From GC-rich DNA binding to the repression of survivin gene for quercetin nickel (II) complex: implications for cancer therapy

The DNA binding and cleavage properties of quercetin nickel (II) complex have been studied, but little attention has been devoted to the relationship between antitumor activity of this complex and DNA-binding properties. In the present study, we report that quercetin nickel (II) complex showed significant cytotoxicity against three tumor cell lines (HepG2, SMMC7721 and A549). Hoechst33258 and AO/EB staining showed HepG2 cells underwent the typical morphologic changes of apoptosis characterized by nuclear shrinkage, chromatin condensation, or fragmentation after exposure to quercetin nickel (II) complex. We also demonstrate that the levels of survivin and bcl-2 protein expression in HepG2 cells decreased concurrently, and the levels of p53 protein increased significantly after treatment with quercetin nickel (II) complex by immunocytochemistry analysis. The relative activity of caspase-3 and caspase-9 increased significantly after treatment with the complex. Furthermore, fluorescence measurements and molecular modeling were performed to learn that the complex could be preferentially bound to DNA in GC region. These results imply that quercetin nickel (II) complex may intercalate into the GC-rich core promoter region of survivin, down-regulating survivin gene expression and promoting tumor cells apoptosis. So our results suggest that antitumor activity of quercetin nickel (II) complex might be related to its intercalation into DNA and DNA-binding selectivity, and that the complex may be a promising agent for cancer therapy.     

Chronotolerance of a Nickel (II) Complex with the 5-Methyl 2-Furaldehyde Thiosemicarbazone Ligand in Male Swiss Mice

In vitro nickel (II) complex presents antimitotic effects. In this work, we have studied the in vivo seasonal effects of nickel (II), ligand and the complex [NiCl₂(M5FTSC)₂] in male Swiss mice. During spring, an intra peritoneal (i.p.) injection of NiCl₂ in aqueous NaCl up to 1.0.10^-2 mmol.kg^-1 body weight (b.w.) killed 10% of the rodents after 6 days. Lethal dose 100% (LD100) was up 1.91.10^-2 mmol.kg^-1 b.w.; ligand was less toxic than Ni (II), while the complex was 25% lethal at 1.37.10^-2 mmol.kg^-1 b.w. In autumn, mice were less sensitive to NiCl₂. The ligand and the complex, on the contrary, were more toxic. This leads us to the conclusion that, in vivo, chronotolerance of nickel (II), ligand and complex in aqueous solution, are quite different in spring and autumn seasons.     

Steric and counterion effects on the structure of dipicolylamine nickel complexes

Four nickel complexes each containing an R-2,2′-dipicolylamine ligand species (RDPA; R = benzyl, isopropyl, or tert-butyl) were synthesized and structurally characterized. In the absence of an interfering coordinating counterion, BzDPA and iPrDPA form 1:2 nickel:ligand complexes, with two facial ligands completing an pseudooctahedral nickel(II) coordination environment. In contrast, the sterically hindered tBuDPA ligand instead forms 1:1 metal:ligand complexes, even in the absence of associating counterions. Two novel tBuDPA nickel complexes with different counterions are described: nickel(II) chloride gives rise to an unusual 2Ni-3Cl dimer complex, while nickel(II) nitrate affords a 1:1 nickel:ligand complex which crystallizes with both fac and mer conformations in the same unit cell.     

Spectroscopic, viscositic and electrochemical studies of DNA interaction with a novel mixed-ligand complex of nickel (II) that incorporates 1-methylimidazole and thiocyanate groups

A novel mixed-ligand nickel(II) complex that contains 1-methylimidazole and thiocyanate, Ni(NCS)(2)(Mim)(4) (Mim=1-methylimidazole), was synthesized and its structure was determined by X-ray crystallography, IR spectrum and elemental analysis, etc. Its DNA-binding properties were studied by electronic absorption spectral, viscositive and electrochemical measurements. The absorption spectral and viscositive results suggest that the nickel(II) complex binds to DNA via partial intercalation. The addition of DNA results in the decrease of the peak current of the nickel(II) complex proved their interaction. The slight differences of peak profiles and electrochemical parameters between free and DNA-bound Ni(NCS)(2)(Mim)(4) showed the formation of an electrochemical inactive complex between Ni(NCS)(2)(Mim)(4) and DNA. The binding site and binding constant of the complex to DNA were determined by electrochemical titration method.     

Structure and O2 uptake properties of a novel nickel(II) complex of pyridyl-pendant dioxocyclam [1-(2-pyridyl)methyl-5,7-dioxo-1,4,8,11-tetraazacyclotetradecane]

 Novel potentially five-coordinate pyridyl–pendant dioxocyclam [1-(2-pyridyl)methyl-5,7-dioxo-1,4,8,11-tetraazacyclotetradecane (H₂L) and its homologs (6-methyl and 6,6-dimethyl derivatives)] have been synthesized to study nickel(II) complexation. A purple nickel(II) complex with a deprotonated amide (NiHL) was isolated from aqueous equimolar solution of H₂L and Ni(ClO₄)₂. A yellow nickel(II) complex with two deprotonated amides (NiL) was crystallized from an H₂O/CH₃CN solution of H₂L and Ni(OH)₂. The X-ray crystal study of NiL showed a square-planar nickel(II) complex with the pyridyl–pendant remaining uncoordinated. It is concluded from the visible absorption and NMR study of NiL in aqueous solution that the four-coordinate NiL is in equilibrium with a five-coordinate square-pyramidal nickel(II) complex with the apical coordination of the pyridyl–pendant. A voltammetric study disclosed a low nickel(II/III) redox potential of +0.29 V vs SCE for NiL at pH 9.5 and 25  °C with 0.10 M Na₂SO₄. The nickel(II) complex NiL absorbed an equimolar amount of O₂ at pH 9.5 and 25  °C, and the O₂ was activated to cleave plasmid DNA. Received: 5 August 1996 / Accepted: 24 October 1996     

In vitro interaction of 63-nickel(II) with chromatin and DNA from rat kidney and liver nuclei

The interaction of nickel(II) with chromatin was studied in vitro and in isolated nuclei from rat liver and kidney. Nickel(II) bound to chromatin, polynucleosomes (DNA + histone octamer protein complex), and to deproteinized DNA both in intact nuclei and in vitro. The amount of nickel(II) bound depended on the concentration of nickel(II), the presence of chromosomal proteins and the binding sites on DNA which provide a stable coordination environment for nickel(II). The binding of nickel(II) to chromatin and to DNA in whole nuclei was much slower than in vitro indicating that assessibility of the DNA binding sites was influenced by the presence of the nuclear membrane, nuclear matrix and nuclear proteins and/or by the condensed nuclear structure of chromatin. Since DNA containing bound nickel(II) was isolated from chromatin, nickel(II) directly interacted with stable binding sites on the DNA molecule in chromatin. Nickel(II) was associated with the histone and non-histone nuclear proteins as well as the DNA in rat liver and kidney chromatin. Nickel(II) was found to bind to calf thymus histones in vitro. Nickel(II)-nuclear protein and -DNA interactions were investigated by gel electrophoretic analysis of in vitro incubation products. Although nickel-histone and nickel-non-histone protein interactions were completely disrupted by the electrophoretic conditions, fluorography revealed the presence of inert nickel(II)-DNA and/or nickel(II)-DNA-protein complexes.     

Synthetic, spectroscopic, biological and X-ray crystallographic structural studies on a novel pyridine-nitrogen-bridged dimeric nickel(II) complex of a pentadentate N3S2 ligand

The Schiff base formed by condensation of 2,6-diacetylpyridine with S-benzyldithiocarbazate (H₂SNNNS) behaves as a pentadentate ligand, forming a nickel(II) complex of empirical formula Ni(SNNNS)·H₂O that is high-spin with a room-temperature magnetic moment of 2.93 B.M. Spectroscopic data indicate that the ligand coordinates with the nickel(II) ion via the pyridine nitrogen atom, the azomethine nitrogen atom and the thiolate sulfur atom. The crystal and molecular structure of the nickel(II) complex was determined by X-ray crystallography. The complex crystallizes in the monoclinic system, space group C2/c, with a=15.849(2), b=18.830(2) and c=18.447(2) Å and =90°, β=102.179(6)°, γ=90° and Z=8. The crystal structure analysis shows that the complex is dinuclear, [Ni(SNNNS)]₂·2H₂O, in which the nickel(II) ions are bridged by the two pyridine nitrogen atoms of two fully deprotonated ligands. The NiN₄S₂ coordination geometry about each nickel(II) ion can be described as a distorted octahedron. The Schiff base and its nickel(II) complex were tested against four pathogenic bacteria (Bacillus subtilis, Pseudomonas aeruginosa, methicillin-resistant Staphylococcus and B. subtilis (wild type B29) and pathogenic fungi (Saccharomyces ceciricae, Candida albicans, Candida lypolitica and Aspergillus ochraceous) to assess their antimicrobial properties. Both compounds exhibit mild antibacterial and antifungal activities against these organisms. The anticancer properties of these compounds were also evaluated against Human T-lymphoblastic leukaemia cell lines. The Schiff base exhibits marked cytotoxicity against these cells, but its nickel(II) complex is inactive.     

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.     

Metal complexes with schiff bases obtained from salicylaldehyde derivatives and 2-aminoethylpyridine

Cobalt(II), cobalt(III), nickel(II), copper(II) and palladium(II) complexes with N-2-(2-pyridyl)ethylring-substituted salicylideneiminates (abbreviated as X-Sal-2-Epy) were synthesized. In addition to Co^III (H-Sal-2-Epy)₃, the complexes of the formula M^II(X-Sal-2-Epy)₂·nH₂O were obtained in crystals. The cobalt(III) complex is diamagnetic and has an electronic absorption spectrum typical of the six-coordinate, octahedral cobalt(III) complex. The cobalt(II) complexes in the solid state show electronic spectra typical of the six-coordinate cobalt(II) complexes. Electronic spectra also indicate that the nickel(II) complexes in the solid state and in non-donor solvents are six-coordinate, octahedral. In the cobalt(II) and nickel(II) complexes, the ligand X-Sal-2-Epy functions as terdentates, while in the cobalt(III) complex it acts as a bidentate ligand. The results are compared with those reported previously for related ligands.     

Mutagenicity of various chemicals including nickel and cobalt compounds in cultured mouse FM3A cells

Employing a suspension culture of FM3A cells, we examined the cytotoxic and mutagenic effects of various chemical compounds. Mutagenicity of various types of mutagens (MNNG, ENNG, sterigmatocystin, mitomycin C, Trp-P-1, and X-rays) was sensitively detected by this assay. Mutagenicity of Trp-P-2 was detected in the presence of an activating enzyme system. Nickel(II) and cobalt(II) compounds (NiCl2, Ni(CH3COO)2, nickel complex [(C2H5)4N]2 [NiCl4], CoCl2, and a cobalt complex [(C2H5)4N]2-[CoCl4]) were cytotoxic to FM3A cells at concentrations of over 1 X 10(-4) M, and produced 2-6-fold increases of the control in the average number of 6-thioguanine-resistant (6TGr) colonies over a very narrow concentration range of 2-4 X 10(-4) M. Comparison of the mutagenicity of various chemical compounds suggested that some of the nickel(II) and cobalt(II) compounds were very weak mutagens.     

Escherichia coli SlyD, more than a Ni(II) reservoir

SlyD interacts with HypB and contributes to nickel insertion during [NiFe]-hydrogenase biogenesis. Herein, we provide evidence of SlyD acting as a nickel storage determinant in Escherichia coli and show that this Ni(II) can be mobilized to HypB in vitro even under competitive conditions. Furthermore, SlyD enhances the GTPase activity of HypB, and acceleration of release of Ni(II) from HypB is more pronounced when HypB is GDP-bound. The data support a model in which a HypB-SlyD complex establishes communication between GTP hydrolysis and nickel delivery and provide insight into the role of the HypB-SlyD complex during [NiFe]-hydrogenase biosynthesis.     

Structural diversity in five-coordinate nickel(II) complexes of the tripyrrin ligand

Three different five coordinate nickel(II) complexes of tripyrrin ligands with chloro, oxalato and nitrato anionic ligands were obtained by ligand exchange reactions from respective trifluoroacetato species prepared in situ. Crystallographic studies of these compounds revealed different coordination geometries as well as different packing pattern. In the solid, the chloride complex accepts one water ligand to form a distorted trigonal bipyramid with two N donor centers in apical and one in an equatorial position. The molecules are organized in the crystal via hydrogen bonds, resulting in endless chains. Oxalate serves as a bridging ligand between two nickel(II) tripyrrins. Again the coordination of nickel(II) is found to be trigonal bipyramidal but with two equatorial and one apical nitrogen donors. The discrete dinuclear complexes are arranged in the crystal in a way as to form channels filled with toluene molecules. The nitrate species displays a η² bound nitrate ligand and short contacts between the nickel(II) center and an ethyl substituent of a neighboring molecule. The complex shows an unusually distorted molecular structure and unexpected differences in the two Ni-O bond lengths.     

Synthesis and characterization of a new binucleating schiff base macrocycle and its nickel(II) and copper(II) complexes

A new binucleating ligand, m-xyl-bis(3-bae)) and its copper(II) and nickel(II) complexes have been prepared and characterized by various physical techniques. Data for the complexes indicate that they both have square-planar geometries. High resolution ¹H and ¹³C NMR confirm the square-planar geometry of the binuclear nickel(II) complex is maintained in non-coordinating solvents. The magnetic moment of the copper(II) complex is typical of square-planar complexes and the EPR spectrum in solution indicates the absence of any magnetic coupling between metal centers. In addition, both metal complexes display irreversible electrochemical behavior on various electrode surfaces.     

Appended 1,2-naphthoquinones as anticancer agents 1: synthesis, structural, spectral and antitumor activities of ortho-naphthaquinone thiosemicarbazone and its transition metal complexes

Copper(II), nickel(II), palladium(II) and platinum(II) complexes of ortho-naphthaquinone thiosemicarbazone were synthesized and characterized by spectroscopic studies. In both solution (NMR) and solid state (IR, single-crystal X-ray diffraction determination) the free ligand NQTS exists as the thione form. The Pd complex (X-ray) crystallizes as the H-bonded dimer, [Pd(NQTS)Cl]₂ · 2DMSO, where palladium(II) coordinates in a square planar configuration to the monodeprotonated, tridentate thiosemicarbazone ligand. The nickel(II) complex shows 1:2 metal to ligand stoichiometry while the other complexes exhibit 1:1 metal-ligand compositions. In vitro anticancer studies on MCF7 human breast cancer cells reveal that adding a thiosemicarbazone pharmacophore to the parent quinone carbonyl considerably enhances its antiproliferative activity. Among the metal complexes, the nickel compound exhibits the lowest IC₅₀ value (2.25 μM) suggesting a different mechanism of action involving inhibition of topoisomerase II activity.     

Nickel(II) and cobalt(II) complexes of hydroxyl-substituted triazamacrocyclic ligand as potential antitumor agents

The stability constants for the formation of nickel(II) and cobalt(II) complexes of the ligand [1,4,7]triazecan-9-ol (L) were presented. Antitumor activity of two complexes was reported. Nuclei of [NiL]-stimulated BEL-7402 cells clearly exhibited condensation and break down into chromatin clumps typical of apoptosis. Also it exhibited perturbation effects to cell cycle, and optimal induction of apoptosis was found by Flow-Cytometric analysis. But CoL complex did not exhibit introduction effects to BEL-7402 cells apoptosis; and could not perturb cell cycle. NiL and CuL complexes could cleave supercoiled DNA (pBR 322 DNA) to nicked and linear DNA, and DNA of cells treated with NiL or CuL complex was obviously damaged; while CoL complex only could cleave supercoiled DNA (pBR 322 DNA) to nicked DNA, and DNA of cells treated with CoL complex had no significant difference with control.     

Triazamacrocyclic complexes with 8- and 9-membered chelate rings. Preparation, structures and agostic interactions in complexes of 1,5,9-triazacyclotetradecane and 1,5,9-triazacyclopentadecane

Cobalt(II), copper(II) and nickel(II) complexes of the ligands 1,5,9-triazacyclotetradecane (tatd) and 1,5,9-triazacyclopentadecane (tapd), which have 8- and 9-membered chelate rings, respectively, have been prepared and characterised. Crystal structures of [Ni(tatd)(NCS)₂]·H₂O and [Co(tatd)(NCS)₂] have been determined. The nickel(II) complex has a distorted square pyramidal geometry and the cobalt(II) complex has a distorted trigonal bipyramidal geometry. Agostic interactions between a hydrogen on the central carbon of the 8-membered chelate ring and the metal ion are observed in both complexes.     

Further structural analysis of GnRH complexes with metal ions

MALDI-TOF mass spectrometry, 1H NMR spectrometry, the continuous variation method and molecular modeling by MM3 calculation confirmed our earlier studies showing that gonadotropin-releasing hormone (GnRH) forms complex with copper(II) ion with the binding ratio 1:1. The copper(II) complex formed at physiological pH has a square planar configuration and GnRH complexes with nickel(II) and cobalt(II) ions are less stable than that of copper(II).     

Nickel(II) complexes of the multihistidine peptide fragments of human prion protein

Nickel(II) complexes of the peptide fragments of human prion protein containing histidyl residues both inside and outside the octarepeat domain have been studied by the combined application of potentiometric, UV-visible and circular dichroism spectroscopic methods. The imidazole-N donor atoms of histidyl residues are the exclusive metal binding sites below pH 7.5, but the formation of stable macrochelates was characteristic only for the peptide HuPrP(76-114) containing four histidyl residues. Yellow colored square planar complexes were obtained above pH 7.5-8 with the cooperative deprotonation of three amide nitrogens in the [N_im,N⁻,N⁻,N⁻] coordination mode. It was found that the peptides can bind as many nickel(II) ions as the number of independent histidyl residues. All data supported that the complex formation processes of nickel(II) are very similar to those of copper(II), but with a significantly reduced stability for nickel(II), which shifts the complex formation reactions into the slightly alkaline pH range. The formation of coordination isomers was characteristic of the mononuclear complexes with a significant preference for the nickel(II) binding at the histidyl sites outside the octarepeat domain. The results obtained for the two-histidine fragments of the protein, HuPrP(91-115), HuPrP(76-114)H85A and HuPrP(84-114)H96A, made it possible to compare the binding ability of the His96 and His111 sites. These data reveal a significant difference in the nickel(II) and copper(II) binding sites of the peptides: His96 was found to predominate almost completely for nickel(II) ions, while the opposite order, but with comparable concentrations, was reported for copper(II).     

Spectroscopic,viscositic and electrochemical studies of DNA interaction with a novel mixed-ligand complex of nickel (II) that incorporates 1-methylimidazole and thiocyanate groups

A novel mixed-ligand nickel(II) complex that contains 1-methylimidazole and thiocyanate, Ni(NCS)₂(Mim)₄ (Mim = 1-methylimidazole), was synthesized and its structure was determined by X-ray crystallography, IR spectrum and elemental analysis, etc. Its DNA-binding properties were studied by electronic absorption spectral, viscositive and electrochemical measurements. The absorption spectral and viscositive results suggest that the nickel(II) complex binds to DNA via partial intercalation. The addition of DNA results in the decrease of the peak current of the nickel(II) complex proved their interaction. The slight differences of peak profiles and electrochemical parameters between free and DNA-bound Ni(NCS)₂(Mim)₄ showed the formation of an electrochemical inactive complex between Ni(NCS)₂(Mim)₄ and DNA. The binding site and binding constant of the complex to DNA were determined by electrochemical titration method.