Discovery of biphenyl-based VEGFR-2 inhibitors. Part 3: design, synthesis and 3D-QSAR studies

Bioorg Med Chem. 2015 Mar 1;23(5):1044-54. doi: 10.1016/j.bmc.2015.01.006. Epub 2015 Jan 9.

Abstract

VEGFR-2 plays an essential role in angiogenesis and is a central target for anticancer drug discovery. In order to develop novel VEGFR-2 inhibitors, we designed and synthesized 33 biphenyl amides based on our previously reported lead compound. The biological results indicated that four compounds (18b, 20e, 20h and 20j) are potent VEGFR-2 inhibitors which are comparable to positive control. Compound 18b displayed the most potent VEGFR-2 inhibition with IC50 value of 2.02nM. Moreover, it exhibited promising antiproliferative activity against MCF-7 and SMMC-7721 cells with IC50 values of 1.47μM and 5.98μM, respectively. Molecular docking and 3D-QSAR studies were also carried out. The results indicated that these biphenyl amides could serve as promising leads for further optimization as novel VEGFR-2 inhibitors.

Keywords: 3D-QSAR; Amide; Anticancer; Biphenyl; VEGFR-2 inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biphenyl Compounds / chemical synthesis
  • Biphenyl Compounds / chemistry
  • Biphenyl Compounds / pharmacology*
  • Cell Line
  • Drug Discovery
  • Drug Screening Assays, Antitumor
  • Humans
  • Molecular Docking Simulation
  • Quantitative Structure-Activity Relationship
  • Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*

Substances

  • Biphenyl Compounds
  • Vascular Endothelial Growth Factor Receptor-2