Solid-Phase Synthesis and In-Silico Analysis of Iron-Binding Catecholato Chelators.

Ranko Gacesa,Agostino Cilibrizzi,Andrea A P Tripodi,Antonella Leggio,Vincenzo Abbate,Robert Hider

doi:10.3390/ijms21207498

Abstract

Siderophores are iron-complexing compounds synthesized by bacteria and fungi. They are low molecular weight compounds (500-1500 Daltons) possessing high affinity for iron(III). Since 1970 a large number of siderophores have been characterized, the majority using hydroxamate or catecholate as functional groups. The biosynthesis of siderophores is typically regulated by the iron levels of the environment where the organism is located. Because of their exclusive affinity and specificity for iron(III), natural siderophores and their synthetic derivatives have been exploited in the treatment of human iron-overload diseases, as both diagnostic and therapeutic agents. Here, solid-phase approach for the preparation of hexadentate, peptide-based tricatecholato containing peptides is described. The versatility of the synthetic method allows for the design of a common scaffolding structure whereby diverse ligands can be conjugated. With so many possibilities, a computational approach has been developed which will facilitate the identification of those peptides which are capable of providing a high affinity iron(III) binding site. This study reports an integrated computational/synthetic approach towards a rational development of peptide-based siderophores.

Highlights

Hexadentate iron(III) specific catecholato ligands have been extensively studied [1], for instance there is a large range of natural hexadentate chelators, termed siderophores, which are used by microorganisms to scavenge iron from the environment [2]
In addition synthetic hexadentate catecholato chelators have been designed to compete with natural siderophores, resulting in antimicrobial properties [3]; to scavenge toxic metals from the environment, for instance plutonium, [4] and to form high affinity complexes of Gd4+, Ga3+, In3+ for medical imaging [5,6,7]
Synthesis of Tricatecholato Ligands Attached to a Peptide Backbone

Summary

Introduction

Hexadentate iron(III) specific catecholato ligands have been extensively studied [1], for instance there is a large range of natural hexadentate chelators, termed siderophores, which are used by microorganisms to scavenge iron from the environment [2]. In addition synthetic hexadentate catecholato chelators have been designed to compete with natural siderophores, resulting in antimicrobial properties [3]; to scavenge toxic metals from the environment, for instance plutonium, [4] and to form high affinity complexes of Gd4+, Ga3+, In3+ for medical imaging [5,6,7] The synthesis of such hexadentate ligands can be complicated in so far as often the synthetic routes consist of over ten consecutive reactions and the deprotection of oligodentate ligands is frequently time consuming and difficult to achieve complete deprotection [8,9]. Raymond and colleagues have previously reported studies on prediction models to rationalise the design of hexadentate catecholato iron ligands [11]

Methods

Results

Conclusion