The multivalent effect in glycosidase inhibition: probing the influence of architectural parameters with cyclodextrin-based iminosugar click clusters |
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Authors: | Decroocq Camille Rodríguez-Lucena David Russo Virginie Mena Barragán Teresa Ortiz Mellet Carmen Compain Philippe |
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Institution: | Laboratoire de Synthèse Organique et Molécules Bioactives, Université de Strasbourg, et CNRS (UMR 7509), Ecole Européenne de Chimie, Polymères et Matériaux, 25 rue Becquerel, 67087 Strasbourg, France. |
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Abstract: | In contrast to most lectins, glycosidases may appear to be unpromising targets for multivalent binding because they display only a single active site. To explore the potential of multivalency on glycosidase inhibition, unprecedented cyclodextrin-based iminosugar conjugates have been designed and prepared. The synthesis was performed by way of Cu(I) -catalyzed azide-alkyne cycloaddition reaction under microwave activation between propargylated multivalent β-cyclodextrins and an azide-armed N-alkyl 1-deoxynojirimycin derivative. Evaluation with a panel of glycosidases of this new class of glycomimetic clusters revealed the strongest affinity enhancement observed to date for a multivalent glycosidase inhibitor, with binding enhancement up to four orders of magnitude over the corresponding monovalent ligand for α-mannosidase. These results demonstrate that the multivalency concept extends beyond carbohydrate-lectin recognition processes to glycomimetic-enzyme inhibition. |
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Keywords: | click chemistry cyclodextrins glycosidases iminosugars inhibitors |
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