SYNTHESIS OF PEPTIDES CONTAINING UNNATURAL, METAL-LIGATING RESIDUES - AMINODIACETIC ACID AS A PEPTIDE SIDE-CHAIN

Peptides possessing a pair of residues separated by one turn in the alpha-helical conformation and potentially capable of ligating a single metal ion in aqueous solution were designed. It was predicted that the resulting cross-link would shift toward alpha-helix the random coil/alpha-helix equilibrium. The syntheses of 10 peptides Ac-Ada(l)Ala(m)Ada(l)(Ala4GluLys)n-NH2 where Ada(l) is an L-alpha-amino acid residue with an aminodiacetic acid bearing side chain, -(CH2)(l)N(CH2CO2H)2 (with values of l, m, and n as follows: 1, 2, 3 (1); 1, 3, 1 (2a); 1, 3, 2 (2b); 1, 3, 3 (2c); 2, 2, 3 (3); 2, 3, 3 (4); 3, 2, 3 (5); 3, 3, 3 (6); 4, 2, 3 (7); 4, 3, 3 (8)) are described using Boc chemistry on p-methylbenzhydrylamine resin. The aminodiacetic acid bearing residues were incorporated with side chains protected as the dibenzyl esters. To avoid side reactions, residues Ada(l) for l = 1 and 2 were incorporated by a block approach. Peptide structures were confirmed by observation of the predicted parent ions in the FAB MS. The circular dichroism spectra of several of these peptides that posses a pair of metal-ligating residues separated by two or three intervening residues have previously been shown to undergo changes on addition of metal ions consistent with appreciable enhancement of helix content.