Synthesis and evaluation of fluorobenzoylated di- and tripeptides as inhibitors of cyclooxygenase-2 (COX-2)

Bioorg Med Chem. 2012 Apr 1;20(7):2221-6. doi: 10.1016/j.bmc.2012.02.021. Epub 2012 Feb 15.

Abstract

A series of fluorobenzoylated di- and tripeptides as potential leads for the development of molecular probes for imaging of COX-2 expression was prepared according to standard Fmoc-based solid-phase peptide synthesis. All peptides were assessed for their COX-2 inhibitory potency and selectivity profile in a fluorescence-based COX binding assay. Within the series of 15 peptides tested, cysteine-containing peptides numbered 7, 8, 11 and 12, respectively, were the most potent COX-2 inhibitors possessing IC(50) values ranging from 5 to 85 μM. Fluorobenzoylated tripeptides 7 and 8 displayed some COX-2 selectivity (COX-2 selectivity index 2.1 and 1.6), whereas fluorobenzoylated dipeptides 11 and 12 were shown not to be COX-2 selective. Fluorbenzoylated tripeptide FB-Phe-Cys-Ser-OH was further used in molecular modeling docking studies to determine the binding mode within the active site of the COX-2 enzyme.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Benzoic Acid / chemistry*
  • Binding Sites
  • Catalytic Domain
  • Cyclooxygenase 2 / chemistry*
  • Cyclooxygenase 2 / metabolism
  • Cyclooxygenase 2 Inhibitors / chemical synthesis*
  • Cyclooxygenase 2 Inhibitors / chemistry
  • Dipeptides / chemical synthesis
  • Dipeptides / chemistry*
  • Fluorine / chemistry
  • Hydrogen Bonding
  • Mice
  • Molecular Dynamics Simulation
  • Oligopeptides / chemical synthesis
  • Oligopeptides / chemistry*
  • Solid-Phase Synthesis Techniques

Substances

  • Cyclooxygenase 2 Inhibitors
  • Dipeptides
  • Oligopeptides
  • Fluorine
  • Benzoic Acid
  • Cyclooxygenase 2