Design, synthesis and structure-activity relationship of novel quinoxaline derivatives as cancer chemopreventive agent by inhibition of tyrosine kinase receptor

Eur J Med Chem. 2013 Nov:69:115-24. doi: 10.1016/j.ejmech.2013.07.049. Epub 2013 Aug 13.

Abstract

The cancer chemopreventive activity of quinoxaline derivatives 1-20 has been evaluated by studying the inhibitory effect on Epstein-Barr virus early antigen (EBV-EA) activation. The quinoxaline derivatives 1-20 showed inhibitory effect on EBV-EA activation without cytotoxicity on Raji cells. All compounds exhibited dose dependent inhibitory activities, most of them showed significant activity at 1000 mol ratio/12-O-tetradecanoylphorbol-13-acetate (TPA). Compounds 7 and 9 exhibited stronger inhibitory effects on the EBV-EA activation than that of the representative control, oleanolic acid, at the highest measured concentration. In addition, compounds 7-10 showed potent and selective inhibition of human tyrosine kinase (TRK) in liver cancer HepG2 and breast cancer MCF-7 cell lines similar to the positive control, doxorubicin.

Keywords: Cancer chemopreventive activity; Docking; Epstein–Barr virus; Protein tyrosine kinase; Quinoxalines; Synthesis.

MeSH terms

  • Antigens, Viral / metabolism*
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Proliferation / drug effects
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Hep G2 Cells
  • Humans
  • MCF-7 Cells
  • Models, Molecular
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Quinoxalines / chemical synthesis
  • Quinoxalines / chemistry
  • Quinoxalines / pharmacology*
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Structure-Activity Relationship

Substances

  • Antigens, Viral
  • Antineoplastic Agents
  • Epstein-Barr virus early antigen
  • Protein Kinase Inhibitors
  • Quinoxalines
  • Receptor Protein-Tyrosine Kinases