Self‐Assembly of an Amphiphilic Iron(III) Chelator: Mimicking Iron Acquisition in Marine Bacteria

Abstract

Iron is one of the most common elements on Earth, but its availability to living organisms is limited because of its extremely low solubility. Siderophores are low-molecularweight iron(iii) chelators that were evolved by microorganisms for the uptake of physiologically essential iron.[1] Among the mechanisms proposed for iron solubilization and transport into cells, [2] the self-assembly of amphiphilic siderophores from marine bacteria observed by Butler et al.[3] is a noteworthy process. Hydrophilic siderophores (marinobactins and aquachelins) with polar peptidic head groups and hydrophobic fatty acid tails are surface-active amphiphiles that form self-assembled structures. We thought that the biologically inspired use of this strategy might allow the resolution of the crucial problem of the hydrophilic/lipophilic balance encountered with abiotic siderophores designed for iron nutrition.[4] Amphiphilic iron chelators may also offer a new approach in iron chelation therapy.Herein, we present a preliminary report on the selfassembly properties of amphiphilic chelators and their iron complexes, and discuss the first results concerning iron nutrition of Erwinia chrysanthemi and some mutants defective in the production of one or both of its siderophores. Three synthetic catechol-based chelators were investigated (Scheme 1).The two monopodal ligands L a and L b were synthesized by reaction of 2,3-dimethoxybenzoyl chloride with dodecylamine and octylamine, respectively, followed by a deprotection step with BBr 3 . The tripodal ligand L T was obtained from our previously described [5] tripodal precursor 2,2,2-tris[3-(2,3-dimethoxybenzamido)propyl]acetic acid (by reaction of the acid chloride with hexadecylamine and then deprotection of the catechol groups). The ligands were characterized by mass spectrometry and 1 H and 13 C NMR spectroscopy (see Supporting Information). The pH-dependent equilibria of the ligand species and their ferric complexes were determined by potentiometric and spectrophotometric titrations to obtain their net charge at physiological pH, which tunes the amphiphilic properties.[ [5] Notably, at pH 9 the spectral parameters (l max = 490 nm, e = 4300 m In water/methanol (95/5, v/v) solution containing 3-(Nmorpholino)propanesulfonic acid (MOPS) buffer at pH 7.4, the free ligands and their iron complexes exhibit tensioactive properties with a critical micelle concentration (CMC) of < 10 À5 m.[10] The low CMC values of the iron-free ligands are in the same range as that for marinobactin.[3a] Dynamic lightscattering studies [11] on solutions (10, and L T in the same medium revealed the presence of spherical particles of diameter 200-250, 100-110, and 130 nm, respectively. In all cases the distribution is rather broad (polydispersity index of 0.2-0.3). The free ligands, which do not scatter light, are probably limited to micellar assembly. Similar observations have been made for the siderophores from marine bacteria.[3a] Cryo-transmission Scheme 1. Chemical formulae of the synthetic amphiphilic ligands.

Design of Iron chelators: Syntheses and iron (III) complexing abilities of tripodal tris-bidentate ligands

“…Contrary to the results of Hider, which are beyond doubt, the biological results obtained with the hydroxyquinoline chelators do not depend on partition coefficient: O-TRENSOX and its iron complex are water soluble and insoluble in lipophilic medium, but exhibit the same biological activity as the amphiphilic COX 750 (Figure 9a). Another recent approach involves chelators possessing an anionic hydrophilic head (the ferric chelate) and a neutral lipophilic tail capable of self-organization, leading to vesicles that mimic the behaviour of marine siderophores (Apostol et al 2005). In this case, the tripodal triscatecholate ligand was obtained by reaction of the 2, 2, 2-tris[3-(2, 3-dimethoxy-benzamido)propyl]-acetic acid precursor (Imbert et al 2000) with the acyl chloride derivative and hexadecylamine, and then deprotection of the catechol groups ( Figure 9b).…”

XAS Study of a Metal-Induced Phase Transition by a Microbial Surfactant

“…7 Some metal chelating surfactants undergo a change in aggregate morphology upon metal coordination. [8][9][10][11][12][13][14][15] For example, micelles of 4,8-dioctyl-3,9-dioxo-6-hydroxy-4,8-diaza-1,11-undecanedicarboxylate undergo a phase transition to vesicles upon coordination of Cu(II) to the dicarboxylate head group. 16 The phospholipid cardiolipin assembles as a lamellar phase in the absence of metals and forms a reverse-hexagonal phase in the presence of certain divalent metal cations.…”

Vesicles to Concentrate Iron in Low‐Iron Media: An Attempt to Mimic Marine Siderophores

“…Keywords: iron · marine siderophore mimics · micelles · self-assembly · vesicles monodentate and tris(bidentate) synthetic catecholate Fe III chelators. [6] We have also shown that the denticity of the ligand did not significantly influence the aggregation processes. These chelators and their Fe III complexes have tensioactive properties, with a critical micelle concentration (CMC) of < 10 À5 m at pH 7.4.…”

“…[7] Herein we present the self-assembling properties of the iron complex of sulfonated monocatechol derivative L S10 as opposed to unsulfonated ligand L a previously studied. [6] Results and discussion Synthesis: Amphiphilic ligand L S10 was prepared by using a straightforward synthesis (Scheme 1). This method affords some advantages over the synthetic pathway previously described [6] because it avoids protection of the catechol moiety and the use of hydrolysable acyl chloride during the amidification step.…”

“…In comparison, the unsulfonated analogue forms a bisA C H T U N G T R E N N U N G (chelate) complex at pH 7.4 and a tris-A C H T U N G T R E N N U N G (chelate) at a pH of around 9. [6] This can be attributed to the high pK a value of the ortho hydroxyl, which does not allow the coordination of a third bidentate unit at neutral pH.…”