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

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

Enhanced nucleophilicity and depressed electrophilicity of peroxide by zinc(II), aluminum(III) and lanthanum(III) ions

The binuclear zinc(II) complex, [Zn2(HPTP)(CH3COO)]2+ was found highly active to cleave DNA (double-strand super-coiled DNA, pBR322 and phix174) in the presence of hydrogen peroxide. However, no TBARS (2-thiobarbituric acid reactive substance) formation was detected in a solution containing 2-deoxyribose (or 2'-deoxyguanosine, etc); where (HPTP) represents N,N,N'-N'-tetrakis(2-pyridylmethyl)-1,3-diamino-2-propanol. These facts imply that DNA cleavage reaction by the binuclear Zn(II)/H2O2 system should be due to a hydrolytic mechanism, which may be attributed to the enhanced nucleophilicity but depressed electrophilicity of the peroxide ion coordinated to the zinc(II) ion. DFT (density-functional theory) calculations on the peroxide adduct of monomeric zinc(II) have supported the above consideration. Similar DFT calculations on the peroxide adducts of the Al(III) and La(III) compounds have revealed that electrophilicity of the peroxide ion in these compounds is strongly reduced. This gives an important information to elucidate the fact that La3+ can enhance the growth of plants under certain conditions.     

Electronic absorption spectroscopy and time-dependent density functional theory calculations on the nickel(II) complex of 1,4-bis(pyrrol-2-ylmethyleneamino)butane

The electronic structure of the 1,4-bis(pyrrol-2-ylmethyleneamino)butane nickel(II) complex has been studied using electronic absorption spectroscopy and density functional theory (DFT) calculations. The DFT optimised structure is in excellent agreement with the X-ray crystal structure of the complex and time-dependent DFT calculations have been used to probe the nature of the transitions observed in the electronic absorption spectrum.     

Copper (II) and cobalt (II) complexes of chiral tetrathiafulvalene-oxazoline (TTF-OX) and tetrathiafulvalene-thiomethyl-oxazoline (TTF-SMe-OX) derivatives

Synthesis and single crystal X-ray structures of the first paramagnetic transition metal complexes containing chiral ethylenedithio-tetrathiafulvalene-oxazoline (EDT-TTF-OX) 1a-c and ethylenedithio-tetrathiafulvalene-thiomethyloxazoline 2 (EDT-TTF-(SMe)OX) ligands based on copper (II) and cobalt (II) are described. The racemic [EDT-TTF-OX][Cu(hfac)₂] complex 3a crystallizes in the triclinic centrosymmetric space group , whereas the enantiopure counterparts 3b-c crystallize in the triclinic non-centrosymmetric space group P1. Cu(II) adopts a distorted square pyramidal coordination geometry, a much weaker Cu?S_TTF interaction also being identified. The same coordination pattern around Cu(II) is observed in the complex [(rac)-EDT-TTF-(SMe)OX][Cu(hfac)₂] (4) in spite of the bidentate nature of the redox active ligand. DFT theoretical calculations afforded two equilibrium configurations for a corresponding model complex, in which the metal centre establishes secondary coordination either with one S_TTF or with the SMe group. The same ligand coordinates the cobalt (II) to afford the octahedral complex [(rac)-EDT-TTF-(SMe)OX][Co(hfac)₂] (5). In all these novel complexes, the paramagnetic centres are structurally and magnetically isolated. Cyclic voltammetry measurements show the stability of the radical cation species.     

Calculating the geometry and Raman spectrum of physiological bis(<Emphasis Type="SmallCaps">l</Emphasis>-histidinato)copper(II): an assessment of DFT functionals for aqueous and isolated systems

Reliable density functional theory (DFT) calculations can be performed in conjuction with spectroscopic measurements to elucidate the structural properties of physiologically important bis(amino acidato)copper(II) compounds in solutions. They can provide insight into the influence of intermolecular interactions on the molecular geometry in the crystal lattice or solution when compared with a DFT gas-phase minimum. Our previous paper [Markovi? et al. (2014) Eur J Inorg Chem 198] reported the DFT-determined geometries and Raman spectra for different conformers of physiological bis(l-histidinato)copper(II) with 20 explicit water molecules, as calculated using the B3LYP functional. The present study examined the reliability of those B3LYP results by applying the M06 functional instead, as it should better account for noncovalent interactions. The water molecules were positioned more compactly around the complex by M06 than by B3LYP. The accuracies of the two functionals when compared to relevant experimental data showed that M06 was better at reproducing in-plane Cu?N bond lengths but B3LYP gave more accurate axial Cu?O distances. Both functionals reproduced the experimental Raman spectrum at pH 8 to similar levels of accuracy and provided precise information on the Cu(II) coordination mode and conformation in aqueous solution. Additionally, we assessed several DFT and DFT-D functionals (BP86, B3LYP, B3LYP-D, M06, M06 L, wB97XD, mPW2PLYPD) by using them to model the geometries of experimental bis(l-histidinato)copper(II) crystalline conformations as isolated systems, and then benchmarking the results against those from high-level second-order pertubation Møller–Plesset (MP2) calculations. Although this assessment resulted in an equivocal conclusion because the MP2 results for the isolated complex were inconsistent with the corresponding DFT outcomes, it does provide new information on future benchmark options.     

Thiolate coordination to Fe(II)-porphyrin NO centers

The interaction of the Fe(II)-porphyrin NO model complex [Fe(TPP)(NO)] (1, TPP=tetraphenylporphyrin) with thiophenolate ligands and tetrahydrothiophene is explored both computationally and experimentally. Complex 1 is reacted with substituted thiophenolates and the obtained six-coordinate adducts of type [Fe(TPP)(SR)(NO)](-) are investigated in solution using electron paramagnetic resonance (EPR) spectroscopy. From the obtained g values and (14)N hyperfine pattern of the NO ligand it is concluded that the interaction of the thiophenolates with the Fe(II) center is weak in comparison to the corresponding 1-methylimidazole adduct. The strength of the Fe-S bond is increased when alkylthiolates are used as evidenced by comparison with the published EPR spectra of ferrous NO adducts in cytochromes P450 and P450nor, which have an axial cysteinate ligand. These results are further evaluated by density functional (DFT) calculations. The six-coordinate model complex [Fe(P)(SMe)(NO)](-) (1-SMe; P=porphine ligand used for the calculations) has an interesting electronic structure where NO acts as a medium strong sigma donor and pi acceptor ligand. Compared to the N-donor adducts with 1-methylimidazole (1-MeIm), etc., donation from the pi(h)( *) orbital of NO to Fe(II) is reduced due to the stronger trans effect of the alkylthiolate ligand. This is reflected by the predicted longer Fe-NO bond length and smaller Fe-NO force constant for 1-SMe compared to the 1-MeIm adduct. Therefore, the Fe(II)-porphyrin NO adducts with trans alkylthiolate coordination have to be described as Fe(II)-NO(radical) systems. The N-O stretching frequency of these complexes is predicted below 1600cm(-1) in agreement with the available experimental data. In addition, 1-SMe has a unique spin density distribution where Fe has a negative spin density of -0.26 from the calculations. The implications of this unusual electronic structure for the reactivity of the Fe(II)-NO alkylthiolate adducts as they occur in cytochrome P450nor are discussed.     

Antibacterial Co(II), Ni(II), Cu(II) and Zn(II) complexes of Schiff bases derived from fluorobenzaldehyde and triazoles

Antibacterial Schiff bases derived from 1,2,4-triazoles as well as their metal complexes incorporating cobalt(II), nickel(II), copper(II) and zinc(II) have been synthesized and characterized. Physico-chemical studies suggest that an octahedral geometry for the cobalt(II), nickel(II) and zinc(II)and square-planer geometry for the copper(II) complexes. These complexes have been screened for antibacterial activity against three Gram-positive (Staphylococcus aureus, Staphylococcus epidermidis and Bacillus subtilis) and two Gram-negative (Salmonella typhi and Pseudomonas aeruginosa) bacterial strains, and results compared with the activity of the free ligands. The metal complexes were found to be more potent against one or more bacterial strains than the free ligands.     

Heterocyclic fluorescent Schiff base chemosensors for the detection of Fe(III) and Cu(II) ions

Two new Schiff bases were synthesized from 1-(2,4-dihydroxyphenyl)ethanone and pyridine derivatives. Both compounds were characterized using infrared, UV–Vis., ¹H NMR, ¹³C NMR and mass spectral studies. Density functional theory (DFT) calculations were performed for both the Schiff bases with 6-31G(d, p) as the basis set. Vibrational frequencies calculated using the theoretical method were in good agreement with the experimental values. Both the Schiff bases were highly fluorescent in nature. The cation-recognizing profile of the compounds was investigated in aqueous methanol medium. The Schiff base 4-(1-(pyridin-4-ylimino)ethyl)benzene-1,3-diol (PYEB) was found to interact with Fe(III) and Cu(II) ions, whereas the Schiff base 4,4′-((pyridine-2,3-diylbis(azanylylidene))bis(ethan-1-yl-1-ylidene))bis(benzene-1,3-diol) (PDEB) was found to detect Cu(II) ions. The mechanism of recognition was established as combined excited state intramolecular proton transfer (ESIPT)–chelation-enhanced fluorescence (CHEF) effect and chelation-enhanced quenching (CHEQ) process for the detection of Fe(III) and Cu(II) ions, respectively. The stability constant of the metal complexes formed during the sensing process was determined. The limit of detection for Fe(III) and Cu(II) ions with respect to Schiff base PYEB was found to be 1.64 × 10⁻⁶ and 2.16 × 10⁻⁷ M, respectively. With respect to Schiff base PDEB, the limit of detection for Cu(II) ion was found to be 4.54 × 10⁻⁴ M. The Cu(II) ion sensing property of the Schiff base PDEB was applied in bioimaging studies for the detection of HeLa cells.     

Cobalt(II) and zinc(II) binding to a ferredoxin maquette

We have examined the Co(II) and Zn(II) affinity of the prototype ferredoxin maquette ligand, NH(2)-KLCEGG.CIACGAC.GGW-CONH2 (IAA), which was originally designed to bind a [4Fe-4S] cluster. UV-Vis spectroscopy demonstrates tight 1:1 complex formation between Co(II) and IAA. The intensity of the S-->Co(II) charge transfer bands at 304 and 340 nm and the ligand field bands between 630 and 728 nm indicate Co(II) coordination by the four cysteine thiolates of IAA in a pseudo-tetrahedral geometry. A dissociation constant value of 5.3 microM was determined for the Co(II)-IAA complex at pH 6.5. Zn(II) readily displaces Co(II) from IAA as evinced by loss of the Co(II) spectral features. The dissociation constant for Zn(II), 20 pM at pH 6.5, was determined be competition experiments with Co(II)-IAA. These results demonstrate that the ferredoxin maquette ligand is an excellent ligand for Zn(II).     

Copper(II), cobalt(II) and nickel(II) complexes of alkyl-substituted tris(2-benzimidazolylmethyl)amines and their ternary copper(II) systems containing several thiolates

Copper(II), cobalt and nickel(II) complexes of tris(benzimidazolylmethyl)amine(1) and of its methyl(2), isobutyl(3) or isopropyl(4)-substituted derivatives of one of the backbone methylene groups were prepared and characterized. The ligands (1)–(3) afforded trigonal bipyramidal copper(II) complexes, whereas ligand (4) gave a tetrahedrally distorted tetragonal one because of the steric hindrance arising from the isopropyl group. All the cobalt(II) complexes prepared were supposed to be tetrahedral or pseudotrigonal bipyramidal, and all the nickel(II) complexes to be slightly tetrahedrally distorted octahedral. Ternary copper(II) systems containing several thiolates as the third component exhibited intense blue, brown or green color under a reduced temperature by virtue of the charge transfer bands, S^? → Cu.     

Antibacterial Co(II), Ni(II), Cu(II) and Zn(II) Complexes of Schiff bases Derived from Fluorobenzaldehyde and Triazoles

Antibacterial Schiff bases derived from 1,2,4-triazoles as well as their metal complexes incorporating cobalt(II), nickel(II), copper(II) and zinc(II) have been synthesized and characterized. Physico-chemical studies suggest that an octahedral geometry for the cobalt(II), nickel(II) and zinc(II)and square-planer geometry for the copper(II) complexes. These complexes have been screened for antibacterial activity against three Gram-positive (Staphylococcus aureus, Staphylococcus epidermidis and Bacillus subtilis) and two Gram-negative (Salmonella typhi and Pseudomonas aeruginosa) bacterial strains, and results compared with the activity of the free ligands. The metal complexes were found to be more potent against one or more bacterial strains than the free ligands.     

Synthesis, physico-chemical characterization and antimicrobial activity of cobalt(II), nickel(II), copper(II), zinc(II) and cadmium(II) complexes with some acyldihydrazones

Complexes of the type [M(bssdh)]Cl and [M(dspdh)]Cl, where M = Co(II), Ni(II), Cu(II), Zn(II) and Cd(II); Hbssdh = benzil salicylaldehyde succinic acid dihydrazone, Hdspdh = diacetyl salicylaldehyde phthalic acid dihydrazone have been synthesized and characterized with the help of elemental analyses, electrical conductance, magnetic susceptibility measurements, electronic, ESR and IR spectra and X-ray diffraction studies. Magnetic moment values and electronic spectral transitions indicate a spin free octahedral structure for Co(II), Ni(II) and Cu(II) complexes. IR spectral studies suggest that both the ligands behave as monobasic hexadentate ligands coordinating through three > C = O, two > C = N- and a phenolate group to the metal. ESR spectra of Cu(II) complexes are axial type and suggest d(x(2)-y(2)) as the ground state. X-ray powder diffraction parameters for [Co(bssdh)]Cl and [Co(dspdh)]Cl complexes correspond to an orthorhombic crystal lattice. The ligands as well as their metal complexes show a significant antifungal and antibacterial activity against various fungi and bacteria. The metal complexes are more active than the parent ligands.     

Antibacterial cobalt(II), nickel(II) and zinc(II) complexes of nicotinic acid-derived Schiff-bases

Nicotinic acid derived Schiff bases and their transition metal [cobalt(II), nickel(II) and zinc(II)] complexes have been prepared and characterized by physical, spectral and analytical data. The Schiff bases act as deprotonated tridentate ligands for the complexation of the above mentioned metal ions. These complexes, possessing the general formula [M(L)2] [where M = Co(II), Ni(II) and Zn(II) and L = HL1-HL4] showed an octahedral geometry of the metal ions. For determining the effect of metal ions upon chelation, the Schiff bases and their complexes have been screened for antibacterial activity against several pathogenic strains of Escherichia coli, Staphylococcus aureus and Pseudomonas aeruginosa. The new metal derivatives reported here were more bactericidal against one or more bacterial species as compared to the uncomplexed Schiff bases.     

Theoretical,in Vitro Antiproliferative,and in Silico Molecular Docking and Pharmacokinetics Studies of Heteroleptic Nickel(II) and Copper(II) Complexes of Thiosemicarbazone-Based Ligands and Pefloxacin

Twelve new heteroleptic nickel(II) and copper(II) complexes of the type [M(L^1–6)(Pfx)₂] ( 1 – 12 ), where L^1–6=2-benzylidenehydrazinecarbothioamide (L¹), 2-benzylidene-N-methylhydrazinecarbothioamide (L²), 2-benzylidene-N-phenylhydrazinecarbothioamide (L³), 2-(4-methylbenzylidene)hydrazinecarbothioamide (L⁴), 2-(4-methylbenzylidene)-N-methylhydrazinecarbothioamide (L⁵) and 2-(4-methylbenzylidene)-N-phenylhydrazinecarbothioamide (L⁶), Pfx=pefloxacin and M=Ni(II) or Cu(II) have been synthesised, and their structures were confirmed by different spectral techniques. The spectral data and density functional theory (DFT) calculations supported the bonding of pefloxacin drug molecule via one of the carboxylate oxygen atoms and the pyridone oxygen atom, and the thiosemicarbazone ligand via the imine nitrogen and the thione sulfur atoms with the metal(II) ion, forming distorted octahedral geometry. In vitro antiproliferative activity of the synthesized complexes was evaluated against three human breast cancer (T47D, estrogen negative (MDA-MB-231) and estrogen positive (MCF-7)) as well as non-tumorigenic human breast epithelial (MCF-10a) cell lines, which showed the higher activity for the copper(II) complexes. The interaction of the synthesized complexes with an oncogenic protein H-ras (121 p) was explored by in silico molecular docking studies. Further, in silico pharmacokinetics and ADMET parameters were also analysed to predict the drug-likeness as well as non-toxic and non-carcinogenic behavior, and safe oral administration of the complexes.     

Metalloantibiotics: synthesis and antibacterial activity of cobalt(II), copper(II), nickel(II) and zinc(II) complexes of kefzol

Kefzol (kzl), a beta-lactam antibiotic, possesses various donor sites for interaction with transition metal(II) ions [Co(II), Cu(II), Ni(II) and Zn(II)] to form complexes of the type [M(kzl)2]Cl2 and [M(kzl)Cl], with molar ratio of metal: ligand (M:L) of 1:2 and 1:1 respectively. These complexes were prepared and characterized by physicochemical and spectroscopic methods. Their IR and NMR spectra suggest that kefzol potentially acts as a bidentate, tridentate as well as monoanionic tetradentate ligand. The complexes have been screened for antibacterial activity and results were compared with the activity of the uncomplexed antibiotic against Staphylococcus aureus, Klebsiella pneumoniae, Pseudomonas aeruginosa, Escherichia coli and Proteus mirabilis. The metal complexes were found to be more potent against one or more bacterial species than the uncomplexed kefzol.     

Photodissociation of a ruthenium(II) arene complex and its subsequent interactions with biomolecules: a density functional theory study

The piano-stool Ru(II) arene complex [(η(6)-benz)Ru(bpm)(py)](2+) (benz?=?benzene, bpm?=?2,2'-bipyrimidine, and py?=?pyridine), which is conventionally nonlabile (on a timescale and under conditions relevant for biological reactivity), can be activated by visible light to selectively photodissociate the monodentate ligand (py). In the present study, the aquation and binding of the photocontrolled ruthenium(II) arene complex [(η(6)-benz)Ru(bpm)(py)](2+) to various biomolecules are studied by density functional theory (DFT) and time-dependent DFT (TDDFT). Potential energy curves (PECs) calculated for the Ru-N (py) bonds in [(η(6)-benz)Ru(bpm)(py)](2+) in the singlet and triplet state give useful insights into the photodissociation mechanism of py. The binding energies of the various biomolecules are calculated, which allows the order of binding affinities among the considered nuleic-acid- or protein-binding sites to be discerned. The kinetics for the replacement of water in the aqua complex with biomolecules is also considered, and the results demonstrate that guanine is superior to other biomolecules in terms of coordinating with the Ru(II) aqua adduct, which is in reasonable agreement with experimental observations.     

Metalloantibiotics: Synthesis and Antibacterial Activity of Cobalt(II), Copper(II), Nickel(II) and Zinc(II) Complexes of Kefzol

Kefzol (kzl), a β-lactam antibiotic, possesses various donor sites for interaction with transition metal(II) ions [Co(II), Cu(II), Ni(II) and Zn(II)] to form complexes of the type [M(kzl)2]Cl2 and [M(kzl)Cl], with molar ratio of metal: ligand (M:L) of 1:2 and 1:1 respectively. These complexes were prepared and characterized by physicochemical and spectroscopic methods. Their IR and NMR spectra suggest that kefzol potentially acts as a bidentate, tridentate as well as monoanionic tetradentate ligand. The complexes have been screened for antibacterial activity and results were compared with the activity of the uncomplexed antibiotic against Staphylococcus aureus, Klebsiella pneumoniae, Pseudomonas aeruginosa, Escherichia coli and Proteus mirabilis. The metal complexes were found to be more potent against one or more bacterial species than the uncomplexed kefzol.