Remove to improve. Removal of the hydroxymethyl groups in 1 to give 2 significantly enhances inhibitory potency towards glucosylceramide β‐glucosidase (GCase) and abolishes inhibition towards α‐glucosidases. Xylitol 2 doubles the residual activity of GCase in fibroblasts from Gaucher patients at subinhibitory concentration (10 nM). This compound is therefore a promising candidate for the development of small‐molecule drugs for the treatment of Gaucher's disease without the side effects associated with α‐glucosidase inhibition.

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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Superball! A dodecavalent iminosugar derivative with a fullerene core (see picture) shows a binding enhancement of up to three orders of magnitude over the corresponding monovalent ligand in glycosidase inhibition assays. This is the first evidence of a significant multivalent effect in glycosidase inhibition.

A series of cyclopeptoid-based iminosugar clusters has been evaluated to finely probe the ligand content-dependent increase in α-mannosidase inhibition. This study led to the largest binding enhancement ever reported for an enzyme inhibitor (up to 4700-fold on a valency-corrected basis), which represents a substantial advance over the multivalent glycosidase inhibitors previously reported. Electron microscopy imaging and analytical data support, for the best multivalent effects, the formation of a strong chelate complex in which two mannosidase molecules are cross-linked by one inhibitor.

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Olefin metathesis is one of the most powerful synthetic tool to access amine-containing heterocycles and alkaloids. A major drawback associated with the use of amines concerns their ability to coordinate to metal-alkylidene complexes and to interfere unproductively with catalytic activity. Based on literature precedents, it has been established as a "dogma" that efficient metathesis reactions are suppressed in the presence of basic amines and that such substrates must invariably be deactivated by conversion of the amines to the corresponding carbamates or ammonium salts. However, an increasing number of examples of amine-containing compounds that are good substrates for metathesis is being reported in the literature. How can this "non-classical" reactivity be rationalized and exploited? The purpose of this review is to provide an overview of successful metathesis reactions performed with aminecontaining compounds in order to allow some guidelines to be formulated. A special emphasis is placed on the different parameters that may influence the outcome of the reaction such as steric effects, amine basicity, and the nature of the catalyst.

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