Xiu-Zhen Wang

Ruthenium(II) complexes: DNA-binding, cytotoxicity, apoptosis, cellular localization, cell cycle arrest, reactive oxygen species, mitochondrial membrane potential and western blot analysis.

The aim of our study was to investigate DNA-binding and cytotoxic activity of the four new Ru(II) polypyridyl complexes [Ru(dmb)₂(HMHPIP)](ClO₄)₂ (1), [Ru(bpy)₂(HMHPIP)](ClO₄)₂ (2), [Ru(phen)₂(HMHPIP)](ClO₄)₂ (3) and [Ru(dmp)₂(HMHPIP)](ClO₄)₂ (4). The complexes interact with DNA through intercalative mode and show relatively high cytotoxic activity against A549 cells, no cytotoxicity toward MG-63 cells. Complexes 1-4 can enhance the levels of ROS in A549 cells and induce the decrease of the mitochondrial membrane potential. These complexes inhibit the cell growth in A549 cells at G0/G1 or S phase. Complex 3 activated caspase 7, and down-regulated the expression of the anti-apoptotic protein Bcl-2. Complexes 1-4 induce apoptosis in A549 cells through ROS-mediated mitochondrial dysfunction pathway.

Apoptosis, autophagy, cell cycle arrest, cell invasion and BSA-binding studies in vitro of ruthenium(II) polypyridyl complexes

Ruthenium(II) polypyridyl complexes show high anticancer activity, and can induce apoptosis. Herein, a new ligand AQTP (AQTP = 12-acenaphtho[1,2-b]quinoxalin-9-yl-4,5,9,14-tetraazabenzo[b]triphenylene) and its four ruthenium(II) polypyridyl complexes [Ru(N-N)2(AQTP)](ClO4)2 (N-N = dmb: 4,4′-dimethyl-2,2′-bipyridine 1; bpy: 2,2′-bipyridine 2; phen: 1,10-phenanthroline 3 and dmp: 2,9-dimethyl-1,10-phenanthroline 4) were synthesized and characterized. The cytotoxic activity in vitro of the complexes against BEL-7402, A549, HeLa, HepG2, MG-63 and normal cell HLF was investigated using the MTT method (MTT = (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide)). The apoptosis was assayed with AO/EB and Hoechst 33258 staining methods. The ROS, mitochondrial membrane potential and autophagy were studied using a fluorescent microscope. The expression of caspases and Bcl-2 family proteins was investigated by western blot analysis. The IC50 values of complexes 1–4 toward A549 cells are 5.0 ± 0.8, 10.0 ± 0.7, 45.0 ± 1.4 and 3.8 ± 0.1 μM. The complexes can increase the levels of reactive oxygen species (ROS), and induce a decrease in the mitochondrial membrane potential. Complexes 1–4 inhibit cell growth at the G0/G1 phase in A549 cells, and the complexes can induce both autophagy and apoptosis, and the complexes induce apoptosis through a ROS-mediated mitochondrial dysfunction pathway.

Cytotoxicity, Cell Cycle Arrest, Antioxidant Activity and Interaction of Dibenzoxanthenes Derivatives with DNA

In this study, we report the DNA interaction and cytotoxicity of four dibenzoxanthene compounds 1-4. The binding behaviors of these compounds to calf thymus DNA were studied by absorption titration, viscosity measurements. The DNA binding constants of compounds 1, 2, 3, and 4 are 5.05×10(4), 2.13×10(3), 5.10×10(4), and 3.03×10(3) M(-1), respectively. The lipophilicity of the compounds was determined by the shake flask method. The cytotoxicity of these compounds has been assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. These compounds exhibit high activity against BEL-7402, Hela, MG-63, and SKBR-3 cells. The cell cycle arrest was analyzed by flow cytometry. These compounds inhibit S phase of BEL-7402 and SKBR-3 cells. The experiments on antioxidant activity show that these compounds exhibit good antioxidant activity against hydroxyl radical ((•)OH).

DNA-binding, antioxidant activity, and bioactivity studies of ruthenium(II) complexes containing amino substituents

Two new Ru(II) complexes, [Ru(dmp)2(dadppz)](ClO4)2 (1) and [Ru(dip)2(dadppz)](ClO4)2 (2), were synthesized and characterized by elemental analysis, ES-MS, and 1H NMR. DNA-binding behaviors were investigated by absorption titration and luminescence spectra. The DNA-binding constants were 3.1 (± 0.2) × 104 and 3.0 (± 0.2) × 105 M−1 for 1 and 2. The antioxidant activity of these complexes against hydroxyl radical ( ) was explored. The cytotoxicities in vitro towards A549, BEL-7402, MG-63, and SKBR-3 cells were studied by 3-(4,5dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method. Complex 1 shows high cytotoxicity, but 2 is not cytotoxic towards the selected cell lines. Apoptosis and cell cycle distribution were studied by flow cytometry. The cellular uptake showed that complexes can enter into the cytoplasm. JC-1 was used as a fluorescence probe in detecting the mitochondrial membrane potential and results indicate that the mitochondrial membrane potential decreases.

Cytotoxicity, apoptosis, interaction with DNA, cellular uptake, and cell cycle arrest of ruthenium(II) polypyridyl complexes containing 4,4′-dimethyl-2,2′-bipyridine as ancillary ligand

Two new ruthenium(II) polypyridyl complexes, [Ru(dmb)2(DNPIP)](ClO4)2 (1) (DNPIP = 2-(2,4-dinitrophenyl)imidazo[4,5-f][1,10]phenanthroline, dmb = 4,4′-dimethyl-2,2′-bipyridine) and [Ru(dmb)2(DAPIP)](ClO4)2 (2) (DAPIP = 2-(2,4-diaminophenyl)imidazo[4,5f][1,10]phenanthroline), were synthesized and characterized. The DNA-binding behaviors of these complexes have been studied by UV-Vis absorption titration, viscosity measurements, and photocleavage. The DNA-binding constants are 7.39 (±0.16) × 104 (s = 2.68) and 2.73 (±0.16) × 104 (mol L−1)−1 (s = 0.64) for 1 and 2, respectively. Their evaluation as cytotoxic agents on different cancer cell lines was investigated with IC50 values of 59.5, 51.3, and 70.3 µmol L−1 for 1, >100, 87.9, and 77.9 µmol L−1 for 2 against BEL-7402, HepG-2, and MCF-7 cells, respectively. Complex 1 is more active than 2 against selected cancer cell lines. The apoptosis induced by these complexes was studied. Cellular uptake showed that these complexes could enter into the cytoplasm and accumulate in the nuclei. The cell cycle arrest and antioxidant activity against hydroxyl radicals were also investigated.

Studies on apoptosis in HeLa cells via the ROS-mediated mitochondrial pathway induced by new dibenzoxanthenes

Two positional isomers of dibenzoxanthenes C1 and C2 were synthesized and characterized. The crystal structures of the compounds were solved by single-crystal X-ray diffraction. Binding the two compounds with CT-DNA (calf thymus DNA)/BSA (bovine serum albumin) was thoroughly investigated by UV-Vis and fluorescence spectroscopy. The compounds interact with DNA through an intercalative mode and show strong affinities with BSA. Their cytotoxicity upon irradiation was investigated in vitro using the MTT method. By comparing the two isomers, C1 and C2, compound C2 showed greater enhanced therapeutic potential upon irradiation with visible light. Significant nuclear damage of HeLa cells was observed after a comet assay. These compounds inhibited cell growth in HeLa cells at the S phase. These compounds have been found to induce apoptosis in HeLa cells using AO/EB staining experiments and flow cytometry. The two compounds can enhance the intracellular reactive oxygen species and decrease the mitochondrial membrane potential. The compounds activated caspase-3, caspase-7, procaspase-7 and down-regulated the expression levels of the anti-apoptotic proteins Bcl-2 and Bcl-x, and up-regulated the expression levels of the pro-apoptotic proteins Bax and Bim. The compounds induced apoptosis of HeLa cells via a ROS-mediated mitochondrial dysfunction pathway.

Synthesis, characterization, cytotoxicity, a poptosis and cell cycle arrest of dibenzoxanthenes derivatives.

Two new dibenzoxanthenes compounds 1 and 2 have been synthesized and characterized by analytical and spectral methods. The crystal structure of compound 2 informs that the five rings of compound are almost planar. The DNA binding properties of two compounds were studied by absorption titration, viscosity measurement and luminescence. These results indicate that two compounds interact with calf thymus DNA through intercalative mode. Agarose gel electrophoresis experiment shows that PBR 322 DNA can be induced to cleave by two compounds under photoactivated condition. Compound 1 exhibits higher cytotoxicity than compound 2 toward MG-63, BEL-7402 and A549 cells. The apoptosis and cellular uptake of MG-63 cells were studied by fluorescence microscopy. Two compounds can also enhance the level of reactive oxygen species (ROS) and decrease the mitochondrial membrane potential. Compound 1 induces cell cycle arrest in G2/M phase and compound 2 induces cell cycle arrest in G0/G1 phase in MG-63.

Synthesis, molecular structure, DNA interaction and antioxidant activity of novel naphthoxazole compound

A novel naphthoxazole compound 1 was synthesized and characterized. The crystal structure of the compound shows that N atom locates at β-position and oxygen atom at α-position in naphthalene cycle. The DNA binding was studied by absorption spectroscopy, viscosity and luminescence spectra. The DNA binding constant was determined to be 6.16×10(3). The stoichiometry of compound/DNA is 1:1. The pBR322 DNA cleavage induced by the compound was investigated. The antioxidant activity of the compound against hydroxyl radical was also explored.

Synthesis of novel dibenzoxanthene derivatives and observation of apoptosis in human hepatocellular cancer cells

We have synthesized dibenzoxanthene derivatives 2a-2i via nucleophilic substitution of methoxyl group and evaluated underlying antitumor molecular mechanism of target compounds. Compounds showed high cytotoxic activities against BEL-7402, A549, HeLa and MG-63 cancer cells in the µM range. These compounds inhibited the cell growth of BEL-7402 cells at S or G2/M phase. The compounds 2a-2i also induced the apoptosis of BEL-7402 cells. In addition, compounds enhanced the level of intramolecular ROS and decreased the mitochondrial membrane potential. Western blot analysis showed caspase-3 were activated and the expression of Bcl-2 and Bcl-xl was down-regulated. According to given results, these dibenzoxanthenes exhibited a broad spectrum of antiproliferative effects on various tumors and therapeutic efficacy. Molecular mechanism indicated that induction of apoptosis was associated with DNA fragmentation, ROS generation, mitochondria dysfunction. Compounds induced apoptosis in BEL-7402 cells through the intrinsic ROS-mediated mitochondrial pathway.

Synthesis, molecular structure, DNA-binding, cytotoxicity, apoptosis and antioxidant activity of compounds containing aryloxazole.

Three novel aryloxazole compounds 1-3 were synthesized and characterized. The crystal structures of compounds 2 and 3 show that N atom locates at β-position and O atom at α-position in naphthalene cycle. The DNA binding constants for compounds 1-3 are 4.44 × 10(3), 5.31 × 10(3) and 2.64 × 10(3) M(-1), respectively. The viscosity measurements indicate that these compounds intercalate between the DNA base pairs. Upon irradiation, compounds 1-3 can effectively cleave pBR322 DNA. The cytotoxicity of the compounds against BEL-7402, A549, MG-63 and SKBR-3 were assayed by MTT method. The apoptosis and cell cycle arrest were investigated towards A549 cells. The antioxidant activities of the compounds against hydroxyl radicals were also explored.