Combinatorial Approaches to Iminosugars as Glycosidase and Glycosyltransferase Inhibitors

Oligosaccharide processing enzymes such as glycosidases and glycosyltransferases are important classes of biocatalysts involved in synthesising specific oligosaccharide structures on proteins and lipids. These enzymes are known to be involved in a wide range of important biological processes, such as intestinal digestion, post-translational processing of glycoproteins, lysosomal catabolism of glycoconjugates and inter-cellular recognition events. Inhibition of these enzymes can disrupt biosynthesis of oligosaccharides, thus interfering in all of these processes. Hence, "glyco-enzyme" inhibitors might have enormous therapeutic potential in many diseases such as viral infection, cancer and diabetes. This very important prospect has led to increasing interest and demand for these compounds. Interference in oligosaccharide processing is the basis for the anti-influenza neuraminidase inhibitors that have recently been marketed and also for the potential use of glycosidase inhibitors against HIV, Gaucher's disease, hepatitis, and cancer. Since a rational design and synthesis of inhibitors are often extremely difficult due to the limited information regarding the structure of the active site, combinatorial approaches are particularly promising. This review will focus on synthetic efforts for the preparation of combinatorial libraries of glyco-enzyme inhibitors.