Development of Methods for the Chemical Synthesis of Glycosaminoglycan Oligosaccharides

Abstract

Glycosaminoglycans are sulfated, cell-surface polysaccharides which can bind to numerous proteins. These interactions, in particular those of heparan sulfate (HS), have been implicated in a range of developmental processes and diseases including cancer, viral infection and Alzheimer’s disease. Due to the heterogeneous nature and structural complexity of glycosaminoglycans, the structural requirements for protein binding are not well defined. The chemical synthesis of structurally-defined oligosaccharides, which offers full control and design over the final structure, is desirable for the investigation of the structural requirements for HS-protein binding, in particular the importance of minor structural motifs. This thesis presents the development of a new method for the chemical synthesis of HS oligosaccharides. The method is underpinned by the chemoselective activation of iduronate thioglycoside donors in the presence of bicyclic iduronate lactone thioglycosides using N-iodosuccinimide/catalytic Lewis acid. This method allows the synthesis of protected oligosaccharides bearing a reducing end anomeric thioglycoside, which can be used for further functionalisation of the oligosaccharide via glycosylation with a suitable alcohol, or for chain extension with another lactone-containing disaccharide. This method only utilises thioglycoside building blocks, which are all shelf stable (avoiding the use of the commonly used, but non shelf-stable, trichloroacetimidate donors) and avoids anomeric manipulation steps between glycosylations. The method was also applied to the synthesis of dermatan sulfate (DS) oligosaccharides. Dermatan sulfate is another member of the glycosaminoglycan family, which also contains iduronic acid residues. The biology of DS has been less widely studied than HS, perhaps in part due to fewer reported syntheses of DS oligosaccharides.

Date of Award	31 Dec 2018
Original language	English
Awarding Institution	The University of Manchester
Supervisor	John Gardiner (Supervisor), Gordon Jayson (Supervisor) & Jordi Bella (Supervisor)