CARBOHYDRATES

Glycosaminoglycan Carbohydrate Chemistry and Chemical Biology

Our research involve developing new synthetic approaches to high value biologically important carbohydrates with collaborations from use a new bimolecular tools through to new drug investigations and translational biomedicine. 

We are working on synthesis and chemical biology and biomedical potential of of oligosaccharides, contributing to understanding the details of the biological mode of action of heparin-related oligosaccharides. This involves discovery and translational work collaboration with Prof Gordon Jayson at the Paterson Institute/Christie Hospital in work which has received substantial funding from Cancer Research UK, and also from a DFPS grant from the Medical Research Council, applications to conjugates with Dr Simon Webb (MIB), single molecule spectroscopic applications with Dr Steven Magennis (University of Glasgow) and other collaborations outside Manchester.

 

To underpin this a new synthetic route to L-iduronic acid derivatives (a key, rare monosaccharide component critical to the biological activity) has been developed, and in addition, the synthesis has provided a route to a series of novel iduronic acid amide derivatives and disaccharides. This has facilitated the synthesis of more complex heparin saccharide units of various types, and a diversity of oligosaccharides up to dodecamers have been efficiently prepared.

Recent highlights include a step-change in the scalability of access to long heparanoids, delivering gram amounts of 12-mers (Orglett, 2013), synthesis of a per-6S heparin 12-mer (Chemical Science, 2013) and a synthesis of end-labelled 12-mer and its in vivo biology (NatureComm, 2013), synthesis of the longest HS like molecules yet (Chemical Science 2015), and the application of new 'superdisarmed/rearmed' iduronic strategy for synthesis of HS and DS fragments (J. Org. Chem 2015 and J. Org. Chem. 2019).

Work is now expanding into various biophysical studies, new synthesis of conjugates and mimetics and various aspects of labelling chemistry applied to HS building blocks. eg see: ChemPhysChem 2016 and Biophys. Journal 2016

Bacterial cell wall antibiotic resistance related carbohydrate chemistry/biology

We are collaborating on work looking at the use of synthetic fragments of key cell wall glycan-containing units related to antibiotic resistance mechanisms.

Stable Isotope Labelled Carbohydrates: Synthetic Methods and Applications

For the study of carbohydrate interactions, specific isotopic-labelling of carbohydrate ligands would be a valuable tool (eg for NMR studies). While certain labelled carbohydrates are available commercially at high cost, this is limited to mono-labelled glucose isomers and per-labelled glucose, 1-13C-galactose and 1-13C-mannose. For extending the utility of NMR as a powerful tool for study of biologically important carbohydrate interactions, availability of different multiply labelled monosaccharides is essential to allow preparation of the requisite novel 13C-labelled oligosaccharides.

This project has developed a practicable protocol for synthesis of regiospecifically 13C-labelled, (and deuterated), isotopomers of several biologically important monosaccharides from readily available achiral materials. The methods are applicable to providing sugars with between 1 and 6 13C labels, with full flexibility on combinations of site-specific 13C-labelling, providing a catalogue of multi-13C-labelled (and/or multi-deuterated) monosaccharides. These tools facilitate new biological NMR applications, and extension of the synthetic work aims to deliver similar isotopomer-versatile access to further saccharides.

Further work is extending stable labeling into rarer monosaccharides related to target bio-active oligosaccharides is ongoing and we have completed a route to a mono-labelled rare monosaccharide found in bioactive oligosaccharides.

Research workers contributing to this project: Dr Martin Penny, Nitesh Panchal and William Stimpson

Multivalent Synthetic Carbohydrate Ligands

Carbohydrate-protein binding is involved in a diversity of critical biochemical events, including cell-cell signalling and adhesion, viral/bacterial infectivity and cancer metastasis, and recognition of oligosaccharide epitopes by antibodies is of fundamental interest. Protein-carbohydrate binding often involves multiple sugar molecules being bound simultaneously, i.e. 'multivalent binding'.

A number of synthetic multivalent systems have demonstrated significantly increased binding affinities and conjugated multivalent systems have been employed as synthetic gene transfection vehicles, and for the delivery of intercalating agents to specific cell types (using the carbohydrate-specific cell surface receptors).

This project aims to develop a novel, structurally versatile 'modular' synthetic methodology for constructing multivalent saccharides, with a range of valencies, and to develop methods for rapid evolution of high affinity novel ligands.

Synthesis of a series of new multivalent ligands has been achieved of differing architecture and fluorescently-labelled systems have also been prepared using a built-in 'tether'. 

© 2017-19 John Gardiner

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