Metal complexes of salicylhydroxamic acid (H2Sha), anthranilic hydroxamic acid and benzohydroxamic acid. Crystal and molecular structure of [Cu(phen)2(Cl)]Cl x H2Sha, a model for a peroxidase-inhibitor complex

Stability constants of iron(III), copper(II), nickel(II) and zinc(II) complexes of salicylhydroxamic acid (H2Sha), anthranilic hydroxamic acid (HAha) and benzohydroxamic acid (HBha) have been determined at 25.0 degrees C, I=0.2 mol dm(-3) KCl in aqueous solution. The complex stability order, iron(III) > copper(II) > nickel(II) approximately = zinc(II) was observed whilst complexes of H2Sha were found to be more stable than those of the other two ligands. In the preparation of ternary metal ion complexes of these ligands and 1,10-phenanthroline (phen) the crystalline complex [Cu(phen)2(Cl)]Cl x H2Sha was obtained and its crystal structure determined. This complex is a model for hydroxamate-peroxidase inhibitor interactions.     

A re-investigation of the reactions between superoxide anion and metal picolinate complexes

Rate constants for the reactions of superoxide with the α-picolinate ion and its complexes with copper(II), iron(III) and zinc(II), and for the reaction of α-picolinate with the hydrated electron, were measured using pulse radiolysis. The rate constant for the reaction of superoxide with copper(II)picolinate at pH 9 [(4.1 ± 0.4) × 10⁷l mol⁻¹ s⁻¹] was an order of magnitude higher than that determined previously (W. H. Bannister, J. V. Bannister, A. J. F. Searle and P. J. Thornally, Inorg. Chim. Acta, 78, 139 (1983)) using a less direct competitive inhibition method. The corresponding rate constant for iron(III)picolinate [(7.5 ± 1.5) X 10³ l mol⁻¹ s⁻] was an order of magnitude lower than a previous pulse radiolysis determination (same reference as above). We are not able to reconcile these two values for iron(III)picolinate, although a possible source of spuriously high results is contamination with the kinetically active copper(II) complex. The likely roles of iron(III)picolinate and other low molecular weight iron complexes as potential catalysts of an in vivo superoxide-driven Fenton reaction are discussed in the light of present measurements.     

Extraction of copper from an oxidized (lateritic) ore using bacterially catalysed reductive dissolution

An oxidized lateritic ore which contained 0.8 % (by weight) copper was bioleached in pH- and temperature-controlled stirred reactors under acidic reducing conditions using pure and mixed cultures of the acidophilic chemolithotrophic bacterium Acidithiobacillus ferrooxidans. Sulfur was provided as the electron donor for the bacteria, and ferric iron present in goethite (the major ferric iron mineral present in the ore) acted as electron acceptor. Significantly more copper was leached by bacterially catalysed reductive dissolution of the laterite than in aerobic cultures or in sterile anoxic reactors, with up to 78 % of the copper present in the ore being extracted. This included copper that was leached from acid-labile minerals (chiefly copper silicates) and that which was associated with ferric iron minerals in the lateritic ore. In the anaerobic bioreactors, soluble iron in the leach liquors was present as iron (II) and copper as copper (I), but both metals were rapidly oxidized (to iron (III) and copper (II)) when the reactors were aerated. The number of bacteria added to the reactors had a critical role in dictating the rate and yield of copper solubilised from the ore. This work has provided further evidence that reductive bioprocessing, a recently described approach for extracting base metals from oxidized deposits, has the potential to greatly extend the range of metal ores that can be biomined.     

Low-temperature crystal structures of tetrakis-mu-3,5-diisopropylsalicylatobis-dimethylformamidodico pper(II) and tetrakis-mu-3,5-diisopropylsalicylatobis-diethyletheratodicopp er(II) and their role in modulating polymorphonuclear leukocyte activity in overcoming seizures

Two binuclear copper(II) complexes of 3,5-diisopropylsalicylic acid were characterized by single crystal X-ray diffraction methods and examined for anti-inflammatory activity using activated polymorphonuclear leukocytes and for anticonvulsant activities using electroshock and metrazol models of seizures. These complexes were crystallized from dimethylformamide (DMF) or diethylether. Tetrakis-mu-3,5-diisopropylsalicylatobis-dimethylformamidodicop per(II) [Cu(II)2(3,5-DIPS)4(DMF)2] I is in space group P 1; a = 10.393 (2), b = 11.258 (2), c = 12.734 (2) A, alpha = 96.64 (2), beta = 92.95 (2), gamma = 94.90 (2) degrees; V = 1471.7 (4) A3; Z = 1. Tetrakis-mu-3,5-diisopropylsalicylatobis-etheratodicopper(II ) [Cu(II)2(3,5-DIPS)4(ether)2] II is in space group P 1; a = 10.409 (3), b = 11.901 (4), c = 12.687 (6) A, alpha = 91.12 (5), beta = 90.84 (5), gamma = 100.90 (4) degrees; V = 1542 (1) A3; Z = 1. The structure of I was determined at 140 K from 4361 unique reflections (I > 2sigma(1)) and refined on F2 to R1 = 0.04 and wR2 = 0.09. The structure of II was determined at 180 K from 4605 unique reflections (I > 2sigma(I)) and refined on F2 to R1 = 0.05 and wR2 = 0.13. Each compound is a crystallographically centrosymmetric binuclear complex with Cu atoms bridged by four 3,5-diisopropylsalicylate ligands related by a symmetry center [Cu-Cu(i): 2.6139 (9) A in I and 2.613 (1) in II]. The four nearest O atoms around each Cu atom form a nearly rectangular planar arrangement with the square pyramidal coordination completed by the dimethylformamide (or diethylether) oxygen atom occupying an apical position, at a distance of 2.129 (2) A in I and 2.230 (3) A in II. Each Cu atom is displaced towards the DMF (or diethylether) ligand, by 0.189 A in I and 0.184 A in II, from the plane of the four O atoms. The crystal structures of I and II are essentially similar to each other, except for the DMF or diethylether accommodation. Many disorder phenomena were found in the crystal structure of I. Copper(II)2(3,5-DIPS)4(DMF)2 inhibited polymorphonuclear leukocyte (PMNL) oxidative metabolism in vitro. This effect was concentration related and significant for concentrations higher than 10 microg or 0.68 nmol/ml. Copper(II)2(3,5-DIPS)4(DMF)2 was more active than the parent ligand, 3,5-DIPS, as has been demonstrated with copper complexes of other non-steroidal anti-inflammatory drugs. The DMF and diethylether ternary complexes of Cu(II)2(3,5-DIPS)4 were found to have anticonvulsant activity in the maximal electroshock model of grand mal epilepsy in doses ranging from 26 to 258 micromol/kg of body mass following intraperitoneal, subcutaneous, or oral treatment. The DMF ternary complex was also found to be effective in the subcutaneous injection of metrazol model of petit mal epilepsy. We conclude that both ternary copper complexes are lipophilic and bioavailable, capable of facilitating the inflammatory response to brain injury and causing the subsidence of this response in bringing about remission of these disease states.     

A functional model for pMMO (particulate methane monooxygenase): Hydroxylation of alkanes with H2O2 catalyzed by beta-diketiminatocopper(II) complexes

The reaction of copper(II) complexes supported by a series of beta-diketiminate ligands ((R1,R2)L, [(Dipp)N-C(R(2))-C(R(1))-C(R(2))-N(Dipp)](-), Dipp=2,6-diisopropylphenyl; see ) and H(2)O(2) has been examined spectroscopically at a low temperature. The beta-diketiminatocopper(II) complexes with R(2)=H (no substituent on the beta-carbon) provided a copper-oxygen intermediate that exhibited the same spectroscopic features as those of the bis(mu-oxo)dicopper(III) complex generated by the reaction of corresponding beta-diketiminatocopper(I) complex and O(2). On the other hand, the beta-diketiminatocopper(II) complexes with methyl substituent on the beta-carbon (R(2)=Me) did not produce such an intermediate in the same reaction. The beta-diketiminatocopper(II) complexes carrying an electron-withdrawing substituent on the alpha-carbon (R(1)=NO(2) or CN) but no beta-substituent (R(2)=H) exhibited a high catalytic activity in the oxygenation reaction of alkanes with H(2)O(2). Mechanism of the catalytic oxygenation reaction as well as the substituent effects of the ligands on the copper(II)-H(2)O(2) reactivity is discussed.     

Enhancement of cytotoxicity of bleomycin by dithiocarbamates: formation of bis(dithiocarbamato) cu(II).

Properties of the reactions of dithiocarbamates and their Cu(II) or Fe(III) complexes with Ehrlich cells were determined and related to their effects on the inhibition of cell proliferation caused by bleomycin and Cu bleomycin. In complete culture medium containing Eagle's minimal essential medium plus Earles salts and 2.5% fetal calf serum, dimethyl- and diethyldithiocarbamates and their copper complexes inhibit cell proliferation and cause cell death. The copper complexes are more effective agents. Ferric tris-diethyldithiocarbamate is also a cytotoxic species. In contrast, when cells are exposed to dimethyldithiocarbamate or its copper complex in Ringer's buffer under metal-restricted condition, washed, and then placed in complete medium, the copper complex is much more active in inhibiting cell growth. The difference is magnified when dihydroxyethyldithiocarbamate and N-methylglucamine dithiocarbamate and their copper complexes are compared in complete media. Incubation of bleomycin or copper bleomycin with Ehrlich cells in Ringer's buffer with or without dimethyldithiocarbamate or bis-dimethyldithiocarbamato Cu(II) leads to no enhancement of cytotoxicity from combinations of agents, except when the two copper complexes are present. Diethyl- or dimethyldithiocarbamate readily extracts copper from Cu(II)bleomycin and iron from Fe(III)bleomycin when ethylacetate is present to remove the tris-dithiocarbamato Fe(III) complex from aqueous solution. When bis-dimethyldithiocarbamato Cu(II) is incubated with Ehrlich cells, copper is released from the complex and bound to high molecular weight and metallothionein fractions. A reductive mode of dissociation of the copper complexes in cells is supported by ESR experiments. Reactions of diethyl- and dimethyldithiocarbamato Cu(II) with thiol compounds demonstrates one possible mechanism of reduction of these complexes.     

Investigations into some aryl substituted bis(thiosemicarbazones) and their copper complexes

The synthesis of three bis(thiosemicarbazone) compounds formed by the reaction of benzil with either thiosemicarbazide, 4-methyl-3-thiosemicarbazide or 4-phenyl-3-thiosemicarbazide are reported. The compounds were characterised by NMR spectroscopy, mass spectrometry and in the case of benzil bis(4-methyl-3-thiosemicarbazone) and benzil bis(4-phenyl-3-thiosemicarbazone) by X-ray crystallography. Attempts to purify benzil bis(thiosemicarbazone) and benzil bis (4-methyl-3-thiosemicarbazone) by recrystallisation resulted in the isolation of cyclised products that were characterised by X-ray crystallography. The 3 bis(thiosemicarbazone) compounds were used to synthesise both Cu(II) and Cu(I) complexes. The copper(II) complexes were formed by the reaction of the proligands with copper(II) acetate which gave neutral copper(II) complexes in which the thiosemicarbazone is doubly deprotonated, acting as a dianionic ligand. The copper(II)-benzil bis(4-phenyl-3-thiosemicarbazonato) complex was characterised by X-ray crystallography to show the copper in an essentially square planar N₂S₂ environment. The copper(I) complexes were synthesised by reacting the bis (thiosemicarbazone) ligands with [Cu(CH₃CN)₄]PF₆ to give cationic complexes. The copper(I)-benzil-bis(thiosemicarbazone) complex was characterised by X-ray crystallography which revealed that the complex was a dimeric dication. Each of the benzil bis(thiosemicarbazone) ligands act as a bidentate N,S donor to each copper(I) atom, forming an overall helical structure in which each copper atom is in a strongly distorted tetrahedral N₂S₂ environment. Electrochemical measurements show that the copper(II)-benzil bis(thiosemicarbazonato) complex undergoes a reversible reduction at biologically accessible potentials.     

Preparation,characterization and crystal structures of manganese(II), iron(III) and copper(II) complexes of the bis[di-1,1-(2-pyridyl)ethyl]amine (BDPEA) ligand; evaluation of their DNA cleavage activities

The synthesis of a new tetrapyridyl ligand, bis[di-1,1-(2-pyridyl)ethyl]amine (BDPEA), is described. Complexation of this ligand with manganese(II), iron(III) or copper(II) chlorides afforded mononuclear complexes: Mn(BDPEA)Cl2 (1) [Fe (BDPEA)Cl2]Cl (2) and [Cu(BDPEA)Cl]Cl (3). In all cases, BDPEA is coordinated to the metal center by three pyridine nitrogen atoms and the secondary amine. The geometrical environments around the metals in Mn(BDPEA)Cl2 and [Fe(BDPEA)Cl2]Cl are best described as distorted octahedrals and in [Cu (BDPEA)Cl]Cl as a slightly distorted square pyramid. The DNA cleavage activities of manganese(II), iron (III) or copper(II) complexes of both BDPEA and another tetrapyridyl ligand, bis[di(2-pyridyl) methyl]amine (BDPMA), in the presence of an oxidant (H2O2) or a reducing agent (ascorbate) with air, are reported. The iron(III) complexes exhibited significantly enhanced efficiencies, compared to copper(II) complexes. [Fe(BDPEA)Cl2]Cl is found to be the most active DNA cleaver, in agreement with a better stability of BDPEA in oxidizing conditions.     

Iron(III)- and copper(II) complexes of an asymmetric, pentadentate salen-like ligand bearing a pendant carboxylate group

The equilibrium and solution structural properties of the iron(III) and copper(II) complexes of an asymmetric salen-like ligand (N,N'-bis(2-hydroxybenzyl)-2,3-diamino-propionic acid, H(3)bhbdpa) bearing a pendant carboxylate group were characterized in aqueous solution by potentiometric, pH-dependent electron paramagnetic resonance (EPR) and UV-Vis (UV-Visible) measurements. In the equimolar systems the pentadentate ligand forms very stable, differently protonated mononuclear complexes with both metal ions. In the presence of iron(III) {NH, PhO(-), COO(-)}, {2NH, 2PhO(-), COO(-)} and {2NH, 2PhO(-), COO(-), OH(-)} coordinated complexes are dominant. The EPR titrations reflected the presence of microscopic complex formation pathways, leading to the formation of binding isomers in case of Cu(H(2)bhbdpa)(+), Cu(Hbhbdpa) and Cu(bhbdpa)(-). The {2NH, 2PhO(-)+COO(-)/H(2)O} coordinated Cu(bhbdpa) is the only species between pH 6-11. At twofold excess of metal ion dinuclear complexes were detected with both iron(III) and copper(II). In presence of iron(III) a mu-carboxylato-mu-hydroxo-bridged dinuclear complex (Fe(2)(bhbdpa)(OH)(3)) is formed from Fe(H(2)bhbdpa)(2+) through overlapping proton release processes, providing one of the rare examples for the stabilization of an endogenous carboxylate bridged diiron core in aqueous solution. The complex Cu(2)(bhbdpa)(+) detected in the presence of copper(II) is a paramagnetic (S=1) species with relatively weakly coupled metal ions.     

Alkylating ability of artemisinin after Cu(I)-induced activation

The reductive activation of artemisinin by copper(I)-dipyrrin or copper(I)-(2-Clip-Phen) complexes generates an artemisinin derived alkylating species leading to covalent artemisinin–copper complex adducts. The reactivity of the peroxide function of artemisinin toward Cu(I) complexes is similar to that of Fe(II) analogues, even though the reaction is more sluggish and product distribution slightly different.     

Metal complexes of the schiff bases 2-pyridinylhydrazine and 2-quinolinyl-hydrazine with 2-pyridinecarboxaldehyde N-oxide,including some N-oxide-bridged antiferromagnetic complexes of cobalt(II) and nickel(II)

Metal complexes of 2-pyridine carboxaldehyde 2′-pyridinylhydrazone 1-oxide (poph) and 2-pyridinecarboxaldehyde 2′-quinolinylhydrazone 1-oxide (poqh) are reported with copper(II), nickel(II), cobalt(II), iron(II) and manganese(II). Each ligand appears to function as an ONN donor, via the pyridine N-oxide oxygen, the imine nitrogen, and a pyridine or quinoline nitrogen. The complexes have been characterised by magnetic susceptibility measurements to liquid nitrogen temperature, and also by electronic, infrared, X-ray powder diffraction, and Mössbauer spectra. No magnetic interaction was detected with the copper(II) complexes. All the complexes of metal nitrates appear to be monomers.The complexes of poph with the halides and thiocyanates of nickel(II) and cobalt(II) appear to be six-coordinate and N-oxide-bridged; they exhibit varying degress of antiferromagnetic interaction and the magnetic data for the nickel(II) complexes have been fitted to various models. In contrast, the bulky ligand poqh produces halide-bridged six-coordinate nickel(II) complexes and monomeric five-coordinate cobalt(II) complexes.This behaviour by poqh resembles that of the related NNN ligands paphy and paqhy, which are the Schiff bases of 2-pyridinecarboxaldehyde with 2-pyridinylhydrazine and 2-quinolinylhydrazine, respectively.     

Model complexes for the high spin iron(II) state in the catalytic cycle of cytochrome P450

Studies using ⁵⁷Fe Mössbauer spectroscopy on frozen concentrated solutions of two iron(II) porphyrins in the presence of a large excess of thiophenol or 2-mercaptoethanol are reported. The iron(II) porphyrins used were photoporphyrin IX iron(II) (PPIXFe(II)) and tetra(p-sulphophenyl)porphinato-iron(II) (TTPPSFe(II)). Evidence for high-spin five-coordinate iron(II) complexes were found for both iron(II) porphyrins with thiophenol, but no reaction was found to occur with 2-mecaptoethanol. In contrast to these findings in solutions dilute in TPPSFe(II) evidence was found (from electronic absorption spectroscopy and spectrophotometric titrations) for both thiophenol and 2-mercaptoethanol acting as axial ligands in high-spin five-coordinate TPPSFe(II) species. Mössbauer data for frozen solutions containing TPPSFe(II), carbon monoxide (CO) and either thiol, are consistent with the presence of only low-spin six-coordinate iron(II) complexes. These latter complexes are deduced to contain both a thiol and a CO molecule as axial ligands> These results are discussed in relation to earlier work on PPIXFe(II)-thiol solutions and also in relation to the high-spin iron(II) state in the catalytic cycle of cytochrome P450.The reactions of TPPSFe(II) with excess of either 2-mercaptoethanol or ethyl 2-mercaptoacetate in air are also reported and their complex nature discussed.     

Synergistic anion-directed coordination of ferric and cupric ions to bovine serum transferrin--an inorganic perspective

A series of new iron(III) and copper(II) complexes of bovine serum transferrin (BTf), with carbonate and/or oxalate as the synergistic anion, are presented. The complexes [Fe(2)(CO(3))(2)BTf], [Fe(2)(C(2)O(4))(2)BTf], [Cu(2)(CO(3))(2)BTf] and [Cu(C(2)O(4))BTf] were prepared by standard titrimetric techniques. The oxalate derivatives were also obtained from the corresponding carbonate complexes by anion-displacement. The site-preference of the transition metal-oxalate synergism has facilitated the preparation and isolation of the mononuclear complex [Cu(C(2)O(4))BTf], the mixed-anion complexes [Cu(2)(CO(3))(C(2)O(4))BTf] and [Fe(2)(CO(3))(C(2)O(4))BTf] and the mixed-metal complex [FeCu(C(2)O(4))(2)BTf]. The sensitivity of electron paramagnetic resonance (EPR) spectroscopy to the nature of the synergistic anions at the specific-binding sites of the transferrins has made this physical technique particularly indispensable to this study. None of the other members of the transferrin family of proteins has ever been demonstrated to bind the ferric and cupric ions one after the other, each occupying a separate specific-binding site of the same transferrin molecule, as a response to the coordination restrictions imposed by the oxalate ion. The bathochromic shift of the visible p(pi)-d(pi*) CT band for iron(III)-BTf and the hypsochromic shift of the p(pi)-d(sigma*) CT band for copper(II)-BTf, on replacing carbonate by oxalate as the associated anion, are consistent with the relative positions of these anionic ligands in the spectrochemical series and the nature of the d-type acceptor orbitals involved in the CT transitions. The binding and spectroscopic properties of bovine serum transferrin--a serum transferrin--very nearly mirror those of human serum transferrin, but differ significantly from those of human lactoferrin.     

Interaction of copper(II) with imidazole pyridine nitrogen-containing ligands in aqueous medium: a spectroscopic study.

UV (300-400 nm) and FT/IR (4000-850 cm(-1)) spectra were considered for a structural discussion of the copper(II) complexes formed with a series of imidazole-containing ligands (namely L-histidine, N-acetyl-L-histidine, histamine, L-histidine methyl ester and carnosine) in aqueous solution (T=25 degrees C, I=0.1 M). A shoulder at 330 nm was recorded for the main copper(II) complexes with all the ligands considered with the exception of carnosine: this singularity is discussed and a spectrum-structure correlation is proposed. epsilon(330) values were evaluated for CuL (59 M(-1) cm(-1)) and Cu(2)L(2)H(-2) (577 M(-1) cm(-1)) complexes with histamine and for CuL(2) (49 M(-1) cm(-1)) and CuL(3) (163 M(-1) cm(-1)) with N-acetyl-L-histidine, thus indicating the usefulness of UV spectra in the explored region for the purpose of structural definition. FT/IR spectra (recorded both in aqueous solution and on the residue of evaporated solutions of carnosine and N-acetyl-L-histidine only) help to reveal a significant conformational rearrangement of the ligand, corresponding to complex formation in solution: in fact, modifications in the fingerprint region of the FT/IR spectrum for the dimer of carnosine are observed. Indications of a copper(II)-imidazole nitrogen interaction are also obtained from FT/IR data in the 1000-1100 cm(-1) range.     

Interactions of quercetin with iron and copper ions: complexation and autoxidation

Quercetin (3,3',4',5,7-pentahydroxyflavone), one of the most abundant dietary flavonoids, has been investigated for its ability to bind Fe(II), Fe(III), Cu(I) and Cu(II) in acidic to neutral solutions. In particular, analysis by UV-visible spectroscopy allows to determine the rate constants for the formation of the 1:1 complexes. In absence of added metal ion, quercetin undergoes a slow autoxidation in neutral solution with production of low hydrogen peroxide (H(2)O(2)) concentrations. Autoxidation is accelerated by addition of the metal ions according to: Cu(I) > Cu(II)>Fe(II) Fe(III). In fact, the iron-quercetin complexes seem less prone to autoxidation than free quercetin in agreement with the observation that EDTA addition, while totally preventing iron-quercetin binding, slightly accelerates quercetin autoxidation. By contrast, the copper-quercetin complexes appear as reactive intermediates in the copper-initiated autoxidation of quercetin. In presence of the iron ions, only low concentrations of H(2)O(2) can be detected. By contrast, in the presence of the copper ions, H(2)O(2) is rapidly accumulated. Whereas Fe(II) is rapidly autoxidized to Fe(III) in the presence or absence of quercetin, Cu(I) bound to quercetin or its oxidation products does not undergo significant autoxidation. In addition, Cu(II) is rapidly reduced by quercetin. By HPLC-MS analysis, the main autoxidation products of quercetin are shown to be the solvent adducts on the p-quinonemethide intermediate formed upon two-electron oxidation of quercetin. Finally, in strongly acidic conditions (pH 1-2), neither autoxidation nor metal complexation is observed but Fe(III) appears to be reactive enough to quickly oxidize quercetin (without dioxygen consumption). Up to ca. 7 Fe(III) ions can be reduced per quercetin molecule, which points to an extensive oxidative degradation.     

Unfolding of iron and copper complexes of human lactoferrin and transferrin

1. Human lactoferrin and transferrin are capable of binding two iron or copper ions into specific binding sites in the presence of bicarbonate. 2. Urea and several alkyl ureas have been effective in unfolding these metal-protein complexes. 3.Biphasic transitions are observed for the unfolding of each of the metal complexes of these proteins as determined by direct visible spectroscopy suggesting the release of iron(III) and Cu(II) ions from both of these metal-binding proteins during the unfolding process. 4. Greater stabilization and increased resistance to protein unfolding is observed for all iron(III) complexes compared to Cu(II) complexes of lactoferrin and transferrin as determined by isothermal unfolding and thermal denaturation. 5. Relative stabilization of the different metal-protein complexes investigated within this study were determined to be as follows: Lf-Fe(III) greater than Lf-Cu(II); Tf-Fe(III) greater than Tf-Cu(II), and Lf-Fe(III) greater than Tf-Fe(III); Lf-Cu(II) greater than Tf-Cu(II).     

Metal-assisted light-induced DNA cleavage activity of 2-(methylthio)phenylsalicylaldimine Schiff base copper(II) complexes having planar heterocyclic bases

Ternary copper(II) complexes [CuLL'](ClO(4)), where HL is NSO-donor Schiff base (2-(methylthio)phenyl)salicylaldimine and L' is NN-donor phenanthroline bases like 1,10-phenanthroline (phen), dipyridoquinoxaline (dpq) and 2,9-dimethyl-1,10-phenanthroline (dmp), are prepared and structurally characterized by X-ray crystallography. The complexes have a distorted square-pyramidal (4+1) CuN(3)OS coordination geometry. While [CuL(phen)](ClO(4)) and [CuL(dpq)](ClO(4)) show axial sulfur ligation, [CuL(dmp)](ClO(4)) has the sulfur bonded at the equatorial site. The one-electron paramagnetic complexes exhibit axial electron paramagnetic resonance (EPR) spectra in dimethylformamide glass at 77 K. The complexes are redox active and a quasireversible electron transfer process near 0.0 V vs saturated calomel electrode (SCE) in DMF-Tris buffer (1:4 v/v at pH 7.2) involving Cu(II)/Cu(I) couple is observed for the phen and dpq complexes. The dmp complex exhibits an irreversible reduction process forming bis(dmp)copper(I) species. A profound effect of the substituents of the phenanthroline bases is observed on the binding of the complexes to the calf thymus (CT) and in the cleavage of supercoiled (SC) pUC19 DNA. The phen and dpq complexes show DNA cleavage activity in presence of mercaptopropionic acid (MPA). The dmp complex is cleavage inactive in presence of MPA. All the complexes show photocleavage activity when irradiated with a monochromatic UV light of 312 nm. The dpq complex also cleaves SC DNA on visible light irradiation at 436, 532 and 632.8 nm but with a longer exposure time and higher complex concentration. The cleavage reactions in presence of MPA are found to involve hydroxyl radical. The photocleavage reactions are found to occur under aerobic conditions showing an enhancement of cleavage in D(2)O and inhibition with azide addition suggesting formation of singlet oxygen as a reactive species. The roles of sulfur of the Schiff base as photosensitizer and the phenanthroline bases as minor groove binder, and their influence on the photocleavage activity are discussed. The quinoxaline ligand exhibits significant photosensitizing effect assisted by the copper(II) center.     

Synthesis and structural analysis of the copper(II) complexes of N2-(2-pyridylmethyl)-2-pyridinecarboxamide

Previous investigations of the potential of metal-organic compounds as inhibitors of human immunodeficiency virus type I protease (HIV-1 PR) showed that the copper(II) complex diaqua [bis(2-pyridylcarbonyl)amido] copper(II) nitrate dihydrate and the complex bis[N2-(2,3,6-trimethoxybenzyl)-4-2-pyridinecarboxamide] copper(II) behaved as inhibitors of HIV-1 PR. In a search for similar readily accessible ligands, we synthesised and studied the structural properties of N2-(2-pyridylmethyl)-2-pyridinecarboxamide (L) copper(II) complexes. Three different crystal structures were obtained. Two were found to contain ligand L simultaneously in a tridentate and bidentate conformation [Cu(L(tri)L(bi))]. The other contained two symmetry-related ligands, coordinated through the pyridine nitrogen and the amide oxygen atoms [Cu(L(bi))(2)]. A search of the Cambridge Structural Database indicated that L(tri) resulting from nitrogen bound amide hydrogen metal substitution is favoured over chelation through the amide oxygen atom. In our case, we calculated that the conformation of L(tri) is 11 kcal/mol more favourable than that of L(bi). ESI-MS experiments showed that the Cu(L(bi))(2) structure could not be observed in solution, while Cu(L(tri)L(bi))-related complexes were indeed present. The lack of protease inhibition of the pyridine carboxamide copper(II) complexes was explained by the fact that the Cu(L(bi)L(tri)) complex could not fit into the HIV-1 active site.     

Sco proteins are involved in electron transfer processes

Sco proteins are widespread in eukaryotic and in many prokaryotic organisms. They have a thioredoxin-like fold and bind a single copper(I) or copper(II) ion through a CXXXC motif and a conserved His ligand, with both tight and weak affinities. They have been implicated in the assembly of the Cu_A site of cytochrome c oxidase as copper chaperones and/or thioredoxins. In this work we have structurally characterized a Sco domain which is naturally fused with a typical electron transfer molecule, i.e., cytochrome c, in Pseudomonas putida. The thioredoxin-like Sco domain does not bind copper(II), binds copper(I) with weak affinity without involving the conserved His, and has redox properties consisting of a thioredoxin activity and of the ability of reducing copper(II) to copper(I), and iron(III) to iron(II) of the cytochrome c domain. These findings indicate that the His ligand coordination is the discriminating factor for introducing a metallochaperone function in a thioredoxin-like fold, typically responsible for electron transfer processes. A comparative structural analysis of the Sco domain from P. putida versus eukaryotic Sco proteins revealed structural determinants affecting the formation of a tight-affinity versus a weak-affinity copper binding site in Sco proteins.