Peptide-Based Trihydroxamates as Models for Desferrioxamines. Iron(III)-Holding Properties of Linear and Cyclic N-Hydroxy Peptides with an l-Alanyl-l-alanyl-N-hydroxy-β-alanyl Sequence

Abstract

A pair of linear and cyclic peptide-based trihydroxamate ligands (1 and 2) have been prepared through fragment condensation of suitably protected Ala-Ala-β(HO)Ala units. These ligands have an eight-atom spacing between hydroxamic acid groups and compare in chain length with natural desferrioxamines of a nine-atom spacing. Ligands 1 and 2 form hexadentate octahedral complexes with iron(III), Fe(III)-1 and Fe(III)-2, in aqueous solution. The complexes show absorptions at λmax 425 nm with ε ca. 2800, characteristic of a 1:3 iron(III) complex with a hydroxamato group. Absorption vs pH profiles give ranges of pH 4−9.5 and 6.7−8.7 for Fe(III)-1 and Fe(III)-2, respectively, where each of them exists as the 1:3 complex. The ligand protonation constants (pK1, pK2, pK3) are determined, and the stability constants [1027 for Fe(III)-1 and 1028 for Fe(III)-2] obtained are rather close to values of 1030 s for ferrioxamines. However, the absorption vs pH profile for the complexes and their iron(III)-exchange kinetics with EDTA show that the iron(III)-holding capacity of these complexes is still lower than that of ferrioxamine B. The kinetic data indicate that Fe(III)-2 holds iron more tightly than Fe(III)-1. The alanine residues exert their chiral influence on the coordination. Fe(III)-1 and Fe(III)-2 reveal large negative and positive Cotton effects at 445 and 360 nm in their CD spectra, showing that the complexes are preferentially in the Δ configuration around the metal ion. Thus, it is concluded that the Ala-Ala-β(HO)Ala sequence is a useful unit for making chiral ligands which form stable iron(III) complexes of well-defined structure.