Synthetic Carbohydrate Chemistry Carbohydrates Are Among the Most

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Synthetic Carbohydrate Chemistry Carbohydrates are among the most difficult class of compounds to synthesize as a result of their limited (polyol) functionality and stereochemical complexity. New approaches are needed to improve methodology for the chemical and chemoenzymatic synthesis of carbohydrates especially those of critical biological and pharmacological importance. Figure. Influenza infection is pandemic and new anti-influenza agents are needed that target both H and N to avoid resistance. Stable glycoside synthesis for novel therapeutics : Carbohydrates, while relatively stable molecules contain functionality, such as glycosidic linkages, that are sensitive to acidic environments and enzymes present within the human body. Oligosaccharide mimetics containing C-glycoside and N-glycoside linkages (bio-isosteres) can offer stable alternatives. Our laboratory was the first to exploit samarium iodide chemistry to prepare C-glycoside analogs of unstable sialic acid containing glycans. Using this chemistry we are performing target-based synthesis of a number of therapeutically relevant glycan structures in an effort to prepare stable therapeutic agents. C-linked polysialic acid is being synthesized as a potential carbohydrate vaccine against meningitis and certain forms of cancer. Figure. Structure of the polysialic acid C-glycoside target being prepared. This C-glycoside target involves a multi-step chemical synthesis. In an effort to rapidly prepare stable glycosides for biological evaluation we have begun to utilize click chemistry to prepare stable N-glycosides. A major target for our library of click glycoside synthesis are anti-influenza agents that target both hemagglutinin (H) and neuraminidase (N) sites on the surface of the influenza virus. Figure. Bivalent click N-glycoside synthesis Chemoenzymatic synthesis of heparin oligosaccharides: The most difficult reaction in carbohydrate synthesis is the glycosylation, as it generally requires the stereoselective reaction of nearly fully protected acceptor and protected and activated donor. Glycosyltransferases stereospecifically catalyze the reaction of an unprotected acceptor and an unprotected activated donor. We chemically synthesize natural and unnatural donors that work with recombinant glycosyltransferases to glycosylate unprotected acceptors affording therapeutic targets. Figure. Chemoenzymatic synthesis of natural and unnatural UDP-donors for enzymatic synthesis of Arixtra, an anticoagulant drug. .

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