Solid phase synthesis and applications of sulfur bridged peptides

Abstract

This thesis describes the development of methodologies for the first total solid phase biomimetic synthesis of an analogue of the ring B of nisin, a polycyclic peptide antibiotic. As part of this research project a new method for the chemoselective oxidation of sulfides to sulfoxides was developed and shown to be a mild, neutral and efficient tool to access peptidic and non-peptidic sulfoxides, both in solution and on the solid phase. Due to its chemoselectivity the method enabled the solid phase synthesis of a methyl cysteine peptide sulfoxide in the presence of a trityl protected cysteine residue which, following synthetic elaborations on resin, allowed the preparation of a dehydro thiol peptide, precursor of ring B of nisin. This cyclised to give the lanthionine derivative as a single diastereoisomer. Preliminary studies were also carried out towards the synthesis of an analogue of the DE ring of nisin.

In addition, an efficient and rapid solid phase route to cysteine derivatives was developed and applied to the synthesis of a library of one of the most potent classes of organogelators discovered to date. The crude peptides were successfully screened and a subclass, the p-halogen benzoyl derivatives, showed outstanding gelating properties. In particular, a new 'super gelator' was identified. The p-fluoro analogue was able to gelatinise DMSO/water mixtures at the remarkably low concentration of 1.3 mM.

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