Synthesis of heparin oligosaccharides and their interaction with eosinophil-derived neurotoxin

Org Biomol Chem. 2012 Jan 28;10(4):760-72. doi: 10.1039/c1ob06415k. Epub 2011 Dec 6.

Abstract

A convenient route for the synthesis of heparin oligosaccharides involving regioselective protection of D-glucosamine and a concise preparation of rare L-ido sugars from diacetone α-D-glucose is described. Stereoselective coupling of a D-glucosamine-derived trichloroacetimidate with a 1,6-anhydro-β-L-idopyranosyl 4-alcohol gave the desired α-linked disaccharide, which was used as repeating unit for dual chain elongation and termination. Stepwise assembly from the reducing to the non-reducing end with a D-glucosamine-derived monosaccharide as starting unit furnished the oligosaccharide skeletons having different chain lengths. A series of functional group transformations afforded the expected heparin oligosaccharides with 3, 5 and 7 sugar units. Interaction of these oligosaccharides with eosinophil-derived neurotoxin (EDN), a cationic ribonuclease and a mediator produced by human eosinophils, was further investigated. The results revealed that at 5 μg mL(-1), the heptasaccharide has sufficiently strong interference to block EDN binding to Beas-2B cells. The tri- and pentasaccharides have moderate inhibitory properties at 50 μg mL(-1) concentration, but no inhibition has been observed at 10 μg mL(-1). The IC(50) values of the tri-, penta- and heptasaccharides are 69.4, 47.2 and 0.225 μg mL(-1), respectively.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anticoagulants / chemical synthesis*
  • Anticoagulants / pharmacology*
  • Cell Line
  • Eosinophil-Derived Neurotoxin / antagonists & inhibitors
  • Eosinophil-Derived Neurotoxin / metabolism*
  • Heparin / chemical synthesis*
  • Heparin / pharmacology*
  • Humans
  • Oligosaccharides / chemical synthesis
  • Oligosaccharides / pharmacology

Substances

  • Anticoagulants
  • Oligosaccharides
  • Heparin
  • Eosinophil-Derived Neurotoxin