Exploration of acridine scaffold as a potentially interesting scaffold for discovering novel multi-target VEGFR-2 and Src kinase inhibitors

Bioorg Med Chem. 2011 Jun 1;19(11):3312-9. doi: 10.1016/j.bmc.2011.04.053. Epub 2011 May 1.


VEGFR-2 and Src kinases both play important roles in cancers. In certain cancers, Src works synergistically with VEGFR-2 to promote its activation. Development of multi-target drugs against VEGFR-2 and Src is of therapeutic advantage against these cancers. By using molecular docking and SVM virtual screening methods and based on subsequent synthesis and bioassay studies, we identified 9-aminoacridine derivatives with an acridine scaffold as potentially interesting novel dual VEGFR-2 and Src inhibitors. The acridine scaffold has been historically used for deriving topoisomerase inhibitors, but has not been found in existing VEGFR-2 inhibitors and Src inhibitors. A series of 21 acridine derivatives were synthesized and evaluated for their antiproliferative activities against K562, HepG-2, and MCF-7 cells. Some of these compounds showed better activities against K562 cells in vitro than imatinib. The structure-activity relationships (SAR) of these compounds were analyzed. One of the compounds (7r) showed low μM activity against K562 and HepG-2 cancer cell-lines, and inhibited VEGFR-2 and Src at inhibition rates of 44% and 8% at 50μM, respectively, without inhibition of topoisomerase. Moreover, 10μM compound 7r could reduce the levels of activated ERK1/2 in a time dependant manner, a downstream effector of both VEGFR-2 and Src. Our study suggested that acridine scaffold is a potentially interesting scaffold for developing novel multi-target kinase inhibitors such as VEGFR-2 and Src dual inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acridines / chemical synthesis
  • Acridines / chemistry*
  • Acridines / toxicity
  • Aminoacridines / chemical synthesis
  • Aminoacridines / chemistry*
  • Aminoacridines / pharmacology
  • Binding Sites
  • Cell Line, Tumor
  • Computer Simulation
  • Humans
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / toxicity
  • Structure-Activity Relationship
  • Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism
  • src-Family Kinases / antagonists & inhibitors*
  • src-Family Kinases / metabolism


  • 6-chloro-2-methoxy-N-(2-methoxybenzyl)acridin-9-amine
  • Acridines
  • Aminoacridines
  • Protein Kinase Inhibitors
  • Vascular Endothelial Growth Factor Receptor-2
  • src-Family Kinases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3