New Nitrogen-Containing Glycomimetics: Synthesis and Application in Metabolic and Neurological Disorders

Iminosugars and azasugars, fascinating monosaccharide analogues in which a nitrogen atom replaces the endocyclic oxygen or the anomeric carbon, have been extensively investigated as glycosidases and glycosyltransferases inhibitors. More recently, they became attractive as potential therapeutic agents towards some metabolic disorders, such as lysosomal storage disorders (LSDs), in view of the observed counter-intuitive increase of enzymatic activity when they are employed at sub-inhibitory concentration. In such conditions, imino- and azasugars stabilize and enhance the activity of the misfolded enzyme responsible for the occurrence of the disorder, thus acting as pharmacological chaperones. In addition, the well-established connection between lysosomal enzymes activity and development of neurodegenerative disorders, make such pharmacological chaperones good candidates also for the treatment of neurodegenerative disorders, like Parkinson’s disease. Our efforts in the development of straightforward and innovative synthetic strategies to access diversely functionalized imino- and azasugars from inexpensive carbohydrate will be presented, together with the most relevant results obtained towards therapeutically relevant targets, some of which privilege the interaction with multivalent ligands, such as imino- and azasugar-based dendrimers and nanoparticles. Recent progress in mechanism elucidation by determining the protonation state of iminosugars inside the human enzyme active cavity will be also discussed.