Ternary Copper Complexes Research Articles

Ternary Phenolate-Based Thiosemicarbazone Complexes of Copper(II): Magnetostructural Properties, Spectroscopic Features and Marked Selective Antiproliferative Activity against Cancer Cells.

The new diprotic ligand 3,5-di-tert-butylsalicylaldehyde 4-ethyl-3-thiosemicarbazone, abbreviated H2(3,5-t-Bu2)-sal4eT, exists as the thio-keto tautomer and adopts the E-configuration with respect to the imine double bond, as evidenced by single-crystal X-ray analysis and corroborated by spectroscopic characterisation. Upon treatment with Cu(OAc)2·H2O in the presence of either 2,9-dimethyl-1,10-phenanthroline (2,9-Me2-phen) or 1,10-phenanthroline (phen) as a co-ligand in MeOH, this thiosemicarbazone undergoes conformational transformation (relative donor-atom orientations: syn,anti → syn,syn) concomitantly with tautomerisation and double deprotonation to afford the ternary copper(II) complexes [Cu{(3,5-t-Bu2)-sal4eT}(2,9-Me2-phen)] (1) and [Cu2{3,5-t-Bu2)-sal4eT}2(phen)] (2). Crystallographic elucidation has revealed that complex 1 is a centrosymmetric dimer of mononuclear copper(II) complex molecules brought about by intermolecular H-bonding. The coordination geometry at the copper(II) centre is best described as distorted square pyramidal in accordance with the trigonality index (τ = 0.14). The co-ligand adopts an axial-equatorial coordination mode; hence, there is a disparity between its two Cu-N coordinate bonds arising from weakening of the apical one as a consequence of the tetragonal distortion. The axial X-band ESR spectrum of complex 1 is consistent with retention of this structure in solution. Complex 2 is a centrosymmetric dimer of dinuclear copper(II) complex molecules exhibiting intermolecular H-bonding and π-π-stacking interactions. The two copper(II) centres, which are 4.8067(18) Å apart and bridged by the thio-enolate nitrogen of the quadridentate thiosemicarbazonate ligand, display two different coordination geometries, one distorted square planar (τ4 = 0.082) and the other distorted square pyramidal (τ5 = 0.33). Such dinuclear copper(II) thiosemicarbazone complexes, which are crystallographically characterised, are extremely rare. In vitro, complexes 1 and 2 outperform cisplatin as antiproliferative agents in terms of potency and selectivity towards HeLa and MCF-7 cancer cell lines.

Heteroleptic Copper(II) Complexes Containing an Anthraquinone and a Phenanthroline as Synthetic Nucleases and Potential Anticancer Agents

Two ternary copper(II) complexes with an anthraquinone and a N,N-heterocyclic donor, [Cu(dmp)(L)(H2O)](ClO4) (1), [Cu(bpy)(L)(dmso)](ClO4) (2), in which dmp = 2,9-dimethyl-1,10-phenanthroline, bpy = 2,2′-bipyridine, and HL = 1-hydroxyanthracene-9,10-dione were synthesized and fully characterized by conductivity, elemental, and spectral analyses (FTIR and UV-Vis; EPR and ESI-MS). The structure of 1 reveals that Cu(II) is bound to two oxygens of L, two nitrogens of dmp, and a molecule of water in the fifth position. In complex 2.1, Cu(II) is also pentacoordinated with an O-bonded dmso in the axial position. The presence of the heteroleptic complexes in solution was evidenced by ESI-MS, EPR in dmso solution and UV-Vis spectrophotometry. All complexes bind to CT-DNA with affinity constants of approximately 104. Complex 2 can nick plasmid DNA but no cleavage was performed by complex 1. The investigation of DNA interactions by spectrofluorimetry using ethidium bromide (EB) showed that it was displaced from DNA sites by the addition of the complexes. The complexes inhibited the growth of chronic myelogenous leukemia and human squamous carcinoma cells with low IC50 values, complex 1 being the most effective.

Structural, Vibrational, Thermal, and Cytotoxic Characterization of Aqua(1,10‐Phenanthroline)(L‐Serinato)Copper(II) Nitrate Complex Combined with DFT Calculations

AbstractIn this study, X‐ray diffraction confirms the crystallization of aqua(1,10‐phenanthroline)(L‐serinato)copper(II) nitrate in the triclinic system (P‐1). Density functional theory calculations are used to assign the vibration bands of Cu2+ ion and phenanthroline (phen) and L‐serine (L‐ser) ligands obtained by Raman and Fourier‐transform infrared spectroscopy. Physical and analytical properties, evaluated by computational study utilizing CrystalExplorer software, show the prevalence of H···O/O···H interaction. Thermal analyses show that the complex is stable in the temperature interval of 300–390 K. For temperatures above 390 K, the elimination of coordinated water molecules (380–430 K), mass loss of serine (440–660 K), and material decomposition process above 660 K. The solubility of the complex in water reaches 21.4 mg mL−1 at 35 °C. Parameters of drug‐likeness and assessment of absorption, distribution, metabolism, and excretion (ADME) properties are calculated. The in vitro cytotoxic assays against the cancer cell line of the HCT‐116 type (human colorectal carcinoma) exhibits toxicity (IC50 = 1.88 µm and selectivity index of 2.17) for the complex. The results highlight the potential of ternary copper complexes such as [Cu(phen)(L‐ser)(H2O)]NO3 for anticancer drug development as attractive, efficient, and low‐cost materials.

The supramolecular hybrid inorganic–organic l-argininato-based copper(II) materials – preparation, structural, spectroscopic and thermal properties

Synthesis and characterization of the single crystal of new ternary copper(II) complexes containing l−arginine of formulae {[Cu(μ−O,O’−NO3)(l−Arg)(bpy)]NO3}n (1) and [CuCl(l−Arg)(bpy)]Cl·3H2O (2) (l−Arg =l−arginine; bpy=2,2′−bipyridine) with one−dimensional polymeric and monomeric nature, respectively, were the initial goal of the present study. Complete crystal and molecular structures figuration were achieved by powder and single crystal X−ray diffraction supported by Hirshfeld surface analysis, spectroscopic (FT−IR, FT−Raman, X− and Q−bands EPR, NIR−Vis−UV) methods as well as thermal analysis. In 1, the infinite 1D coordination chains are formed by the NO3– ions linking [Cu(l−Arg)(bpy)]2+ units. In 2, the self−assembled [Cu(l-Arg)(bpy)Cl]+ dimers are linked into 1D zig-zag chains. The intermolecular interactions in both crystals were explored by using Hirshfeld surface and 2D fingerprint plots analysis. The Q−band spectra displayed the anisotropic signals allowing to determine the g|| parameters. The thermal decomposition of complexes 1 and 2 occur by the formation of “creatine−proline” as a product of l−Arg decomposition.

Stability constants of the ternary copper(II) complexes with 2-(benzo(d)oxazol-2-yl)nicotinic acid and some amino acids

In this work, we present the results from a study of the speciation of the ternary systems formed by copper(II),2-(benzo(d)oxazol-2-yl)nicotinic acid (Oxa, HL) as the main ligand, and the amino acids Serine (Ser, A–), Threonine (Thr, A–), Methionine (Met, A–), Phenylalanine (Phe, A–), Aspartate (Asp, A2–), Glutamate (Glu, A2–), and Histidine (His, A–) as secondary ones. The potentiometric data was analyzed using the computational program LETAGROP for systems in aqueous solution at 25 °C and 1.0 M KNO3 as the ionic medium. The ternary complexes [Cu(L)(HA)]+, [Cu(L)(A)], [Cu(L)2(A)]–, [Cu(L)(A)2]–, [Cu(L)(A)(OH)]– and [Cu(L)(A)(OH)2]2– were detected. The relative stability of the ternary complexes was compared to the binary ones considering the values of ΔlogK and logχ (defined in text of results and analysis). Subsequently using the formation constants, the species distribution diagrams were generated and are briefly discussed. The UV–visible spectra of the ternary complexes show a maximum at 610–654 nm indicating that the Cu2+ is penta-coordinated.

A perception into binary and ternary copper (II) complexes: synthesis, characterization, DFT modeling, antimicrobial activity, protein binding screen, and amino acid interaction

Ensuring healthy lives and promoting well-being for all at all ages is the third goal of the sustainable development plan, so it was necessary to identify the most important problems that threaten health in our world. The World Health Organization declared that antibiotic resistance is one of the uppermost global public health threats facing humanity and searching for new antibiotics is slow. This problem can be approached by improving available drugs to combat various bacterial threats. To circumvent bacterial resistance, three copper(II) complexes based on the pefloxacin drug were prepared and characterized using analytical, spectroscopic, and thermal techniques. The resulting data suggested the formation of one octahedral binary and two distorted square pyramidal ternary complexes. Fluorescence spectra results revealed the formation of a turn-on fluorophore for amino acid detection. Computational calculations investigated quantum and reactivity parameters. Molecular electrostatic potential profiles and noncovalent bond interaction-reduced density gradient analysis indicated the active sites on the complex surface. The complexes were subjected to six microbial species, where the octahedral binary complex provoked its antimicrobial potency in comparison with ternary complexes. The enhanced antimicrobial activity against gram-negative bacterium E-coli compared to gentamicin was exhibited by the three complexes. Docking simulation was performed based on the crystal structure of E. coli and S. pneumoniae receptors using 5I2D and 6O15 codes. The binary complex exhibited a potent fitness score with 5I2D (TBE = − 107 kcal/mol) while ternary complexes displayed the highest docked score of fitness with 6O15.

Ternary copper(ii) complexes of 1,10-phenanthroline and coumarin-based oxylacetates as pro-apoptotic UPR CHOP inducers

Six new mixed copper complexes able to induce pro-apoptotic UPR CHOP were prepared. Coumarin carboxylate derivatives were chosen as auxiliary ligands.

A new ternary copper (Ⅱ) complex of 2,4-dihydroxybenzoic acid: Synthesis, crystal structure and its catalytic decomposition effect on AP and RDX

In order to solve the unclear problems of structure and composition for 2,4-dihydroxybenzoic acid (2,4-DHBA) copper salt (β-Cu), a new insoluble ternary copper (Ⅱ) complex of 2,4-DHBA ([Cu(C12H8N2)2(C7H5O4)](C7H5O4)) was designed and synthesized in water. The ternary complex crystallizes in the monoclinic system with the space group P21/n. The central Cu2+ is coordinated with four nitrogen atoms from two 1,10-phenanthroline ligands and one carboxyl oxygen atom from a 2,4-DHBA anion. The other 2,4-DHBA anion does not participate in coordination and only provides the action of balance charge. In addition, compared with β-Cu, no water molecules exist in the ternary complex. The thermal stability of the ternary complex was investigated, as well as its catalytic decomposition activity on AP and RDX. With the addition of the ternary complex, the exothermic decomposition peak temperatures of AP and RDX were reduced from 406.5 to 353.9 ​°C, and 242.3 to 181.4 ​°C respectively, and the apparent activation energies were reduced from 293.1 to 207.4 ​kJ ​mol−1, and 239.6 to 177.5 ​kJ ​mol−1, respectively. Moreover, the addition of the ternary complex has greatly improved the heat release of AP and RDX. The catalytic decomposition performance of the new ternary complex on AP and RDX is much better than that of the traditional β-Cu. Moreover, the new copper (Ⅱ) complex completely changed the thermal decomposition process of RDX from melting decomposition to direct solid phase decomposition, and such catalytic effect is uncommon. Therefore, the new ternary copper (Ⅱ) complex presents a better potential application for modified double-base propellant of RDX.

Synthesis and Characterization of the Nanogold-Bound Ternary Copper(II) Complex of Phenanthroline and Cysteine as Potential Anticancer Agents.

The aim of this study was to synthesize and characterize a nanogold–{[(Cu)(phen)(cys)(H2O)]NO3}n conjugate and to evaluate its antiproliferative property against the breast cancer cell line (MCF7) and normal cell line (MCF10A). Nanogold solution was prepared using the Turkevich method. In one approach, a ternary copper(II) complex of 1,10-phenanthroline with l-cysteine, [(Cu)(phen)(cys)(H2O)]NO3, was first prepared and then tethered with the gold nanoparticles. In another approach, gold nanoparticles were reacted with l-cysteine, copper(II) nitrate, and 1,10-phenanthroline subsequently. The synthesized [(Cu)(phen)(cys)(H2O)]NO3 complex was characterized by Fourier transform infrared (FTIR) and electrospray ionization mass spectrometry techniques, which showed that l-cysteine was bound to the copper through carboxylic and amino groups, with the thiol moiety remaining free. The free thiol group was bound to the nanogold surface to form the nanogold–{[(Cu)(phen)(cys)(H2O)]NO3}n conjugate, as evidenced by the increase in the surface plasmon absorption band in ultraviolet–visible and the absence of a thiol peak in FTIR of the nanogold–copper complex conjugate. The anticancer activity of the nanogold–copper complex conjugate and the free copper complex against a breast cancer cell line (MCF7) and their toxicity on a normal cell line (MCF10A) were examined using the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxy phenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay. Results suggested that the nanogold–{[(Cu)(phen)(cys)(H2O)]NO3}n conjugate demonstrates a selective antiproliferative and proapoptotic effect on the breast cancer cells, confirming the potential of the nanogold–copper complex conjugate as an anticancer agent.

Chemical speciation, antioxidant activity and molecular docking of copper(II) complexes with pyridinedicarboxylic acids and different ligands of low molecular mass

ABSTRACT Analyses of potentiometric measurements were conducted on ternary complexes of copper(II) with dipicolinic acid and quinolinic acid, as well as lactic acid, oxalic acid, citric acid, and phosphoric acid, which are components of blood plasma. Studies on chemical speciation showed that ternary compounds were more likely to be formed. In systems with quinolinic acid, the solubility was small, and most complexes precipitated at pH ≤ 2. In situ isolated ternary and binary complexes of CuDiPic(H2O)2 were evaluated for antioxidant activity, as shown by their inhibiting activity of superoxide anion (O2.−), which demonstrates copper(II) complexes provide protective effects. Docking studies of ligands with a protein kinase revealed that the Cu(II) metal centre is crucial for the successful interaction of the complex with the receptor’s active site.

Induction of Apoptosis and Autophagy by Ternary Copper Complex Towards Breast Cancer Cells.

Copper complex has been gaining much attention in anticancer research as a targeted agent since cancer cells uptake more copper than non-cancerous cells. Our group synthesised a ternary copper complex, which is composed of 1,10-phenanthroline and tyrosine [Cu(phen)(L-tyr)Cl].3H20. These two payloads have been designed to cleave DNA and inhibit protein degradation system (proteasome) concurrently in cancer cells, making this copper complex a dual-target compound. The current study was carried out to investigate the mode of cell death and the role of autophagy induced by [Cu(phen)(L-tyr)Cl].3H20 in MCF-7 and MDA-MB-231 breast cancer cells. Growth inhibition of [Cu(phen)(L-tyr)Cl].3H20 towards MDA-MB-231 and human non-cancerous MCF10A breast cells was determined by MTT assay. Annexin-V-FITC/PI and cell cycle analysis were evaluated by flow cytometry. The expression of p53, Bax, caspase-9, caspase-7, caspase-3 and LC3 was determined using western blot analysis. The cells were then co-treated with hydroxychloroquine to ascertain the role of autophagy induced by [Cu(phen)(L-tyr)Cl].3H20. [Cu(phen)(L-tyr)Cl].3H20 inhibited the growth of cancer cells dose-dependently with less toxicity towards MCF10A cells. Additionally, [Cu(phen)(L-tyr)Cl].3H20 induced apoptosis and cell cycle arrest towards MCF-7 and MDA-MB-231 breast cancer cells possibly via regulation of p53, Bax, caspase-9, caspase-3 and capase-7. The expression of LC3II was upregulated in both cancer cell lines upon treatment with [Cu(phen)(L-tyr) Cl].3H20, indicating the induction of autophagy. Co-treatment with autophagy inhibitor hydroxychloroquine significantly enhanced growth inhibition of both cell lines, suggesting that autophagy induced by [Cu(phen)(L-tyr) Cl].3H20 in both breast cancer cells promoted cell survival. [Cu(phen)(L-tyr)Cl].3H20 holds great potential to be developed for breast cancer treatment.

A Ternary Copper (II) Complex with 4-Fluorophenoxyacetic Acid Hydrazide in Combination with Antibiotics Exhibits Positive Synergistic Effect against Salmonella Typhimurium.

Salmonella spp. continues to figure prominently in world epidemiological registries as one of the leading causes of bacterial foodborne disease. We characterised 43 Brazilian lineages of Salmonella Typhimurium (ST) strains, characterized drug resistance patterns, tested copper (II) complex as control options, and proposed effective antimicrobial measures. The minimum inhibitory concentration was evaluated for seven antimicrobials, isolated and combined with the copper (II) complex [Cu(4-FH)(phen)(ClO4)2] (4-FH = 4-fluorophenoxyacetic acid hydrazide and phen = 1,10-phenanthroline), known as DRI-12, in planktonic and sessile ST. In parallel, 42 resistance genes were screened (PCR/microarray). All strains were multidrug resistant (MDR). Resistance to carbapenems and polymyxins (86 and 88%, respectively) have drawn attention to the emergence of the problem in Brazil, and resistance is observed also to CIP and CFT (42 and 67%, respectively), the drugs of choice in treatment. Resistance to beta-lactams was associated with the genes blaTEM/blaCTX-M in 39% of the strains. Lower concentrations of DRI-12 (62.7 mg/L, or 100 μM) controlled planktonic and sessile ST in relation to AMP/SUL/TET and AMP/SUL/TET/COL, respectively. The synergistic effect provided by DRI-12 was significant for COL/CFT and COL/AMP in planktonic and sessile ST, respectively, and represents promising alternatives for the control of MDR ST.

Enhanced antitumor effect of L-buthionine sulfoximine or ionizing radiation by copper complexes with 2,2´-biquinoline and sulfonamides on A549 2D and 3D lung cancer cell models.

Two ternary copper(II) complexes with 2,2'-biquinoline (BQ) and with sulfonamides: sulfamethazine (SMT) or sulfaquinoxaline (SDQ) whose formulae are Cu(SMT)(BQ)Cl and Cu(SDQ)(BQ)Cl·CH3OH, in what follows SMTCu and SDQCu, respectively, induced oxidative stress by increasing ROS level from 1.0μM and the reduction potential of the couple GSSG/GSH2. The co-treatment with L-buthionine sulfoximine (BSO), which inhibits the production of GSH, enhanced the effect of copper complexes on tumor cell viability and on oxidative damage. Both complexes generated DNA strand breaks given by-at least partially-the oxidation of pyrimidine bases, which caused the arrest of the cell cycle in the G2/M phase. These phenomena triggered processes of apoptosis proven by activation of caspase 3 and externalization of phosphatidylserine and loss of cell integrity from 1.0μM. The combination with BSO induced a marked increase in the apoptotic population. On the other hand, an improved cell proliferation effect was observed when combining SDQCu with a radiation dose of 2Gy from 1.0μM or with 6Gy from 1.5μM. Finally, studies in multicellular spheroids demonstrated that even though copper(II) complexes did not inhibit cell invasion in collagen gels up to 48h of treatment at the higher concentrations, multicellular resistance outperformed several drugs currently used in cancer treatment. Overall, our results reveal an antitumor effect of both complexes in monolayer and multicellular spheroids and an improvement with the addition of BSO. However, only SDQCu was the best adjuvant of ionizing radiation treatment.

Ternary Copper (II) Complex Induced Apoptosis and Cell Cycle Arrest in Colorectal Cancer Cells.

The lack of specificity, severe side effects, and development of drug resistance have largely limited the use of platinum-based compounds in cancer treatment. Therefore, copper complexes have emerged as potential alternatives to platinum-based compounds. Ternary copper (II) complex incorporated with 1-10-phenanthroline and L-tyrosine was investigated for its anti-cancer effects in HT-29 colorectal cancer cells. Cytotoxic effects of ternary copper (II) complex in HT-29 cells was evaluated using MTT assay, Real-Time Cell Analysis (RTCA) and lactate dehydrogenase (LDH) assay. Cell cycle analysis was performed using flow cytometry. Apoptosis induction was studied by Annexin V-FITC/Propidium Iodide (PI) staining and mitochondrial membrane potential analysis (JC-10 staining) using flow cytometry. Intracellular Reactive Oxygen Species (ROS) were detected by DCFH-DA assay. The expression of proteins involved in the apoptotic signalling pathway (p53, caspases, and PARP-1) was evaluated by western blot analysis. Ternary copper (II) complex reduced the cell viability of HT-29 cells in a time- and dose-dependent manner, with IC50 of 2.4 ± 0.4 and 0.8 ± 0.04 μM at 24 and 48 hours, respectively. Cell cycle analysis demonstrated induction of S-phase cell cycle arrest. Morphological evaluation and Annexin V-FITC/PI flow cytometry analysis confirmed induction of apoptosis that was further supported by cleavage and activation of caspase-8, caspase-9, caspase-3, and PARP- 1. Mutant p53 was also downregulated in a dose-dependent manner. No LDH release, mitochondrial membrane potential disruption, and ROS production were observed. Ternary copper (II) complex holds great potential to be developed for colorectal cancer treatment.

Speciation of the binary and ternary complexes of Copper(II) with 2-(benzo[d]thiazol-2-yl)nicotinic acid and some amino acids

ABSTRACT In this work, we present the results from a chemical speciation study of binary and ternary complexes formed by Cu(II) with 2-(benzo[d]thiazol-2-yl)nicotinic acid (HL) and the amino acids: Aspartic acid (H2Asp, H2B), Glutamic acid (H2Glu, H2B), Histidine (HHis, HB), Serine (HSer, HB), Threonine (Thr, HB), Phenylalanine (HPhe, HB) and Methionine (HMet, HB). The analysis is based on the use of potentiometric data analysed with the least-squares programme LETAGROP in 1 M NaCl aqueous solution at 25°C.

Copper(II) Complexes of Pyridine-2,6-dicarboxamide Ligands with High SOD Activity.

Copper(II) complexes of pyridine-based ligands functionalized with alanine (PydiAla) and tyrosine (PydiTyr) moieties have been synthesized as novel superoxide dismutase mimics. The complexes were characterized by pH-potentiometric, spectroscopic (UV-vis, circular dichroism, mass spectrometry, electron paramagnetic resonance spectroscopy), computational (DFT), and X-ray diffraction methods. Both ligands form high stability copper(II) complexes via the (Npy,N-,N-) donor set supported by the binding of the carboxylate pendant arms. Although the coordination mode is the same for the two systems, the tyrosine containing counterpart exhibits increased copper(II) binding affinity, which is most likely due to the presence of the aromatic moiety of the side chains. Both copper(II) complexes are capable of binding N-methylimidazole, and the formation of the corresponding ternary species was observed at physiological pH. The binary and ternary copper(II) complexes exhibit high SOD activity. The PydiTyr complex exhibits about 1 order of magnitude higher activity than the PydiAla complex. This is probably due to the presence of the phenolic OH group in the former species, which promotes the binding of the superoxide anion radical to the metal center. The results serve as a basis for designing highly efficient copper(II) mimics for medical and practical applications.

Sparfloxacin - Cu(II) - aromatic heterocyclic complexes: synthesis, characterization and in vitro anticancer evaluation.

Two new copper(II) complexes of sparfloxacin (sf), [Cu(Hsf)(HPB)(H2O)](ClO4)2 (1) and [Cu(Hsf)(PBT)(H2O)](ClO4)2 (2) (where HPB = 2-(2'-pyridyl)benzimidazole and PBT = 2-(4'-pyridyl) benzothiazole), have been synthesized and characterized by physicochemical and spectroscopic techniques. The oil-water partition coefficient (log P) values of complexes 1 and 2 were 1.47 and 1.71, respectively. By studying the interaction between the complexes and DNA, it was found that the complexes could bind to DNA through an intercalation mode. Moreover, both complexes were evaluated for antitumor activity, revealing that the complexes displayed good inhibitory activity toward the tested cancer cell lines (human lung carcinoma A549 cells, human hepatocellular carcinoma Bel-7402 cells and human esophageal carcinoma Eca-109 cells), but showed relatively low toxicity against normal human hepatic LO2 cells. In particular, the antitumor mechanism of the complexes on Eca-109 cells was investigated by morphological analysis, apoptosis analysis and determination of cell cycle arrest, mitochondrial membrane potential, reactive oxygen species (ROS) levels, and release of cytochrome c and Ca2+. The results demonstrated that the complexes could induce loss of intracellular mitochondrial functions and increase of ROS levels, which led to an increase of Ca2+ levels and the release of cytochrome c into the cytoplasm. In addition, the cell cycle was arrested in the G2/M phase, and western blot analysis showed that the caspase family was activated. These results fully proved that the complexes could induce apoptosis through DNA damage and loss of mitochondrial functions, accompanied by the regulation of endogenous proteins.

Anticancer chiral and racemic ternary copper(II) complexes: Multiple mechanisms and epigenetic histone methyltransferase enzymes as novel targets

Copper complexes have the potential to overcome the limitations of platinum anticancer drugs and to provide a solution to difficult to cure metastatic breast cancer. The anticancer properties of a set of ternary copper(II) complex salts, viz. [Cu(phen)(l-ala)(H2O)]NO31, rac-[Cu(phen)(ala)(H2O)]NO32, rac-[Cu(phen)(4MeOCA)(H2O)]NO33 (1,10-phenanthroline, phen; alanine, ala; 4-methyl-oxazolidine-4-carboxylate, 4MeOCA) are reported herein. The main focus is on their potency and mechanism of action towards metastatic breast MDA-MB-231 cancer cells. They were more cytotoxic than cisplatin by 24 fold. The results of a 5-dose screening of 1 and 3 on the NCI panel of 60 human cancer cell lines, and their structure activity relationship (SAR) analysis revealed novel feature of overcoming drug resistance. Other studies include cellular and nuclear morphological studies of 1 – 3 on metastatic breast cancer MDA-MB-231, normal breast MCF10A and Chang Liver cells together with (i) apoptosis and cell cycle analysis, (ii) ROS assays (PNDA and DCFH-DA), (iii) JC-1 mitochondrial membrane potential assay, and (iv) proteasome inhibition assay on MDA-MB-231 cells. In addition, the docking of the L- and D-enantiomers of [Cu(phen)(ala)(H2O)]+ cations in the proteolytic sites of the 20S provided new insight on their mechanism of proteasome inhibition. A preliminary epigenetic study on MDA-MB-231 and T47D breast cancer cells treated with 1 – 3 to monitor their EZH1, EZH2 and H3K27me3 protein expression indicated new mode of action involving histone methylating enzymes. The results showed for the first time the unusual effect of EZH1 and EZH2 knockdown in the two cell lines on apoptosis induced by copper(II) complex 3 to be cell subtype dependent.

An insight into non-covalent interactions in binary, ternary and quaternary copper (II) complexes: Synthesis, X-ray structure, DFT calculations, antimicrobial activity and molecular docking studies

Levofloxacin is a synthetic antibacterial agent that effectively inhibits DNA replication and is commonly used for the treatment of genitourinary, respiratory, and gastrointestinal tract infections. Metallodrugs interact with DNA, RNA, proteins, receptors, and lipids, making them unique and more effective as chemotherapy agents than their parent drugs. On this basis, herein four copper(II) complexes assembled from antibacterial levofloxacin ligand were synthesized and characterized using different analytical and spectroscopic measurements. X- ray perceived the formation of a ternary dimer and a ternary monomer complexes both in distorted square pyramidal geometry, with the existence of levofloxacin in a zwitterionic form. The other two complexes were verified, as binary and quaternary complexes having distorted octahedral geometry. Structure elucidation of these complexes was also explored by density functional theory methods and optimized geometrical parameters. Ternary dimer complex demonstrated higher stability than the ternary monomer complex. Natural bond orbital (NBO) analysis and molecular electrostatic potential (MESP)were investigated. Electronic absorption spectra of the optimized structure were performed using the time-dependent density functional theory (TD-DFT)/CAM-B3LYP method with LANL2DZ basis set in the gas phase. Binary copper complex exhibited significant antimicrobial activity and ternary monomer complex was more potent than ternary dimer complex. Interestingly levofloxacin and ternary copper complexes were completely devoid of antifungal activity, whereas octahedral binary and quaternary copper complexes displayed antifungal activity. In-silico molecular docking studies were accomplished with 3T88 (E-Coli) and 2GNP (S. pneumonia) receptors. Results proved powerful interaction at the docked site through the formation of hydrogen bond and van der wall interactions.

Exploring the permeation of fluoroquinolone metalloantibiotics across outer membrane porins by combining molecular dynamics simulations and a porin-mimetic in vitro model

The misuse and overuse of fluoroquinolones in recent years have triggered alarming levels of resistance to these antibiotics. Porin channels are crucial for the permeation of fluoroquinolones across the outer membrane of Gram-negative bacteria and modifications in porin expression are an important mechanism of bacterial resistance. One possible strategy to overcome this problem is the development of ternary copper complexes with fluoroquinolones. Compared to fluoroquinolones, these metalloantibiotics present a larger partition to the lipid bilayer and a more favorable permeation, by passive diffusion, across bacteriomimetic phospholipid-based model membranes. To rule out the porin-dependent pathway for the metalloantibiotics, we explored the permeation through OmpF (one of the most abundant porins present in the outer membrane of Gram-negative bacteria) using a multi-component approach. X-ray studies of OmpF porin crystals soaked with a ciprofloxacin ternary copper complex did not show a well-defined binding site for the compound. Molecular dynamics simulations showed that the translocation of the metalloantibiotic through this porin is less favorable than that of free fluoroquinolone, as it presented a much larger free energy barrier to cross the narrow constriction region of the pore. Lastly, permeability studies of different fluoroquinolones and their respective copper complexes using a porin-mimetic in vitro model corroborated the lower rate of permeation for the metalloantibiotics relative to the free antibiotics. Our results support a porin-independent mechanism for the influx of the metalloantibiotics into the bacterial cell. This finding brings additional support to the potential application of these metalloantibiotics in the fight against resistant infections and as an alternative to fluoroquinolones.