A collection of new reversible glycosidase inhibitors of the iminoalditol type featuring N-substituents containing perfluorinated regions has been prepared for evaluation of physicochemical, biochemical and diagnostic properties. The vast variety of feasible oligofluoro moieties allows for modular approaches to customised structures according to the intended applications, which are influenced by the fluorine content as well as the distance of the fluorous moiety from the ring nitrogen. The first examples, in particular in the D-galacto series, exhibited excellent inhibitory activities. A preliminary screen with two human cell lines showed that, at subinhibitory concentrations, they are powerful pharmacological chaperones enhancing the activities of the catalytically handicapped lysosomal D-galactosidase mutants associated with GM1 gangliosidosis and Morquio B disease.
Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Galactosidases/antagonists & inhibitors , Gangliosidosis, GM1/drug therapy , Sugar Alcohols/chemistry , Sugar Alcohols/pharmacology , Cell Line , Coffee/enzymology , Enzyme Inhibitors/therapeutic use , Escherichia coli/enzymology , Fibroblasts/drug effects , Fibroblasts/enzymology , Galactosidases/metabolism , Halogenation , Humans , Imines/chemistry , Imines/pharmacology , Imines/therapeutic use , Rhizobium/enzymology , Sugar Alcohols/therapeutic use
The Amadori rearrangement was introduced as a key step for the conjugation of carbohydrate moieties with suitable amines such as aliphatic amines and amino acid derivatives. The rearrangement products were further transformed into the corresponding 1-N,2-O cyclic carbamates employing triphosgene to obtain anomerically stable glycoconjugates. The reaction conditions were probed on a model substrate, 3,5-di-O-benzyl-alpha,beta-d-glucofuranose and further applied to d-glycero-d-gulo-heptose, which gave 'd-gluco-conjugates' in the alpha-anomeric form exclusively in high isolated yields.
Glycoconjugates/chemical synthesis
