| GD3 is a minor ganglioside found in most normal tissue, except placenta and thymus, and has also been described as specifically expressed on the surface of a small subset of normal human peripheral blood T cells. It is highly expressed only during development and in pathological conditions. The regulation of ganglioside biosynthesis and consequently of GD3 is not only poorly established but also complex. In our laboratory, we are interested in the synthesis of C-glycoside analogs because such glycoconjugates are expected to be resistant to catabolism and have increased biological half-lives, leading to derivatives with significant therapeutic potential.;The target is the "double" C-glycoside analog of GD3, using samarium-mediated C-glycosylation, which provides an analog with two carbon linkages between two sialic acids and lactoside. This target is predicted to have improved biological and pharmacological activities based on an anticipated longer half-life, making this GD3 analog a potentially useful new therapeutic agent. Our goal is not only to replace the O-linkage by the more stable C-linkage but also insert one carbon atom into the sialic acid residues to be a carbon-"extended" neuraminic disaccharide. This carbon-extended Neu5Ac C-disaccharide will be the ideal mimic of GD3 sialic acid moiety and will theoretically imitate the natural O-glycoside of GD3. However, the critical point of the synthesis remains the addition of one carbon atom to the Neu5Ac acceptor. If this problem can be solved, the original target alpha(2→8) GD3 ganglioside can be synthesized.;Polysaccharides play a wide variety of biological roles. At the microbiological level, polysaccharides and other carbohydrates are abundant on bacterial, fungal, parasitic, and viral surface structures in pathogenic and non-pathogenic organisms. Polysaccharides are considered as T cell-independent antigens based on the lack of T cell-dependent responses to these typically negatively charged or uncharged molecules. However, bacterial zwitterionic polysaccharides (ZPSs) represent an unusual group of bacterial carbohydrates and show the ability to activate T cells. ZPSs have unique immunological properties such as they are small molecules which can elicit a potent CD4+ T cell response in vitro.;We have been working on the samarium-mediated synthesis of C -glycosides of Neu5Ac for many years, it there would be a significant advantage to introduce C-glycoside analogs into zwitterionic structures. Thus, we designed a strategy to couple Neu5Ac residues, using reductive amination, to form new Neu5Ac oligosaccharides, " N,C-glycosides". These N,C-glycosides carry nitrogen-containing functional groups at two positions, the original 5-acetamido group and a new amino group at the linker. The amino groups at the linker are the first positions that will be converted into positively charged NH 3+ groups to form a different zwitterionic species, having positive charges at the linker rather than at an exocyclic position.;Every year, during the flu season, influenza viruses circulate worldwide and are the cause of a great number of fatalities, particularly in the young children and the elderly. Influenza viruses gain entry into the cells using their neuraminidases by binding to hemagglutinin onto sialic acid residues and hydrolyzing them. Therefore, neural-minidase inhibitors have been developed and introduced to the market. However, with only two effective neuraminidase inhibitors on the market, the different forms of influenza viruses have developed resistance through genetic mutations. Recently, the synthesis of 4-triazole-modified Zanamivir analogs, using click chemistry, have been reported and led to the discovery of some analogs possessing EC50 values comparable to Zanamivir. The biologically benign 1,2,3-triazole group is thus able to replace the guanidine group in the C-4 position of Zanamivir without loss of activity.;A new strategy has been developed to access N-glycosides of sialic acid by reacting an azido sialic acid donor with alkynes derivatives using copper (I)-catalyzed azide-alkyne Huisgen cycloaddition in high yield, high stereoselectivity and in a short amount of time. The 1,2,3-triazole of sialic acids thus obtained constitute a new class of potential neuraminidase inhibitors. In this work, a 1,2,3-triazole-linked sialic acid has been synthesized as a model compound for proof of concept and the strategy has then been applied to the synthesis of 1,2,3-triazole-linked sialic acid disaccharide and dendrimer. The efficiency of click chemistry procedure allowed access to these compounds in excellent yields. This work is still ongoing with the preparation of a library of sialic acids derivatives using this methodology. |
