EPR investigations of the influence of N,N′-methylene-bisacrylamide (NNMBA) crosslinks on the coordination structure of Cu(II) complexes of poly (N-2-aminoethylacrylamide)s

Summary The coordination structures of Cu(II) complexes of amino functions supported on polyacrylamides with varying extents of NNMBA-crosslinks were followed by EPR techniques. The geometry of the Cu(II) complexes changes with increasing crosslinking. The covalency of the Cu-N bond also depends on the extent of the NNMBA-crosslinking in the polymer-support.     

Investigating Alkylated Prodigiosenes and Their Cu(II)-Dependent Biological Activity: Interactions with DNA,Antimicrobial and Photoinduced Anticancer Activity

Prodigiosenes are a family of red pigments with versatile biological activity. Their tripyrrolic core structure has been modified many times in order to manipulate the spectrum of activity. We have been looking systematically at prodigiosenes substituted at the C ring with alkyl chains of different lengths, in order to assess the relevance of this substituent in a context that has not been investigated before for these derivatives: Cu(II) complexation, DNA binding, self-activated DNA cleavage, photoinduced cytotoxicity and antimicrobial activity. Our results indicate that the hydrophobic substituent has a clear influence on the different aspects of their biological activity. The cytotoxicity study of the Cu(II) complexes of these prodigiosenes shows that they exhibit a strong cytotoxic effect towards the tested tumor cell lines. The Cu(II) complex of a prodigiosene lacking any alkyl chain excelled in its photoinduced anticancer activity, thus demonstrating the potential of prodigiosenes and their metal complexes for an application in photodynamic therapy (PDT). Two derivatives along with their Cu(II) complexes showed also antimicrobial activity against Staphylococcus aureus strains.     

A spectroscopic study of Cu(II)-complexes of chelating resins containing nitrogen and sulfur atoms in the chelating groups

The structures of different Cu(II)-thiol, dithiocarbamate, methylthiourea and amino complexes have been investigated on the basis of their spectroscopic properties. The influence of the chemical structure, both the nature of the functional groups and the spacers, on the resin chelating behaviour towards Cu(II) ions in diluted solution has been evaluated. The resins are macroporous polystyrene–divinylbenzene polymer functionalized with two spacer groups, poly(ethylene glycol) and poly(ethylene imine) chains, supporting thiol, dithiocarbamate, methylthiourea and amino groups. Electron paramagnetic resonance (EPR) was employed to show the coordination of Cu(II) ions into the complexes. Cu(II)-dithiocarbamate complexes have a square planar coordination with two dithiocarbamate groups bound to the metal. The resins with methylthiourea as functional group form Cu(II)-complexes in tetragonal symmetry with four nitrogen atoms as equatorial ligands. Further, a partial reduction of Cu(II) to diamagnetic Cu(I) with formation of Cu(I)-methylthiourea complexes, where copper is S-bonded to the methylthiourea group, could be suggested. In Cu(II)-thiol complexes, Cu(II) ions are bound through sulfur bridges.     

Synthesis,Characterization and Biological Evaluation of Transition Metal Complexes Derived from N,S Bidentate Ligands

Two bidentate NS ligands were synthesized by the condensation reaction of S-2-methylbenzyldithiocarbazate (S2MBDTC) with 2-methoxybenzaldehyde (2MB) and 3-methoxybenzaldehyde (3MB). The ligands were reacted separately with acetates of Cu(II), Ni(II) and Zn(II) yielding 1:2 (metal:ligand) complexes. The metal complexes formed were expected to have a general formula of [M(NS)₂] where M = Cu²⁺, Ni²⁺, and Zn²⁺. These compounds were characterized by elemental analysis, molar conductivity, magnetic susceptibility and various spectroscopic techniques. The magnetic susceptibility measurements and spectral results supported the predicted coordination geometry in which the Schiff bases behaved as bidentate NS donor ligands coordinating via the azomethine nitrogen and thiolate sulfur. The molecular structures of the isomeric S2M2MBH (1) and S2M3MBH (2) were established by X-ray crystallography to have very similar l-shaped structures. The Schiff bases and their metal complexes were evaluated for their biological activities against estrogen receptor-positive (MCF-7) and estrogen receptor-negative (MDA-MB-231) breast cancer cell lines. Only the Cu(II) complexes showed marked cytotoxicity against the cancer cell lines. Both Schiff bases and other metal complexes were found to be inactive. In concordance with the cytotoxicity studies, the DNA binding studies indicated that Cu(II) complexes have a strong DNA binding affinity.     

Synthesis,crystal structure,DNA binding properties and antioxidant activities of transition metal complexes with 3-carbaldehyde-chromone semicarbazone

3-Carbaldehyde-chromone semicarbazone (L) and its Cu(II), Zn(II), Ni(II) complexes were synthesized and characterized on the basis of crystal structure and other structural characterization methods. The metal ions and Schiff base ligand can form mononuclear five-coordination complexes with 1:1 metal-to-ligand stoichiometry at the metal ions as centres. The transition metal complexes may be used as potential anticancer drugs, because they bind to calf thymus DNA via an intercalation binding mode with the binding constants at the order of magnitude 10⁵–10⁶ M^? 1, and the metal complexes present stronger DNA binding affinities than the free ligand alone. In addition, the antioxidant activities of the ligand and its metal complexes were investigated through scavenging effects for superoxide anion and hydroxyl radical in vitro, indicating that the compounds show stronger antioxidant activities than some standard antioxidants, such as mannitol and vitamin C.     

Antioxidant vs. Prooxidant Properties of the Flavonoid,Kaempferol, in the Presence of Cu(II) Ions: A ROS-Scavenging Activity,Fenton Reaction and DNA Damage Study

Kaempferol is a flavonoid that occurs in tea and in many vegetables and fruits, including broccoli, cabbage, beans, grapes, apples, and strawberries. The efficacy of Kaempferol has been demonstrated in the treatment of breast, esophageal, cervical, ovarian, and liver cancers and leukemia, which very likely arises from its prooxidant properties and the activation of pro-apoptotic pathways. Indeed, this matter has already been the focus of a number of published studies and reviews. The aim of the present study was to elucidate the antioxidant vs. prooxidant properties of flavonoids in the presence of the redox-active metal, copper (II) ion, by means of the Fenton reaction. The specific motivation of this work is that, since an increased level of Cu(II) ions is known to be associated with many disease states such as neurological conditions (Alzheimer’s disease) and cancer, any interaction between these ions and flavonoids might affect the outcome of therapeutic uses of the latter. The structure of the Cu-kaempferol complex in DMSO was investigated by means of low temperature EPR spectroscopy, which confirmed the existence of at least two distinct coordination environments around the copper (II) ion. UV vis-spectra of kaempferol and its Cu(II) complex in DMSO revealed an interaction between the 5-OH (A ring) group and the 4-CO (C ring) group of kaempferol with Cu(II) ions. An ABTS assay confirmed that kaempferol acted as an effective radical scavenger, and that this effect was further enhanced in the form of the Cu(II)-kaempferol complex. Quantitative EPR spin trapping experiments, using DMPO as the spin trap, confirmed suppression of the formation of a mixture of hydroxyl, superoxide, and methyl radicals, in a Fenton reaction system, upon coordination of kaempferol to the redox-active Cu(II) ions, by 80% with respect to the free Cu(II) ions. A viscometric study revealed a better DNA-intercalating ability of the Cu-kaempferol complex than for free kaempferol, essential for conferring anticancer activity of these substances. The results of the viscometric measurements were compared with those from a DNA damage study of Cu-kaempferol complexes in a Fenton reaction system, using gel electrophoresis. At low concentrations of kaempferol (Cu–kaempferol ratios of 1:1 and 1:2), a very weak protective effect on DNA was noted, whereas when kaempferol was present in excess, a significant DNA-protective effect was found. This can be explained if the weakly intercalated kaempferol molecules present at the surface of DNA provide protection against attack by ROS that originate from the Fenton reaction involving intercalated Cu(II)-kaempferol complexes. Following the application of ROS scavengers, L-histidine, DMSO, and SOD, gel electrophoresis confirmed the formation of singlet oxygen, hydroxyl radicals, and superoxide radical anions, respectively. We propose that the prooxidant properties of Cu-kaempferol complexes may provide anticancer activity of these substances. When present in excess, kaempferol displays antioxidant properties under Cu-Fenton conditions. This suggests that kaempferol might prove a suitable candidate for the prevention or treatment of oxidative stress related medical conditions that involve a disturbed metabolism of redox metals such as copper, for example, Menkes disease, and neurological disorders, including Alzheimer’s disease. For the potential use of kaempferol in clinical practice, it will be necessary to optimize the dose size and critical age of the patient so that this flavonoid may be beneficial as a preventive drug against cancer and neurological disorders.     

L-蛋氨酸多吡啶铜(Ⅱ)三元配合物的合成及与DNA的相互作用

文章合成了三种L-蛋氨酸多吡啶铜(II)三元混配配合物,[Cu(Met)(Phen)(ClO4)](ClO4)(1)(Phen=1,10-菲咯啉),[Cu(Met)(IP)(ClO4)](ClO4)(2)(IP=咪唑并[4,5-f]1,10-菲咯啉)和[Cu(Met)(PIP)(ClO4)](ClO4)(3)(PIP=2-苯基-咪唑并[4,5-f]1,10-菲咯啉)。采用电子吸收光谱和荧光光谱等方法研究了配合物与小牛胸腺DNA的相互作用,用凝胶电泳方法研究了配合物对pBR322DNA的氧化切割活性。结果表明,虽配合物与DNA的作用较弱,但多吡啶配体的平面大小可直接影响到配合物与DNA的相互作用,而氨基酸辅助配体可起到进一步的调控作用。     

Immobilization cyclen copper (II) on merrifield resin: Efficient oxidative cleavage of plasmid DNA

Merrifield resin‐supported cyclen (MRC) was directly prepared by attaching 1, 4, 7, 10‐tetraazacyclododecane (cyclen) to Merrifield resin (MR). Subsequent coordination with Cu(II), Co(II), and Ni(II) gave immobilized cyclen complex MRC‐Cu, MRC‐Co, and MRC‐Ni as “solid artificial enzymes.” These complexes were characterized by elemental analysis, IR spectroscopy, ICP‐AES, and scanning electron microscopy (SEM). Furthermore, the DNA cleavage activities of these complexes were investigated by agarose gel electrophoresis. The results indicated that MRC‐Cu was superior to other solid artificial enzymes, and the cleavage process was carried out via oxidative pathway. Moreover, the solid catalyst MRC‐Cu was very stable and it could be reused at least four times without any loss of catalytic activity. © 2008 Wiley Periodicals, Inc. J Appl Polym Sci, 2009     

Synthesis, Spectral and Antibacterial Studies of Copper(II) Tetraaza Macrocyclic Complexes

A novel family of tetraaza macrocyclic Cu(II) complexes [CuLX(2)] (where L = N(4) donor macrocyclic ligands) and (X = Cl(-), NO(3) (-)) have been synthesized and characterized by elemental analysis, magnetic moments, IR, EPR, mass, electronic spectra and thermal studies. The magnetic moments and electronic spectral studies suggest square planar geometry for [Cu(DBACDT)]Cl(2) and [Cu(DBACDT)](NO(3))(2) complexes and distorted octahedral geometry to the rest of the ten complexes. The biological activity of all these complexes against gram-positive and gram-negative bacteria was compared with the activity of existing commercial antibacterial compounds like Linezolid and Cefaclor. Six complexes out of twelve were found to be most potent against both gram-positive as well as gram-negative bacteria due to the presence of thio group in the coordinated ligands.     

Effect of Copper(II) Ion Binding by Porin P1 Precursor Fragments from Fusobacterium nucleatum on DNA Degradation

Fusobacterium nucleatum is one of the most notorious species involved in colorectal cancer. It was reported that numerous outer membrane proteins (OMP) are actively involved in carcinogenesis. In this paper, the structure and stability of certain complexes, as well as DNA cleavage and ROS generation by fragments of OMP, were investigated using experimental and theoretical methods. Mass spectrometry, potentiometry, UV-Vis, CD, EPR, gel electrophoresis and calculations at the density functional theory (DFT) level were applied. Two consecutive model peptides, Ac-AKGHEHQLE-NH₂ and Ac-FGEHEHGRD-NH₂, were studied. Both of these were rendered to form a variety of thermodynamically stable complexes with copper(II) ions. All of the complexes were stabilized, mainly due to interactions of metal with nitrogen and oxygen donor atoms, as well as rich hydrogen bond networks. It was also concluded that these complexes in the presence of hydrogen peroxide or ascorbic acid can effectively produce hydroxyl radicals and have an ability to cleave the DNA strands. Surprisingly, the second studied ligand at the micromolar concentration range causes overall DNA degradation.     

Oxidation of 2,6-di-tert-butylphenols to Diphenoquinones Catalysed by Schiff Base-Cu(II) Systems Immobilized on Polymer Support

Benzoquinone, diphenoquinones and its derivatives are important intermediates for industrial synthesis of a wide variety of special chemicals, such as pharmaceuticals, dyes and agricultural chemicals. The useful catalyst were obtained by aminolysis of vinylbenzyl chloride/divinylbenzene copolymer with ethylenediamine (1) or urotropine (2) and then modification by salicylaldehyde (1A, 2A) or picolinaldehyde (1B, 2B). The catalytic activity of Cu(II) complexes with Schiff base immobilized on the synthesized supports were tested in the oxidation reaction of 2,6-di-tert-butylphenol (DTBP) to diphenoquinone (PQ) with tert-butylhydroperoxide. The best oxidation degree of DTBP (60-70%) and the selectivity towards PQ (80%) is revealed by Cu(II) complexes with long Schiff base ligands derived from salicylaldimine (1A), which have CuL structure (EPR measurement).     

Tetrachloridocuprates(II)-Synthesis and Electron Paramagnetic Resonance (EPR) Spectroscopy

Ionic liquids (ILs) on the basis of metal containing anions and/or cations are of interest for a variety of technical applications e.g., synthesis of particles, magnetic or thermochromic materials. We present the synthesis and the results of electron paramagnetic resonance (EPR) spectroscopic analyses of a series of some new potential ionic liquids based on tetrachloridocuprates(II), [CuCl(4)](2-), with different sterically demanding cations: hexadecyltrimethylammonium 1, tetradecyltrimethylammonium 2, tetrabutylammonium 3 and benzyltriethylammonium 4. The cations in the new compounds were used to achieve a reasonable separation of the paramagnetic Cu(II) ions for EPR spectroscopy. The EPR hyperfine structure was not resolved. This is due to the exchange broadening, resulting from still incomplete separation of the paramagnetic Cu(II) centers. Nevertheless, the principal values of the electron Zeemann tensor (g(║) and g(┴)) of the complexes could be determined. Even though the solid substances show slightly different colors, the UV/Vis spectra are nearly identical, indicating structural changes of the tetrachloridocuprate moieties between solid state and solution. The complexes have a promising potential e.g., as high temperature ionic liquids, as precursors for the formation of copper chloride particles or as catalytic paramagnetic ionic liquids.     

Metal complexes as DNA intercalators

DNA has a strong affinity for many heterocyclic aromatic dyes, such as acridine and its derivatives. Lerman in 1961 first proposed intercalation as the source of this affinity, and this mode of DNA binding has since attracted considerable research scrutiny. Organic intercalators can inhibit nucleic acid synthesis in vivo, and they are now common anticancer drugs in clinical therapy. The covalent attachment of organic intercalators to transition metal coordination complexes, yielding metallointercalators, can lead to novel DNA interactions that influence biological activity. Metal complexes with σ-bonded aromatic side arms can act as dual-function complexes: they bind to DNA both by metal coordination and through intercalation of the attached aromatic ligand. These aromatic side arms introduce new modes of DNA binding, involving mutual interactions of functional groups held in close proximity. The biological activity of both cis- and trans-diamine Pt(II) complexes is dramatically enhanced by the addition of σ-bonded intercalators. We have explored a new class of organometallic "piano-stool" Ru(II) and Os(II) arene anticancer complexes of the type [(η(6)-arene)Ru/Os(XY)Cl](+). Here XY is, for example, ethylenediamine (en), and the arene ligand can take many forms, including tetrahydroanthracene, biphenyl, or p-cymene. Arene-nucleobase stacking interactions can have a significant influence on both the kinetics and thermodynamics of DNA binding. In particular, the cytotoxic activity, conformational distortions, recognition by DNA-binding proteins, and repair mechanisms are dependent on the arene. A major difficulty in developing anticancer drugs is cross-resistance, a phenomenon whereby a cell that is resistant to one drug is also resistant to another drug in the same class. These new complexes are non-cross-resistant with cisplatin towards cancer cells: they constitute a new class of anticancer agents, with a mechanism of action that differs from the anticancer drug cisplatin and its analogs. The Ru-arene complexes with dual functions are more potent towards cancer cells than their nonintercalating analogs. In this Account, we focus on recent studies of dual-function organometallic Ru(II)- and Os(II)-arene complexes and the methods used to detect arene-DNA intercalation. We relate these interactions to the mechanism of anticancer activity and to structure-activity relationships. The interactions between these complexes and DNA show close similarities to those of covalent polycyclic aromatic carcinogens, especially to N7-alkylating intercalation compounds. However, Ru-arene complexes exhibit some new features. Classical intercalation and base extrusion next to the metallated base is observed for {(η(6)-biphenyl)Ru(ethylenediamine)}(2+) adducts of a 14-mer duplex, while penetrating arene intercalation occurs for adducts of the nonaromatic bulky intercalator {(η(6)-tetrahydroanthracene)Ru(ethylenediamine)}(2+) with a 6-mer duplex. The introduction of dual-function Ru-arene complexes introduces new mechanisms of antitumor activity, novel mechanisms for attack on DNA, and new concepts for developing structure- activity relationships. We hope this discussion will stimulate thoughtful and focused research on the design of anticancer chemotherapeutic agents using these unique approaches.     

DFT investigation of copper–peptide complexes related to the octarepeat domain of the prion protein

Recently, it has been demonstrated that the prion protein binds Cu(II) ions by the N-terminal domain [Chem. Eur. J. 6 (2000) 4195; Biochemistry 38 (1999) 11560], which is composed of four or more repeats of the eight-residue sequence PHGGGWGQ (octarepeat). X-ray diffraction experiments [Biochemistry 41 (2002) 3991] have shown that the peptide HGGGW embraces the fundamental Cu²⁺ binding unit and EPR and circular dichroism (CD) experiments, carried out on the Cu(HGGG) complex, show subtle differences in the local coordination geometry with respect to the Cu(HGGGW) species. In this contribution we have investigated Ac–HGGG–NH₂/Cu²⁺ model complexes by means of DFT calculations, showing that the relative stabilities of four- and five-coordinated species are affected by the extent of the H-bond network and by peptide strain. However, when these contributions are not significant, square-planar coordination of Cu is definitely preferred. These observations fit well with the data from EPR experiments [Biochem. J. 344 (1999) 1; Trends Neurosci. 24 (2001) 85; Curr. Opin. Chem. Biol. 4 (2000) 184] that pointed out how a modification in the coordination environment of Cu can take place by going from Cu(HGGGW) to Cu(HGGG).     

Synthesis and the magnetic properties of novel metal(II) complexes of polyamides

Novel polyamides DTPA and DTPyA are prepared from 2,2′-diamino-4,4′-bisthiazole and aromatic polycarbonyl chloride. The complexes of Fe(II) and Cu(II) metal of the polyamides are also prepared. The complexes as well as the polyamides are characterized through IR and EPR, and the magnetic property of each complex are measured through MPMS. It is found the Fe(II) complexes of both DTPA and DTPyA reveal magnetization ability, especially the Fe(II) DTPA complex. © 2001 John Wiley & Sons, Inc. J Appl Polym Sci 82: 818–822, 2001     

三齿仲胺配合物的合成、表征及生物活性的研究

合成了一种三齿配体N-(4-甲基苯)-N′-(2-(4-甲基苯氨基)乙基)乙烷-1,2-二胺,并制备了它的3种过渡金属配合物[ML(H2O)2Cl]Cl(M=CuⅡ,CoⅡ,NiⅡ),用元素分析、核磁、红外和摩尔电导等表征了配体及其金属配合物的组成和结构。对Ni—L进行了单晶结构解析,配合物为六配位的八面体结构,配体采用三齿配位。利用紫外光谱和荧光光谱法研究了配合物与小牛胸腺DNA的作用方式,结果表明,3种金属配合物可能以静电方式与DNA作用。Cu—L、Ni—L、Co—L3种配合物与DNA的结合常数分别为2.99×104、9.78×103、3.66×103。     

A Theoretical-Experimental Study on the Structure and Activity of Certain Quinolones and the Interaction of Their Cu(II)-Complexes on a DNA Model

Theoretical electronic Structure methods have been employed to study the structure and activity of certain (free) quinolones and the interaction of their Cu(II)-complexes on a DNA model (Rhodamine 6G (rhod)). As a manner of assessing the generated geometries, the nalidixic acid geometrical parameters obtained were tested against the crystallographic ones and it was found that the average error in the calculated geometries is small. The present study allows us to (1) Rationalize the observed differences in antibiotic activities through their electronic hardnesses. (2) Suggest a plausible mechanism of action for these drugs through formation of a reactive intermediate (or carrier) which would consist of a quinolone anion coordinated to an adequate metal center (Cu(II) in this study). (3) We find that, through this model of DNA (modeled with rhod) the interaction seems to be mediated by an effective pi-pi stacking. (4) Finally, an in vitro experiment was designed so that the intercalation process in DNA could be experimentally modeled as well. The quenching of the rhod fluorescence is proportional to the strength of the Cu(II)-complex-rhod interaction and therefore provides a quantitative measurement of the "intercalating" capacity of the quinolones and their copper complexes. These results agree well with the theoretical total adduct formation energies.     

Studies on various divalent metal complexes of poly(2-hydroxy-4-acryloyloxybenzophenone) in aqueous medium

2-Hydroxy-4-acryloyloxybenzophenone (2H4ABP) prepared by reacting acryloyl chloride with 2,4-dihydroxybenzophenone, was polymerized in 2-butanone at 65°C using benzoyl peroxide as initiator. Polychelates were obtained in the alkaline solution of poly(2H4ABP) with aqueous solutions of metal ions such as Ni(II), Mn(II), Co(II), Ca(II), Cd(II) and Zn(II). The polymer and polychelates were characterized by elemental analyses and spectral studies. Elemental analyses of the polychelates suggest that the metal-to-ligand ratio is 1: 2. The IR spectral data of the polychelates indicate that the metals were coordinated through the oxygen of the keto group and oxygen of the phenolic −OH group. The diffuse reflectance spectra, EPR and magnetic moments studies reveal that the polychelates of Cu(II) complex are square planar, and Ni(II), Mn(II) and Co(II) complexes are octahedral, while Ca(II), Cd(II) and Zn(II) complexes are tetrahedral. X-ray diffraction studies revealed that the polychelates are highly crystalline. The thermal and electrical properties of polymer and polymer–metal complexes are discussed. © 1998 SCI.     

Synthesis,crystal structure of copper(II) complexes comprising 2-(biphenylazo)phenol and 1-(biphenylazo)naphthol ligands and their catalytic activity in nitroaldol reaction

New series of copper(II) complexes of the type [Cu(L)₂] (L = L₁–L₅) comprising bidentate 2-(biphenylazo)phenol (HL₁–HL₄) and 1-(biphenylazo)naphthol (HL₅) ligands have been synthesized. The composition of complexes and ligands (HL₁–HL₄) has been established by elemental analysis and spectral (FT–IR, UV–Vis, ¹H NMR and EPR) methods. Molecular structures of copper complexes [Cu(L₃)₂] (3) and [Cu(L₅)₂] (5) were established by X-ray crystallography. These Copper(II) biphenylazo complexes exhibit a very good catalytic activity towards nitroaldol reaction of various aldehydes with nitromethane.