Tripodal peptide hydroxamates as siderophore models. Iron(III) binding with ligands containing H-(alanyl)n-beta-(N-hydroxy)alanyl strands (n = 1-3) anchored by nitrilotriacetic acid.

Abstract

Combining three units of one of H-(alanyl)n-beta-(HO)alanyl peptides (n = 1-3) with nitrilotriacetic acid affords tripodal peptide hydroxamate ligands (1L, 1D, 2LL, 2DL, and 3LLL, where each L or D denotes the L- or D-alanyl residue). These ligands form six-coordinate octahedral complexes (Fe-1L, Fe-1D, Fe-2LL, Fe-2DL, and Fe-3LLL) with iron(III) in aqueous near neutral pH solution, and the stability and the chirality of the complexes formed depend on the alanyl residues incorporated. Thus Fe-2LL is the most stable against attack of H+ and OH- ions and the least labile in the iron(III) removal by EDTA. The CD spectra show a predominance of the A configuration for Fe-1D, Fe-2LL, Fe-2DL, and Fe-3LLL, but the opposite delta configuration for Fe-1L. These ligands and their gallium(III) complexes are studied by 1H NMR spectroscopy in DMSO-d6 solution. CD and NMR spectral analysis, aided by molecular model examinations, indicates that critical factors in controlling the configuration and the stability of the complexes are (1) the hydroxamate-carrying alanyl residue, (2) the expanse of an interior space in the ligand, and (3) an interstrand amide NH hydrogen bond; the latter bonding is possible with ligands 2LL and 2DL. A microbial growth promotion activity test shows that ligands 1L, 2LL, and 3LLL all act as iron-transporting agents.