Hydrophilic and Lipophilic Iron Chelators with the Same Complexing Abilities

Imbert, Daniel; Baret, Paul; Gaude, Didier; Gautier‐Luneau, Isabelle; Gellon, Gisèle; Thomas, Fabrice; Serratrice, Guy; Pierre, Jean‐Louis

doi:10.1002/1521-3765(20020301)8:5<1091::aid-chem1091>3.0.co;2-y

Cited by 24 publications

(26 citation statements)

References 19 publications

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“…Vice versa, changes in pFe should reflect modifications in the metal coordination sphere. Thus, the same pFe values are observed for O-TRENSOX and for the POE-grafted chelators (Imbert et al 2002).…”

Section: The Role Of the Spacer And The Connecting Mode Of The Chelatsupporting

confidence: 90%

“…An elegant strategy has been developed by Shanzer and collaborators in which the lipophilic ferrichrome analogues with masked hydrophilic moieties (Figure 8a) A series of three tris-hydroxyquinolinate derivatives of O-TRENSOX containing a C-pivotal atom as spacer and grafted with various polyoxyethylene chains (POE) has been prepared in our group (Figure 9a, Imbert et al 2002), leading to the observation that the hydrophilic-lipophilic balance (quantified by the partition coefficients) of the overall neutral ferric complexes is tuned by the length of the polyoxyethylene chain. This aspect was particularly well illustrated by Hider and gave conflicting results with the ligands of the 8-hydroxyquinoline family (Thomas et al 1999a, b;Henry et al 2001;Imbert et al 2002). 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).…”

Section: Lipophilic and Amphiphilic Siderophoressupporting

confidence: 71%

“…The sulphonated compounds are highly water-soluble and the ionised derivatives insoluble in lipophilic medium. A more discerning approach, based on the grafting of polyoxyethylene chains (Imbert et al 2002), can allow both water and lipophilic solubility without introducing ionisable (i.e. -SO 3 H) or charged groups (i.e.…”

Section: Water Solubilitymentioning

confidence: 99%

“…Lipophilic chelators derived from EDTA (Galey et al 2000;Serratrice et al 2001) or trisaminophenol (Bollinger et al 1995) have also been reported. An elegant strategy has been developed by Shanzer and collaborators in which the lipophilic ferrichrome analogues with masked hydrophilic moieties (Figure 8a) A series of three tris-hydroxyquinolinate derivatives of O-TRENSOX containing a C-pivotal atom as spacer and grafted with various polyoxyethylene chains (POE) has been prepared in our group (Figure 9a, Imbert et al 2002), leading to the observation that the hydrophilic-lipophilic balance (quantified by the partition coefficients) of the overall neutral ferric complexes is tuned by the length of the polyoxyethylene chain. This aspect was particularly well illustrated by Hider and gave conflicting results with the ligands of the 8-hydroxyquinoline family (Thomas et al 1999a, b;Henry et al 2001;Imbert et al 2002).…”

Section: Lipophilic and Amphiphilic Siderophoresmentioning

confidence: 99%

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

et al. 2006

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The interest in synthetic siderophore mimics includes therapeutic applications (iron chelation therapy), the design of more effective agents to deliver Fe to plants and the development of new chemical tools in order to study iron metabolism and iron assimilation processes in living systems. The design of ligands needs a rational approach for the understanding of the metal ion complexing abilities. The octahedral arrangement of donor atoms is the most favourable geometry, allowing the maximum possible distance between their formal or partial negative charges. Hexadentate chelators, usually of the tris-bidentate type, can accommodate the metal coordination sphere and are well-suited to obtain high pFe values. The first part of this review is dedicated to selected synthetic routes, taking into account (i) the nature of the chelating subunits, connecting groups and spacers, (ii) the water-solubility and hydrophilic/lipophilic balance, (iii) the chirality and (iv) the possibility of grafting probes or vectors. In the second part, we discuss the role of the molecular design on complexing abilities (thermodynamics and kinetics). The bidentate 8-hydroxyquinoline moiety offers an alternative to the usual coordinating hydroxamic acids, catechols and/or alpha-hydroxycarboxylic acids groups encountered in natural siderophores. The promizing results obtained with the tris-hydroxyquinoline-based ligand O-TRENSOX are summarized. O-TRENSOX exhibits a high and selective affinity for Fe(III) complexation. Its efficiency in delivering Fe to plants, iron mobilization, cell protection, and antiproliferative effects has been evidenced. Other chelators derived from O-TRENSOX (mixed catechol/8-hydroxyquinoline ligands, lipophilic ligands) are also described. Some results question the relevance of partition coefficients to foresee the activity of iron chelators. The development of probes (fluorescent, radioactive, spin labelled) based on the O-TRENSOX backbone is in progress in order to get insights in the complicated iron metabolism processes.

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Section: The Role Of the Spacer And The Connecting Mode Of The Chelatsupporting

confidence: 90%

Section: Lipophilic and Amphiphilic Siderophoressupporting

confidence: 71%

Section: Water Solubilitymentioning

confidence: 99%

Section: Lipophilic and Amphiphilic Siderophoresmentioning

confidence: 99%

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

et al. 2006

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“…They have been shown to be more effective at pH = 7.4 than the parent homopodal ligands TRENCAMS and O‐TRENSOX. Another series of tripodal ligands bearing a C‐pivot scaffold with either 8‐hydroxyquinoline (C‐SOX,21 COX22) or catechol subunits (CacCAM23) has also been developed in our laboratory. A C‐pivot allows the grafting of any desired substituent, e.g.…”

Section: Introductionmentioning

confidence: 99%

Mechanism of the Stepwise Dissociation of Fe^III Complexes with Tripodal Ligands as Siderophore Models

et al. 2004

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The acid hydrolysis and formation kinetics of 1:1 ferric complexes with several tripodal hexadentate ligands were investigated over the [H + ] range of 0.02−1.0 M at 25°C and at an ionic strength of 2.0 M (NaClO 4 /HClO 4 ). These ligands are based on a tris(2-aminoethyl)amine (TREN) spacer connected through a tris(amide) moiety to identical pendant bidentate chelating group arms such as catecholate (TREN-CAMS,Mixed ligands with chelating arms such as catecholate and 8-hydroxyquinolinate (TRENSOX2CAMS, L 1 and TRENSOXCAMS2, L 2 ) were also investigated. An analogue of L 0 (C-SOX, L 4 ) with a C-pivot scaffold instead of TREN was studied for comparison. The acid hydrolysis reaction was found to proceed in four kinetically distinguishable stages. A common mechanism in the series was followed when the ligand structure was varied. The first stage is very fast and can be attributed to the dissociation of one arm of the tripodal ligand. The second and third stages involve protonation of the complex which in-

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

et al. 2005

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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.

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Hydrophilic and Lipophilic Iron Chelators with the Same Complexing Abilities

Cited by 24 publications

References 19 publications

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

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

Mechanism of the Stepwise Dissociation of Fe^III Complexes with Tripodal Ligands as Siderophore Models

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

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Hydrophilic and Lipophilic Iron Chelators with the Same Complexing Abilities

Cited by 24 publications

References 19 publications

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

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

Mechanism of the Stepwise Dissociation of FeIII Complexes with Tripodal Ligands as Siderophore Models

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

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Mechanism of the Stepwise Dissociation of Fe^III Complexes with Tripodal Ligands as Siderophore Models