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The late-onset form of Tay-Sachs disease displays when the activity levels of human β-hexosaminidase A (HexA) fall below 10% of normal, due to mutations that destabilise the native folded form of the enzyme and impair its trafficking to the lysosome. Competitive inhibitors of HexA can rescue disease-causative mutant HexA, bearing potential as pharmacological chaperones, but often also inhibit the enzyme O-glucosaminidase (GlcNAcase; OGA), a serious drawback for translation into the clinic. We have designed sp²-iminosugar glycomimetics related to GalNAc that feature a neutral piperidine-derived thiourea or a basic piperidine-thiazolidine bicyclic core and behave as selective nanomolar competitive inhibitors of human Hex A at pH 7 with a ten-fold lower inhibitory potency at pH 5, a good indication for pharmacological chaperoning. They increased the levels of lysosomal HexA activity in Tay-Sachs patient fibroblasts having the G269S mutation, the highest prevalent in late-onset Tay-Sachs disease. [ABSTRACT FROM AUTHOR]

An efficient synthetic pathway to guanidine-type iminosugars based on the ability of the carbonyl group of an l-idose precursor to act as the electrophilic target for the nitrogen atom of a guanidine substituent located at the C-5 position is described. Biological evaluation of the new glycomimetics confirms a strong influence of the nature of the substituents at the nitrogen atoms on the glycosidase inhibitory properties.

Research has been conducted on the polyhydroxylated 6-oxa-nor-tropanes. The synthesis of these compounds which incorporate the structural features of calystegine B (sub)2 from 5-deoxy-5-thioureido and 5-ureido-L-idofuranose precursors has been carried out and the results are discussed.

Research examines the molecular recognition processes in carbohydrates with reference to the binding properties of the multitopic sugar-thiourea conjugates. Data on the complex stoichiometry and association constant for glutarate and octyl-beta-D-glucopyranoside are discussed in terms of the number of hydrogen bond donating sites and ligand binding efficiency.

Research has been conducted on the synthesis of aminoketalic castanospermine analogues. The analysis of the polyhydroxylated bicyclic system is presented.

Research was conducted to characterize ionic intermediates through a comparative analysis of base- and acid-catalayzed transformations in S-linked thiooligosaccharides and their O-linked counterparts. In this study, the 1-O(S)-D-glucopyranosyl-D-fructose disaccharide model was utilized. Results confirm the important role played by sulfur atom participation reactions in thiooligosaccharide chemistry.

Existing procedures help prepared 3-deoxy-3-isothiocyanato derivatives of D-glucose, D-allose and D-galactose. These derivatives undergo intramolecular cyclization, generating enantiomerically pure 2-thioxotetrahydro-1,3-O,N-heterocycles with chirality at C-4. Configuration of the sugar controls the outcome of the reaction and the fully unprotected D-gluco derivative undergoes a nucleophile addition of the gamma-oxo group to the NCS group, producing 4-(trihydroxypropyl)tetrahydrooxazine-2-thione.

6-deoxydi-O-isopropylidene-6-isothiocyanato-aldoses are deprotected and 6-amino-6-deoxy sugars interact with thiophosgene to synthesize chiral oxazolidine-2-thiones, which are obtained from sugar. Temporary 6-deoxy -6-isothiocyanato- or 6-(chlorothioformamido)-6-deoxy aldoses act as channels for the derivation of intramolecular 6,5-cyclic thiocarbamates due to the complex regioselectivity of the interactions. A pseudo-C-nucleoside geometry is observed in the oxazolidine-2-thiones. Steady compounds of 6-deoxy-6-isothiocyanatoaldopyranosides are formed when 6-amino-6-deoxyladopyranosides interact with thiophosgene. Bicyclic 2-thioxotetrahydro-1,3-oxazines are formed due to base-stimulated extramolecular cyclization.

The preparation of bicyclic carbohydrate mimics related to (+)-castanospermine incorporating a thiohydantoin moiety is described. Biological evaluation of the new [sp.sup.2]-iminosugar-type glycomimetics has shown a strong e ffect of the nature of the substituents at the nitrogen or oxygen atoms on the glycosidase inhibitory properties.

An efficient strategy is described for the synthesis of large-ring cyclodextrin (CD) analogs alternating [alpha],[alpha]E-trehalose disaccharide subunits and pseudoamide segments (cyclotrehalans (CTs)). The higher mobility of the pseudoamide bridges when compared with classical glycosidic linkages has provided these hosts with induced fitting capabilities toward smaller guests.

A modular and efficient method for the synthesis of cyclooligosaccharide receptors consisting of [alpha],[alpha]'-trehalose building blocks linked through pseudoamide segments, namely cyclotrehalans (CTs) is described. The results based on NMR and molecular mechanics and dynamics studies showed that CTs exhibited a convex-shaped hydrophobic cavity in which the [beta]-face of the monosaccharide subunits is oriented toward the inner side.

An efficient strategy is described for the synthesis of multi-valent mannosides based on a selectively functionalized carbohydrate scaffold. Molecular dynamics on representative glyco-conjugates has shown structural features such as rigidity of the scaffold for presenting the ligands and highly flexible mannone counterparts.

The xylylene moiety is employed as a rigid tether in the spacer-mediated synthesis of difructose dianhydrides (DFAs), a unique class of bis-spiroacetal derivatives present in food products. The rigid spacer concept is implemented to favor intermolecular processes leading to higher macrocyclic architectures that incorporate the bis-spiro fructodisaccharide subunit.

An efficient procedure of construction of 21-antennary heteroglycoclusters that is based on the beta-cyclodextrin (BetaCD) core is reported. Development, differentiation, morphogenesis, fertilization, the immune response, implantation, cell migration, and cancer metastasis are the some of the implications in which the heteroglycoclusters play an important role.

The modification of the glycosidase inhibitory properties of pyrolidine homoazasugars through the incorparation of the key ring nitrogen into liner or cyclic pseudoamide functionalities is discussed. This provides a new direction to development of highly selective glycosidase inhibitors.