Discovery of novel taspine derivatives as antiangiogenic agents

Bioorg Med Chem Lett. 2010 Jan 15;20(2):718-21. doi: 10.1016/j.bmcl.2009.11.073. Epub 2009 Dec 14.

Abstract

VEGFR-2 plays a critical role in vasculogenesis and inhibitors of VEGFR-2 could be used in the treatment of cancer. Taspine was one of the active ingredients screened by using an endothelial cell membrane chromatography and showed inhibition against VEGFR-2. In our research, we explored how the lactone ring and biphenyl scaffold in taspine influence its potent in vitro anticancer and antiangiogenesis activities. Accordingly, we report the design, synthesis, and preliminary evaluation of four novel taspine derivatives as VEGFR-2 inhibitors. The preliminary biological test showed that one of the compounds showed much better inhibitory activities against CACO-2 (IC(50)=52.5nM) and ECV304 (IC(50)=2.67nM) than taspine. This result enlarges the interest in ring-opened taspine derivative skeleton in the search of new antiangiogenesis agents.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkaloids / chemical synthesis
  • Alkaloids / chemistry*
  • Alkaloids / pharmacology
  • Angiogenesis Inhibitors / chemical synthesis
  • Angiogenesis Inhibitors / chemistry*
  • Angiogenesis Inhibitors / pharmacology
  • Binding Sites
  • Biphenyl Compounds / chemistry
  • Catalytic Domain
  • Cell Line, Tumor
  • Computer Simulation
  • Drug Discovery
  • Humans
  • Hydrogen Bonding
  • Lactones / chemistry
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology
  • Structure-Activity Relationship
  • Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

  • Alkaloids
  • Angiogenesis Inhibitors
  • Biphenyl Compounds
  • Lactones
  • Protein Kinase Inhibitors
  • biphenyl
  • Vascular Endothelial Growth Factor Receptor-2
  • taspine