Chemical Modification of Glycosaminoglycan Polysaccharides

Abstract

The linear anionic class of polysaccharides, glycosaminoglycans (GAGs), are critical throughout the animal kingdom for developmental processes and the maintenance of healthy tissues. They are also of interest as a means of influencing biochemical processes. One member of the GAG family, heparin, is exploited globally as a major anticoagulant pharmaceutical and there is a growing interest in the potential of other GAGs for diverse applications ranging from skin care to the treatment of neurodegenerative conditions, and from the treatment and prevention of microbial infection to biotechnology. To realize the potential of GAGs, however, it is necessary to develop effective tools that are able to exploit the chemical manipulations to which GAGs are susceptible. Here, the current knowledge concerning the chemical modification of GAGs, one of the principal approaches for the study of the structure-function relationships in these molecules, is reviewed. Some additional methods that were applied successfully to the analysis and/or processing of other carbohydrates, but which could be suitable in GAG chemistry, are also discussed.

Keywords: chemical modification; glycosaminoglycans; polysaccharides; sulfation.

Figure 1

Typical repeating disaccharides of chondroitin ((A), upper) and dermatan ((A), lower) sulfates ((A), lower) and repeating disaccharides of heparan sulfate ((B), upper) and heparin ((B), lower).

Figure 2

De-O and N-sulfation reactions in heparin, combinations which allow systematic modification of the substitution patterns of heparin at I-2, A-6, and A-2 positions.

Figure 3

Reactions of 2-O-sulfated L-IdoA 2-sulfate in heparin and heparan sulfate under basic conditions and subsequent opening in acid or base. Treatment in strong base creates de-O-sulfated α L-iduronate residues, while treatment in acid generates α L-galacturonate residues involving inversion of the stereochemistry at positions 2 and 3.

Figure 4

Potential selective de-N-acetylation of β-D-galactosamine in CS or DS achieved using hydrazine hydrate with ammonium salts as catalysts.

Figure 5

Terminal 1,6-anhydro-D-mannosamine residues (upper left) formed during depolymerization under basic conditions, during enoxaparin manufacture, are oxidized by periodate to cleave the carbon to carbon (C2-C3) bond. The aldehydes formed can be reduced further to alcohols (lower right). Terminal 1,6-anhydro-D-glucosamine residues (upper right) in enoxaparin are not susceptible to periodate oxidation.