Design, synthesis and antitumor activities of novel bis-aryl ureas derivatives as Raf kinase inhibitors

Bioorg Med Chem. 2012 Jul 15;20(14):4323-9. doi: 10.1016/j.bmc.2012.05.051. Epub 2012 May 30.

Abstract

A series of novel bis-aryl ureas containing trifluoromethyl imidazolyl group targeting Raf kinase were designed and synthesized based on the lead compound of Sorafenib. All the prepared compounds were evaluated for their in vitro antiproliferative activities against three human cancer cell lines including MDA-MB-231 (breast), BGC-823 (gastric), and SMMC-7721 (liver). Several compounds from the series exhibited excellent antitumor activities against all three tested cancer lines. Further their inhibitory activities against Raf kinase were investigated, and three compounds (11c, 11d, and 11p) demonstrated better activities than contrast drug Sorafenib. Especially compound 11c was found to be a potent and selective Raf kinase inhibitor and could be considered as a candidate compound for further development.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / toxicity
  • Benzenesulfonates / chemistry
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Drug Design*
  • Drug Screening Assays, Antitumor
  • Humans
  • Niacinamide / analogs & derivatives
  • Phenylurea Compounds
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / toxicity
  • Pyridines / chemistry
  • Sorafenib
  • Structure-Activity Relationship
  • Urea / analogs & derivatives*
  • Urea / chemical synthesis
  • Urea / toxicity
  • raf Kinases / antagonists & inhibitors*
  • raf Kinases / metabolism

Substances

  • Antineoplastic Agents
  • Benzenesulfonates
  • Phenylurea Compounds
  • Protein Kinase Inhibitors
  • Pyridines
  • Niacinamide
  • Urea
  • Sorafenib
  • raf Kinases