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.
Chemistry. 2011 Dec 2;17(49):13825-31. doi: 10.1002/chem.201102266. Epub 2011 Nov 3.
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.
与大多数凝集素不同，糖苷酶似乎不太可能成为多价结合的靶标，因为它们只显示出一个单一的活性位点。为了探索多价结合对糖苷酶抑制的潜力，设计并制备了前所未有的基于环糊精的亚氨基糖缀合物。该合成是通过在微波激活下，通过 Cu(I) 催化的叠氮-炔环加成反应，在多价 β-环糊精和带有叠氮基的 N-烷基 1-去氧野尻霉素衍生物之间进行的。对该新型糖模拟类糖簇的一系列糖苷酶进行评估，发现其对多价糖苷酶抑制剂的亲和力增强是迄今为止观察到的最强的，与相应的单价配体相比，α-甘露糖苷酶的结合增强高达四个数量级。这些结果表明，多价概念不仅扩展到碳水化合物-凝集素识别过程，还扩展到糖模拟-酶抑制。
