New approaches for the stereoselective synthesis of glycans of therapeutic interest

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It is now recognized that carbohydrates and their conjugates are involved in a plethora of important biological processes such as the immune response and bacterial infections. Well-defined glycans are urgently needed for the in-depth understanding of these mechanisms as well as for the development of sugar-based medicines. In the last years, advances in chemical synthesis have made possible the preparation of complex glycans free from biological contaminants, some of which have been approved as therapeutics. However, carbohydrate chemists are still facing important challenges such as the need for non-traditional and eco-friendly synthetic routes as well as the lack of general procedures for the formation of glycosidic bonds. The long-term goal of our research program is to develop novel and straightforward synthetic approaches to access oligosaccharides and glycoconjugates of therapeutic interest. Our first research theme is to achieve the total synthesis of sponge-derived glycolipids of unique structural features following an innovative “programmed” glycosylation reaction. Found within marine sponges of the New Zealand coral reef, the pharmacological potential of these glycolipids has yet to be explored due to the scarcity of the natural source coupled with the tedious purification procedures. The glycolipids will be synthesized in a minimal number of steps based on the differential reactivity of sugars and evaluated in vitro for their biological activities (anticancer, antibiotic, immunostimulant). In a second research theme, novel glycosylation methodologies for the synthesis of bacterial sugars of atypical configurations will be developed and the reaction mechanisms studied. These methods will be applied to the preparation of biologically relevant glycans, such as heptosides and Kdo glycosides, found in the surface polysaccharides of human pathogenic bacteria. Burkholderia pseudomallei, a potential bioterrorism threat, Campylobacter jejuni, the world's leading cause of bacterial diarrhea, as well as Neisseria meningitidis, the causative agent of meningitis, are all expressing these sugars on their surface. Considered as virulence factors and protective antigens, the synthesis of heptosides and Kdo glycosides is still problematic for chemists. We thus propose to tackle this challenge by developing general and efficient synthetic routes to access them. By providing rapid and eco-friendly glycosylation methodologies, breaking with classical approaches, our work will help make accessible the synthesis of complex glycans by non-experts in the field. In addition to enhance the fundamental scientific knowledge in organic chemistry, the proposed research program could trigger the discovery of sugar-based medicines that could find applications to treat human diseases, to kill resistant pathogens and to develop novel adjuvants, diagnostics and vaccines.