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Tested Compounds (tested + compound)
Selected AbstractsGlycogen: A novel branched polysaccharide chiral selector in CEELECTROPHORESIS, Issue 6 2010Jiaquan Chen Abstract Various chiral selectors have been employed in CE and among them linear polysaccharides exhibited powerful enantioselective properties. Different from linear polysaccharides, the use of branched polysaccharides as chiral selectors in CE has not been reported previously. In this study glycogen belonging to the class of branched polysaccharides was used as a novel chiral selector for the enantiomeric separations for the first time. Since glycogen is electrically neutral, the method is applicable to ionic compounds. Eighteen chiral compounds including 12 basic drugs and six acidic drugs have been tested to demonstrate the potential of this chiral selector. BGE and selector concentrations and buffer pH were systematically optimized in order to obtain successful chiral separations. Among the tested compounds, the enantiomers of ibuprofen, which is an acidic drug, were successfully recognized by 3.0%,w/v glycogen with 90,mM Tris-H3PO4 buffer (pH 7.0). The enantiomers of basic drugs such as citalopram, cetirizine and nefopam were also baseline-resolved with 50,mM Tris-H3PO4 buffer (pH 3.0) containing 3.0% glycogen. Amlodipine belonging to basic compound only gave partial enantioseparation under the above-mentioned condition. [source] Impact of five selected xenobiotics on isolated ammonium oxidizers and on nitrifying activated sludgeENVIRONMENTAL TOXICOLOGY, Issue 4 2006S. N. Dokianakis Abstract Sewage treatment plants (STPs) are usual receptors of xenobiotic compounds that have to be cotreated with municipal wastewaters before being discharged to the water environment. The presence of organic contaminants, such as surfactants, polycyclic aromatic hydrocarbons (PAHs), phthalates, and their primary degradation products in the influents of STPs may inhibit irreversibly sensitive biological processes, such as nitrification. The first step of nitrification, i.e., the oxidation of ammonium to nitrite (nitritification), is particularly sensitive. Inhibition of this step under uncontrolled conditions may completely inhibit biological nitrogen removal. The aim of this work was to study the possible inhibitory effect of five selected xenobiotics on (a) a mixed culture of ammonium-oxidizing bacteria isolated from activated sludge and (b) nitrifying activated sludge directly. The xenobiotics that were tested include nonylphenols (NP), nonylphenolethoxylates (NPEO), linear alkylbenzene sulfonates (LAS), di(2-ethylhexyl) phthalate (DEHP), as a representative phthalate ester, and the PAH phenanthrene. Remarkable inhibitory effects for all tested compounds were observed in this study even at xenobiotic concentrations as low as 1 mg/L. The observed inhibition of xenobiotics on nitrifying activated sludge was less pronounced, because of the masking effect exerted by the sludge flocs, but was still significant for many of the tested substances at concentrations up to 10 mg/L. © 2006 Wiley Periodicals, Inc. Environ Toxicol 21: 310,316, 2006. [source] In vitro and in vivo estrogenicity and toxicity of o -, m -, and p -dichlorobenzeneENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 2 2003Bram J. Versonnen Abstract The estrogenicity of o -, m -, and p -dichlorobenzene (DCB) was evaluated with a yeast estrogen screen (YES) and zebrafish (Danio rerio) vitellogenin (VTG) assays. With the YES, p -DCB and m -DCB were found to be estrogenic in a concentration-responsive manner. The relative potency measured with the YES (relative to 17,-estradiol) was 2.2 × 10,7 for p -DCB and 1.04 × 10,8 for m -DCB. Following acute toxicity tests with the zebrafish, plasma VTG production was measured to examine the in vivo estrogenic activity of the three compounds after a 14-d exposure. Adult zebrafish were exposed to different concentrations of o -, m - and p -DCB, ranging from 0.1 to 32 mg/L; ethynylestradiol ([EE2]; 5 ng/L, 10 ng/L, 50 ng/L, and 100 ng/L) was used as a positive control. After exposure, blood samples were taken and protein electrophoresis was performed to determine the relative VTG content. Gonadosomatic indices (GSI) and condition factors (CF) were also calculated. Elevated VTG levels and decreased female GSIs were found in fish exposed to ,5 ng EE2/L and in fish exposed to ,10 mg p -DCB/L. Low GSIs coincided with high levels of VTG in the blood of female zebrafish. This relation was not only found in fish exposed to EE2 but also in controls and fish exposed to DCB. Therefore, a direct or indirect effect of VTG on the GSI is suggested rather than a direct toxic effect of the tested compounds on the gonads. [source] Application of sewage sludge to arable land,soil concentrations of polybrominated diphenyl ethers and polychorinated dibenzo- p -dioxins, dibenzofurans, and biphenyls, and their accumulation in earthwormsENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 12 2002Nadja Matscheko Abstract Soils from five agricultural sites, three research sites, and two privately owned farms were analyzed for polychlorinated dibenzo- p -dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), polychlorinated biphenyls (PCBs), and polybronimated diphenylethers (PBDEs). In soils that had not been treated with sludge (reference soils), the international toxic equivalents (I-TEQs) were 0.6 to 1.5 pg/g dry matter (DM) for the PCDD/Fs, which are low compared to generally reported background soil levels in Europe. The concentrations of sum of six penta- and hexa-PCBs were 450 to 1,400 pg/g DM. The PBDEs 47 and 99 dominated among the tri- to hepta-PBDEs analyzed (8,80 pg/g DM). The impact of adding 1 to 3 tonnes of sludge (DM) per hectare per year on the concentrations was studied at the three research sites by calculating ratios of the compounds in sludge-treated soil to reference soil (S/R ratio). The concentrations of I-TEQs did not increase in the sludge-treated soil, whereas the S/R ratios for PBDEs were greater than one. Also, although the PCB contents were higher in the sludge-treated soils, the background sources were more important for the concentrations of PCBs than of PBDEs. The largest increase in the S/R ratios was found at a private farm where large amounts of sludge had been used in the past. Accumulation of the compounds in earthworms from the sites also was investigated. The biota-soil accumulation factors (BSAFs) of the tested compounds declined in the following order: ortho -PCBs , PBDEs > non-ortho -PCBs > 2,3,7,8-substituted PCDD/Fs. The average BSAF for ortho -PCBs was five (organic matter/lipids), and the lowest BSAFs (0.1,0.8) found were for octachlorodibenzo- p -dioxin. To our knowledge, accumulation of PBDEs in earthworms has not been published previously. [source] Discrepancy between acute and chronic toxicity induced by imidacloprid and its metabolites in Apis melliferaENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 11 2001Séverine Suchail Abstract Imidaclopridi a systemic nitroguanidine insecticide that belongs to theneonicotinoid family. As an agonist of the acetylcholine receptor, it attacks the insect nervous system and is extremely effective against various sucking and mining pests. Oral acute and chronic toxicity of imidacloprid and its main metabolites (5-hydroxyimidacloprid, 4,5-dihydroxyimidacloprid, desnitroimidacloprid, 6-chloronicotinic acid, olefin, and urea derivative) were investigated in Apis mellifera. Acute intoxication by imidacloprid or its metabolites resulted in the rapid appearance of neurotoxicity symptoms, such as hyperresponsiveness, hyperactivity, and trembling and led to hyporesponsiveness and hypoactivity. For acute toxicity tests, bees were treated with doses of toxic compounds ranging from 1 to 1,000 ng/bee (10,10,000 ,g/kg). Acute toxicity (LD50) values of imidacloprid were about 60 ng/bee (600 ,g/kg) at 48 h and about 40 ng/bee (400 ,g/kg) at 72 and 96 h. Out of the six imidacloprid metabolites tested, only two (5-hydroxyimidacloprid and olefin) exhibited a toxicity close to that of imidacloprid. Olefin LD50 values were lower than those of imidacloprid. The 5-hydroxyimidacloprid showed a lower toxicity than imidacloprid with a LD50 four to six times higher than that of imidacloprid. Urea also appeared as a compound of nonnegligible toxicity by eliciting close to 40% mortality at 1,000 ng/bee (10,000 ,g/kg). However, no significant toxicity was observed with 4,5-dihydroxyimidacloprid, 6-chloronicotinic acid, and desnitroimidacloprid in the range of doses tested. To test chronic toxicity, worker bees were fed sucrose solutions containing 0.1, 1, and 10 ,g/L of imidacloprid and its metabolites for 10 d. Fifty percent mortality was reached at approximately 8 d. Hence, considering that sucrose syrup was consumed at the mean rate of 12 ,l/d and per bee, after an 8-d period the cumulated doses were approximately 0.01, 0.1, and 1 ng/bee (0.1, 1, and 10 ,g/kg). Thus, all tested compounds were toxic at doses 30 to 3,000 (olefin), 60 to 6,000 (imidacloprid), 200 to 20,000 (5-OH-imidacloprid), and >1,000 to 100,000 (remaining metabolites) times lower than those required to produce the same effect in acute intoxication studies. For all products tested, bee mortality was induced only 72 h after the onset of intoxication. [source] Exploring the primary electron acceptor (QA)-site of the bacterial reaction center from Rhodobacter sphaeroidesFEBS JOURNAL, Issue 4 2002Binding mode of vitamin K derivatives The functional replacement of the primary ubiquinone (QA) in the photosynthetic reaction center (RC) from Rhodobacter sphaeroides with synthetic vitamin K derivatives has provided a powerful tool to investigate the electron transfer mechanism. To investigate the binding mode of these quinones to the QA binding site we have determined the binding free energy and charge recombination rate from QA, to D+ (kAD) of 29 different 1,4-naphthoquinone derivatives with systematically altered structures. The most striking result was that none of the eight tested compounds carrying methyl groups in both positions 5 and 8 of the aromatic ring exhibited functional binding. To understand the binding properties of these quinones on a molecular level, the structures of the reaction center-naphthoquinone complexes were predicted with ligand docking calculations. All protein,ligand structures show hydrogen bonds between the carbonyl oxygens of the quinone and AlaM260 and HisM219 as found for the native ubiquinone-10 in the X-ray structure. The center-to-center distance between the naphthoquinones at QA and the native ubiquinone-10 at QB (the secondary electron acceptor) is essentially the same, compared to the native structure. A detailed analysis of the docking calculations reveals that 5,8-disubstitution prohibits binding due to steric clashes of the 5-methyl group with the backbone atoms of AlaM260 and AlaM249. The experimentally determined binding free energies were reproduced with an rmsd of ,,4 kJ·mol,1 in most cases providing a valuable tool for the design of new artificial electron acceptors and inhibitors. [source] Synthesis and properties of some 2,3-disubstituted 6-fluoro-7-(4-methyl-1-piperazinyl)quinoxalinesJOURNAL OF HETEROCYCLIC CHEMISTRY, Issue 5 2000Raid J. Abdel-Jalil The 2,3-disubstituted 6-fluoro-7-(4-methyl-1-piperazinyl)-quinoxalines (3,11) were synthesized for bioassay via reaction of 1.2-diamino-4-fluoro-5-(4-methyl-1-piperazinyl)benzene (2) with the appropriate 1,2-dicarbonyl compounds. However, none of the tested compounds 3,11 showed significant in vitro activ ity against E. coli ATCC11229, S. aureus ATCC6538 and C.albicans SATCC10231. [source] Detection and validated quantification of nine herbal phenalkylamines and methcathinone in human blood plasma by LC-MS/MS with electrospray ionizationJOURNAL OF MASS SPECTROMETRY (INCORP BIOLOGICAL MASS SPECTROMETRY), Issue 2 2007Jochen Beyer Abstract The herbal stimulants Ephedra species, Catha edulis (khat), and Lophophora williamsii (peyote) have been abused for a long time. In recent years, the herbal drug market has grown owing to publicity on the Internet. Some ingredients of these plants are also ingredients of cold remedies. The aim of the presented study is to develop a multianalyte procedure for detection and validated quantification of the phenalkylamines ephedrine, pseudoephedrine, norephedrine, norpseudoephedrine, methylephedrine, methylpseudoephedrine, cathinone, mescaline, synephrine (oxedrine), and methcathinone in plasma. After mixed-mode solid-phase extraction of 1 ml of plasma, the analytes were separated using a strong cation exchange separation column and gradient elution. They were detected using a Q-Trap LC-ESI-MS/MS system (MRM mode). Calibration curves were used for quantification using norephedrine- d3, ephedrine- d3, and mescaline- d9 as internal standards. The method was validated according to international guidelines. The assay was selective for the tested compounds. It was linear from 10 to 1000 ng/ml for all analytes. The recoveries were generally higher than 70%. Accuracy ranged from , 0.8 to 20.0%, repeatability from 2.5 to 12.3%, and intermediate precision from 4.6 to 20.0%. The lower limit of quantification was 10 ng/ml for all analytes. No instability was observed after repeated freezing and thawing or in processed samples. The applicability of the assay was tested by analysis of authentic plasma samples after ingestion of different cold medications containing ephedrine or pseudoephedrine, and after ingestion of an aqueous extract of Herba Ephedra. After ingestion of the cold medications, only the corresponding single alkaloids were detected in human plasma, whereas after ingestion of the herb extract, all six ephedrines contained in the plant were detected. The presented LC-MS/MS assay was found applicable for sensitive detection and accurate and precise quantification of all studied analytes in plasma. Copyright © 2006 John Wiley & Sons, Ltd. [source] Kinetic and thermodynamic characterization of HIV-1 protease inhibitorsJOURNAL OF MOLECULAR RECOGNITION, Issue 2 2004Cynthia F. Shuman Abstract Interaction kinetic and thermodynamic analyses provide information beyond that obtained in general inhibition studies, and may contribute to the design of improved inhibitors and increased understanding of molecular interactions. Thus, a biosensor-based method was used to characterize the interactions between HIV-1 protease and seven inhibitors, revealing distinguishing kinetic and thermodynamic characteristics for the inhibitors. Lopinavir had fast association and the highest affinity of the tested compounds, and the interaction kinetics were less temperature-dependent as compared with the other inhibitors. Amprenavir, indinavir and ritonavir showed non-linear temperature dependencies of the kinetics. The free energy, enthalpy and entropy (,G, ,H, ,S) were determined, and the energetics of complex association (,Gon, ,Hon, ,Son) and dissociation (,Goff, ,Hoff, ,Soff) were resolved. In general, the energetics for the studied inhibitors was in the same range, with the negative free energy change (,G,<,0) due primarily to increased entropy (,S,>,0). Thus, the driving force of the interaction was increased degrees of freedom in the system (entropy) rather than the formation of bonds between the enzyme and inhibitor (enthalpy). Although the ,Gon and ,Goff were in the same range for all inhibitors, the enthalpy and entropy terms contributed differently to association and dissociation, distinguishing these phases energetically. Dissociation was accompanied by positive enthalpy (,Hoff,>,0) and negative entropy (,Soff,<,0) changes, whereas association for all inhibitors except lopinavir had positive entropy changes (,Son,>,0), demonstrating unique energetic characteristics for lopinavir. This study indicates that this type of data will be useful for the characterization of target,ligand interactions and the development of new inhibitors of HIV-1 protease. Copyright © 2004 John Wiley & Sons, Ltd. [source] ,-Hydroxybutyrate binds to the synaptic site recognizing succinate monocarboxylate: A new hypothesis on astrocyte,neuron interaction via the protonation of succinateJOURNAL OF NEUROSCIENCE RESEARCH, Issue 7 2008Tünde Molnár Abstract Succinate (SUC), a citrate (CIT) cycle intermediate, and carbenoxolone (CBX), a gap junction inhibitor, were shown to displace [3H],-hydroxybutyrate ([3H]GHB), which is specifically bound to sites present in synaptic membrane subcellular fractions of the rat forebrain and the human nucleus accumbens. Elaboration on previous work revealed that acidic pH-induced specific binding of [3H]SUC occurs, and it has been shown to have a biphasic displacement profile distinguishing high-affinity (Ki,SUC = 9.1 ± 1.7 ,M) and low-affinity (Ki,SUC = 15 ± 7 mM) binding. Both high- and low- affinity sites were characterized by the binding of GHB (Ki,GHB = 3.9 ± 0.5 ,M and Ki,GHB = 5.0 ± 2.0 mM) and lactate (LAC; Ki,LAC = 3.9 ± 0.5 ,M and Ki,LAC = 7.7 ± 0.9 mM). Ligands, including the hemiester ethyl-hemi-SUC, and the gap junction inhibitors flufenamate, CBX, and the GHB binding site-selective NCS-382 interacted with the high-affinity site (in ,M: Ki,EHS = 17 ± 5, Ki,FFA = 24 ± 13, Ki,CBX = 28 ± 9, Ki,NCS-382 = 0.8 ± 0.1 ,M). Binding of the Na+,K+ -ATPase inhibitor ouabain, the proton-coupled monocarboxylate transporter (MCT)-specific ,-cyano-hydroxycinnamic acid (CHC), and CIT characterized the low-affinity SUC binding site (in mM: Ki,ouabain = 0.13 ± 0.05, Ki,CHC = 0.32 ± 0.07, Ki,CIT = 0.79 ± 0.20). All tested compounds inhibited [3H]SUC binding in the human nucleus accumbens and had Ki values similar to those observed in the rat forebrain. The binding process can clearly be recognized as different from synaptic and mitochondrial uptake or astrocytic release of SUC, GHB, and/or CIT by its unique GHB selectivity. The transient decrease of extracellular SUC observed during epileptiform activity suggested that the function of the synaptic target recognizing protonated succinate monocarboxylate may vary under different (patho)physiological conditions. Furthermore, we put forward a hypothesis on the synaptic activity-regulated signaling between astrocytes and neurons via SUC protonation. © 2008 Wiley-Liss, Inc. [source] The comparison of solid phase microextraction-GC and static headspace-GC for determination of solvent residues in vegetable oilsJOURNAL OF SEPARATION SCIENCE, JSS, Issue 2 2008Magdalena Ligor Abstract The objective of these investigations has been the determination of volatile organic compounds including residue solvents present in vegetable oil samples. Some olive oil, rape oil, sunflower oil, soy-bean oil, pumpkin oil, grape oil, rice oil as well as hazel-nut oil samples were analysed. Among residue solvents the following compounds have been mentioned: acetone, n -hexane, benzene, and toluene. Some experiments for the solid phase microextraction (SPME),GC-flame ionisation detection (FID) were performed to examine extraction conditions such as fiber exposure time, temperature of extraction, and temperature of desorption. Various SPME fibers such as polydimethylsiloxane, Carboxen/polydimethylsiloxane and polydimethylsiloxane/divinylbenzene coatings were used for the isolation of tested compounds from vegetable oil samples. After optimisation of SPME, real vegetable oil samples were examined using SPME-GC/MS. Based on preliminary experiments the qualitative and quantitative analyses for the determination of acetone, n -hexane, benzene and toluene were performed by SPME-GC-FID and static head-space (SHS)-GC-FID methods. The regression coefficients for calibration curves for the examined compounds were R2 , 0.992. This shows that the used method is linear in the examined concentration range (0.005,0.119 mg/kg for SPME-GC-FID and 0.003,0.728 mg/kg for SHS-GC-FID). Chemical properties of analysed vegetable oils have been characterised by chemometric procedure (cluster analysis). [source] Determination of the pesticides considered as endocrine-disrupting compounds (EDCs) by solid-phase extraction followed by gas chromatography with electron capture and mass spectrometric detectionJOURNAL OF SEPARATION SCIENCE, JSS, Issue 12 2007Vasiliki I. Valsamaki Abstract An SPE method followed by GC-electron capture detection (ECD) with confirmation by MS for the trace determination of four pesticides considered as endocrine-disrupting compounds (EDCs) in natural waters and sediments has been developed. Target analytes, fenarimol, fenvalerate, pendimethalin, and vinclozolin, belong to different chemical groups and are used mainly in agriculture. In the present study, analysis employs an offline SPE step for the extraction of the target analytes from natural waters. Sonication and subsequent SPE clean-up was used for extraction and purification of the sediment samples which were finally treated with activated copper powder. The type of SPE disk, eluents as well as solution parameters including pH value, and concentrations of salts and humic substances were examined for the efficiency of the method. The recoveries of all pesticides were in relatively high levels, ranging from 75 to 97% for waters and 71 to 84% for sediment samples. Both methods were applied to real water and sediment samples and the presence of the tested compounds was investigated. [source] Cytotoxic and antimitotic effects of N -containing Monascus metabolites studied using immortalized human kidney epithelial cellsMOLECULAR NUTRITION & FOOD RESEARCH (FORMERLY NAHRUNG/FOOD), Issue 4-5 2006Anja Knecht Abstract Recently the first Monascus metabolites with a pyridine ring were detected, the monascopyridines A and B. They are formally dehydrogenated derivatives of the red rice pigments rubropunctamine and monascorubramine. Because of their structural similarity, the toxicological effects of these secondary metabolites were studied using immortalized human kidney epithelial cells. The cytotoxicity was determined with the following different endpoint detection methods: metabolic activity, trypan blue exclusion, and electronic cell counting. The compounds led to EC50 values between 11 and 31 ,mol/L but the pigments caused a stronger reduction of the cell viability. Also, the apoptotic potential was examined by measuring caspase 3 activity and detecting apoptotic bodies, but none of the tested compounds induced apoptosis. All four substances caused a rise of the mitotic index to about 9% (100 ,mol/L monascopyridine A and B) and 20% (25 ,mol/L rubropunctamine and monascorubramine). The significant decrease of the ratio of cells in the ana- and telophase to cells in the prometa- and metaphase proved a stop of the mitosis at the meta- to anaphase control point. The compounds caused mitotic arrest and the formation of structural damages like c-mitosis through interaction with the mitotic spindle. These effects point to an aneuploidy inducing potential, which is linked to cancer formation. [source] Identification of a high-affinity binding site for dinotefuran in the nerve cord of the American cockroachPEST MANAGEMENT SCIENCE (FORMERLY: PESTICIDE SCIENCE), Issue 4 2006Satoshi Miyagi Abstract The binding of the neonicotinoid insecticide dinotefuran to insect nicotinic acetylcholine receptors (nAChRs) was examined by a centrifugation method using the nerve cord membranes of American cockroaches and [3H]dinotefuran (78 Ci mmol,1). The Kd and Bmax values of [3H]dinotefuran binding were estimated to be 13.7 nM and 14.8 fmol 40 µg,1 protein respectively by Scatchard analysis. Epibatidine, an nAChR agonist, showed a rather lower affinity to the dinotefuran binding site (IC50 = 991 nM) than dinotefuran (IC50 = 5.02 nM). Imidacloprid and nereistoxin displayed lower potencies than dinotefuran but higher potencies than epibatidine. The potencies of five dinotefuran analogues in inhibiting the specific binding of [3H]dinotefuran to nerve cord membranes were determined. A good correlation (r2 = 0.970) was observed between the ,log IC50 values of the tested compounds and their piperonyl butoxide-synergised insecticidal activities (,log LD50 values) against German cockroaches. The results indicate that a high-affinity binding site for dinotefuran is present in the nerve cord of the American cockroach and that the binding of ligands to the site leads to the manifestation of insecticidal activity. Copyright © 2006 Society of Chemical Industry [source] Antioxidant diterpenoids from the roots of Salvia barrelieriPHYTOCHEMICAL ANALYSIS, Issue 4 2009Ufuk Kolak Abstract Introduction The phytochemical and biological studies carried out on Salvia species showed that their extracts and constituents have various biological activities. Objective The aim of this study was the isolation of diterpenoids from the roots of Salvia barrelieri Ettling and the determination of the antioxidant activity. Methodology Chromatographic methods were used for fractionation and isolation, respectively. Structure elucidation was established by spectroscopic methods. Five antioxidant assays were performed. Results Three new abietane diterpenoids barreliol, royleanone 12-methyl ether and 7-epi-salviviridinol, and six known diterpenoids, with a known dammarane triterpenoid, pyxinol were isolated. The absolute stereochemistry of pyxinol was confirmed by X-ray analysis. Conclusion Taxodione exhibited the highest antioxidant activity among the tested compounds. Copyright © 2009 John Wiley & Sons, Ltd. [source] Antihyperglycaemic and protective effects of flavonoids on streptozotocin,induced diabetic ratsPHYTOTHERAPY RESEARCH, Issue S2 2010Amélia P. Rauter Abstract The antihyperglycaemic effect of eight standard flavonoids, previously identified in the ethanol extract of the claimed antidiabetic plant Genista tenera, was evaluated on streptozotocin (STZ)-induced diabetic Wistar rats. The aglycones apigenin, chrysoeriol and genistein, the monoglucosides apigenin 7- O -glucoside, luteolin 7- O -glucoside and genistein 7- O -glucoside and the diglycosides rutin and luteolin 7,3,-di- O -glucoside were administered i.p. for 7 days (4,mg/kg b.w./day). The protective effect of these compounds over liver and kidneys of STZ,diabetic models was also evaluated by the determination of seric AST, ALT and urea levels. After 7 days of treatment, apigenin, chrysoeriol and genistein significantly lowered the blood glucose levels of diabetic animals; this effect was more pronounced (P < 0.01) in the oral glucose tolerance test. Glucose tolerance was also significantly improved in the rutin (P < 0.01) and in the genistein 7,O,glucoside (P < 0.05) treated groups. In addition, almost all the tested compounds effectively protected the liver and kidneys against STZ-induced damage in rats. Copyright © 2010 John Wiley & Sons, Ltd. [source] Synthesis and Structure-Activity Relationship Studies of Pyrazole-based Heterocycles as Antitumor AgentsARCHIV DER PHARMAZIE, Issue 7 2010Ahmad M. Farag Abstract Several 4-cyano-1,5-diphenylpyrazoles attached to different heterocyclic ring systems at position 3 were synthesized starting from ethyl 4-cyano-1,5-diphenyl-1H -pyrazole-3-carboxylate 1. The newly synthesized compounds were tested in vivo for their anti-estrogenic effects and evaluated in vitro for their cytotoxic properties against estrogen-dependent tumors. 3-(5-Mercapto-1,3,4-oxadiazole-2-yl)-1,5-diphenyl-1H -pyrazole-4-carbonitrile 13 revealed the highest cytotoxic activity with a GI50 value equal to 40 nM against the IGROVI ovarian tumor cell line. It also showed an anti-estrogen activity 1.6 more effective than the reference drug, in addition to a high tolerable dose. 3-(5-(Methylthio)-4-phenyl-4H -1,2,4-triazol-3-yl)-1,5-diphenyl-1H -pyrazole-4-carbonitrile 7 was found to have the highest anti-estrogenic activity, while 1,5-diphenyl-3-[5-(phenylamino)-1,3,4-thiadiazol-2-yl]-1H -pyrazole-4-carbonitrile 11 showed the lowest activity. The oral LD50 values revealed that most of the tested compounds are relatively nontoxic. [source] Synthesis and Antidepressant Evaluation of Five Novel Heterocyclic Tryptophan-Hybrid DerivativesARCHIV DER PHARMAZIE, Issue 5 2010Gamal A. Elmegeed Abstract This study aimed at evaluating the reactivity of L -Tryptophan (TRP) 1 towards various chemical reagents to produce new bi- and tri-heterocyclic systems providing basic pharmacological activities. Indol-3-yl hydroxyoxazol-2-yl acetonitrile derivatives 5 and 6, indol-3-yl-hydroxyoxazol-2-yl-1,2,4-triazine derivatives 8 and 9, indol-3-yl-hydroxyoxazol-2-yl-aminopyrazole derivatives 11a, b, and indol-3-yl-hydroxyoxazol-2-yl-aminoisoxazole derivative 12 were synthesized via straightforward and efficient methods. The structures were characterized by spectral data (IR, 1H-NMR, 13C-NMR, and MS) and the purity was ascertained by microanalysis. Also, this work was extended to study the potential role of the novel synthesized TRP derivatives 5, 6, 9, 11a, and 12 as antidepressant and sedative agents in comparison with TRP. All compounds showed significant antidepressant activity in the forced-swimming test at two doses (50 or 100 mg/kg). Also, all tested compounds (at 50 or 100 mg/kg) produced a significant decrease in locomotor activity of mice during a 30 min observation period. The most potent antidepressant and sedative effect was produced by the tri-heterocyclic compounds 9 and 12, followed by 11a and TRP. [source] Facile Synthesis and In-Vitro Antitumor Activity of Some Pyrazolo[3,4- b]pyridines and Pyrazolo[1,5- a]pyrimidines Linked to a Thiazolo[3,2- a]benzimidazole MoietyARCHIV DER PHARMAZIE, Issue 1 2010Hatem A. Abdel-Aziz Abstract The key precursor E -3-(N,N -dimethylamino)-1-(3-methylthiazolo[3,2- a]benzimidazol-2-yl)prop-2-en-1-one 4 was synthesized in good yield using Gold's reagent. The reaction of enaminone 4 with 5-amino-3-aryl-1 - phenylpyrazoles 5a, b in refluxing acetic acid in the presence of sulphuric acid, yielded pyrazolo[3,4- b]pyridines 7a, b. Similarly, pyrazolo[1,5- a]pyrimidines 10a, b and 14a,f were prepared by reaction of enaminone 4 with 5-amino-1H -pyrazoles 8a, b and 12a,f, respectively. The structure of pyrazolo[1,5- a]pyrimidine 10b was determined by X-ray diffraction. The synthesized compounds were tested for their in-vitro antitumor activity against the colon cancer cell line CaCo-2; their cytotoxicity against the normal fibroblast cell line BHK was explored as well. Some of the tested compounds exhibited cell growth inhibitory activity. The significant antitumor activity of compound 14f against the CaCo-2 cell line (IC50 = 0.5 ,g/mL) was coupled with a lower toxicity against BHK (IC50 = 2.3 ,g/mL). [source] Synthesis and Biological Evaluation of Novel 5,8-Disubstituted-2-methyl-2,3,4,5-tetrahydro-1H -pyrido[4,3- b] indoles as 5-HT6 and H1 Receptors AntagonistsARCHIV DER PHARMAZIE, Issue 12 2009Alexandre V. Ivachtchenko Abstract Synthesis, biological evaluation, and structure-activity relationships (SAR) for a series of novel ,-carboline analogues of Dimebon are described. Among the studied compounds, tetrahydro-,-carboline 5b (2,8-dimethyl-5-[cis -2-pyridin-3-ylvinyl]-2,3,4,5-tetrahydro-carboline) has been identified as the most potent small molecule antagonist, in particular against histamine H1 and serotonin 5-HT6 receptors (IC50 < 0.45 ,M and IC50 = 0.73 ,M, respectively). A thorough comparative SAR study performed for the tested compounds has revealed significant correlations between the nature of side substituents and the related antagonistic activity. [source] Synthesis of Novel Uracil Non-Nucleoside Derivatives as Potential Reverse Transcriptase Inhibitors of HIV-1ARCHIV DER PHARMAZIE, Issue 11 2009Nasser R. El-Brollosy Abstract Novel emivirine and TNK-651 analogues 5a,d were synthesized by reaction of chloromethyl ethyl ether and / or benzyl chloromethyl ether, respectively, with uracils having 5-ethyl and 6-(4-methylbenzyl) or 6-(3,4-dimethoxybenzyl) substituents. A series of new uracil non-nucleosides substituted at N-1 with cyclopropylmethyloxymethyl 9a,d, 2-phenylethyloxymethyl 9e,h, and 3-phenylprop-1-yloxymethyl 9i,l were prepared on treatment of the corresponding uracils with the appropriate acetals 8a,c. Some of the tested compounds showed good activity against HIV-1 wild type. Among them, 1-cyclopropylmethyloxymethyl-5-ethyl-6-(3,5-dimethylbenzyl)uracil 9c and 5-ethyl-6-(3,5-dimethylbenzyl)-1-(2-phenylethyloxymethyl)uracil 9g showed inhibitory potency equally to emivirine against HIV-1 wild type. Furthermore, compounds 9c and 9g showed marginal better activity against NNRTI resistant mutants than emivirine. [source] Synthesis and Pharmacological Evaluation of Thiazole and Isothiazole Derived ApomorphinesARCHIV DER PHARMAZIE, Issue 10 2009Attila Sipos Abstract We have presented the synthesis of novel thiazolo- and isothiazolo-apomorphines 12,17 resulting,in part,from an unexpected isomerization step occurred during the acid-catalyzed rearrangement of precursor thiazolo-morphinandienes 3,5. These 2,3-disubstituted apomorphines represent a new group of A-ring substituted aporphines. The receptor binding studies revealed that with the exception of two derivatives all the tested compounds have limited affinity for dopamine-receptor subtypes. Functional calcium assay for the most active isothiazolo-apomorphine showed higher affinities for D1 and D2L subtypes. The docking of these ligands has been modelled to human D2 and D3 receptors. On the basis of the predicted models, we identified an important cation-p interaction for the binding of isothiazolo-apomorphine 16. [source] Parallel Synthesis of O -Phenoxyethyl and O -Adamantyl N- acyl Thiocarbamates Endowed with Antiproliferative ActivityARCHIV DER PHARMAZIE, Issue 6 2009Andrea Spallarossa Abstract In order to further explore the antiproliferative properties of O -phenoxyethyl and O -adamantyl acylthiocarbamates (ATCs), a series of 14 derivatives was prepared by a parallel adaptation of a highly convergent one-pot three-step procedure. Ten acylthiocarbamates were selected by the National Cancer Institute drug evaluation program and screened against a panel of 55 to 58 cell lines derived from nine different types of human cancers. In general, the tested compounds showed a widespread micromolar activity with some specificity against leukemia, renal UO-31, central nervous system (CNS) SNB-75, and non-small cell lung HOP-92 cancer cell lines. Bioinformatic COMPARE analyses were carried out to identify possible mechanism(s) of action for acylthiocarbamate antiproliferative activity. [source] Synthesis and Biological Evaluation of Some Novel Polysubstituted Pyrimidine Derivatives as Potential Antimicrobial and Anticancer AgentsARCHIV DER PHARMAZIE, Issue 5 2009Sherif A. F. Rostom Abstract Synthesis and evaluation of the antimicrobial and cytotoxic activity of two series of polysubstituted pyrimidines comprising the thioether functionality and other pharmacophores, reported to contribute to various chemotherapeutic activities are described. All newly synthesized compounds were subjected to in-vitro antibacterial and antifungal screening. Out of the compounds tested, 18 derivatives displayed an obvious inhibitory effect on the growth of the tested Gram-positive and Gram-negative bacterial strains, with special effectiveness against the Gram-positive strains. Compounds 1, 2, 6, 7, 9, 10, 11, 21, and 24 revealed remarkable broad antibacterial spectrum profiles. Among those, compounds 1, 2, 6, 7, 9, and 24 exhibited an appreciable antifungal activity against C. albicans. Compound 2 proved to be the most active antimicrobial member identified here as it showed twice the activity of ampicillin against B. subtilis and the same activity of ampicillin against M. Luteus and P. aeruginosa together with a moderate antifungal activity. Further, eleven analogs were evaluated for their in-vitro cytotoxic potential utilizing the standard MTT assay against a panel of three human cell lines: breast adenocarcinoma MCF7, hepatocellular carcinoma HePG2, and colon carcinoma HT29. The obtained data revealed that six of the tested compounds 1, 3, 7, 12, 13, and 15 showed a variable degree of cytotoxic activity against the tested cell lines at both the LC50 and LC90 levels. Compound 7 proved to be the most active cytotoxic member in this study with special effectiveness against the colon carcinoma HT29 and breast cancer MCF7 human cell lines for LC50 and LC90. Thus, compounds 1 and 7 could be considered as possible dual antimicrobial-anticancer agents. [source] Investigation of lipophilicity of anticancer-active thioquinoline derivativesBIOMEDICAL CHROMATOGRAPHY, Issue 2 2007Marek Bajda Abstract The lipophilicity of a series of anticancer propargylthioquinoline derivatives has been investigated using chromatographic and computational methods. The parameters of relative lipophilicity (RMO and logk0) of the tested compounds were determined experimentally both by reversed-phase thin layer (RP-TLC), and high-performance liquid chromatographic methods (RP-HPLC, LiChrospher RP18 column), with mixtures of acetonitrile and water as mobile phases. Their phospholipophilicity (logk0IAM) was determined using immobilized artificial membrane HPLC (IAM. PC DD2 Regis column). Mobile phase acetonitrile concentrations were in the ranges 50,90% (RP-TLC), 55,90% (RP-HPLC) and 35,60% (IAM-HPLC). The RM, logk and logkIAM values of the compounds investigated were linearly dependent on acetonitrile concentration. The analysis led to the calculation of RMO, logk0 and logk0IAM parameter values for each of the tested compounds. Their partition coefficients (logP) were also calculated with the Pallas and CAChe programs. The obtained results indicated that, among experimental methods, both RP-TLC and RP-HPLC gave similar results, and these methods enable the determination of lipophilicity of derivatives of thioquinolines. Using the IAM-HPLC technique a simple method of estimation of phospholipoplilicity was described. The CAChe program might better predict calculated lipophilicity logP values, and therefore is a useful tool for the early stage of design of new propargyl thioquinolines. Copyright © 2006 John Wiley & Sons, Ltd. [source] Differences in the Effects of Solution Additives on Heat- and Refolding-Induced AggregationBIOTECHNOLOGY PROGRESS, Issue 2 2008Hiroyuki Hamada Although a number of low-molecular-weight additives have been developed to suppress protein aggregation, it is unclear whether these aggregation suppressors affect various aggregation processes in the same manner. In this study, we evaluated the differences in the effect of solution additives on heat- and refolding-induced aggregation in the presence of guanidine (Gdn), arginine (Arg), and spermidine (Spd), and the comparable analysis showed the following differences: (i) Gdn did not suppress thermal aggregation but increased the yield of oxidative refolding. (ii) Spd showed the highest effect for heat-induced aggregation suppression among tested compounds, although it promoted aggregation in oxidative refolding. (iii) Arg was effective for both aggregation processes. Lysozyme solubility assay and thermal unfolding experiment showed that Spd was preferentially excluded from native lysozyme and Arg and Gdn solubilized the model state of intermediates during oxidative refolding. This preference of additives to protein surfaces is the cause of the different effect on aggregation suppression. [source] Research Letter: New Potent Indole Derivatives as Hyaluronidase InhibitorsCHEMICAL BIOLOGY & DRUG DESIGN, Issue 6 2007Süreyya Ölgen Because of the physiologic importance of hyaluronidases, the identification of potent and selective inhibitors of hyaluronidases has become increasingly important. A variety of assay methods have been used for such a purpose, i.e. classical turbidimetric, viscometric and colorimetric. In this study, a modified enzymatic assay has been used to obtain a microtiter plate-based sensitive activity screening. All inhibitors were tested in a stains-all assay at pH 7 and in a Morgan-Elson assay at pH 3.5. Among the tested compounds, 1, 2, 3, 6, 7, 8, 16, 17 and 18 showed good inhibition of more than 50%, so the IC50 values of these derivatives were determined in the range of 25,41 ,m. The IC50 value of the most active hyaluronidase inhibitor Vcpal (6-palmitoyl- l -ascorbic acid) was measured as 8.36 ,m. All inhibitors including Vcpal showed twofold less activity at pH 3.5 in a Morgan-Elson assay. Examination of substituent effects on the activity showed that para -positions of benzamide needs to be chlorinated or fluorinated to obtain good inhibitory effect. It was found that the introduction of a p -fluoro benzyl ring in the indole nitrogen has a positive effect for the inhibitory effects of both indole-2- and 3-carboxamide derivatives. [source] Organoplatinum(II) Complexes with Nucleobase Motifs as Inhibitors of Human Topoisomerase II Catalytic ActivityCHEMISTRY - AN ASIAN JOURNAL, Issue 10 2010Ping Wang Abstract Platinum(II) complexes bearing acetylide ligands containing nucleobase motifs are prepared and their impact on human topoisomerase II (TopoII) is evaluated. Both platinum(II) complexes [PtII(C^N^N)(C,CCH2R)] (1,a,c) and [PtII(tBu3terpy)(C,CCH2R)]+ (2,a,c) (C^N^N=6-phenyl-2,2,-bipyridyl, tBu3terpy=4,4,,4,,-tri-tert-butyl-2,2,:6,,2,,-terpyridyl, and R=(a) adenine, (b) thymine, and (c) 2-amino-6-chloropurine) are stable in aqueous solutions for 48,hours at room temperature. The binding constants (K) for the platinum(II) complexes towards calf thymus DNA are in the order of 105,dm3,mol,1 as estimated by using UV/Vis absorption spectroscopy. Of the complexes examined, only complexes 1,a,c are found to behave as intercalators. Both complexes 1,a,c and 2,a,c inhibit TopoII-induced relaxation of supercoiled DNA, while 2,c is the most potent TopoII inhibitors among the tested compounds. Inhibition of DNA relaxation is detected at nanomolar concentrations of 2,c. All of the platinum(II) complexes are cytotoxic to human cancer cells with IC50 values of 0.5,13.7,,M, while they are less toxic against normal cells CCD-19,Lu. [source] Benzo[d]isothiazol-3-yl-benzamidines: a Class of Protective Agents on Culture of Human Cartilage and Chondrocytes Stimulated by IL-1,CHEMMEDCHEM, Issue 1 2007Paola Vicini Prof. Abstract New derivatives of N -benzo[d]isothiazol-3-yl-benzamidine 6,a were synthesized as nonacidic anti-inflammatory/antidegenerative agents. We investigated the influence of the amidines 6,a,j on the production of NO, PGE2, MMP-3, COX-2, ROS, and GAGs, key molecules involved in cartilage destruction in osteoarthritic diseases. The antidegenerative properties of the novel designed derivatives 6,b,j were improved with respect to N -benzo[d]isothiazol-3-yl-benzamidine 6,a. All of the compounds 6,a,j promoted the reduction of most of the IL-1,-induced harmful effects. Derivatives 6,d, 6,h, and 6,j were the most potent of all the tested compounds, particularly in the human chondrocyte culture model. [source] | ||||||||||||||||