Synthesis of s-glycolipids and peptidomimetics

Abstract

Chapters one and two of this thesis describe the synthesis of two novel glycosphingolipid derivatives. Glycosphingolipids are amphiphilic molecules consisting of a carbohydrate head group glycosidically linked to a sphingoid lipid chain. Our interest is in the synthesis of - glycosphingolipids of bacterial origin, particularly those isolated from the cell walls of Sphingomonas bacteria. These glycolipid derivatives bear a striking resemblance to the known immunostimulant KRN7000 and have shown activity in both human and mouse models. The Murphy group has previously reported the synthesis of a bacterial glycosphingolipid termed PBS-59 and its glucuronic acid derivative; therefore, this thesis focuses on our efforts to synthesise thio-linked analogues of these lipid derivatives in the hope of improving their in vivo stability and immunostimulatory activity. The synthetic route includes a stereoselective anomerisation reaction to form a-glycosyl thiol precursors as well as a new route to sphinganine chains starting from the Myers pseudoephedrine chiral auxiliary. Chapters three and four investigate the use of carbohydrates as scaffolds for the development of novel biologically active peptidomimetics. Of particular interest is the synthesis of a novel macrocyclic structure with embedded carbohydrates capable of mimicking the a-helical domain. The hydroxyl groups of the carbohydrate act as a functional handle onto which pharmacophoric groups can be grafted. Two key protein-protein interactions (Bcl-2 family of proteins and the p53-MDM2 interaction) were identified as targets for peptidomimetic development. The synthesis of these macrocyclic structures was developed, a route which includes a rare example of the use of a reductive amination/ring closing macrocyclisation sequence, and a number of novel a-helical peptidomimetics were obtained. Some of these mimetics have shown activity in triggering apoptosis in ML-1 cells. Presented in chapter five is the synthesis of a novel bicyclic iminocyclitol derivative. This compound was synthesised via a novel one pot nucleophilic substitution, Huisgen cycloaddition, triazoline decomposition, aziridine formation and aziridine ring opening by an azide anion. The conversion of this compound into a tricyclic derivative is also described showing its potential for use in peptidomimetic development or as a building block in the synthesis of more complex molecules.