Novel Biosynthesis Acceptors and Inhibitors of Glycosylation: Studies of Leukocyte-Endothelial Cell Adhesion Interactions
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The study of glycoconjugates is essential as the carbohydrates in organisms are involved in cell development, cell signaling, cell-to-cell interactions, cancer tumorigenesis and metastasis, inflammation, and infectious diseases. As a result, inhibitors targeting different glycosylation pathways are developed for studying the role of various glycoconjugates in diseases. In this dissertation, a variety of small inhibitors are introduced. The first part of this dissertation aims to identify an effective O-glycosylation inhibitor to perturb the selectin-mediated cell adhesion. The results reveal GalNTGc, a GalNAc analog in which the amide is substituted by sulfhydryl, as an effective inhibitor. This inhibitor down-regulates P- and L-selectin mediated cell adhesion both in vitro and in vivo by inhibiting the O-glycosylation pathway. The second part presents a comparative study on the roles of O-glycosides and thioglycosides in decoy based inhibition. We conclude that thioglycosides are more effective decoys as they are hardly hydrolyzed in cells as O-glycosides. The third part introduced an enhanced photosensitizer for photodynamic therapy by applying the conclusion from the second part. The cellular permeability was improved with GlcNAc conjugation linked by S-glycosidic bond, and this enhanced the efficacy of photodynamic therapy. Overall, this dissertation identifies and characterizes several potent inhibitors of glycosylation, including a novel photosensitizing agent.