In vitro and in vivo activity of a new unsymmetrical dinuclear copper complex containing a derivative ligand of 1,4,7-triazacyclononane: catalytic promiscuity of [Cu2(L)Cl3] (original) (raw)
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Synthesis, characterization, DNA binding, cleavage activity and cytotoxicity of copper(ii) complexes
Dalton Transactions, 2014
Three new mononuclear copper(II) complexes, [Cu(L 2 )] 2+ (1), [Cu(acac)(L)] + (2), and [Cu(acac-Cl)(L)] + (3) (L = 2-(4-pyridine)oxazo[4,5-f ]1,10-phenanthroline (4-PDOP); acac = acetylacetone; acac-Cl = 3-chloroacetylacetone), have been synthesized and characterized by elemental analysis, high resolution mass spectrometry (Q-TOF), and IR spectroscopy. Two of the complexes were structurally characterized by single-crystal X-ray diffraction techniques. Their interactions with DNA were studied by UV-vis absorption and emission spectra, viscosity, thermal melting, DNA unwinding assay and CD spectroscopy. The nucleolytic cleavage activity of the compounds was carried out on double stranded pBR322 circular plasmid DNA by using a gel electrophoresis experiment in the presence and absence of an oxidant (H 2 O 2 ). Active oxygen intermediates such as hydroxyl radicals and hydrogen peroxide generated in the presence of L and complexes 1-3 may act as active species for the DNA scission. The cytotoxicity of the complexes against HepG2 cancer cells was also studied. † Electronic supplementary information (ESI) available. CCDC 930714 and 930715. For ESI and crystallographic data in CIF or other electronic format see
Copper(II) N,N,O-Chelating Complexes as Potential Anticancer Agents
Inorganic Chemistry, 2021
Three novel dinuclear Cu(II) complexes based on a N,N,O-chelating salphen-like ligand scaffold and bearing varying aromatic substituents (-H,-Cl,-Br) have been synthesized and characterized. The experimental and computational data obtained suggest that all three complexes exist in dimeric form in the solid state and adopt 2 the same conformation. MS and EPR results indicate that the dimeric structure coexists with the monomeric form in solution upon solvent (DMSO and water) coordination. The three synthesized Cu(II) complexes exhibit high potentiality as ROS generators, with the Cu(II)/Cu(I) redox potential inside the biological redox window, and thus being able to biologically undergo Cu(II)/Cu(I) redox cycling. The formation of ROS is one of the most promising reported cell-death mechanisms for metal complexes to offer an inherent selectivity to cancer cells. In vitro cytotoxic studies in two different cancer cell lines (HeLa and MCF7) and in a normal fibroblasts cell line show promising selective cytotoxicity for cancer cells (IC50 about 25 µM in HeLa cells, which is in the range of cisplatin and improved respect to carboplatin), hence placing this N,N,O-chelating salphen-like metallic core as a promising scaffold to be explored in the design of future tailor-made Cu(II) cytotoxic compounds.
Inorganica Chimica Acta, 2006
We present here the synthesis, crystal structure, electrochemical behavior, spectroscopic properties (FT-IR, UV-Vis and EPR), nuclease and in vitro antitumor activities against human myeloid leukemia cell line of the mononuclear copper complex [Cu(HPCl-NOL)(Cl)]Cl AE MeOH (1). The reaction of the tetradentate ligand HPClNOL [1-(bis-pyridin-2-ylmethyl-amino)-3-chloropropan-2-ol] and 1 equiv. of [Cu(OH 2 ) 6 ](Cl) 2 , in methanol, resulted in 1, which crystallizes as blue monoclinic crystals. The complex is pentacoordinated with a distorted square-pyramidal geometry. The activity of complex 1 toward plasmid DNA and THP-1 carcinogenic cells was investigated. Complex 1 promotes the cleavage of supercoiled DNA (pBlueScript KS + DNA) to nicked circular and linear DNA forms. In addition to the three typical KS + DNA forms, the cleavage resulted in a fourth band, which was visualized above of the nicked circular form. The results reveal that the cleavage mechanism is radical-independent. Furthermore, complex 1 is able to promote cell death of THP-1 cells by apoptosis, as confirmed by fluorescent microscopy, cell morphology and DNA degradation.
Journal of inorganic biochemistry, 2009
We have studied the protonation equilibria of a dicopper(II) complex [Cu(2)(micro-OH)(C(21)H(33)ON(6))](ClO(4))(2).H(2)O, (1), in aqueous solution, its interactions with DNA, its cytotoxic activity, and its uptake in tumoral cells. C(21)H(33)ON(6) corresponds to the ligand 4-methyl-2,6-bis[(6-methyl-1,4-diazepan-6-yl)iminomethyl]phenol. From spectrophotometric data the following pKa values were calculated 3.27, 4.80 and 6.10. Complex 1 effectively promotes the hydrolytic cleavage of double-strand plasmid DNA under anaerobic and aerobic conditions. The following kinetic parameters were calculated k(cat) of 2.73 x 10(-4)s(-1), K(M) of 1.36 x 10(-4)M and catalytic efficiency of 2.01 s(-1)M(-1), a 2.73 x 10(7) fold increase in the rate of the reaction compared to the uncatalyzed hydrolysis rate of DNA. Competition assays with distamycin reveal minor groove binding. Complex 1 inhibited the growth of two tumoral cell lines, GLC4 and K562, with the IC(50) values of 14.83 microM and 34.21 m...
Medicinal Chemistry Research, 2014
Two ternary copper(II) complexes of DL-threonine and polypyridyl ligands with formula of [Cu(Thr) (Byp)Cl]ÁH 2 O (1) and [Cu(Thr)(Phen)H 2 O]ClÁ2H 2 O were synthesized. The complexes were characterized by spectral (NMR, FT-IR, and UV-Vis), CHN elemental analysis and have been structurally elucidated by X-ray crystallography. Both of the complexes formed slightly distorted square-pyramidal coordination geometry. The electronic absorption spectra of the complexes showed a very low intensity d-d electronic band in the range of 610-620 nm in Tris-HCl/NaCl (5:5 mM) pH 7.2 buffer solution. The DNA binding interaction with calf-thymus DNA (CT-DNA) was investigated by electronic absorption spectral titration and viscosity measurements. The results revealed that the phenanthroline complex (2) interact with CT-DNA through intercalation while bipyridyl complex (1) through the groove binding mode. The calculated intrinsic binding constant (K b ) of (1) and (2) were 0.5 and 4.4 9 10 5 M -1 , respectively. Both the complexes were found to promote efficient DNA cleavage activities at low concentration in the presence of H 2 O 2 . The results showed that (2) has the highest DNA binding and nuclease activity.
Polyhedron, 2011
The copper complexes [Cu(Pyimpy)(H 2 O)](ClO 4 ) 2 (1), [Cu(Pyimpy) 2 ](ClO 4 ) 2 (2), [Cu(Pyimpy)(Cl) 2 ]Á2H 2 O (3Á2H 2 O), [Cu(Pyimpy)(N 3 )(ClO 4 )] 2 (4) and [Cu(Pyimpy)(SCN)(ClO 4 )] 2 (5) were synthesized and characterized by spectroscopic techniques, crystal structures and electrochemical studies (Pyimpy: (2-((2-phenyl-2-(pyridin-2-l)hydrazono)methyl)pyridine)). The superoxide scavenging activity of the two water soluble complexes 1 and 3 was examined. DNA interaction studies by UV-Vis absorption spectral changes during a titration experiment indicated the generation of new species. These small molecule SOD mimics exhibited excellent DNA cleavage activity in the presence of H 2 O 2 as well as 2-mercaptoethanol. Complexes 1-5 exhibited better cytotoxicity compared to CuCl 2 Á2H 2 O and the ligand Pyimpy, and showed more potency than cisplatin for MCF-7, PC-3 and HEK-293 cells. Complex 3 exhibited the highest potency for MCF-7, PC-3 and HEK-293 cells compared to the other complexes.
Inorganic Chemistry Communications, 2012
Two new tetradentate ligands Timpy (1,2-bis((E)-(2-phenyl-2-(pyridine-2-yl)hydrozono)methyl)benzene) and Gimpy ((1Z,2Z)-1,2-bis(2-phenyl-2-(pyridine-2-yl)hydrozono)ethane) were synthesized and characterized. Mononuclear complexes [Cu(Timpy)(ClO 4 )](ClO 4 ) (1) and [Cu(Gimpy)](ClO 4 ) 2 (2) were synthesized and characterized by IR, UV-visible and conductivity measurements. The molecular structure of [Cu(Timpy)(ClO 4 )] (ClO 4 ) (1) was determined by single crystal X-ray diffraction and structural index parameter (τ =0.4725) supported distorted square planar geometry at the metal centre. Electrochemical studies for 1 and 2 were investigated. Two-fold applications of these complexes were examined. First, self-activated DNA cleavage activity of complexes 1 and 2 and mechanism of nuclease activity. Second, the complexes were utilized as fluorescence probe for the detection of nitric oxide in solution.
Background: To overcome the hurdles of cisplatin, majorly its toxicity and resistance, there has been extensive search for alternative anti-cancer metal-based compounds. Here, three Cu(II)-complexes, Cu(Sal-Gly)(phen), Cu(Sal-Gly)(pheamine), Cu(Sal-Gly)(phepoxy) are characterized for their interaction with DNA, cytotoxicity and mechanism of action. Methods: The binding ability of the complexes to Calf-Thymus DNA was evaluated by competition fluorescence studies with thiazole-orange, UV-Vis and circular dichroism spectroscopic titrations. Cytotoxicity was evaluated by MTT analysis. The DNA damage was analyzed through cleavage of supercoiled DNA via agarose gel-electrophoresis, and 8-oxo-guanidine and ɣH2AX staining in cells. Apoptosis was detected via DNA condensation/fragmentation, mitochondrial membrane potential, Annexin V staining and caspase 3/7 activity. Formation of reactive oxygen species was determined by DCFDA-and GSSG/GSH-analysis. Results: Binding constants to DNA were evaluated as 1.7 × 10 6 (Cu(Sal-Gly)(phen)), 2.5 × 10 6 (Cu(Sal-Gly)(pheamine)) and 3.2 × 10 5 (Cu(Sal-Gly)(phepoxy)). All compounds induced DNA damage. Apoptosis was the main form of cell death. There was an increase in ROS, which is most likely responsible for the observed DNA-damage. Although the compounds were cytotoxic to all tested cancer cell lines, only Cu(Sal-Gly)(pheamine) displayed significantly lower toxicity towards non-cancer cells, its associated phenotypes differing from the other two Cu-complexes. Thus, Cu(Sal-Gly)(pheamine) was further assayed for molecular changes in response to drug treatment using a custom designed RT-qPCR array. Results showed that Harakiri was significantly upregulated. Presence of p53 was not required for apoptosis in response to Cu-complexes. Conclusions and general significance: These Cu-complexes, namely Cu(Sal-Gly)(pheamine), may be considered promising anticancer agents with activity in cancer cells even with deficient p53 status.
Journal of Biological …, 2007
We characterized the pro-apoptotic activity of two new synthesized isatin-Schiff base copper(II) complexes, obtained from isatin and 1,3-diaminopropane or 2-(2-aminoethyl)pyridine: (Cu(isapn)) and (Cu(isaepy) 2 ), respectively. We demonstrated that these compounds trigger apoptosis via the mitochondrial pathway. The early induction of the p53/p21 system indicates a role for p53 in cell death, however, experiments carried out with small interfering RNA against p53, or with cells lacking p53, support that a p53-independent mechanism can also occur. The extent of apoptosis mirrors the kinetics of intracellular copper uptake. Particularly, Cu(isaepy) 2 enters the cells more efficiently and specifically damages nuclei and mitochondria, as evidenced by atomic absorption analysis of copper content and by the extent of nuclear and mitochondrial integrity. Conversely, Cu(isapn), although less permeable, induces a widespread oxidative stress, as demonstrated by analyses of reactive oxygen species concentration, and oxidation of proteins and lipids. The increase of the antioxidant defense, through the overexpression of Cu,Zn-SOD, partially counteracts cell death; whereas retinoic acid-mediated differentiation completely rescues cells from apoptosis induced by both compounds. The activation of JNK-and Akt-mediated phosphorylative pathways has been found to be not functional for apoptosis induction. On the contrary, apoptosis significantly decreased when the analogous zinc complex was used or when Cu(isaepy) 2 was incubated in the presence of a copper chelator. Altogether, our data provide evidence for a dual role of these copper(II) complexes: they are able to vehicle copper into the cell, thus producing reactive oxygen species, and could behave as delocalized lipophilic cation-like molecules, thus specifically targeting organelles.
Inorganica Chimica Acta, 2009
Two new copper(II) complexes of the type [Cu(L)X 2), where L = (E)-N-phenyl-2-[phenyl (pyridine-2yl)methylene]hydrazinecarboxamide X = Cl/Br have been synthesized and characterized by elemental analyses, FAB (fast atomic bombardment) magnetic measurements, electronic absorption, conductivity measurements cyclic voltammetry (CV) and Electron paramagnetic resonance (epr) spectroscopy. The structures of these complexes determined by single crystal X-ray crystallography show a distorted square based pyramidal (DSBP) geometry around copper(II) metal center. The distorted CuN 2 OX (X = Cl/Br) basal plane in them is comprised of two nitrogen and one oxygen atoms of the meridionally coordinated ligand and a chloride or bromide ion and axial position is occupied by other halide ion. The epr spectra of these complexes in frozen solutions of DMSO showed a signal at g ca. 2. The trend in g-value (g || > g \ > 2.00) suggest that the unpaired electron on copper(II) has d x 2 Ày 2 character. Biological activities in terms of superoxide dismutase (SOD) and antimicrobial properties of copper(II) complexes have also been measured. The superoxide dismutase activity reveals that these two complexes catalyze the fast disproportionation of superoxide in DMSO solution.