Synthesis and Characterization of Linker-Armed Fucose-Based Glycomimetics

Glycomimetic molecules can be used to antagonize the action of carbohydrate-binding proteins (lectins) involved in biological processes of high relevance for human and plant disease. In this paper we describe the derivatization with appropriate linkers of a previously described glycomimetic containing an α-fucosyl amide anchor that is known to act as antagonist of the dendritic cell lectin DC-SIGN. Key steps of the functionalization were the stereoselective epoxidation of an intermediate β-amino-cyclohexene-carboxylic acid derivative, followed by regioselective opening with 2-chloroethanol. Introduction of the linker does not alter the DC-SIGN binding properties of the molecule, as shown by Surface Plasmon Resonance and NMR studies. Whereas the fucose-based anchor allows the mimic to interact efficiently with fucose-binding lectins, the linker could also be exploited for the synthesis of glycodendrimers, as well as for the study of ligand interactions with commercially available lectins by array technology. In particular, a tetravalent fucosylated dendrimer was obtained that displayed a low-micromolar range of activity against DC-SIGN. Additionally, screening of the ligand against lectins with common fucose specificity in an array format allowed the lectin from the bacterium Ralstonia solanacearum (RSL) to be identified as a potential target protein and suggested that even simple glycomimetic structures can attain a significant amount of selectivity among lectins with analogous specificity.