Design and synthesis of multi-galactosides resistant to glycosidases

M.L. UHRIG; A.J. CAGNONI; S.G. GOUIN; O. VARELA; J. KOVENSKY

Tokio

Congreso; International Carbohydrate Symposium 2010; 2010

International Carbohydrate Organization

Galectins are a family of conserved proteins defined by their affinity for beta-galactosides. They are involved in inflammatory process, immunologic responses and cancer growth, events which require the formation of galectin-carbohydrate lattices, from multivalent ligands occurring in glycoproteins and glycolipids. To interfere with galectin-carbohydrate interactions, a current challenge is the synthesis of specific galectin inhibitors for therapeutic purposes, designed to be compatible with biological systems. The use of hydrophilic carbohydrate scaffolds for the synthesis of multivalent galactosides represents an interesting approach to improve their farmacokinetics and bioavailability.2 In addition, replacing the anomeric oxygen by a sulfur in the galactoside epitope recognized by the lectin will increase its stability toward glycosidases. A variety of 1-beta-thiogalactosides linked to a terminal triple bond through PEG-chains of variable lengths have been synthesized. On the other hand, we have prepared oligosaccharidic scaffolds derived from trehalose, maltose and maltotriose containing azide groups, by direct azidation of the free oligosaccharides with NaN3/PPh3/CBr4. The coupling of the thiogalactoside residues to the scaffolds was achieved by Cu(I) catalized cycloaddition under MW irradiation. Thus, a family of compounds containing 2 to 4 residues of 1-beta-thiogalactose have been obtained in excellent to moderate yields, depending on the valency of the desired product. Deacetylation with TEA/MeOH/H2O led to the final products. After complete characterization by NMR spectroscopy and HR-MS techniques, the new multivalent ligands have been evaluated as inhibitors of E.coli beta-galactosidase.