Synthesis and biological evaluation of a sialyl Lewis X mimic with significantly improved E-selectin inhibition

Bioorg Med Chem Lett. 2001 Apr 9;11(7):923-5. doi: 10.1016/s0960-894x(01)00092-0.

Abstract

The synthesis of the highly potent E-selectin inhibitor 5 is described. Sialyl Lewis X mimic 5 was rationally designed by combining two previously disclosed beneficial sLe(x) modifications in a single molecule. The compound was found to be 30-fold more potent than sLe(x) in a static, cell-free equilibrium assay. Furthermore, compound 5 was highly active (IC50 = 10 microM) in a dynamic non-equilibrium assay in which sLe(x) did not inhibit neutrophil rolling at up to 1000 microM.

MeSH terms

  • Cell Movement / drug effects*
  • Drug Design
  • Drug Evaluation, Preclinical
  • E-Selectin / drug effects*
  • Endothelium / cytology
  • Glucosamine / chemistry
  • Humans
  • Inhibitory Concentration 50
  • N-Acetylneuraminic Acid / chemistry
  • Neutrophils / drug effects*
  • Neutrophils / physiology
  • Oligosaccharides / chemical synthesis*
  • Oligosaccharides / chemistry*
  • Oligosaccharides / pharmacology*
  • Sialyl Lewis X Antigen
  • Umbilical Veins / cytology

Substances

  • E-Selectin
  • Oligosaccharides
  • Sialyl Lewis X Antigen
  • N-Acetylneuraminic Acid
  • Glucosamine