Cheng-Zhi Xie

Study on potential antitumor mechanism of a novel Schiff base copper(II) complex: synthesis, crystal structure, DNA binding, cytotoxicity and apoptosis induction activity.

A new cytotoxic copper(II) complex with Schiff base ligand [Cu(II)(5-Cl-pap)(OAc)(H(2)O)]·2H(2)O (1) (5-Cl-pap=N-2-pyridiylmethylidene-2-hydroxy-5-chloro-phenylamine), was synthesized and structurally characterized by X-ray diffraction. Single-crystal analysis revealed that the copper atom shows a 4+1 pyramidal coordination, a water oxygen appears in the apical position, and three of the basal positions are occupied by the NNO tridentate ligand and the fourth by an acetate oxygen. The interaction of Schiff base copper(II) complex 1 with DNA was investigated by UV-visible spectra, fluorescence spectra and agarose gel electrophoresis. The apparent binding constant (K(app)) value of 6.40×10(5) M(-1) for 1 with DNA suggests moderate intercalative binding mode. This copper(II) complex displayed efficient oxidative cleavage of supercoiled DNA, which might indicate that the underlying mechanism involve hydroxyl radical, singlet oxygen-like species, and hydrogen peroxide as reactive oxygen species. In addition, our present work showed the antitumor effect of 1 on cell cycle and apoptosis. Flow cytometric analysis revealed that HeLa cells were arrested in the S phase after treatment with 1. Fluorescence microscopic observation indicated that complex 1 can induce apoptosis of HeLa cells, whose process was mediated by intrinsic mitochondrial apoptotic pathway owing to the activation of caspase-9 and caspase-3.

Activities of a novel Schiff Base copper(II) complex on growth inhibition and apoptosis induction toward MCF-7 human breast cancer cells via mitochondrial pathway

In this study, we investigated the newly synthesized Schiff base copper(II) complex, [Cu(II)(5-Cl-pap)(OAc)(H(2)O)]·2H(2)O (1) (5-Cl-pap=N-2-pyridiylmethylidene-2-hydroxy-5-chloro-phenylamine), inducing growth inhibition and apoptosis in human breast cancer cell line MCF-7 and its potential antitumor mechanism. The results of cytotoxicity research, fluorescence microscopic observation and flow cytometric analysis revealed that complex 1 could significantly suppress MCF-7 cell viability and induce apoptosis. Comet assay indicated that severe DNA fragmentation in MCF-7 cells was induced after treatment with complex 1. Flow cytometric analysis showed that the antitumor effect of complex 1 on MCF-7 cells was associated with the cell cycle arrest. In addition, atomic absorption analyses displayed that complex 1 caused a rapid increase of intracellular copper uptake in MCF-7 cells in a time-dependent manner. The present work suggested that the antitumor mechanism of complex 1 on MCF-7 cells might be via the mitochondrial pathway, based on the up-regulated expression of Bax and activation of caspase-9 and caspase-3.

Thiosemicarbazone Cu(II) and Zn(II) complexes as potential anticancer agents: syntheses, crystal structure, DNA cleavage, cytotoxicity and apoptosis induction activity.

Four novel thiosemicarbazone metal complexes, [Cu(Am4M)(OAc)]·H2O (1), [Zn(HAm4M)Cl2] (2), [Zn2(Am4M)2Br2] (3) and [Zn2(Am4M)2(OAc)2]·2MeOH (4) [HAm4M=(Z)-2-(amino(pyridin-2-yl)methylene)-N-methylhydrazinecarbothioamide], have been synthesized and characterized by X-ray crystallography, elemental analysis, ESI-MS and IR. X-ray analysis revealed that complexes 1 and 2 are mononuclear, which possess residual coordination sites for Cu(II) ion in 1 and good leaving groups (Cl(-)) for Zn(II) ion in 2. Both 3 and 4 displayed dinuclear units, in which the metal atoms are doubly bridged by S atoms of two Am4M(-) ligands in 3 and by two acetate ions in bi- and mono-dentate forms, respectively, in 4. Their antiproliferative activities on human epithelial cervical cancer cell line (HeLa), human liver hepatocellular carcinoma cell line (HepG-2) and human gastric cancer cell line (SGC-7901) were screened. Inspiringly, IC50 value (11.2±0.9 μM) of complex 1 against HepG-2 cells was nearly 0.5 fold of that against human hepatic cell lines LO2, showing a lower toxicity to human liver cells. Additionally, it displayed a stronger inhibition on the viability of HepG-2 cells than cisplatin (IC50=25±3.1 μM), suggesting complex 1 might be a potential high efficient antitumor agent. Furthermore, fluorescence microscopic observation and flow cytometric analysis revealed that complex 1 could significantly suppress HepG-2 cell viability and induce apoptosis. Several indexes, such as DNA cleavage, reactive oxygen species (ROS) generation, comet assay and cell cycle analysis indicated that the antitumor mechanism of complex 1 on HepG-2 cells might be via ROS-triggered apoptosis pathway.

Two polypyridyl copper(II) complexes: synthesis, crystal structure and interaction with DNA and serum protein in vitro

Two polypyridyl copper(II) complexes, [Cu(acac)(p-CPIP)(CH3OH)](NO3) (1) and [Cu(acac)(o-NPIP)(NO3)] (2) (acac = acetylacetonate, p-CPIP = 2-(4-chlorophenyl)imidazo[4,5-f]1,10-phenanthroline, o-NPIP = 2-(2-nitrophenyl)imidazo[4,5-f]1,10-phenanthroline), have been synthesized and characterized by single-crystal analysis, IR and electronic spectroscopy. X-ray analyses reveal that both 1 and 2 possess a triclinic crystal system with Pmn1 and mononuclear five-coordinated square pyramidal geometry, which were further linked to a one-dimensional structure through π–π stacking and intermolecular hydrogen bonds. The interaction of the Cu(II) complex with calf thymus DNA (CT-DNA) was investigated by UV-visible and fluorescence emission spectrometry, as well as agarose gel electrophoresis. The apparent binding constant (Kapp) values of 2.47 × 104 M−1 for 1 and 3.04 × 104 M−1 for 2 suggest moderate intercalative binding mode between the complexes and DNA. Both complexes displayed efficient oxidative cleavage of supercoiled DNA in the presence of external agents. In addition, fluorescence spectrometry of bovine serum albumin (BSA) with the complexes showed that the quenching mechanism of 1 might be a dynamic procedure, while 2 showed a combined dynamic and static quenching mechanism. For both 1 and 2, the number of binding sites was about one for BSA. Moreover, synchronous fluorescence spectral experiments revealed that 1 and 2 affect the microenvironment of tryptophan residues of BSA.

Synthesis, characterization, DNA interaction, cytotoxicity, and apoptosis induction of a mixed-ligand copper(II) complex

A mixed-ligand complex, [Cu(Hptc)(Me2bpy)(H2O)]·3H2O (1) (H3ptc = pyridine-2,4,6-tricarboxylic acid; Me2bpy = 4,4′-dimethyl-2,2′-dipyridine), has been synthesized and characterized by elemental analysis, IR, and single-crystal X-ray diffraction. In the discrete mononuclear structure of 1, the copper core is in a distorted octahedral environment (CuN3O3) derived from tridentate chelate Hptc2−, bidentate chelate Me2bpy and a coordinated water. The interaction of 1 with CT-DNA was investigated by UV–vis spectra, fluorescence spectra and viscosity, which reveals that 1 binds to CT-DNA by partial intercalation. Gel electrophoresis assay demonstrated that the complex displays efficient oxidative cleavage of supercoiled DNA with H2O2 as an oxidant. The in vitro cytotoxicity of 1 on HeLa cells was assessed by MTT and clonogenic assay, where IC50 equals 4.24 ± 0.03 μM. Fluorescence microscopic observations indicated that 1 can induce apoptosis of HeLa cells.

Synthesis, crystal structures, DNA binding, and cytotoxicity activities of two copper(II) complexes based on unsymmetrical tripodal ligands

[Cu(L1)Cl2]∙3H2O (1) and [Cu(L2)Cl]∙2H2O (2) based on new unsymmetrical tripodal ligands (L1 = {(N-methyl-imidazolylmethyl)[N-methyl-N-(N-methyl-imidazolylmethyl)imidazolylmethyl]amino}ethanesulfonic acid, L2 = [bis(2-pyridylmethyl)amino]ethanesulfonic acid) have been synthesized and characterized by elemental analysis, IR, and single-crystal X-ray diffraction. In the discrete mononuclear structures of 1 and 2, copper is five-coordinate in a distorted trigonal bipyramidal structure. Interaction of the complexes with CT-DNA was investigated by UV–vis spectra, fluorescence spectra, and viscosity; the data reveal that 1 and 2 bind to CT-DNA by partial intercalation. Gel electrophoresis assays demonstrate that these two complexes display efficient oxidative cleavage of supercoiled DNA in the presence of H2O2, and MTT assays indicated that both 1 and 2 showed significant cytotoxicity toward human hepatoma cell HepG-2.

Synthesis, structure, spectroscopic, and DNA binding properties of Co(III) and Ni(II) complexes with ((E)-2-(amino((pyridin-2-ylmethylene)amino)methylene)maleonitrile)

Two new complexes, [Co(L)2]Cl·(MeOH)2 (1) and [Ni(L)2]4·EtOH (2) (L = (E)-2-(amino((pyridin-2-ylmethylene)amino)methylene)maleonitrile), were synthesized and characterized by X-ray crystallography, IR, UV, and fluorescence spectroscopy. According to X-ray crystallographic studies, each metal was six-coordinate with six nitrogens from two ligands. Both complexes form two-dimensional supramolecular networks via hydrogen bonding and π–π interactions. Ultraviolet and visible spectra showed that absorptions arise from π–π ∗, MLCT, and d–d electron transitions. Fluorescence spectroscopy revealed moderate intercalative binding of these two complexes with EB–DNA, with apparent binding constant (K app) values of 9.14 × 105 and 3.20 × 105 M−1 for Co(III) and Ni(II) complexes, respectively. UV–visible absorption spectra showed that the absorption of DNA at 260 nm was quenched for 2 but quenched then improved for 1 with addition of complexes, tentatively attributed to the effect of the combined intercalative binding and electrostatic interaction for 1.

A copper(II) complex of 1,4,7-triazacyclononane featuring acetate pendant: an efficient DNA cleavage agent

A new water-soluble copper(II) complex, Cu(TACNA)Br · 0.375H2O (1) [TACNA = 1,4,7-triazacyclononane-N-acetate], has been synthesized to serve as artificial nucleases. The X-ray crystal structure of 1 indicates that one bromide and an oxygen from acetate pendant coordinate to copper(II) in addition to the nitrogen atoms in the TACN macrocycle, resulting in a five-coordinate complex with square-pyramidal geometry. The interaction of 1 with calf thymus DNA (ct-DNA) has been investigated by UV absorption and fluorescence spectroscopies, and the mode of ct-DNA binding for 1 has been proposed. In the absence of external agents, supercoiled plasmid DNA cleavage by 1 was performed under aerobic condition; the influences on DNA cleavage of different complex concentrations and reaction times were also studied. The cleavage of plasmid DNA likely involves oxidative mechanism.

A dinuclear nickel(II) complex with dissimilar bridges: synthesis, crystal structure, and magnetic characterization

Using 3,5-pyrazoledicarboxylic acid (H3pdc), 2,2-bipyridine (2,2-bipy) and NaN3, a dinuclear nickel(II) compound with dissimilar bridges, [Ni2(2,2-bipy)2(pdc)(N3)(H2O)2] ⋅ 2H2O (1), has been isolated under hydrothermal conditions. Compound 1 is dinuclear, bridged by two nitrogens in the pyrazole ring of pdc3− and µ1,3 . The dinuclear units and lattice water molecules are further linked by extensive hydrogen bonds to form 2-D infinite planes, which are further linked through π–π stacking to construct a 3-D supramolecular structure. Variable temperature magnetic susceptibility of 1 from 2 to 300 K indicates anti-ferromagnetic interactions. The magnetic exchange coupling constants J = −12.65 cm−1 and zj ′ = 3.34 cm−1 for 1 can be obtained through the fit of the magnetic data.

Three Pt(II) complexes based on thiosemicarbazone: synthesis, HSA interaction, cytotoxicity, apoptosis and cell cycle arrest

Three thiosemicarbazone-based platinum(II) complexes [Pt(MH-TSC)Cl] (1), [Pt(ME-TSC)Cl] (2) and [Pt(NH-TSC)2]Cl (3) (MH-TSC = (E)-2-(1-(pyridin-2-yl)ethylidene)hydrazinecarbothioamide, ME-TSC = (E)-N-ethyl-2-(1-(pyridin-2-yl)ethylidene) hydrazinecarbothioamide, NH-TSC = (Z)-2-(amino(pyridin-2-yl)methylene)hydrazinecarbothioamide) were synthesized and structurally characterized. X-ray analyses revealed that 1 and 2 possessed similar a neutral mononuclear unit in which one tridentate TSC ligand and one leaving group (Cl−) coordinated to Pt(II) ion, while 3 was cationic and formed by two NH-TSC ligands surrounding one Pt atom in a meridional arrangement. UV-visible and fluorescence spectra of human serum albumin (HSA) with the complexes displayed that the quenching mechanism of HSA by 1–3 might be a static binding mode. Moreover, synchronous fluorescence experiments proved that 1–3 affected the microenvironment of tryptophan residues of HSA. In addition, the antiproliferative activities against MCF-7 (human breast cancer lines), HepG-2 (human liver hepatocellular carcinoma cell line), NCI-H460 (non-small cell lung cancer lines) and HeLa (human epithelial cervical cancer cell line) were screened for 1–3. Inspiringly, their cytotoxic activity (IC50 = 1.7–9.6 μM) appeared much better than that of cisplatin (IC50 = 5.2–13.5 μM) against different cell lines, respectively. Among them, complex 3 exhibited the strongest inhibition on the viability of all tested cell lines with IC50 values of 1.7–2.2 μM. Inductively-coupled plasma mass spectrometry (ICP-MS) showed that 3 accumulated rapidly in cells and reached intracellular levels of up to 10-fold higher than those determined for 1 and 2. Furthermore, fluorescence microscopic observation and flow cytometric analysis revealed that 1–3 could effectively induce apoptosis of HeLa cells, which were arrested in the S phase after treatment with 1 (30.31%) and 3 (46.96%), and in G2 phase with 2 (20.2%). All the results mentioned above suggest that complexes 1–3 might be efficient antitumor agents.