Design, synthesis and biological evaluation of c-Met kinase inhibitors bearing 2-oxo-1,2-dihydroquinoline scaffold

Bioorg Med Chem Lett. 2016 Sep 15;26(18):4483-4486. doi: 10.1016/j.bmcl.2016.07.077. Epub 2016 Jul 30.

Abstract

A series of 2-oxo-1,2-dihydroquinoline-containing c-Met inhibitors were designed, synthesized and evaluated for their in vitro activities targeting c-Met. Most compounds showed high potency against c-Met with IC50 values in the single-digit nM range. Among these compounds, two target compounds, namely 1h and 1n, stood out as the most potent c-Met inhibitors with IC50s of 0.6 and 0.7nM, respectively. And 1a exhibited higher potency than BMS-777607 did with respect to the inhibition of cell proliferation. The introduction of electron-donating substituent was favorable for the activities of the compounds to some extent. Furthermore, molecular docking studies also gave encouraging results that supported this work.

Keywords: Antiproliferative activity; Synthesis; c-Met.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Drug Screening Assays, Antitumor
  • Humans
  • Inhibitory Concentration 50
  • Molecular Docking Simulation
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Proteins c-met / antagonists & inhibitors*
  • Quinolines / chemistry*

Substances

  • Protein Kinase Inhibitors
  • Quinolines
  • MET protein, human
  • Proto-Oncogene Proteins c-met