Design and synthesis of novel benzoxazole analogs as Aurora B kinase inhibitors

Bioorg Med Chem Lett. 2016 Jul 1;26(13):3067-3072. doi: 10.1016/j.bmcl.2016.05.017. Epub 2016 May 7.

Abstract

A novel series of benzoxazole analogs was designed and synthesized, and their inhibitory activities against Aurora kinases were evaluated. Some of the tested compounds exhibited a promising activity with respect to the inhibition of Aurora B kinase. A structure-activity relationship study indicated that linker length, regiochemistry, and halogen substitution play important roles in kinase inhibitory potency. The binding modes between representative compounds and Aurora kinases were interpreted through a molecular docking study to explain the inhibitory activity and selectivity for Aurora A and B kinases. Compounds 13l and 13q also show an antiproliferative effect on the human tumor cell lines in a dose-dependent manner. The most potent 13q demonstrated good efficacy in the prostate cancer PC-3 tumor xenograft model.

Keywords: Antiproliferation; Aurora B kinase; Benzoxazole analogs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Aurora Kinase B / antagonists & inhibitors*
  • Aurora Kinase B / metabolism
  • Benzoxazoles / chemical synthesis
  • Benzoxazoles / chemistry
  • Benzoxazoles / pharmacology*
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Humans
  • Mice
  • Mice, Nude
  • Models, Molecular
  • Molecular Structure
  • Neoplasms, Experimental / drug therapy*
  • Neoplasms, Experimental / pathology
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Benzoxazoles
  • Protein Kinase Inhibitors
  • AURKB protein, human
  • Aurora Kinase B