Glycodendrimer mediation of galectin-3 cancer processes and indium(III) as a glycosylation promoter
Michel, Anna Kaczmarek.
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Galectin-3 is a carbohydrate-binding protein that is found inside and at the surface of most healthy cells, where it plays a role in cellular differentiation, proliferation, and death. Galectin-3 is also overexpressed in many forms of cancer, where it interacts with beta-galactosides on the surface of the transmembrane protein Mucin 1 (MUC1), which is also upregulated in many cancers. The interaction between MUC1 and galectin-3 leads to enhanced tumor formation, invasion, and metastasis. Glycodendrimers were synthesized and used as tools to probe the galectin- 3/MUC1 mediated cancer cellular aggregation. Cellular aggregation assays were designed and performed using three different cancer cell lines. Results indicate that cellular aggregation can either be inhibited or intensified depending on the size of the dendrimer and on the number of carbohydrate endgroups present. Confocal micrographs of cancer cells confirm that the pattern of galectin-3 on the outside of the cell is altered in the presence of glycodendrimers. These finding indicate that glycodendrimers mediate cellular aggregation properties, giving insight into the mechanism of action. The results also establish glycodendrimers as potential targeting agents and prodrug delivery systems when considering cancer drug design. A dendrimer bearing a matrix metalloproteinase (MMP) substrate was synthesized to explore dendritic potential as drug delivery systems. Results show that the substrate can be cleaved from the dendrimer when incubated with cancer cells known to overexpress MMP, indicating a potential for glycodendrimers as a prodrug carrier. A novel method for glycosylation was also explored. Indium(III) provides many advantages over standard glycosylation promoters (such as BF 3 x OEt 2) in that it is not air-or water-sensitive, and there is no need for additional purification of In(III) before use. Carbohydrate donors with a variety of protecting groups were tested against a range of glycosyl acceptors, including a carbohydrate. Results show that using In(III) as a glycosylation promoter gives comparable yields in less time when compared to a common glycosylation promoter.