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A molecular-diversity-oriented approach for the preparation of bicyclic sp(2)-iminosugar glycomimetics related to nojirimycin and galactonojirimycin is reported. The synthetic strategy takes advantage of the ability of endocyclic pseudoamide-type atoms in five-membered cyclic iso(thio)ureas and guanidines to undergo intramolecular nucleophilic addition to the masked carbonyl group of monosaccharides. The stereochemistry of the resulting hemiaminal stereocenter is governed by the anomeric effect, with a large preference for the axial (pseudo-α) orientation. A library of compounds differing in the stereochemistry at the position equivalent to C-4 in monosaccharides (D-gluco and D-galacto), the heterocyclic core (cyclic isourea, isothiourea or guanidine) and the nature of the exocyclic nitrogen substituent (apolar, polar, linear or branched) has been thus prepared and the glycosidase inhibitory activity evaluated against commercial glycosidases. Compounds bearing lipophilic substituents behaved as potent and very selective inhibitors of β-glucosidases. They further proved to be good competitive inhibitors of the recombinant human β-glucocerebrosidase (imiglucerase) used in enzyme replacement therapy (ERT) for Gaucher disease. The potential of these compounds as pharmacological chaperones was assessed by measuring their ability to inhibit thermal-induced denaturation of the enzyme in comparison with N-nonyl-1-deoxynojirimycin (NNDNJ). The results indicated that amphiphilic sp(2)-iminosugars within this series are more efficient than NNDNJ at stabilizing β-glucocerebrosidase and have a strong potential in pharmacological chaperone (PC) and ERT-PC combined therapies.

organic and biomolecular chemistry

Bicyclic (galacto)nojirimycin analogues as glycosidase inhibitors: Effect of structural modifications in their pharmacological chaperone potential towards β-glucocerebrosidase