Date of Award
Doctor of Philosophy
Nicola L. Pohl
Infectious disease associated-oligosaccharides are important target molecules for synthesis to enable studies of their functions in infection mechanisms both in humans and animals. Unlike solid-phase automated chemical syntheses of oligonucleotides and oligopeptides that serve to provide these molecules for systematic structure-function relationships, automated chemical synthesis of oligosaccharides has been restricted due to the need to manage stereochemistry of each linkage and to the greater complexity of the monomeric carbohydrate building blocks. A new solution-phase automation platform that relies on fluorous solid-phase extraction (FSPE) to purify intermediates potentially offers easier access to complicated oligosaccharides with several features such as simpler monitoring of reactions, only 2-3 equivalents of building block usage per glycosylation cycle, labor savings, and easier access to previously constructed compounds. In addition, the fluorous allyl-tag used to simplify purification in the automation platform also allows not only direct incorporation into microarrays but also ready modification of the tag for facile conjugation to polymeric vehicles. Herein are reported the development of methods for this automation platform for the first construction of HIV- and Leishmania-associated oligosaccharides. Automated methods to make phosphate-linked sugars as well as conventional glycosidic linkages are demonstrated. Several Leishmania-associated oligosaccharides--including capping structures, phosphate-linked capping structures and phosphoglycan repeats--were synthesized as probes for carbohydrate microarrays to screen sera of infect animals. The further development of efficient conjugation chemistry allowed the multivalent modification of latex beads and degradable micro-/nanoparticles with these bioactive oligosaccharides to probe carbohydrate-related structure/function relationships in the stimulation of cellular immune responses.
Song, Eun-ho, "Automated solution-phase synthesis of HIV- and Leishmania-associated oligosaccharides to probe structure-dependent immune responses" (2009). Graduate Theses and Dissertations. 11053.