Nondegradative Sulfation of Polysaccharides. Synthesis and Structure Characterization of Biologically Active Heparan Sulfate Mimetics

Abstract

Reproducible and nondegradative preparation of sulfated molecules exhibiting diverse biological properties requires caring out sulfation reactions under ready controlled mild conditions. Although, to date, sulfur trioxide is the most used sulfation agent, its highly acid character has brought its use in association with different nitrogen bases as sulfur trioxide−nitrogen base complexes and/or by introduction of basic solvents as pyridine. We have applied sulfur trioxide and other sulfation agents including protocols for the synthesis of biologically active sulfated polysaccharides and demonstrated that these agents provoke cleavage of glycosidic bonds and other acid labile functions as amides, esters and even ethers. These facts prompted us to develop new reaction conditions for a general and nondestructive sulfation protocol. Our approach consists of the introduction of 2-methyl-2-butene as an acid scavenger of neutral character. Application of the method leads to an efficient, reproducible, and controlled synthesis of acid labile dextran derivatives well-known to be active in tissue repair and recently proposed for example as a new therapeutic agent for prion diseases. A novel 1H NMR structural analysis of this kind of macromolecules is presented. This method offers a new advance for more efficient synthesis of biologically active sulfated macromolecules.

A Synthetic Glycosaminoglycan Mimetic Binds Vascular Endothelial Growth Factor and Modulates Angiogenesis

“…Synthesis of OTR4120-OTR4120 is a carboxymethyl-dextran sulfate with a degree of substitution of 1.13 for sulfate residues and 0.46 for carboxymethyl residues, for a maximal degree of substitution of 3.0 (29,30). These substitution degrees are similar to those assayed in heparin used as a control.…”

RGTA OTR4120, a heparan sulfate mimetic, is a possible long‐term active agent to heal burned skin

“…31 We developed a family of heparan sulfate mimetics called RGTAs. These polymers are engineered and selected to express a low anticoagulant activity compared with heparin 23 while preserving the protecting and potentiating effects of heparin on heparin-binding growth factor activities. 17,32,33 The aim of this work was to evaluate the effect of the RGTA OTR4120 on the quality of matrix remodeling in an animal model of skin burn injury.…”

“…The RGTA OTR4120 was obtained from OTR3 and prepared as described in Ref. 23. Briefly, this water-soluble dextran derivative was prepared from T40 dextran by carboxymethylation with monochloracetic acid treatment, followed by O-sulfonation with SO 3 -DMF complex in the presence of 2-methyl-2-butene.…”

Insights on a new path of pre-mitochondrial apoptosis regulation by a glycosaminoglycan mimetic

“…The structure characterization of this water-soluble dextran derivative has been described elsewhere. 37 Briefly, the product is composed of about 200 glucosidic units bounded by b1-6 linkages. This compound contains carboxylic and sulfate substitutions in contents comparable to those found in heparin: the sulfate degree of substitution was 1.1 and that of carboxylate (dsC) was 0.5.…”