C-glycosides and aza-C-glycosides as potential glycosidase and glycosyltransferase inhibitors.
Glycosylation as one of most important post-translational modification of gene products is often critical to specific cellular biological functions. Since elevated glycoprocessing enzyme activities have been implicated in the development of various diseases including cancer metastasis, glycosidases and glycosyltransferases are considered as therapeutic targets. Azasugars, the first generation of enzyme inhibitors, have been extensively investigated and two azasugar-based drugs (Miglitol and Miglustat) have been approved. Aza-C-glycosides, molecules with an azasugar core and various C-aglycons attached at the pseudo anomeric center, have the potential to become the second-generation inhibitors with improved specificity and membrane permeability. In this review, C-glycosides, aza-C-glycosides, and aza-C-disaccharides are introduced as glycoprocessing enzyme inhibitors. The synthetic approaches toward those molecules are described based on the key reactions, which include reductive amination, nucleophilic ring opening of epoxides, nucleophilic addition to imines (C=N), and hetero-Michael additions. Aza-C-glycoside-based libraries are also described for the discovery of promising second-generation inhibitors.
Zou
Wei
W
Institute for Biological Sciences, National Research Council of Canada, Ottawa, Ontario, Canada K1A 0R6. wei.zou@nrc-cnrc.gc.ca
D004187:Disaccharides / Q000138:chemical synthesis / Q000737:chemistry; D015195:Drug Design; D006026:Glycoside Hydrolases / Q000037:antagonists & inhibitors*; D006027:Glycosides / Q000138:chemical synthesis* / Q000737:chemistry; D016695:Glycosyltransferases / Q000037:antagonists & inhibitors*; D009711:Nucleotides / Q000138:chemical synthesis / Q000737:chemistry
D004187:Disaccharides; D006027:Glycosides; D009711:Nucleotides; D016695:Glycosyltransferases; D006026:Glycoside Hydrolases