DNA targeting polyaza macrobicyclic dizinc(II) complexes promoting high in vitro caspase dependent anti-proliferative activity against human carcinoma cancer cells

A series of macrobicyclic dizinc(II) complexes Zn2L1-2B](ClO4)(4) (1-6) have been synthesized and characterized (L1-2 are polyaza macrobicyclic binucleating ligands, and B is the N,N-donor heterocyclic base (viz. 2,2'-bipyridine (bipy) and 1,10-phenanthroline (phen)). The DNA and protein binding, DNA hydrolysis and anticancer activity of these complexes were investigated. The interactions of complexes 1-6 with calf thymus DNA were studied by spectroscopic techniques, including absorption, fluorescence and CD spectroscopy. The DNA binding constant values of the complexes were found to range from 2.80 x 10(5) to 5.25 x 10(5) M-1, and the binding affinities are in the following order: 3 > 6 > 2 > 5 > 1 > 4. All the dizinc(II) complexes 1-6 are found to effectively promote the hydrolytic cleavage of plasmid pBR322 DNA under anaerobic and aerobic conditions. Kinetic data for DNA hydrolysis promoted by 3 and 6 under physiological conditions give observed rate constants (k(obs)) of 5.56 +/- 0.1 and 5.12 +/- 0.2 h(-1), respectively, showing a 10(7)-fold rate acceleration over the uncatalyzed reaction of dsDNA. Remarkably, the macrobicyclic dizinc(II) complexes 1-6 bind and cleave bovine serum albumin (BSA), and effectively promote the caspase-3 and caspase-9 dependent deaths of HeLa and BeWo cancer cells. The cytotoxicity of the complexes was further confirmed by lactate dehydrogenase enzyme levels in cancer cell lysate and content media.

Nuclear targeting terpyridine iron(II) complexes for cellular imaging and remarkable photocytotoxicity

Iron(II) complexes Fe(L)(2)](2+) as perchlorate (1-3) and chloride (1a-3a) salts, where L is 4'-phenyl-2,2':6',2 `'-terpyridine (phtpy in 1, 1a), 4'-(9-anthracenyl)-2,2':6',2 `'-terpyridine (antpy in 2, 2a) and 4'-(1-pyrenyl)-2,2':6',2 `'-terpyridine (pytpy in 3, 3a), were prepared and their photocytotoxicity studied. The diamagnetic complexes 1-3 having an FeN6 core showed an Fe(III)-Fe(II) redox couple near 1.0 V vs. saturated calomel electrode in MeCN-0.1 M tetrabutylammonium perchlorate. Complexes 2 and 3, in addition, displayed a quasi-reversible ligand-based redox process near 0.0 V. The redox and spectral properties are rationalized from the theoretical studies. The complexes bind to DNA in a partial intercalative mode. The pytpy complex efficiently photo-cleaves DNA in green light via superoxide and hydroxyl radical formation. The antpy and pytpy complexes exhibited a remarkable photocytotoxic effect in HeLa cancer cells (IC50, similar to 9 mu M) in visible light (400-700 nm), while remaining essentially nontoxic in dark (IC50, similar to 90 mu M). Formation of reactive oxygen species (ROS) inside the HeLa cells was evidenced from the fluorescence enhancement of dichlorofluorescein upon treatment with the pytpy complex followed by photo-exposure. The antpy and pytpy complexes were used for cellular imaging. Confocal imaging and dual staining study using propidium iodide (PI) showed nuclear localization of the complexes. (c) 2012 Elsevier Inc. All rights reserved.

Oxidative DNA cleavage, cytotoxicity and antimicrobial studies of L-ornithine copper (II) complexes

New ternary copper (II) complexes, Cu(L-orn)(B)(Cl)](Cl center dot 2H(2)O) (1-2) where L-orn is L-ornithine, B is an N,N-donor heterocyclic base, viz. 2,2'-bipyridine (bpy, 1) and 1,10-phenanthroline (phen, 2), were synthesized and characterized by various spectroscopic techniques. Complex 2 is characterized by the X-ray single crystallographic method. The complex shows a distorted square-pyramidal (4 + 1) CuN3OCl coordination sphere. Binding interactions of the complexes with calf thymus DNA (CT-DNA) were investigated by UV-Vis absorption titration, ethidium bromide displacement assay, viscometric titration experiment and DNA melting studies. Complex 2 shows appreciable chemical nuclease activity in the presence of 3-mercaptopropionic acid (MPA). The complexes were subjected to in vitro cytotoxicity studies against carcinomic human alveolar basal epithelial cells (A-549) and human epithelial (HEp-2) cells. The IC50 values of 1 and 2 are less than that of cisplatin against HEp-2 cell lines. MIC values for 1 against the bacterial strains Streptococcus mutans and Pseudomonas aeruginosa are 0.5 mM. (C) 2012 Elsevier Ltd. All rights reserved.

Photo-induced anticancer activity of polypyridyl platinum(II) complexes

Polypyridyl platinum(II) complexes (1-5), viz., Pt(pyphen)Cl]Cl (1), Pt(pyphen)(C CFc)]Cl (2), Pt(pydppz)Cl]Cl (3), Pt(pydppz)(C CPh)]Cl (4) and Pt(pydppz)(C CFc)]Cl (5), where pyphen is 6-(2-pyridyl)-1,10-phenanthroline, pydppz is 6-(2-pyridyl)-dipyrido-3,2-a:2',3'-c]-phenazine, FcC CH is ferrocenyl acetylene and PhC CH is phenyl acetylene, were synthesized, characterized and their DNA binding and photocytotoxic properties studied. The complexes showed strong binding affinity to calf-thymus DNA giving K-app of similar to 10(6)-10(7) M-1. Complexes 4 and 5 showed dual mode of binding to ct-DNA. The pydppz complexes 3-5 having a photoactive phenazine moiety showed photocytotoxicity in HeLa and MCF-7 cells in UV-A light of 365 nm with apoptotic cell death as evidenced from the acridine orange/ethidium bromide dual staining and the FACS data. (C) 2012 Elsevier Masson SAS. All rights reserved.

Cobalt(II), Nickel(II) and Copper(II) complexes of a tetradentate Schiff base as photosensitizers: Quantum yield of O-1(2) generation and its promising role in anti-tumor activity

In the present investigation, a Schiff base N'(1),N'(3)-bis(E)-(5-bromo-2-hydroxyphenyl)methylidene]benzene-1,3-d icarbohydrazide and its metal complexes have been synthesized and characterized. The DNA-binding studies were performed using absorption spectroscopy, emission spectra, viscosity measurements and thermal denatuaration studies. The experimental evidence indicated that, the Co(II), Ni(II) and Cu(II) complexes interact with calf thymus DNA through intercalation with an intrinsic binding constant K-b of 2.6 x 10(4) M-1, 5.7 x 10(4) M-1 and 4.5 x 10(4) M-1, respectively and they exhibited potent photo-damage abilities on pUC19 DNA, through singlet oxygen generation with quantum yields of 0.32, 0.27 and 0.30 respectively. The cytotoxic activity of the complexes resulted that they act as a potent photosensitizers for photochemical reactions. (C) 2012 Elsevier B.V. All rights reserved.

Synthesis, characterization and phosphotriesterase mimetic activity of some Zn(II) and Cu(II) complexes

We report here the synthesis and characterization of a few phenolate-based ligands bearing tert- amino substituent and their Zn(II) and Cu(II) metal complexes. Three mono/binuclear Zn(II) and Cu(II) complexes Zn(L1)(H2O)].CH3OH.H2O (1) (H (2) L1 = 6,6(')-(((2-dimethylamino)ethylazanediyl)bis(methylene))bis(2, 4-dimethylphenol), Zn-2(L2)(2)] (2) (H (2) L2 = 2,2(')-(((2-dimethylamino)ethyl)azanediyl)bis(methylene)bis(4- methylphenol) and Cu-2(L3)(2).CH2 Cl-2] (3) (H (2) L3 = (6,6(')-(((2-(diethylamino)ethyl)azanediyl)bis(methylene)) bis(methylene))bis(2,4-dimethylphenol) were synthesized by using three symmetrical tetradendate ligands containing N2O2 donor sites. These complexes are characterized by a variety of techniques including; elemental analysis, mass spectrometry, H-1, C-13 NMR spectroscopic and single crystal X-ray analysis. The new complexes have been tested for the phosphotriesterase (PTE) activity with the help of P-31 NMR spectroscopy. The P-31 NMR studies show that mononuclear complex Zn(L1)(H2O)].CH3OH.H2O (1) can hydrolyse the phosphotriester i.e., p-nitrophenyl diphenylphosphate (PNPDPP), more efficiently than the binuclear complexes Zn-2(L2)(2)] (2) and Cu-2(L3)(2).CH2Cl2] (3). The mononuclear Zn(II) complex (1) having one coordinated water molecule exhibits significant PTE activity which may be due to the generation of a Zn(II)-bound hydroxide ion during the hydrolysis reactions in CHES buffer at pH 9.0.

Air oxygenation chemistry of 4-TBC catalyzed by chloro bridged dinuclear copper(II) complexes of pyrazole based tridentate ligands: synthesis, structure, magnetic and computational studies

Four dinuclear bis(mu-Cl) bridged copper(II) complexes, Cu-2(mu-Cl)(2)(L-X)(2)](ClO4)(2) (L-X = N,N-bis(3,5-dimethylpyrazole-1-yl)-methyl]benzylamine with X = H(1), OMe(2), Me(3) and Cl(4)), have been synthesized and characterized by the single crystal X-ray diffraction method. In these complexes, each copper(II) center is penta-coordinated with square-pyramidal geometry. In addition to the tridentate L-X ligand, a chloride ion occupies the last position of the square plane. This chloride ion is also bonded to the neighboring Cu(II) site in its axial position forming an SP-I dinuclear Cu(II) unit that exhibits small intramolecular ferromagnetic interactions and supported by DFT calculations. The complexes 1-3 exhibit methylmonooxygenase (pMMO) behaviour and oxidise 4-tert-butylcatechol (4-TBCH2) with molecular oxygen in MeOH or MeCN to 4-tert-butyl-benzoquinone (4-TBQ), 5-methoxy-4-tert-butyl-benzoquinone (5-MeO-4-TBQ) as the major products along with 6,6'-Bu-t-biphenyl-3,4,3',4'-tetraol and others as minor products. These are further confirmed by ESI- and FAB-mass analyses. A tentative catalytic cycle has been framed based on the mass spectral analysis of the products and DFT calculations on individual intermediates that are energetically feasible.

New metal-organic precursors for MOCVD applications: Synthesis, characterization, crystal structure and thermal properties of mixed-ligand Mg(II) complexes

In an effort to develop new MOCVD precursors, mixed-ligand metal-organic complexes, bis (acetylacetonato-k(2)O,O') (2,2'-bipyridine-k(2)N,N') magnesium(II), and his (acetylacetonato-k(2)O,O') (1,10-phenanthroline-k(2)N,N') magnesium(II) were synthesized. Spectroscopic characterization and crystal structures confirmed them to be monomeric and stable complexes. Crystal structure analysis suggests in each of the magnesium(II) complexes, the metal center has a distorted octahedral coordination geometry. Thermo-gravimetric analysis (TGA/DTA) suggests that these complexes are volatile and thermally stable. The thermal characteristics of newly designed complexes make them attractive precursors for MOCVD applications. (c) 2012 Elsevier B.V. All rights reserved.

Palladium(II) complexes as biologically potent metallo-drugs: Synthesis, spectral characterization, DNA interaction studies and antibacterial activity

Four novel mononuclear Pd(II) complexes have been synthesized with the biologically active Schiff base ligands (L-1-L-4) derived from 3-amino-2-methyl-4(3H)-quinazolinone. The structure of the complexes has been proposed by elemental analysis, molar conductance, IR, H-1 NMR, mass, UV-Vis spectrometric and thermal studies. The investigation of interaction of the complexes with calf thymus DNA (CT-DNA) has been performed with absorption and fluorescence spectroscopic studies. The nuclease activity was done using pUC19 supercoiled DNA by gel-electrophoresis. All the ligands and their Pd(II) complexes have also been screened for their antibacterial activity by discolor diffusion technique. (C) 2013 Elsevier B.V. All rights reserved.

Photocytotoxic ferrocene-appended (L-tyrosine)copper(II) complexes of phenanthroline bases

Copper(II) complexes of ferrocene(Fc)-conjugated reduced Schiff base of L-tyrosine (Fc-TyrH), viz., Cu(Fc-Tyr)(L)](ClO4), where L is 1,10-phenanthroline (phen, 1), dipyrido3,2-d:2',3'-f]quinoxaline (dpq, 2), dipyrido3,2-a:2',3'-c]phenazine (dppz, 3) and 2-(naphthalen-1-yl)-1H-imidazo4,5-f]1,10]phenanthroline (nip, 4), were prepared and tested for their photocytotoxicity in cancer cells. Cu(Fc-Phe)(phen)](-ClO4) (5) of L-phenylalanine and Cu(Ph-Tyr)(L)(ClO4)] of the reduced Schiff base Ph-TyrH derived from benzaldehyde and L-tyrosine having phen (6) and dppz (7), and Cu(Ph-Phe)(phen)(ClO4)] (8) using L-phenylalanine were prepared and used as controls. Complexes 5 and 6 were structurally characterized by X-ray crystallography. A copper(II)-based d-d band near 600 nm and a ferrocenyl band at similar to 450 nm were observed in DMF-Tris-HCI buffer (1:4 v/v) in respective complexes. The complexes are photocleavers of pUC19 DNA in visible light forming (OH)-O-center dot radicals. They are cytotoxic in HeLa (human cervical cancer) and MCF-7 (human breast cancer) cells showing an enhancement of cytotoxicity in visible light. Fluorescence imaging shows nuclear localization of the complexes.

DNA and protein targeting 1,2,4-triazole based water soluble dinickel(II) complexes enhances antiproliferation and lactate dehydrogenase inhibition

Water soluble dinickel(II) complexes Ni-2(L)(2)(1-2)](NO3)(4) (1-2), where L1-2 are triazole based dinucleating ligands, were synthesized and characterized. The DNA binding, protein binding, DNA hydrolysis and anticancer properties were investigated. The interactions of complexes 1 and 2 with calf thymus DNA were studied by spectroscopic techniques, including absorption and fluorescence spectroscopy. The DNA binding constant values of the complexes 1 and 2 were found to be 2.36 x 10(5) and 4.87 x 10(5) M-1 and the binding affinities are in the following order: 2 > 1. Both the dinickel(II) complexes 1 and 2, promoted the hydrolytic cleavage of plasmid pBR322 DNA under both anaerobic and aerobic conditions. Kinetic data for DNA hydrolysis promoted by 1 and 2 under physiological conditions give the observed rate constants (k(obs)) of 5.05 +/- 0.2 and 5.65 +/- 0.1 h(-1), respectively, which shows 10(8)-fold rate acceleration over the uncatalyzed reaction of ds-DNA. Meanwhile, the interactions of the complex with BSA have also been studied by spectroscopy. Both the complexes 1 and 2 display strong binding propensity and the binding constant (K-b), number of binding sites (n) were obtained are 0.71 x 10(6) 1.47] and 5.62 x 10(6) 1.98] M-1, respectively. The complexes 1 and 2 also promoted the apoptosis against human carcinoma (HeLa, and BeWo) cancer cells. Cytotoxicity of the complexes was further confirmed by lactate dehydrogenase enzyme level in cancer cell lysate and content media. (c) 2013 Elsevier Ltd. All rights reserved.

Photocytotoxicity of copper(II) complexes of curcumin and N-ferrocenylmethyl-L-amino acids

Copper(II) complexes Cu(Fc-aa)(cur)] (1-3) of curcumin (Hcur) and N-ferrocenylmethyl-L-amino acids (Fc-aa), viz., ferrocenylmethyl-L-tyrosine (Fc-TyrH), ferrocenylmethyl-L-tryptophan (Fc-TrpH) and ferrocenylmethyl-L-methionine (Fc-MetH), were prepared and characterized. The DNA photocleavage activity, photocytotoxicity and cellular localization in HeLa and MCF-7 cancer cells of these complexes were studied. Acetylacetonate (acac) complexes Cu(Fc-aa)(acac)] (4-6) were prepared and used as controls. The chemical nuclease inactive complexes showed efficient pUC19 DNA cleavage activity in visible light. Complexes 1-3 showed high photocytotoxicity with low dark toxicity thus giving remarkable photodynamic effect. FACScan analysis showed apoptosis of the cancer cells. Fluorescence microscopic studies revealed primarily cytosolic localization of the complexes. (C) 2013 Elsevier Masson SAS. All rights reserved.

C-H center dot center dot center dot O-nitrate synthon assisted molecular assembly of hydrogen bonded Ni(II) and Cu(II) complexes

Two Schiff base metal complexes Cu-SPETNNO3 (1) and Ni-SPETNNO3 (2) SPETN=2,2-propane,1,3-diylbis(nitrilomethyldyne)pyridyl,phenolate] ] with hydrogen bonding groups have been synthesized and characterized by single-crystal X-ray diffraction. In both of the compounds nitrates occupy a crystallographic general position. In 1 the lattice nitrates are on the 2(1) screw axis while in 2 they are at the crystallographic inversion center. C-HOnitrate synthons (formed by the nitrate anions and peripheral hydrogen bonding groups of the metal complexes) are non-covalent building blocks in molecular-assembly and packing of the cationic Schiff base metal complexes (M=Ni2+, Cu2+), resulting in 2-D hydrogen bonded networks. The CuCu non-bonding contact in 1 is 3.268 angstrom while the Ni-Ni bonding distance in 2 is 3.437 angstrom.

Remarkable anticancer activity of ferrocenylterpyridine platinum(II) complexes in visible light with low dark toxicity

Ferrocenyl platinum(II) complexes (1-3), viz. Pt(Fc-tpy)Cl]Cl (1), Pt(Fc-tpy)(NPC)]Cl (2, HNPC = N-propargyl carbazole) and Pt(Fc-bpa)Cl]Cl (3), were prepared, characterized and their anti-proliferative properties in visible light in human keratinocyte (HaCaT) cell lines have been studied. Pt(Ph-tpy)Cl]Cl (4) was prepared and used as a control. Complexes 1 and 3, structurally characterized by X-ray crystallography, show distorted square-planar geometry for the platinum(II) centre. Complexes 1 and 2 having the Fc-tpy ligand showed an intense absorption band at similar to 590 nm. The ferrocenyl complexes are redox active showing the Fc(+)-Fc couple near 0.6 V vs. SCE in DMF-0.1 M tetrabutylammonium perchlorate (TBAP). Complexes 1-3 showed external binding to calf thymus DNA. Both 1 and 2 showed remarkable photocytotoxicity in HaCaT cell lines giving respective IC50 values of 9.8 and 12.0 mu M in visible light of 400-700 nm with low dark toxicity (IC50 > 60 mu M). Fluorescent imaging studies showed the spread of the complexes throughout the cell localising both in cytoplasm and the nucleus. The ferrocenyl complexes triggered apoptosis on light exposure as evidenced from the Annexin V-FITC/PI and DNA ladder formation assays. Spectral studies revealed the formation of ferrocenium ions upon photo-irradiation generating cytotoxic hydroxyl radicals via a Fenton type mechanism. The results are rationalized from a TDDFT study that shows involvement of ferrocene and the platinum coordinated terpyridine moiety as respective HOMO and LUMO.

mu-Oxamido binuclear copper (II) complexes: Synthesis, crystal structure, DNA interaction and antibacterial studies

Four binuclear copper (II) complexes Cu(oxpn)Cu(B)](2+) (2-5) bridged by N, N'-bis3-(methylamino) propyl] oxamide (oxpn), where, B is N, N-donor heterocyclic bases (viz. 2,2'-bipyridine (bpy, 2), 1,10-phenathroline (phen, 3), dipyrido3,2-d:2',3'-f]quinoxaline (dpq, 4) and dipyrido3,2-a:2',3'-c]phenazine (dppz, 5) are synthesized, characterized by different spectroscopic and single crystal X-ray data technique. The phen (3) and dpq (4) complexes were structurally characterized by X-ray data analysis. Their DNA binding, oxidative cleavage and antibactirial activities were studied. The dpq (4) and dppz (5) complexes are avid binders to the Calf thymus DNA (CT-DNA). The phen (3), dpq (4) and dppz (5) complexes show efficient oxidative cleavage of supercoiled DNA (SC DNA) through hydroxyl radical ((OH)-O-center dot) pathway in the presence of Mercaptopropionic acid (MPA). (C) 2013 Elsevier Ltd. All rights reserved.