Synthesis and physiochemical characterization of new siderophore-inspired peptide-chelators with 1-hydroxypridine-2-one (1,2-HOPO).

Abstract

Compounds containing hydroxamate moieties (N-hydroxyl amides) in their structure have found a vast range of therapeutic applications such as antibacterial, anti-tumour, anti-immune suppressor, and for iron overloading treatment. Hydroxamate chelators binds to Fe (III) tightly through its electron donating oxygens. The binding strength is maximized in compounds containing three hydroxamic moieties due to the so called “chelate effect”. As all microorganisms require iron for surviving, they develop endogenous siderophores to acquire iron from the surroundings. Siderophores contain hydroxamate, catecholates, α-hydroxy carboxylates groups, among others, in their structures. The acquisition of iron by siderophores in microorganisms goes through specific cycles that includes sequestration of Fe(III), recognition and uptake of the ferrisiderophore through the cell membrane, and then release of the iron in the cytoplasm. Many natural hydroxamate siderophores contain a peptidyl backbone. In this work, peptides containing one or more units of 1,2-hydroxypyridine-N-oxide (1,2-HOPO) have been synthesized. The introduction of these units on the peptides has been done by means of 4- carboxy-1-hydroxypyridil-2-one (1,2-HOPO-4-COOH) using solid-phase peptides synthesis (SPPS) protocols. The obtention of the new “siderophores” containing three 1,2-HOPO units have been done by two different approaches, sequential and convergent. The compounds have been evaluated as potential iron chelators. Thus, the pKa values and the thermodynamic constants of all ligands have been spectrophotometrically determined. The Fe(III) affinities of the two hexadentate ligands (ligand B and ligand C) have been determined by competition experiments against EDTA. The results showed that the iron complex ligand B is stronger that the iron complex EDTA since the last is not be able to replace it. Hence, this new siderophore could be a promising candidate to be used in further therapeutic applications.