Design and synthesis of multi-galactosides resistant to glycosidases

MARÍA LAURA UHRIG; ALEJANDRO J. CAGNONI; SÉBASTIEN S. GOUIN; OSCAR VARELA; JOSÉ KOVENSKY

Chiba, Tokyo, Japón

Simposio; 25th International Carbohydrate Symposium; 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 that occur in glycoproteins and glycolipids. A current challenge is the synthesis of specific galectin inhibitors for therapeutic purposes. They are designed to interfere with galectin-carbohydrate interactions, being compatible with biological systems. The use of hydrophilic carbohydrate scaffolds for the synthesis of multivalent galactosides represents an interesting approach to improve their pharmacokinetics and bioavailability. In addition, replacing the anomeric oxygen by sulfur in the galactoside epitope recognized by the lectin, will increase its stability towards glycosidases. We report here the synthesis of a variety of 1-beta-thiogalactosides linked to a terminal triple bond through polyethyleneglycol chains of variable lengths. Also, azide containing oligosaccharide scaffolds were prepared from trehalose, maltose and maltotriose, by direct azidation with NaN3/PPh3/CBr4. Click reaction between the thiogalactoside residues and the azide scaffolds under MW irradiation, afforded a family of compounds containing 2 to 4 residues of 1-beta-thiogalactose. The yields went from moderate to excellent depending on the valency of the desired product, which was attributed to entropic effects. Deacetylation with Et3N/MeOH/H2O led to the final products. After complete characterization by NMR spectroscopy and HR-MS techniques, the resistance of the new multivalent ligands to E. coli beta-galactosidase has been evaluated.