Wright, Karen; (1997) Synthesis of glycoconjugates affecting cell adhesion. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

In recent years, it has been recognised that carbohydrates play an important role in specific cell interactions. The formation of metastases from a primary tumour is a major cause of treatment failure and mortality in cancer patients. A sialic acid-nucleoside conjugate was previously found to reduce the metastatic potential of some carcinoma cell lines. Analogues of this compound, with modifications in the nucleoside or sialic acid moiety were synthesised by silver ion promoted sialylation of the corresponding nucleosides. The tetrasaccharide sialyl Lewis X and trisaccharide Lewis X epitopes have been the subject of intense research interest in recent years because of their involvement in leucocyte migration mediated by selectins in inflammatory processes. Analogues with increased selectin binding activity over the naturally occurring structures have been widely sought. This research requires the use of the natural compounds as references. A gram-scale synthesis of the trisaccharide and tetrasaccharide was developed using relatively cheap processes. Methyl-thioglycosides were used as donors to construct the desired compounds in a stepwise manner in dimethyl(methylthio)sulphonium triflate promoted glycosidations. A disaccharide benzyl 3-O-(2,3,4-tri-O-benzyl-α-L-fucopyranosyl)-2-acetamido-6-O-benzyl-2-deoxy-α-D-glucopyranoside was a key structure in these syntheses and was synthesised in large scale. Difficulties were encountered in the formation of a β-D-galactoside of this structure, which were overcome by the use of donors with benzyl-type protection. α-Sialylation of a trisaccharide acceptor afforded the anticipated tetrasaccharide and also a structure formed by intramolecular transesterification. Thio-linked oligosaccharides are of interest because of their increased resistance to enzymatic cleavage and hydrolysis over the natural O-linked structures. The synthesis of thio-linked analogues of the Lewis X and Lewis A trisaccharides were attempted using displacement of triflate by thiols to form S-glycosides.

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