Separation of geometric isomers of a dicopper complex by using a (19)F-labeled ligand: dynamics, structures, and DFT calculations.

Introducing a fluorine group on two pyridines of the HL(CH(3)) ligand (2,6-bis[(bis(2-pyridylmethyl)amino)methyl]-4-methylphenol) allows the separation of two geometric isomers after complexation by two copper(II) ions. Methods for isolating the isomers (1(meso) and 1(rac)) as a mu-phenoxo,mu-hydroxo dicopper(II) complex as a crystalline product have been developed. Both isomers (1(meso) and 1(rac)) have been characterized by X-ray crystallography and (19)F NMR. The isomerism is determined by the disposition of the fluorine atoms with respect to the plane containing the Cu(2)O(2) core. Density functional theory calculations using different functionals were performed to provide additional support for the existence of these two forms. Dissolution of 1(meso) in acetone or acetonitrile causes its spontaneous isomerization into the 1(rac) form at room temperature. Combined experimental studies (UV-vis, (19)F NMR) and theoretical calculations support this process. Paramagnetic (19)F NMR appears as a unique and powerful probe for distinguishing the two isomers and supplying direct evidence of this isomerization process in solution.

Oxinobactin, a siderophore analogue to enterobactin involving 8-hydroxyquinoline subunits: synthesis and iron binding ability.

Oxinobactin, a siderophore analogue to enterobactin but possessing 8-hydroxyquinoline instead of catechol complexing subunits, has been synthesized starting from L-serine and 8-hydroxyquinoline. Comparative iron binding studies showed that oxinobactin is as effective as enterobactin for the complexation of Fe(III) at physiological pH but with improved complexing ability at acidic pH.

New polydentate ligand and catalytic properties of the corresponding ruthenium complex during sulfoxidation and alkene epoxidation.

Bis(diimine)-ruthenium complexes constitute a class of catalysts with good activity for oxidation reactions, such as sulfoxidation and epoxidation. The synthesis and the full characterization of a new ruthenium complex bearing an original pentadentate ligand (L5pyr for 2,6-bis-(6-ethyl-2,2'-bipyridyl)-pyridine) is reported. Comparison of its activity with regard to[Ru(bpy)2(CH3CN)2](2+) and [Ru(bpy)2(py)(CH3CN)](2+) during alkene and sulfide oxidation allowed us to conclude that the addition of a fifth pyridine ligand in the coordination sphere improves the efficiency of the catalyst. Moreover, under these oxidation conditions a hydroxylation of the ligand L5pyr led to a better activity than its analogue [Ru(bpy)2(py)(CH3CN)](2+), especially during epoxidation of alkenes by PhI(OAc)2.

Vesicles to concentrate iron in low-iron media: an attempt to mimic marine siderophores.

Amphiphilic catechol-type iron chelators were studied with the aim of mimicking the properties of marine bacterial siderophores. The Fe(III) complexation constants and aqueous solution speciation of L(S10), a sulfonated catechol unit that has a C(10) lipophilic carbon chain connected by an amide linkage, were determined by spectrophotometric titration. The calculated value of pFe3+ is 18.1 at pH 7.4. Cryogenic transmission electron microscopy showed that the tris(catecholate) ferric complex formed at physiological pH initially assembles into micelles, in which the catecholate-iron units stay on the exterior of the micelle. The average diameter of these micelles was estimated to be 4.2 nm. The micelles then slowly rearrange into clusters of different sizes, which leads to the formation of unilamellar and bilamellar vesicles. The reorganization processes are comparable to those observed by Butler et al. for the marinobactin siderophores produced by marine bacteria, but in contrast to the marinobactins, vesicles of the Fe3+-L(S10) complex form without an excess of iron relative to ligand concentration. The time-dependent micelle-to-vesicle transition is discussed herein.

Structural, kinetic, and theoretical studies on models of the zinc-containing phosphodiesterase active center: medium-dependent reaction mechanisms.

Dinuclear zinc(II) complexes [Zn(2)(bpmp)(mu-OH)](ClO(4))(2) (1) and [Zn(2)(bpmp)(H(2)O)(2)](ClO(4))(3) (2) (H-BPMP=2,6-bis[bis(2-pyridylmethyl)aminomethyl]-4-methylphenol) have been synthesized, structurally characterized, and pH-driven changes in metal coordination observed. The transesterification reaction of 2-hydroxypropyl p-nitrophenyl phosphate (HPNP) in the presence of the two complexes was studied both in a water/DMSO (70:30) mixture and in DMSO. Complex 2 was not reactive whereas for 1 considerable rate enhancement of the spontaneous hydrolysis reaction was observed. A detailed mechanistic investigation by kinetic studies, spectroscopic measurements ((1)H, (31)P NMR spectroscopy), and ESI-MS analysis in conjunction with ab initio calculations was performed on 1. Based on these results, two medium-dependent mechanisms are presented and an unusual bridging phosphate intermediate is proposed for the process in DMSO.

Iron-citrate complexes and free radicals generation: is citric acid an innocent additive in foods and drinks?

The generation of free radicals (Fenton chemistry) from various iron citrate complexes has been studied. Spin trapping methods have been used. The results can question concerning the innocence of added citric acid in foods and cold drinks. We concluded that in absence of pathological situation citric acid is probably not dangerous but it may become dangerous in situation of oxidative stress and/or iron overload.

Up to four phenoxyl radicals coordinated to two metal ions in copper and zinc complexes?

Neutral copper(II) and zinc(II) complexes of the mono- and dinucleating Schiff base ligands (2,4-di-tert-butyl-6-({2-[(3,5-di-tert-butyl-2-hydroxy-benzylidene)-amino]-phenylimino}-methyl)-phenol) and (2,4-di-tert-butyl-6-({2,4,5-tri-[(3,5-di-tert-butyl-2-hydroxy-benzylidene)-amino]-phenylimino}-methyl)-phenol) respectively were synthesized and characterized. The monometallic complex can be oxidized into a mono and a dication, while oxidation of the dimetallic one affords up to a tetracation. Whatever the ligand and metal are, oxidation takes place at the phenolate moieties, which were oxidized into coordinated phenoxyl radicals, i.e. the oxidation locus is not correlated to the ligand nuclearity. These results could be rationalized with previous ones by considering the hybridization of the coordinating nitrogens and the nature of the O-donor groups.

Multifrequency EPR and redox reactivity investigations of a bis(mu-thiolato)-dicopper(II,II) complex.

From a new tripodal ligand [N2SS'H] with mixed N, S(thioether), and S(thiolate) donor set, the corresponding bis(mu-thiolato)dicopper(II) complex has been prepared and characterized. X-ray crystallographic analysis of the complex [Cu2(N2SS')2](ClO4)2.C4H10O (1) demonstrates that the two five-coordinated Cu atoms are bridged by two thiolates leading to a nearly planar Cu2S2 core with a Cu1...Cu1* distance of 3.418(8) A and a large bridging angle Cu1S1Cu1* of 94.92 degrees. X-band (10 GHz), Q-band (34 GHz), and F-Band (115 GHz) EPR spectra of 1 are consistent with a weakly coupled dicopper(II,II) center attributed to an S = 1 state. Simulations for the three frequencies are obtained with a unique set of electronic parameters. The mean values of the spin Hamiltonian parameters for 1 are D = 0.210(3) cm(-1), E = 0.0295(5) cm(-1), |E/D| = 0.140, gx = 2.030(2), gy = 2.032(2), gz = 2.128(2). The electrochemical one-electron reduction of 1 generates the mixed-valent CuIICuI species. EPR and UV-vis spectra are consistent with a type I localized mixed-valent species, while dinuclear CuA centers of native cytochrome c oxidase (CcO)1-3 or nitrous oxide reductase (N2OR)4 have a delocalized CuIICuI mixed-valent state. After reoxidation of the CuIICuI species, the initial complex 1 is regenerated through a reversible interconversion process.

Galactose Oxidase models: 19F NMR as a powerful tool to study the solution chemistry of tripodal ligands in the presence of copper(II).

In copper(ii) complexes of tripodal ligands, the protonation state of the phenol moiety, and its position (axial vs. equatorial), are easily assessed by (19)F NMR.

Modulation of cell proliferation and polyamine metabolism in rat liver cell cultures by the iron chelator O-trensox.

The antiproliferative effects of the iron chelator O-trensox and the ornithine-decarboxylase (ODC) inhibitor alpha-difluoromethylornithine (DFMO) were characterized in the rat hepatoma cell line FAO, the rat liver epithelial cell line (RLEC) and the primary rat hepatocyte cultures stimulated by EGF. We observed that O-trensox and DFMO decreased cell viabilty and DNA replication in the three culture models. The cytostatic effect of O-trensox was correlated to a cytotoxicity, higher than for DFMO, and to a cell cycle arrest in G0/G1 or S phases. Moreover, O-trensox and DFMO decreased the intracellular concentration of spermidine in the three models without changing significantly the spermine level. We concluded that iron, but also polyamine depletion, decrease cell growth. However, the drop in cell proliferation obtained with O-trensox was stronger compared to DFMO effect. Altogether, our data provide insights that, in the three rat liver cell culture models, the cytostatic effect of the iron chelator O-trensox may be the addition of two mechanisms: iron and polyamine depletion.

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

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.

Catecholase activity of a copper(II) complex with a macrocyclic ligand: unraveling catalytic mechanisms.

We report the structure, properties and a mechanism for the catecholase activity of a tetranuclear carbonato-bridged copper(II) cluster with the macrocyclic ligand [22]pr4pz (9,22-dipropyl-1,4,9,14,17,22,27,28,29, 30-decaazapentacyclo[22.2.1.1(4,7).1(11,14). 1(17,20)]triacontane-5,7(28),11(29),12,18, 20(30),24(27),25-octaene). In this complex, two copper ions within a macrocyclic unit are bridged by a carbonate anion, which further connects two macrocyclic units together. Magnetic susceptibility studies have shown the existence of a ferromagnetic interaction between the two copper ions within one macrocyclic ring, and a weak antiferromagnetic interaction between the two neighboring copper ions of two different macrocyclic units. The tetranuclear complex was found to be the major compound present in solution at high concentration levels, but its dissociation into two dinuclear units occurs upon dilution. The dinuclear complex catalyzes the oxidation of 3,5-di-tert-butylcatechol to the respective quinone in methanol by two different pathways, one proceeding via the formation of semiquinone species with the subsequent production of dihydrogen peroxide as a byproduct, and another proceeding via the two-electron reduction of the dicopper(II) center by the substrate, with two molecules of quinone and one molecule of water generated per one catalytic cycle. The occurrence of the first pathway was, however, found to cease shortly after the beginning of the catalytic reaction. The influence of hydrogen peroxide and di-tert-butyl-o-benzoquinone on the catalytic mechanism has been investigated. The crystal structures of the free ligand and the reduced dicopper(I) complex, as well as the electrochemical properties of both the Cu(II) and the Cu(I) complexes are also reported.

Valence tautomerism in octahedral and square-planar phenoxyl-nickel(II) complexes: are imino nitrogen atoms good friends?

The two tetradentate ligands H(2)L and H(2)L(Me) afford the slightly distorted square-planar low-spin Ni(II) complexes 1 and 2, which comprise two coordinated phenolate groups. Complex 1 has been electrochemically oxidized into 1(+), which contains a coordinated phenoxyl radical, with a contribution from the nickel orbital. In the presence of pyridine, 1(+) is converted into 1(Py) (+), an octahedral phenolate nickel(III) complex with two pyridines axially coordinated: An intramolecular electron transfer (valence tautomerism) is promoted by the geometrical changes, from square planar to octahedral, around the metal center. The tetradentate ligand H(2)L(Me), in the presence of pyridine, and the hexadentate ligand H(2)L(Py) in CH(2)Cl(2) afford, respectively, the octahedral high-spin Ni(II) complexes 2(Py) and 3, which involve two equatorial phenolates and two axially coordinated pyridines. At 100 K, the one-electron-oxidized product 2(Py) (+) comprises a phenoxyl radical ferromagnetically coupled to the high-spin Ni(II) ion, with large zero-field splitting parameters, while 3(+) involves a phenoxyl radical antiferromagnetically coupled to the high-spin Ni(II) ion.

Cyclodecapeptides to mimic the radical site of tyrosyl-containing proteins.

Tyrosyl radicals are involved in many biologically important processes. The development of model compounds to mimic radical enzyme active sites, such as galactose oxidase (GO), has widely contributed to an enhanced understanding of their spectral properties, structural attributes and even reactivity. An emerging approach towards the synthesis of such active site mimetics is the use of peptidic ligands. The potential of cyclodecapeptides to bear phenoxyl radicals has been evaluated through three compounds. LH(4) (2+) is a cyclodecapetide containing two histidine residues (mimicking His(496) and His(581) of GO) and two tyrosine residues (mimicking Tyr(495) and the Tyr(272)* radical of GO). L(tBu)H(4) (2+) and L(OMe)H(4) (2+) incorporate 2,4,6-protected phenols in place of each tyrosine in LH(4) (2+). The deprotonation constants of each peptide determined by potentiometric titrations showed that there are some interactions between the acido-basic residues. Cyclic voltammetric studies revealed that only the peptides incorporating 2,4,6-protected phenolates exhibit reversible redox couples and are thus precursors of radicals stable enough to persist in solution. These studies also showed L(OMe2-) to possess the lower oxidation potential, indicating that this peptide, in its radical form, is the most stabilized. The electrochemically generated radical species have been characterized by EPR spectroscopy.

The new orally active iron chelator ICL670A exhibits a higher antiproliferative effect in human hepatocyte cultures than O-trensox.

By comparing the antiproliferative effect of the iron chelators ICL670A and O-trensox in the human hepatoma cell line HUH7 and human hepatocyte cultures, we have shown that ICL670A decreased cell viability, inhibited DNA replication and induced DNA fragmentation more efficiently than O-trensox. O-trensox and ICL670A induced a cell cycle blockade in G0-G1 and S phases respectively. In parallel, ICL670A inhibited polyamine biosynthesis by decreasing ornithine decarboxylase and spermidine/spermine N(1)-acetyltransferase activities. O-trensox increased polyamine biosynthesis and particularly putrescine level by stimulating spermidine-spermine N(1)-acetyltransferase activity which could activate the polyamine retro-conversion pathway. Moreover, the two chelators exhibit some cytotoxic effect in the two culture models; ICL670A was more cytotoxic than O-trensox and higher concentrations of the two chelators were necessary to induce a cytotoxicity in primary cultures versus hepatoma cells. These results suggested that ICL670A has the most efficient antitumoral effect, blocks cell proliferation by a pathway different of O-trensox and may constitute a potential drug for anticancer therapy.

Fine tuning of the oxidation locus, and electron transfer, in nickel complexes of pro-radical ligands.

A large number of complexes of the first-row transition metals with non-innocent ligands has been characterized in the last few years. The localization of the oxidation site in such complexes can lead to discrepancies when electrons can be removed either from the metal center (leading to an M((n+1)+) closed-shell ligand) or from the ligand (leading to an M(n+) open-shell ligand). The influence of the ligand field on the oxidation site in square-planar nickel complexes of redox-active ligands is explored herein. The tetradentate ligands employed herein incorporate two di-tert-butylphenolate (pro-phenoxyl) moieties and one orthophenylenediamine spacer. The links between the spacer and both phenolates are either two imines ([Ni(L1)]), two amidates ([Ni(L3)]2-), or one amidate and one imine ([Ni(L2)]-). The structure of each nickel(II) complex is presented. In the noncoordinating solvent CH2Cl2, the one-electron-oxidized forms are ligand-radical species with a contribution from a singly occupied d orbital of the nickel. In the presence of an exogenous ligand, such as pyridine, a Ni(III) closed-shell ligand form is favored: axial ligation, which stabilizes the trivalent nickel in its octahedral geometry, induces an electron transfer from the metal(II) center to the radical ligand. The affinity of pyridine for the phenoxylnickel(II) species is correlated to the N-donor ability of the linkers.

Catecholase activity of a mu-hydroxodicopper(II) macrocyclic complex: structures, intermediates and reaction mechanism.

The monohydroxo-bridged dicopper(II) complex (1), its reduced dicopper(I) analogue (2) and the trans-mu-1,2-peroxo-dicopper(II) adduct (3) with the macrocyclic N-donor ligand [22]py4pz (9,22-bis(pyridin-2'-ylmethyl)-1,4,9,14,17,22,27,28,29,30- decaazapentacyclo -[22.2.1(14,7).1(11,14).1(17,20)]triacontane-5,7(28),11(29),12,18,20(30), 24(27),25-octaene), have been prepared and characterized, including a 3D structure of 1 and 2. These compounds represent models of the three states of the catechol oxidase active site: met, deoxy (reduced) and oxy. The dicopper(II) complex 1 catalyzes the oxidation of catechol model substrates in aerobic conditions, while in the absence of dioxygen a stoichiometric oxidation takes place, leading to the formation of quinone and the respective dicopper(I) complex. The catalytic reaction follows a Michaelis-Menten behavior. The dicopper(I) complex binds molecular dioxygen at low temperature, forming a trans-mu-1,2-peroxo-dicopper adduct, which was characterized by UV-Vis and resonance Raman spectroscopy and electrochemically. This peroxo complex stoichiometrically oxidizes a second molecule of catechol in the absence of dioxygen. A catalytic mechanism of catechol oxidation by 1 has been proposed, and its relevance to the mechanisms earlier proposed for the natural enzyme and other copper complexes is discussed.

Sulfur ligation in copper enzymes and models.

Biological copper-sulfur entities display versatile and unusual coordination chemistry. The role of the sulfur ligation is briefly reviewed through examples from selected copper enzymes and relevant biomimetic models. Copper thiolate complexes are of particular interest because of their key roles in a number of ubiquitous metalloenzymes such as Type I (blue copper proteins) or in the binuclear Cu(A) electrons transfer site found in both cytochrome c oxidase (CcO) and nitrous oxide reductase (N2OR). The possible roles of the S(Met) ligand in monoxygenases are described in relation to recently proposed pathways. Some prospective regarding the biological relevance of disulfide copper ligation and possible radical copper bonds in catalytic cycle are also discussed.

Proton NMR spectroscopy and magnetic properties of a solution-stable dicopper(II) complex bearing a single mu-hydroxo bridge.

The reaction of copper(II) perchlorate with the macrocyclic ligand [22]py4pz in the presence of base leads to formation of a dinuclear complex [Cu(2)([22]py4pz)(mu-OH)](ClO(4))(3)xH(2)O, in which two copper ions are bridged by a single mu-hydroxo bridge. Each copper ion is further surrounded by four nitrogen atoms of the ligand. The mu-hydroxo bridge mediates a strong antiferromagnetic coupling (2J = -691(35) cm(-1)) between the metal centers, leading to relatively sharp and well-resolved resonances in the (1)H NMR spectrum of the complex in solution. We herein report the crystal structure, the magnetic properties, and the full assignment of the hyperfine-shifted resonances in the NMR spectrum of the complex, as well as the determination of the exchange coupling constant in solution through temperature-dependent NMR studies.

Discovery of powerful uranyl ligands from efficient synthesis and screening.

New tripodal gem-(bis-phosphonates) uranophiles were discovered by a screening method that allowed for the selection of ligands with strong uranyl-binding properties in a convenient microtiter-plate format. The method is based on competitive uranium binding by using Sulfochlorophenol S as chromogenic chelate. This dye compound was found to present high uranyl complexation properties and allowed to highlight ligands presenting association constants for UO(2+)(2) up to 10(18) at pH 7.4 and 10(20) at pH 9. A collection of 40 known ligands including polycarboxylate, hydroxamate, catecholate, hydroxypyridonate and hydroxyquinoline derivatives was tested. Also screened was a combinatorial library prepared from seven amine scaffolds and eight acrylates bearing diverse chelating moieties. Among these 96 tested candidates, a tripod derivative bearing gem-bis-phosphonates moieties was found to present the highest complexation properties over a wide range of pH and was further studied.