A Comparison of In Vitro Studies between Cobalt(III) and Copper(II) Complexes with Thiosemicarbazone Ligands to Treat Triple Negative Breast Cancer.

Metal complexes have gained significant attention as potential anti-cancer agents. The anti-cancer activity of [Co(phen)2(MeATSC)](NO3)3•1.5H2O•C2H5OH 1 (where phen = 1,10-phenanthroline and MeATSC = 9-anthraldehyde-N(4)-methylthiosemicarbazone) and [Cu(acetylethTSC)Cl]Cl•0.25C2H5OH 2 (where acetylethTSC = (E)-N-ethyl-2-[1-(thiazol-2-yl)ethylidene]hydrazinecarbothioamide) was investigated by analyzing DNA cleavage activity. The cytotoxic effect was analyzed using CCK-8 viability assay. The activities of caspase 3/7, 9, and 1, reactive oxygen species (ROS) production, cell cycle arrest, and mitochondrial function were further analyzed to study the cell death mechanisms. Complex 2 induced a significant increase in nicked DNA. The IC50 values of complex 1 were 17.59 µM and 61.26 µM in cancer and non-cancer cells, respectively. The IC50 values of complex 2 were 5.63 and 12.19 µM for cancer and non-cancer cells, respectively. Complex 1 induced an increase in ROS levels, mitochondrial dysfunction, and activated caspases 3/7, 9, and 1, which indicated the induction of intrinsic apoptotic pathway and pyroptosis. Complex 2 induced cell cycle arrest in the S phase, ROS generation, and caspase 3/7 activation. Thus, complex 1 induced cell death in the breast cancer cell line via activation of oxidative stress which induced apoptosis and pyroptosis while complex 2 induced cell cycle arrest through the induction of DNA cleavage.

Copper(II), Nickel(II) and Zinc(II) Complexes of Peptide Fragments of Tau Protein.

Copper(II), nickel(II) and zinc(II) complexes of various peptide fragments of tau protein were studied by potentiometric and spectroscopic techniques. All peptides contained one histidyl residue and represented the sequences of tau(91-97) (Ac-AQPHTEI-NH2), tau(385-390) (Ac-KTDHGA-NH2) and tau(404-409) (Ac-SPRHLS-NH2). Imidazole-N donors of histidine were the primary metal binding sites for all peptides and all metal ions, but in the case of copper(II) and nickel(II), the deprotonated amide groups were also involved in metal binding by increasing pH. The most stable complexes were formed with copper(II) ions, but the presence of prolyl residues resulted in significant changes in the thermodynamic stability and speciation of the systems. It was also demonstrated that nickel(II) and especially zinc(II) complexes have relatively low thermodynamic stability with these peptides. The copper(II)-catalyzed oxidation of the peptides was also studied. In the presence of H2O2, the fragmentation of peptides was detected in all cases. In the simultaneous presence of H2O2 and ascorbic acid, the fragmentation of the peptide is less preferred, and the formation of 2-oxo-histidine also occurs.

Synthesis and Biological Activity of a New Indenoisoquinoline Copper Derivative as a Topoisomerase I Inhibitor.

Topoisomerases are interesting targets in cancer chemotherapy. Here, we describe the design and synthesis of a novel copper(II) indenoisoquinoline complex, WN198. The new organometallic compound exhibits a cytotoxic effect on five adenocarcinoma cell lines (MCF-7, MDA-MB-231, HeLa, HT-29, and DU-145) with the lowest IC50 (0.37 ± 0.04 µM) for the triple-negative MDA-MB-231 breast cancer cell line. Below 5 µM, WN198 was ineffective on non-tumorigenic epithelial breast MCF-10A cells and Xenopus oocyte G2/M transition or embryonic development. Moreover, cancer cell lines showed autophagy markers including Beclin-1 accumulation and LC3-II formation. The DNA interaction of this new compound was evaluated and the dose-dependent topoisomerase I activity starting at 1 µM was confirmed using in vitro tests and has intercalation properties into DNA shown by melting curves and fluorescence measurements. Molecular modeling showed that the main interaction occurs with the aromatic ring but copper stabilizes the molecule before binding and so can putatively increase the potency as well. In this way, copper-derived indenoisoquinoline topoisomerase I inhibitor WN198 is a promising antitumorigenic agent for the development of future DNA-damaging treatments.

Efficient Synthesis for a Wide Variety of Patellamide Derivatives and Phosphatase Activity of Copper-Patellamide Complexes.

Copper complexes of patellamides have shown catalytic activity in a variety of reactions but their biological function remains unknown. There are significant differences between the natural macrocycles and synthetic analogues in the various catalytic activities. It therefore is essential to be able to perform in vivo and ex vivo reference measurements with the natural patellamide macrocycles, very similar derivatives and a large range of synthetic analogues. The preparative method described allows for a highly adaptable synthetic process producing building blocks for a large range of patellamide derivatives: apart from natural compounds, a new synthetic patellamide was prepared that does not have any substituents at any of the four heterocycles. Together with the variation of substituents at the aliphatic backbone, this allowed to elucidate the catalytic activity for phosphoester hydrolysis as a function of the structure and dynamics of the dicopper(II)-patellamide complexes, both by experiment and DFT-based mechanistic studies.

Synthesis, characterization, antioxidant, antileishmanial, anticancer, DNA and theoretical SARS-CoV-2 interaction studies of copper(II) carboxylate complexes.

Copper(II) carboxylate complexes [Cu2(OOCR)4L2] (1) and [Cu2(OOCR`)4OCO(R`)CuL2]n (2), where L = 2-methyl pyridine, R = 2-chlorophenyl acetate and R` = 2-fluorophenyl acetate were synthesized and characterized by FT-IR spectroscopy and single crystal X-ray analysis. Complex 1 exhibits the typical paddlewheel array of a dinuclear copper(II) complex with carboxylate ligands. In complex 2, this scaffold is further extended into a polymeric arrangement based on alternate paddlewheel and square planar moieties with distinct coordination spheres. The complexes showed better 2,2-diphenyl-1-picrylhydrazyl (DPPH) and hydroxyl radical scavenging activities and have been found to be more potent antileishmanial agents than their corresponding free ligand acid species. UV-Vis absorption titrations revealed good DNA binding abilities {Kb = 9.8 × 104 M-1 (1) and 9.9 × 104 M-1 (2)} implying partial intercalation of the complexes into DNA base pairs along with groove binding. The complexes displayed in vitro cytotoxic activity against malignant glioma U-87 (MG U87) cell lines. Computational docking studies further support complex-DNA binding by intercalation. Molecular docking investigations revealed probable interactions of the complexes with spike protein, the nucleocapsid protein of SARS-CoV-2 and with the angiotensin converting enzyme of human cells.

Electrocatalytic CO2 Reduction and H2 Evolution by a Copper (II) Complex with Redox-Active Ligand.

The process of electrocatalytic CO2 reduction and H2 evolution from water, regarding renewable energy, has become one of the global solutions to problems related to energy consumption and environmental degradation. In order to promote the electrocatalytic reactivity, the study of the role of ligands in catalysis has attracted more and more attention. Herein, we have developed a copper (II) complex with redox-active ligand [Cu(L1)2NO3]NO3 (1, L1 = 2-(6-methoxypyridin-2-yl)-6-nitro-1h-benzo [D] imidazole). X-ray crystallography reveals that the Cu ion in cation of complex 1 is coordinated by two redox ligands L1 and one labile nitrate ligand, which could assist the metal center for catalysis. The longer Cu-O bond between the metal center and the labile nitrate ligand would break to provide an open coordination site for the binding of the substrate during the catalytic process. The electrocatalytic investigation combined with DFT calculations demonstrate that the copper (II) complex could homogeneously catalyze CO2 reduction towards CO and H2 evolution, and this could occur with great performance due to the cooperative effect between the central Cu (II) ion and the redox- active ligand L1. Further, we discovered that the added proton source H2O and TsOH·H2O (p-Toluenesulfonic acid) could greatly enhance its electrocatalytic activity for CO2 reduction and H2 evolution, respectively.

Structures of Dimer-of-Dimers Type Defect Cubane Tetranuclear Copper(II) Complexes with Novel Dinucleating Ligands.

Only a limited number of multinucleating ligands can stably maintain multinuclear metal structures in aqueous solutions. In this study, a water-soluble dinucleating ligand, 2,6-bis{[N-(carboxylatomethyl)-N-methyl-amino]methyl}-4-methylphenolate ((sym-cmp)3-), was prepared and its copper(II) complexes were structurally characterized. Using the single-crystal X-ray diffraction method, their dimer-of-dimers type defect cubane tetranuclear copper(II) structures were characterized for [Cu4(sym-cmp)2Cl2(H2O)2] and [Cu4(sym-cmp)2(CH3O)2(CH3OH)2]. In the complexes, each copper(II) ion has a five-coordinate square-pyramidal coordination geometry. The coordination bond character was confirmed by the density functional theory (DFT) calculation on the basis of the crystal structure, whereby we found the bonding and anti-bonding molecular orbitals. From the cryomagnetic measurement and the magnetic analysis, overall antiferromagnetic interaction was observed, and this magnetic behavior is also explained by the DFT result. Judging from the molar conductance and the electronic spectra, the bridging chlorido ligand dissociates in water, but the dinuclear copper(II) structure was found to be maintained in an aqueous solution. In conclusion, the tetranuclear copper(II) structures were crystallographically characterized, and the dinuclear copper(II) structures were found to be stabilized even in an aqueous solution.

Effect of the hydroxamate group in the antitumoral activity and toxicity toward normal cells of new copper(II) complexes.

The synthesis, physico-chemical characterization and cytotoxicity of four copper(II) coordination complexes, i.e. [Cu(HBPA)Cl2] (1), [Cu(BHA)2] (2), [Cu(HBPA)(BHA)Cl] CH3OH (3) and [Cu(HBPA)2]Cl2·4H2O (4), are reported. HBPA is the tridentate ligand N-(2-hydroxybenzyl)-N-(2-pyridylmethyl)amine and HBHA is the benzohydroxamic acid. The reaction between the HBHA and CuCl2.2H2O has resulted in the new complex (2) and the reaction between complex (1) and HBHA has resulted in the new complex (3). X-ray diffraction studies for complex (3) indicated the effective coordination of HBHA as BHA-. Their cytotoxicity was evaluated against three human tumoral cell lines (Colo-205, NCI-H460 and U937) and PBMC (peripheral blood mononuclear cells), using the MTT cytotoxic assay. The results toward PBMC reveal that the new copper(II) complex (2) presents lower toxicity toward normal cells. Furthermore, complex (2) presents IC50 values lower than cisplatin toward NCI-H460 and the best selectivity index obtained towards NCI-H460 (SI = 2.2) and U937 cell lines (SI = 2.0), as a result of the presence of two molecules of HBHA in its structure. Complex (3) presents IC50 values lower than cisplatin toward NCI-H460, Colo-205 and comparable to cisplatin toward U937. The evaluation of the cell death type promoted by complexes (2) and (4) was investigated toward NCI-H460 revealing better results than the standard drug cisplatin, according to the Annexin V and propidium iodide (PI) labeling experiment. Based on the studies here performed, HBHA seems to be related to lower toxicity toward PBMC and HBPA is improving directly the cytotoxity.

Antiproliferative and antibacterial properties of biocompatible copper(II) complexes bearing chelating N,N-heterocycle ligands and potential mechanisms of action.

In an attempt to propose new applications for the biomedical field, complexes with mixed ligands {[Cu(bpy)2(µ2OClO3)]ClO4}n (1) and [Cu(phen)2(OH2)](ClO4)2 (2) (bpy: 2,2'-biyridine; phen and 1,10-phenantroline) were evaluated for their antibacterial and cytotoxicicity features and for the elucidation of some of the mechanisms involved. Complex (2) proved to be a very potent antibacterial agent, exhibing MIC and MBEC values 2 to 54 times lower than those obtained for complex (1) against both susceptible or resistant Gram-positive and Gram-negative strains, in planktonic or biofilm growth state. In exchange, complex (1) exhibited selective cytotoxicity against melanoma tumor cells (B16), proving a promising potential for developing novel anticancer drugs. The possible mechanisms of both antimicrobial and antitumor activity of the copper(II) complexes is their DNA intercalative ability coupled with ROS generation. The obtained results recommend the two complexes for further development as multipurpose copper-containing drugs.

Evaluation of catacholase mimicking activity and apoptosis in human colorectal carcinoma cell line by activating mitochondrial pathway of copper(II) complex coupled with 2-(quinolin-8-yloxy)(methyl)benzonitrile and 8-hydroxyquinoline.

To evaluate the cytotoxic potential of metal-based chemotherapeutic candidate towards the colorectal cancer, we have synthesized a new copper(II) complex [Cu(qmbn)(q)(Cl)] (1) (where, qmbn = 2-(quinolin-8-yloxy)(methyl)benzonitrile and q = 8-hydroxyquinoline) and structurally characterized by single crystal X-ray, Powder-XRD, FTIR and thermogravimetric analysis (TGA). The structural analysis reveals that copper(II) ions exist in a distorted square pyramidal (τ = ~0.1), with ligation of a chloride ion, oxygen atom and two nitrogen atoms at equatorial position and one oxygen atom at apical position. The cytotoxicity potential of complex 1 was executed against human colorectal cell lines (HCT116), which showed that 1 induces mitochondrion-mediated apoptotic cell death via activation of the Bax (pro-apoptotic protein) caspases-3 and 9 proteins. Interestingly, complex 1 was found to be a good candidate as electron-transfer catalyst which mimics catacholase with high turnover frequency (kcat = 1.03 × 102 h-1) for the conversion of the model substrate 3,5-di-tertbutylcatechol (3,5-DTBC) to 3,5-di-tertbutylquinone (3,5-DTBQ). Furthermore, molecular docking studies revealed that complex 1 was successfully localized inside the binding pocket of protein kinase (Akt), which validate the mechanism and mode of interaction of 1 that displayed cytotoxic activity experimentally. The obtained outcomes reveal that the complex 1 could be utilized as an encouraging perspective in the development of new therapeutic candidate for colon cancer.

Computational and experimental studies of Metallo organic framework on human epidermal cell line and anticancer potential.

The pentadentate ligand and the precursors were combined to form complexes by green approach. The ligand formation was confirmed by UV-Vis, FT-IR, 1H-NMR, and LC-MS. The optimised stable structure was obtained by molecular simulation studies and the complexes were interpreted by conductivity measurements, UV-Vis, FT-IR, magnetic susceptibility, VSM, and ESR spectral studies. The redox nature of the complexes was investigated by cyclic voltammetry. The cyclic voltammogram shows complexes exhibited single electron transfer from Cu+2/Cu+1. Complexes and penta-dentate ligand were screened for in vitro cytotoxicity by MTT assay method on A431 skin cancer cell line. The ligand structural stability and biological activity were confirmed by theoretical computational studies. The magnetic behaviour showed antiferromagnetic properties at low temperature. The complexes were used as high bar magnets. Similarly, the redox behaviour showed that the complexes could be used in electroplating techniques and sensors. Clinical application revealed that the complexes had effective cytotoxicity. From the data obtained, the complexes were in the form [MLR], where L was the penta-dentate ligand and R = [C6H5COO] & R = [C6H4COO (OH)].

Encapsulation of Synthesized Plant Growth Regulator Based on Copper(II) Complex in Chitosan/Alginate Microcapsules.

A new copper complex, trans-diaqua-trans-bis [1-hydroxy-1,2-di (methoxycarbonyl) ethenato] copper (abbreviation Cu(II) complex), was synthesized and its plant growth regulation properties were investigated. The results show a sharp dependence of growth regulation activity of the Cu(II) complex on the type of culture and its concentration. New plant growth regulator accelerated the development of the corn root system (the increase in both length and weight) but showed a smaller effect on the development of the wheat and barley root systems. Stimulation of corn growth decreased with increasing Cu(II) complex concentration from 0.0001% to 0.01% (inhibition at high concentrations-0.01%). The development of corn stems was also accelerated but to a lesser extent. Chitosan-coated calcium alginate microcapsules suitable for delivery of Cu(II) complex to plants were prepared and characterized. Analysis of the FTIR spectrum showed that complex molecular interactions between functional groups of microcapsule constituents include mainly electrostatic interactions and hydrogen bonds. Microcapsules surface exhibits a soft granular surface structure with substructures consisting of abundant smaller particles with reduced surface roughness. Release profile analysis showed Fickian diffusion is the rate-controlling mechanism of Cu(II) complex releasing. The obtained results give new insights into the complexity of the interaction between the Cu(II) complex and microcapsule formulation constituents, which can be of great help in accelerating product development for the application in agriculture.

Influence of Complexation of Thiosemicarbazone Derivatives with Cu (II) Ions on Their Antitumor Activity against Melanoma Cells.

A series of thiosemicarbazone derivatives was prepared and their anti-tumor activity in vitro was tested. The X-ray investigation performed for compounds T2, T3 and T5 confirmed the synthesis pathway and assumed molecular structures of analyzed thiosemicarbazones. The conformational preferences of the thiosemicarbazone system were characterized using theoretical calculations by AM1 method. Selected compounds were converted into complexes of Cu (II) ions. The effect of complexing on anti-tumor activity has been investigated. The copper(II) complexes, with Schiff bases T1, T10, T12, T13, and T16 have been synthesized and characterized by chemical and elemental analysis, FTIR spectroscopy and TGA method. Thermal properties of coordination compounds were studied using TG-DTG techniques under dry air atmosphere. G361, A375, and SK-MEL-28 human melanoma cells and BJ human normal fibroblast cells were treated with tested compounds and their cytotoxicity was evaluated with MTT test. The compounds with the most promising anti-tumour activity were then selected and their cytotoxicity was verified with cell cycle analysis and apoptosis/necrosis detection. Additionally, DNA damages in the form of a basic sites presence and the expression of oxidative stress and DNA damage response genes were evaluated. The obtained results indicate that complexation of thiosemicarbazone derivatives with Cu (II) ions improves their antitumor activity against melanoma cells. The observed cytotoxic effect is associated with DNA damage and G2/M phase of cell cycle arrest as well as disorders of the antioxidant enzymes expression.

Synthesis, Characterization, DNA/HSA Interactions, and Anticancer Activity of Two Novel Copper(II) Complexes with 4-Chloro-3-Nitrobenzoic Acid Ligand.

The purpose of this study was to identify new metal-based anticancer drugs; to this end, we synthesized two new copper(II) complexes, namely [Cu(ncba)4(phen)] (1) and [Cu(ncba)4(bpy)] (2), comprised 4-chloro-3-nitrobenzoic acid as the main ligand. The single-crystal XRD approach was employed to determine the copper(II) complex structures. Binding between these complexes and calf thymus DNA (CT-DNA) and human serum albumin (HSA) was explored by electronic absorption, fluorescence spectroscopy, and viscometry. Both complexes intercalatively bound CT-DNA and statically and spontaneously quenched DNA/HSA fluorescence. A CCK-8 assay revealed that complex 1 and complex 2 had substantial antiproliferative influences against human cancer cell lines. Moreover, complex 1 had greater antitumor efficacy than the positive control cisplatin. Flow cytometry assessment of the cell cycle demonstrated that these complexes arrested the HepG2 cell cycle and caused the accumulation of G0/G1-phase cells. The mechanism of cell death was elucidated by flow cytometry-based apoptosis assays. Western blotting revealed that both copper(II) complexes induced apoptosis by regulating the expression of the Bcl-2(Bcl-2, B cell lymphoma 2) protein family.

Biological Activity of Triazolopyrimidine Copper(II) Complexes Modulated by an Auxiliary N-N-Chelating Heterocycle Ligands.

Novel complexes of type [Cu(N-N)(dmtp)2(OH2)](ClO4)2·dmtp ((1) N-N: 2,2'-bipyridine; (2) L: 1,10-phenantroline and dmtp: 5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine) were designed in order to obtain biologically active compounds. Complexes were characterized as mononuclear species that crystallized in the space group P-1 of the triclinic system with a square pyramidal geometry around the copper (II). In addition to the antiproliferative effect on murine melanoma B16 cells, complex (1) exhibited low toxicity on normal BJ cells and did not affect membrane integrity. Complex (2) proved to be a more potent antimicrobial in comparison with (1), but both compounds were more active in comparison with dmtp-both against planktonic cells and biofilms. A stronger antimicrobial and antibiofilm effect was noticed against the Gram-positive strains, including methicillin-resistant Staphylococcus aureus (MRSA). Both electron paramagnetic resonance (EPR) and Saccharomyces cerevisiae studies indicated that the complexes were scavengers rather than reactive oxygen species promoters. Their DNA intercalating capacity was evidenced by modifications in both absorption and fluorescence spectra. Furthermore, both complexes exhibited nuclease-like activity, which increased in the presence of hydrogen peroxide.

In vitro and in vivo antitumoral activity of a ternary copper (II) complex.

Recently, a high number of copper derivatives has been evaluated as DNA-targeting metallodrugs, due to the lower toxicity and its potential to cleave DNA. Several strategies have been testing to develop metal compounds effective against tumour cells. In this work, the ternary copper (doxycycline)-(1,10-phenanthroline) complex [Cu(dox)(phen)]2+ was especially designed as an antitumoral drug, previously showing high cytotoxicity and DNA cleavage activity. We aimed to further investigate the in vitro cytotoxic activity in both tumoral and non-tumoral cells, in vitro genotoxic potential, and in vivo antitumor activity using BALB/C mouse injected with sarcoma S180 and Ehrlich cell lines. Our results indicated that this compound exhibits a moderate genotoxic potential, with selective growth inhibition of tumor cells, especially the murine melanoma B16F10. Its main mechanism of action seems to be through ROS generation. We have further shown a significant reduction of the implanted tumor size in the animal model, suggesting that this compound has great antitumoral potential against many tumor types. [Cu(dox)(phen)]2+ is selectively cytotoxic for melanoma B16F10 and showed high chemotherapeutic potential in vivo against implanted sarcoma S180 and Ehrlich ascites tumours.

Copper(II) Complexes with Mixed Heterocycle Ligands as Promising Antibacterial and Antitumor Species.

Complexes with mixed ligands [Cu(N-N)2(pmtp)](ClO4)2 ((1) N-N: 2,2'-bipyridine; (2) L: 1,10-phenanthroline and pmpt: 5-phenyl-7-methyl-1,2,4-triazolo[1,5-a]pyrimidine) were synthesized and structurally and biologically characterized. Compound (1) crystallizes into space group Pa and (2) in P-1. Both complexes display an intermediate stereochemistry between the two five-coordinated ones. The biological tests indicated that the two compounds exhibited superoxide scavenging capacity, intercalative DNA properties, and metallonuclease activity. Tests on various cell systems indicated that the two complexes neither interfere with the proliferation of Saccharomyces cerevisiae or BJ healthy skin cells, nor cause hemolysis in the active concentration range. Nevertheless, the compounds showed antibacterial potential, with complex (2) being significantly more active than complex (1) against all tested bacterial strains, both in planktonic and biofilm growth state. Both complexes exhibited a very good activity against B16 melanoma cells, with a higher specificity being displayed by compound (1). Taken together, the results indicate that complexes (1) and (2) have specific biological relevance, with potential for the development of antitumor or antimicrobial drugs.

DNA cleavage, DNA/HSA binding study, and antiproliferative activity of a phenolate-bridged binuclear copper(II) complex.

A novel phenolate-bridged binuclear copper(II) complex, [Cu 2II (L-3H)Cl] (1, where L = 2,6-bis[((2-hydroxybenzyl)(2-pyridylmethyl)amino)methyl]-4-methylphenol), have been synthesized and characterized. The antiproliferative activity of the complex has been tested in vitro against the human cervical cancer cell line HeLa, human non-small-cell lung cancer cell line A-549, the human breast cancer cell line MCF-7, and the human hepatic cell line LO2. The results show the complex has the low micromolar range (9.4-11.2 µM) of IC50 values towards the three cancer cell lines, which is markedly comparable to those of cisplatin. However 1 exhibited 10.6-fold less toxicity than cisplatin toward normal cells LO2, suggesting that complex 1 had high selectivity between tumor cells and normal cells. The interactions with DNA were investigated by UV-Vis absorption, fluorescence, circular dichroism, and gel electrophoresis. The results show that the copper(II) complex could strongly bind to DNA mainly by the groove binding mode and efficiently cleave the pBR322 plasmid DNA into its nicked and linear forms in the presence of excessive ascorbic acid. In addition, the evaluation of the protein binding ability shows that complex 1 could bind to human serum albumin (HSA) with a moderate binding affinity and quench the intrinsic fluorescence of HSA.

Synthesis, characterization, and in vitro effect of the Cu(II) complex with niflumic acid and 3-picoline on paraoxanase-I.

Niflumic acid is used to treat inflammatory rheumatoid diseases, pain, and fever. The present study reports the experimental, spectroscopic, thermal, structural analyses, and biological activities of this complex. The nonsteroidal anti-inflammatory drug niflumic acid, 3-picoline, and copper(II) chloride were utilized to synthesize a new complex: [Cu2 Cl 2 (nif) 2 (3-pic) 4 ]. The crystal structure of [Cu 2 Cl 2 (nif) 2 (3-pic) 4 ] was determined by X-ray crystallography. The complex crystallizes in the triclinic space group P-1 and each Cu(II) center displayed six-coordinated distorted octahedral geometry. Two Cu(II) centers are connected by a chloro-bridge to form the binuclear metal core. Finally, the in vitro effects of the synthesized new complex and free niflumic acid were evaluated on the human serum paraoxonase 1 enzyme. At low doses, both the new complex and free niflumic acid showed very good inhibition activity with different inhibition mechanisms. In addition, the results showed that the new complex has more inhibition activity than free niflumic acid.

Syntheses, Crystal Structures, and Antitumor Activities of Copper(II) and Nickel(II) Complexes with 2-((2-(Pyridin-2-yl)hydrazono)methyl)quinolin-8-ol.

Two transition metal complexes with 2-((2-(pyridin-2-yl)hydrazono)methyl)quinolin-8-ol (L), [Cu(L)Cl2]2 (1) and [Ni(L)Cl2]·CH2Cl2 (2), were synthesized and fully characterized. Complex 1 exhibited high in vitro antitumor activity against SK-OV-3, MGC80-3 and HeLa cells with IC50 values of 3.69 ± 0.16, 2.60 ± 0.17, and 3.62 ± 0.12 µM, respectively. In addition, complex 1 caused cell arrest in the S phase, which led to the down-regulation of Cdc25 A, Cyclin B, Cyclin A, and CDK2, and the up-regulation of p27, p21, and p53 proteins in MGC80-3 cells. Complex 1 induced MGC80-3 cell apoptosis via a mitochondrial dysfunction pathway, as shown by the significantly decreased level of bcl-2 protein and the loss of Δψ, as well as increased levels of reactive oxygen species (ROS), intracellular Ca2+, cytochrome C, apaf-1, caspase-3, and caspase-9 proteins in MGC80-3 cells.