N-Hydroxy Amides. X. Synthesis of a Nonapeptide with an Ala-(HO)Gly-Ala Sequence and Its Spectral and Iron(III) Holding Properties

Abstract

A nonapeptide with an Ala–(HO)Gly–Ala sequence has been synthesized via condensation of appropriately protected tripeptide units. 1H NMR and CD spectral data indicate that the nonapeptide has a disordered structure in DMSO and water. The peptide forms a 1 : 3 complex of iron(III) with hydroxamate groups at neutral pH when mixed with an aqueous iron(III) solution. The complex shows λmax at 410 nm with an ε of 2160 at pH 7. Alanine residues influence the hydroxamate groups to produce a chiral complex, the CD spectrum of which reveals bands at 355 nm (Δε+0.8) and 435 nm (Δε−1.8), showing a preference for the Δ-configuration around the iron.

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

“…Chirality of Complexes. Alanine residues exert their chiral influence during iron(III) complexation, as was the case with the nonapeptide . This influence is even more evident in the present case.…”

“…The stability constants for the two complexes are much larger than the 10 17 value reported for the iron(III) nonapeptide . The stability constant for Fe(III)- 2 (10 28.3 ) is slightly larger than that for Fe(III)- 1 (10 27.4 ), probably due to its stronger iron-holding capacity and higher protonation constants.…”

“…The preparation of a pair of linear and cyclic peptide-based ligands ( 1 and 2 ) is useful for examining the features of a unit sequence and the ligands obtained. By addition of three methylene units to the nonapeptide reported previously, the ligands become much less strained but still have constraint relative to desferrioxamines. Characterization of the linear and cyclic pair ligands allows us to better understand the iron(III)-holding behavior of the peptide-based chelators.…”

“…Using electronic spectroscopy, the stability of iron(III) complexes against H + or OH - attack can be estimated from the span of a top plateau region in a plot of ε (at 425 nm) vs pH (Figure ). Fe(III)- 1 has a constant region over pH 4.0−9.5 which is much wider than that (pH 6.5−8.5) of the previous nonapeptide …”

“…Furthermore, peptides themselves constitute a rich source of useful information regarding structure−property and structure−function relationships. Desferrioxamine-like trihydroxamates can be obtained as sequential peptides by joining suitable N -hydroxy peptide segments, and a few of tris( N -hydroxy peptides) have already been prepared from α-amino acid units. − A previous paper described the synthesis of a nonapeptide trihydroxamic acid with an Ala-(HO)Gly-Ala 19 sequence, together with the formation of its octahedral chiral iron complex . As indicated by its low stability constant and weak CD intensity, the complex was not sufficiently stable or isomerically pure, owing to a chain constraint caused by a short distance between the hydroxamato groups .…”