Studies towards synthetic macrocyclic receptors for small peptides

Henley, Peter Dominic (1998) Studies towards synthetic macrocyclic receptors for small peptides. University of Southampton, Doctoral Thesis.

Record type: Thesis (Doctoral)

Abstract

This thesis describes the synthesis of bicycle receptors designed to bind to protected peptides and amino acids primarily through the interaction of the free carboxylic acid of the guest and a 2,6-diamidopyridine moiety on the host.

Firstly an established receptor for protected peptides and amino acids was re-synthesised and further binding studies were carried out with Z-β-Ala-D/L-Lac-OH in order to compare the binding with the antibiotic vancomycin. The guest Z-β-Ala-D-Ala-OH was previously found to be strongly bound to the host and extensive ¹H NMR and molecular modelling was undertaken to gain an insight into the binding properties of the macrocycle.

The third chapter describes the attempted synthesis of a modified version of the same macrocycle containing a lysine residue. It was hoped that when protonated, the amine groups would increase the water solubility of the macrocycle. Unfortunately the synthesis of the modified portion was poor and led to only a small amount of the protected macrocycle. Removal of the protecting groups was largely unsuccessful but did give a small amount of water soluble material.

Chapter four describes the synthesis of a macrocycle similar to those above but with a rigidifying component, provided by incorporating a tyrosine derivative. Water solubility was planned through the use of glutamic acid residues. However the t-Bu esters protecting groups for glutamic acid were found to be incompatible with the formation of the macrocycle.

Finally, the synthesis of a macrocycle exactly the same as the one in chapter four is described except for the use of methyl esters in place of the t-Bu esters. Binding studies in deuterochloroform are given and show a significant increase in selectivity compared to the original macrocycle described in chapter two.

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