Discovery of oxime-bearing naphthalene derivatives as a novel structural type of Nrf2 activators.

Recent studies have demonstrated that oxidative stress insult is one of major causes of tumor formation. Therefore, identify the effective anti-oxidative agents as a preventive approach to stop cancer progression has widely explored. Although, many potent anti-oxidative ingredients in the natural products have been identified but the amount from the nature source hindrances the clinical application. Compound which can activate Nrf2 signaling pathway result unregulated the cellular antioxidant-responses has been demonstrated as an effective chemopreventive approach for cancer treatment. In the present study, certain oxime-bearing naphthalene derivatives were synthesized and evaluated for their Nrf2 activation and anti-proliferative activities. Results indicated (E)-1-(naphthalen-2-yloxy)propan-2-one oxime (11) which increased 2.04-fold Nrf2/ARE-driven luciferase activity was more active than its 1-substituted isomer 10 (1.17-fold) and t-BHQ (1.77-fold), the known Nrf2 activator. The activities were further increased by the replacement of the peripheral methyl group with the phenyl ring in which (Z)-2-(naphthalen-2-yloxy)-1-phenylethanone oxime (13a) exhibited 3.49-fold potency of the positive control. It is worth to mention that compounds 11, 13a, and 13b which showed significant Nrf2 activation are non-cytotoxic to the tested cells with IC50>50µM. This observation strongly suggested that these compounds can be used for chemoprevention. Mechanism studies indicated that these compounds were capable of inducing the phosphorylation of Nrf2 protein at serine 40 which led to the activation of the Nrf2 transcriptional activity.

Effect of methoxychlor on Ca²âº homeostasis and apoptosis in HA59T human hepatoma cells.

Methoxychlor, an organochlorine pesticide, is thought to be an endocrine disrupter that affects Ca²âº homeostasis and cell viability in different cell models. This study explored the action of methoxychlor on cytosolic free Ca²âº concentrations ([Ca²âº]i) and apoptosis in HA59T human hepatoma cells. Fura-2, a Ca²âº-sensitive fluorescent dye, was applied to measure [Ca²âº]i. Methoxychlor at concentrations of 0.1-1 µM caused a [Ca²âº]i rise in a concentration-dependent manner. Removal of external Ca²âº abolished methoxychlor's effect. Methoxychlor-induced Ca²âº influx was confirmed by Mn²âº-induced quench of fura-2 fluorescence. Methoxychlor-induced Ca²âº entry was inhibited by nifedipine, econazole, SK&F96365, and protein kinase C modulators. Methoxychlor killed cells at concentrations of 10-130 µM in a concentration-dependent fashion. Chelation of cytosolic Ca²âº with 1,2-bis(2-aminophenoxy) ethane-N,N,N',N'-tetraacetic acid/AM (BAPTA/AM) did not prevent methoxychlor's cytotoxicity. Methoxychlor (10 and 50 µM) induced apoptosis concentration-dependently as determined by using Annexin V/propidium iodide staining. Together, in HA59T cells, methoxychlor induced a [Ca²âº]i rise by inducing Ca²âº entry via protein kinase C-sensitive Ca²âº-permeable channels, without causing Ca²âº release from stores. Methoxychlor also induced apoptosis that was independent of [Ca²âº]i rises.

Synthesis and antiproliferative evaluation of amide-containing anthraquinone, xanthone, and carbazole.

Certain amide-containing anthraquinone, xanthone, and carbazole derivatives have been synthesized and evaluated in vitro for their antiproliferative activities against a panel of human cancer cell lines including nasopharyngeal carcinoma (NPC-TW01), lung carcinoma (NCI-H661), and leukemia (Jurkat). Among them, 2-(9,10-dioxo-9,10-dihydroanthracen-2-yloxy)-N-(naphthalen-2-yl)acetamide (13) was the most active against NPC-TW01 with an IC50 value of 2.62 µM while its xanthone and dibenzofuran counterparts, 14 and 15, were inactive with an IC50 value of 16.10 and 11.09 µM, respectively. Studies on NPC-TW01 cell cycle distribution revealed that compound 13 inhibited proliferation of NPC-TW01 by the alteration of cell division and the accumulation of cells in G0/G1 phase.

Effect of fluoxetine on [Ca²âº]i and cell viability in OC2 human oral cancer cells.

Fluoxetine is a serotonin-specific reuptake inhibitor that has been used as an antidepressant. This study examined the effect of fluoxetine on cytosolic free Ca²âº concentrations ([Ca2⁺]i) and viability in OC2 human oral cancer cells. The Ca²âº-sensitive fluorescent dye fura-2 was used to measure [Ca²âº]i, and the water soluble tetrazolium (WST-1) regent was used to measure viability. Fluoxetine induced [Ca²âº]i rises concentration-dependently. The response was reduced by half by removing extracellular Ca²âº. Fluoxetine-induced Ca²âº entry was enhanced by activation of protein kinase C (PKC) with phorbol 12-myristate 13 acetate (PMA) but was inhibited by inhibition of the enzyme with GF109203X. In Ca²âº-free medium, treatment with the endoplasmic reticulum Ca²âº pump inhibitor 2,5-di-tert-butylhydroquinone (BHQ) or thapsigargin abolished fluoxetine-evoked [Ca²âº]i rise. Conversely, treatment with fluoxetine inhibited BHQ/thapsigargin-evoked [Ca²âº]i rise. Inhibition of phospholipase C (PLC) with U73122 abolished fluoxetine-induced [Ca²âº]i rise. At 20-80 µM, fluoxetine decreased cell viability concentration-dependently, which was not altered by chelating cytosolic Ca²âº with 1,2-bis(2- aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester (BAPTA/AM). At 20-60 µM, fluoxetine induced apoptosis as detected by annexin V/propidium iodide (PI) staining. Together, in OC2 cells, fluoxetine induced [Ca²âº]i rises by evoking PLC-dependent Ca²âº release from the endoplasmic reticulum and Ca²âº entry via PKC-regulated mechanisms. Fluoxetine also caused Ca²âº-independent apoptosis.

Effect of clotrimazole on cytosolic Ca(2+) rise and viability in HA59T human hepatoma cells.

Abstract Clotrimazole is an antimycotic imidazole derivative that interferes with cellular Ca(2+) homeostasis. This study examined the effect of clotrimazole on cytosolic Ca(2+) concentrations ([Ca(2+)](i)) and viability in HA59T human hepatoma cells. The Ca(2+)-sensitive fluorescent dye fura-2 was applied to measure [Ca(2+)](i). Clotrimazole induced [Ca(2+)](i) rises in a concentration-dependent manner. The response was reduced by removing extracellular Ca(2+). Clotrimazole-evoked Ca(2+) entry was suppressed by store-operated channel inhibitors (nifedipine, econazole and SK&F96365) and protein kinase C modulators (GF109203X and phorbol, 12-myristate, 13-acetate). In Ca(2+)-free medium, incubation with the endoplasmic reticulum Ca(2+) pump inhibitor 2,5-di-tert-butylhydroquinone abolished clotrimazole-induced [Ca(2+)](i) rise. Inhibition of phospholipase C with U73122 abolished clotrimazole-induced [Ca(2+)](i) rise. At 10-40 µM, clotrimazole inhibited cell viability, which was not reversed by chelating cytosolic Ca(2+). Clotrimazole at 10 and 30 µM also induced apoptosis. Collectively, in HA59T cells, clotrimazole-induced [Ca(2+)](i) rises by evoking phospholipase C-dependent Ca(2+) release from the endoplasmic reticulum and Ca(2+) entry via store-operated Ca(2+) channels. Clotrimazole also caused apoptosis.

Mechanisms of resveratrol-induced changes in [Ca(2+)]i and cell viability in PC3 human prostate cancer cells.

Resveratrol is a natural compound that affects cellular Ca(2+) homeostasis and viability in different cells. This study examined the effect of resveratrol on cytosolic free Ca(2+) concentrations ([Ca(2+)]i) and viability in PC3 human prostate cancer cells. The Ca(2+)-sensitive fluorescent dye fura-2 was used to measure [Ca(2+)]i and WST-1 was used to measure viability. Resveratrol-evoked [Ca(2+)]i rises concentration-dependently. The response was reduced by removing extracellular Ca(2+). Resveratrol-evoked Ca(2+) entry was not inhibited by nifedipine, econazole, SKF96365 and the protein kinase C inhibitor GF109203X, but was nearly abolished by the protein kinase C activator phorbol 12-myristate 13 acetate. In Ca(2+)-free medium, treatment with the endoplasmic reticulum Ca(2+) pump inhibitor 2,5-di-tert-butylhydroquinone decreased resveratrol-evoked rise in [Ca(2+)]i. Conversely, treatment with resveratrol inhibited BHQ-evoked rise in [Ca(2+)]i. Inhibition of phospholipase C with U73122 did not alter resveratrol-evoked rise in [Ca(2+)]i. Previous studies showed that resveratrol between 10 and 100 µM induced cell death in various cancer cell types including PC3 cells. However, in this study, resveratrol (1-10 µM) increased cell viability, which was abolished by chelating cytosolic Ca(2+) with 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetra-acetic acid-acetoxymethyl ester (BAPTA/AM). Therefore, it is suggested that in PC3 cells, resveratrol had a dual effect on viability: at low concentrations (1-10 µM) it induced proliferation, whereas at higher concentrations it caused cell death. Collectively, our data suggest that in PC3 cells, resveratrol-induced rise in [Ca(2+)]i by evoking phospholipase C-independent Ca(2+) release from the endoplasmic reticulum and Ca(2+) entry, via protein kinase C-regulated mechanisms. Resveratrol at 1-10 µM also caused Ca(2+)-dependent cell proliferation.

Effect of caffeic acid on Ca(2+) homeostasis and apoptosis in SCM1 human gastric cancer cells.

Caffeic acid is a natural phenolic compound that affects cellular Ca(2+) homeostasis and viability in different cells. This study examined the effect of caffeic acid on cytosolic free Ca(2+) concentrations ([Ca(2+)] i ) and viability in SCM1 human gastric cancer cells. The Ca(2+)-sensitive fluorescent dye fura-2 was used to measure [Ca(2+)] i . Caffeic acid-evoked [Ca(2+)] i rises concentration dependently. The response was reduced by removing extracellular Ca(2+). Caffeic acid-evoked Ca(2+) entry was inhibited by store-operated channel inhibitors (nifedipine, econazole, and SK&F96365) and protein kinase C activator (phorbol 12-myristate 13 acetate, PMA), but not by protein kinase C inhibitor (GF109203X). In Ca(2+)-free medium, treatment with the endoplasmic reticulum Ca(2+) pump inhibitor thapsigargin or 2,5-di-tert-butylhydroquinone (BHQ) abolished caffeic acid-evoked [Ca(2+)] i rise. Conversely, treatment with caffeic acid decreased thapsigargin or BHQ-evoked [Ca(2+)] i rise. Inhibition of phospholipase C with U73122 abolished caffeic acid-evoked [Ca(2+)] i rise. At 200-800 µM, caffeic acid inhibited cell viability, which was not changed by chelating cytosolic Ca(2+) with 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester (BAPTA/AM). Caffeic acid between 400 and 800 µM also induced apoptosis. Collectively, in SCM1 cells, caffeic acid-induced [Ca(2+)] i rises by evoking phospholipase C-dependent Ca(2+) release from the endoplasmic reticulum and Ca(2+) entry via store-operated Ca(2+) channels. Caffeic acid also caused Ca(2+)-independent apoptosis.

U74389F, a 21-aminosteroid antioxidant, improves neoendothelial morphology, but not neointimal thickening after balloon catheter injury.

U74389F is a compound in a family of 21-aminosteroids devoid of classical glucocorticoid action that inhibit lipid peroxidation. These compounds improve neurologic function and tissue survival after head or spinal cord injury. Dexamethasone inhibits development of intimal hyperplasia (IH) and improves attenuated nitric oxide (NO) production of the rabbit aorta subsequent to balloon catheter injury. We tested the hypothesis that U74389F is protective in a catheter-induced endothelial-denuded and arterial injury model. A 4-Fr Fogarty balloon (BALL) embolectomy catheter was passed through the thoracic aorta of New Zealand White rabbits treated with 15 mg/kg U74389F (LAZ) 2 days before and 1 week after injury. Animals were killed at 4 weeks after surgical intervention, and formation of IH was determined by calculating the intimal/medial ratio (I/M). The treatment groups of animals were injured untreated (BALL), injured treated (BALL/LAZ), uninjured treated (CONTROL/LAZ), and sham-operated treated (SHAM/LAZ). Scanning electron microscopy revealed that after injury lazaroid treatment produced an improvement of the neoendothelium (alignment in the direction of blood and fewer intercellular gaps) as compared with injured but untreated aortas. Relaxation to acetylcholine (NO formation) was impaired in aortic rings from catheterized animals; lazaroid treatment improved the relaxation to 10-6 mol/L acetylcholine but not to lower concentrations. I/M for SHAM/LAZ, BALL, and BALL/LAZ was 0.02 +/- 0.02, 21.6 +/- 1.6, and 17.2 +/- 2.5, respectively; BALL vs. BALL/LAZ, p < 0.06. An increased contractile response to 120 mmol/L KCl was observed after lazaroid treatment. This is the first report of lazaroid-mediated improvement in the neoendothelial morphology, improved neoendothelial NO generation, and augmented hypopolarizing contractile response, but no attenuation in the development of IH.

Synthesis and antiproliferative evaluation of amide-containing flavone and isoflavone derivatives.

Certain amide-containing flavone and isoflavone derivatives were synthesized and evaluated for their antiproliferative activities. These compounds were synthesized via alkylation of hydroxyl precursors followed by the reaction with H(2)SO(4) and NaN(3) (Schmidt reaction). The preliminary assays indicated that the inhibitory activity against the growth of NCI-H661 decreased in an order of linked chromophore flavone-6-yl 16a-d>flavone-7-yl 17a-d>flavone-3-yl 15a-d and isoflavone-7-yl 18a-d. Among these flavone-6-yl derivatives, N-(4-methoxyphenyl)-2-(4-oxo-2-phenyl-4H-chromen-6-yloxy)acetamide (16c) was the most potent with a GI(50) value of 0.84 microM. The inhibitory activity against the growth of NPC-TW01 decreased in an order of linked chromophore flavone-6-yl 16a-d>isoflavone-7-yl 18a-d>flavone-7-yl 17a-d>flavone-3-yl 15a-d. Flavone-6-yl derivatives 16a-d demonstrated significant inhibitory activities against the growth of NPC-TW01 cell with an average GI(50) value of 0.84 microM. The oxime derivatives 1 and 2 caused accumulation of NPC-TW01 cell in G(2)/M phase which were distinct from that of their amide isomers 16b and 16c, respectively, which induced cell-cycle arrest in G(0)/G(1) phase followed by apoptosis. Therefore, the antiproliferative mechanism of flavone derivatives was affected not only by the phenyl benzopyran-4-one pharmacophore but also by the peripheral substituents.

Expression of the GM2 activator protein in mouse testis.

The GM2-activator protein (GM2-AP), revealed by Li et al. in 1973 in human liver, was initially identified as a protein cofactor that stimulated ß-hexosaminidase A to hydrolyze N-acetylgalactosamine from GM2 ganglioside. This cofactor was found to be missing in human variant AB Tay-Sachs disease. Over the years, the GM2-AP has also been shown to be involved in kidney vesicular transport, lipid presentation by CD1 molecule to T-cells, and interaction of human sperm with zona pellucida. Since the expression of the GM2-AP via mRNA detection in mouse tissues was found to be the highest in testis, we became interested in the localization of the GM2-AP at cellular level in mouse testis during spermatogenesis. Using immunohistochemical analysis and electron microscopy, we found that the GM2-AP was predominantly localized in the basal cytoplasm and the attenuated processes of Sertoli cells. The stained structure appeared to be lysosomes. The most interesting finding was the association of the GM2-AP with the acrosomal apparatus in early spermatids. A modest to intense staining was observed in some acrosomal granules and acrosomal caps. The GM2-AP seemed to disappear from acrosomal caps in the later stage of spermatids, in which the nucleus became elongated and condensed. These results suggest that the GM2-AP may be involved in the normal functions of Sertoli cells and play important roles during the development of acrosomal caps in the early spermatids.

Synthesis and anticancer evaluation of certain 4-anilinofuro[2,3-b]quinoline and 4-anilinofuro[3,2-c]quinoline derivatives.

Certain linear 4-anilinofuro[2,3-b]quinoline and angular 4-anilinofuro[3,2-c]quinoline derivatives were synthesized and evaluated in vitro against the full panel of NCI's 60 cancer cell lines. For the linear 4-anilinofuro[2,3-b]quinoline derivatives, 1-[4-(furo[2,3-b]quinolin-4-ylamino)phenyl]ethanone (5a) is the most cytotoxic with a mean GI50 value of 0.025 microM. Substitution at either furo[2,3-b]quinoline ring (2a, 2b, and 5b) or 4-anilino moiety (3-7) led to a decrease of cytotoxicity. For the angular 4-anilinofuro[3,2-c]quinoline derivatives, (E)-1-[3-(furo[3,2-c]quinolin-4-ylamino)phenyl]ethanone oxime (14a) exhibited potent inhibitory activities on UO-31, UACC-257, and UACC-62, with GI50 values of 0.03,<0.01, and<0.01 microM respectively. The same cytotoxicity profile was observed for its methyl counterpart, 14b, in which the GI50 values against UO-31, UACC-257, and UACC-62 was<0.01, 0.04 and<0.01 microM respectively. These results deserve full attention especially because 14a and 14b are relatively non-cytotoxic with the mean GI50 value of 7.73 and 8.91 microM respectively.

Synthesis, and cytotoxic and antiplatelet activities of oxime- and methyloxime-containing flavone, isoflavone, and xanthone derivatives.

A series of oxime- and methyloxime-containing flavone, isoflavone, and xanthone derivatives (1-12) were synthesized (Scheme) and evaluated for their cytotoxic (Table 1) and antiplatelet activities (Table 2). The in vitro anticancer assay indicated that the cytotoxicity of structurally related compounds decreases in the order isoflavones (7a-7c) > flavones (8a-8c) > xanthones (9a-9c), electron-releasing substituents (R) on the Ph ring being favorable (mean GI50 values of 2.84, 12.3, and 20.9 microM for 7c, 8c, and 9c, resp.). The inhibition of platelet aggregation induced by arachidonic acid (AA) similarly decreased from the isoflavone 1 (IC50 = 2.97 microM) to the flavone 2 (7.70 microM) to the xanthone 3 (inactive). Thereby, compound 1 seems to be a promising lead, since it was not only the most-potent aggregation inhibitor (IC50 = 2.97 microM), but was also found to be noncytotoxic at a concentration of 100 microM.

Synthesis and cytotoxic evaluation of certain 4-(phenylamino)furo[2,3-b]quinoline and 2-(furan-2-yl)-4-(phenylamino)quinoline derivatives.

Certain 4-(phenylamino)furo[2,3-b]quinoline and 2-(furan-2-yl)-4-(phenylamino)quinoline derivatives were synthesized and evaluated in vitro against the full panel of NCIs 60 cancer cell lines. The preliminary results indicated these tricyclic 4-(phenylamino)furo[2,3-b]quinolines were more cytotoxic than their corresponding 2-(furan-2-yl)-4-(phenylamino)quinoline isomers. For the 4-(phenylamino)furo[2,3-b]quinolines, compounds 2a and 3d are two of the most potent with a mean GI50 value of 0.025 microM in each case. Inactivity of 2b and 2c (positional isomers of 2a) indicated that both electronic environment, and the distance between intercalating pharmacophore and H-bond-donating MeO group are important. For the 2-(furan-2-yl)-4-(phenylamino)quinoline isomers, compound 12 (a mean GI50 of 4.36 microM), which bears a para-COMe substituent, is more active than its meta-substituted counterpart 13 (10.5 microM). However, the electron-donating MeO substituent is preferred at the meta-position, and the cytotoxicity for the meta-substituted derivatives decreased in the order: MeO derivative 14b (3.05 microM) > oxime 16 (6.85 microM) > ketone 13 (10.5 microM) > methyl oxime 18 (20.6 microM).

Local structure distortion induced by Ti dopants boosting the pseudocapacitance of RuO2-based supercapacitors.

Binary oxides with atomic ratios of Ru/Ti = 90/10, 70/30, and 50/50 were fabricated using H2O2-oxidative precipitation with the assistance of a cetyltrimethylammonium bromide (CTAB) template, followed by a thermal treatment at 200 °C. The characteristics of electron structure and local structure extracted from X-ray absorption spectroscopy (XAS) and transmission electron microscopy (TEM) analyses indicate that incorporation of Ti into the RuO2 lattice produces not only the local structural distortion of the RuO6 octahedra in (Ru-Ti)O2 with an increase in the central Ru-Ru distance but also a local crystallization of RuO2. Among the three binary oxides studied, (Ru70-Ti30)O2 exhibits a capacitance improvement of about 1.4-fold relative to the CTAB-modified RuO2, mainly due to the enhanced crystallinity of the distorted RuO6 structure rather than the surface area effect. Upon increasing the extent of Ti doping, the deteriorated supercapacitive performance of (Ru50-Ti50)O2 results from the formation of localized nano-clusters of TiO2 crystallites. These results provide insight into the important role of Ti doping in RuO2 that boosts the pseudocapacitive performance for RuO2-based supercapacitors. The present result is crucial for the design of new binary oxides for supercapacitor applications with extraordinary performance.

Novel oxime-bearing coumarin derivatives act as potent Nrf2/ARE activators in vitro and in mouse model.

We have designed and synthesized certain novel oxime- and amide-bearing coumarin derivatives as nuclear factor erythroid 2 p45-related factor 2 (Nrf2) activators. The potency of these compounds was measured by antioxidant responsive element (ARE)-driven luciferase activity, level of Nrf2-related cytoprotective genes and proteins, and antioxidant activity. Among them, (Z)-3-(2-(hydroxyimino)-2-phenylethoxy)-2H-chromen-2-one (17a) was the most active, and more potent than the positive t-BHQ in the induction of ARE-driven luciferase activity. Exposure of HSC-3 cells to various concentrations of 17a strongly increased Nrf2 nuclear translocation and the expression level of Nrf2-mediated cytoprotective proteins in a concentration-dependent manner. HSC-3 cells pretreated with 17a significantly reduced t-BOOH-induced oxidative stress. In the animal experiment, Nrf2-mediated cytoprotective proteins, such as aldo-keto reductase 1 subunit C-1 (AKR1C1), glutathione reductase (GR), and heme oxygenase (HO-1), were obviously elevated in the liver of 17a-treated mice than that of control. These results suggested that novel oxime-bearing coumarin 17a is able to activate Nrf2/ARE pathway in vivo and are therefore seen as a promising candidate for further investigation.

Synthesis and antiinflammatory evaluation of 9-anilinoacridine and 9-phenoxyacridine derivatives.

Mast cells, neutrophils, and macrophages are important inflammatory cells that have been implicated in the pathogenesis of acute and chronic inflammatory diseases. To explore a novel antiinflammatory agent, we have synthesized two types of acridines, 9-anilinoacridine and 9-phenoxyacridine derivatives, for evaluation on the grounds that acridine is a versatile heterocycle possessing a wide variety of biological properties. The title compounds were synthesized by reaction of 9-chloroacridine with appropriate Ar-NH(2) and Ar-OH, and their antiinflammatory activities on inhibitory effects on the activation of mast cells, neutrophils, and macrophages were studied. Three acridine derivatives 4, 10, and 11 were proved to be more potent than the reference inhibitor mepacrine for the inhibition of rat peritoneal mast cell degranulation with similar IC(50) values (16-21 microM). Compound 3 also showed potent inhibitory activity (IC(50) = 8.2 and 4.4 microM, respectively) for the secretion of lysosomal enzyme and beta-glucuronidase from neutrophils. Moreover, compounds 5 and 9 were shown to be efficacious inhibitors of TNF-alpha production in macrophage-like cell lines RAW 264.7. Compounds 2 and 12 were the potent inhibitors of TNF-alpha production in murine microglial cell lines N9. To further explore the cytotoxic properties of these acridine derivatives, (E)-12 was selected for NCI's in vitro disease-oriented tumor cells screen. The results indicated that this compound had no significant cytotoxicity with a mean GI(50) of 58.0 microM. These results indicated that the antiinflammatory effects of acridine derivatives were mediated, at least in part, through the suppression of chemical mediators released from mast cells, neutrophils, and macrophages and that these compounds have the potential to be novel antiinflammatory agents with no significant cytotoxicity.

Capacitive performance enhancements of RuO2 nanocrystals through manipulation of preferential orientation growth originated from the synergy of Pluronic F127 trapping and annealing.

The capacitive performances of RuO2 prepared by oxidation precipitation of Ru precursors (RuCl3·xH2O) surrounded with tri-block co-polymer, Pluronic F127, in aqueous media can be enhanced through manipulating its preferential orientation growth of nanocrystals. From the heterogeneous surface chemistry viewpoints with the support of structure characterizations, such enhancement originates from the preferential orientation growth of the {101} facet due to the adsorption of the highly polarisable, non-ionic ligands of Pluronic F127 on the high surface energy facets on RuO2 nanocrystallites. In this case, the F127-trapped sample with annealing at 300 °C enhances the specific capacitance 1.6-fold in comparison to its counterpart without F127. With the mechanistic insight into the heterogeneous surface crystal growth pathways, our results materialize the development of RuO2 with tuneable capacitive performances. Furthermore, due to the different propagation models of RuO2 with and without F127 trapping, a schematic diagram is proposed to interpret such a unique crystal growth evolution phenomenon.

Allyl isothiocyanate inhibits cell metastasis through suppression of the MAPK pathways in epidermal growth factor­stimulated HT29 human colorectal adenocarcinoma cells.

Allyl isothiocyanate (AITC) has been found to present sources from consumed cruciferous vegetables. AITC is known to possess pharmacological and anticancer activities. The present study was designed to test the hypothesis that AITC suppressed the invasion and migration of epidermal growth factor (EGF)-stimulated HT29 cells and to elucidate the mechanisms for the antimetastatic abilities in vitro. The invasion and migration of EGF-stimulated HT29 cells were determined individually by Transwell cell invasion and wound-healing assays. Our results showed that AITC effectively inhibited both the invasive and migratory ability of HT29 cells. Furthermore, AITC downregulated the protein levels of matrix metalloproteinase-2 (MMP-2), MMP-9 and mitogen-activated protein kinases (MAPKs) (p-JNK, p-ERK and p-p38) by western blot analysis in HT29 cells following EGF induction. Thus, the metastatic responses in AITC-treated HT29 cells after EGF stimulation were mediated by the MMP-2/-9 and MAPK signaling pathways. We also used gene expression microarrays to investigate the gene levels related to cell growth, G-protein coupled receptor, angiogenesis, cell adhesion, cell cycle and mitosis, cell migration, cytoskeleton organization, DNA damage and repair, transcription and translation, EGFR and PKB/mTOR signals. In summary, it is possible that AITC suppresses the invasion and migration of EGF-induced HT29 cells, resulting from MMP-2/-9 and MAPKs. Hence, AITC may be beneficial in the treatment of human colorectal adenocarcinoma in the future.

Synthesis and antiproliferative activities of N-(naphthalen-2-yl)acetamide and N-(substituted phenyl)acetamide bearing quinolin-2(1H)-one and 3,4-dihydroquinolin-2(1H)-one derivatives.

Certain N-(naphthalen-2-yl)acetamide and N-(substituted phenyl)acetamide bearing quinolin-2(1H)-one and 3,4-dihydroquinolin-2(1H)-one derivatives have been synthesized and evaluated in vitro for their antiproliferative activities against a panel of human cancer cell lines including nasopharyngeal (NPC-TW01), lung carcinoma (H661), hepatoma (Hep3B), renal carcinoma (A498), and gastric cancer (MKN45). Among them, N-(naphthalen-2-yl)-2-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yloxy)acetamide (18) was the most active against NPC-TW01 with an IC(50) value of 0.6 µM. Studies on NPC-TW01 cell cycle distribution revealed that compound 18 inhibited proliferation of NPC-TW01 by the alteration of cell division, accumulation of cells in S phase in a time- and concentration-dependent manners. In addition, compound 18 demonstrated very specific cytotoxicity against human nasopharyngeal carcinoma (NPC-TW01) cell lines with no detectable cytotoxicity against peripheral blood mononuclear cells (PBMCs) at a concentration of up to 50 µM.

Synthesis, antiproliferative, and antiplatelet activities of oxime- and amide-containing quinolin-2(1H)-one derivatives.

Certain oxime- and amide-containing quinolin-2(1H)-one derivatives were synthesized and evaluated for their antiproliferative and antiplatelet activities. These compounds were synthesized via alkylation of hydroxyl precursors followed by the reaction with NH(2)OH or NaN(3) (Schmidt reaction). The preliminary assays indicated that amide derivatives are either weakly active or inactive while the oxime counterparts exhibited potent inhibitory activities against platelet aggregation induced by collagen, AA (arachidonic acid), and U46619 (the stable thromboxan A(2) receptor agonist). Among them, (Z)-6-[2-(4-methoxyphenyl)-2-hydroxyiminoethoxy]quinolin-2(1H)-one (7c) was the most active against AA induced platelet aggregation with an IC(50) of 0.58microM and was inactive against cell proliferation. For the inhibition of U46619 induced aggregation, 7a and 8a-c exhibited very potent activities with IC(50) values in a range between 0.54 and 0.74microM. For the antiproliferative evaluation, N-(biphenyl-4-yl)-2-(2-oxo-1,2-dihydroquinolin-7-yloxy)acetamide (11d) was the most potent with GI(50) values of <10, 10.8, and <10microM against the growth of MT-2, NCI-H661, and NPC-Tw01, respectively, and possessed only a weak antiplatelet activity. Further evaluation of 11d as a potential anticancer agent is on-going.