New Cyclodextrin‐Bearing 8‐Hydroxyquinoline Ligands as Multifunctional Molecules

Recent investigations have rekindled interest in 8‐hydroxyquinolines as therapeutic agents for cancer, Alzheimer’s disease, and other neurodegenerative disorders. Three new β‐cyclodextrin conjugates of 8‐hydroxyquinolines and their copper(II) and zinc(II) complexes have been synthesized and characterized spectroscopically. In addition to improving aqueous solubility, due to the presence of the cyclodextrin moiety, the hybrid systems have interesting characteristics including antioxidant activity, and their copper(II) complexes are efficient superoxide dismutase (SOD) mimics. The ligands and their copper(II) complexes show low cytotoxicity, attributed to the presence of the cyclodextrin moiety. These compounds have potential as therapeutic agents in diseases related both to metal dyshomeostasis and oxidative stress.     

Catalytic asymmetric transfer hydrogenation of alpha-ketoesters with hantzsch esters

C2-symmetric chiral copper(II)-bisoxazolines function as alcohol dehydrogenase mimics and catalyze highly enantioselective transfer hydrogenations of alpha-ketoesters with Hantzsch esters as a synthetic NADH analogue to give alpha-hydroxy esters in excellent enantioselectivities. [reaction: see text].     

The electrochemical reactions of copper(II) and copper(I) chloride in n,n-dimethylformamide

Polarographic, voltammetric and controlled-potential coulometric studies of copper(II) and copper(I) chloride in dimethylformamide are reported. The two chloride complexes of copper(II) are reduced in a total of three electrochemical steps to two copper(I)-chloride complexes and to copper(0). The two copper(I)-chloride species are reduced to copper(0) and oxidized to copper(II)-chloride complexes. The dissociation constant of the tetrachlorocuprate(II) complex has been polarographically estimated to be 10^-25.     

Hepatocyte Targeting and Intracellular Copper Chelation by a Thiol-Containing Glycocyclopeptide

Metal overload plays an important role in several diseases or intoxications, like in Wilson's disease, a major genetic disorder of copper metabolism in humans. To efficiently and selectively decrease copper concentration in the liver that is highly damaged, chelators should be targeted at the hepatocytes. In the present work, we synthesized a molecule able to both lower intracellular copper, namely Cu(I), and target hepatocytes, combining within the same structure a chelating unit and a carbohydrate recognition element. A cyclodecapeptide scaffold displaying a controlled conformation with two independent faces was chosen to introduce both units. One face displays a cluster of carbohydrates to ensure an efficient recognition of the asialoglycoprotein receptors, expressed on the surface of hepatocytes. The second face is devoted to metal ion complexation thanks to the thiolate functions of two cysteine side-chains. To obtain a chelator that is active only once inside the cells, the two thiol functions were oxidized in a disulfide bridge to afford the glycopeptide P(3). Two simple cyclodecapeptides modeling the reduced and complexing form of P(3) in cells proved a high affinity for Cu(I) and a high selectivity with respect to Zn(II). As expected, P(3) becomes an efficient Cu(I) chelator in the presence of glutathione that mimics the intracellular reducing environment. Finally, cellular uptake and ability to lower intracellular copper were demonstrated in hepatic cell lines, in particular in WIF-B9, making P(3) a good candidate to fight copper overload in the liver.     

Oxygen binding and activation by the complexes of PY2- and TPA-appended diphenylglycoluril receptors with copper and other metals

The copper(I) complexes of diphenylglycoluril basket receptors and , appended with bis(2-ethylpyridine)amine (PY2) and tris(2-methylpyridine)amine (TPA), respectively, and their dioxygen adducts were studied with low-temperature UV-vis and X-ray absorption spectroscopy (XAS). The copper(I) complex of, [.Cu(I)2] or, forms a micro-eta2:eta2 dioxygen complex, whereas the copper(I) complex of, [.Cu(I)2] or, does not form a well defined dioxygen complex, but is oxidized to Cu(II). Dioxygen is bound irreversibly to and the formed complex is stable over time. The coordination geometries of the above complexes were determined by XAS, which revealed that pyridyl groups and amine N-donors participate in the coordination to Cu(I) ions in the complexes of both receptors. The catalytic activities of various metal complexes of and , that were designed as mimics of dinuclear copper enzymes that can activate dioxygen, were investigated. Phenolic substrates that were expected to undergo aromatic hydroxylation, showed oxidative polymerization without insertion of oxygen. The mechanism of this polymerization turns out to be a radical coupling reaction as was established by experiments with the model substrate 2,4-di-tert-butylphenol. In addition to Cu(II), the Mn(III) complex of and the Fe(II) complex of were tested as oxidation catalysts. Oxidation of catechol was observed for the Cu(II) complex of receptor but the other metal complexes did not lead to oxidation.     

A Study on Some Copper (II) Complexes of Polyaza Cryptands and Planar Macrocycles—Synthesis,Characterization and Superoxide Dismutase Activity

Two kinds of macrocyclic copper(II) complexes were synthesized. One of them is composed of copper(II) cryptates of ligands L¹‐L⁴ which are condensation products of 5‐R‐2‐methoxy‐1,3‐phenyldialdehyde (R=OCH₃, L¹) with tris(2‐aminoethyl) amine and 5‐R‐2‐methothoxy‐1, 3‐phenyldialdehyde (R= CH₃, L³) with tris(2‐aminopropyl)amine as well as their reduced products of L¹ and L³ (L² and L⁴). The other is composed of two‐dimensional macrocyclic copper(II) complexes of ligands L⁵‐L⁸ of condensation products of diethylene triamine with 4‐R‐l‐methoxy‐2,6‐phenyldialdehyde (R= Cl, Br. CH₃, OCH₃). The relationship between their structures and superoxide dismutase (SOD) activity was investigated. The results can provide some clues to the synthesis of SOD mimics.     

An In Vitro Study of the Interaction of Copper(II) Salicylates with Genomic DNA Using Gel Electrophoresis and Gel Permeation Chromatography

This papers describes the in vitro interaction of copper(II) acetylsalicylate and copper(II) salicylate with genomic DNA isolated from human blood. The two drug substances were found to bind to DNA after incubation with whole blood over night. Bonding was confirmed by detection of separated DNA electrophoresis bands for copper, copper(II) acetylsalicylate, copper(II) salicylate, acetylsalicylic acid and salicylic acid. Drug–DNA interactions were observed during electrophoresis in the form of fragmentation by formation of two bands when compared to controls. Gel permeation chromatography parameters also confirmed the occurrence of fragmentation. The use of gel permeation chromatography parameters as a measure of fragmentation of DNA is discussed. The fragmentation of genomic DNA after incubation with copper(II) acetylsalicylate and copper(II) salicylate suggested that these drug substances might be responsible for cytotoxicity in vivo.     

Redox-adaptable copper hosts. Pyridazine-linked cryptands accommodate copper in a range of redox States

A series of structurally characterized copper complexes of two pyridazine-spaced cryptands in redox states + (I,I), (II,I), (II), (II,II) are reported. The hexaimine cryptand L(I) [formed by the 2 + 3 condensation of 3,6-diformylpyridazine with tris(2-aminoethyl)amine (tren)] is able to accommodate two non-stereochemically demanding copper(I) ions, resulting in [Cu(I)(2)L(I)](BF(4))(2) 1, or one stereochemically demanding copper(II) ion, resulting in [Cu(II)L(I)()](BF(4))(2) 3. Complex 3 crystallizes in two forms, 3a and 3b, with differing copper(II) ion coordination geometries. Addition of copper(I) to the monometallic complex 3 results in the mixed-valence complex [Cu(I)Cu(II)L(I)](X)(3) (X = PF(6)(-), 2a; X = BF(4)(-), 2b) which is well stabilized within this cryptand as indicated by electrochemical studies (K(com) = 2.1 x 10(11)). The structurally characterized, octaamine cryptand L(A), prepared by sodium borohydride reduction of L(I), is more flexible than L(I) and can accommodate two stereochemically demanding copper(II) ions, generating the dicopper(II) cryptate [Cu(II)(2)L(A)](BF(4))(4) 4. Electrochemical studies indicate that L(A) stabilizes the copper(II) oxidation state more effectively than L(I); no copper redox state lower than II,II has been isolated in the solid state using this ligand.     

An In Vitro Study of the Interaction of Copper(II) Salicylates with Genomic DNA Using Gel Electrophoresis and Gel Permeation Chromatography

This papers describes the in vitro interaction of copper(II) acetylsalicylate and copper(II) salicylate with genomic DNA isolated from human blood. The two drug substances were found to bind to DNA after incubation with whole blood over night. Bonding was confirmed by detection of separated DNA electrophoresis bands for copper, copper(II) acetylsalicylate, copper(II) salicylate, acetylsalicylic acid and salicylic acid. Drug–DNA interactions were observed during electrophoresis in the form of fragmentation by formation of two bands when compared to controls. Gel permeation chromatography parameters also confirmed the occurrence of fragmentation. The use of gel permeation chromatography parameters as a measure of fragmentation of DNA is discussed. The fragmentation of genomic DNA after incubation with copper(II) acetylsalicylate and copper(II) salicylate suggested that these drug substances might be responsible for cytotoxicity in vivo.

     

Comparative Study of Antioxidant and Pro-Oxidant Properties of Homoleptic and Heteroleptic Copper Complexes with Amino Acids,Dipeptides and 1,10-Phenanthroline: The Quest for Antitumor Compounds

In a search for new antitumoral agents, a series of homoleptic copper(II) complexes with amino acids and dipeptides, as well as heteroleptic complexes containing both dipeptides and 1,10-phenanthroline, were studied. Furthermore, a single-crystal structure containing alanyl-leucinato ([Cu₃(AlaLeu)₃(H₂O)₃(CO₃)]·PF₆·H₂O), which is the first homotrinuclear carbonato-bridged copper(II) complex with a dipeptide moiety, is presented. To assess possible antitumor action mechanisms, we focused on the comparative analysis of pro- and antioxidant behaviors. Pro-oxidant activity, in which the reactive oxygen species (ROS) formed by the reaction of the complexes with H₂O₂ produce oxidative damage to 2-deoxy-d-ribose, was evaluated using the TBARS method. Additionally, the antioxidant action was quantified through the superoxide dismutase (SOD)-like activity, using a protocol based on the inhibitory effect of SOD on the reduction of nitrobluetetrazolium (NBT) by the superoxide anion generated by the xanthine/xanthine oxidase system. Our findings show that Cu–amino acid complexes are strong ROS producers and moderate SOD mimics. Conversely, Cu–dipeptide–phen complexes are good SOD mimics but poor ROS producers. The activity of Cu–dipeptide complexes was strongly dependent on the dipeptide. A DFT computational analysis revealed that complexes with high SOD-like activity tend to display a large dipole moment and condensed-to-copper charge, softness and LUMO contribution. Moreover, good ROS producers have higher global hardness and copper electrophilicity, lower copper softness and flexible and freely accessible coordination polyhedra.     

The benzoyloxylation of norbornadiene and homologues by copper(III) and copper(II) benzoate complexes

Oxidation of norbornadiene and benzonorbornadiene by copper(III) and copper(II) benzoate complexes in pyridine gave the corresponding 7-benzoyloxy derivatives. The proposed mechanism suggests two single-electron oxidations by copper(III) and/or copper(II).     

Galactose oxidase models: solution chemistry, and phenoxyl radical generation mediated by the copper status

Galactose oxidase (GO) is an enzyme that catalyzes two-electron oxidations. Its active site contains a copper atom coordinated to a tyrosyl radical, the biogenesis of which requires copper and dioxygen. We have recently studied the properties of electrochemically generated mononuclear Cu(II)-phenoxyl radical systems as model compounds of GO. We present here the solution chemistry of these ligands under various copper and dioxygen statuses: N(3)O ligands first chelate Cu(II), leading, in the presence of base, to [Cu(II)(ligand)(CH(3)CN)](+) complexes (ortho-tert-butylated ligands) or [(Cu(II))(2)(ligand)(2)](2+) complexes (ortho-methoxylated ligands). Excess copper(II) then oxidizes the complex to the corresponding mononuclear Cu(II)-phenoxyl radical species. N(2)O(2) tripodal ligands, in the presence of copper(II), afford directly a copper(II)-phenoxyl radical species. Addition of more than two molar equivalents of copper(II) affords a Cu(II)-bis(phenoxyl) diradical species. The donor set of the ligand directs the reaction towards comproportionation for ligands possessing an N(3)O donor set, while disproportionation is observed for ligands possessing an N(2)O(2) donor set. These results are discussed in the light of recent results concerning the self-processing of GO. A path involving copper(II) disproportionation is proposed for oxidation of the cross-linked tyrosinate of GO, supporting the fact that both copper(I) and copper(II) activate the enzyme.     

铜印迹螯合树脂对金属离子的吸附特性

研究了铜印迹螯合树脂与非印迹螯合树脂对金属离子的吸附性能，结果表明：铜印迹树脂对Cu^2 、Ni^2 、Zn^2 的吸附量比非印迹树脂有显著增大,两者对Cu^2 的吸附速率均较快，其表观吸附速率分别为0．044s^-1和0．040s^-1；印迹树脂对Cu^2 的吸附可用Langmuir或Freundlish等温式来描述；其动态吸附曲线与离子的起始浓度相关；用0．5mol／L HCl即可快速洗脱吸附的Cu^2 ，树脂具有较强的再生能力，可以重复使用。     

Sorption Behavior of Copper(II) on Freshly Precipitated Aluminum Hydroxide

The isotherms of copper(II) sorption from aqueous solutions on freshly precipitated aluminum hydroxide obtained by hydrolysis of pentahydroxomonochlorodialuminum were studied. The sorption efficiency of copper(II) was studied as influenced by pH. Sorption of copper(II) by two different mechanisms is discussed.     

Complex of Copper(II) with Ethylenediamine and Decyl Sulfate Ions. Formation in Water and Crystal Structure

Decyl sulfate ions form strong associates with ethylenediammonium cations and copper(II) ethylenediamine complexes. A solid compound of the composition copper(II):ethylenediamine:decyl sulfate ion = 1:2:2 was isolated from the aqueous solution; its crystal structure was studied to find that it comprises a regular combination of formula units of an inner-sphere complex bis(ethylenediamine)bis(decyl sulfato)copper(II) and a complex associate of two decyl sulfate ions with diaquabis(ethyenediamine)copper(II).     

Superoxide dismutase activity of iron(II)TPEN complex and its derivatives

Superoxide is involved in the pathogenesis of various diseases, such as inflammation, ischemia-reperfusion injury and carcinogenesis. Superoxide dismutases (SODs) catalyze the disproportionation reaction of superoxide to produce oxygen and hydrogen peroxide, and can protect living cells against the toxicity of free radicals derived from oxygen. Thus, SODs and their functional mimics have potential value as pharmaceuticals. We have previously reported that Fe(II)tetrakis-N,N,N',N'-(2-pyridylmethyl)ethylenediamine (Fe(II)TPEN) has an excellent SOD activity (IC50 = 0.5 microM) among many iron complexes examined (J. Biol. Chem., 264, 9243-9249 (1989)). Fe(II)TPEN can act like native SOD in living cells, and protect Escherichia coli cells from free radical toxicity caused by paraquat. In order to develop more effective SOD functional mimics, we synthesized Fe(II)TPEN derivatives with electron-donating or electron-withdrawing groups at the 4-position of all pyridines of TPEN, and measured the SOD activities and the redox potentials of these complexes. Fe(II) tetrakis-N,N,N',N'-(4-methoxy-2-pyridylmethyl)ethylenediamine (Fe(II)(4MeO)4TPEN) had the highest SOD activity (IC50 = 0.1 microM) among these iron-based SOD mimics. In addition, a good correlation was found between the redox potential and the SOD activity of 15 Fe(II) complexes, including iron-based SOD mimics reported in the previous paper (J. Organometal. Chem., in press). Iron-based SOD mimics may be clinically applicable, because these complexes are generally tissue-permeable and show low toxicity. Therefore our findings should be significant for the development of clinically useful SOD mimics.     

An electsochemical study of copper(II) nitrate and perchlorate in n,n-dimethylformamide

Polarographic, cyclic voltammetric and controlled-potential coulometric studies of copper(II) nitrate and perchlorate in dimethylformamide are reported. Copper(II) in copper(II) perchlorate solutions is directly reduced in a 2e step to copper metal at platinum electrodes and to a copper amalgam at mercury electrodes. Copper(II) in the presence of nitrate forms a complex of composition Cu(N0₃)₂ in DMF; the dissociation constant, measured polarographically, is 9 × lO^-5. The copper(II) nitrate complex is electrochemically reduced in two steps consisting of a reversible dissociation of the complex followed by direct reduction of copper(II) ion to copper(0). The diffusion coefficients of copper(II) ion and the copper(II) nitrate complex are 4.91 × lO^-6 cm² s^-1 and 4.33 × 10^-6 cm² s^-1, respectively.     

Experimental investigation on the mechanism of chelation-assisted, copper(II) acetate-accelerated azide-alkyne cycloaddition

A mechanistic model is formulated to account for the high reactivity of chelating azides (organic azides capable of chelation-assisted metal coordination at the alkylated azido nitrogen position) and copper(II) acetate (Cu(OAc)(2)) in copper(II)-mediated azide-alkyne cycloaddition (AAC) reactions. Fluorescence and (1)H NMR assays are developed for monitoring the reaction progress in two different solvents, methanol and acetonitrile. Solvent kinetic isotopic effect and premixing experiments give credence to the proposed different induction reactions for converting copper(II) to catalytic copper(I) species in methanol (methanol oxidation) and acetonitrile (alkyne oxidative homocoupling), respectively. The kinetic orders of individual components in a chelation-assisted, copper(II)-accelerated AAC reaction are determined in both methanol and acetonitrile. Key conclusions resulting from the kinetic studies include (1) the interaction between copper ion (either in +1 or +2 oxidation state) and a chelating azide occurs in a fast, pre-equilibrium step prior to the formation of the in-cycle copper(I)-acetylide, (2) alkyne deprotonation is involved in several kinetically significant steps, and (3) consistent with prior experimental and computational results by other groups, two copper centers are involved in the catalysis. The X-ray crystal structures of chelating azides with Cu(OAc)(2) suggest a mechanistic synergy between alkyne oxidative homocoupling and copper(II)-accelerated AAC reactions, in which both a bimetallic catalytic pathway and a base are involved. The different roles of the two copper centers (a Lewis acid to enhance the electrophilicity of the azido group and a two-electron reducing agent in oxidative metallacycle formation, respectively) in the proposed catalytic cycle suggest that a mixed valency (+2 and +1) dinuclear copper species be a highly efficient catalyst. This proposition is supported by the higher activity of the partially reduced Cu(OAc)(2) in mediating a 2-picolylazide-involved AAC reaction than the fully reduced Cu(OAc)(2). Finally, the discontinuous kinetic behavior that has been observed by us and others in copper(I/II)-mediated AAC reactions is explained by the likely catalyst disintegration during the course of a relatively slow reaction. Complementing the prior mechanistic conclusions drawn by other investigators, which primarily focus on the copper(I)/alkyne interactions, we emphasize the kinetic significance of copper(I/II)/azide interaction. This work not only provides a mechanism accounting for the fast Cu(OAc)(2)-mediated AAC reactions involving chelating azides, which has apparent practical implications, but suggests the significance of mixed-valency dinuclear copper species in catalytic reactions where two copper centers carry different functions.     

Iron(II), cobalt(III), nickel(II) and copper(II) chelates of furan and thiophene azo-oximes

Summary Complexes of furan and thiophene azo-oximes with iron(II), cobalt(III), nickel(II) and copper(II) have been prepared and characterised. Iron(II), cobalt(III) and copper(II) complexes are diamagnetic in the solid state. The diamagnetism of the copper(II) chelates is suggestive of antiferromagnetic interaction between two copper centres.¹H n.m.r. spectral data suggest atrans-octahedral geometry for the tris-chelates of cobalt(III). Nickel(II) complexes are paramagnetic, in contrast to the diamagnetism of the analogous complexes of arylazooximes. The electronic spectra are suggestive of octahedral geometry for the iron(II), cobalt(III) and nickel(II) complexes, andD _4h -symmetry for copper(II). Infrared data indicate N-bonding of the oximino-group to the metal ions.     

Crystal structures of triazine-3-thione derivatives by reaction with copper and cobalt salts

The reaction of 5-methoxy-5,6-diphenyl-4,5-dihydro-2H-[1,2,4]triazine-3-thione L1H2OCH3 with copper(II) chloride leads to the formation of an organic molecule L2 containing two triazine rings linked by a new S-S bond. A binuclear copper(II) complex, 1, containing L1 is also isolated. The reaction of L1H2OCH3 with copper(I) chloride yields a hexanuclear cluster of copper(I), 2, in which the copper atoms form a distorted octahedron with the ligand L1 acting as an NS chelate and sulfur bridge, giving to the copper ion a trigonal geometry by one N and two S atoms. In any reaction of the disulfide L2 with metal salts, complexes containing this molecule are isolated. Reactions with copper(I) and copper(II) chloride and nickel(II) and cadmium(II) nitrate produce the S-S bond cleavage, giving complexes containing the triazine L1 behaving as the NS anion, which show spectroscopic characteristics identical with those formed by reaction with L1H2OCH3. However, the reaction with cobalt(II) nitrate gives a low-spin octahedral cobalt(III) complex, in which an asymmetric rupture of the disulfide L2 has been produced, giving an unexpected complex with a new ligand and keeping the S-S bond.