Synthetic Alkyl Glycolipids as Therapeutic Agents: Their Synthesis as Potential iNKT Cell Stimulators and their Anti- Microbial Properties

The focus of the novel research reported in this thesis is the synthesis of glycolipids for anti-microbial studies and to act as iNKT cell stimulatory ligands. Simple glycolipids, L-aspartic acid based glycolipids, glycoglycerolipids and L-serine based glycolipids were explored. Simple galactosyl glycolipids containing O- and N-glycosidic linkages and L-aspartic acid based glycolipids were constructed as in Chapter 2 with a view to test their anti-microbial properties against cystic fibrosis pathogens (Burkholderia cepacia complex). Preliminary testing of these glycolipids revealed promising anti-microbial activities. Glycolipids were also tested for their organogelator properties, whereby two of the compounds exhibited supramolecular assembly to form gels. Gl-X is a naturally occurring glycolipid found in the cell walls of certain Mycobacteriaceae species and has been reported to be involved in important biochemical processes. Intramolecular aglycon delivery, an elegant synthetic strategy for the construction of difficult 1,2-cis glycosidic linkages, was used in the formation of a Gl-X analogue described in Chapter 3. A series of L-serine based analogues of KRN7000, a potent iNKT cell ligand, were investigated in Chapter 4 to probe their potential application as immunomodulators. Focus was applied to the synthesis of a suitable building block which could provide access to a range of different analogues, possessing α- and β- glycosidic linkages. A short chain α-analogue of KRN7000 was successfully synthesised. A benzyl ether protected analogue of KRN7000, containing a 1,4- disubstituted 1,23-triazole moiety was also synthesised by a copper catalysed azide alkyne cycloaddition. Preliminary investigations into a new class of rigid macrocyclic L-serinyl analogues of KRN7000 was explored in Chapter 5 using a copper catalysed azide alkyne cycloaddition as the key synthetic step. The synthesis of a monomeric macrocycle and a dimeric macrocycle was explored, both compounds protected as benzyl ethers to ultimately function as a new class of rigid iNKT cell stimulatory ligands