Synthesis and Evaluation of Isourea-Type Glycomimetics Related to the Indolizidine and Trehazolin Glycosidase Inhibitor Families

A practical synthesis of reducing isourea-derived azasugar glycomimetics related to the indolizidine and trehazolin glycosidase inhibitor families with different pK(a) values is disclosed. The polyhydroxylated bicyclic system was built from readily accessible hexofuranose derivatives through a synthetic scheme that involves the preparation of a 5-deoxy-5-carbodiimido adduct by triphenylphosphine-mediated tandem Staudinger--aza-Wittig-type coupling of azide and isothiocyanate precursors, intramolecular cyclization of a transient vic-hydroxycarbodiimide derivative, and nucleophilic addition of the endocyclic nitrogen atom of the generated 2-amino-2-oxazoline intermediate, with a pseudo-C-nucleoside structure, to the masked aldehyde group of the monosaccharide. The last step is pH-dependent so that the final compounds can pivot between the furanose and the 2-oxaindolizidine forms. Nevertheless, the indolizidine tautomer having the R configuration at the aminoacetalic center, fitting the anomeric effect, was the only species detected in solution at neutral or slightly acidic pH when starting from solutions at basic pH. Glycosidase inhibition tests (K(i) values down to 1.9 microM) showed a marked dependence of the selectivity and potency toward alpha- and beta-glucosidases upon the nature of the substituent at the exocyclic isourea nitrogen, shifting from alpha- to beta-selectivity when going from hydrophilic to hydrophobic substituents. Enzyme inhibition is also pH dependent, supporting a dominant role for the uncharged form of the polyhydroxyiminoindolizidine system in the inhibition of beta-glucosidases.