Part 1: Synthesis of heparin oligosaccharides and mimetics; Part 2: Development towards ganglioside based anticancer vaccines

Heparin and heparan sulfate are implicated in cell signaling and a host of other biological processes. The main issue in evaluating these interactions is the sheer number of possible oligosaccharides and the fact that chemical synthesis of pure oligosaccharides continues to be long and arduous. Use of the natural sulfotransferase enzymes can allow the divergent synthesis of multiple sulfation patterns from a single backbone, greatly simplifying the synthesis of a library of heparin and heparan sulfate oligosaccharides. Herein a single hexasaccharide backbone has been elaborated into 7 different sulfation patterns utilizing both chemical and enzymatic sulfation. These along with other oligosaccharides have been used to make a carbohydrate microarray to evaluate binding with FGF-2. Another route utilizing heparin mimetics was also explored.;Part 2 entails the development of anticancer vaccine based on the GM2 tumor-associated carbohydrate. GM2 was chemically synthesized and conjugated to the virus-like Qbeta particle. Conjugation using copper-catalyzed azide-alkyne cycloaddition efficiently linked GM2 but the resulting product only produced significant antibodies against the triazole ring formed by coupling. Switching to a thiourea linker produced a construct that elicited a strong immune response including IgG antibodies that could bind GM2-positive tumor cells and were found to be effective in complement dependant cytotoxicity.