The biological activity of carbohydrates extends far beyond their classical roles as energy source or structural building blocks. The molecular recognition of sugars by protein receptors can be found in many biological processes like cell-cell communication, immune response, infection, etc. The success of protein-carbohydrate interactions is conditioned to the fulfillment of conformational requirements imposed by the recognition site in the protein over the, inherently flexible, carbohydrate ligand. Hence, the study of the conformational preferences of saccharides is fundamental for the understanding of protein-carbohydrate interactions. The flexibility of sugars is mainly dependent on the free rotation around the inter-glycosidic bond and the hydroxymethyl group (C5-C6), being saccharides with (1-6) connections among the most flexible structures. The rotation around C5-C6 is, in turn, determined by the configuration of the stereocenter C4, the type of substitution on hydroxyl C6, the configuration of the anomeric carbon, and the nature of the aglycone substituent. Towards a better understanding of the effects that the aglycone substituent has over the conformational properties around C5-C6 bond, we are designing and synthesizing a series of model glycosides of rutinose (αRha(1→6)βGlcOR) and studying their conformational preferences in solution by NMR. Given the inherent flexibility of the (1→6) linkage, the hydrophobic nature of the rhamnose moiety, and the simplicity of the NMR spectra, rutinose constitutes a convenient model saccharide for performing these studies. We have synthesized a series of six rutinosides of alkyl alcohols with different molecular volumes to shed light about the influence of the aglycone’s steric properties over the conformational preferences around interglycosidic linkages in these saccharides. Based on the conformational analysis of the interglycosidic linkage by NMR, we found a conformational shift from <i>gt </i>conformer to a <i>tg </i>conformer as the bulkiness of anomeric substituent increases. This finding thus opens the door to further studies related to the correlation between conformation and binding affinities in saccharides using fish protein (CSL-3) as the receptor for testing the affinity of rutinosides by Isothermal caloriemetry (ITC).

Rutinose glycosides as model compounds for the design of conformational glycomimetics

ACS Spring 2022

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