Cytotoxic effect, differentiation, inhibition of growth and theoretical calculations of an N,N-donor ligands and its platinum(II), palladium(II) and copper(II) complexes

The new pyrazole ligand 5-(2-hydroxyphenyl)-3-methyl-1-(2-pyridylo)-1H-pyrazole-4-carboxylic acid methyl ester (2) and the corresponding Pt(II), Pd(II) and Cu(II) complexes 3-5 have been synthesized as potential anticancer compounds, and characterized using IR, and (1)H NMR as well as mass spectrometry. The 3-D structures of the Cu(II) complexes were determined by quantum mechanic calculation DFT methodology (density functional theory). The cytotoxicity assay of the ligand and complexes has been performed on leukemia cell lines. In general, the complexes showed lower cytotoxicity than cisplatin, and the Pt(II) and Cu(II) complexes were found to be more efficient in the induction of leukemia cell death than the Pd(II) complex. Our investigations indicate that the antiproliferating activity of the Pt(II) and Cu(II) complexes was partly due to the modulation of cellular differentiation.     

Cytotoxic activity, X-ray crystal structures and spectroscopic characterization of cobalt(II), copper(II) and zinc(II) coordination compounds with 2-substituted benzimidazoles

Herein we present the synthesis, structural and spectroscopic characterization of coordination compounds of cobalt(II), copper(II) and zinc(II) with 2-methylbenzimidazole (2mbz), 2-phenylbenzimidazole (2phbz), 2-chlorobenzimidazole (2cbz), 2-benzimidazolecarbamate (2cmbz) and 2-guanidinobenzimidazole (2gbz). Their cytotoxic activity was evaluated using human cancer cell lines, PC3 (prostate), MCF-7 (breast), HCT-15 (colon), HeLa (cervic-uterine), SKLU-1 (lung) and U373 (glioblastoma), showing that the zinc(II) and copper(II) compounds [Zn(2mbz)₂Cl₂]·0.5H₂O, [Zn(2cmbz)₂Cl₂]·EtOH, [Cu(2cmbz)Br₂]·0.7H₂O and [Cu(2gbz)Br₂] had significant cytotoxic activity. The isostructural cobalt(II) complexes showed not significant activity. The cytotoxic activity is related to the presence of halides in the coordination sphere of the metal ion. Recuperation experiments with HeLa cells, showed that the cells recuperated after removing the copper(II) compounds and, on the contrary, the cells treated with the zinc(II) compounds did not. These results indicate that the mode of action of the coordination compounds is different.     

Antitumor activity of phenylene bridged binuclear bis(imino-quinolyl)palladium(II) and platinum(II) complexes

Antitumor effects of a known bis(imino-quinolyl)palladium(II) complex 1 and its newly synthesized platinum(II) analogue 2 were evaluated against human breast (MCF-7) and human colon (HT-29) cancer cell lines. The complexes gave cytotoxicity profiles that were better than the reference drug cisplatin. The highest cytotoxic activities were pronounced in complex 2 across the two examined cancer cell lines. Both compounds represent potential active drugs based on bimetallic complexes.     

Novel palladium(II) and Zinc(II) Schiff base complexes: Synthesis,biophysical studies,and anticancer activity investigation

BackgroundSchiff base metal complexes are considered promising chemotherapeutic agents due to their potential application in cancer therapy.MethodsThe current work sought to synthesize a brand-new Schiff base ligand obtained from 2-hydroxybenzohydrazide and (E)− 1-(2-(p-tolyl)hydrazono)propan-2-one with metal ions which included Pd(II) and Zn(II) ions. Elemental analyses, FT-IR, mass spectra, 1H NMR, UV-Vis spectrometer, and computational analysis characterized the compound's structure. In vitro, the breast cancer cell line (MCF-7) was tested for its sensitivity to Schiff base (HL) and its Pd(II) and Zn(II) complexes. The half-maximal inhibitory concentration IC₅₀ of the compounds was determined and used to perform the comet assay, which was carried out to reveal the photo-induced DNA damaging ability of the compounds of individual cells. Moreover, the compounds' effects on antioxidant defense systems of enzymes in cells: superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activities and oxidant Malondialdehyde (MDA) were examined in MCF-7 cells.ResultsThe Pd(II) complex displayed approximately the same IC₅₀ as Cisplatin, while Zn(II) complex had better activity than Cisplatin with very low IC₅₀, 1.40 μg/ml. Significant alterations in SOD, CAT, GPx, and MDA production were discovered, inducing oxidative stress, enlarging ROS production, and reducing the antioxidant amount. This change was approximately similar in most compounds. Consequently, it promoted apoptosis, particularly the Zn(II) complex, which demonstrated an improved impact because of its ability to influence the antioxidant defense systems of enzymes, mostly SOD and GPx, besides increasing MDA levels.ConclusionIt can be concluded that Zn(II) complex is the most effective anticancer drug since it induced a very similar genotoxic effect as Cisplatin and has a very low IC₅₀ value.     

Enantiomeric Specificity of Biologically Significant Cu(II) and Zn(II) Chromone Complexes Towards DNA

Novel chiral Schiff base ligands (R)/(S)‐2‐amino‐3‐(((1‐hydroxypropan‐2‐yl)imino)methyl)‐4H‐chromen‐4‐one (L₁ and L₂) derived from 2‐amino‐3‐formylchromone and (R/S)‐2‐amino‐1‐propanol and their Cu(II)/Zn(II) complexes ( R1 , S1 , R2 , and S2 ) were synthesized. The complexes were characterized by elemental analysis, infrared (IR), hydrogen (¹H) and carbon (¹³C) nuclear magnetic resonance (NMR), electrospray ionization‐mass spectra (ESI‐MS), and molar conductance measurements. The DNA binding studies of the complexes with calf thymus were carried out by employing different biophysical methods and molecular docking studies that revealed that complexes R1 and S1 prefers the guanine–cytosine‐rich region, whereas R2 and S2 prefers the adenine–thymine residues in the major groove of DNA. The relative trend in K_b values followed the order R1 S1 R2 S2 . This observation together with the findings of circular dichroic and fluorescence studies revealed maximal potential of (R)‐enantiomeric form of complexes to bind DNA. Furthermore, the absorption studies with mononucleotides were also monitored to examine the base‐specific interactions of the complexes that revealed a higher propensity of Cu(II) complexes for guanosine‐5′‐monophosphate disodium salt, whereas Zn(II) complexes preferentially bind to thymidine‐5′‐monophosphate disodium salt. The cleavage activity of R1 and R2 with pBR322 plasmid DNA was examined by gel electrophoresis that revealed that they are good DNA cleavage agents; nevertheless, R1 proved to show better DNA cleavage ability. Topoisomerase II inhibitory activity of complex R1 revealed that the complex inhibits topoisomerase II catalytic activity at a very low concentration (25 μM). Furthermore, in vitro antitumor activity of complexes R1 and S1 were screened against human carcinoma cell lines of different histological origin. Chirality 24:977–986, 2012. © 2012 Wiley Periodicals, Inc.     

Synthesis characterization and cytotoxicity studies of platinum(II) complexes with reduced amino pyridine schiff base and its derivatives as ligands

A series of reduced amino pyridine Schiff base platinum(II) complexes were prepared as potential anticancer drugs, and characterized by NMR, IR spectroscopy, elemental analysis, and molar conductivity. UV and CD results showed the binding mode between these compounds and salmon sperm DNA may be intercalation. The cytotoxicity of these complexes was validated against A549, Hela, and MCF-7 cell lines by MTT assay. Some complexes exhibited better cytotoxic activity than cisplatin against Hela and MCF-7 cell lines.     

Synthesis, structural characterization and antiproliferative and toxic bio-activities of copper(II) and nickel(II) citronellal N-ethylmorpholine thiosemicarbazonates

This paper reports the syntheses and characterization of ethylmorpholine substituted citronellal thiosemicarbazone copper(II) and nickel(II) metal complexes. The compounds were characterized through elemental analyses and spectroscopic (IR, UV-Vis, NMR, MS) methods. The X-ray analysis of the two complexes shows that both Ni and Cu derivatives present a square planar coordination, where the coordinating homologous donor atoms bind in trans to each other. The compounds were tested for their biological activity after determination of their octanol-saline partition coefficients, followed by their radical scavenging properties. Eventually the complexes were tested for their proliferation inhibition on human histiocytic lymphoma U937 cell line. The GI₅₀ values resulted to be 2.3 μM for the copper derivative and 12.3 μM for the nickel derivative.     

Metal based drugs: design,synthesis and in-vitro antimicrobial screening of Co(II), Ni(II), Cu(II) and Zn(II) complexes with some new carboxamide derived compounds: crystal structures of N-[ethyl(propan-2-yl)carbamothioyl]thiophene-2-carboxamide and its copper(II) complex

A new series of compounds derived from thiophene-2-carboxamide were synthesized and characterized by IR, ¹H-NMR and ¹³C-NMR, mass spectrometry and elemental analysis. These compounds were further used to prepare their Co(II), Ni(II), Cu(II) and Zn(II) metal complexes. All metal(II) complexes were air and moisture stable. Physical, spectral and analytical data have shown the Ni(II) and Cu(II) complexes to exhibit distorted square-planar and Co(II) and Zn(II) complexes tetrahedral geometries. The ligand (L¹) and its Cu(II) complex were characterized by the single-crystal X-ray diffraction method. All the ligands and their metal(II) complexes were screened for their in-vitro antimicrobial activity. The antibacterial and antifungal bioactivity data showed that the metal(II) complexes were found to be more potent than the parent ligands against one or more bacterial and fungal strains.     

Antibacterial dimeric copper(II) complexes with chromone-derived compounds

A new series of six chromone-derived compounds and their Cu(II) complexes have been synthesized and characterized by their physical, spectral and analytical data. The ligands and their Cu(II) complexes were screened for their in vitro antibacterial activity against four Gram-negative (Escherichia coli, Pseudomonas aeruginosa, Salmonella typhi, Shigella flexneri) and two Gram-positive (Bacillus subtilis, Staphylococcus aureus) bacterial strains by agar-well diffusion method. The ligands were found to exhibit either no or low-to-moderate activities against one or more bacterial species whereas, the Cu(II) complexes exhibited moderate-to-high activity. The ligands which were inactive before complexation became active upon complexation with the Cu(II) metal ion and less active became more active.     

Copper(II) complexes of diclofenac: Spectroscopic studies and DNA strand breakage

Copper(II) complexes of diclofenac with interesting anti-inflammatory profiles have been prepared and studied by infrared and electronic spectroscopy. In the solid state and in polar and coordinating solvents, all the complexes are solvated binuclear carboxylato-bridged complexes, [Cu(L)²(S)]², where L is monodeprotonated diclofenac and S is the axially bonded solvent. The effect of the copper(II) complexes on the in vitro DNA strand breakeage was studied by agarose gel electrophoresis. Relaxation or double stranded scissions of pDNA were observed leading to the formation of linear pDNA. Treatment of pDNA with high concentrations of these compounds caused a disappearance of pDNA. For the parent drug, sodium diclofenac, no effect on the pDNA was observed. This study presents some indications that the binuclear copper(II) complexes, [Cu(L)²(S)]², could have some relevance in the treatment of tumor cell lines.     

Synthesis and multi‐spectroscopic study on DNA‐binding,cleavage and biological properties of M(II) complexes based on N2O2 donor Schiff base ligand

A novel Schiff base, (S,Z)‐4‐(methylthio)‐2‐((3‐oxo‐2,3‐dihydro‐1H‐inden‐1‐ylidene)amino)butanoic acid (L) and four M(II) complexes (where M = Co, Cu, Ni and Zn) were synthesized and characterized. The DNA‐binding characteristics of the complexes were investigated using various spectroscopic methods and viscosity measurements. Analysis of the results suggests that all the complexes bind to calf thymus DNA via intercalation. Among the four, Cu(II) complex was found to promote the photocleavage of plasmid DNA pBR322 under irradiation at 365 nm. These complexes also exhibit good antioxidant activities against 2,2‐diphenyl‐1‐picrylhydrazyl radical. In vitro antibacterial and antifungal assay indicates that these complexes are good antimicrobial agents.     

Structural and DNA cleavage of sugar-derived Schiff base ligands and their dinuclear Cu(II) complexes

Neutral dinuclear Cu(II) complexes of Schiff base ligands derived from d-glucose have been synthesized and structurally characterized. These complexes were evaluated for their interaction with DNA, and DNA cleavage was observed even in the presence of radical inhibitors.     

Anticancer,antibacterial and antifungal activity of new ni (ii) and cu (ii) complexes of imidazole-phenanthroline derivatives

Two new nickel(II) and copper(II) complexes of 2-(Furan-2-yl)-1H-Imidazo[4,5-f][1,10]Phenanthroline (FIP) and 2-(thiophen-2-yl)-1H-imidazo[4,5-f][1,10]phenanthroline (TIP), imidazophen derivatives were synthesized. The structures of the compounds were determined by UV-visible and FT-IR spectroscopic methods and elemental analysis. The biological activities of Ni and Cu complexes, as anticancer agents, were tested against chronic myelogenous leukemia cell line, K562, at micromolar concentration. The MTT studies showed Cc₅₀ values are 21 and 160 µM for Cu and Ni(II) complexes, respectively; suggesting that Ni (II) complex has Cc₅₀ almost seven times of that obtained for cisplatin. Biological activity of the Ni(II) and Cu(II) complexes were also assayed against selective microorganisms by disc diffusion method. These results showed that the Cu(II) complex is antifungal agent but Ni(II) complex has antibacterial activity.     

Synthesis, characterization, and antibacterial activity of novel Mn(II), Co(II), Ni(II), Cu(II), and Zn(II) complexes with vitamin K3-thiosemicarbazone

Vitamin K3-thiosemicarbazone (C12H11N3NaO4S2 x 5H2O, abbreviated as VT), a new Schiff base derivative, has been synthesized. Its crystal structure, determined by X-ray diffraction, is triclinic, space group P1. We have also prepared five novel complexes of VT with transition metals: [M(VT)(2)2H2O] x nH2O, (n = 1 and 2 for M = Cu(II) and Zn(II), respectively) and [M'(HVT)2Cl2] x mH2O, (m = 4, 5, and 7 for M' = Co(II), Mn(II), and Ni(II), respectively). These compounds were characterized by IR and UV-Vis spectroscopy, molar conductivity, thermal analyses, complexometric titration, and elemental analysis. In all the complexes, the VT ligand coordinates through sulfur and oxygen atoms, and the geometry around metal atom is best described as octahedral. In vitro tests of antibacterial activity showed that VT and its complexes with Mn(II), Co(II), Ni(II), Cu(II), and Zn(II) all had strong inhibitory actions against G(+) Staphylococcus aureus, G(+) Hay bacillus, and G(-) Escherichia coli.     

In vitro anti-proliferative,and in silico ribonucleotide reductase and pharmacokinetics studies of heteroleptic silver(I), nickel(II) and copper(II) complexes of 4-methyl-3-thiosemicarbazones and ibuprofen

ObjectivesThe present research focuses on the in vitro anti-proliferative, and in silico ribonucleotide reductase and pharmacokinetics studies of twelve heteroleptic metal complexes of the general formulae [Ag(L¹⁻⁴)(ibu)] (1–4) and [M(L¹⁻⁴)(ibu)₂] (5–12), where L¹⁻⁴ = 2-(1-(4-substitutedphenyl)ethylidene)-N-methylhydrazinecarbothioamide, ibu = non-steroidal anti-inflammatory drug (ibuprofen), and M = Cu(II) and Ni(II).MethodsVarious spectroscopic techniques were used to authenticate the structure of the synthesized complexes. UV-Vis and cyclic voltammetry techniques were used to analyse the stability and the reducing ability of the complexes. In vitro anti-proliferative studies by MTT assay, apoptotic behaviour and cellular uptake studies were investigated followed by the in silico interaction with ribonucleotide reductase (RNR) enzyme.ResultsThe spectral studies predicted distorted tetrahedral geometry around silver(I) ion and distorted octahedral geometry around nickel(II) and copper(II) ions. The reducing ability of the copper(II) complexes was analysed using ascorbic acid by UV-Vis and cyclic voltammetry techniques, which authenticate the reducing ability of the complexes and the possible interactions within the cells. The in vitro anti-proliferative activity of the synthesized complexes against three cancerous (estrogen positive (MCF-7), estrogen negative (MDA-MB-231) and pancreatic (PANC-1)) and one normal (MCF-10a) cell lines by MTT assay showed enhanced activity for copper(II) complexes 11 and 12 containing the hydrophobic substituents. The apoptotic and cellular uptake studies showed that the complex 12 is readily taken up by PANC-1 cell lines and induces ROS-mediated mitochondrial and caspase-dependent apoptosis. The in silico studies indicated hydrogen bonding, hydrophobic and π-pair (π–π, π–σ and π–cation) interactions between the complexes and the ribonucleotide reductase (RNR) enzyme. The in silico pharmacokinetics studies of the complexes predicted the drug-likeness characteristics of the complexes.ConclusionThe synthesized complexes are found to be less toxic to normal cells and inhibit the growth of cancerous cells by inducing mitochondrial-mediated and caspase dependent apoptotic pathway in PANC-1 cells.     

Electrochemical synthesis and crystal structure of iron(II), cobalt(II), nickel(II) and copper(II) complexes of dianionic tetradentate N4 Schiff base ligand

The electrochemical oxidation of anodic metal (iron, cobalt, nickel and copper) in an acetonitrile solution of the potentially chelating Schiff base N,N(dithiodiethylenebis-(aminylydenemethylydene)-bis(1,2-phenylene)ditosylamide (H₂L) afforded stable complexes of empirical formula [ML]. The compounds obtained have been characterized by microanalysis, IR spectroscopy and ES-MS mass spectrometry. The crystal and molecular structures of [FeL]·CH₃CN (1) [CoL]·CH₃CN (2), [NiL]·CH₃CN (3) and [CuL]·CH₃CN (4) have been determined by X-ray diffraction in all complexes, the metal atom is in a distorted tetrahedral environment with the Schiff base acting as a tetradentate N4 donor.     

Comparison of the SOD-like activity of hexacoordinate Mn(II), Fe(II) and Ni(II) complexes having isoindoline-based ligands

Recently, a series of Fe(II) complexes have been published by our group with 3 N-donor 1,3-bis(2′-Ar-imino)isoindoline ligands containing various Ar-groups (pyridyl, 4-methylpyridyl, thiazolyl, benzimidazolyl and N-methylbenzimidazolyl). The superoxide scavenging activity of the compounds showed correlation with the Fe(III)/Fe(II) redox potentials. Analogous, electroneutral chelate complexes with Mn(II) and Ni(II) in 2:1 ligand:metal composition are reported here. Each Mn(II) complex exhibits one reversible redox wave that is assigned as the Mn(III)/Mn(II) redox transition. The E_1/2 spans a 180 mV range from − 98 (Ar = 3-methylpyridyl) to 82 mV (Ar = thiazolyl) vs. the Fc⁺/Fc depending on the Ar-sidearm. The SOD-like (SOD=superoxide dismutase)activity of all complexes was determined according to the McCord-Fridovich method. The Mn(II) isoindolinates have IC₅₀ values - determined with 50 μM cytochrome c Fe(III) - that range from (3.22 ± 0.39) × 10^− 6 (Ar = benzimidazolyl) to (10.80 ± 0.54) × 10^− 6 M (Ar = N-methylbenzimidazolyl). In contrast with the Fe(II) complexes, the IC₅₀ concentrations show no significant dependence on the E_1/2 values in this narrow potential range emphasizing that the redox potential is not the governing factor in the Mn(II)-containing scavengers. The analogous Ni(II) compounds show no redox transitions in the thermodynamically relevant potential range (− 0.40 to 0.65 V vs. SCE) and accordingly, their superoxide scavenging activity (if any) is below the detection level.     

Imidazolate-bridged dicopper(II) and copper(II)–zinc(II) complexes of macrocyclic ligand with methylimidazol pendants: Model study of copper(II)–zinc(II) superoxide dismutase

Two new homo- and hetero-dinuclear complexes, [Cu₂L(im)](ClO₄)₃4H₂O (1) and [CuZnL(im)](ClO₄)₃4H₂O (2) (where Im=1H-1midazole and L = 3, 6, 9, 16, 19, 22-hexaaza-6, 19-bis(1H-imidazol-4-ylmethyl)tricycle[22, 2, 2, 2^11,14]triaconta-1, 11, 13, 24, 27, 29-hexaene) were synthesized and characterized as model compounds for the active site of copper(II)–zinc(II) superoxide dismutase (Cu₂Zn₂–SOD). X-ray crystal structure analysis revealed that the metal centers in both complexes exhibit distorted trigonal-bipyramid coordination geometry and the CuCu and CuZn distances are both 6.02 Å. Magnetic and ESR spectral measurements of 1 showed antiferromagnetic exchange interactions between the imidazolate-bridged Cu(II) ions. The ESR spectrum of 2 displays typical signals of mononuclear Cu(II) complex, demonstrating the formation of heterodinuclear complex 2 rather than a mixture of homodinuclear Cu(II)/Zn(II) complexes. pH-dependent ESR and UV–visible spectral measurements manifest that the imidazolate exists as a bridging ligand from pH 6 to 11 for both complexes. The IC₅₀ values of 1.96 and 1.57 μM [per Cu(II) ion] for 1 and 2 suggest that they are good models for the Cu₂Zn₂–SOD.     

Antimicrobial, spectral, magnetic and thermal studies of Cu(II), Ni(II), Co(II), UO(2)(VI) and Fe(III) complexes of the Schiff base derived from oxalylhydrazide

The Schiff base ligand, oxalic bis[(2-hydroxybenzylidene)hydrazide], H(2)L, and its Cu(II), Ni(II), Co(II), UO(2)(VI) and Fe(III) complexes were prepared and tested as antibacterial agents. The Schiff base acts as a dibasic tetra- or hexadentate ligand with metal cations in molar ratio 1:1 or 2:1 (M:L) to yield either mono- or binuclear complexes, respectively. The ligand and its metal complexes were characterized by elemental analyses, IR, (1)H NMR, Mass, and UV-Visible spectra and the magnetic moments and electrical conductance of the complexes were also determined. For binuclear complexes, the magnetic moments are quite low compared to the calculated value for two metal ions complexes and this shows antiferromagnetic interactions between the two adjacent metal ions. The ligand and its metal complexes were tested against a Gram + ve bacteria (Staphylococcus aureus), a Gram -ve bacteria (Escherichia coli), and a fungi (Candida albicans). The tested compounds exhibited high antibacterial activities.     

Spectroscopic and Structural Characterization,Enzyme Inhibitions,and Antioxidant Effects of New Ru(II) and Ni(II) Complexes of Schiff Base

The new complex compounds [RuLCl(p‐cymene)] ? 3H₂O and [NiL₂(H₂O)₂] ? 3H₂O (L: 1‐{4‐[(2‐hydroxy‐3‐methoxybenzylidene)amino]phenyl}ethanone) were prepared and characterized using FT‐IR, ¹H‐ and ¹³C‐NMR, mass spectroscopy, TGA, elemental analysis, X‐ray powder diffraction and magnetic moment techniques. Octahedral geometry for new Ni(II) and Ru(II) complexes was proposed. Thermal decomposition confirmed the existence of lattice and coordinated water molecule in the complexes. To determine the antioxidant properties of Schiff base ligand and its Ni(II), Ru(II) metal complexes, FRAP, CUPRAC, ABTS and DPPH methods of antioxidant assays were used. Moreover, enzyme inhibition of complexes was evaluated against carbonic anhydrase I and II isoenzymes (CA I and CA II) and acetylcholinesterase (AChE). For CA I and CA II, the best inhibition enzymes, was the Ni(II) complex with 62.98±18.41, 86.17±23.62 Ki values, whereas this inhibition effect showed ligand with 24.53±2.66 Ki value for the AChE enzyme.