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 λ max 425 nm with 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 (pK 1, pK 2 , pK 3 ) are determined, and the stability constants [10 27 for Fe(III)-1 and 10 28 for Fe(III)-2] obtained are rather close to values of 10 30 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 ∆ 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.

Novel trihydroxamate‐containing peptides: Design, synthesis, and metal coordination

“…P1 , P2 , P11 , and DFO had different λ max 's at 448, 446, 441, and 430 nm, respectively. These results are similar to those reported in the liter ature 34–38. As the concentration of Fe(III) was increased, the absorbance was correspondingly increased with minor shifts of λ max to shorter wavelengths.…”

“…The resulting cis conformation brings the (NOH)Phe aromatic ring in close proximity to the Leu residue, leading to the up‐ and downfield shifts of the Leu5, 9 resonances due to the shielding and deshielding effects of the aromatic ring current. As previously reported,34–38 Ga(III)–peptide complexes may adopt stable C‐ cis or N‐ cis series of isomers of the Ga–hydroxamate Δ configuration, depending on whether the C atom of the hydroxamate group is above the N atom, and on whether the five‐membered Ga(III)–hydroxamate rings have the same ( cis ) or opposite ( trans ) orientation. In case of the P1 –Ga(III) complex, the number of isomers may increase due to cis / trans conformers of the Ala–Pro amide linkage.…”

“…The continued use of DFO , despite its lack of oral bioavailability and difficulties in patient compliance, strongly suggested it as a lead compound for developing novel metal‐binding peptides with improved oral bioavailability and more selective activities. Early efforts to explore DFO and other siderophore analogs were reported by the Akiyama,34–38 the Bergeron,39–41 the Miller,42, 43 and the Raymond44–46 groups. More recently, we also designed and synthesized trihydroxamate‐containing analogs of DFO 12, 47–49 and other siderophore analogs as potential oral therapeutics for iron‐overload diseases.…”

Peptide‐bond modification for metal coordination: Peptides containing two hydroxamate groups

“…41,42 More recent studies 43,44 by Hara et al have focused on iron complexation by oligomers of Ala-Ala-⌿[CO-NOH]-␤-Ala. In contrast, we initially focused on N,NЈ-dihydroxypeptides.…”

N-hydroxy-amide analogues of MHC-class I peptide ligands with nanomolar binding affinities

“…Until now the insertion of the [CO-N(OH)] modification into small peptides was carried out in solution using N-hydroxy-amino acid residues [9,10] while on solid phase only a few examples for the synthesis of C-terminal peptide hydroxamic acids were reported [11,12]. In order to explore the interesting features of the N-hydroxy-amide group using automated solid phase synthesis and combinatorial techniques [13], we developed a method for the preparation of N-hydroxy peptide ligands for major histocompatibility complex class I (MHC-I) molecules.…”