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In 1983, Linus Pauling and colleagues reported about enhanced antitumor activity of the Cu(II) complex of the simplest ATCUN (amino terminal Cu(II) and Ni(II)-binding motif) peptide (NH 2 -Gly-Gly-His-COOH, GGH) in the presence of ascorbate as an additive. In the following 4 decades, structural modifications of this complex were implemented, however, anticancer activity could not be significantly increased. This has led to neglecting the ATCUN motif and its Cu(II) complexes as potential chemotherapeutic agents. Furthermore, the addition of ascorbate with its positive effect on the anticancer activity has fallen into oblivion. In this work, we compared Cu(II) GGH with Cu(II) ATCUN peptides bearing β-Ala instead of Gly at the 2nd position of the peptide sequence regarding their in vitro complex stability and cytotoxicity (MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and annexin V-FITC (fluorescein isothiocyanate) apoptosis assay) towards three cancer cell lines (AGS, HeLa and NCI-N87). Such an exchange of amino acids led to an up to three-fold higher cytotoxic effect in the presence of ascorbate. We thus achieved a significant increase in the otherwise moderate cytotoxicity of Cu(II) ATCUN-like complexes. Lipophilicity assays (n-octanol/water coefficient, log P values) of the studied complexes were used to evaluate differences in the antiproliferative activity., Competing Interests: Declarations. Conflict of interests: The authors declare no competing interests. Ethical approval: N/A., (© 2024. The Author(s).)

The main aim of the study was to investigate the molecular mechanism of action of the potentially anti-cancer agent copper(II) complex with 1-allylimidazole [Cu(1-allim) 4 (NO 3 ) 2 ] using the A549 lung cancer line, toward which it is selectively cytotoxic. Gene expression analysis showed that the complex caused apoptosis through WNT, JAK-STAT, and TGF-β pathways. The complex induced DNA damage, ROS production, and depolarization of the mitochondrial membrane, suggesting that its toxicity is likely due to induction of the intrinsic apoptosis pathway. It also arrested the cell cycle at G2/M phase. Particularly noteworthy is that it inhibited the WNT pathway, a target for lung cancer therapies. Its complex mechanism of action may hinder the acquisition of immunity by cancer cells., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024. Published by Elsevier Inc.)

Copper metalloenzymes ascorbate oxidase (AOase), amine oxidase (AmOase), and catechol oxidase (COase) possess copper(II) sites of coordination, which are trimeric, homodimeric, and dimeric, respectively. Two newly mononuclear copper(II) complexes, namely, [Cu(L)(bpy)](ClO 4 ) (1) and [Cu(L)(phen)](ClO 4 ) (2) where HL = Schiff base, have been synthesized. UV-visible, EPR and single-crystal X-ray diffraction examinations were used to validate the geometry in solution and solid state. For complex 1, the metal exhibits a coordination sphere between square pyramidal and trigonal bipyramidal geometry (τ, 0.49). A positive Cu II / I redox potential indicates a stable switching between Cu II and Cu I redox states. Despite the monomeric origin, both homogeneous catalysts (1 or 2) in MeOH were found to favor three distinct chemical transformations, namely, ascorbic acid (H 2 A) to dehydroascorbic acid (DA), benzylamine (Ph-CH 2 -NH 2 ) to benzaldehyde (Ph-CHO), and 3,5-di-tert-butylcatechol (3,5-DTBC) to 3,5-di-tert-butylquinone (3,5-DTBQ) [k cat : AOase, 9.6 (1) or 2.0 × 10 6  h -1 (2); AmOase, 13.4 (1) or 9.4 × 10 6  h -1 (2); COase, 2.0 (1) or 1.9 × 10 3  h -1 (2)]. They exhibit higher levels of AOase activity as indicated by their k cat values compared to the AOase enzyme. The k cat values for COase activity in buffer solution [5.93 (1) or 2.95 × 10 5  h -1 (2)] are one order lower than those of the enzymes. This is because of the labile nature of the coordinated donor, the flexibility of the ligand, the simplicity of the catalyst-substrate interaction, and the positive Cu II / I redox potential. Interestingly, more efficient catalysis is promoted by 1 and 2 concerning that of other mono- and dicopper(II) complexes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

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-NH 2 ), tau(385-390) (Ac-KTDHGA-NH 2 ) and tau(404-409) (Ac-SPRHLS-NH 2 ). 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 H 2 O 2 , the fragmentation of peptides was detected in all cases. In the simultaneous presence of H 2 O 2 and ascorbic acid, the fragmentation of the peptide is less preferred, and the formation of 2-oxo-histidine also occurs., Competing Interests: The authors declare no conflicts of interest.

This article deals with the experimental and theoretical evaluations of N-pyridoxal-salicylic acid hydrazide (H 2 pd-sah) 1 and its mixed-ligand copper(II) complex with 2-methylimidazole, [Cu(pd-sah)(MeImdH)] 2 . The compounds were characterized based on spectral (UV/Vis. IR) methods, powder-XRD, elemental analysis, and molar conductivity measurements. Both compounds' molecular structure and charge analysis were computed through B3LYP with 6-311 G (d, p) and LANL2DZ basic set using the Gaussian 09 W program package. The time-dependent density functional theory (TD-DFT) approach is used in gas-phase electronic transitions of 2 using the LANL2DZ basis set. Also, the computed UV-Vis based upon TD-DFT results and IR spectra were simulated for comparison with the experimental ones. The molecular structure based on theoretical investigation reveals that compound 2 adopts a distorted square planer N 2 O 2 coordination sphere around the Cu(II). The ONO donor atoms of hydrazone moiety and one nitrogen of 2-methylimidazole constitute the N 2 O 2 basal plane. Moreover, the in-vitro antioxidant activity was evaluated by DPPH assay in both compounds. In addition, Molecular docking studies were performed to predict the binding interaction between compound 2 and the Human Serum Albumin HSA (PDB ID: 1H9Z).Communicated by Ramaswamy H. Sarma.

Background: Intrinsic resistance of cancer cells is a major concern for the success of chemotherapy, and this undesirable feature stimulates further research into the design of new compounds and/or alternative multiple drug chemotherapy protocols., Methods: In this study, we investigated the antitumoral potential of the coordination compounds [Cu(HPClNOL)Cl]Cl (1), [Fe(HPClNOL)Cl 2 ]NO 3 (2) and [Mn(HPClNOL)Cl 2 ] (3). Using the human, MCF-7 and A549, and the murine melanoma, B16-F10, cell lines, we determined the cytotoxicity, DCFH oxidation, disruption of mitochondrial membrane potential (ΔΨm), Sub-G1 and TUNEL positive cells, and caspase 8 and 9 activities. Fractional inhibitory concentration (FIC) and xenograft models were also assessed to evaluate the efficacy of antitumoral potential., Results: We observed that only complex 1 was cytotoxic. The treatment of cancer cells with complex 1 triggered ROS generation and promoted the disruption of ΔΨm. Complex 1 increased the number of Sub-G1 and TUNEL positive cells, and the measurement of caspase 8 and 9 activity confirmed that apoptosis was triggered by the intrinsic pathway. FIC demonstrated that the combination of complex 1 with cisplatin was additive for the A549 cells whilst it was synergic for MCF-7 and B16-F10. Treatment with complex 1, either alone or combined with cisplatin, reduced tumor growth on xenograft models., Conclusions: The present study brings new clues regarding the mechanism of action of [Cu(HPClNOL)Cl]Cl, either alone or in combination with cisplatin., General Significance: These results indicate that complex 1, administered either singly or in combination with current drugs, has real potential for use in cancer therapy., (Copyright © 2021. Published by Elsevier B.V.)

Chemotherapy continues to be the most commonly applied strategy for cancer. Despite the impressive clinical success obtained with several drugs, increasing numbers of (multi)drug-resistant tumors are reported. To overcome this shortcoming, novel drug candidates and delivery systems are urgently needed. Herein, a therapeutic copper polypyridine complex encapsulated in natural nanocarrier apoferritin is reported. The generated nanoparticles showed higher cytotoxicity toward various (drug-resistant) cancer cell lines than noncancerous cells. The study of the mechanism revealed that the compound triggers cell autophagy-dependent apoptosis. Promisingly, upon injection of the nanodrug conjugate into the bloodstream of a mouse model bearing a multidrug-resistant colon tumor, a strong tumor growth inhibition effect was observed. To date, this is the first study describing the encapsulation of a copper complex in apoferritin that acts by autophagy-dependent apoptosis.

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.

The synthesis, physico-chemical characterization and cytotoxicity of four copper(II) coordination complexes, i.e. [Cu(HBPA)Cl 2 ] (1), [Cu(BHA) 2 ] (2), [Cu(HBPA)(BHA)Cl] CH 3 OH (3) and [Cu(HBPA) 2 ]Cl 2 ·4H 2 O (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 CuCl 2 .2H 2 O 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 IC 50 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 IC 50 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.

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.

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 (k cat  = 1.03 × 10 2 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., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Complexes with mixed ligands [Cu(N-N) 2 (pmtp)](ClO 4 ) 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.

The interaction of Cu(NO 3 ) 2 ·3H 2 O with the sulfonyl o-pyridine carboxamidoxime N'-(4-nitrophenylsulfonyloxy)picolinimidamide (L) resulted in the mononuclear complex [Cu(L 1 ) 2 ](L 2 ) 2 (1), where L 1  = pyridine-2-carboxamidine ligand and (L 2 ) - = 4-nitrobenzenesulfonate anion derived from the homolytic cleavage of the NO bond of L. The complex was characterized by diverse techniques including single-crystal X-ray crystallography. From the antimicrobial tests performed, complex 1 seems to be active against gram-negative bacterial strains. The complex binds tightly and reversibly to serum albumins and tightly to calf-thymus DNA via an intercalative mode and also via electrostatic interactions (as expected due to its cationic nature). Additionally, it interacts with (pBluescriptSK(+)) plasmid DNA in a concentration-dependent manner. The results from the present in silico molecular modeling simulations provide useful complementary insights for the elucidation of the mechanism of action of the studied complex at a molecular level. Molecular modeling calculations provide a molecular basis for the understanding of both the impairment of DNA by its binding with the studied complex and the ability of this compound to act as an antibacterial agent, most probably by its activity against DNA-gyrase, as well as for transportation through serum albumins and possible interaction with other protein targets involved in various diseases., Competing Interests: Declaration of competing interest There are no conflicts to declare., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Mcl-1 is an anti-apoptotic member of Bcl-2 family proteins. The development of inhibitors of Mcl-1 has been challenging. To develop metal-based Mcl-1inhibitors, twenty two copper(II) complexes 25-46 with 9-substituted β-carboline derivatives were reported. Complexes 38 and 39 showed higher cytotoxicity than the corresponding ligands or cisplatin. The most potent complex 39 presented higher selectivity to Mcl-1 than other Bcl-2 family proteins, and killed cancer cells via Bax/Bak mediated apoptosis. Complex 39 showed an excellent safety profile in mouse model, and significantly inhibited the tumor growth in NCI-H460 tumor bearing model, which is more potent than AZD5991 at the same dosage. Complex 39 prolonged the survival time of the tumor bearing mice. Complex 39 is the first metal-based Mcl-1 inhibitor acting as a potential anticancer agent., (Crown Copyright © 2019. Published by Elsevier Masson SAS. All rights reserved.)

In an attempt to enhance the previously observed antiproliferative capacity of 1-(p-toluenesulfonyl)cytosine (N-1-tosylcytosine, ligand 1), its copper(II) complex (Cu(1-TsC-N3) 2 Cl 2 , complex 2) was prepared and tested in vitro on various carcinoma and leukemia cells. The comparative in vitro studies using the ligand 1, the complex 2, CuCl 2 x2H 2 O salt (salt 3) and the 1:2 mixture of the salt 3 and ligand 1 (mixture 4) were performed on normal (WI38), human carcinoma (HeLa, CaCo2, MiaPaCa2, SW620), lymphoma (Raji) and leukemia (K562) cell lines. Significantly elevated concentration of the intracellular copper after treatment of K562 cells and HeLa cells during 2h with complex 2 (7.83 vs. 5.4 times) was detected by atomic absorption spectroscopy. Cytotoxicity was analyzed by MTT assay. We found that antiproliferative capacity of the tested compounds varies (IC 50 after 72h of exposure: 0.6×10 -6 M to>100×10 -6 M). Leukemia and lymphoma cells were found the most sensitive to complex 2 which showed more than 100 times higher in vitro activity against K562 cells than ligand 1. Apoptotic morphological changes, an externalization of phosphatydilserine, and changes in the mitochondrial membrane potential of treated cells were found. The caspase-3 activity in HeLa and K562 cells was measured by caspase-3 colorimetric assay kit. Caspase-3 was not activated in the treated K562 cells while salt 3 and the mixture 4 in the HeLa cells significantly increased tested enzyme activity. These findings suggest that copper(II) in the molecular complex 2 by improving entry of the N-1-tosylcytosine 1 into cells increases its antiproliferative capacity. In summary, the present study demonstrated that complex 2 possesses an antileukemic effect on K562 cells, and its anticancer activity was attributed with induction of apoptosis. The exact mechanism of apoptosis induction by complex 2 must be further investigated., (Copyright © 2017 Elsevier GmbH. All rights reserved.)

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: [Cu 2 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., (© 2019 Deutsche Pharmazeutische Gesellschaft.)

A new copper(II) complex, [Cu(pse)(phen)Cl 2 ]; in which phen = 1,10-phenanthroline and pse = pseudoephedrine hydrochloride drug; was synthesized and characterized by FT-IR, Mass and UV-Vis spectroscopy in combination with computational methods. Binding interaction of this complex with calf thymus DNA (ct-DNA) has been investigated by absorption, emission, circular dichroism, molecular docking and viscosity measurements. The complex displays significant binding properties of ct-DNA. The results of fluorescence and UV-Vis absorption spectroscopy indicated that, this complex interacted with ct-DNA in a groove-binding mode, and the binding constant was 8 × 10 4 L mol -1 . Competitive fluorimetric studies with Hoechst 33258 have shown that Cu(II) complex exhibit the ability to displace the DNA-bound Hoechst 33258 indicating that it binds to DNA in strong competition with Hoechst 33258 for the groove binding. Furthermore, the complex induces detectable changes in the CD spectrum of ct-DNA and does not induce any changes in DNA viscosity which verified the groove-binding mode. The molecular modeling results illustrated that the complex strongly binds to groove of DNA by relative binding energy of docked structure (-27.61 kJ mol -1 ).

Five new copper(II) acrylate complexes (acr is the acrylate anion: C₃H₃O₂) with imidazole derivatives (2-methylimidazole/2-MeIm, 5-methylimidazole/5-MeIm, 2-ethylimidazole/2-EtIm) of type: cis -[Cu(2-RIm)₂(acr)₂]·xH₂O (( 1 ): R = ⁻CH₃, x = 2; ( 4 ): R = ⁻CH₂⁻CH₃, x = 0), trans -[Cu(2-RIm)₂(acr)₂] (( 2 ): R = ⁻CH₃; ( 5 ): R = ⁻CH₂⁻CH₃) and trans -[Cu(5-RIm)₂(acr)₂] (( 3 ): R = ⁻CH₃) have been prepared and characterized by elemental analysis, Fourier Transform Infrared spectrometry (FTIR), Electron Paramagnetic Resonance (EPR), electronic reflectance spectroscopy, scanning electron microscopy, and mass spectrometry. The single crystal X-ray diffraction study of complexes ( 2 ) and ( 5 ) reveals that the copper(II) ion is located on an inversion center and show elongated octahedral geometry completed by two coplanar bidentate acrylates and two unidentate imidazole derivatives displayed in trans positions. For complex ( 4 ) the single crystal X-ray diffraction shows that the copper(II) ion is in a distorted octahedral environment which can be easily confused with a trigonal prism completed by two bidentate acrylates and two unidentate imidazole derivatives displayed in cis positions. These results indicate the fact that complexes ( 4 ) and ( 5 ) are the geometric isomers of the same compound bis(acrylate)-bis(2-ethylimidazole)-copper(II). Complexes ( 1 ) and ( 2 ), as well as ( 4 ) and ( 5 ), were produced simultaneously in the reaction of the corresponding copper(II) acrylate with imidazole derivatives in methanol solution. Furthermore, in order to be able to formulate potential applications of the obtained compounds, our next goal was to investigate the in vitro antimicrobial activity of the synthesized complexes against Gram-positive and Gram-negative bacteria, as well as fungal strains, of both clinical and ecological importance (biodeterioration of historical buildings). The trans isomers ( 2 ) and ( 5 ), followed by ( 4 ) have shown the broadest range of antimicrobial activity. In case of ( 1 ) and ( 2 ) isomers, the trans isomer ( 2 ) was significantly more active than cis ( 1 ), while the cis isomer ( 4 ) proved to be more active than trans ( 5 ). Taken together, the biological evaluation results indicate that the trans ( 2 ) was the most active complex, demonstrating its potential for the development of novel antimicrobial agents, with potential applications in the biomedical and restoration of architectural monuments fields.

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 IC 50 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 Ca 2+ , cytochrome C, apaf-1, caspase-3, and caspase-9 proteins in MGC80-3 cells.

A copper(II) complex [Cu II (quamol)Cl]·H 2 O, where H(quamol) is N-2-(quinolyl-methylidene)aminophenol, has been isolated. The solution structure of the complex has been assessed to be distorted square-planar. The complex displays a ligand field band in the visible region (608nm) and also show axial EPR spectrum in DMF at 77K with g || >g ⊥ indicating a d x 2 -y 2 ground state. The g || and A || values of 2.265 and 153×10 -4 cm -1 , respectively, conform to a square-based CuN 2 OCl chromophore. The interaction of the complex with calf thymus (CT) DNA has been explored by using absorption (K b =2.48×10 5 M -1 ), emission (K app =7.72×10 4 M -1 ) and circular dichroic (CD) spectral measurements, which reveals that a complex interacts strongly with DNA through partial intercalation. The electrochemical studies indicate that Cu(II) binds to DNA more strongly than Cu(I). It cleaves ϕX174 supercoiled phage DNA in the presence of ascorbic acid as a reducing agent. Meanwhile, the interaction of the complex with bovine serum albumin (BSA) indicates that the complex can markedly quench the intrinsic fluorescence of BSA via a static quenching process and cause its conformational change. Interestingly, the observed IC 50 values for the cell lines EVSA-T (breast cancer) and M19 MEL (melanoma) are in the range of those observed with cisplatin while M19 MEL cancer cell line, complex is more active than 5-fluorouracil. The complex is non-toxic to healthy cells., (Copyright © 2017 Elsevier B.V. All rights reserved.)

In this study, the interaction between human serum albumin (HSA) and a copper complex of carmoisine dye; [Cu(carmoisine) 2 (H 2 O) 2 ], was studied in vitro using multi-spectroscopic methods. It was found that the intrinsic fluorescence of HSA was quenched by the addition of the [Cu(carmoisine) 2 (H 2 O) 2 ] complex and the quenching mechanism was considered as static quenching by formation of a [Cu(carmoisine) 2 (H 2 O) 2 ]-HSA complex. The binding constant was about 10 4  M -1 at room temperature. The values of the calculated thermodynamic parameters (ΔH < 0 and ΔS > 0) suggested that both hydrogen bonds and the hydrophobic interactions were involved in the binding process. The site marker competitive experiments revealed that the binding of [Cu(carmoisine) 2 (H 2 O) 2 ] to HSA primarily occurred in subdomain IIIA (site II) of HSA. The results of circular dichroism (CD) and UV-vis spectroscopy showed that the micro-environment of amino acid residues and the conformation of HSA were changed after addition of the [Cu(carmoisine) 2 (H 2 O) 2 ] complex. Finally, the binding of the [Cu(carmoisine) 2 (H 2 O) 2 ] complex to HSA was modelled by a molecular docking method. Excellent agreement was obtained between the experimental and theoretical results with respect to the binding forces and binding constant., (Copyright © 2017 John Wiley & Sons, Ltd.)

Ultraviolet-visible, emission and circular dichroism spectroscopic methods were used in transfer RNA (tRNA) interaction studies performed for polyethyleneimine-copper(II) complexes [Cu(phen)(l-Tyr)BPEI]ClO 4 (where phen =1,10-phenanthroline, l-Tyr = l-tyrosine and BPEI = branched polyethyleneimine) with various degrees of coordination (x = 0.059, 0.149, 0.182) in the polymer chain. The results indicated that polyethyleneimine-copper(II) complexes bind with tRNA mostly through surface binding, although other binding modes, such as hydrogen bonding and van der Waals interactions, might also be present. Dye-exclusion, sulforhodamine B and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays of a polyethyleneimine-copper(II) complex with a higher degree of coordination against different cancer cell lines proved that the complex exhibited cytotoxic specificity and a significant cancer cell inhibition rate. Antimicrobial screening showed activity against some human pathogens., (Copyright © 2016 John Wiley & Sons, Ltd.)

Tuberculosis (TB) is a disease caused by Mycobacterium tuberculosis . Cessation of treatment before the recommended conclusion may lead to the emergence of multidrug-resistant strains. The aim of this study was to develop nanostructured lipid carriers (NLCs) for use in the treatment of M. tuberculosis . The NLCs comprised the following lipid phase: 2.07% polyoxyethylene 40 stearate, 2.05% caprylic/capric triglyceride, and 0.88% polyoxyl 40 hydrogenated castor oil; the following aqueous phase: 3.50% poloxamer 407 (F1-F6), and 0.50% cetyltrimethylammonium bromide (F7-F12); and incorporated the copper(II) complexes [CuCl 2 (INH) 2 ]·H 2 O (1), [Cu(NCS) 2 (INH) 2 ]·5H 2 O (2), and [Cu(NCO) 2 (INH) 2 ]·4H 2 O (3) to form compounds F11.1, F11.2, and F11.3, respectively. The mean diameter of F11, F11.1, F11.2, and F11.3 ranged from 111.27±21.86 to 134.25±22.72 nm, 90.27±12.97 to 116.46±9.17 nm, 112.4±10.22 to 149.3±15.82 nm, and 78.65±6.00 to 122.00±8.70 nm, respectively. The polydispersity index values for the NLCs ranged from 0.13±0.01 to 0.30±0.09. The NLCs showed significant changes in zeta potential, except for F11.2, with F11, F11.1, F11.2, and F11.3 ranging from 18.87±4.04 to 23.25±1.13 mV, 17.03±1.77 to 21.42±1.87 mV, 20.51±1.88 to 22.60±3.44 mV, and 17.80±1.96 to 25.25±7.78 mV, respectively. Atomic force microscopy confirmed the formation of nanoscale spherical particle dispersions by the NLCs. Differential scanning calorimetry determined the melting points of the constituents of the NLCs. The in vitro activity of copper(II) complex-loaded NLCs against M. tuberculosis H 37 R v showed an improvement in the anti-TB activity of 55.4, 27.1, and 41.1 times the activity for complexes 1, 2, and 3, respectively. An in vivo acute toxicity study of complex-loaded NLCs demonstrated their reduced toxicity. The results suggest that NLCs may be a powerful tool to optimize the activity of copper(II) complexes against M. tuberculosis ., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

The possibility to influence the physiological concentration of copper ions through the careful choice of ligands is emerging as a novel intriguing strategy in the treatment of pathologies such as cancer and Alzheimer. Thiosemicarbazones play an important role in this field, because they offer a wide variety of potential functionalizations and different kinds of coordination modes. Here we report the synthesis of some 8-hydroxyquinoline thiosemicarbazone ligands containing an ONN'S donor set and their Zn(II) and Cu(II) complexes. The metal complexes were characterized in solution and in the solid state and the X-ray structure of one of the copper(II) complex is reported. The Cu(II) complexes were characterized also by means of quantum mechanical calculations. The Cu(II) complexes displayed cytostatic activity in different cancer cell models. In particular, the most active Cu(II) complex significantly inhibited cell proliferation with an IC 50 value lower than 1 μM; this effect was associated with a block of the cell cycle in the G 2 /M phase. This Cu(II) complex induced neither the production of reactive oxygen species (ROS) nor the accumulation of p53 protein, suggesting the lack of DNA damage., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

The interaction of a new macrocyclic copper complex, [CuL(NO 3 ) 2 ] in which L is 1,3,6,10,12,15-hexaaza tricyclo[13.3.1.1 6,10 ] eicosane was investigated in vitro under simulated physiological conditions by multi-spectroscopic techniques and molecular modeling study. The fluorescence spectroscopy and UV absorption spectroscopy indicated the complex interacted with ct-DNA in a groove binding mode while the binding constant of UV-vis and the number of binding sites were 1.0±0.2×10 4 Lmol -1 and 1.01, respectively. The fluorometric studies showed that the reaction between the complex with ct-DNA is exothermic (ΔH=14.85kJmol -1 ; ΔS=109.54Jmol -1 K -1 ). Circular dichroism spectroscopy (CD) was employed to measure the conformational change of DNA in the presence of [CuL(NO 3 ) 2 ] complex. Furthermore, the complex induces detectable changes in the viscosity of DNA. The molecular modeling results illustrated that the complex strongly binds to groove of DNA. Experimental and molecular modeling results showed that Cu(II) complex bound to DNA by a groove binding mode., (Copyright © 2016 Elsevier B.V. All rights reserved.)

In an effort to better understand the biological efficacy of the tridentate aroyl hydrazone Cu(II) complexes, the Cu(II) complex of di-2-pyridyl ketone isonicotinoyl hydrazone ligand (HL), {[Cu(L)(H 2 O)]·H 2 O·NO 3 } n (C1) was synthesized and characterized. Single crystal X-ray study reveals that complex C1 forms 1D zigzag chains in solid state. In water, the hydrolysis of the 1D zigzag chains was observed, and finally formation of monomeric species. In vitro studies revealed that complex C1 showed significantly more anticancer activity than the ligand alone. Investigation of the anticancer mechanisms of C1, confirmed that the Cu(II) complex exhibit a strong capacity to promote productions of reactive oxygen species (ROS), leading to caspase-dependent apoptotic cell death.

Three mononuclear Cu(II) complexes Cu(HL 1 )Cl 2 (1), Cu(HL 2 )Cl 2 (2), and Cu(L 3 )SCN (3) have been synthesized based on chelating hydrazone ligands HL 1 , HL 2 , and HL 3 , respectively. These new compounds gave satisfactory IR-spectroscopic data and were further characterized by elemental and X-ray diffraction analyses. Their urease inhibitory evaluation was tested in vitro against jack bean urease. The results showed that the inhibitory activities of the copper complexes are all superior to the positive reference. Enzyme kinetics studies were undertaken to estimate the inhibition mechanism of the copper complexes. Molecular docking simulations have been performed to rationalize their binding models. In addition, their interactions with serum albumin were also studied., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The coordination compound of the antihypertensive ligand irbesartan (irb) with copper(II) (CuIrb) was synthesized and characterized by FTIR, FT-Raman, UV-visible, reflectance and EPR spectroscopies. Experimental evidence allowed the implementation of structural and vibrational studies by theoretical calculations made in the light of the density functional theory (DFT). This compound was designed to induce structural modifications on the ligand. No antioxidant effects were displayed by both compounds, though CuIrb behaved as a weak 1,1-diphenyl-2-picrylhydrazyl radical (DPPH(·)) scavenger (IC50 = 425 μM). The measurements of the contractile capacity on human mesangial cell lines showed that CuIrb improved the antihypertensive effects of the parent medication. In vitro cell growth inhibition against prostate cancer cell lines (LNCaP and DU 145) was measured for CuIrb, irbesartan and copper(II). These cell lines have been selected since the angiotensin II type 1 (AT1) receptor (that was blocked by the angiotensin receptor blockers, ARB) has been identified in them. The complex exerted anticancer behavior (at 100 μM) improving the activity of the ligand. Flow cytometry determinations were used to determine late apoptotic mechanisms of cell death. Experimental and DFT characterization of an irbesartan copper(II) complex has been performed. The complex exhibits low scavenging activity against DPPH(·) and significant growth inhibition of LNCaP and DU 145 prostate cancer cell lines. Flow cytometry determinations were used to determine late apoptotic mechanisms of cell death. This compound improved the antihypertensive effect of irbesartan. This effect was observed earlier for the mononuclear Cu-candesartan complex, but not in structurally modified sartans forming dinuclear or octanuclear Cu-sartan compounds.

To construct the model of metallohydrolase, two inclusion complexes [MLCl 2 (β-CD)] (1, M=Zn(II); 2, M=Cu(II); L=N,N'-bis(2-pyridylmethyl)amantadine; β-CD=β-cyclodextrin) were synthesized by mixing β-CDs with the pre-synthesized complexes G1, [ZnLCl 2 ] and G2, [CuLCl 2 ]. Structures of G1, G2, 1 and 2 were characterized by X-ray crystallography, respectively. In solution, two chloride anions of G1 and G2 underwent ligand exchange with solvent molecules according to ESI-MS analysis. The chemical equilibrium constants were determined by potentiometric pH titration. The kinetics of bis(4-nitrophenyl) phosphate (BNPP) hydrolysis catalyzed by G1, G2, 1 and 2 were examined at pHs ranging from 7.50 to 10.50 at 308±0.1K. The pH profile of rate constant of BNPP hydrolysis catalyzed by 1 exhibited an exponential increase with the second-order rate constant of 2.68×10 -3 M -1 s -1 assigned to the di-hydroxo species, which was approximately an order of magnitude higher than those of reported mono-Zn(II)-hydroxo species. The high reactivity was presumably hydroxyl-rich microenvironment provided by β-CDs, which might effect in stabilizing either the labile zinc-hydroxo species or the catalytic transition state., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The human topoisomerase IB inhibition and the antiproliferative activity of 3-(4-bromophenyl)-1-pyridin-2-ylprop-2-en-1-one thiosemicarbazone HPyCT4BrPh alone and its copper(II) complex [Cu(PyCT4BrPh)Cl] was investigated. [Cu(PyCT4BrPh)Cl] inhibits both the DNA cleavage and religation step of the enzyme, whilst the ligand alone does not display any effect. In addition we show that coordination to copper(II) improves the cytotoxicity of HPyCT4BrPh against THP-1 leukemia and MCF-7 breast cancer cells. The data indicate that the copper(II) thiosemicarbazone complex may hit human topoisomerase IB and that metal coordination can be useful to improve cytotoxicity of this versatile class of compounds., (Copyright © 2016 Elsevier Inc. All rights reserved.)

To evaluate the biological preference of chiral drug candidates for molecular target DNA, the synthesis and characterization of a chiral copper(II) complex (2) of a chiral ligand N,N'-(pyridin-2-ylmethylene) dehydroabietylamine (1) was carried out. The interactions of 1 and 2 with salmon sperm DNA were investigated by viscosity measurements, UV, fluorescence and circular dichroism (CD) spectroscopic techniques. Absorption spectral, emission spectral and viscosity analysis reveal that 1 and 2 interacted with DNA through intercalation and 2 exhibited a higher DNA binding ability. In the absence/presence of ascorbic acid, 1 and 2 cleaved supercoiled pBR322 DNA by single-strand and 2 displayed stronger DNA cleavage ability. In addition, in vitro cytotoxicity of 1 and 2 against HeLa, SiHa, HepG-2 and A431 cancer cell lines study show that they exhibited effective cytotoxicity against the tested cell lines, notably, 2 showed a superior cytotoxicity than the widely used drug cisplatin under identical conditions, indicating it has the potential to act as effective anticancer drug. Flow cytometry analysis indicates 2 produced death of HeLa cancer cells through an apoptotic pathway. Cell cycle analysis demonstrates that 2 mainly arrested HeLa cells at the S phase. The study represents the first step towards understanding the mode of the promising chiral rosin-derivative based copper complexes as chemotherapeutics., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Binary [Cu(PAIC)(H2O)2]·H2O (1) and mixed ligand [Cu(PAIC)(L)]·2H2O complexes, where PAIC=phenylalanine imidazole carboxylic acid, L=diimine coligands [2,2'-bipyridine (bpy) (2) and 1,10-phenanthroline (phen) (3)] have been synthesized and fully characterized by analytical and spectral techniques. The X-ray structure of [Cu(PAIC)(phen)]·2H2O (3) shows a N4O coordination with square pyramidal geometry around the copper (II) atom. The spin Hamiltonian parameters calculated for the complexes account for the distorted square planar structure and rules out the possibility of a trigonal bipyramidal structure. Interaction of the complexes (1-3) with calf thymus DNA (CT DNA) was studied by using different techniques (absorption titration, fluorescence quenching and thermal melting) and the studies suggest that these complexes bind to CT DNA through intercalation. The DNA-binding affinity of the complexes has further been explained by DFT computational results. Binding activity of Bovine serum albumin (BSA) reveals that the complexes can strongly quench the intrinsic fluorescence of BSA through a static quenching mechanism. DNA cleavage experiments using plasmid DNA pUC 19 show that the complexes exhibit efficient chemical nuclease activity even in the absence of any external additives. The cytotoxicity of the complexes against human normal cell line (HBL 100) and human breast cancer cell line (MCF-7) shows that metal complexation of the ligands results in a significant enhancement in the cell death of MCF-7. Finally, docking studies on DNA and protein binding interactions were performed., (Copyright © 2016 Elsevier B.V. All rights reserved.)

In an effort to better understand the biological efficacy of the tridentate aroyl hydrazone Cu(II) complexes, three Cu(II) complexes of acetylpyridine benzoyl hydrazone (HL), [Cu(L)(NO3) (H2O)]·H2O (C1), [Cu(L)2] (C2) and [Cu(L)(HL)]·(NO3)(Sas) (C3) (Sas=salicylic acid) were synthesized and characterized. X-ray crystal structures and infrared (IR) spectra of the complexes reveal that the L(-) ligand of C1 and C2 are predominantly in the enolate resonance form, while one L(-) ligand in C3 is represented enolate resonance form and the other HL ligand exhibits keto resonance form. All Cu(II) complexes showed significantly more anticancer activity than the ligand alone. Interestingly, the Cu complexes where the ligand/metal ratio was 1:1 (C1) rather than 2:1 (C2 and C3) had higher antitumor efficacy. Moreover, the 1:1 Cu/ligand complex, C1, promotes A549 cell apoptosis possibly through the intrinsic reactive oxygen species (ROS) mediated mitochondrial pathway, accompanied by the regulation of Bcl-2 family proteins., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The folate (FA)-functionalized human serum albumin (HSA) carrier (FA-HSA) is promising for improving the target and efficiency of anticancer drugs. To develop FA-HSA carrier for metal anticancer drugs, we investigated anticancer properties and mechanism of FA-HSA carrier for Cu(II) complexes derived from plumbagin. The fluorescence spectroscopy and molecular docking revealed that Cu(II) complexes bind to IIA subdomain of HSA. Compared with Cu(II) complex alone, FA-HSA-metallodrug complex enhances cytotoxicity to FA-positive cancer cells (HeLa) but do not raise cytotoxicity levels in normal cells in vitro through selectively accumulating in cancer cells to some extent; FA-HSA-metallodrug complex has a stronger capacity for cell cycle arrest in the G2/M phase of HeLa cells, and down-regulating the expression of cyclin-dependent kinase 1 (CDK1) and cyclin B1. Moreover, FA-HSA-metallodrug complex promotes HeLa cells apoptosis through intrinsic reactive oxygen species (ROS) mediated mitochondrial pathway, accompanied by the regulation of Bcl-2 family proteins., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Colistin and transition metal ions are commonly used as feed additives for livestock animals. This work presents the results of an analysis of combined potentiometric and spectroscopic (UV-vis, EPR, CD, NMR) data which lead to conclude that colistin is able to effectively chelate copper(II) ions. In cell-free system the oxidative activity of the complex manifests itself in the plasmid DNA destruction with simultaneous generation of reactive OH species, when accompanied by hydrogen peroxide or ascorbic acid. The degradation of RNA occurs most likely via a hydrolytic mechanism not only for complexed compound but also colistin alone. Therefore, huge amounts of the used antibiotic for nontherapeutic purposes might have a potential influence on livestock health., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Copper(II) complexes with fluoroquinolones in the presence of the nitrogen donor heterocyclic ligands 1,10-phenanthroline have been considered in detail. The phenanthroline moiety was introduced into the ligand environment with the aim to determine whether the nuclease activity is feasible. All suitable X-ray structures of the complexes under study reveal a distorted square pyramidal coordination geometry for Cu(II) atom. The conformational and spectroscopic (FT-IR and UV-visible) behavior has been analyzed and has been interpreted with respect to B3LYP/6-311G* calculations including molecular dynamics. The ability of the complexes to cleave DNA was studied by agarose gel electrophoresis with plasmid DNA pBSK+. The results have confirmed that the complexes under study behave as the chemical nucleases. Nuclease like activity in the absence of hydrogen peroxide allows us to deduce an interaction of the complexes with the DNA resulting in the conversion of supercoiled circular DNA to the nicked form. The DNA cleavage activity enhanced by the presence of hydrogen peroxide demonstrates the participation of reactive oxygen species, such as superoxide radical anions and hydroxyl radicals which presence was confirmed independently using the standard radical scavenging agents. It has been suggested that the radical formation through the Fenton/Haber-Weiss reaction is mediated by the redox cycling mechanisms with the participation of cupric/cuprous ions. Cytotoxic activity was evaluated as the 50% cytotoxic concentration (CC50). The potential effects of tested compounds on replication of murine gammaherpesvirus 68 (MHV-68) under in vitro conditions were also evaluated. However, no antiviral activity against MHV-68 was observed., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The ligand 2,6-bis[(N-phenyl)amido]-4-methylphenol (receptor 1) and its copper(II) complex (receptor 2) having amide moiety have been designed and synthesized for selective sensing of anions. The anion recognition behavior of the receptor 1 and its copper complex (receptor 2) has been studied in acetonitrile. Quenching of fluorescence was observed for both receptors in presence of HSO4(-) anion whereas other physiologically and environmentally important anions such as F(-), Cl(-), Br(-), I(-), CN(-), OAc(-), HCO₃(-), H₂PO₄(-), NO₃(-), NO₂(-) and SO₄(2-) show fluorescence enhancement behavior. The sensing protocol has been studied both spectrophotometrically as well as spectrofluorometrically. Fluorescence quenching is suggested to proceed via both dynamic and static processes., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Copper(II) coordination polymers have attracted considerable interest due to their catalytic, adsorption, luminescence and magnetic properties. The reactions of copper(II) with 2-amino-4-sulfobenzoic acid (H(2)asba) in the presence/absence of the auxiliary chelating ligand 1,10-phenanthroline (phen) under ambient conditions yielded two supramolecular coordination polymers, namely (3-amino-4-carboxybenzene-1-sulfonato-κO(1))bis(1,10-phenanthroline-κ(2)N,N')copper(II) 3-amino-4-carboxybenzene-1-sulfonate monohydrate, [Cu(C7H6N2O5S)(C12H8N2)2](C7H6N2O5S)·H2O, (1), and catena-poly[[diaquacopper(II)]-μ-3-amino-4-carboxylatobenzene-1-sulfonato-κ(2)O(4):O(4')], [Cu(C7H6N2O5S)(H2O)2]n, (2). The products were characterized by FT-IR spectroscopy, thermogravimetric analysis (TGA), solid-state UV-Vis spectroscopy and single-crystal X-ray diffraction analysis, as well as by variable-temperature powder X-ray diffraction analysis (VT-PXRD). Intermolecular π-π stacking interactions in (1) link the mononuclear copper(II) cation units into a supramolecular polymeric chain, which is further extended into a supramolecular double chain through interchain hydrogen bonds. Supramolecular double chains are then extended into a two-dimensional supramolecular double layer through hydrogen bonds between the lattice Hasba(-) anions, H2O molecules and double chains. Left- and right-handed 21 helices formed by the Hasba(-) anions are arranged alternately within the two-dimensional supramolecular double layers. Complex (2) exhibits a polymeric chain which is further extended into a three-dimensional supramolecular network through interchain hydrogen bonds. Complex (1) shows a reversible dehydration-rehydration behaviour, while complex (2) shows an irreversible dehydration-rehydration behaviour.

Two new mononuclear copper(II) complexes [Cu (L) (NO3)2] (1) and [Cu (L) Br2] (2) where (L=bis(1-(pyridin-2-ylmethyl)-benzimidazol-2-ylmethyl)ether) are synthesized and characterized by single-crystal X-ray diffraction analysis, elemental analysis, UV-Visible, IR spectroscopy, EPR and cyclic voltammetry. The complexes exhibit different coordination structures; the E1/2 value of the complex (1) is found to be relatively more cathodic than that of complex (2). X-band EPR spectra at low temperature in DMF supports a tetragonally distorted complex (1) while complex (2) shows three different g values suggesting a rhombic geometry. These complexes were utilized as a catalyst for the aerobic oxidation of o-phenylenediamine to 2,3-diaminophenazine assisted by molecular oxygen. The initial rate of reaction is dependent on the concentration of Cu(II) complex as well as substrate, and was found to be higher for the nitrate bound complex, while presence of acetate anion acts as a mild inhibitor of the reaction, as it is likely to pick up protons generated during the course of reaction. The inhibition suggests that the generated protons are further required in another important catalytic step., (Copyright © 2015 Elsevier B.V. All rights reserved.)

This study investigates chromotropism of newly synthesized 3,3'-(ethane-1,2-diylbis(benzylazanediyl))dipropanamide copper(II) perchlorate complex. The compound was structurally characterized by physico-chemical and spectroscopic methods. X-ray crystallography of the complex showed that the copper atom achieved a distorted square pyramidal environment through coordination of two amine N atoms and two O atoms of the amide moieties. The pH effect on the visible absorption spectrum of the complex was studied which functions as pH-induced "off-on-off" switches through protonation and deprotonation of amide moieties along with the CuO to CuN bond rearrangement at room temperature. The complex was also observed to show solvatochromism and ionochromism. The distinct solution color changes mainly associated with hemilability of the amide groups. The solvatochromism of the complex was investigated with different solvent parameter models using stepwise multiple linear regression method. The results suggested that the basicity power of the solvent has a dominant contribution to the shift of the d-d absorption band of the complex. Density functional theory, DFT calculations were performed in order to study the electronic structure of the complex, the relative stabilities of the CuN/CuO isomers, and to understand the nature of the halochromism processes taking place. DFT computational results buttressed the experimental observations indicating that in the natural pH (5.8) the CuO isomer is more stable than its linkage isomer and conversely in alkaline aqueous solution., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The preparation and X-ray and spectroscopic studies of the title copper(II) complex, [Cu(C12H8N3O2)(CN)(H2O)], are reported. The Cu(II) cation is five-coordinated, forming a distorted square-planar pyramid with an Addison τ parameter of 0.14. The UV-vis spectrum shows a d-d transition of the Cu(II) centre at 638 nm, and the electron paramagnetic resonance (EPR) spectrum confirms that the Cu(II) cation has an axial symmetry coordination and that the unpaired electrons occupy the d(x(2)-y(2)) orbital. Cyclic voltammetric studies show two irreversible oxidation and reduction peaks.

The novel polymeric complexes catena-poly[[diaquamanganese(II)]-μ-2,2'-bipyrimidine-κ(4)N(1),N(1'):N(3),N(3')-[diaquamanganese(II)]-bis(μ-terephthalato-κ(2)O(1):O(4))], [Mn2(C8H4O4)2(C8H6N4)(H2O)4]n, (I), and catena-poly[[[aquacopper(II)]-μ-aqua-μ-hydroxido-μ-terephthalato-κ(2)O(1):O(1')-copper(II)-μ-aqua-μ-hydroxido-μ-terephthalato-κ(2)O(1):O(1')-[aquacopper(II)]-μ-2,2'-bipyrimidine-κ(4)N(1),N(1'):N(3),N(3')] tetrahydrate], {[Cu3(C8H4O4)2(OH)2(C8H6N4)(H2O)4]·4H2O}n, (II), containing bridging 2,2'-bipyrimidine (bpym) ligands coordinated as bis-chelates, have been prepared via a ligand-exchange reaction. In both cases, quite unusual coordination modes of the terephthalate (tpht(2-)) anions were found. In (I), two tpht(2-) anions acting as bis-monodentate ligands bridge the Mn(II) centres in a parallel fashion. In (II), the tpht(2-) anions act as endo-bridges and connect two Cu(II) centres in combination with additional aqua and hydroxide bridges. In this way, the binuclear [Mn2(tpht)2(bpym)(H2O)4] entity in (I) and the trinuclear [Cu3(tpht)2(OH)2(bpym)(H2O)4]·4H2O coordination entity in (II) build up one-dimensional polymeric chains along the b axis. In (I), the Mn(II) cation lies on a twofold axis, whereas the four central C atoms of the bpym ligand are located on a mirror plane. In (II), the central Cu(II) cation is also on a special position (site symmetry -1). In the crystal structures, the packing of the chains is further strengthened by a system of hydrogen bonds [in both (I) and (II)] and weak face-to-face π-π interactions [in (I)], forming three-dimensional metal-organic frameworks. The Mn(II) cation in (I) has a trigonally deformed octahedral geometry, whereas the Cu(II) cations in (II) are in distorted octahedral environments. The Cu(II) polyhedra are inclined relative to each other and share common edges.

A great majority of Cu(II) complexes currently studied in the anticancer research field exert their antiproliferative activities through ligand exchange. In this work, we present the synthesis and structural characterization of two novel Cu(II) complexes, {[Cu3(ZL)2(H2O)6]·6H2O}n (1) (ZL = 1-hydroxy-2-(1H-imidazol-1-yl)ethane-1,1-diyldiphosphonic acid) and [Cu(IPrDP)2]·3H2O (2) (IPrDP = 1-hydroxy-3-(1H-imidazol-1-yl)propane-1,1-diyldiphosphonic acid). Due to the insolubility of polymer 1 in common solvents, only the biological activities of complex 2 were investigated. The antitumor activity of complex 2 was evaluated against a panel of human cancer cell lines, including U2OS, A549, HCT116, MDA-MB-231 and HepG2. Complex 2 exhibited comparable cytotoxic effect to cisplatin (CDDP) against the human colon carcinoma cells HCT116, and superior selectivity for inhibiting human hepatocarcinoma cells rather than normal liver cells. The cell cycle distribution analysis indicates that complex 2 inhibits human carcinoma cells by inducing the cell cycle arrest at the G2/M phase, showing a similar mechanism of action to that of CDDP. The binding interaction of complex 2 with calf thymus DNA (CT-DNA) has been explored by UV-vis absorption and circular dichroism (CD), demonstrating complex 2 has a moderate binding affinity for DNA through intercalation., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Two new Cu(II) complexes of Schiff base-hydrazone ligands, hydroxy-N'-[(1Z)-1-(4-hydroxyphenyl)ethylidene]benzohydrazide [H₃L(1)] and ethyl 2-(4-(1-(2-(4-(2-ethoxy-2-oxoethoxy)benzoyl)hydrazono)ethyl)phenoxy)acetate (HL(2)) have been synthesized and then characterized by microcopy and spectral studies. X-ray powder diffraction illustrates that [Cu(L(2))₂] complex is crystalline in nature whereas [Cu(H₂L(1))₂]·2H₂O has an amorphous structure. Binding of the copper complexes with Calf thymus DNA (CT-DNA) has been investigated by UV-visible spectra, exhibiting non-covalent binding to CT-DNA. DNA cleavage experiments have been also investigated by agarose gel electrophoresis in the presence and absence of an oxidative agent (H₂O₂). The effect of complex concentration on the DNA cleavage reaction has been also studied. Both copper complexes show nuclease activity, which significantly depends on concentrations of the complexes, in the presence of H₂O₂ through oxidative mechanism whereas they slightly cleavage DNA in the absence an oxidative agent., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Copper (Cu) compounds are a promising candidate for next generation metal anticancer drugs and have been extensively studied. Therefore, four binuclear copper(II) compounds derived from Schiff base thiosemicarbazones (L1-L4), namely [CuCl(L1)]2 (C1), [CuNO3(L2)]2 (C2), [Cu(NCS) (L3)]2 (C3) and [Cu(CH3COO) (L4)]2 (C4) were synthesized and characterized. Four of these compounds showed very high cytotoxicity to cancer cell lines in vitro. These Cu(II) compounds strongly promoted the apoptosis of BEL-7404 cells. The formation of reactive oxygen species (ROS), change in mitochondrial membrane potential and western blot analysis revealed that Cu compounds could induce cancer cell apoptosis through the intrinsic ROS-mediated mitochondrial pathway accompanied by the regulation of Bcl-2 family proteins., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Three novel copper(II) complexes CuL(1)Cl2 (1) (L(1)=4'-(3-methoxyphenyl)-2,2':6'- 2″-terpyridine), CuL(2)Cl2 (2) (L(2)=4'-(4-methoxyphenyl)-2,2':6'-2″-terpyridine) and CuL(3)Cl2 (3) (L(3)=4'-(3,5-dimethoxyphenyl)-2,2':6'-2″-terpyridine) have been synthesized and characterized. Absorption spectral titration experiments, ethidium bromide displacement assays, and cyclic voltammetric experiments were carried out and the results suggested that these complexes bound to DNA through an intercalative mode. Moreover, these complexes were found to cleave pBR322 DNA efficiently in the presence of glutathione (GSH), and exhibited good anticancer activity against HeLa, Hep-G2 and BEL-7402 cell lines. Nuclear chromatin cleavage was also observed by acridine orange/ethidium bromide (AO/EB) staining assays and comet assays. These results demonstrated that these three Cu(II) complexes caused DNA damage and induced the apoptosis of HeLa cells. Mechanistic investigations revealed the participation of reactive oxygen species which can be trapped by reactive oxygen species (ROS) radical scavengers and ROS sensors., (Copyright © 2014 Elsevier Inc. All rights reserved.)

One of the hallmarks of Alzheimer's disease (AD) in the brain are amyloid-β (Aβ) plaques, and metal ions such as copper(II) and zinc(II) have been shown to play a role in the aggregation and toxicity of the Aβ peptide, the major constituent of these extracellular aggregates. Metal binding agents can promote the disaggregation of Aβ plaques, and have shown promise as AD therapeutics. Herein, we describe the syntheses and characterization of an acetohydrazone (8-H2QH), a thiosemicarbazone (8-H2QT), and a semicarbazone (8-H2QS) derived from 8-hydroxyquinoline. The three compounds are shown to be neutral at pH7.4, and are potent antioxidants as measured by a Trolox Equivalent Antioxidant Capacity (TEAC) assay. The ligands form complexes with Cu(II), 8-H2QT in a 1:1 metal:ligand ratio, and 8-H2QH and 8-H2QS in a 1:2 metal:ligand ratio. A preliminary aggregation inhibition assay using the Aβ1-40 peptide showed that 8-H2QS and 8-H2QH inhibit peptide aggregation in the presence of Cu(II). Native gel electrophoresis/Western blot and TEM images were obtained to give a more detailed picture of the extent and pathways of Aβ aggregation using the more neurotoxic Aβ1-42 in the presence and absence of Cu(II), 8-H2QH, 8-H2QS and the drug candidate PBT2. An increase in the formation of oligomeric species is evident in the presence of Cu(II). However, in the presence of ligands and Cu(II), the results match those for the peptide alone, suggesting that the ligands function by sequestering Cu(II) and limiting oligomer formation in this assay., (Copyright © 2014 Elsevier Inc. All rights reserved.)

A novel binuclear copper(II) complex (complex 1) with taurine Schiff base and imidazole has been synthesized and structurally characterized by single crystal X-ray diffraction, elemental analysis, ESI-MS spectrometry, UV-vis and IR spectroscopy. Single-crystal analysis revealed that 1 displays the sulfonate-bridged dinuclear copper(II) centers. Both copper atoms are five-coordinated and exhibit slightly distorted square pyramidal geometries. Each of copper atom is surrounded by three oxygen atoms and one nitrogen atom from different taurine Schiff base ligands, and one nitrogen atom from one imidazole ligand. The interaction between 1 and calf thymus DNA (CT-DNA) was investigated by UV-vis, fluorescence, circular dichroism (CD) spectra and agarose gel electrophoresis. The experimental results indicated that 1 could bind to CT-DNA via an intercalative mode and show efficient cleavage activity. In addition, 1 showed an antitumor effect on cell cycle and apoptosis. Flow cytometric analysis revealed that MGC-803 cells were arrested in the S phase after treatment with 1. Fluorescence microscopic observation indicated that 1 could induce apoptosis of MGC-803 cells., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The title compound, catena-poly[[[diaqua(methanol-κO)copper(II)]-μ-N-(4-methylpyrimidin-2-yl-κN(1))pyrazin-2-amine-κ(2)N(1):N(4)] [[aqua(aqua/methanol-κO)(perchlorato-κO)copper(II)]-μ-N-(4-methylpyrimidin-2-yl-κN(1))pyrazin-2-amine-κ(2)N(1):N(4)] tris(perchlorate) methanol monosolvate 1.419-hydrate], {[Cu(C9H9N5)(CH3OH)(H2O)2][Cu(C9H9N5)(ClO4)(CH3OH)0.581(H2O)1.419](ClO4)3·CH3OH·1.419H2O}n, is a one-dimensional straight-chain polymer of N-(4-methylpyrimidin-2-yl)pyrazin-2-amine (L) with Cu(ClO4)2. The complex consists of two crystallographically independent one-dimensional chains in which the Cu(II) atoms exhibit two different octahedral coordination geometries. The L ligand coordinates to two Cu(II) centres in a tridentate manner, with the pyrazine ring acting as a bridge linking the Cu(II) coordination units and building an infinite one-dimensional chain. Extensive hydrogen bonding among perchlorate anions, water molecules and L ligands results in three-dimensional networks.

Elesclomol is a novel anticancer agent that has been evaluated in a number of late stage clinical trials. A new and convenient synthesis of elesclomol and its copper complex is described. X-ray crystallographic characterization and the electrochemical properties of the elesclomol copper(II) complex are discussed. The copper(II) cation is coordinated in a highly distorted square-planar geometry to each of the sulphur and amide nitrogen atoms of elesclomol. Electrochemical measurements demonstrate that the complex undergoes a reversible one-electron reduction at biologically accessible potentials. In contrast the free elesclomol is found electrochemically inactive. This evidence is in strong support of the mechanism of action we proposed for the anticancer activity of elesclomol., (© 2013.)