Design and synthesis of hydrolytically stable multivalent ligands bearing thiodigalactoside analogues for peanut lectin and human galectin-3 binding.

Abstract

Herein, we describe the design and synthesis of a novel family of hydrolytically stable glycoclusters bearing thiodigalactoside (TDG) analogues as recognition elements of β-galactoside binding lectins. The TDG analogue was synthesized by thioglycosylation of a 6-S-acetyl-α-D-glucosyl bromide with the isothiouronium salt of 2,3,4,6-tetra-O-acetyl-β-D-galactose. Further propargylation of the TDG analogue allowed the coupling to azido-functionalized oligosaccharide scaffolds through copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) under microwave activation. The final mono-, di-, and tetravalent ligands were resistant to enzymatic hydrolisis by Escherichia coli β-galactosidase. Binding affinities to peanut agglutinin and human galectin-3 were measured by isothermal titration calorimetry which showed K(a) constants in the micromolar range as well as a multivalent effect. Monovalent ligand exhibited a binding affinity higher than that of thiodigalactoside. Docking studies performed with a model ligand on both β-galactoside binding lectins showed additional interactions between the triazole ring and lectin amino acid residues, suggesting a positive effect of this aromatic residue on the biological activity.

DOI: 10.1021/jo500883v

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@article{Cagnoni2014DesignAS, title={Design and synthesis of hydrolytically stable multivalent ligands bearing thiodigalactoside analogues for peanut lectin and human galectin-3 binding.}, author={Alejandro J. Cagnoni and Jos{\'e} Kovensky and Mar{\'i}a Laura Uhrig}, journal={The Journal of organic chemistry}, year={2014}, volume={79 14}, pages={6456-67} }