Solid phase and combinatorial synthesis of receptors for small peptides.
The first part of this thesis describes the attempted solid phase synthesis of a macrocyclic receptor 41, featuring a 2,6-diamidopyridine based carboxylic acid binding site (CBS) which was derivatised to allow attachment to a solid support. The synthesis of the CBS, side wall and rim fragments for the macrocyclic receptor is described, as well as their attempted coupling on the solid phase.
In the second part attention is switched to tweezer like receptors based on 2,6-diamidopyridine core. The synthesis of dansyl-labelled tweezer receptor 119 is described which was used in screening experiments with 1000 member library of peptides 138 attached to TentaGel resin via the amino terminus. Screening conditions in various aqueous buffer systems (different buffer concentrations and pHs), organic solvents, and mixtures of solvents of different ratios were also tested without success.
In the third part of the synthesis of libraries of 2,6-diamidopyridine based tweezer receptors 171 and 172 is described and the results of screening experiments with these libraries and tripeptide guests 140, 146 and 155 in CHCl3 and CH3CN are discussed. Tweezer receptor 185 with the peptide "side-arm" Phe-Val-Leu-Trp was identified by Edman sequencing on three out of 10 analysed resin beads from a screening experiment by receptor library 171 against guest 140 in CHCl3, and two out of five cases in the corresponding experiment in CH3CN. Tweezer receptor 185 was synthesised on large scale and, in fluorescence titration studies against tripeptide guest 140 in CHCl3 containing 2% DMSO, a binding constant Ka = 2.6 x 105 M-1 was found.