Synthesis towards Chondroitin Sulfate Fragments and Modifications towards Conjugation

Abstract

Carbohydrates are one of the largest classes of naturally occurring substances, usually found conjugated with other large biomolecules such as proteins or lipids. The synthesis of various carbohydrates has always been advancing, aiming to obtain new structures and pure products more efficiently in higher yield and with more convenient methods. Among the most diverse and biologically relevant carbohydrate types are glycosaminoglycans (GAGs), which are found in many biological locations and roles. Whilst the heparin/ heparan sulfate (H/HS) family of GAGs has been most reported, research has become increasingly interested in chondroitin sulfate (CS) as well as dermatan sulfate (DS) because they can interact with a wide variety of key molecules, such as growth factors and chemokines via specific saccharide domains within the chains, just like H/HS, but have many different roles of biomedical significance. Synthetic methods for providing differentiated pure fragments and those suitable for conjugation to report or effect units are of importance. In this thesis, novel synthetic routes towards structure-defined chondroitin sulfate-E (CS-E) tetrasaccharide repeating units with galactosamine (GalN) and glucuronic acid (GlcA) monosaccharide derivative building blocks were reported after several routes were tested unsuccessfully. The developed method gave a fully protected CS tetra-thioglycoside with the non-reducing end bearing a levulinoyl group. Both ends of the tetrasaccharide were investigated for deprotection and further elongation. PEG linker was deployed for potential conjugation and propargylation on the other end. Then, a “click” reaction was undertaken; however, it did not give the desired result. This project still has the potential for further study on developing more conjugation strategies.

Date of Award	29 Oct 2024
Original language	English
Awarding Institution	The University of Manchester
Supervisor	John Gardiner (Supervisor) & Sabine Flitsch (Supervisor)