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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. [ABSTRACT FROM AUTHOR]

Abstract: Two new ligands APIP, HAPIP and their relative ruthenium(II) complexes [Ru(bpy)2(APIP)](ClO4)2 1 and [Ru(bpy)2(HAPIP)](ClO4)2 2 have been synthesized and characterized. The DNA binding constants for complexes 1 and 2 have been determined to be 6.08 (±0.29)×104 M−1 and 1.78 (±0.30)×105 M−1. The results suggest that these complexes intercalate between the base pairs of DNA. The cytotoxicity of complexes has been evaluated by MTT assay. The apoptosis assay was carried out with AO/EB staining methods. The cellular uptake was observed under fluorescence microscopy. The studies on the mechanism of photocleavage demonstrate that superoxide anion radical (O2 −) and singlet oxygen (1O2) may play an important role. The antioxidant activity against hydroxyl radical ( OH) was also studied. [Copyright &y& Elsevier]

Abstract: The glutathione–ascorbate (GSH–ASC) cycle in plants plays an important role in detoxifying reactive oxygen species. Little is known about how the enzymes and antioxidants in the maize GSH–ASC cycle respond to stress. We clarified the genome positions, exon–intron structures and predicted subcellular locations of the ascorbate peroxidase (APX), monodehydroascorbate reductase (MDAR), dehydroascorbate reductase (DHAR) and glutathione reductase (GR) families in maize. ABA treatment increased the transcript levels of most of the APX genes except ZmAPX3 and ZmAPX6, upregulated the transcription of ZmMDAR1 and downregulated the transcriptions of ZmMDAR3 and ZmMDAR4. However, it had little effect on the expressions of the ZmDHAR and ZmGR gene families. ABA treatment increased the activities of only 2 enzymes, ZmAPX and ZmDHAR. The PEG treatment led to similar expression patterns as that of ABA. ZmAPX1.1 and ZmAPX2 exhibited the same expression patterns under PEG treatment conditions. Enzyme activities were not affected by the PEG treatment with the exception of a significant decrease in MDAR activity that was observed after 6h. Compared to the ABA and PEG treatments, the NaCl treatment only slightly affected the transcription of the four gene families but significantly increased the activity of ZmGR. The ABA and PEG treatments elevate the ASC levels and decrease the GSSG level. Our results show that the gene families of the maize GSH–ASC redox cycle respond differently to abiotic stresses and suggest that APX and MDAR may play more important roles in stress tolerance in plants. [Copyright &y& Elsevier]

Two new ruthenium(II) complexes, [Ru(phen)2(DNPIP)](ClO4)2 (1) and [Ru(phen)2(DAPIP)](ClO4)2 (2), were synthesized and characterized. The DNA-binding properties of these complexes were investigated using UV/vis absorption titration, viscosity measurements, thermal denaturation, and photoactivated cleavage. The DNA binding constants for complexes 1 and 2 are 2.63 ± 0.25 × 105 M−1 ( s = 2.45) and 1.51 ± 0.18 × 105 M−1 ( s = 1.34). The results indicated that these complexes interacted with DNA through the intercalative mode. The cytotoxicity in vitro of complexes 1 and 2 were assessed against BEL-7402, HepG-2, and MCF-7 cell lines by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Apoptosis was studied with the acridine orange/ethidium bromide staining method. The antiproliferative mechanism was explored with flow cytometry. Cellular uptake studies showed that complexes 1 and 2 can enter into the cytoplasm and accumulate in the nuclei. Cell cycle arrest and antioxidant activity were also investigated. [ABSTRACT FROM AUTHOR]

Two ruthenium (II) complexes [Ru(dmb)2(APIP)](ClO4)2 (APIP = 2-(2-aminophenyl)imidazo[4,5-f ][1,10]phenanthroline, dmb = 4,4′-dimethyl-2,2′-bipyridine; 1) and [Ru(dmb)2(HAPIP)](ClO4)2 (HAPIP = 2-(2-hydroxyl-4-aminophenyl)imidazo[4,5-f ][1,10]phenanthroline; 2) were synthesized and characterized. DNA binding was investigated by electronic absorption titration, luminescence spectra, thermal denaturation, viscosity measurements, and photocleavage. The DNA binding constants for complexes 1 and 2 were 4.20 (±0.14) × 104 and 5.45 (±0.15) × 104 M−1. The results suggest that these complexes partially intercalate between the base pairs. The cytotoxicity of complexes 1 and 2 was evaluated by MTT assay. Cellular uptake was observed under fluorescence microscopy; complexes 1 and 2 can enter into the cytoplasm and accumulate in the nuclei. Apoptosis and the antioxidant activity against hydroxyl radicals (•OH) were also explored. [ABSTRACT FROM AUTHOR]

Abstract: Ruthenium(II) polypyridyl complexes [Ru(phen)2(APIP)](ClO4)2 1 and [Ru(phen)2(HAPIP)](ClO4)2 2 have been synthesized and characterized. The DNA-binding behaviors were investigated by electronic absorption titration, luminescence spectra, viscosity measurements, thermal denaturation and photoactivated cleavage. The DNA-binding constants K b for complexes 1 and 2 were determined to be 3.38 (±0.42) × 105 M−1 (s = 1.48) and 3.93 (±0.60) × 105 M−1 (s = 3.14), respectively. The studies on the photocleavage demonstrated that the effects of cleavage are concentration-dependent. The results showed that complexes 1 and 2 interact with CT-DNA by intercalative mode. The cytotoxicity of complexes 1 and 2 has been evaluated by MTT method. The apoptosis assay was carried out with acridine orange/ethidium bromide (AO/EB) staining methods. The cellular uptake showed that complexes can enter into the cytoplasm and accumulate in the nuclei. The antioxidant activity studies suggested that the ligands and complexes may be potential drugs to eliminate the radical. [Copyright &y& Elsevier]

Abstract: Two new ligands maip (1a), paip (1b) with their ruthenium (II) complexes [Ru(bpy)2(maip)](ClO4)2 (2a) and [Ru(bpy)2(paip)](ClO4)2 (2b) have been synthesized and characterized. The results show that complexes 2a and 2b interact with DNA through intercalative mode. The cytotoxicity of these compounds has been evaluated by MTT assay. The experiments on antioxidant activity show that these compounds exhibit good antioxidant activity against hydroxyl radical (OHmple-para> [Copyright &y& Elsevier]

Abstract: Two new ruthenium(II) polypyridyl complexes [Ru(dmb)2(Fpp)](ClO4)2 1 (Fpp=2-(3′,3′-difluoro-3,4-methylenedioxyphenyl)imidazo[4,5-f][1,10]phenanthroline, dmb=4,4′-dimethyl-2,2′-bipyridine) and [Ru(bpy)2(Fpp)](ClO4)2 2 (bpy=2,2′-bipyridine) have been synthesized and characterized by elemental analysis, FAB-MS, ES-MS, IR, 1H NMR and 13C NMR. The DNA-binding behaviors of these complexes were investigated by absorption spectroscopic titration, viscosity measurements, thermal denaturation and photocleavage. The mechanism studies of photocleavage reveal that singlet oxygen (1O2) and superoxide anion radical (O2 −) may play an important role in the photocleavage. The cytotoxicity of complexes 1 and 2 have been evaluated by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) method. [Copyright &y& Elsevier]

Cytosolic NADPH can be directly oxidized by a calcium-dependent NADPH dehydrogenase, NDB1, present in the plant mitochondrial electron transport chain. However, little is known regarding the impact of modified cytosolic NADPH reduction levels on growth and metabolism. Nicotiana sylvestris plants overexpressing potato (Solanum tuberosum) NDBT1 displayed early bolting, whereas sense suppression of the same gene led to delayed bolting, with consequential changes in flowering time. The phenotype was dependent on light irradiance but not linked to any change in biomass accumulation. Whereas the leaf NADPH/NADP+ ratio was unaffected, the stem NADPH/NADP+ ratio was altered following the genetic modification and strongly correlated with the bolting phenotype. Metabolic profiling of the stem showed that the NADP(H) change affected relatively few, albeit central, metabolites, including 2-oxoglutarate, glutamate, ascorbate, sugars, and hexose-phosphates. Consistent with the phenotype, the modified NDB1 level also affected the expression of putative floral meristem identity genes of the SQUAMOSA and LEAFY types. Further evidence for involvement of the NADPH redox in stem development was seen in the distinct decrease in the stem apex NADPH/NADP+ ratio during bolting. Additionally, the potato NDB1 protein was specifically detected in mitochondria, and a survey of its abundance in major organs revealed that the highest levels are found in green stems. These results thus strongly suggest that NDB1 in the mitochondrial electron transport chain can, by modifying cell redox levels, specifically affect developmental processes. [ABSTRACT FROM AUTHOR]

Two Ru(II) complexes [Ru(dmb)2(dtmi)](ClO4)2 (1) (dmb = 4, 4'-dimethyl-2, 2'-bipyridine, dtmi = 3-(pyrazin-2-yl)-as-triazino[5, 6-f]-5-methoxylisatin) and [Ru(dmb)2(dtni)](ClO4)2 (2) (dtni = 3-(pyrazin-2-yl)-as-triazino[5, 6-f]-5-nitroisatin) have been synthesized and characterized by elemental analysis, ES-MS, and 1H NMR. DNA-binding behaviors of these complexes have been investigated by spectroscopic titration, viscosity measurements, and thermal denaturation. The results indicate that the two complexes interact with calf thymus DNA by intercalation. [ABSTRACT FROM AUTHOR]

Two polypyridine ruthenium(II) complexes, [Ru(dmp)2(MCMIP)]2+ (1) (MCMIP = 2-(6-methyl-3-chromonyl)imidazo[4,5-f][1,10]-phenanthroline, dmp = 2,9-dimethyl-1,10-phenanthroline) and [Ru(dmb)2(MCMIP)]2+ (2) (dmb = 4,4'-dimethyl-2,2'-bipyridine), have been synthesized and characterized by elemental analysis, ES-MS and 1H NMR. The DNA-binding behaviors of these complexes were investigated by electronic absorption titration, fluorescence spectroscopy, viscosity measurements and thermal denaturation. The results show that 1 and 2 effectively bind to CT-DNA; the DNA-binding affinities are closely related to the ancillary ligand. [ABSTRACT FROM AUTHOR]

The perchlorate salts of two new ruthenium(II) complexes incorporating 2-(2'-pyridyl)naphthoimidazole are synthesized in good yield. Complexes [Ru(phen)2(PYNI)]2+ (phen = 1,10-phenanthroline) 1 and [Ru(dmp)2(PYNI)]2+ (dmp = 2,9-dimethyl-1,10-phenanthroline, PYNI = 2-(2'-pyridyl)naphthoimidazole) 2 are fully characterized by elemental analysis, FAB-MS, ES-MS, 1H NMR and cyclic voltammetric methods. The DNA-binding behavior of the complexes have been studied by spectroscopic titration, viscosity measurements and thermal denaturation. Absorption titration and thermal denaturation studies reveal that these complexes are moderately strong binders of calf-thymus DNA (CT-DNA), with their binding constants spanning the range (2.73-5.35) × 104 M-1. The experimental results show that 1 interacts with calf thymus DNA (CT-DNA) by intercalative mode, while 2 binds to CT-DNA by partial intercalation. [ABSTRACT FROM AUTHOR]

Abstract: Two new ligands, 3-(pyrazin-2-yl)-as-triazino[5,6-f]-5-methoxylisatin (dtmi), 3-(pyrazin-2-yl)-as-triazino[5,6-f]-5-nitroisatin (dtni) and their ruthenium(II) complexes [Ru(phen)2(dtmi)](ClO4)2 (1) and [Ru(phen)2(dtni)](ClO4)2 (2) have been prepared and characterized by elemental analysis, FAB-MS, ES-MS and 1H NMR. The DNA-binding behaviors of complexes have been studied by spectroscopic titration, viscosity measurements, thermal denaturation and circular dichromism (CD). The results indicate that the complexes 1 and 2 interact with calf thymus DNA (CT-DNA) by intercalative mode. The DNA-binding affinity of the complexes 2 is larger than that complex 1 does. [Copyright &y& Elsevier]

Abstract: A novel technique for controllable assembly of [Ru(bpy)2ITATP]3+/2+ (where bpy=2,2′-bipyridine, ITATP=isatino[1,2-b]-1,4,8,9-tetraazatriphenylene) on an ITO electrode in the absence and presence of calf thymus DNA is proposed. The [Ru(bpy)2ITATP]3+/2+ and double stranded DNA is assembled onto the ITO electrode using repetitive voltammetric sweeping. The assembly is confirmed by ex situ cyclic voltammetry and the fluorescence microscopy. A pair of diffusion-controlled waves and prewaves for [Ru(bpy)2ITATP]3+/2+ is observed in the voltammetric sweeping process. The formal potential of the prewaves is found to be much negative than that of the diffusion-controlled waves. The controllable assembly of [Ru(bpy)2ITATP]3+/2+ on the ITO surface is accelerated by DNA and affected by ionic strength. With this DNA-prompted electrochemical technique, a multifunctional biomolecular film containing surface-confined redox center of controllable thickness is fabricated. [Copyright &y& Elsevier]

Abstract: Two novel Ru(II) complexes [Ru(bpy)2(MCMIP)]2+ (1) and [Ru(phen)2(MCMIP)]2+ (2) (bpy=2,2′-bipyridine; phen=1,10-phenanthroline; MCMIP=2-(6-methyl-3-chromonyl)imidazo[4,5-f][1,10]-phenanthroline) have been synthesized and characterized by elemental analysis, mass spectra and 1H NMR. The DNA-binding properties of the complexes were investigated by absorption, emission, melting temperature and viscosity measurements. Experimental results indicate that the two complexes can intercalate into DNA base pairs. Upon irradiation at 365nm, two Ru(II) complexes were found to promote the cleavage of plasmid pBR 322 DNA from supercoiled form I to nicked form II, and the mechanisms for DNA cleavage by the complexes were also investigated. [Copyright &y& Elsevier]

Abstract: A novel asymmetric bidentate ligand, 2-(pyrazin-2-yl)naphthoimidazole (PZNI), and its Ru(II) complexes [Ru(bpy)2(PZNI)]2+ (1) and [Ru(phen)2(PZNI)]2+ (2) have been synthesized and characterized by elemental analysis, mass spectra, 1H NMR, and electronic spectroscopy. The electrochemical behaviors of the novel complexes were studied by cyclic voltammetry. The DNA-binding properties of the complexes were investigated by spectroscopic methods and viscosity measurements. The experimental results indicate that the complexes 1 and 2 interact with calf thymus DNA by intercalative mode via the terminal naphthyl ring into the base pairs of DNA. The two Ru(II) complexes have also been found to promote the cleavage of plasmid pBR 322 DNA from the supercoiled form I to the open circular form II upon irradiation. [Copyright &y& Elsevier]

Abstract: A novel asymmetric bidentate ruthenium (II) complex, [Ru(bpy)2(PYNI)]2+ (bpy=2,2′-bipyridine, PYNI=2-(2′-pyridyl)naphthoimidazole), has been synthesized and characterized by elemental analysis, ES-MS (electrospray mass spectra) and 1H NMR. The electrochemical behaviors of this complex were studied by cyclic voltammetry. DNA interaction studies suggest that [Ru(bpy)2(PYNI)]2+ binds to calf thymus DNA (CT-DNA) in an intercalative mode. Interestingly, this new Ru(II) complex has also been found to promote cleavage of plasmid pBR 322 DNA from the supercoiled form I to the open circular form II upon irradiation. [Copyright &y& Elsevier]

Two new copper(II) complexes of sparfloxacin (sf), [Cu(Hsf)(HPB)(H2O)](ClO4)2 (1) and [Cu(Hsf)(PBT)(H2O)](ClO4)2 (2) (where HPB = 2-(2′-pyridyl)benzimidazole and PBT = 2-(4′-pyridyl) benzothiazole), have been synthesized and characterized by physicochemical and spectroscopic techniques. The oil–water partition coefficient (log P) values of complexes 1 and 2 were 1.47 and 1.71, respectively. By studying the interaction between the complexes and DNA, it was found that the complexes could bind to DNA through an intercalation mode. Moreover, both complexes were evaluated for antitumor activity, revealing that the complexes displayed good inhibitory activity toward the tested cancer cell lines (human lung carcinoma A549 cells, human hepatocellular carcinoma Bel-7402 cells and human esophageal carcinoma Eca-109 cells), but showed relatively low toxicity against normal human hepatic LO2 cells. In particular, the antitumor mechanism of the complexes on Eca-109 cells was investigated by morphological analysis, apoptosis analysis and determination of cell cycle arrest, mitochondrial membrane potential, reactive oxygen species (ROS) levels, and release of cytochrome c and Ca2+. The results demonstrated that the complexes could induce loss of intracellular mitochondrial functions and increase of ROS levels, which led to an increase of Ca2+ levels and the release of cytochrome c into the cytoplasm. In addition, the cell cycle was arrested in the G2/M phase, and western blot analysis showed that the caspase family was activated. These results fully proved that the complexes could induce apoptosis through DNA damage and loss of mitochondrial functions, accompanied by the regulation of endogenous proteins. [ABSTRACT FROM AUTHOR]

A new ligand ITAP and its complex [Ru(dmb)2(ITAP)](ClO4)2 (ITAP = isatino [1,2-b]-1,4,8, 9-tetraazatriphenylene, dmb = 4,4'-dimethyl-2,2'-bipyridine) have been synthesized and characterized by elemental analysis, Fast atom bombardment mass spectra, Electrospray mass spectra, and 1H NMR. Thermal denaturation and absorption titration experiments show the complex binds to calf thymus DNA (CT-DNA) with moderate affinities. Viscosity measurements and thermal denaturation indicate that the DNA-binding mode could be intercalative interaction. The Ru(II) complex in the presence of plasmid pBR322 DNA has been found to promote the cleavage of plasmid pBR322 DNA from the supercoiled Form I to the open circular Form II upon irradiation. Mechanisms for DNA cleavage by the complex were also investigated. [ABSTRACT FROM AUTHOR]

Abstract: A novel ligand 2′-(2″-nitro-3″,4″-methylenedioxyphenyl)imidazo[4′,5′-f][1,10]-phenanthroline (NMIP) and its complex [Ru(phen)2(NMIP)]2+ have been synthesized and characterized by mass spectroscopy, 1H NMR and cyclic voltammetry. Binding of the complex with calf thymus DNA (CT DNA) has been investigated by spectroscopic methods, viscosity and electrophoresis measurements. The experimental results indicate that [Ru(phen)2(NMIP)]2+ binds to DNA via partial intercalative mode and the individual enantiomers of it bind to DNA in different rates. [Ru(phen)2(NMIP)]2+ has also been found to promote cleavage of plasmid pBR 322 DNA from the supercoiled Form I to the open circular Form II upon irradiation. [Copyright &y& Elsevier]

In our previous work, we have synthesized a series of dibenzoxanthenes which showed antitumor activity. However the antiproliferation ability toward gastric cancer cells and the mechanism still is not known. Three new dibenzoxanthenes were synthesized by oxidized the binaphthol in this study. We studied the interaction between compounds and Calf thymus (CT-DNA) by electronic absorption titration, luminescence spectra, viscosity experiments and DFT computation. The mode of compounds binding with DNA was intercalation. We demonstrated that compounds inhibited the proliferation of gastric cancer cells by MTT assay. The antitumor effect of these compounds was triggered by S phase cell cycle arrest and induced the apoptosis of cells. The mitochondrial pathway of apoptosis was confirmed by the loss of mitochondrial membrane potential, the release of cyto C, the decrease expression of Bcl-2 protein and the increase expression of cleaved PARP, Bax, Bid, Bad proteins. Compounds also enhanced the concentration of calcium and ROS in SGC-7901 cells. All the above results indicated that compounds 4a-4c strongly suppressed the proliferation of gastric cancer cells via inducing cell cycle arrest and cell apoptosis, suggesting that compounds are potential novel therapeutic agents for gastric cancer. A new series of dibenzoxanthene derivatives 4a-4c were synthesized and the molecular mechanisms of anti-antiproliferation activities toward gastric cancer cells were investigated. Image 1 • Three new dibenzoxanthene compounds were synthesized and characterized. • The cytotoxicity of these compounds was evaluated by MTT method. • Compounds also induced the apoptosis of gastric cancer cells. • Compounds induced apoptosis through mitochondrial signaling pathway. [ABSTRACT FROM AUTHOR]

Two iridium(III) polypyridyl complexes [Ir(ppy) 2 (HPIP)](PF 6) (Ir-1), [Ir(ppy) 2 (BHPIP)](PF 6) (Ir-2) and their liposomes Ir-1-Lipo and Ir-2-Lipo were synthesized and characterized by elemental analysis, IR, 1H NMR and 13C NMR. The anticancer activity in vitro and in vivo was evaluated. The cytotoxic activity in vitro of the complexes and their liposomes Ir-1-Lipo and Ir-2-Lipo against cancer cells was investigated by MTT methods. Ir-1 and Ir-2 show no cytotoxic activity, while Ir-1-Lipo and Ir-2-Lipo exhibit high cytotoxic effect. The IC 50 values range from 5.2 ± 0.8 to 22.3 ± 1.8 μM. The apoptosis, reactive oxygen species, the change of mitochondrial membrane potential, intracellular Ca2+ levels and a release of cytochrome c were investigated. The effect of Ir-1-Lipo and Ir-2-Lipo on microtubules was also explored. In the C57BL/6 mice model, Ir-1 only displays a tumor inhibitory rate of 23.21%, while lr-1-Lipo exhibits satisfactory in vivo antitumor efficacy with tumor inhibitory rate of 72.55%. This study demonstrates that complexes encapsulated in liposomes induce apoptosis in B16 through ROS-mediated lysosomal-mitochondria dysfunction, inhibition of polymerization of microtubules and induce cell cycle arrest at S phase. Two iridium(III) complexes [Ir(ppy) 2 (HPIP)](PF 6) (Ir - 1) and [Ir(ppy) 2 (BHPIP)](PF 6) (Ir - 2) were synthesized and characterized. The complexes Ir-1 and Ir-2 were encapsulated in liposomes Ir-1-Lipo and Ir-2-Lipo. The anticancer activity of the complexes and liposomes was investigated by apoptosis, comet assay, ROS, mitochondrial membrane potential, release of cytochrome c , tubules and Western blot analysis and in vivo antitumor activity. Image 1 • Two iridium(III) complexes Ir-1 and Ir-2 and their liposomes Ir-1-Lipo and Ir-2-Lipo were synthesized and characterized. • The cytotoxicity in vitro or in vivo of the complexes and liposomes was investigated. • The apoptosis and cell cycle distribution were assayed by flow cytometry. • ROS and mitochondrial membrane potential were studied under fluorescence microscope. • The expression of Bcl-2 family proteins was assayed by western blot analysis. [ABSTRACT FROM AUTHOR]

This work mainly introduces the synthesis and characterization of three iridium(III) complexes [Ir(ppy) 2 (adppz)](PF 6) (Ir-1), [Ir(bzq) 2 (addpz)](PF 6) (Ir-2) and [Ir(piq) 2 (adppz)](PF 6) (Ir-3). The complexes are more cytotoxic than cisplatin against tumor cell lines such as SGC-7901, A549, HeLa, Eca-109, HepG2 and BEL-7402. The toxicity test results indicated that complexes Ir-1 , Ir-2 and Ir-3 can effectively inhibit the cell growth of SGC-7901 cells, and the measured IC 50 values are 1.8 ± 0.4, 1.6 ± 0.3 and 0.8 ± 0.1 μM, respectively. AO/EB staining and flow apoptosis confirmed that SGC-7901 cells were caused apoptosis after being treated with the complexes. Along with the increase of endogenous ROS and Ca2+ levels, mitochondrial membrane potential collapse and massive release of cytochrome c , it is fully demonstrated that these complexes induce apoptosis through ROS-mediated mitochondrial pathway. At the same time, the complex Ir-3 is outstanding in the inhibition of tumor growth in vivo. Combined with the above results, it provides a favorable foundation for the future development of more effective anti-tumor drugs. Three new iridium(III) complexes were synthesized and characterized. The cytotoxicity in vitro and in vivo was investigated. The complexes show high anticancer activity in vitro and in vivo. Image 1 • The iridium(III) complexes were synthesized and characterized. • The cytotoxicity in vitro was studied by MTT method. • The apoptosis, cell cycle arrest and intracellular ROS levels were assayed. • The effect of the complex on the tumor growth was evaluated. [ABSTRACT FROM AUTHOR]

In this study, we designed and synthesized three new iridium(iii) complexes [Ir(ppy)2(dmdppz)](PF6) (ppy = 2-phenylpyridine) (1), [Ir(bzq)2(dmdppz)](PF6) (bzq = benzo[h]quinolone) (2) and [Ir(piq)2(dmdppz)](PF6) (piq = 1-phenylisoquinoline, dmdppz = 5,8-dimethoxylpyrido[3,2-a:2′,3′-c]phenazine) (3). All the complexes were tested for anticancer activity by the 3-(4,5-dimethylthiazole)-2,5-diphenyltetrazolium bromide (MTT) method. These complexes showed high anticancer activity against SGC-7901 cells, and the IC50 values are 4.1 ± 0.5 for 1, 0.7 ± 0.1 for 2 and 0.6 ± 0.2 μM for 3. Additionally, complex 3 can inhibit the tumor growth in xenograft nude mice in vivo with an inhibitory percentage of tumor growth of 48.21%. Morphological studies show that the cells treated with the complexes exhibit typical apoptotic morphological characteristics such as nuclear fragmentation and chromatin condensation. Quantitative analysis by flow cytometry showed that the apoptosis rate increased sharply after the cells were exposed to the complexes, and NAC (an inhibitor that inhibits the production of ROS) can inhibit the increase of the apoptosis rate. Cell cycle studies show that complex 1 can block the SGC-7901 cell cycle at the G0/G1 phase, and complexes 2 and 3 can cause cycle arrest at the S phase. All the complexes can increase the intracellular reactive oxygen species level, and reduce the mitochondrial membrane potential, which further prompts the release of cytochrome c. In addition, the complexes can damage DNA and cause disruption of the microtubule network. In conclusion, the complexes can effectively induce cancer cell apoptosis and may be potential anticancer agents for gastric cancer. [ABSTRACT FROM AUTHOR]

Three new ruthenium(II) polypyridyl complexes were synthesized and characterization. The cytotoxic activity in vitro, apoptosis, comet assay, cell cycle arrest, mitochondrial membrane potential and the expression of Bcl-2 family proteins were investigated. In recent years, ruthenium complexes have attracted extensive attention as new anticancer drugs. In this paper, three new ruthenium complexes [Ru(dmb) 2 (HMNPIP)](PF 6) 2 (1), [Ru(bpy) 2 (HMNPIP)](PF 6) 2 (2) and [Ru(phen) 2 (HMNPIP)](PF 6) 2 (3) (HMNPIP = 2-hydroxy-3-methoxy-5-nitrophenylimidazo[4,5-f][1,10]phenanthroline) were synthesized and characterized by elemental analysis, ESI-MS, 1H NMR and 13C NMR. The MTT assays showed that the complexes have no cytotoxic activity in vitro. However, upon irradiation with white light, the complexes display high anticancer activity toward A549 cells. The cell cycle distribution and apoptosis of A549 cells induced by the complexes were investigated by flow cytometry. The intracellular ROS and calcium ion levels were studied. The change of mitochondrial membrane potential, cell invasion were also investigated. The expression of caspase 3, p53 and Bcl-2 family proteins was explored by western blot. The complexes induce apoptosis in A549 cells through intrinsic pathway. [ABSTRACT FROM AUTHOR]

Abstract: Three iridium(III) polypyridyl complexes [Ir(ppy)2(PYTA)](PF6) (1) (ppy = 2-phenylpyridine), [Ir(bzq)2(PYTA)](PF6) (2) (bzq = benzo[h]quinolone) and [Ir(piq)2(PYTA)](PF6) (3) (piq = 1-phenylisoquinoline, PYTA = 2,4-diamino-6-(2′-pyridyl)-1,3,5-triazine) were synthesized and characterized by elemental analysis, IR, 1H NMR and 13C NMR. The cytotoxic activity of the complexes toward cancer SGC-7901, Eca-109, A549, HeLa, HepG2, BEL-7402 and normal LO2 cell lines was investigated by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. Complex 3 shows the most effective on inhibiting the above cell growth among these complexes. The complexes locate at the lysosomes and mitochondria. AO/EB, Annex V and PI and comet assays indicate that the complexes can induce apoptosis in SGC-7901 cells. Intracellular ROS and mitochondrial membrane potential were examined under fluorescence microscopy. The results demonstrate that the complexes increase the intracellular ROS levels and induce a decrease in the mitochondrial membrane potential. The complexes can enhance intracellular Ca2+ concentration and cause a release of cytochrome c. The autophagy was studied using MDC staining and western blot. Complexes 1-3 can effectively inhibit the cell invasion with a concentration-dependent manner. Additionally, the complexes target tubules and inhibit the polymerization of tubules. The antimicrobial activity of the complexes against S. aureus, E. coli, Salmonella and L. monocytogenes was explored. The mechanism shows that the complexes induce apoptosis in SGC-7901 cells through ROS-mediated lysosomal-mitochondrial, targeting tubules and damage DNA pathways.Graphical Abstract: Three iridium(III) complexes [Ir(N-C)2(PYTA)](PF6) (N-C = ppy, 1; bzq, 2; piq, 3) were synthesized and characterized. The anticancer activity of the complexes against SGC-7901 cells was studied by apoptosis, comet assay, autophagy, ROS, mitochondrial membrane potential, intracellular Ca2+ levels, release of cytochrome c, tubules and western blot analysis. The antibacterial activity in vitro was also assayed. [ABSTRACT FROM AUTHOR]

Graphical abstract A new iridium(III) complex was synthesized and characterization. The cytotoxic activity in vitro, apoptosis, comet assay, lysosomal membrane permeabilization, cell cycle arrest, mitochondrial membrane potential and the expression of Bcl-2 family proteins were investigated. Abstract A new iridium(III) polypyridyl complex [Ir(ppy) 2 (DPBD)](PF 6) (ppy = 2-phenylpyridine, DPBD = 4-(dipyrido[3,2- a :2′,3′- c ]phenazin-11-yl)benzene-1,2-diamine, Ir-1) was synthesized and characterized by element analysis, ESI-MS, IR, 1H NMR and 13C NMR. The cytotoxicity in vitro of the complex against cancer BEL-7402, A549, Eca-109 and normal LO2 cells was evaluated by 3-(4,5-dimethylthiazole)-2,5-diphenyltetraazolium bromide (MTT) method. The IC 50 values of the complex toward BEL-7402, A549 and Eca-109 are 13.8 ± 0.7, 14.5 ± 0.6 and 15.2 ± 2.4 µM, respectively. The apoptosis was studied with acridine orange (AO) and ethidium bromide (EB) staining method and comet assay. The reactive oxygen species including superoxide anion and NO, the location of the complex at lysosomes, lysosomal membrane permeabilization, location of the complex at mitochondria and the change of mitochondrial membrane potential were assayed under a fluorescent microscope. The complex can enhance the intracellular Ca2+ levels and induce a release of cytochrome c. In addition, the complex can cause autophagy and upregulate the expression of LC-3 and Beclin-1 proteins. The complex inhibits the cell growth at S phase. The effects of the complex on the expression of caspase 3 and Bcl-2 family proteins were explored. The results show that the complex induces apoptosis in BEL-7402 cells through lysosome–mitochondrial dysfunction pathway, which was accompanied by the regulation of Bcl-2 family proteins. [ABSTRACT FROM AUTHOR]

Abstract This study aimed to elucidate the effect of miR-1306–3p on metastasis of hepatocellular carcinoma (HCC) and potential mechanism involved. miR-1306–3p promoted migration and invasion of HCC in vivo and in vitro. Moreover, miR-1306–3p inhibited snail to enhance its expression via directly targeting FBXL5, thus inducing the epithelial-mesenchymal transition (EMT) in HCC. Intriguingly, miR-1306–3p expression was transcriptionally enhanced by FoxM1. Consistently, miR-1306–3p was upregulated in HCC compared with paracarcinoma and correlated with poor prognosis of HCC patients. Our researches suggest that miR-1306–3p is a tumor enhancer in regulating of HCC metastasis, and miR-1306–3p may be clinically utilized as a factor for the clinical diagnosis and prognosis of HCC. Graphical abstract Image 1 Highlights • miR-1306–3p may be potential biomarker for the clinical prognosis of HCC. • miR-1306–3p may be effective target for the treatment of HCC. • miR-1306–3p regulates Snail-mediated metastasis through targeting FBXL5. • miR-1306–3p is transcripted by FOXM1 to promote HCC progression. [ABSTRACT FROM AUTHOR]

Abstract A new series of dibenzoxanthene derivatives 4a–4d (4a : 1-oxo-5-bromo-11-cyano-13c-methoxy-1,13c-dihydroxyl-dibenzo[a,kl]xanthene , 4b : 1-oxo-5-bromo-11-cyano-13c-ethoxy-1,13c-dihydroxyl-dibenzo[a,kl]xanthene , 4c: 1-oxo-5-bromo-11-cyano-13c-propoxy-1,13c-dihydroxyl-dibenzo[a,kl]xanthene and 4d : 1-oxo-5-bromo-11-cyano-13c-butoxy-1,13c-dihydroxyl-dibenzo[a,kl]xanthene) were synthesized and the molecular mechanisms of anti-cancer activities were investigated. These compounds showed excellent anti-tumor activity against A549, Eca-109, HeLa, HepG2 and SGC-7901 cell lines. Compounds 4a–4d could effectively inhibit the migration and invasion of HeLa cells in wound healing and transwell assays. Compounds induced the DNA damage and arrested in cell cycle distribution at G0/G1 phase. Apoptosis induced by compounds was detected using morphological observation of nuclear changes and FITC-Annexin V/PI staining. Additionally, compounds also induced the autophagy of HeLa cells through observing AO staining and upregulated the expression of LC3II and Beclin-1 proteins. Furthermore, treatment with autophagy inhibitor 3-methyladenine induced an obvious decrease in apoptotic rate in HeLa cells. This indicated that autophagy further promoted the HeLa cells apoptosis. Compounds 4a–4d enhanced the intracellular Ca2+ and ROS. Then the mitochondrial membrane potential of HeLa cells was depolarized and the cytochrome C was released from mitochondria into cytoplasm. Activities of the apoptotic factors Bcl-2, Bax, caspase-3 were measured using western blotting. After HeLa cells were exposed to compounds, the expressions of PI3K and Akt protein were decreased. Compounds exhibit anti-cancer activity via apoptosis and autophagy through inhibition of PI3K/Akt signaling pathway in HeLa cells. Graphical Abstract A new series of dibenzoxanthene derivatives 4a–4d were synthesized and the molecular mechanisms of anti-cancer activities were investigated. Unlabelled Image Highlights • Four new dibenzoxanthene compounds were synthesized and characterized. • The cytotoxicity of these compounds was evaluated by MTT method. • Compounds also induced the apoptosis and the autophagy of HeLa cells. • Compounds induced apoptosis and autophagy through inhibition of PI3K/Akt signaling pathway. [ABSTRACT FROM AUTHOR]

Three new iridium (III) complexes [Ir (ppy) 2 (ipbc)](PF 6 ) ( 1 ), [Ir (bzq) 2 (ipbc)](PF 6 ) ( 2 ) and [Ir (piq) 2 (ipbc)](PF 6 ) ( 3 ) were designed and synthesized. All the complexes were tested for anticancer activity using 3-(4,5-dimethylthiazole)-2,5-diphenyltetraazolium bromide (MTT) method. The complexes show no cytotoxic activity toward cancer BEL-7402, SGC-7901, Eca-109, A549, HeLa and HepG2 cells. However, upon irradiation with white light, the complexes display high cytotoxicity against BEL-7402 cells with an IC 50 value of 5.5 ± 0.8, 7.3 ± 1.3 and 11.5 ± 1.6 μM for 1 , 2 and 3 , respectively. AO/EB staining and comet assay show that the complexes can induce apoptosis in BEL-7402 cells. The complexes can increase intracellular ROS and Ca 2+ levels and cause a decrease in the mitochondrial membrane potential. Autophagic assays exhibit that the complexes can induce autophagy and regulate the expression of Beclin-1 and LC3 proteins. The cell cycle distribution in BEL-7402 cells was carried out by flow cytometry. The expression of Bcl-2 family proteins was studied by western blot. Additionally, the complexes can release cytochrome c and inhibit the polymerization of α-tubulin. Our study reveals that the complexes inhibit the cell growth in BEL-7402 cells through an ROS-mediated mitochondria dysfunction and targeting tubules pathways. These complexes are a promising new entity for the development of multi-target anticancer drugs. [ABSTRACT FROM AUTHOR]

An iridium (III) complex [Ir(ppy) 2 (BDPIP)]PF 6 ( Ir-1 ) was reported to show high anticancer activity and may be used as a potent anticancer drug. In the current study, we designed and synthesized a novel iridium (III) complex and evaluated its potential inhibitory effect on the cancer cell growth in vitro and in vivo. This complex was found to display high cytotoxic activity in vitro and in vivo against A549 cell with a low IC 50 value of 3.6 ± 0.3 μM and inhibiting percentage of tumor growth is 63.84% compared with the control. The complex also exhibited potencies superior to that of cisplatin toward A549 cell in vitro and in vivo. Further studies revealed that the complex can induce apoptosis and autophagy, enhance the ROS level, cause a decrease in the mitochondrial membrane potential and inhibit the cell invasion. Our findings indicated that the complex induced apoptosis in A549 through mitochondria dysfunction and PI3K/AKT/mTOR signaling pathways. [ABSTRACT FROM AUTHOR]

A new ligand THPDP (THPDP = 11-(6,7,8,9-tetrahydrophenazin-2-yl)dipyrido[3,2- a :2′,3′- c ]phenazine) and its iridium(III) complex [Ir(ppy) 2 (THPDP)]PF 6 ( Ir-1 ) was synthesized and characterized by elemental analysis, IR, ESI-MS, 1 H NMR and 13 C NMR. The cytotoxicity in vitro of the complex against cancer cells B16, A549, Eca-109, SGC-7901, BEL-7402 and normal NIH 3T3 cell lines was evaluated using MTT method. The IC 50 values of the complex toward B16, A549 and Eca-109 cells are 1.0 ± 0.02, 1.4 ± 0.03 and 1.6 ± 0.06 μM, respectively. The apoptosis was investigated with AO/EB and DAPI staining methods. The complex shows strong ability to inhibit the cell growth in B16, A549 and Eca-109 cells. Ir-1 can induce apoptosis, increase the intracellular ROS level, and cause a decrease in the mitochondrial membrane potential. The intracellular Ca 2+ level and the release of cytochrome c were studied under a fluorescent microscope. The cell invasion and autophagy were also performed, and the cell cycle arrest was assayed by flow cytometry. The expression of Bcl-2 family proteins, PI3K, AKT, mTOR, P-mTOR was investigated by western blot. The results show that the complex induces apoptosis through ROS-mediated mitochondria dysfunction and inhibition of AKT/mTOR pathways. These findings are helpful for design and synthesis of iridium(III) complexes as potent anticancer drugs. [ABSTRACT FROM AUTHOR]

A new ligand MHPIP (MHPIP = 2-(1-methyl-1 H -pyrazol-4-yl)-1 H -imidazo[4,5- f ][1,10]phenanthroline) and its three ruthenium (II) complexes [Ru(N-N) 2 (MHPIP)](ClO 4 ) 2 (N-N = phen: 1,10-phenanthroline 1 ; dmp = 2,9-dimethyl-1,10-phenanthroline 2 ; ttbpy = 4,4′-ditertiarybutyl-2,2′-bipyridine 3 ) were synthesized and characterized. The cytotoxic activity in vitro was studied by MTT method. The complexes 1 – 3 show moderate cytotoxic effects on the cell growth in HepG2 cells with an IC 50 value of 25.5 ± 3.5, 35.6 ± 1.9 and 27.4 ± 2.3 μM, respectively. The apoptosis was investigated with AO/EB and Annex V/PI staining methods and comet assay. The reactive oxygen species, mitochondrial membrane potential were investigated under a fluorescent microscope. Autophagy assay shows that the complexes can cause autophagy and up-regulate the expression of Beclin-1 protein. Additionally, the complexes inhibit the cell growth in HepG2 cells at G0/G1 phase, and the complexes can regulate the expression of caspase 3 and Bcl-2 family proteins. The studies demonstrate that the complexes induce apoptosis in HepG2 cells through DNA damage and ROS-mediated mitochondrial dysfunction pathways. [ABSTRACT FROM AUTHOR]

An Ir(III) organometallic complex, [Ir(ppy) 2 (paip)]PF 6 ( 1 ), (ppy and paip denote 2-phenylpyridine and 2-(4-aminophenyl) imidazo [4,5-f] [1,10] phenanthroline, respectively) was synthesized and characterized by elemental analysis, ESI-MS, 1 H and 13 C NMR. The cytotoxic activity in vitro of the complex was evaluated by MTT (MTT = (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide)) method. The complex shows higher cytotoxic activity against PC-12 cells than cisplatin. The intracellular ROS generation and mitochondrial membrane potential (MMP) changes were determined by fluorescent microscope and flow cytometry. The cellular uptake and location of complex 1 , as well as cell cycle distribution and matrigel invasion in PC-12 cells treated with the complex were investigated. Meanwhile, Bcl-2 family proteins expression was also explored by western blot. The results indicate that the complex shows efficient cellular uptake and cumulates in nucleus as well as in mitochondria, and inhibits both the growth at G0/G1 phase and the invasion in extracellular matrix. It is rationally concluded that complex 1 induces apoptosis in PC-12 cell through a ROS-mediated mitochondrial dysfunction pathway with an increase in ROS level and a decrease in MMP. [ABSTRACT FROM AUTHOR]

Two new ligand PTTP (2-phenoxy-1,4,8,9-tetraazatriphenylene) and FTTP (2-(3-fluoronaphthalen-2-yloxy)-1,4,8,9-tetraazatriphenylene) and their six ruthenium(II) polypyridyl complexes [Ru(N-N) 2 (PTTP)](ClO 4 ) 2 and [Ru(N-N) 2 (FTTP)](ClO 4 ) 2 (N-N = dmb: 4,4′-dimethyl-2,2′-bipiridine; dmp: 2,9-dimethyl-1,10-phenanthroline; ttbpy: 4,4′-ditertiarybutyl-2,2′-bipyridine) were synthesized and characterized. The cytotoxic activity of the complexes against cancer cells HeLa, BEL-7402, A549, HepG-2, HOS and normal cell LO2 was evaluated by MTT method. The IC 50 values range from 1.5 ± 0.1 to 55.9 ± 7.5 μM. Complex 3 shows the highest cytotoxic activity toward BEL-7402 cells (IC 50 = 1.5 ± 0.1 μM). Complex 5 displays most effective inhibition of the cell growth in A549 and HOS cells with low IC 50 values of 2.5 ± 0.6 and 2.6 ± 0.1 μM, respectively. The apoptosis, reactive oxygen species, mitochondrial membrane potential, DNA damage, autophagy and anti-metastasis assay were investigated under a fluorescent microscope. The cell cycle arrest was assayed by flow cytometry, and the expression of caspases and Bcl-2 family proteins was studied by western blot. The results obtained show that the complexes induce apoptosis in BEL-7402 cells through a ROS-mediated mitochondrial dysfunction pathway. [ABSTRACT FROM AUTHOR]

A new ligand PFPIP (PFPIP = 2-(2,3,4,5,6-pentafluorophenyl)[4,5- f ]imadazo [1,10]phenanthroline) and its four ruthenium(II) polypyridyl complexes [Ru(N N) 2 (PFPIP)](ClO 4 ) 2 (N N = dmb: 4,4′-dimethyl-2,2′-bipyridine, 1 ; bpy: 2,2′-bipyridine, 2 ; phen: 1,10-phenanthroline, 3 ; dmp: 2,9-dimethyl-1,10-phenanthroline, 4 ) were synthesized and characterized by elemental analysis, IR, 1 H NMR, 13 C NMR and ESI-MS. The cytotoxic activity in vitro of the ligand and complexes toward BEL-7402, A549, HeLa, HepG2 and MG-63 cell lines was evaluated using MTT method (MTT = (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide). Complexes 1 , 3 and 4 show moderate cytotoxic effect on the cell growth in BEL-7402 cells with IC 50 values of 32.1 ± 0.9, 37.9 ± 1.7 and 42.1 ± 3.0 μM, respectively. The apoptosis in BEL-7402 cell was investigated with AO/EB and Hoechst 33,258 staining methods. The autophagy in BEL-7402 cell induced by complexes was assayed using MDC staining cell nuclei. The cell invasion, reactive oxygen species (ROS), mitochondrial membrane potential, cell cycle arrest, cellular uptake, comet assay and wound healing were studied under a fluorescent microscope. The complexes can cause autophagy and inhibit the cell invasion, and increase the ROS levels and induce a decrease in the mitochondrial membrane potential. The expression of the proteins related with apoptosis induced by the complexes was assayed by western blot analysis. [ABSTRACT FROM AUTHOR]

A new ligand BTCP and its iridium(III) complex [Ir(ppy)(BTCP)]PF ( Ir-1) were synthesized and characterized by elemental analysis, ESI-MS, IR, H NMR and C NMR. The cytotoxic activity in vitro of the ligand and its complex against SGC-7901, HeLa, HOS, PC-12, BEL-7402, MG-63, SiHa, A549, HepG2 and normal cell LO2 were evaluated by 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 reactive oxygen species (ROS), mitochondrial membrane potential, autophagy and cell invasion were studied under fluorescent microscope. The expression of caspases and Bcl-2 family proteins were investigated by western blot. The IC values of complex toward SGC-7901, BEL-7402 and MG-63 cells are 3.9 ± 0.5, 5.4 ± 1.2 and 4.2 ± 0.6 µM. The complex can increase the levels of ROS, and induce a decrease in the mitochondrial membrane potential. Ir-1 inhibits the cell growth at G0/G1 phase in SGC-7901 cells, and the complex can induce both autophagy and apoptosis and inhibit the cell invasion. And the complex induces apoptosis through a ROS-mediated mitochondrial dysfunction pathway. [ABSTRACT FROM AUTHOR]

As one of the major cell regulated center, mitochondria are closely associated with cell proliferation, apoptosis of tumor cell. In this work, four new ruthenium (II) polypyridyl complexes [Ru(bpy) 2 (FTTP)](ClO 4 ) 2 ( 1 ) (FTTP = 11-(3-fluoro-naphthalen-2-yloxy)-4,5,9,14-tetraaza-benzo[ b ]triphenylene, bpy = 2,2′-bipyridine), [Ru(phen) 2 (FTTP)](ClO 4 ) 2 ( 2 ) (phen = 1,10-phenanthroline), [Ru(bpy) 2 (PTTP)](ClO 4 ) 2 ( 3 ) (PTTP = 2-phenoxy-1,4,8,9-tetraazatriphenylene) and [Ru(phen) 2 (PTTP)](ClO 4 ) 2 ( 4 ) were synthesized and characterized by elemental analysis, ESI-MS, 1 H NMR and 13 C NMR. The cytotoxic activity, ability of inhibiting cell invasion, cell cycle arrest and apoptosis-inducing mechanism of these Ru(II) complexes have been investigated in detail by MTT (3-(4,5-dimethylthiazole)-2,5-diphenyltetrazolium bromide) method, invasion assay, comet assay as well as western blotting techniques. Notably, complexes 1 – 4 displayed high cytotoxic activity against liver carcinoma HepG2 cells and the IC 50 values of complexes 1 – 4 against HepG2 cells are 10.4 ± 1.2, 9.3 ± 0.6, 29.1 ± 1.5 and 5.6 ± 1.2 μM, respectively. The comet assay showed that the complexes can induce DNA damage. The acridine orange (AO) and ethidium bromide (EB) staining method indicated that the complexes can cause apoptosis in HepG2 cells. Further studies showed that complexes 1 – 4 caused cell cycle arrest at G0/G1 phase and induced HepG2 cells apoptosis through a ROS-mediated mitochondrial dysfunction pathway, which involved an increase in the levels of reactive oxygen species (ROS), a decrease in the mitochondrial membrane potential, activation of caspases and Bcl-2 family proteins. [ABSTRACT FROM AUTHOR]

In this article, the in vitro cytotoxicity of platycodin D was evaluated in human PC-12, SGC-7901, BEL-7402, HeLa and A549 cancer cell lines. PC-12 cells were sensitive to platycodin D treatment, with an IC 50 value of 13.5 ± 1.2 μM. Morphological and comet assays showed that platycodin D effectively induced apoptosis in PC-12 cells. Platycodin D increased the levels of reactive oxygen species (ROS) and induced a decrease in mitochondrial membrane potential. Platycodin D induced cell cycle arrest at the G0/G1 phase in the PC-12 cell line. Platycodin D can induce autophagy. In addition, platycodin D can down-regulate the expression of Bcl-2 and Bcl-x, and up-regulate the levels of Bid protein in the PC-12 cells. The results demonstrated that platycodin D induced PC-12 cell apoptosis through a ROS-mediated mitochondrial dysfunction pathway. [ABSTRACT FROM AUTHOR]

Four new ruthenium(II) polypyridyl complexes [Ru(N–N) 2 (dhbn)](ClO 4 ) 2 (N–N = dmb: 4,4′-dimethyl-2,2′-bipyridine 1 ; bpy = 2,2′-bipyridine 2 ; phen = 1,10-phenanthroline 3 ; dmp = 2,9-dimethyl-1,10-phenanthroline 4 ) were synthesized and characterized. The cytotoxicity in vitro of the ligand and complexes toward HepG-2, HeLa, MG-63 and A549 were assayed by MTT method. The IC 50 values of the complexes against the above cells range from 17.7 ± 1.1 to 45.1 ± 2.8 μM. The cytotoxic activity of the complexes against HepG-2 cells follows the order of 4 > 2 > 3 > 1 . Ligand shows no cytotoxic activity against the selected cell lines. Cellular uptake, apoptosis, comet assay, reactive oxygen species, mitochondrial membrane potential, cell cycle arrest, and the expression of proteins involved in apoptosis pathway induced by the complexes were investigated. The results indicate that complexes 1–4 induce apoptosis in HepG-2 cells through an intrinsic ROS-mediated mitochondrial dysfunction pathway. [ABSTRACT FROM AUTHOR]

The DNA-binding, photocleavage, and antitumor activity of three free base pyridyl corroles 1, 2, and 3 have been investigated. The binding affinity toward CT-DNA decreases with increasing number of pentafluorophenyl, whereas the photocleavage activity toward pBR322 DNA becomes more efficient. Singlet oxygen was demonstrated as active species responsible for DNA cleavage. These corroles exhibited high cytotoxicity against three tested cancer cells (Hela, HapG2, and A549) and the cytotoxicity could be further enhanced under irradiation. Intracellular reactive oxygen species level was also monitored using HeLa Cells upon the combined treatment of corroles and light. These corroles could be absorbed by HeLa cells at low concentration. They can induce the decrease of mitochondrial membrane potential and apoptosis of tumor cells under irradiation. [ABSTRACT FROM AUTHOR]

A new ligand TCPI and its three ruthenium(II) polypyridyl complexes [Ru(N-N) 2 (TCPI)](PF 6 ) 2 (N-N = bpy: 2,2′-bipyridine 1 ; phen: phenanthroline 2 ; dmp: 2,9-dimethyl-1,10-phenanthroline 3 ) were synthesized and characterized by elemental analysis, ESI-MS, 1 H NMR, IR, absorption and emission spectra. The cytotoxic activity in vitro of the ligand and complexes against cancer cells SGC-7901, PC-12, HepG-2, SiHa, Eca-109, HeLa and normal cell LO2 was evaluated by MTT method. Complex 3 shows the highest cytotoxic activity toward SGC-7901 cell among the complexes. Interestingly, the complexes show low or no cytotoxic activity against normal cell LO2. The apoptosis in SGC-7901 cell was investigated with AO/EB staining method. The ROS levels and the changes of mitochondrial membrane potential were studied under fluorescent microscope and flow cytometry. The cell invasion, cell cycle arrest and the expression of Bcl-2 family proteins were studied in detail. The results demonstrate that the complexes induce apoptosis in SGC-7901 cell through a ROS-mediated mitochondrial dysfunction pathway, which was accompanied by the regulation of Bcl-2 family proteins. [ABSTRACT FROM AUTHOR]

Four new ruthenium(II) polypyridyl complexes [Ru( N - N ) 2 (bddp)](ClO 4 ) 2 1–4 (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 , bddp = benzilo[2,3- b ]-1,4-diazabenzo[ i ]dipyrido[3,2- a :2′,3′- c ]phenazine) were synthesized and characterized by elemental analysis, ESI-MS and 1 H NMR. The cytotoxicity in vitro of the complexes against BEL-7402, HeLa, MG-63 and A549 cell lines was investigated by MTT method. The complexes show high cytotoxic activity toward the selected cell lines with an IC 50 value ranging from 5.3 ± 0.6 to 15.7 ± 3.6 μM. The apoptosis was studied with acridine orange (AO)/ethdium bromide (EB) and Hoechst 33258 staining methods. The cellular uptake was investigated with DAPI staining method. The reactive oxygen species (ROS) and mitochondrial membrane potential were performed under fluorescent microscope and flow cytometry. The complexes can induce an increase in the ROS levels and a decrease in the mitochondrial membrane potential. The comet assay was studied with fluorescent microscope. The percentage in apoptotic and necrotic cells and cell cycle arrest were assayed by flow cytometry. The effects of the complexes on the expression of caspases and Bcl-2 family proteins were studied by western blot analysis. The results show that the complexes induce apoptosis in A549 cells through an ROS-mediated mitochondrial dysfunction pathway, which was accompanied by regulating the expression of Bcl-2 family proteins. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Four new ruthenium(II) polypyridyl complexes [Ru(dmb) 2 (dqtbt)](ClO 4 ) 2 ( 1 ) (dqtbt = 12-(2,3-diphenyl-quinoxalin-6-yl)-4,5,10,13-tetraazabenzo[ b ]triphenylene, dmb = 4,4′-dimethyl-2,2′-bipyridine), [Ru(bpy) 2 (dqtbt)](ClO 4 ) 2 ( 2 ) (bpy = 2,2′-bipyridine), [Ru(phen) 2 (dqtbt)](ClO 4 ) 2 ( 3 ) (phen = 1,10-phenanthroline) and [Ru(dmp) 2 (dqtbt)](ClO 4 ) 2 ( 4 ) (dmp = 2,9-dimethyl-1,10-phenanthroline) were synthesized and characterized. The cytotoxicity in vitro of the complexes was evaluated against human BEL-7402, A549, HeLa, HepG-2 and MG-63 cancer cell lines. These complexes are sensitive to BEL-7402 cells, the IC 50 values are 4.9 ± 0.5, 4.6 ± 0.4, 7.7 ± 1.8 and 1.9 ± 0.3 μM toward BEL-7402 cells. The complexes can increase the levels of reactive oxygen species and induce the decrease of mitochondrial membrane potential. Morphological and comet assay studies show that the complexes can effectively induce apoptosis in BEL-7402 cells. Complexes 1 – 4 inhibit the cell growth at G0/G1 phase in BEL-7402 cell line. The complexes can downregulate the expression of Bcl-2 and Bcl-x proteins and upregulate the levels of Bid protein in BEL-7402 cells. The results show that the complexes induce BEL-7402 cell apoptosis through a ROS-mediated mitochondrial dysfunction pathway. In addition, the complexes show strong protein-binding affinities. [ABSTRACT FROM AUTHOR]

Four new ruthenium(II) polypyridyl complexes [Ru(dmb) 2 (DQTT)](ClO 4 ) 2 ( 1 ) (DQTT = 12-(1,4-dihydroquinoxalin-6-yl)-4,5,9,14-tetraazabenzo[b]triphenylene, dmb = 4,4′-dimethyl-2,2′-bipyridine), [Ru(bpy) 2 (DQTT)](ClO 4 ) 2 ( 2 ) (bpy = 2,2′-bipyridine), [Ru(phen) 2 (DQTT)](ClO 4 ) 2 ( 3 ) (phen = 1,10-phenanthroline) and [Ru(dmp) 2 (DQTT)](ClO 4 ) 2 ( 4 ) (dmp = 2,9-dimethyl-1,10-phenanthroline) were synthesized and characterized by elemental analysis, ESI-MS, 1 H NMR and 13 C NMR. The cytotoxic activity in vitro of the complexes was evaluated against human BEL-7402, A549, HeLa, HepG-2 and MG-63 cancer cell lines by MTT (3-(4,5-dimethylthiazole)-2,5-diphenyltetrazolium bromide) method. The IC 50 values of complexes 1 – 4 against BEL-7402 cells are 31.8 ± 1.0, 35.8 ± 1.6, 29.0 ± 0.8 and 25.0 ± 0.9 μM, respectively. The morphological apoptosis was investigated with AO/EB (acridine orange/ethidium bromide) and Hoechst 33258 staining methods. The DNA damage was assayed by comet assay. The inhibition of cell migration was evaluated by the wound healing assay. The levels of ROS (reactive oxygen species) and the changes of mitochondrial membrane potential were studied under fluorescent microscope. The percentages in the cells of apoptotic and necrotic cells and the cell cycle arrest were determined by flow cytometry. The expression of Bcl-2 family proteins was investigated by western blot analysis. The results show that the complexes induce BEL-7402 cells apoptosis through a ROS-mediated mitochondrial dysfunction pathway, which was accompanied by regulation of the expression of Bcl-2 family proteins. [ABSTRACT FROM AUTHOR]

A new ligand Adbdp and its four ruthenium(II) polypyridyl complexes [Ru(N-N) 2 (Adbdp)](ClO 4 ) 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 , Adbdp = acenaphtheno[2,3-b]-1,4-diazabenzo[i]dipyrido[3,2- a :2′,3′- c ]phenazine] were synthesized and characterized by elemental analysis, ESI-MS and 1 H NMR. The cytotoxicity in vitro of the complexes against BEL-7402, HeLa, MG-63 and A549 cells was studied by MTT method. The IC 50 values are 24.2 ± 1.9, 11.5 ± 3.6, 3.4 ± 0.3 and 9.7 ± 0.5 μM for complexes 1 , 2 , 3 and 4 toward A549 cells, respectively. The apoptosis was assayed with AO/EB and Hoechst 33258 staining methods. The cellular uptake was investigated with DAPI-stained cell nuclei. The reactive oxygen species and mitochondrial membrane potential were performed under fluorescent microscope. The cell cycle distribution was studied by flow cytometry and the protein expression of Bcl-2 family proteins was analyzed by western blot. The results show that the complexes induce A549 cell apoptosis through a ROS-mediated mitochondrial dysfunction pathway. [ABSTRACT FROM AUTHOR]

Two dibenzoxanthene isomers 3 and 4 were synthesized and characterized. The crystal structures of the two compounds were solved by single-crystal X-ray diffraction. Binding of two compounds with calf thymus DNA (CT DNA) and BSA (bovine serum albumin) has been thoroughly investigated by UV-Vis and fluorescence spectroscopy. The DNA-binding constants were determined to be 2.51 (± 0.09) × 10(3) for compound 3 and 4.55 (± 0.10) × 10(3) for compound 4. Two compounds can cleave pBR322 DNA upon irradiation. Significant nuclear damages of BEL-7402 cells were observed with compound treatment in a comet assay. The cytotoxicity in vitro was investigated by MTT method. These compounds have been found to induce nuclear condensation and fragmentation in BEL-7402 cells. The two compounds can enhance intracellular reactive oxygen species and decrease the mitochondrial membrane potential. The compounds activated caspase-3 and caspase-7, down-regulated the expression levels of anti-apoptotic protein Bcl-2, and up-regulated the expression levels of pro-apoptotic protein Bax. These compounds induce apoptosis of BEL-7402 cells through an ROS-mediated mitochondrial dysfunction pathway. [ABSTRACT FROM AUTHOR]

A Ru(II) polypyridyl complex [Ru(bpy) 2 (HMSPIP)](ClO 4 ) 2 ( 1 ) (bpy = 2,2′-bipyridine, HMSPIP = 2-(4-methylsulfonyl)phenyl-1H-imidazo[4,5- f ][1,10] phenanthroline) was synthesized. The IC 50 value of the complex against human hepatocellular cell BEL-7402 is 21.6 ± 2.7 μM. The complex shows no cytotoxic activity toward human lung adenocarcinoma cell A549, human osteosarcoma cell MG-63 and human breast cancer cell SK-BR-3 cells. It is easily for complex 1 to be taken up by BEL-7402 cells. The complex can enhance the reactive oxygen species (ROS) levels and induce the decrease in the mitochondrial membrane potential. The complex inhibits the cell growth in BEL-7402 cells at G2/M phase. Complex 1 can regulate the expression of Bcl-2 family proteins. The results show that the complex induces apoptosis of BEL-7402 cells through a ROS-mediated mitochondrial dysfunction pathway. [ABSTRACT FROM AUTHOR]

A new ruthenium(II) polypyridyl complex [Ru(dmp) 2 (pddppn)](ClO 4 ) 2 Ru1 was synthesized and characterized. The cytotoxic activity in vitro of the complex was evaluated by MTT method. Ru1 shows high effect on the inhibition of the cell growth against BEL-7402, HeLa, MG-63 and A549 cells with low IC 50 values of 1.6 ± 0.4, 9.0 ± 0.8, 1.5 ± 0.2 and 1.5 ± 0.3 μM, respectively. The cellular uptake indicates that Ru1 can enter into the cytoplasm and accumulate in the cell nuclei. Ru1 can induce apoptosis in A549 cells and enhance the levels of reactive oxygen species (ROS) and induce the decrease of mitochondrial membrane potential. In addition, Ru1 can down-regulate the levels of Bcl-2, Bcl-x, Bak, and Bim expression and up-regulate the expression of Bag-1 and Bad. The complex induces apoptosis of A549 cells through an intrinsic ROS-mediated mitochondrial dysfunction pathway, which was accompanied by regulating the expression of caspases and Bcl-2 family proteins. [ABSTRACT FROM AUTHOR]