Synthesis and structure-activity relationships of boswellic acid derivatives as potent VEGFR-2 inhibitors

Bioorg Med Chem. 2015 May 1;23(9):1982-93. doi: 10.1016/j.bmc.2015.03.022. Epub 2015 Mar 14.

Abstract

A series of AKBA derivatives were synthesized, and evaluated as potent VEGFR-2 inhibitors. The initial biological evaluation indicated that the introduction of C-24 amide group or a heterocycle at C-2,3 position effectively improved the potency. Further structure-activity relationship analysis showed that amide (7, 23, 25, and 26) and heterocycle (19, 34, and 36) substituted AKBA derivatives displayed more potential anti-proliferation activities than AKBA (1) on HUVECs that express high levels of VEGFR-2. Among all tested compounds, compounds 7 and 19 exhibited the best potency (IC₅₀: 2.36 and 2.13 μM) and obvious inhibitory activities with VEGFR-2 inhibition rates of 96% and 94% at 50 μM, respectively.

Keywords: Acetyl-11-keto-β-boswellic acid; Structure–activity relationship; Synthesis; VEGFR-2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Human Umbilical Vein Endothelial Cells / drug effects
  • Humans
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Structure-Activity Relationship
  • Triterpenes / chemical synthesis
  • Triterpenes / chemistry
  • Triterpenes / pharmacology*
  • Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

  • Protein Kinase Inhibitors
  • Triterpenes
  • boswellic acid
  • Vascular Endothelial Growth Factor Receptor-2