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Lin, Yun-Ming; Miller, Marvin J.; Möllmann, Ute

doi:10.1023/a:1016666414848

Cited by 12 publications

(2 citation statements)

References 13 publications

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“…Siderophore-mediated iron uptake is an important determinant of bacterial growth 3 and there is suggestive evidence that iron proteins and siderophores are involved in cell signaling cascades and quorum sensing. − Amphiphiles are a significant and widely distributed subset of siderophores, having been found in pathogens, − terrestrial symbionts, and marine microorganisms. − Mycobactins, lipophilic siderophores of Mycobacter smegmatis , have shown beneficial activity for the treatment of arteriosclerosis, breast cancer, and postischemic reperfusion injury . A synthetic, amphiphilic analogue of desferoxamine has been reported to inhibit malaria , and another lipophilic tripeptide ornithine-based hydroxamate chelator was found to effectively promote growth of Mycobacter smegmatis . Strategies for the design of antibiotic “Trojan Horse” siderophore conjugates have been described .…”

Section: Introductionmentioning

confidence: 99%

“…18 A synthetic, amphiphilic analogue of desferoxamine has been reported to inhibit malaria 19,20 chelator was found to effectively promote growth of Mycobacter smegmatis. 21 Strategies for the design of antibiotic "Trojan Horse" siderophore conjugates have been described. 22 The ubiquity of amphiphilic siderophores, the mechanisms of their exploitation by pathogens, and their promising pharmacological activities focus attention on the structures and functions of these little-studied natural products.…”

Section: Introductionmentioning

confidence: 99%

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Synthesis, Structure, and Molecular Dynamics of Gallium Complexes of Schizokinen and the Amphiphilic Siderophore Acinetoferrin

2004

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A new general synthesis of the citrate-based siderophores acinetoferrin (Af) and schizokinen (Sz) and their analogues is described. The molecular structure of gallium schizokinen, GaSz, was determined by combined (1)H NMR, Hartree-Fock ab initio calculations, DFT, and empirical modeling of vicinal proton NMR spin-spin couplings. The metal-coordination geometry of GaSz was determined from NOE contacts to be cis-cis with respect to the two chelating hydroxamates. One diaminopropane adopts a single chairlike conformation while another is a mixture of two ring pucker arrangements. Both amide hydrogens are internally hydrogen bonded to metal-ligating oxygen atoms. The acyl methyl groups are directed away from each other with an average planar angle of ca. 130 degrees. The kinetics of GaSz racemization were followed by selective, double spin-echo inversion-recovery (1)H NMR spectroscopy over the temperature range of 10-45 degrees C. The racemization proceeds by a multistep mechanism that is proton independent between pD 5 and 12 (k(0) = 1.47 (0.15 s(-1))) and acid catalyzed below pD 4 (k(1) = 2.25 (0.15) x 10(4) M(-1) s(-1)). The activation parameters found for the two sequential steps of the proton independent pathway were DeltaH(++) = 25 +/- 3 kcal M(-1), DeltaS(++) = 25 +/- 7 cal M(-1) K(-1) and DeltaH(++) = 17.1 +/- 0.2 kcal M(-1), DeltaS(++) = 0.3 +/- 2.7 cal M(-1) K(-1). The first step of the proton-independent mechanism was assigned to the dissociation of the carboxyl group. The second step was assigned to complex racemization. The proton-assisted step was assigned to a complete dissociation of the alpha-hydroxy carboxyl group at pD < 4. The ab initio modeling of gallium acinetoferrin, GaAf, and analogues derived from the structure of GaSz has shown that the pendant trans-octenoyl fragments are oriented in opposite directions with the average planar angle of ca. 130 degrees. This arrangement prevents GaAf from adopting a phospholipid-like structural motif. Significantly, iron siderophore complex FeAf was found to be disruptive to phospholipid vesicles and is considerably more hydrophilic than Af, with an eight-fold smaller partition coefficient.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Synthesis, Structure, and Molecular Dynamics of Gallium Complexes of Schizokinen and the Amphiphilic Siderophore Acinetoferrin

2004

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Natural and Biomimetic Hydroxamic Acid Based Siderophores

Shanzer

Felder

Barda

2010

Patai's Chemistry of Functional Groups

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Introduction Physical and Chemical Properties of Hydroxamate‐Based Siderophores Iron Metabolism Biomimetic Chemistry Natural and Biomimetic Hydroxamic Acid Based Siderophores Siderophore Conjugates Biomimetic Siderophores in Health and Disease Acknowledgments

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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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Cited by 12 publications

References 13 publications

Synthesis, Structure, and Molecular Dynamics of Gallium Complexes of Schizokinen and the Amphiphilic Siderophore Acinetoferrin

Synthesis, Structure, and Molecular Dynamics of Gallium Complexes of Schizokinen and the Amphiphilic Siderophore Acinetoferrin

Natural and Biomimetic Hydroxamic Acid Based Siderophores

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

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