been presented by a molecular docking study by docking representative compound 8c with VEGFR-2.