Synthesis of the Tetrasaccharide GlcNAcLex Fragment of Tumor Associated Carbohydrate Antigen Dimeric Lewis X
In living systems, carbohydrates play critical roles in various biological processes, including cell signaling and immunity. It has been observed that tumor cells overexpress abnormal oligosaccharides on their surfaces, known as Tumor-Associated Carbohydrate Antigen (TACAs). The overexpression of these TACAs makes them valuable targets for developing anti-cancer therapeutics. One TACA of interest to our research group is dimLex; a hexasaccharide reported to accumulate in colonic and hepatic carcinomas. Even though dimeric Lex (dimLex ) is tumor specific, it is known that its Lex trisaccharide fragment is displayed at the surface of many healthy cells. Recently, our group discovered that monoclonal antibodies SH2 and 1G5F6 raised against dimLex and polymeric Lex, respectively, retained binding to the dimLex tetrasaccharide fragment GlcNAc- Lex while anti-Lex mAb SH1 did not recognize this tetrasaccharide. Therefore, this tetrasaccharide is particularly interesting in our search for TACA-based cancer immunotherapeutics targeting dimLex. This thesis describes the total synthesis of the novel of GlcNAc-Lex as hexyl and aminohexyl glycosides. The diversity of these two tetrasaccharides will allow conjugation to a carrier protein, analysis by isothermal titration microcalorimetry and nuclear magnetic resonance techniques. The work presented here is a significant contribution to developing potential anti-dimlex therapeutics.