Luteoloside inhibits Aß1-42 fibrillogenesis, disintegrates preformed fibrils, and alleviates amyloid-induced cytotoxicity.

Abnormal aggregation and fibrillogenesis of amyloid-ß protein (Aß) can cause Alzheimer's disease (AD). Thus, the discovery of effective drugs that inhibit Aß fibrillogenesis in the brain is crucial for the treatment of AD. Luteoloside, as one of the polyphenolic compounds, is found to have a certain therapeutic effect on nervous system diseases. However, it remains unknown whether luteoloside is a potential drug for treating AD by modulating Aß aggregation pathway. In this study, we performed diverse biophysical and biochemical methods to explore the inhibition of luteoloside on Aß1-42 which is linked to AD. The results demonstrated that luteoloside efficiently prevented amyloid oligomerization and cross-ß-sheet formation, reduced the rate of amyloid growth and the length of amyloid fibrils in a dose-dependent manner. Moreover, luteoloside was able to influence aggregation and conformation of Aß1-42 during different fiber-forming phases, and it could disintegrate already preformed fibrils of Aß1-42 and convert them into nontoxic aggregates. Furthermore, luteoloside protected cells from amyloid-induced cytotoxicity and hemolysis, and attenuated the level of reactive oxygen species (ROS). The molecular docking study showed that luteoloside interacted with Aß1-42 mainly via Conventional Hydrogen Bond, Carbon Hydrogen Bond, Pi-Pi T-shaped, Pi-Alkyl and Pi-Anion, thereby possibly preventing it from forming the aggregates. These observations indicate that luteoloside, a natural anti-oxidant molecule, may be applicable as an effective inhibitor of Aß, and promote further exploration of the therapeutic strategy against AD.

Formononetin Inhibits Hepatic I/R-Induced Injury through Regulating PHB2/PINK1/Parkin Pathway.

Formononetin (FN), an isoflavone compound mainly isolated from soy and red clover, had showed its anti-inflammation, antioxidative effects in some degenerative diseases and cholestasis. However, the role of FN in protecting ischemia/reperfusion- (I/R-) induced liver injury and the possible mechanism were unclear. In this study, effects of FN on liver injury were investigated in a rat hepatic I/R model; further, mitophagy-related proteins were measured by immunoblotting or immunofluorescence. The possible roles of PHB2 and PINK1 in regulating mitophagy by FN were verified using adeno-associated virus knockdown. The results showed that FN had protective effects against hepatic I/R injury through regulating PINK1/Parkin-regulated mitophagy. Further, we found that FN inhibited PARL expression and prevented PGAM5 cropped by increasing the expression of PHB2. The knockdown of PINK1 or PHB2 both abolished the protective effects of FN. Taken together, our findings indicated that the isoflavone compound FN promoted PHB2/PINK1/Parkin-mediated mitophagy pathway to protect liver from I/R-induced injury. These results provided novel insights into the potential prevention strategies of FN and its underlying mechanisms.

Ketoplatin in triple-negative breast cancer cells MDA-MB-231: High efficacy and low toxicity, and positive impact on inflammatory microenvironment.

Triple-negative breast cancer (TNBC) shares the molecular features facilitating epithelial-to-mesenchymal transition (EMT), which contributed to tumor invasion and metastasis. A platinum(IV) conjugate ketoplatin deriving from FDA-approved drugs cisplatin and ketoprofen was designed and prepared to enhance antitumor activity and suppress EMT in TNBC via positive impact on inflammatory microenvironment by modulating COX-2 signal. As a prodrug, ketoplatin afforded 50.26-fold higher cytotoxicity than cisplatin against TNBC mesenchymal-stem cell-like MDA-MB-231 cells, partly attributing to its dramatic increase of cellular uptake and DNA damage. More importantly, EMT progress in MDA-MB-231 was markedly restrained by ketoplatin, resulting from the suppression of vimentin and N-cadherin mediated by down-regulated COX-2. Further in vivo investigation exhibited that ketoplatin effectively inhibited tumor growth and reduced systemic toxicity compared to cisplatin. Overall, ketoplatin possessed high antitumor activity and low toxicity against TNBC MDA-MB-231 in vitro and in vivo.

A facile and green strategy to simultaneously enhance the flame retardant and mechanical properties of poly(vinyl alcohol) by introduction of a bio-based polyelectrolyte complex formed by chitosan and phytic acid.

There are still some key problems in the process of the flame retardant treatment of poly vinyl alcohol (PVA): poor compatibility, deteriorating mechanical properties and potential toxicity to human health and environment. To solve these issues, a green and eco-friendly bio-based polyelectrolyte complex (PEC) formed by chitosan and phytic acid was designed to enhance the flame retardant and mechanical properties of PVA by a facile ultrasonic-assisted solution blending method. Moreover, the mechanical and flame retardant properties could be regulated by varying the ratio of each component in the PEC. Thermogravimetric analysis (TGA) indicated that after the introduction of PEC, PVA/PEC composites maintained better thermal stability and char formation ability. Besides, when the addition of PEC reached 20 wt%, the limited oxygen index (LOI) value of cured PVA increased from 18% to 25.9%, 30.8% and 35.6% for PVA/20(2 : 1) PEC, PVA/20(1 : 2) PEC and PVA/20(1 : 8) PEC, respectively. Moreover, UL-94 V-0 rating was achieved except for the PVA/20(2 : 1) PEC. Compared with pure PVA, the peak heat release rate (pHRR) and the total heat release (THR) of PVA/20(1 : 8) PEC demonstrated a sharp decrease by 69.9% and 45.5%, respectively, in the microscale combustion calorimeter measurements (MCC). These results indicate that PEC can endow PVA with excellent flame retardancy. Furthermore, the microscopic investigations on char residues of all samples by scanning electron microscopy, Fourier transform infrared spectra and Raman spectroscopy revealed the possible flame retardant mechanisms in condensed and gaseous phases. In addition, PVA/PEC composites have better mechanical properties owing to their harder backbones of chitosan, formation of phosphonate bonds and the PVA molecular chain movement blocked by PEC. As a result, the facile processing technology and eco-friendly flame retardants are expected to be applied in practice.

Anticancer Melatplatin Prodrugs: High Effect and Low Toxicity, MT1-ER-Target and Immune Response In Vivo.

Multitargeted therapy could rectify various oncogenic pathways to block tumorigenesis and progression. The combination of endocrine-, immune-, and chemotherapy might exert a highly synergistic effect against certain tumors. Herein, a series of smart Pt(IV) prodrugs 3-6, named Melatplatin, were rationally designed not only to multitarget DNA, MT1, and estrogen receptor (ER) but also to activate immune response. Melatplatin, conjugating first-line chemotherapeutic Pt drugs with human endogenous melatonin (MT), significantly enhanced drug efficacy especially in ER high-expression (ER+) cells, among which 3 presented the most potent cytotoxicity toward ER+ MCF-7 with nanomolar IC50 values 100-fold lower than cisplatin. Melatplatin could bind well to melatonin receptor (MT1) according to molecular docking. Besides, 3 evidently increased intracellular accumulation and DNA damage, upregulated γH2AX and P53, and silenced NF-κB to induce massive apoptosis. Most strikingly, 3 effectively inhibited tumor growth and attenuated systemic toxicity compared to cisplatin in vivo, promoting lymphocyte proliferation in spleen to achieve immune modulation.

Eco-friendly flame retardant coating deposited on cotton fabrics from bio-based chitosan, phytic acid and divalent metal ions.

With the increasing awareness of environmental protection, the greening of flame retardants has become an inevitable choice for flame retardant technology. Bio-based materials have the advantages of wide source, recyclability and green environmental protection, and have received extensive attention. In this work, chitosan and phytic acid as intumescent flame retardant system and metal ion as a synergist were built on cotton fabrics to achieve efficient flame retardancy by facile dip-pad-dry process. Microscale combustion calorimetry results manifested that the heat release rate values of coated samples were lower than that of uncoated samples. The peak heat release rate and total heat release of uncoated samples were 333.1 W/g and 13.1 kJ/g, while these values of samples coated CH/PA/Ba/PA were 129.1 W/g and 5.4 kJ/g respectively and char residues also were increased sharply owing to the phosphate groups promote the formation of char layer covering the surface of the cotton fabrics, which can prevent heat transfer. Scanning electron microscopy confirmed that there were much more bubbles on the surface of fibers for the coated CH/PA/Ba/PA after horizontal flame tests. The results indicated that the synergy of the intumescent flame retardant system was achieved by the addition of metal ions which could accelerate the produce of a large number of nonflammable gases. Horizontal flame test and limit oxygen index (LOI) test showed that the burning rate and LOI values of samples coated CH/PA/Ba/PA, CH/PA /CH/PA, PA/Ba/PA/Ba were 1.5 mm/s and 22.0, 2.0 mm/s and 20.2 and 2.5 mm/s and 18.0 respectively, compared to 3.3 mm/s and 16.2 of uncoated samples. The samples with intumescent flame retardant system and metal ions (CH/PA/Ba/PA) had best flame retardant performance. Moreover its weight gain (5.2%) was less than that (10.7%) of the sample only with intumescent flame retardant system (CH/PA /CH/PA). The less weight gain had less effect on the softness of cotton fabrics. As a result, the coating is expected to be applied in practice.

Fuplatin: An Efficient and Low-Toxic Dual-Prodrug.

As FDA-approved chemotherapeutic agents, cisplatin, oxaliplatin, and 5-fluorouracil are widely used in clinic but limited by severe side-effects. To ameliorate their respective defects, a series of "dual-prodrug" by linking oxoplatin and 5-FU were designed and synthesized. The assembled compounds 10-17, named Fuplatin, exhibited much higher cytotoxicity against the tested cancer cells while lower cytotoxicity toward the human normal lung cells than free drugs or their combinations. Among them, 14 enhanced cellular accumulation with 62- and 825-fold amount of oxaliplatin and 8 at 9 h, respectively, significantly induced DNA damage and cell apoptosis, and inhibited migration and invasion in HCT-116 cells. Compound 14 arrested the cell cycle at S and G2 phases and up-regulated thymidylate synthase and p53, consistent with the results of the combination, suggesting 14 adopted a collaborative mode of 5-FU and oxaliplatin to kill cancer cells. In vivo, compound 14 showed high antitumor effect and no observable toxicity in NOD/SCID mice bearing HCT-116 tumors.

New NSAID-Pt(IV) prodrugs to suppress metastasis and invasion of tumor cells and enhance anti-tumor effect in vitro and in vivo.

The great interest in epithelial-to-mesenchymal transition (EMT) programme lies in its association with process of metastasis and invasion, which is a crucial cause of cancer-related death. Herein, we designed and reported three new NSAID-Pt(IV) prodrugs, taking Non-Steroid Anti-Inflammatory Drugs (NSAIDs) to disrupt EMT programme and assist genotoxic platinum-based drugs as a cytotoxicity booster, to offer a class of potential anticarcinogens with a multi-functional action mechanism. The NSAID-Pt(IV) prodrugs, especially Eto-Pt(IV), highly enhanced cellular uptake with amount up to 42-fold at 3 h compared with CDDP, and greatly increased DNA damage and cell apoptosis, showing much higher cytotoxicity than cisplatin in the tested cancer cells even in A549/cis cells. Among of them, Eto-Pt(IV) and Car-Pt(IV) exhibited more excellent activity than Sul-Pt(IV), arising from their reduction-labile and favorable lipophilicity. Most strikingly, Eto-Pt(IV) markedly inhibited metastasis and invasion of MCF-7 cells, owing to its COX-2 suppression that down-regulated active MMP-2, vimentin protein and up-regulated E-cadherin. In vivo, Eto-Pt(IV) displayed potent antitumor activity and no observable toxicity in BALB/c nude mice bearing MCF-7 tumors.

Chlorambucil-conjugated platinum(IV) prodrugs to treat triple-negative breast cancer in vitro and in vivo.

Modification of platinum (II) into lipophilic platinum (IV) compounds by introducing biologically active molecules were widely employed to develop new platinum-based prodrugs in the past decade. In this paper, two chlorambucil platinum (IV) complexes, CLB-Pt and CLB-Pt-CLB, were synthesized and displayed very potent antiproliferative activity against all the tested cancer cell lines, such as A549, HeLa and MCF-7, especially to treat the well-known refractory triple-negative breast cancer. CLB-Pt-CLB significantly improved cell-killing effect in triple-negative subtype MDA-MB-231 cells, and showed much stronger cytotoxicity than either monotherapy or combination of cisplatin and chlorambucil. CLB-Pt-CLB prodrug entered cells in dramatically increased amount compared with cisplatin and enhanced DNA damage, inducing cancer cell apoptosis. It exhibited high anticancer activity and no observable toxicity in BALB/c nude mice bearing MDA-MB-231 tumors. The chlorambucil moiety not only greatly assisted the passive diffusion of CLB-Pt-CLB into cells, but also produced the synergism with cisplatin in targeting DNA.

Highly selective and sensitive turn-on fluorescent sensor for detection of Al3+ based on quinoline-base Schiff base.

A new aluminum ion fluorescent probe (4-(diethylamino)-2-hydroxybenzylidene)isoquinoline-1-carbohydrazide (HL1) has been conveniently synthesized and characterized. HL1 exhibited a highly selective and pronounced enhancement for Al3+ in the fluorescence emission over other common cations by forming a 2:1 complex, with a recognition mechanism based on excited-state intramolecular proton transfer (ESIPT) and intramolecular charge transfer (ICT). The strong fluorescent emission can be observed even at ppm level concentration of the probe in the presence of Al3+ with 41 fold intensity enhancement at 545 nm. HL1 displays good linear relationship with Al3+ in the low concentration and the limit of detection is 8.08 × 10-8 mol/L. Similar molecules with different substituents on salicylaldehyde phenyl ring were synthesized for studying the structure-activity relationship. Density-functional theory (DFT) calculations are in agreement with the proposed mechanism. It is confirmed that HL1 could be used to detect Al3+ ions in real sample by fluorescence spectrometry and Al3+ ions in cells by bioimaging.

Synthesis of a novel adamantyl nitroxide derivative with potent anti-hepatoma activity in vitro and in vivo.

In this study, a novel adamantyl nitroxide derivative was synthesized and its antitumor activities in vitro and in vivo were investigated. The adamantyl nitroxide derivative 4 displayed a potent anticancer activity against all the tested human hepatoma cells, especially with IC50 of 68.1 µM in Bel-7404 cells, compared to the positive control 5-FU (IC50=607.7 µM). The significant inhibition of cell growth was also observed in xenograft mouse model, with low toxicity. Compound 4 suppressed the cell migration and invasion, induced the G2/M phase arrest. Further mechanistic studies revealed that compound 4 induced cell death, which was accompanied with damaging mitochondria, increasing the generation of intracellular reactive oxygen species, cleavages of caspase-9 and caspase-3, as well as activations of Bax and Bcl-2. These results confirmed that adamantyl nitroxide derivative exhibited selective antitumor activities via mitochondrial apoptosis pathway in Bel-7404 cells, and would be a potential anticancer agent for liver cancer.

Safflower yellow B suppresses HepG2 cell injury induced by oxidative stress through the AKT/Nrf2 pathway.

Oxidative stress plays an important role in the pathogenesis of various liver diseases. Safflower yellow B (SYB) has been reported to protect the brain against damage induced by oxidative stress; however, whether SYB can also protect hepatocytes from oxidative stress remains unknown. In the present study, to determine whether pre-treatment with SYB reduces hydrogen peroxide (H2O2)­induced oxidative stress in HepG2 cells, we investigated H2O2-induced oxidative damage to HepG2 cells treated with or without SYB. Cell viability was measured by MTT assay and cytotoxicity was evaluated by lactate dehydrogenase (LDH) assay. The activities of the antioxidant enzymes, glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) were determined using respective kits. Intracellular reactive oxygen species (ROS) accumulation in the HepG2 cells was monitored using the fluorescent marker, 2',7'-dichlorodihydrofluorescein diacetate (H2DCF-DA). Cell apoptosis was evaluated by determining the activity of caspase-3 and by Annexin V/propidium iodide (PI) double staining. Protein expression levels were measured by western blot analysis, and the levels of related cellular kinases were also determined. H2O2 induced pronounced injury to the HepG2 cells, as evidenced by increased levels of malondialdehyde (MDA) and ROS, the decreased activity of SOD and GSH-Px, the increased activitation of caspase-3 and cell apoptosis, and the loss of mitochondrial membrane potential. SYB significantly inhibited the damaging effects of H2O2, indicating that it protected the cells against H2O2-induced oxidative damage. Moreover, pre-treatment with SYB increased the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase 1 (HO-1) and NAD(P)H dehydrogenase, quinone 1 (NQO1) which are peroxiredoxins. SYB also significantly increased the phosphorylation of AKT. However, this inductive effect was blunted in the presence of the AKT inhibitor, LY294002. The findings of our study suggest that the activation of the AKT/Nrf2 pathway is involved in the cytoprotective effects of SYB against oxidative stress. Our findings provide new insight into the cytoprotective effects of SYB and the possible mechanisms underlying these effects. Thus, SYB may prove to be of therapeutic value for the treatment of various liver diseases.

Pharmacokinetics and bioavailability in healthy Chinese volunteers of a novel rabeprazole sterile powder formulation for injection.

Rabeprazole sterile powder for injection (RSPI) is a new formulation, compared with rabeprazole enteric coated tablets. The aim of this study was to evaluate the pharmacokinetic properties and bioavailability of RSPI in healthy Chinese volunteers. Pharmacokinetic studies included an ascending single dose of 10, 20, 40 mg, and a multiple doses of 20 mg. A bioavailability study was evaluated following a single dose of 20 mg between RSPI and Pariet® Pharmacokinetic parameters of rabeprazole given in each treatment period were calculated using non-compartmental analysis. In the PK study, after a single intravenous dose of 10, 20, and 40 mg, the main pharmacokinetic parameters for rabeprazole were as follows: Cmax 566.88, 897.23, 2,171.6 ng/mL; AUClast/794.31, 1,122.76, 2,446.85 ng×h/mL, respectively. After multiple doses of 20 mg, the main pharmacokinetic parameters for rabeprazole were Cmax 991.90 ng/mL, AUClast 1,261.08 ng×h/mL. In the BA study, after a single oral dose of Pariet® 20 mg, the main pharmacokinetic parameters for rabeprazole were Cmax 582.74 ng/mL, AUClast 1,135.5 ng×h/mL. RSPI produced a less-than-proportional increase in exposure with increasing dose in healthy subjects. The accumulation ratio was 1.0, suggesting RSPI displayed no accumulation after repeated administration. The bioavailability of RSPI was increased by ~ 11% as measured by AUClast compared with Pariet® after a single oral administration.

Association of structural modifications with bioactivity in three new copper(II) complexes of Schiff base ligands derived from 5-chlorosalicylaldehyde and amino acids.

Three novel structurally associated copper(II) complexes [Cu(II)(SalCl-Gly)(H2O)2] (1), [Cu(II)(SalCl-Ala)(H2O)] (2) and [Cu(II)(SalCl-Gly)(bipy)]·0.5H2O (3) (SalCl-Gly=5-chloro-2-hydroxybenzylidene-glycine, SalCl-Ala=5-chloro-2-hydroxybenzylidene-alanine, bipy=2,2'-bipyridine) have been synthesized and characterized by X-ray crystallography, elemental analysis, IR and fluorescence spectroscopy. Single-crystal diffraction reveals that complex 1 is an infinite 1D zigzag chain in which SalCl-Gly serves as both a chelating and a bridging ligand, while complexes 2 and 3 are mononuclear. Cu(II) ions in complexes 1-3 exhibit distorted quasi-hexacoordinated octahedral, tetracoordinated square planar, and pentacoordinated square pyramid geometry, respectively. Their interactions with calf thymus DNA (CT-DNA) have been investigated by viscosity measurements and fluorescence spectroscopy. The apparent binding constant (Kapp) values for 1-3 are 1.02×10(5), 0.98×10(5) and 1.57×10(5)M(-1), respectively. All complexes displayed efficient oxidative cleavage of supercoiled DNA in the presence of H2O2. Complex 2, whose ligand can be regarded as a methyl-modification of SalCl-Gly of 1, showed a reduced DNA cleavage activity and a little-changed DNA-binding ability compared with 1. While attaching a 2,2'-bipyridine group to 1, the resulting complex 3 was conferred an enhanced intercalation into DNA. Moreover, cytotoxicity studies of three complexes against HepG-2 (human liver hepatocellular carcinoma) and NCI-H460 (human large-cell lung carcinoma) cells indicated that, thereto, complex 3 possessed the highest inhibition on viability of tested cells.

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.

Biological evaluation of a cytotoxic 2-substituted benzimidazole copper(II) complex: DNA damage, antiproliferation and apoptotic induction activity in human cervical cancer cells.

Exploring novel chemotherapeutic agents is a great challenge in cancer medicine. To that end, 2-substituted benzimidazole copper(II) complex, [Cu(BMA)Cl2]·(CH3OH) (1) [BMA = N,N'-bis(benzimidazol-2-yl-methyl)amine], was synthesized and its cytotoxicity was characterized. The interaction between complex 1 and calf thymus DNA was detected by spectroscopy methods. The binding constant (K b = 1.24 × 10(4 )M(-1)) and the apparent binding constant (K app = 6.67 × 10(6 )M(-1)) of 1 indicated its moderate DNA affinity. Complex 1 induced single strand breaks of pUC19 plasmid DNA in the presence of H2O2 through an oxidative pathway. Cytotoxicity studies proved that complex 1 could inhibit the proliferation of human cervical carcinoma cell line HeLa in both time- and dose-dependent manners. The results of nuclei staining by Hoechst 33342 and alkaline single-cell gel electrophoresis proved that complex 1 caused cellular DNA damage in HeLa cells. Furthermore, treatment of HeLa cells with 1 resulted in S-phase arrest, loss of mitochondrial potential, and up-regulation of caspase-3 and -9 in HeLa cells, suggesting that complex 1 was capable of inducing apoptosis in cancer cells through the intrinsic mitochondrial pathway.

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.

Synthesis, characterization, DNA binding and cleavage, BSA interaction and anticancer activity of dinuclear zinc complexes.

Three new zinc(II) complexes: [Zn(2)(L(1))(2)Cl(2)](ClO(4))(2)·C(2)H(5)OH (1) and [ZnL(2)X(4)]·2CH(3)CN (X = Br for 2, Cl for 3), utilizing two new and interrelated di-nucleating polypyridyl ligands (L(1), L(2)), have been synthesized and characterized by using various physico-chemical techniques. The interactions of three complexes with CT-DNA have been explored by using absorption, emission and CD spectral methods, which reveal that three complexes bind to CT-DNA by partial intercalation binding modes. Notably, in the presence of H(2)O(2) as a revulsant or an activator, the cleavage abilities of all complexes are obviously enhanced. The hydrolytic mechanism was demonstrated by adding standard radical scavengers and anaerobic reaction. Further, the protein binding ability has been monitored by quenching of tryptophan emission in the presence of complexes using BSA as a model protein. The quenching mechanisms of BSA by the complexes are static procedures. In addition, the in vitro cytotoxicity of the complexes on three human tumor cells lines (HeLa, MCF-7 and RL952) and the apoptosis-inducing activity of were assessed by MTT, Clonogenic assay, Hoechst 33342 staining, Cell cycle and Annexin V binding experiments.

Preclinical pharmacokinetic analysis of felotaxel (SHR110008), a novel derivative of docetaxel, in rats and its protein binding ability in vitro.

Felotaxel (SHR110008), currently under clinical investigation in phase I trial, is a new taxane with potent antitumor effects. The purpose of this research was to evaluate the pharmacokinetic profiles of felotaxel in rats and the protein binding in plasma. Data were collated from several preclinical investigations, where the plasma pharmacokinetics, tissue distribution and excretion of felotaxel were assessed after a single intravenous (i.v.) injection (5 mg/kg) to rats. Samples felotaxel concentration was determined by a LC-MS/MS method. The plasma concentration versus time data was analyzed non-compartmental model. Plasma protein binding was assessed using ultrafiltration. Pharmacokinetic properties of felotaxel were similar to the previous data from the rats. Felotaxel was rapidly distributed to normal tissues, drug concentrations in the tissues tested except the brain were two to eight times higher than those in plasma, but half-lives and mean residence times were similar. The kidneys manifested as the dominant organs with high exposure that might be responsible for elimination of felotaxel. Approximately 0.21% and 0.72% of felotaxel was excreted via the urine and feces within 24 h; 0.25% was excreted into the bile up to 12 h after a single dose. The protein binding ability of felotaxel with concentration 100-5000 ng/mL in the plasma was nearly linear. This study first provided the full absorption, distribution, and excretion characteristics of felotaxel, which would be helpful for its clinical regiment design.

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.