Novel methods in glycosaminoglycan and proteoglycan synthesis

Thesis

Glycosaminoglycans (GAGs) in general and heparin/heparan sulfate in particular are implicated in various biological functions by interacting with various protein partners. To elucidate the structure activity relationship (SAR) of these carbohydrate chains, considerable efforts towards the synthesis of these complex molecules have been made. Because of the heterogonous structure of these highly negatively charged molecules, a general approach towards synthesis of these molecules has not been possible. The central objective of this thesis was to develop a generic modular approach for the synthesis of defined thiomimics of heparin and heparan sulfate. Specifically we sought to utilize the unsaturation developed at the non-reducing end of heparin/heparan sulfate oligosaccharides by the action of lyases, for thiol-ene radical reaction to generate defined thiomimics of heparin

Chapter -2 Thiol-ene radical reaction on model substrates

The thiol-ene radical reaction on endocyclic double bonds in sugar molecules was initially established on protected model substrates and more importantly on deprotected model substrates in aqueous conditions. This demonstrates the first example of radical reaction in aqueous conditions for glycosylation between two carbohydrate substrates.

Chapter-3 Towards building S-linked heparin and heparan sulfate mimics using thiol-ene chemistry

The thiol-ene radical glycosylation strategy established on model substrates was utilized on both non-sulfated and sulfated building blocks of heparin/heparan sulfate to build novel thiomimics of heparin/heparan sulfate. The labile sulfate groups of heparin were found to be compatible with the reaction conditions. Initial biological studies done with the synthesized thiomimics did not show significant binding activity, probably due to the small size of the synthesized mimics.

Chapter -4 Glycosyltransferase utilization for heparin thiomimic synthesis

Natural glycosyltransferases were investigated for extension of the carbohydrate backbone of the thio mimics. Specifically, it was shown by MS for the first time that glucuronyltransferase can accept a thio mimic with unnatural stereochemistry as an acceptor.

Authors: Modak, A

• DOI: 10.5287/ora-9e5nnrb1v
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: carbohydrates; glycosaminoglycans
• Subjects: Chemistry, Organic; Chemical Biology