Conor O’Shea
Chemical Synthesis of S-linked Glycosaminoglycans
O’Shea, Conor
Authors
Contributors
Gavin Miller
Supervisor
Abstract
Heparan sulfate (HS), a sulfated linear carbohydrate that decorates the cell surface and extracellular matrix, is ubiquitously distributed throughout the animal kingdom and represents a key regulator of biological processes. An example of a glycosaminoglycan, HS is composed of D-glucosamine (GlcN) α(1→4)-linked to L-iduronic acid (IdoA) or its C-5 epimer D-glucuronic acid (GlcA). Its microstructure is diverse: the amino sugar can be N-sulfated (D-GlcNS) or N-acetylated (D-GlcNAc), while D-GlcA and L-IdoA are variably substituted with O-sulfate groups at C-2. D-GlcN is commonly O-sulfated at C-6 and occasionally at C-3. Due to its chemical heterogeneity, structure-to-function correlations with HS-binding proteins are often difficult. Therefore, methods to improve the understanding of such interactions are of huge importance.
Herein, the synthesis of novel S-linked GlcN-α(1→4)-GlcA disaccharides is detailed. Such disaccharide offers the potential to be used as a glycomimetic of native HS disaccharides, where the hydrolytically more stable S-glycosidic has previously demonstrated utility as a chemical biology tool and inhibitor of carbohydrate-binding proteins.
Initial attempts at constructing the desired disaccharide via a S-glycosylation approach failed, with D-GlcN donors and D-Glc/GlcA acceptors showing no coupling reactivity. When reversing the reactivity polarity of the monosaccharide building blocks, subsequent SN2 coupling using GlcN thiohemiacetals and galactosyl triflates successfully facilitated disaccharide formation. Subsequent oxidation furnished the desired S-linked GlcN-α(1→4)-GlcA disaccharide. From here, automated glycan assembly (AGA) mediated synthesis of S-linked HS oligosaccharides using the modified disaccharide unit was attempted. However, owing to donor deactivation, iterative synthesis was not accomplished.
Finally, the synthesis of a novel UDP-C4’’-deoxy GlcA glycomimetic was explored to access a potential inhibitor of HS biosynthesis. Successful chemical mediated C-4 deoxygenation of GlcA was accomplished; however, subsequent enzymatic conversion towards its UDP counterpart failed to materialise.
Citation
O’Shea, C. (2025). Chemical Synthesis of S-linked Glycosaminoglycans. (Thesis). Keele University. https://keele-repository.worktribe.com/output/1280018
Thesis Type | Thesis |
---|---|
Online Publication Date | Jun 26, 2025 |
Deposit Date | Jun 18, 2025 |
Publicly Available Date | Jun 27, 2025 |
Public URL | https://keele-repository.worktribe.com/output/1280018 |
Award Date | 2025-06 |
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