A combinatorial approach to glycotherapeutics : template synthesis

Abstract

In this thesis, general synthetic methods applicable to the development of carbohydrate mimetics were achieved. With such methodology in hand we turned to the development of inhibitor libraries for: a) Trypanosoma cruzi trans-sialidase, an essential enzyme involved in the onset of South American Chagas' disease. Octyl galactoside is recognised by the enzyme so chemical modifications of this structure would be possible. The synthesis of octyl 6- azido-6-deoxy galactoside has been achieved by using two different chemical methods. b) E. coli 0157 (verotoxin) is a food poisoning toxin (Wishaw, central Scotland). The minimum active component for interaction of sugar and toxin is galabiose [αGal-(1-4)- βGal-(l-4)-OMe] In this thesis, the synthesis of galabiose and various galabiose template mimics are described. Modification of the galabiose structure at the 2 position (methoxycarbonylmethyl) and at the 6 position (amine) or both was successfully achieved. These structures are ready to be incorporated onto a solid-support or a dendrimer base for further evaluation. A small array of 6-amino functionalised galabiose compounds has been successfully achieved.