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Cancer associated glycan epitopes via Ionic Catch and Release Oligosaccharide Synthesis (ICROS)

Final Report Summary - ICROS (Cancer-associated glycan epitopes via ionic catch and release oligosaccharide synthesis)

Carbohydrates and their glycoconjugates are one of the most important classes of macrobiomolecules in nature which play key structural and functional roles in a diverse range of biological recognition processes. The full characterisation of the set of carbohydrates in the human body (glycome) and their interactions with proteins is essential for understanding life and disease mechanisms; hence, there is a growing global interest in deciphering the human glycome.

Carbohydrate antigens of tumour cells are uniquely effective targets for antibody-mediated active and passive cancer immunotherapy and have also proven to be effective targets for immune recognition and attack. The gastrointestinal tract possess a protective epithelial barrier as part of the basic innate protective system, which produces a secreted mucus layer that contains hundreds of different mucin type O-linked oligosaccharides known to be connected with diseases such as breast and colon cancers.

However, little is known about the specific role of this family of oligosaccharides in disease due to the lack of tools for study. Access to structurally defined complex carbohydrates is still a very laborious process and combinatorial approaches to prepare diverse libraries of oligosaccharides remain limited. An automated synthesis of oligosaccharides will provide access to diversity-orientated oligosaccharide libraries to enhance not only glycobiology research, but also carbohydrate-based drug discovery.

In this programme we have established new methodologies that address some of the main hurdles in oligosaccharide synthesis:

- We have developed a new strategy for the synthesis and rapid purification of carbohydrates that is based on using ionic liquids (ILs) as soluble functional support. The proposed technique - ionic catch and release oligosaccharide synthesis (ICROS) - makes possible to successfully perform reactions under conditions typically used for solution-phase chemistry while the ionic labels are linked to the substrates, without the need for chromatography between steps, since non-IL tagged materials can selectively be washed away with the appropriate solvents, an important advantage with respect to other supported strategies.

- In another aspect, we have explored the scope of ILs as dual solvent / catalysts for room temperature glycosylation reactions that can be recycled.

- Concomitantly, we have aimed at validating the new synthetic strategies by synthesising oligosaccharide components of the mucin family of proteins, for which the function and properties have yet to be investigated. The synthesis of defined fragments of this class of glycans will be critical to help us understand their biological and disease implications, which will subsequently have significant impact in glycoarray screening, diagnostic tests, vaccine synthesis and glycan therapeutics.

- More recently, we have functionalised fluorescent quantum dots (QD) glyco-nanoparticles with structurally defined O-glycans and use them in preliminary study as biotracers in live cells.

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