Design, synthesis and biological evaluation of pazopanib derivatives as antitumor agents

Chem Biol Drug Des. 2014 Mar;83(3):306-16. doi: 10.1111/cbdd.12243. Epub 2014 Feb 1.

Abstract

A novel series of pazopanib derivatives were designed, synthesized, and evaluated for their inhibitory activity against a series of kinases including VEGFR-2, EGFR, AKT1, ALK1, and ABL1. The anti-angiogenic activities ex vivo of some compounds were also investigated. Compounds P2d and P2e demonstrated outstanding inhibitory activity against VEGFR-2 and ABL1 and higher anti-angiogenic activity compared with Pazopanib, the reference standard. These two compounds (P2d and P2e) could be used as novel lead compounds for further development of anticancer agents.

Keywords: anti-angiogenesis; antitumor agent; pazopanib derivatives; synthesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Aorta / cytology
  • Aorta / drug effects
  • Aorta / metabolism
  • Cell Survival / drug effects
  • Cells, Cultured
  • Drug Design*
  • Enzyme Activation / drug effects
  • Indazoles / chemical synthesis*
  • Indazoles / chemistry
  • Indazoles / pharmacology*
  • Male
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins c-abl / antagonists & inhibitors
  • Proto-Oncogene Proteins c-abl / metabolism
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry*
  • Pyrimidines / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis*
  • Sulfonamides / chemistry*
  • Sulfonamides / pharmacology*
  • Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

  • 4-((4-((2,3-dimethyl-2H-indazole-6-yl)(methyl)amino)pyrimidin-2-yl)amino)-N-(4,6-dimethylpyrimidin-2-yl)benzenesulfonamide
  • 4-((4-((2,3-dimethyl-2H-indazole-6-yl)(methyl)amino)pyrimidin-2-yl)amino)-N-(4-methylpyrimidin-2-yl)benzenesulfonamide
  • Antineoplastic Agents
  • Indazoles
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Sulfonamides
  • pazopanib
  • Vascular Endothelial Growth Factor Receptor-2
  • Proto-Oncogene Proteins c-abl