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Sample records for benzamides

  1. Synthesis and biological activity of benzamide DNA minor groove binders.

    Science.gov (United States)

    Khan, Gul Shahzada; Pilkington, Lisa I; Barker, David

    2016-02-01

    A range of di- and triaryl benzamides were synthesised to investigate the effect of the presence and nature of a polar sidechain, bonding and substitution patterns and functionalisation of benzylic substituents. These compounds were tested for their antiproliferative activity as well as their DNA binding activity. The most active compounds in all assays were unsymmetrical triaryl benzamides with a bulky or alkylating benzylic substituent and a polar amino sidechain.

  2. An Unusual N-Boc Deprotection of Benzamides under Basic Conditions

    Institute of Scientific and Technical Information of China (English)

    YIN Biaolin; ZHANG Yuanxiu

    2009-01-01

    For the first time,an unusal cleavage of N-tert-butyloxycarbonyl(N-Boc)protection from N-Boc-protected benzamide under basic conditions in excellent yields is reported.The deprotection involves the N-Boc emigration from the benzamide to form 2-O-Boo group followed by O-Boc deprotection on the phenyl ring.

  3. Discovery of benzamide analogues as a novel class of 5-HT3 receptor agonists

    DEFF Research Database (Denmark)

    Jørgensen, Charlotte Grube; Frølund, Bente Flensborg; Kehler, Jan;

    2011-01-01

    A 5-HT(3) receptor agonist based on a benzamide scaffold was identified in a screening of a small commercial compound library, and an elaborate SAR study originating from this hit was performed. The design, synthesis, and functional characterisation of benzamide analogues at the 5-HT(3) A receptor...... yielded substantial information concerning the analogues as 5-HT(3) receptor agonists. However, the potencies of the derived analogues were not significantly improved over that of the initial hit. The benzamide scaffold constitutes a novel type of 5-HT(3) receptor agonist, as it does not possess...

  4. The challenging case of the theophylline-benzamide cocrystal.

    Science.gov (United States)

    Fischer, Franziska; Schmidt, Martin U; Greiser, Sebastian; Emmerling, Franziska

    2016-03-01

    Theophylline has been used as an active pharmaceutical ingredient (API) in the treatment of pulmonary diseases, but due to its low water solubility reveals very poor bioavailability. Based on its different hydrogen-bond donor and acceptor groups, theophylline is an ideal candidate for the formation of cocrystals. The crystal structure of the 1:1 benzamide cocrystal of theophylline, C7H8N4O2·C7H7NO, was determined from synchrotron X-ray powder diffraction data. The compound crystallizes in the tetragonal space group P41 with four independent molecules in the asymmetric unit. The molecules form a hunter's fence packing. The crystal structure was confirmed by dispersion-corrected DFT calculations. The possibility of salt formation was excluded by the results of Raman and (1)H solid-state NMR spectroscopic analyses. PMID:26942431

  5. Halogenated benzamides as ligands for cerebral dopamine receptors

    International Nuclear Information System (INIS)

    In the past several years the authors' has synthesized a series of high affinity iodine-123 and fluorine-18 labeled substituted benzamide ligands for SPECT and PET visualization of the dopamine D-2 receptors in brain regions with low receptor density outside the striatum. Radioiodination and radiofluorination in high yield and high specific activity was achieved by using the tributyltin precursor and nucleophilic displacement of the saturation analysis revealed that the optimal striatum-to-cerebellum uptake ratio in the rat brain is highly correlated with the product of Kw and KD. The authors have used [125I] and [123I] epidepride to detect extra striatal dopamine D2 receptors in vitro by saturation analysis and in vivo with high resolution SPECT imaging

  6. Crystal Structure Prediction could have helped the Experimentalists with Polymorphism in Benzamide!

    OpenAIRE

    2008-01-01

    Abstract Benzamide was the first molecular material for which polymorphism was reported as long as 176 years ago. Unfortunately, due to very similar cell metrics leading to massive peak overlap, the metastable form reported by Liebig escaped structural characterization by XRD until recently. With the help of crystal structure prediction this old riddle of ?Liebig's? polymorph of benzamide could have been solved many years earlier. Performing state of the art crystal structure predi...

  7. Synthesis, characterization and antibacterial studies of 2-chloro-5-fluoro-N-[dibenzyl carbamothioyl] benzamide thiourea

    Energy Technology Data Exchange (ETDEWEB)

    Sapari, Suhaila; Yamin, Bohari M.; Hasbullah, Aishah; Ibrahim, Nazlina [School of Chemical Science and Food Technology, Faculty of Science and Technology, The National University of Malaysia, 43600, Bangi, Selangor (Malaysia)

    2014-09-03

    Synthesis, characterization and antibacterial studies of 2-chloro-5-fluoro-N-[dibenzyl carbamothioyl] benzamide thiourea has been reported. The compound characterized by using elementary analysis CHNS, IR, {sup 1}H NMR and {sup 13}C NMR spectroscopies. The compounds have been screened for their antibacterial studies.

  8. Temperature-controlled redox-neutral ruthenium(ii)-catalyzed regioselective allylation of benzamides with allylic acetates.

    Science.gov (United States)

    Manikandan, Rajendran; Jeganmohan, Masilamani

    2016-08-10

    Substituted aromatic amides reacted efficiently with allylic acetates in the presence of a cationic ruthenium complex in ClCH2CH2Cl at room temperature providing ortho allylated benzamides in a highly regioselective manner without any oxidant and base. The whole catalytic reaction occurred in a Ru(ii) oxidation state and thus the oxidation step is avoided. By tuning the reaction temperature, ortho allyl and vinyl benzamides were prepared exclusively. Later, ortho allyl and vinylated benzamides were converted into biologically useful six- and five-membered benzolactones in the presence of HCl. PMID:27456467

  9. Synthesis and Pharmacological Activities of N-(3-HydroxyphenylBenzamide and its 3-O-Derivatives

    Directory of Open Access Journals (Sweden)

    M. A. Abbasi

    2014-03-01

    Full Text Available N-(3-hydroxyphenyl benzamide (3 was synthesized by the condensation of 3-hydroxyaniline (1 with benzoyl chloride (2 in aqueous medium. From this parent molecule 3, various 3-O-derivatives, 5a-f, were prepared via O-alkylation, by reacting it with different alkyl halides, 4a-f, for 2 h under reflux conditions in the presence of mixture of Na-ethoxide and C2H5OH as solvent. The synthesized compounds were characterized by using different spectroscopic techniques and were subjected to enzyme inhibition activity against butylcholinesterase, acetylcholinesterase, and lipoxygenase enzymes.

  10. Characterization of Antiviral Activity of Benzamide Derivative AH0109 against HIV-1 Infection

    OpenAIRE

    Chen, Liyu; Ao, Zhujun; Jayappa, Kallesh Danappa; Kobinger, Gary; Liu, ShuiPing; Wu, Guojun; Wainberg, Mark A.; Yao, Xiaojian

    2013-01-01

    In the absence of an effective vaccine against HIV-1 infection, anti-HIV-1 strategies play a major role in disease control. However, the rapid emergence of drug resistance against all currently used anti-HIV-1 molecules necessitates the development of new antiviral molecules and/or strategies against HIV-1 infection. In this study, we have identified a benzamide derivative named AH0109 that exhibits potent anti-HIV-1 activity at an 50% effective concentration of 0.7 μM in HIV-1-susceptible CD...

  11. Substituted Benzamides Containing Azaspiro Rings as Upregulators of Apolipoprotein A-I Transcription

    Directory of Open Access Journals (Sweden)

    Bin Hong

    2012-06-01

    Full Text Available Apolipoprotein A-I (Apo A-I is the principal protein component of high density lipoprotein (HDL, which is generally considered as a potential therapeutic target against atherosclerosis. The understanding of the Apo A-I regulation mechanism has fuelled the development of novel HDL targeted therapeutic approaches. To identify novel agents that can upregulate Apo A-I expression, we performed a cell-based reporter assay to screen 25,600 small molecules. Based on the dataset obtained from screening, a series of novel analogs of substituted benzamides containing azaspiro rings were assessed for their ability to induce the transcription of the Apo A-I gene, and the structure-activity relationship (SAR around these analogs was also proposed. The results indicated that the trifluoromethyl substituted benzamide containing an azaspiro ring is a promising backbone for designing Apo A-I transcriptional upregulator and could be viable leads for development of new drugs to prevent and treat atherosclerosis in the future.

  12. High affinity dopamine D2 receptor radioligands. 1. Regional rat brain distribution of iodinated benzamides

    Energy Technology Data Exchange (ETDEWEB)

    Kessler, R.M.; Ansari, M.S.; de Paulis, T.; Schmidt, D.E.; Clanton, J.A.; Smith, H.E.; Manning, R.G.; Gillespie, D.; Ebert, M.H. (Vanderbilt University School of Medicine, Nashville, TN (USA))

    1991-08-01

    Five 125I-labeled substituted benzamides, which are close structural analogues of (S)-sulpiride, eticlopride, and isoremoxipride, were evaluated for their selective in vivo uptake into dopamine D2 receptor rich tissue of the rat brain. Iodopride (KD 0.88 nM), an iodine substituted benzamide structurally related to sulpiride, displayed a maximal striatum: cerebellar uptake ratio of 7.6. Demonstration of saturation of the receptor with (125I)iodopride in striatum required uptake in frontal cortex to be used, rather than cerebellar uptake, to define nonspecific binding. Two other ligands structurally related to eticlopride, iclopride (KD 0.23 nM) and itopride (KD 0.16 nM), displayed maximal striatal: cerebellar uptake ratios of 9.8 and 3.3, respectively. The most potent ligands, epidepride (KD 0.057 nM) and ioxipride (KD 0.070 nM) showed striatal:cerebellar uptake ratios of 234 and 65, respectively. The observed uptake ratios correlated poorly with the affinity constants for the dopamine D2 receptor alone, but were highly correlated (r = 0.92) with the product of the receptor dissociation constant (KD) and the apparent lipophilicity (kw), as determined by reverse-phase HPLC at pH 7.5. Total striatal uptake also appeared dependent on lipophilicity, with maximal uptake occurring for ligands having log kw 2.4-2.8.

  13. High affinity dopamine D2 receptor radioligands. 1. Regional rat brain distribution of iodinated benzamides

    International Nuclear Information System (INIS)

    Five 125I-labeled substituted benzamides, which are close structural analogues of (S)-sulpiride, eticlopride, and isoremoxipride, were evaluated for their selective in vivo uptake into dopamine D2 receptor rich tissue of the rat brain. Iodopride (KD 0.88 nM), an iodine substituted benzamide structurally related to sulpiride, displayed a maximal striatum: cerebellar uptake ratio of 7.6. Demonstration of saturation of the receptor with [125I]iodopride in striatum required uptake in frontal cortex to be used, rather than cerebellar uptake, to define nonspecific binding. Two other ligands structurally related to eticlopride, iclopride (KD 0.23 nM) and itopride (KD 0.16 nM), displayed maximal striatal: cerebellar uptake ratios of 9.8 and 3.3, respectively. The most potent ligands, epidepride (KD 0.057 nM) and ioxipride (KD 0.070 nM) showed striatal:cerebellar uptake ratios of 234 and 65, respectively. The observed uptake ratios correlated poorly with the affinity constants for the dopamine D2 receptor alone, but were highly correlated (r = 0.92) with the product of the receptor dissociation constant (KD) and the apparent lipophilicity (kw), as determined by reverse-phase HPLC at pH 7.5. Total striatal uptake also appeared dependent on lipophilicity, with maximal uptake occurring for ligands having log kw 2.4-2.8

  14. Terahertz Absorption Spectroscopy of Benzamide, Acrylamide, Caprolactam, Salicylamide, and Sulfanilamide in the Solid State

    Directory of Open Access Journals (Sweden)

    Ye Jiang

    2014-01-01

    Full Text Available Terahertz (THz absorption spectra of the similarly structured molecules with amide groups including benzamide, acrylamide, caprolactam, salicylamide, and sulfanilamide in the solid phase at room temperature and 7.8 K for salicylamide are reported and compared to infrared vibrational spectral calculations using density functional theory. The results of THz absorption spectra show that the molecules have characteristic bands in the region of 0.2–2.6 THz (~7–87 cm−1. THz technique can be used to distinguish different molecules with amide groups. In the THz region benzamide has three bands at 0.83, 1.63, and 1.73 THz; the bands are located at 1.44 and 2.00 THz for acrylamide; the bands at 1.24, 1.66 and 2.12 THz are observed for caprolactam. The absorption bands are located at 1.44, 1.63, and 2.39 THz at room temperature, and at 1.22, 1.46, 1.66, and 2.41 THz at low temperature for salicylamide. The bands at 1.63, 1.78, 2.00, and 2.20 THz appear for sulfanilamide. These bands in the THz region may be related to torsion, rocking, wagging, and other modes of different groups in the molecules.

  15. Removal of Uranium (VI from aqueous solution by Uranium Benzamide Complex using AC_Fe3O4 Nanocomposite

    Directory of Open Access Journals (Sweden)

    Z Akbari Jonoush

    2014-07-01

    Conclusion: The removal of U(VI on AC_Fe3O4 nanocomposite with the aid of benzamide is a rapid and highly pH depended process. The maximum sorption capacity (15/87 mg/g of AC_Fe3O4 nanocomposite shows that this method is a suitable method for Uranium removal.

  16. One-pot synthesis of novel 1, 8-dioxo-decahydroacridines containing phenol and benzamide moiety and their synthetic uses

    Indian Academy of Sciences (India)

    Ali Dorehgiraee; Esmat Tavakolinejad Kermani; Hojatollah Khabazzadeh

    2014-07-01

    An efficient synthesis of some new 1, 8-dioxo-decahydroacridines is achieved via one-pot, threecomponent condensation of aromatic aldehydes, cyclic diketone, and 4-amino benzamide/4-aminophenol. Reaction of these acridines with dimethylacetylene dicarboxylate and triphenylphosphine or cyclohexylisocyanide gives stable phosphorus ylides or 4H-chromene derivatives, respectively, with good yields.

  17. N-[2-(maleimido)ethyl]-3-(trimethylstannyl)benzamide, a molecule for radiohalogenation of proteins and peptides

    DEFF Research Database (Denmark)

    Aneheim, Emma; Foreman, Mark R StJ; Jensen, Holger;

    2015-01-01

    In this work a new coupling reagent, N-[2-(maleimido)ethyl]-3-(trimethylstannyl)benzamide, for radiohalogenation has been synthesized and characterized. The reagent is intended to either be attached to reduced disulfide bridges of proteins (making the halogenation site-specific) or to free termin...

  18. [125]I-spectramide: A novel benzamide displaying potent and selective effects at the D2 dopamine receptor

    International Nuclear Information System (INIS)

    The new substituted benzamide Spectramide, (N-[2-[4-iodobenzyl-N-methylamino]-2-methoxy-4-ethyl]-5-chloro-methylamine benzamide) labelled with 125I was used as a potent and highly selective dopamine-D2 receptor antagonist in rat striatal homogenates for in vitro receptor binding. Kinetic experiments demonstrated the reversibility of the binding and the estimated Kd from saturation analysis was 25 pM, with a Bmax of 20 pmol/g of tissue. Competition studies showed that spectramide did not interact potently with the D1 or dopamine-uptake site. Drugs known to interact with other receptor system were weak competitors of the binding, while binding was potently inhibited by other D2 antagonists, such as spiperone and eticlopride. These data indicate that Spectramide binds selectively and with high affinity to the dopamine D2 receptors, and may prove to be a useful tool for the study of these receptors in vivo using PET or SPECT

  19. Photocatalytic/Cu-Promoted C-H Activations: Visible-light-Induced ortho-Selective Perfluoroalkylation of Benzamides.

    Science.gov (United States)

    Chen, Xiang; Tan, Ze; Gui, Qingwen; Hu, Liang; Liu, Jidan; Wu, Jing; Wang, Guangwei

    2016-04-25

    A visible-light-induced and copper-promoted perfluoroalkylation of benzamides was successfully developed under the assistance of an 8-aminoquinoline directing group. It provides a straightforward method for the synthesis of ortho-perfluoroalkyl-substituted benzoic acid derivatives. The reaction employs a cheap organic dye eosin Y as the photoredox catalyst and is run under the irradiation of a 26 W fluorescent LED light bulb. PMID:26933840

  20. Synthesis and Evaluation of Astatinated N-[2-(Maleimido)ethyl]-3-(trimethylstannyl)benzamide Immunoconjugates.

    Science.gov (United States)

    Aneheim, Emma; Gustafsson, Anna; Albertsson, Per; Bäck, Tom; Jensen, Holger; Palm, Stig; Svedhem, Sofia; Lindegren, Sture

    2016-03-16

    Effective treatment of metastasis is a great challenge in the treatment of different types of cancers. Targeted alpha therapy utilizes the short tissue range (50-100 μm) of α particles, making the method suitable for treatment of disseminated occult cancers in the form of microtumors or even single cancer cells. A promising radioactive nuclide for this type of therapy is astatine-211. Astatine-211 attached to tumor-specific antibodies as carrier molecules is a system currently under investigation for use in targeted alpha therapy. In the common radiolabeling procedure, astatine is coupled to the antibody arbitrarily on lysine residues. By instead coupling astatine to disulfide bridges in the antibody structure, the immunoreactivity of the antibody conjugates could possibly be increased. Here, the disulfide-based conjugation was performed using a new coupling reagent, maleimidoethyl 3-(trimethylstannyl)benzamide (MSB), and evaluated for chemical stability in vitro. The immunoconjugates were subsequently astatinated, resulting in both high radiochemical yield and high specific activity. The MSB-conjugate was shown to be stable with a long shelf life prior to the astatination. In a comparison of the in vivo distribution of the new immunoconjugate with other tin-based immunoconjugates in tumor-bearing mice, the MSB conjugation method was found to be a viable option for successful astatine labeling of different monoclonal antibodies. PMID:26791409

  1. Could N-(diethylcarbamothioyl)benzamide be a good ionophore for sensor membranes?

    Science.gov (United States)

    Fraga, Ana Rosa Lazo; Destri, Giovanni Li; Forte, Giuseppe; Rescifina, Antonio; Punzo, Francesco

    2010-09-01

    Nuclear Magnetic Resonance, Density Functional Theory and Molecular Dynamics calculations together with X-ray diffraction analysis have been used to enlighten the structural properties of N-(diethylcarbamothioyl)benzamide, a ionophore for sensor applications. Focusing the attention over the molecular conformation in different phases - i.e. solid state, solution and gas - before and after the interaction with a heavy metal ion, the behaviour of the molecule as a ionophore in a typical Ion Selective Electrode membrane was simulated. The whole structural analysis has been carried out as a comparison with an already studied and similar compound also used for the same purpose. To achieve this goal the available single crystal structure has been used to model the X-ray powder diffraction pattern. Although the condensed phase structure was not used as a starting guess for the gas phase model, it fits the possible conformers suggested for the gas phase. As the structure transition solid → gas takes place with a substantial identity preservation, an analogous structure in the liquid phase was suggested. As a consequence, a detailed interaction mechanism between the title compound and the Pb 2+ ion in solution has been depicted. Analogies and differences among the different structures and homologies with compounds of the same class, help the understanding of the ionophore behaviour in the electrode and its potential applications.

  2. Modulation of gastrointestinal afferent sensitivity by a novel substituted benzamide (ecabapide).

    Science.gov (United States)

    Jiang, W; Grundy, D

    2000-01-14

    The effects of ecabapide, a novel substituted benzamide compound (3-[2-(3,4-dimethoxyphenyl)ethylcarbamoylmethyl]amino-N-methylb enzamide) that has gastrointestinal prokinetic action, were examined on the discharge of extrinsic afferent nerves supplying the stomach and jejunum in anaesthetized rats. Ecabapide (60 and 180 microg kg(-1), i.v.) had no effect on the baseline discharge of vagal gastric distension-sensitive afferents or the stimulus-response profile to gastric distension. Ecabapide also had no effect on either spontaneous jejunal mesenteric afferent nerve discharge or responses to intestinal distension. Ecabapide (180 microg kg(-1)) significantly inhibited the maximum discharge of jejunal afferents induced by cholecystokinin (CCK8; 50 pmol, i.v.), whereas it failed to inhibit the excitatory action of 2-methyl-5-hydroxytryptamine (2Me-5-HT; 10 microg, i.v.), a selective 5-HT3 receptor agonist. A model of acute focal intestinal ischaemia was used to evaluate the actions of ecabapide on the discharge of activated jejunal afferents. Ischaemia produced a substantial increase in afferent discharge which was reproducible when the duration of ischaemia was limited to less than 10 min and repeated every 15 min. Ecabapide at doses of 60 and 180 microg kg(-1) significantly reduced ischaemia-induced increases in afferent discharge. In addition to its therapeutic efficacy as a gastrointestinal prokinetic agent, these findings show also that ecabapide may also have an inhibitory action on the discharge of intestinal afferents activated by ischaemia.

  3. Identification of a Benzamide Derivative that Inhibits Stress-Induced Adrenal Corticosteroid Synthesis

    Directory of Open Access Journals (Sweden)

    Jing Xu

    2009-09-01

    Full Text Available Elevated serum glucocorticoid levels contribute to the progression of many diseases, including depression, Alzheimer’s disease, hypertension, and acquired immunodeficiency syndrome. Here we show that the benzamide derivative N-[2-(4-cyclopropanecarbonyl-3-methyl-piperazin-1-yl-1-(tert-butyl-1H-indol-3-yl-methyl-2-oxo-ethyl]-4-nitrobenzamide (SP-10 inhibits dibutyryl cyclic AMP (dbcAMP-induced corticosteroid synthesis in a dose-dependent manner in Y-1 adrenal cortical mouse tumor cells, without affecting basal steroid synthesis and reduced stress-induced corticosterone increases in rats without affecting the physiological levels of the steroid in blood. SP-10 did not affect cholesterol transport and metabolism by the mitochondria but was unexpectedly found to increase 3-hydroxy-3-methylglutaryl-coenzyme A, low density lipoprotein receptor, and scavenger receptor class B type I (SR-BI expression. However, it also markedly reduced dbcAMP-induced NBD-cholesterol uptake, suggesting that this is a compensatory mechanism aimed at maintaining cholesterol levels. SP-10 also induced a redistribution of filamentous (F- and monomeric (G- actin, leading to decreased actin levels in the submembrane cytoskeleton suggesting that SP-10-induced changes in actin distribution might prevent the formation of microvilli–cellular structures required for SRBI-mediated cholesterol uptake in adrenal cells.

  4. Copper(II)-Mediated Intermolecular C(sp(2))-H Amination of Benzamides with Electron-Rich Anilines.

    Science.gov (United States)

    Singh, Bijaya Kumar; Polley, Arghya; Jana, Ranjan

    2016-05-20

    Despite significant progress, copper-catalyzed/mediated C-H amination reactions with electron-rich anilines remain an unsolved problem due to catalyst deactivation and deleterious side reactions. Herein, we report a copper(II)-mediated C(sp(2))-H amination of benzamides with electronically neutral or electron-rich anilines. A dramatic influence of silver(I) and tetrabutylammonium bromide was observed on the reaction outcome. The present protocol also demonstrates the synthesis of a number of nonsteroidal anti-inflammatory drugs. PMID:27148754

  5. Assembling an isomer grid: the isomorphous 4-, 3- and 2-fluoro-N'-(4-pyridyl)benzamides

    OpenAIRE

    Donnelly, Katie; Gallagher, John F.; Lough, Alan J.

    2008-01-01

    The three title isomers, 4-, (I), 3-, (II), and 2-fluoro-N'-(4-pyridyl)benzamide, (III), all C₁₂H₉FN₂O, crystallize in the P21/c space group (No. 14) with similar unit-cell parameters and are isomorphous and isostructural at the primary hydrogen-bonding level. An intramolecular C-H...O=C interaction is present in all three isomers [C...O = 2.8681 (17)-2.884 (2) Å and C-H...O117-118°], with an additional N-H...F [N...F = 2.7544 (15) Å] interaction in (III). Intermolecular amide-pyridine N-H......

  6. Effects of organophosphorus donors in the extraction of Uranium(VI) with N-acetyl benzamide in chloroform

    International Nuclear Information System (INIS)

    The liquid-liquid extraction of Uranium(VI) from aqueous nitrate solution by a mixture of N-acetyl benzamide and Organophosphorus donors in chloroform is reported. Concentration of the metal was measured by fluorescence technique and synergism was observed in the extraction of Uranium(VI). Stoichiometries of extracted species in both individual and mixed extraction were ascertained by slope ratio analysis. From the extraction data, overall equilibrium constants for binary and ternary extractions were calculated. Thermodynamic parameters controlling the nature of extraction were also evaluated. (author)

  7. Cobalt-Catalyzed Cyclization of N-Methoxy Benzamides with Alkynes using an Internal Oxidant through C-H/N-O Bond Activation.

    Science.gov (United States)

    Sivakumar, Ganesan; Vijeta, Arjun; Jeganmohan, Masilamani

    2016-04-18

    The cyclization of substituted N-methoxy benzamides with alkynes in the presence of an easily affordable cobalt complex and NaOAc provides isoquinolone derivatives in good to excellent yields. The cyclization reaction is compatible with a range of functional group-substituted benzamides, as well as ester- and alcohol-substituted alkynes. The cobalt complex [Co(III) Cp*(OR)2 ] (R=Me or Ac) serves as an efficient catalyst for the cyclization reaction. Later, isoquinolone derivatives were converted into 1-chloro and 1-bromo substituted isoquinoline derivatives in excellent yields in the presence of POCl3 or PBr3 . PMID:26951887

  8. Determination and structural correlation of pKBH+ for meta- and para- substituted benzamides in sulfuric acid solutions

    Directory of Open Access Journals (Sweden)

    EMIL POPOVSKI

    2006-10-01

    Full Text Available The protonation of some meta and para substituted benzamides in sulfuric acid solutions was studied by UV spectroscopy in the 190–350 nm region. Principal component analysis was applied to separate the effect of protonation from the medium effect. The spectral region 200–350 nm was used for the calculation of the ionization ratio from coefficient of the first principal component, which explains about 95–98 % of the total variability. The dissociation constants as well as the solvation parameters m* and f were calculated using the excess acidity method and the Bunnett–Olsen method. The pKBH+ values obtained with the HA function (defined by the average m* -values are in satisfactory agreement with those calculated with the previously mentioned methods. The pKBH+ values were correlated with structure using the Hammett (r = – 0.91 and Taft approach. It was found that the inductive effect is more relevant than the resonance one for both substituted benzamides (meta and para.

  9. Synthesis, crystal structure, and cytotoxic activity of novel cyclic systems in [1,2,4]thiadiazolo[2,3-a]pyridine benzamide derivatives and their copper(II) complexes.

    Science.gov (United States)

    Adhami, Forogh; Safavi, Maliheh; Ehsani, Maryam; Ardestani, Sussan K; Emmerling, Franziska; Simyari, Farzaneh

    2014-06-01

    Three N-(pyridine-2-ylcarbamothioyl)benzamide derivatives were synthesized by the reaction of potassium thiocyanate, benzoyl chloride, and 2-amino pyridine derivatives in one pot. The obtained derivatives were oxidized using copper(ii) chloride. During the oxidation, two hydrogen atoms were removed, cyclization of the derivatives occurred, and finally, three new N-(2H-[1,2,4]thiadiazolo[2,3-a]pyridine-2-ylidene)benzamide derivatives were produced. Coordination of these three new derivative ligands to the copper(II) ion resulted in the formation of three new complexes: dichlorobis(N-(2H-[1,2,4]thiadiazolo[2,3-a]pyridine-2-ylidene)benzamide)copper(II), dichlorobis(N-(7-methyl-2H-[1,2,4]thiadiazolo[2,3-a]pyridine-2ylidene)benzamide)copper(II), and dichlorobis(N-(5-methyl-2H-[1,2,4]thiadiazolo[2,3-a]pyridine-2-ylidene)benzamide)copper(II). All the synthesized products were characterized by IR, (1)H NMR, and (13)C NMR spectroscopies. Crystal structures of the obtained N-(pyridine-2-ylcarbamothioyl)benzamide derivatives, N-(2H-[1,2,4]thiadiazolo[2,3-a]pyridine-2-ylidene)benzamide derivatives, and complexes were determined using X-ray single-crystal diffraction; the positions of atoms, bond lengths, bond angles, and dihedral angles were also determined. In all complexes, the coordination of two large monodentate ligands and two chloride anions to the copper(ii) ion resulted in the formation of a stable planar geometry around the central ion. Three N-(pyridine-2-ylcarbamothioyl)benzamide derivatives, three N-(2H-[1,2,4]thiadiazolo[2,3-a]pyridine-2-ylidene)benzamide derivatives, and three complexes were evaluated for their cytotoxicity against five human cancer cell lines (breast cancer cell line MDA-MB-231, neuroblastoma cell line SK-N-MC, prostate adenocarcinoma cell line LNCap, nasopharyngeal epidermoid carcinoma cell line KB, and liver cancer cell line HEPG-2) using an in vitro analysis. The N-(pyridine-2-ylcarbamothioyl)benzamide derivatives showed no cytotoxic

  10. Synthesis, crystal structure, and cytotoxic activity of novel cyclic systems in [1,2,4]thiadiazolo[2,3-a]pyridine benzamide derivatives and their copper(II) complexes.

    Science.gov (United States)

    Adhami, Forogh; Safavi, Maliheh; Ehsani, Maryam; Ardestani, Sussan K; Emmerling, Franziska; Simyari, Farzaneh

    2014-06-01

    Three N-(pyridine-2-ylcarbamothioyl)benzamide derivatives were synthesized by the reaction of potassium thiocyanate, benzoyl chloride, and 2-amino pyridine derivatives in one pot. The obtained derivatives were oxidized using copper(ii) chloride. During the oxidation, two hydrogen atoms were removed, cyclization of the derivatives occurred, and finally, three new N-(2H-[1,2,4]thiadiazolo[2,3-a]pyridine-2-ylidene)benzamide derivatives were produced. Coordination of these three new derivative ligands to the copper(II) ion resulted in the formation of three new complexes: dichlorobis(N-(2H-[1,2,4]thiadiazolo[2,3-a]pyridine-2-ylidene)benzamide)copper(II), dichlorobis(N-(7-methyl-2H-[1,2,4]thiadiazolo[2,3-a]pyridine-2ylidene)benzamide)copper(II), and dichlorobis(N-(5-methyl-2H-[1,2,4]thiadiazolo[2,3-a]pyridine-2-ylidene)benzamide)copper(II). All the synthesized products were characterized by IR, (1)H NMR, and (13)C NMR spectroscopies. Crystal structures of the obtained N-(pyridine-2-ylcarbamothioyl)benzamide derivatives, N-(2H-[1,2,4]thiadiazolo[2,3-a]pyridine-2-ylidene)benzamide derivatives, and complexes were determined using X-ray single-crystal diffraction; the positions of atoms, bond lengths, bond angles, and dihedral angles were also determined. In all complexes, the coordination of two large monodentate ligands and two chloride anions to the copper(ii) ion resulted in the formation of a stable planar geometry around the central ion. Three N-(pyridine-2-ylcarbamothioyl)benzamide derivatives, three N-(2H-[1,2,4]thiadiazolo[2,3-a]pyridine-2-ylidene)benzamide derivatives, and three complexes were evaluated for their cytotoxicity against five human cancer cell lines (breast cancer cell line MDA-MB-231, neuroblastoma cell line SK-N-MC, prostate adenocarcinoma cell line LNCap, nasopharyngeal epidermoid carcinoma cell line KB, and liver cancer cell line HEPG-2) using an in vitro analysis. The N-(pyridine-2-ylcarbamothioyl)benzamide derivatives showed no cytotoxic

  11. Synthesis, in vitro binding and biodistribution in B16 melanoma-bearing mice of new iodine-125 spermidine benzamide derivatives

    Energy Technology Data Exchange (ETDEWEB)

    Moreau, Marie-France [INSERM UMR 484, BP 184, 63000 Clermont-Ferrand cedex (France); Univ d' Auvergne, F-63000 Clermont-Ferrand (France); Centre Jean Perrin, F-63000 Clermont-Ferrand (France); Papon, Janine [INSERM UMR 484, BP 184, 63000 Clermont-Ferrand cedex (France); Univ d' Auvergne, F-63000 Clermont-Ferrand (France); Centre Jean Perrin, F-63000 Clermont-Ferrand (France); Labarre, Pierre [INSERM UMR 484, BP 184, 63000 Clermont-Ferrand cedex (France); Univ d' Auvergne, F-63000 Clermont-Ferrand (France); Centre Jean Perrin, F-63000 Clermont-Ferrand (France); Moins, Nicole [INSERM UMR 484, BP 184, 63000 Clermont-Ferrand cedex (France); Univ d' Auvergne, F-63000 Clermont-Ferrand (France); Centre Jean Perrin, F-63000 Clermont-Ferrand (France)]. E-mail: moins@inserm484.u-clermont1.fr; Borel, Michele [INSERM UMR 484, BP 184, 63000 Clermont-Ferrand cedex (France); Univ d' Auvergne, F-63000 Clermont-Ferrand (France); Centre Jean Perrin, F-63000 Clermont-Ferrand (France); Bayle, Martine [INSERM UMR 484, BP 184, 63000 Clermont-Ferrand cedex (France); Univ d' Auvergne, F-63000 Clermont-Ferrand (France); Centre Jean Perrin, F-63000 Clermont-Ferrand (France); Bouchon, Bernadette [INSERM UMR 484, BP 184, 63000 Clermont-Ferrand cedex (France); Univ d' Auvergne, F-63000 Clermont-Ferrand (France); Centre Jean Perrin, F-63000 Clermont-Ferrand (France); Madelmont, Jean-Claude [INSERM UMR 484, BP 184, 63000 Clermont-Ferrand cedex (France); Univ d' Auvergne, F-63000 Clermont-Ferrand (France); Centre Jean Perrin, F-63000 Clermont-Ferrand (France)

    2005-05-01

    In the course of our investigations aimed at improving the biological characteristics of iodobenzamides for melanoma therapeutic applications, four new derivatives containing a spermidine chain have been prepared and radiolabeled with {sup 125}I. In vitro studies showed that all compounds displayed high affinity for melanin superior to the reference compound BZA, thus validating our experimental approach. In vivo biodistribution was investigated in B16 melanoma-bearing mice. All four compounds, particularly benzamide 3, showed accumulation in the tumor, but lower, however, than that of BZA. Moreover, high concentrations of radioactivity in other organs, namely, the liver and lung, demonstrated nonspecific tumoral uptake. In view of these results, compounds 1 2 3 4 do not appear to be suitable radiopharmaceuticals for melanoma radionuclide therapy.

  12. Species-specific pharmacology of Trichloro(sulfanylethyl benzamides as transient receptor potential ankyrin 1 (TRPA1 antagonists

    Directory of Open Access Journals (Sweden)

    Immke David C

    2007-12-01

    Full Text Available Abstract Agonists of TRPA1 such as mustard oil and its key component AITC cause pain and neurogenic inflammation in humans and pain behavior in rodents. TRPA1 is activated by numerous reactive compounds making it a sensor for reactive compounds in the body. Failure of AITC, formalin and other reactive compounds to trigger pain behavior in TRPA1 knockout mice, as well as the ability of TRPA1 antisense to alleviate cold hyperalgesia after spinal nerve ligation, suggest that TRPA1 is a potential target for novel analgesic agents. Here, we have characterized CHO cells expressing human and rat TRPA1 driven by an inducible promoter. As reported previously, both human and rat TRPA1 are activated by AITC and inhibited by ruthenium red. We have also characterized noxious cold response of these cell lines and show that noxious cold activates both human and rat TRPA1. Further, we have used CHO cells expressing human TRPA1 to screen a small molecule compound library and discovered that 'trichloro(sulfanylethyl benzamides' (AMG2504, AMG5445, AMG7160 and AMG9090 act as potent antagonists of human TRPA1 activated by AITC and noxious cold. However, trichloro(sulfanylethyl benzamides' (TCEB compounds displayed differential pharmacology at rat TRPA1. AMG2504 and AMG7160 marginally inhibited rat TRPA1 activation by AITC, whereas AMG5445 and AMG9090 acted as partial agonists. In summary, we conclude that both human and rat TRPA1 channels show similar AITC and noxious cold activation profiles, but TCEB compounds display species-specific differential pharmacology at TRPA1.

  13. In vitro cytotoxicity activity on several cancer cell lines of acridone alkaloids and N-phenylethyl-benzamide derivatives from Swinglea glutinosa (Bl.) Merr.

    Science.gov (United States)

    Braga, P A C; Dos Santos, D A P; Da Silva, M F D G F; Vieira, P C; Fernandes, J B; Houghton, P J; Fang, R

    2007-01-01

    The methanol extract from the stems and fruits of Swinglea glutinosa (Rutaceae) afforded 11 known acridone alkaloids and three N-phenylethyl-benzamide derivatives, glycocitrine-IV, 1,3,5-trihydroxy-4-methoxy-10-methyl-2,8-bis(3-methylbut-2-enyl)acridin-9(10H)-one, 1,3,5- trihydroxy-2,8-bis(3-methylbut-2-enyl)-10-methyl-9-acridone, citbrasine, citrusinine-II, citrusinine-I, 5-dihydroxyacronycine, pyranofoline, 3,4-dihydro-3,5,8-trihydroxy-6-methoxy-2,2,7-trimethyl-2H-pyrano[2,3-a]acridin-12(7H)-one, 2,3-dihydro-4,9-dihydroxy-2-(2-hydroxy-propan-2-yl)-11-methoxy-10-methylfuro[3,2-b]acridin-5(10H)-one, bis-5-hydroxyacronycine, N-(2-{4-[(3,7-dimethylocta-2,6-dien-1-yl)oxy]phenyl}ethyl)benzamide, N-(2-{4-[(3,7-dimethyl-4-acethyl-octa-2,6-dien-1-yl)oxy]phenyl}ethyl)benzamide, and severine acetate. All compounds isolated were examined for their activity against three cancer cell lines: human lung carcinoma (COR-L23), human breast adenocarcinoma (MCF7), human melanoma (C32), and normal human fetal lung cell line, MRC-5. The acridones tested exhibited weak cytotoxicity but the amides showed moderate nonselective cytotoxic activity. PMID:17365689

  14. Super acid catalysed sequential hydrolysis/cycloisomerization of -(acetylenic)benzamides under microwave condition: Synthesis, antinociceptive and antiinflammatory activity of substituted isocoumarins

    Indian Academy of Sciences (India)

    Chandrasekaran Praveen; P Dheenkumar; P T Perumal

    2013-01-01

    Synthesis of isocoumarins and related compounds via triflic acid promoted hydrolysis/cyclization sequence of 2-(alkynyl)benzamides under microwave condition was achieved. The substrate scope of the reaction was broad to include not only aromatic but also polyaromatic and heteroaromatic motifs, thus highlighting the significance of this methodology. One-pot operation, short reaction time, good chemical yields and excellent regioselectivity are the advantages of this protocol. All the synthesized compounds were evaluated for their antinociceptive and antiinflammatory activities using in vivo rodent models.

  15. The combination of benzamides/NCS as nitrogen/halogen sources for aminohalogenation of β-nitrostyrenes resulting in dichlorinated haloamides

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    The combination of benzamide and NCS was found to be an efficient nitrogen/halogen source for aminohalogenation of β-nitrostyrenes.The reaction was convenient to carry out by using 4-dimethylaminopyridine as the catalyst,resulting in vicinal dichlorinated haloamino nitroalkanes with opposite regiochemistry to that generated from other electron-deficient olefins observed previously.The reaction proceeded smoothly at room temperature with good yields and excellent regioselectivities.A mechanism involving a chloronium intermediate was proposed to explain the resulting regiochemistry.The current system explored a new type of nitrogen sources for aminohalogenation of functionalized olefins.

  16. Radiolabelling of 4-iodo-N-(2-morpholinoethyl)benzamide with Na{sup 123}I and Na{sup 125}I

    Energy Technology Data Exchange (ETDEWEB)

    Tsopelas, C

    1999-07-01

    4-Iodo-N-(2-morpholinoethyl)benzamide (1) is a new benzamide that is an analogue of the antidepressant moclobemide. The synthesis of (1) is described and the radiolabelling conditions with Na{sup 123}I and Na{sup 125}I were optimized using the Cu(I)-added exchange labelling reaction. The reaction was found to perform best in the presence of Cu{sup +} and a stannous reducing agent, in the absence of Cu{sup 2+} and potassium iodide, and at [H{sup +}] = 1.8-7.9 mM with a ligand (1) concentration = 2.6-5.6 mg/mL cold kit. Above a [H{sup +}] of 7.9 mM, the hydrolysis of (1) gave 4-iodo[{sup 125}I]benzoic acid in high amounts. The radiochemical conversion was routinely >95% and >98% after anion exchange Sep-Pak treatment. The radiolabelled product is stable at room temperature for at least 4 h.

  17. In Vitro Bactericidal Activity of 4- and 5-Chloro-2-hydroxy-N-[1-oxo-1-(phenylaminoalkan-2-yl]benzamides against MRSA

    Directory of Open Access Journals (Sweden)

    Iveta Zadrazilova

    2015-01-01

    Full Text Available A series of nine substituted 2-hydroxy-N-[1-oxo-1-(phenylaminoalkan-2-yl]benzamides was assessed as prospective bactericidal agents against three clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA and S. aureus ATCC 29213 as the reference and quality control strain. The minimum bactericidal concentration was determined by subculturing aliquots from MIC determination onto substance-free agar plates. The bactericidal kinetics of compounds 5-chloro-2-hydroxy-N-[(2S-3-methyl-1-oxo-1-{[4-(trifluoromethylphenyl]amino}butan-2-yl]benzamide (1f, N-{(2S-1-[(4-bromophenylamino]-3-methyl-1-oxobutan-2-yl}-4-chloro-2-hydroxybenzamide (1g, and 4-chloro-N-{(2S-1-[(3,4-dichlorophenylamino]-3-methyl-1-oxobutan-2-yl}-2-hydroxybenzamide (1h was established by time-kill assay with a final concentration of the compound equal to 1x, 2x, and 4x MIC; aliquots were removed at 0, 4, 6, 8, and 24 h time points. The most potent bactericidal agent was compound 1f exhibiting remarkable rapid concentration-dependent bactericidal effect even at 2x MIC at 4, 6, and 8 h (with a reduction in bacterial count ranging from 3.08 to 3.75 log10 CFU/mL and at 4x MIC at 4, 6, 8, and 24 h (5.30 log10 CFU/mL reduction in bacterial count after incubation against MRSA 63718. Reliable bactericidal effect against other strains was maintained at 4x MIC at 24 h.

  18. Synthesis, radiosynthesis, and in vitro evaluation of [131I]-5-iodo-N-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline-2-yl)-ethyl] -2-methoxy-benzamide as a potential tumor imaging agent

    International Nuclear Information System (INIS)

    This work reports the synthesis, radiolabeling and preliminary in vitro evaluation of [131I]-5-iodo-N-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline-2-yl)-ethyl] -2-methoxy-benzamide. The tributylstannylprecursor was synthesized with a yield of 38%. Radiolabeling was performed using an electrophilic iododestannylation. Tracer yield was 94%, radiochemical purity was >95%. The tracer showed high uptake in MCF-7 breast cancer cell line and therefore will be evaluated further

  19. Optimized Anti-pathogenic Agents Based on Core/Shell Nanostructures and 2-((4-Ethylphenoxyethyl-N-(substituted-phenylcarbamothioyl-benzamides

    Directory of Open Access Journals (Sweden)

    Mariana Carmen Chifiriuc

    2012-10-01

    Full Text Available The purpose of this study was to design a new nanosystem for catheter surface functionalization with an improved resistance to Staphylococcus aureus ATCC 25923 and Pseudomonas aeruginosa ATCC 27853 colonization and subsequent biofilm development. New 2-((4 ethylphenoxymethyl-N-(substituted-phenylcarbamothioyl-benzamides were synthesized and used for coating a core/shell nanostructure. Their chemical structures were elucidated by NMR, IR and elemental analysis, being in agreement with the proposed ones. Fe3O4/C12 of up to 5 nm size had been synthesized with lauric acid as a coating agent and characterized by XRD, FT-IR, TGA, TEM and biological assays. The catheter pieces were coated with the fabricated nanofluid in magnetic field. The microbial adherence ability was investigated in 6 multiwell plates by using culture based methods and Scanning Electron Microscopy (SEM. The nanoparticles coated with the obtained compounds 1a–c inhibited the adherence and biofilm development ability of the S. aureus and P. aeruginosa tested strains on the catheter functionalized surface, as shown by the reduction of viable cell counts and SEM examination of the biofilm architecture. Using the novel core/shell/adsorption-shell to inhibit the microbial adherence could be of a great interest for the biomedical field, opening new directions for the design of film-coated surfaces with improved anti-biofilm properties.

  20. Synthesis, Crystal Structure and Biological Activity of 2-Chloro-N-{2-fluoro-5-[N-(phenylsulfonyl) phenyl- sulfonamido] phenyl} benzamide

    Institute of Scientific and Technical Information of China (English)

    LI Wen-ming; WANG Jian-guo; LI Zheng-ming; SONG Hai-bin

    2008-01-01

    2-Chloro-N-{2-fluoro-5-[N-(phenylsulfonyl)phenylsulfonamido]phenyl}benzamide was synthesized and its crystal structure was also determined by X-ray single-crystal diffraction. The title compound(C25H18C1FN2O5S2) belongs to monoclinic, space group P21/n with a=0.7377(3) nm, b=1.2036(5) nm, c=2.6846(11) nm, β=90.895(9)°,V=2.3833(16) nm3, Mr=544.98, Z=4, Dc= 1.519 g/cm3, μ=0.385 mm-1, F(000)=1120, R1=0.0632, and wR2=0. 1438. Its crystal structure belongs to a novel class that has not been reported yet, and its preliminary herbicidal activity was also tested. Its inhibition rate to seedling growth of barnyard grass reaches 15.1% at 100 μg/mL.

  1. Tumor Response and Apoptosis of N1-S1 Rodent Hepatomas in Response to Intra-arterial and Intravenous Benzamide Riboside

    International Nuclear Information System (INIS)

    Purpose: Benzamide riboside (BR) induces tumor apoptosis in multiple cell lines and animals. This pilot study compares apoptosis and tumor response in rat hepatomas treated with hepatic arterial BR (IA) or intravenous (IV) BR. Methods: A total of 106 N1-S1 cells were placed in the left hepatic lobes of 15 Sprague-Dawley rats. After 2 weeks, BR (20 mg/kg) was infused IA (n = 5) or IV (n = 5). One animal in each group was excluded for technical factors, which prevented a full dose administration (1 IA and 1 IV). Five rats received saline (3 IA and 2 IV). Animals were killed after 3 weeks. Tumor volumes after IA and IV treatments were analyzed by Wilcoxon rank sum test. The percentage of tumor and normal liver apoptosis was counted by using 10 fields of TUNEL (terminal deoxynucleotidyl transferase dUTP nick-end labeling)-stained slides at 40× magnification. The percentage of apoptosis was compared between IV and IA administrations and with saline sham-treated rats by the Wilcoxon rank sum test. Results: Tumors were smaller after IA treatment, but this did not reach statistical significance (0.14 IA vs. 0.57 IV; P = 0.138). There was much variability in percentage of apoptosis and no significant difference between IA and IV BR (44.49 vs. 1.52%; P = 0.18); IA BR and saline (44.49 vs. 33.83%; P = 0.66); or IV BR and saline (1.52 vs. 193%; P = 0.18). Conclusions: Although differences in tumor volumes did not reach statistical significance, there was a trend toward smaller tumors after IA BR than IV BR in this small pilot study. Comparisons of these treatment methods will require a larger sample size and repeat experimentation.

  2. Efficacy of the repellent N,N-diethyl-3-methyl-benzamide (DEET) against tabanid flies on horses evaluated in a field test in Switzerland.

    Science.gov (United States)

    Herholz, C; Kopp, C; Wenger, M; Mathis, A; Wägeli, S; Roth, N

    2016-05-15

    Female tabanid flies (Diptera: Tabanidae) can be a serious nuisance for horses because of their painful bites during blood feeding. They also play a primary role in mechanical transmission of a lentivirus causing Equine Infectious Anemia (EIA), a virus that has spread within Europe in recent years. According to the European law for products intended for use as a repellent on horses (recreational and sport horses), a field test is mandatory to demonstrate sufficient repellency of such a substance against the specific target fly species, but currently no agreed protocols are available for testing of potential repellents. The aim of the present study was to establish a protocol for a field test to investigate the efficacy of N,N-diethyl-3-methyl-benzamide (DEET, Brum®, Huebeli-Stud Horse Care AG) in a 15-17% oil-water emulsion against tabanid flies on horses up to four hours. Between July and August 2015, four horses on three farms each were tested on two consecutive days in a cross-over design. The four horses on Farm A were used in the pre-test as well as in the main test. Two and a half hours after repellent application the horses were lunged until sweating. Tabanid fly infestations were both photographed and directly counted during five minutes 3 and 4h after repellent application on the right side of the horses in the area from the head to the flank, belly and first third of the foreleg. Without repellent application, up to 29 tabanid flies were counted on a horse, whereas the maximum for the repellent treated horses was four. In 50% of the horses treated with DEET there were no Tabanids observed (efficacy 100%), and in all horses the tabanid fly counts were lower than in the control horses with one exemption at 4h. The efficacy of the DEET repellent was at least 80% and 71% respectively, three or four hours after application (with a confidence level of 89%). A fly trap (Horse Pal) revealed the presence of the tabanid species Tabanus brominus and Haematopota

  3. In vitro evaluation of anti-pathogenic surface coating nanofluid, obtained by combining Fe3O4/C12 nanostructures and 2-((4-ethylphenoxy)methyl)- N-(substituted-phenylcarbamothioyl)-benzamides

    Science.gov (United States)

    Anghel, Ion; Limban, Carmen; Grumezescu, Alexandru Mihai; Anghel, Alina Georgiana; Bleotu, Coralia; Chifiriuc, Mariana Carmen

    2012-09-01

    In this paper, we report the design of a new nanofluid for anti-pathogenic surface coating. For this purpose, new 2-((4-ethylphenoxy)methyl)- N-(substituted-phenylcarbamothioyl)-benzamides were synthesized and used as an adsorption shell for Fe3O4/C12 core/shell nanosized material. The functionalized specimens were tested by in vitro assays for their anti-biofilm properties and biocompatibility. The optimized catheter sections showed an improved resistance to Staphylococcus aureus ATCC 25923 and Pseudomonas aeruginosa ATCC 27853 in vitro biofilm development, as demonstrated by the viable cell counts of biofilm-embedded bacterial cells and by scanning electron microscopy examination of the colonized surfaces. The nanofluid proved to be not cytotoxic and did not influence the eukaryotic cell cycle. These results could be of a great interest for the biomedical field, opening new directions for the design of film-coated surfaces with improved anti-biofilm properties.

  4. Crystal structures of two 18-crown-6 complexes: With the sodium salt of N-(Diiso-propoxyphosphoryl)benzamide and with the potassium salt of N-(Di-iso-propoxyphosphoryl)thiobenzamide

    International Nuclear Information System (INIS)

    Approximately isomorphous crystal structures of two 18-crown-6 complexes were determined: with the sodium salt of N-(diiso-propoxyphosphoryl)benzamide (I) and with the potassium salt of N-(di-iso-propoxyphosphoryl)thiobenzamide (II). Both I and II are (1:1:1) guest-host complexes containing two different hosts (the crown ether and a bidentate organophosphorus anion) and their common guest (an Na+ or K+ cation). Despite a certain similarity between complexes I and II, significant structural distinctions between them resulting from the difference in the ionic radii of Na+ and K+ cations were revealed. In complex I, the Na+ cation is hexacoordinated, and in complex II, the K+ cation is octacoordinated. In I, the crown ether has an asymmetric monoangular conformation, whereas in II, its conformation approximates that described by the D3d symmetry

  5. Discovery of 4-(4-aminopyrazolo[1,5-a][1,3,5]triazin-8-yl)benzamides as novel, highly potent and selective, orally bioavailable inhibitors of Tyrosine Threonine Kinase, TTK.

    Science.gov (United States)

    Laufer, Radoslaw; Li, Sze-Wan; Liu, Yong; Ng, Grace; Lang, Yunhui; Feher, Miklos; Brokx, Richard; Beletskaya, Irina; Hodgson, Richard; Mao, Guodong; Plotnikova, Olga; Awrey, Donald E; Mason, Jacqueline M; Wei, Xin; Lin, Dan Chi-Chia; Che, Yi; Kiarash, Reza; Madeira, Brian; Fletcher, Graham C; Mak, Tak W; Bray, Mark R; Pauls, Henry W

    2016-08-01

    TTK/Mps1 is a key kinase controlling progression of cell division via participation in the mitotic spindle assembly checkpoint and is overexpressed in a number of human cancers. Herein we report the discovery of 4-(4-aminopyrazolo[1,5-a][1,3,5]triazin-8-yl)benzamides as a potent, novel class of TTK inhibitors. The series was identified by means of bioisosteric replacement of the related imidazopyrazine and imidazopyridazine scaffolds. Optimization led to the identification of compounds with excellent potency (Ki=0.8nM) and exceptional kinase selectivity. The SAR indicates a strong dependence of activity on the presence of the N-cyclopropyl-2-methylbenzamide moiety delineating the geometry for 1½ type kinase inhibitor. Molecular modeling indicates the extensive and optimal contacts, mediated through H-bonds and hydrophobic interactions, are responsible for the selectivity and potency of the inhibitors. The compounds demonstrate a strong anti-proliferative activity in a panel of human cancer cell lines (HCT116 GI50<15nM) and good rodent pharmacokinetics (oral %F 97%). PMID:27335255

  6. Structural Basis for Small Molecule NDB (N-Benzyl-N-(3-(tert-butyl)-4-hydroxyphenyl)-2,6-dichloro-4-(dimethylamino) Benzamide) as a Selective Antagonist of Farnesoid X Receptor α (FXRα) in Stabilizing the Homodimerization of the Receptor.

    Science.gov (United States)

    Xu, Xing; Xu, Xin; Liu, Peng; Zhu, Zhi-yuan; Chen, Jing; Fu, Hai-an; Chen, Li-li; Hu, Li-hong; Shen, Xu

    2015-08-01

    Farnesoid X receptor α (FXRα) as a bile acid sensor plays potent roles in multiple metabolic processes, and its antagonist has recently revealed special interests in the treatment of metabolic disorders, although the underlying mechanisms still remain unclear. Here, we identified that the small molecule N-benzyl-N-(3-(tert-butyl)-4-hydroxyphenyl)-2,6-dichloro-4-(dimethylamino) benzamide (NDB) functioned as a selective antagonist of human FXRα (hFXRα), and the crystal structure of hFXRα ligand binding domain (hFXRα-LBD) in complex with NDB was analyzed. It was unexpectedly discovered that NDB induced rearrangements of helix 11 (H11) and helix 12 (H12, AF-2) by forming a homodimer of hFXRα-LBD, totally different from the active conformation in monomer state, and the binding details were further supported by the mutation analysis. Moreover, functional studies demonstrated that NDB effectively antagonized the GW4064-stimulated FXR/RXR interaction and FXRα target gene expression in primary mouse hepatocytes, including the small heterodimer partner (SHP) and bile-salt export pump (BSEP); meanwhile, administration of NDB to db/db mice efficiently decreased the gene expressions of phosphoenolpyruvate carboxykinase (PEPCK), glucose 6-phosphatase (G6-pase), small heterodimer partner, and BSEP. It is expected that our first analyzed crystal structure of hFXRα-LBD·NDB will help expound the antagonistic mechanism of the receptor, and NDB may find its potential as a lead compound in anti-diabetes research. PMID:26100621

  7. 2-(Prop-2-enyloxy)benzamide

    Science.gov (United States)

    Bugenhagen, Bernhard; Al Jasem, Yosef; Barkhad, Farah; Hindawi, Bassam al; Thiemann, Thies

    2012-01-01

    In the title mol­ecule, C10H11NO2, the benzene ring forms dihedral angles of 33.15 (2) and 6.20 (2)° with the mean planes of the amide and propen­oxy groups, respectively. The amide –NH2 group is oriented toward the propen­oxy substituent and forms a weak intra­molecular N—H⋯O hydrogen bond to the propen­oxy O atom. The conformation of the propen­oxy group at the Csp 2—Csp 3 and Csp 3—O bonds is synperiplanar and anti­periplanar, respectively. In the crystal, N—H⋯O hydrogen bonds involving the amide groups generate C(4) and R 2 3(7) motifs that organize the mol­ecules into tapes along the a-axis direction. There are C—H⋯π inter­actions between the propen­oxy –CH2 group and the aromatic system of neighboring mol­ecules within the tape. The mean planes of the aromatic ring and the propen­oxy group belonging to mol­ecules located on opposite sites of the tape form an angle of 83.16 (2)°. PMID:23284483

  8. 2-(Prop-2-enyloxy)benzamide

    OpenAIRE

    Bugenhagen, Bernhard; Al Jasem, Yosef; Barkhad, Farah; Hindawi, Bassam al; Thiemann, Thies

    2012-01-01

    In the title mol­ecule, C10H11NO2, the benzene ring forms dihedral angles of 33.15 (2) and 6.20 (2)° with the mean planes of the amide and propen­oxy groups, respectively. The amide –NH2 group is oriented toward the propen­oxy substituent and forms a weak intra­molecular N—H⋯O hydrogen bond to the propen­oxy O atom. The conformation of the propen­oxy group at the Csp 2—Csp 3 and Csp 3—O bonds is synperiplanar and anti­periplanar, respectively. In the crystal, N—H⋯O hydrogen bonds involving th...

  9. Studies on coordination and addition compounds and anti microbial activity of some mixed ligand complexes of Au(III), Mo(II), Co(II) and Cd(II) with dibasic acid and heterocyclic amines and addition compounds of As(III) and Sb(III) halides with benzamide and acetophenon

    International Nuclear Information System (INIS)

    Three new mixed ligand complexes of Au(III) and Mo(II) with dibasic acid e.g., homophthalic acid, oxalic acid and heterocylic amines e.g., quinonine, iso-quinonine, bipyridine, Phenylanaline and the two new addition compounds of As(III) and Sb(III) halides with N-donor ligands viz. benzamide and acetophenone and one complex [Cd(DPH)(IQ)2], where IQ = Iso-quinoline and DPH = Deprotonated phthalic acid have been prepared according to the procedure in the literature. Their conventional physical and chemical analyses have been done. Their antibacterial studies against nine gram positive and five gram negative pathogenic bacteria and antifungal activities against eight plant and three human fungi have been evaluated. Kanamycin and Nystatin have been used as a standard for carrying out experiments of antibacterial and antifungal activities, respectively. The minimum inhibitory concentration (MIC) values of these compounds, as antibiotic against two gram positive and two gram negative pathogenic bacteria, have also been carried out and in this case, Amoxacilin antibiotic has been used as a standard antibiotic. (author)

  10. 对硝基苯甲醛缩对氨基乙酰苯胺希夫碱的室温固相合成及其可逆热致变色研究%Research on Solid State Synthesis and Reversible Thermochromic Behavior of N-methyl-4-(4-nitrobenzylidene amino)Benzamide Schiff Base

    Institute of Scientific and Technical Information of China (English)

    梁小蕊; 张勇; 王磊; 韩红宾; 杨秉东

    2011-01-01

    A Schiff base N-methyl-4-(4-nitrobenzylidene amino)benzamide were prepared by solid state reaction of 4-ni-trobenzaldehyde with 4-amino-N-methylbenzamide at room temperature. Element analysis and H1NMR confirmed the structure of the product and the color change process were studied by DSC spectra. The results indicated that the structure of the synthesized compound were consistent with that of the target product, the productive rate were higher, the melting ranges were narrower, the purity higher, and the reaction effect desirable. As a thermochromatic material the title compound has the advantages such as sharp swift color change speed, obvious color contrast, good reversibility and high color change temperature. In conclusion, the materials have good applied future.%以对硝基苯甲醛和对氨基乙酰苯胺为原料,通过室温固相反应合成了一种希夫碱衍生物,用元素分析、核磁共振等方法对产物进行了表征,并利用DSC技术对其变色过程进行了研究.结果表明,采用室温固相反应的方法合成的化合物结构和目标产物一致,且产率较高,熔程较短,纯度较高,反应效果理想.标题化合物作为热致变色材料具有变色敏锐、颜色对比明显、可逆性好以及变色温度高等特点,是一种具有良好应用前景的可逆热致变色材料.

  11. Synthesis of novel flavone derivatives possessing substituted benzamides and their biological evaluation against human cancer cells.

    Science.gov (United States)

    Yun, Bo Hee; Lee, Young Hun; Park, Kyung Tae; Jung, Su Jin; Lee, Yong Sup

    2016-09-01

    Baicalein is a well-known flavone derivative that possesses diverse biological properties, such as anticancer, antioxidant and anti-inflammatory activities. Numerous baicalein derivatives, including 5,6,7-trimethoxyflavone, have been synthesized with the aim of enhancing its inherent biological activities. In the present work, new flavones, possessing an N-aroylamine-substituent on the B-ring, were synthesized to improve the cytotoxicity of baicalein and 5,6,7-trimethoxyflavone against human cancer cell lines. The majority of the flavones synthesized exhibited greater cytotoxicity than baicalein and 5,6,7-trimethoxyflavone against HepG2 and MCF-7 cells. Among them, compounds 5n, possessing a 3-methoxybenzoylamino group, exhibited great cytotoxic effects on HepG2 (GI50=7.06μM) and MCF-7 (GI50=7.67μM) cells. In contrast, N-aroylamine-substituted 5-hydroxy-6,7-dimethoxyflavone derivatives showed greater cytotoxicity against MCF-7 than HepG2 cells, indicating that the replacement of a 5-methoxy group on the A-ring with a 5-hydroxy group has a marked influence on the cytotoxicity profile. PMID:27503682

  12. Synthesis and Crystal Structure of 3,5-Dichloro-N-(2-methoxyphenyl)benzamide

    Institute of Scientific and Technical Information of China (English)

    Aamer Saeed; Ulrich Fl(o)rke

    2013-01-01

    The title compound was synthesized by the direct reaction of 3,5-dichlorobenzoic acid with 2-methoxyaniline in the presence of DCC and HOBT.The structure was supported by the spectroscopic data and unambiguously confirmed by the single-crystal X-ray diffraction studies.It crystallizes from a methanol solution in the monoclinic space group P21/c with unit cell dimensions of a =4.9369(16),b =13.351(5),c =20.168(7) (A),β=96.755(8)°,V=1320.1(8) (A)3 and Z=4.

  13. First-pass cerebral extraction of benzamide-derivative radiotracers for SPECT

    International Nuclear Information System (INIS)

    Central dopaminergic receptors are widely studied for their importance in the pathophysiology of neurological and psychiatric diseases. We have investigated the cerebral delivery kinetics of three dopaminergic ligands in rats through the use of an indicator fractionation method to measure the tracer's regional influx rate constant with respect to regional blood flow. The aim is to collect the in vivo kinetic parameters of the radioligand cerebral distribution, which are necessary if, dealing with SPECT and 'trapped' tracers, one wishes to analyse data using a graphical approach

  14. Crystal structure of 4-methoxy-N-[(pyrrolidin-1-ylcarbothioyl]benzamide

    Directory of Open Access Journals (Sweden)

    Khairi Suhud

    2015-04-01

    Full Text Available In the title compound, C13H16N2O2S, the pyrrolidine ring has a twisted conformation on the central –CH2–CH2– bond. Its mean plane is inclined to the 4-methoxybenzoyl ring by 72.79 (15°. In the crystal, molecules are linked by N—H...O and C—H...O hydrogen bonds to the same O-atom acceptor, forming chains along [001]. The chains are linked via slipped parallel π–π interactions [inter-centroid distance = 3.7578 (13 Å], forming undulating slabs parallel to (100.

  15. 4-Chloro-N-(2,3-dimethyl­phen­yl)benzamide

    OpenAIRE

    Rodrigues, Vinola Z.; Kameníček,, Jiří; Gowda, B. Thimme; Kožíšek, Jozef

    2011-01-01

    In the title compound, C15H14ClNO, the ortho- and meta-methyl substituents in the aniline ring are anti to the N—H bond. The dihedral angle between the benzoyl and aniline benzene rings is 95.0 (1)°. N—H⋯O hydrogen bonds and C—H⋯π inter­actions link the mol­ecules in the crystal structure.

  16. Benzamide capped peptidomimetics as non-ATP competitive inhibitors of CDK2 using the REPLACE strategy.

    Science.gov (United States)

    Premnath, Padmavathy Nandha; Craig, Sandra N; Liu, Shu; McInnes, Campbell

    2016-08-01

    Inhibition of cyclin dependent kinase 2 (CDK2) in complex with cyclin A in G1/S phase of the cell cycle has been shown to promote selective apoptosis of cancer cells through the E2F1 pathway. An alternative approach to catalytic inhibition is to target the substrate recruitment site also known as the cyclin binding groove (CBG) to generate selective non-ATP competitive inhibitors. The REPLACE strategy has been applied to identify fragment alternatives and substituted benzoic acid derivatives were evaluated as a promising scaffold to present appropriate functionality to mimic key peptide determinants. Fragment Ligated Inhibitory Peptides (FLIPs) are described which potently inhibit both CDK2/cyclin A and CDK4/cyclin D1 and have preliminary anti-tumor activity. A structural rationale for binding was obtained through molecular modeling further demonstrating their potential for further development as next generation non ATP competitive CDK inhibitors.

  17. Benzamide capped peptidomimetics as non-ATP competitive inhibitors of CDK2 using the REPLACE strategy.

    Science.gov (United States)

    Premnath, Padmavathy Nandha; Craig, Sandra N; Liu, Shu; McInnes, Campbell

    2016-08-01

    Inhibition of cyclin dependent kinase 2 (CDK2) in complex with cyclin A in G1/S phase of the cell cycle has been shown to promote selective apoptosis of cancer cells through the E2F1 pathway. An alternative approach to catalytic inhibition is to target the substrate recruitment site also known as the cyclin binding groove (CBG) to generate selective non-ATP competitive inhibitors. The REPLACE strategy has been applied to identify fragment alternatives and substituted benzoic acid derivatives were evaluated as a promising scaffold to present appropriate functionality to mimic key peptide determinants. Fragment Ligated Inhibitory Peptides (FLIPs) are described which potently inhibit both CDK2/cyclin A and CDK4/cyclin D1 and have preliminary anti-tumor activity. A structural rationale for binding was obtained through molecular modeling further demonstrating their potential for further development as next generation non ATP competitive CDK inhibitors. PMID:27297568

  18. Nicotinamide and other benzamide analogs as agents for overcoming hypoxic cell radiation resistance in tumours

    International Nuclear Information System (INIS)

    Oxygen deficient hypoxic cells, which are resistant to sparsely ionising radiation, have now been identified in most animal and some human solid tumours and will influence the response of those tumours to radiation treatment. This hypoxia can be either chronic, arising from an oxygen diffusion limitation, or acute, resulting from transient stoppages in microregional blood flow. Extensive experimental studies, especially in the last decade, have shown that nicotinamide and structurally related analogs can effectively sensitize murine tumours to both single and fractionated radiation treatments and that they do so in preference to the effects seen in mouse normal tissues. The earliest studies suggested that this enhancement of radiation damage was the result of an inhibition of the repair mechanisms. However, recent studies in mouse tumours have shown that these drugs prevent transient cessations in blood flow, thus inhibiting the development of acute hypoxia. This novel discovery led to the suggestion that the potential role of these agents as radiosensitizers would be when combined with treatments that overcame chronic hypoxia. The combined nicotinamide with hyperthermia proved that the enhancement of radiation damage by both agents together was greater than that seen with each agent alone. Similar results were later seen for nicotinamide combined with a perfluorochemical emulsion, carbogen breathing, and pentoxifylline, and in all these studies the effects in tumours were always greater than those seen in appropriate normal tissues. Of all the analogs, it is nicotinamide itself which has been the most extensively studied as a radiosensitizer in vivo and the one that shows the greatest effect in animal tumours. It is also an agent that has been well established clinically, with daily doses of up to 6 g, associated with a low incidence of side effects. This human dose is equivalent to 100-200 mg/kg in mice and such doses will maximally sensitize murine tumours to radiation. These findings have now resulted in clinical trials of nicotinamide, in combination with carbogen breathing, as a potential radiosensitizing treatment. (EG)

  19. Conformational and Chiral Properties of Cyclic-tri(N-methyl-meta-benzamide) Bearing Amidino Groups.

    Science.gov (United States)

    Nishiyama, Shizuka; Urushibara, Ko; Masu, Hyuma; Azumaya, Isao; Kagechika, Hiroyuki; Tanatani, Aya

    2015-08-01

    Cyclic triamides bearing amidino groups at the meta position of the phenyl rings were synthesized, and their conformational properties in the crystal and in solution were examined. Compound exists as a capsule-type dimer of the enantiomers with a bowl-shaped syn conformation in the crystal state. Compound exists mainly in the syn form in solution, and chiral induction was observed upon addition of a chiral acid to a solution of.

  20. The family of N9-adenine: New entry for adenine-benzamide conjugates linked via versatile spacers

    Indian Academy of Sciences (India)

    Prabhpreet Singh

    2014-01-01

    We have prepared 4-nitrobenzamide-adenine conjugates (8, 13 and 14) linked with versatile spacer such as triethylene glycol (TEG), aminocaproic acid and ethyl chains which were eventually reduced to obtain the corresponding 4-aminobenzamide-adenine conjugates (1-3) in good yields. These conjugates bear a nucleobase for DNA recognition or self-assembly through base-pair complementarity, a biocompatible linker for interfacing with biological system, and a p-aminobenzamide moiety for pharmacological applications. The use of hydrophilic or lipophilic linkers may tune the dispersibility of these conjugates in different solvents, as well as impart different properties. In the preliminary experiments the versatility and application of these linkers has been tested for functionalization of SWCNTs.

  1. Design, Synthesis and Biological Activity of Substituted-N-[4- (substituted-phenylsulfamoyl)phenyl]benzamide as Potential AHAS Inhibitors

    Institute of Scientific and Technical Information of China (English)

    Jian Guo WANG; Yong Jun XIAO; Yong Hong LI; Xing Hai LIU; Zheng Ming LI

    2006-01-01

    Based on the crystal structure of AHAS/sulfonylurea complex, we obtained 296compounds with low binding energy towards AHAS via virtual screening. One series of them have been synthesized. Preliminary bioassay indicated that some compounds displayed good herbicidal activity on rape and barnygrass and inhibited AHAS to some extent. This study indicated the rationality of our molecular design based on the crystal structure of target enzyme.

  2. Conformational arm-wrestling: battles for stereochemical control in benzamides bearing matched and mismatched chiral 2- and 6-substituents.

    Science.gov (United States)

    Clayden, Jonathan; Foricher, Yann J Y; Helliwell, Madeleine; Johnson, Paul; Mitjans, David; Vinader, Victoria

    2006-02-01

    The orientation of a tertiary amide group adjacent to an aromatic ring may be governed by the stereochemistry of an adjacent chiral substituent. With a chiral substituent in both ortho positions, matched/mismatched pairs of isomers result. Evidence for matched stereochemistry is provided by the clean NMR spectra of single conformers, while mismatching gives poor or unexpected selectivities in the formation of chiral substituents, or mixtures of amide conformers. Attempts to use the match-mismatch effect to select for racemic pairs of enantiomeric substituents, and hence develop a "racemate-sequestering" reagent, are described, along with the use of "matching" to scavenge a single enantiomer of a diamine from material of incomplete enantiomeric purity. PMID:16446801

  3. Shelf-life of ɛ-lysyl-3-(trimethylstannyl)benzamide immunoconjugates, precursors for 211At labeling of antibodies

    DEFF Research Database (Denmark)

    Aneheim, Emma; Halleröd, Jenny; Albertsson, Per;

    2015-01-01

    Astatine-211 is possibly the most promising radionuclide for targeted α-particle therapy when it comes to the treatment of occult disseminated cancer. Preclinical research has proven effective, and patient studies have been initiated based on these results. However, a lack of production capacity...

  4. 4-N-pyridin-2-yl-benzamide nanotubes compatible with mouse stem cell and oral delivery in Drosophila

    Energy Technology Data Exchange (ETDEWEB)

    Yadav, Jhillu S; Das, Pragna P; Bag, Indira; Krishnan, Anita; Jagannadh, Bulusu; Mohapatra, Debendra K; Bhadra, Manika Pal [Division of Organic Chemistry-I, Indian Institute of Chemical Technology, Uppal Road, Hyderabad 500007 (India); Lavanya, Madugula P; Bhadra, Utpal [Functional Genomics and Gene Silencing Group, Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad 500007 (India)

    2010-04-16

    p-aminobenzoic acid (PABA), a structural moiety of many commercial drugs, is self-assembled with linker alkyl side chains to form tubular nanostructures. The tubes exhibited fluorescence either intrinsic or from fluorescent molecules embedded in the wall during self-assembly. Uptake and inter-cellular delivery of the conjugated nanotubes in human cancer cells and in mouse embryonic stem cells were demonstrated by fluorescence imaging and flow cytometry. Biocompatibility, cytotoxicity and clearance were monitored both ex vivo in mouse multipotent embryonic stem cells and in vivo in adult Drosophila. Accumulation of nanotubes had no adverse effects and abnormalities on stem cell morphology and proliferation rate. A distinct distribution of two separate nanotubes in various internal organs of Drosophila interprets that accumulation of nanomaterials might be interdependent on the side chain modifications and physiological settings of cell or tissue types. Unlike carbon nanomaterials, exposure of PABA nanotubes does not produce any hazards including locomotion defects and mortality of adult flies. Despite differential uptake and clearance from multiple live tissues, the use of self-assembled nanotubes can add new dimensions and scope to the development of dual-purpose oral carriers for the fulfilment of many biological promises.

  5. 4-Meth-oxy-N-[(4-methyl-phen-yl)sulfon-yl]benzamide including an unknown solvate.

    Science.gov (United States)

    Sreenivasa, Swamy; Palakshamurthy, Bandrehalli Siddagangaiah; Tonannavar, Jagdish; Jayashree, Yenagi; Sudha, Achar Gurumurthy; Suchetan, Parameshwar Adimoole

    2013-10-19

    In the title compound, C15H15NO4S, the dihedral angle between the benzene rings is 78.62 (16)°. In the crystal, adjacent mol-ecules are linked along the c axis into C(4) chains through strong N-H⋯O hydrogen bonds. Mol-ecules are further connected through C-H⋯O hydrogen bonds into a hexa-meric unit generating an R (6) 6(66) motif. Another C-H⋯O inter-action connects the mol-ecules along the c axis, forming C(5) chains. A region of disordered electron density, most probably disordered methanol-water solvent mol-ecules, was treated with the SQUEEZE routine in PLATON [Spek (2009 ▶). Acta Cryst. D65, 148-155]. The formula mass and unit-cell characteristics do not take into account this disordered solvent. PMID:24454100

  6. 4-N-pyridin-2-yl-benzamide nanotubes compatible with mouse stem cell and oral delivery in Drosophila

    Science.gov (United States)

    Yadav, Jhillu S.; Lavanya, Madugula P.; Das, Pragna P.; Bag, Indira; Krishnan, Anita; Jagannadh, Bulusu; Mohapatra, Debendra K.; Pal Bhadra, Manika; Bhadra, Utpal

    2010-04-01

    p-aminobenzoic acid (PABA), a structural moiety of many commercial drugs, is self-assembled with linker alkyl side chains to form tubular nanostructures. The tubes exhibited fluorescence either intrinsic or from fluorescent molecules embedded in the wall during self-assembly. Uptake and inter-cellular delivery of the conjugated nanotubes in human cancer cells and in mouse embryonic stem cells were demonstrated by fluorescence imaging and flow cytometry. Biocompatibility, cytotoxicity and clearance were monitored both ex vivo in mouse multipotent embryonic stem cells and in vivo in adult Drosophila. Accumulation of nanotubes had no adverse effects and abnormalities on stem cell morphology and proliferation rate. A distinct distribution of two separate nanotubes in various internal organs of Drosophila interprets that accumulation of nanomaterials might be interdependent on the side chain modifications and physiological settings of cell or tissue types. Unlike carbon nanomaterials, exposure of PABA nanotubes does not produce any hazards including locomotion defects and mortality of adult flies. Despite differential uptake and clearance from multiple live tissues, the use of self-assembled nanotubes can add new dimensions and scope to the development of dual-purpose oral carriers for the fulfilment of many biological promises.

  7. Crystal structures of 3-fluoro-N-[2-(tri­fluoro­meth­yl)phen­yl]benzamide, 3-bromo-N-[2-(tri­fluoro­meth­yl)phen­yl]benzamide and 3-iodo-N-[2-(tri­fluoro­meth­yl)phen­yl]benzamide

    Science.gov (United States)

    Suchetan, P. A.; Suresha, E.; Naveen, S.; Lokanath, N. K.

    2016-01-01

    In the title compounds, C14H9F4NO, (I), C14H9BrF3NO, (II), and C14H9F3INO, (III), the two benzene rings are inclined to one another by 43.94 (8)° in mol­ecule A and 55.66 (7)° in mol­ecule B of compound (I), which crystallizes with two independent mol­ecules in the asymmetric unit, but by only 10.40 (12)° in compound (II) and 12.5 (2)° in compound (III). In the crystals of all three compounds, N—H⋯O hydrogen bonds link the mol­ecules to form chains propagating along the a-axis direction for (I), and along the b-axis direction for (II) and (III). In the crystal of (I), –A–B–A–B– chains are linked by C—H⋯O hydrogen bonds, forming layers parallel to (010). Within the layers there are weak offset π–π inter­actions present [inter­centroid distances = 3.868 (1) and 3.855 (1) Å]. In the crystals of (II) and (III), the chains are linked via short halogen–halogen contacts [Br⋯Br = 3.6141 (4) Å in (II) and I⋯I = 3.7797 (5) Å in (III)], resulting in the formation of ribbons propagating along the b-axis direction. PMID:27308050

  8. Crystal structures of 3-fluoro-N-[2-(tri-fluoro-meth-yl)phen-yl]benzamide, 3-bromo-N-[2-(tri-fluoro-meth-yl)phen-yl]benzamide and 3-iodo-N-[2-(tri-fluoro-meth-yl)phen-yl]benzamide.

    Science.gov (United States)

    Suchetan, P A; Suresha, E; Naveen, S; Lokanath, N K

    2016-06-01

    In the title compounds, C14H9F4NO, (I), C14H9BrF3NO, (II), and C14H9F3INO, (III), the two benzene rings are inclined to one another by 43.94 (8)° in mol-ecule A and 55.66 (7)° in mol-ecule B of compound (I), which crystallizes with two independent mol-ecules in the asymmetric unit, but by only 10.40 (12)° in compound (II) and 12.5 (2)° in compound (III). In the crystals of all three compounds, N-H⋯O hydrogen bonds link the mol-ecules to form chains propagating along the a-axis direction for (I), and along the b-axis direction for (II) and (III). In the crystal of (I), -A-B-A-B- chains are linked by C-H⋯O hydrogen bonds, forming layers parallel to (010). Within the layers there are weak offset π-π inter-actions present [inter-centroid distances = 3.868 (1) and 3.855 (1) Å]. In the crystals of (II) and (III), the chains are linked via short halogen-halogen contacts [Br⋯Br = 3.6141 (4) Å in (II) and I⋯I = 3.7797 (5) Å in (III)], resulting in the formation of ribbons propagating along the b-axis direction. PMID:27308050

  9. Synthesis and biological activity of N-{l_brace}5-(4-methylphenyl) diazenyl-4-phenyl-1, 3-thiazole-2-yl{r_brace}benzamide derivatives

    Energy Technology Data Exchange (ETDEWEB)

    Prajapati, Ashishkumar K.; Modi, Vishal P. [The M.S. University of Baroda, Gujarat (India). Faculty of Technology and Engineering. Applied Chemistry Dept.

    2011-07-01

    In the present study, various amides of 2-amino-5-(4-methylphenyl)-diazenyl-4-phenyl-1, 3-thiazole was synthesized and their biological activities were evaluated. All the synthesized compounds were characterized by the combination of elemental analysis and standard spectroscopic methods. They are screened for anti-bacterial activity against Escherichia coli and Staphylococcus aureus as well as screened for antifungal activity against Aspergillus niger and Aspergillus oryzae by cup plate method at 1 {mu}g/ mL concentration in DMF. (author)

  10. Bioevaluation of novel anti-biofilm coatings based on PVP/Fe3O4 nanostructures and 2-((4-ethylphenoxy)methyl)-N- (arylcarbamothioyl)benzamides.

    Science.gov (United States)

    Limban, Carmen; Missir, Alexandru Vasile; Grumezescu, Alexandru Mihai; Oprea, Alexandra Elena; Grumezescu, Valentina; Vasile, Bogdan Stefan; Socol, Gabriel; Trușcă, Roxana; Caproiu, Miron Teodor; Chifiriuc, Mariana Carmen; Gălățeanu, Bianca; Costache, Marieta; Morușciag, Laurențiu; Pîrcălăbioru, Grațiela; Nuță, Diana Camelia

    2014-01-01

    Novel derivatives were prepared by reaction of aromatic amines with 2-(4-ethylphenoxymethyl)benzoyl isothiocyanate, affording the N-[2-(4-ethylphenoxymethyl) benzoyl]-Nꞌ-(substituted phenyl)thiourea. Structural elucidation of these compounds was performed by IR, NMR spectroscopy and elemental analysis. The new compounds were used in combination with Fe3O4 and polyvinylpyrrolidone (PVP) for the coating of medical surfaces. In our experiments, catheter pieces were coated by Matrix Assisted Pulsed Laser Evaporation (MAPLE) technique. The microbial adherence ability was investigated in 6 multi-well plates by using culture based methods. The obtained surfaces were also assessed for their cytotoxicity with respect to osteoblast cells, by using fluorescence microscopy and MTT assay. The prepared surfaces by advanced laser processing inhibited the adherence and biofilm development ability of Staphylococcus aureus and Pseudomonas aeruginosa tested strains while cytotoxic effects on the 3T3-E1 preosteoblasts embedded in layer shaped alginate hydrogels were not observed. These results suggest that the obtained medical surfaces, based on the novel thiourea derivatives and magnetic nanoparticles with a polymeric shell could represent a promising alternative for the development of new and effective anti-infective strategies. PMID:25120054

  11. Preparation and biological evaluation of cyclopentadienyl-based {sup 99m}Tc-complexes [(Cp-R){sup 99m}Tc(CO){sub 3}] mimicking benzamides for malignant melanoma targeting

    Energy Technology Data Exchange (ETDEWEB)

    Peindy N' Dongo, Harmel W. [Institute of Inorganic Chemistry, University of Zuerich, 190, CH-8057 Zurich (Switzerland); Raposinho, Paula D.; Fernandes, Celia; Santos, Isabel [Unidade de Ciencias Quimicas e Radiofarmaceuticas, Instituto Tecnologico e Nuclear, Estrada Nacional 10, 2686-953 Sacavem (Portugal); Can, Daniel; Schmutz, Paul; Spingler, Bernhard [Institute of Inorganic Chemistry, University of Zuerich, 190, CH-8057 Zurich (Switzerland); Alberto, Roger [Institute of Inorganic Chemistry, University of Zuerich, 190, CH-8057 Zurich (Switzerland)], E-mail: ariel@aci.uzh.ch

    2010-04-15

    The biological evaluation of half-sandwich {sup 99m}Tc-complexes that surrogate iodobenzamide with a high affinity for melanin tumor tissue is described. We have synthesized via retro Diels-Alder reaction two models of {sup 99m}Tc complexes which possess the piano stool [Cp{sup 99m}Tc(CO){sub 3}] motif instead of a phenyl ring as in the original iodobenzamide {sup 123}I-N-(N-benzylpiperidin-4-yl)-2-iodobenzamide (2-IBP) and N-(2-diethylaminoethyl)-4-iodobenzamide (BZA). Diels-Alder products - (HCp-CONHR){sub 2} (, R=2-diethylaminoethyl; , R=benzylpiperidin-4-yl) were prepared and reacted with fac-[{sup 99m}Tc(H{sub 2}O){sub 3}(CO){sub 3})]{sup +}1 in water to produce the corresponding {sup 99m}Tc complexes [(){sup 99m}Tc(CO){sub 3})] and [(){sup 99m}Tc(CO){sub 3})] . The structures of the {sup 99m}Tc complexes on the no-carrier-added level have been confirmed by chromatographic comparison with the corresponding rhenium complexes and , macroscopically characterized by IR, NMR, ESI-MS and X-ray crystallography for [triclinic, P-1, a=7.3518(1) A, b=8.0309(2) A, c=17.5536(3) A, {alpha}=99.1260(5){sup o}, {beta}=90.4215(14){sup o}, {gamma}=117.0187(11){sup o}]. The radioconjugate showed good in vitro stability. In murine melanoma B16F1 cells, significant cellular uptake (43.9% of the total applied activity) was attained after 4 h at 37 deg. C with about 50% of the cell-associated radioactivity being internalized in the cells (22% of the applied activity). Furthermore, in melanoma-bearing C57BL6 mice, tumor uptake values of 3.39{+-}0.50 %ID g{sup -1} and 3.21{+-}0.26 %ID g{sup -1} at 1 and 4 h postinjection, respectively, were observed indicating a good retention of in the tumor.

  12. A combined CoMFA and CoMSIA 3D-QSAR study of benzamide type antibacterial inhibitors of the FtsZ protein in drug-resistant Staphylococcus aureus.

    Science.gov (United States)

    Andrades, J; Campanini, J; Vásquez, D; Silvestri, C; Morales, C; Romero, J; Mella, J

    2015-01-01

    A major problem today is bacterial resistance to antibiotics and the small number of new therapeutic agents approved in recent years. The development of new antibiotics capable of acting on new targets is urgently required. The filamenting temperature-sensitive Z (FtsZ) bacterial protein is a key biomolecule for bacterial division and survival. This makes FtsZ an attractive new pharmacological target for the development of antibacterial agents. There have been several attempts to develop ligands able to inhibit FtsZ. Despite the large number of synthesized compounds that inhibit the FtsZ protein, there are no quantitative structure-activity relationships (QSAR) that allow for the rational design and synthesis of promising new molecules. We present the first 3D-QSAR study of a large and diverse set of molecules that are able to inhibit the FtsZ bacterial protein. We summarize a set of chemical changes that can be made in the steric, electrostatic, hydrophobic and donor/acceptor hydrogen-bonding properties of the pharmacophore, to generate new bioactive molecules against FtsZ. These results provide a rational guide for the design and synthesis of promising new antibacterial agents, supported by the strong statistical parameters obtained from CoMFA (r(2)(pred) = 0.974) and CoMSIA (r(2)(pred) = 0.980) analyses. PMID:26505124

  13. Melanin Targeted Pre-clinical PET Imaging of Melanoma Metastasis

    OpenAIRE

    Ren, Gang; Miao, Zheng; Liu, Hongguang; Jiang, Lei; Limpa-Amara, Naengnoi; Mahmood, Ashfaq; Gambhir, Sanjiv S.; Cheng, Zhen

    2009-01-01

    Dialkylamino-alkyl-benzamide possess affinities for melanin, suggesting that such 18F-labeled benzamides could potentially be used as melanin targeted positron emission tomography (PET) probes to identify melanotic melanoma metastases in vivo with high sensitivity and specificity. In this report, we describe the synthesis, in vitro and in vivo evaluation of 18F-N-[2-(diethylamino)ethyl]-4-fluoro-Benzamide (18F-FBZA) in mouse tumor models.

  14. Cobalt-catalyzed C-H olefination of aromatics with unactivated alkenes.

    Science.gov (United States)

    Manoharan, Ramasamy; Sivakumar, Ganesan; Jeganmohan, Masilamani

    2016-08-18

    A cobalt-catalyzed C-H olefination of aromatic and heteroaromatic amides with unactivated alkenes, allyl acetates and allyl alcohols is described. This method offers an efficient route for the synthesis of vinyl and allyl benzamides in a highly stereoselective manner. It is observed that the ortho substituent on the benzamide moiety is crucial for the observation of allylated products in unactivated alkenes.

  15. Novas N-benzoiltiraminas de Swinglea glutinosa (Rutaceae)

    OpenAIRE

    Cristovam do Nascimento Cerqueira; Djalma A. P. dos Santos; Karla da Silva Malaquias; Murilo Marinho de Castro Lima; Maria Fátima das Graças Fernandes da Silva; João Batista Fernandes; Paulo Cezar Vieira

    2012-01-01

    Phytochemical studies of the leaves and fruits have led to the identification of the known amides (E)-N-methyl-cinnamamide, N-benzoyltyramine, N-benzoyl-O-geranyltyramine, N-benzoyl-O-(4-acetoxyl)-geranyltyramine, in addition to the new N-{2-[4-(butoxyl-3-one)phenyl]ethyl}benzamide, N-{2-[4-(2,3-dihydroxy-2-methyl-butoxylanal)phenyl]ethyl}benzamide, N-{2-[4-(2,3-dihydroxy-2-methyl-butoxyloic)phenyl]ethyl}benzamide, N-benzoyl-O-(4-acetoxyl-6,7-epoxy)-geranyltyramine, N-benzoyl-O-(4-acetoxyl-6,...

  16. Synthesis and evaluation of (S)-5-[125I]iodo-2,3-methylenedioxybenzamide

    International Nuclear Information System (INIS)

    Recent reports have demonstrated that benzamides possessing 2,3-dimethoxy-5-iodo- and 2,3-dihydroxybenzofuran-5-iodo- substitution patterns (termed epidepride and IBF, respectively) are potent dopamine D-2 antagonists. A closely related benzamide ((S)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-2,3-methylenedioxy-5-[I-125]iodo-benzamide, termed IMD) has been synthesized and its activity compared to that of epidepride and IBF. The synthetic pathway and both in vitro and in vivo behavior of the compound are discussed

  17. 舒必利治疗精神病患者拒食行为的疗效观察%The effect of sulpiride on sitieirgia of psychotic

    Institute of Scientific and Technical Information of China (English)

    张长军; 王振英; 吕应春

    2003-01-01

    @@ BACKGROUND: Sulpiride belongs to derivative of benza-mide, which is also called dogmatil. It has the affect of an-ti-psychosis and is effective to tension, indifference, introversion and withdrawal.

  18. N-(4,6-二取代嘧啶-2-基)苯甲酰胺类化合物的合成与杀菌活性%Synthesis and Fungicidal Activity of N-(4,6-Disubstitued pyrimidin-2-yl)-benzamides

    Institute of Scientific and Technical Information of China (English)

    黄明智; 罗晓艳; 任叶果; 张承来; 张俐; 徐满才

    2007-01-01

    为了寻找高效、安全的杀菌活性化合物,设计并合成了8个N-(4,6-二取代嘧啶-2-基)苯甲酰胺类化合物,其化学结构经1H NMR、IR、LC/MS和元素分析确证.初步生物活性测定结果表明,该类化合物具有一定的杀菌活性,当浓度为25 mg/L时,化合物4g对稻瘟病菌Pyricularia oryzae的抑制率达85.1%,化合物4f对小麦赤霉病菌Gibberella zeae的抑制率达92.9%.

  19. Triphenylethanamine Derivatives as Cholesteryl Ester Transfer Protein Inhibitors: Discovery of N-[(1R)-1-(3-Cyclopropoxy-4-fluorophenyl)-1-[3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl]-2-phenylethyl]-4-fluoro-3-(trifluoromethyl)benzamide (BMS-795311).

    Science.gov (United States)

    Qiao, Jennifer X; Wang, Tammy C; Adam, Leonard P; Chen, Alice Ye A; Taylor, David S; Yang, Richard Z; Zhuang, Shaobin; Sleph, Paul G; Li, Julia P; Li, Danshi; Yin, Xiaohong; Chang, Ming; Chen, Xue-Qing; Shen, Hong; Li, Jianqing; Smith, Daniel; Wu, Dauh-Rurng; Leith, Leslie; Harikrishnan, Lalgudi S; Kamau, Muthoni G; Miller, Michael M; Bilder, Donna; Rampulla, Richard; Li, Yi-Xin; Xu, Carrie; Lawrence, R Michael; Poss, Michael A; Levesque, Paul; Gordon, David A; Huang, Christine S; Finlay, Heather J; Wexler, Ruth R; Salvati, Mark E

    2015-11-25

    Cholesteryl ester transfer protein (CETP) inhibitors raise HDL-C in animals and humans and may be antiatherosclerotic by enhancing reverse cholesterol transport (RCT). In this article, we describe the lead optimization efforts resulting in the discovery of a series of triphenylethanamine (TPE) ureas and amides as potent and orally available CETP inhibitors. Compound 10g is a potent CETP inhibitor that maximally inhibited cholesteryl ester (CE) transfer activity at an oral dose of 1 mg/kg in human CETP/apoB-100 dual transgenic mice and increased HDL cholesterol content and size comparable to torcetrapib (1) in moderately-fat fed hamsters. In contrast to the off-target liabilities with 1, no blood pressure increase was observed with 10g in rat telemetry studies and no increase of aldosterone synthase (CYP11B2) was detected in H295R cells. On the basis of its preclinical profile, compound 10g was advanced into preclinical safety studies.

  20. Copper-catalysed intramolecular O-arylation: a simple and efficient method for benzoxazole synthesis.

    Science.gov (United States)

    Wu, Fengtian; Zhang, Jie; Wei, Qianbing; Liu, Ping; Xie, Jianwei; Jiang, Haojie; Dai, Bin

    2014-12-21

    A wide range of 2-substituted benzoxazoles can be efficiently synthesized from N-(2-iodo-/bromo-phenyl)benzamides, and even the less reactive N-(2-chlorophenyl)benzamides, via Cu-catalysed intramolecular coupling cyclization reactions using methyl 2-methoxybenzoate as the ligand under mild reaction conditions. In addition, the benzoxazoles can be easily prepared from the primary amides coupling with o-dihalobenzenes in a single step.

  1. SYNTHESIS AND BIOLOGICAL EVALUATION OF SOME NOVEL 2-CHLORO-4- (METHYLSULFONYL) PHENYL CONTAINING ACYLTHIOUREA AND 1,3- THIAZOLIDIN-4-ONE AS PROMISING ANTIMICROBIAL AGENTS. Synthese und biologische Bewertung einiger NEUE 2-Chlor-4- (Methylsulfonyl) phenyl MIT Acylthioharnstoff und 1,3 - THIAZOLIDIN-4-ONE als aussichtsreiche ANTIMIKROBIELLE MITTEL.

    OpenAIRE

    Chandra Kant Belwal, Kaushik A. Joshi

    2013-01-01

    A series of acylthiourea derivatives, 2-chloro-4-(methylsulfonyl)-N-(arylcarbamothioyl) benzamides were synthesized by reaction of 2-chloro-4-(methylsulfonyl) benzoyl chloride with ammonium thiocyanate and substituted aromatic amines. Cyclocondensation of acylthiourea derivatives, 2-chloro-4-(methylsulfonyl)-N-(arylcarbamothioyl) benzamides with tert-butyl chloroacetate yielded thiazolidinone derivatives, 3-{[2-chloro-4-(methylsulfonyl) phenyl]carbonyl}-2-(imino)-1,3-thiazolidin-4-one. S...

  2. Reações de carbociclização radicalar de orto-iodoaliloxibenzoatos derivados de d-glicose e d-galactose e comparação com as reações de seus análogos benzamidas Radical carbocyclization reactions of ortho-iodoallyloxybenzoate derivatives of d-glucose and d-galactose and comparison with the reactions of their benzamide analogs

    Directory of Open Access Journals (Sweden)

    Ildefonso Binatti

    2005-12-01

    Full Text Available Two ortho-iodoallyloxybenzoates, methyl 4-O-allyl-2,3-di-O-benzyl-6-O-(2-iodobenzoyl- alpha-D-glucopyranoside (3 and methyl 4-O-allyl-2,3-di-O-benzyl-6-O-(2-iodobenzoyl- alpha-D-galactopyranoside (4 were synthesized in seven conventional steps from methyl alpha-D-glucopyranoside and methyl alpha-D-galactopyranoside, respectively. Bu3SnH-mediated aryl radical cyclization of 3 provided exclusively the hydrogenolysis product 12. The reaction of 4 gave the reduced uncyclized product 13 and only traces of 4A, resulting from 11-endo aryl radical cyclization. In previous papers we described that in similar Bu3SnH-mediated radical reaction of ortho-iodoallyloxybenzamides, analogs of 3 and 4, we obtained macrolactams resulting from 11-endo cyclization. An hypothesis to explain the differences is presented. It was assumed that in the aryl radical formed from iodobenzamides there is a suitable conformation to cyclization, which is stabilized by an intramolecular hydrogen bond.

  3. Novas N-benzoiltiraminas de Swinglea glutinosa (Rutaceae

    Directory of Open Access Journals (Sweden)

    Cristovam do Nascimento Cerqueira

    2012-01-01

    Full Text Available Phytochemical studies of the leaves and fruits have led to the identification of the known amides (E-N-methyl-cinnamamide, N-benzoyltyramine, N-benzoyl-O-geranyltyramine, N-benzoyl-O-(4-acetoxyl-geranyltyramine, in addition to the new N-{2-[4-(butoxyl-3-onephenyl]ethyl}benzamide, N-{2-[4-(2,3-dihydroxy-2-methyl-butoxylanalphenyl]ethyl}benzamide, N-{2-[4-(2,3-dihydroxy-2-methyl-butoxyloicphenyl]ethyl}benzamide, N-benzoyl-O-(4-acetoxyl-6,7-epoxy-geranyltyramine, N-benzoyl-O-(4-acetoxyl-6,7-dihydroxy-geranyltyramine and N-benzoyl-O-(6-acetoxyl-4,7-dihydroxy-geranyltyramine. The isolated compounds clearly point to Swinglea phytochemical affinities with other Aurantioideae species.

  4. Novel N-benzoyltyramines of Swinglea glutinosa (Rutaceae)

    International Nuclear Information System (INIS)

    Phytochemical studies of the leaves and fruits have led to the identification of the known amides (E)-N-methyl-cinnamamide, N-benzoyltyramine, N-benzoyl-O-geranyl tyramine, N-benzoyl-O-(4-acetoxyl)-geranyl tyramine, in addition to the new N-{2-[4-(butoxyl-3-one)phenyl]ethyl}benzamide, N-{2-[4-(2,3-dihydroxy-2-methyl-butoxylanal)phenyl]ethyl}benzamide, N-{2-[4-(2,3-dihydroxy-2-methyl-butoxyloic) phenyl]ethyl}benzamide, N-benzoyl-O-(4-acetoxyl-6,7-epoxy)-geranyltyramine, N-benzoyl-O-(4-acetoxyl-6,7-dihydroxy)-geranyltyramine and N-benzoyl-O-(6-acetoxyl-4,7-dihydroxy)-geranyltyramine. The isolated compounds clearly point to Swinglea phytochemical affinities with other Aurantioideae species. (author)

  5. Novel N-benzoyltyramines of Swinglea glutinosa (Rutaceae); Novas N-benzoiltiraminas de Swinglea glutinosa (Rutaceae).

    Energy Technology Data Exchange (ETDEWEB)

    Cerqueira, Cristovam do Nascimento; Santos, Djalma A.P. dos; Malaquias, Karla da Silva; Lima, Murilo Marinho de Castro; Silva, Maria Fatima das Gracas Fernandes da; Fernandes, Joao Batista; Vieira, Paulo Cezar, E-mail: dmfs@ufscar.br [Universidade Federal de Sao Carlos (UFSCAR), SP (Brazil). Dept. de Quimica

    2012-07-01

    Phytochemical studies of the leaves and fruits have led to the identification of the known amides (E)-N-methyl-cinnamamide, N-benzoyltyramine, N-benzoyl-O-geranyl tyramine, N-benzoyl-O-(4-acetoxyl)-geranyl tyramine, in addition to the new N-{l_brace}2-[4-(butoxyl-3-one)phenyl]ethyl{r_brace}benzamide, N-{l_brace}2-[4-(2,3-dihydroxy-2-methyl-butoxylanal)phenyl]ethyl{r_brace}benzamide, N-{l_brace}2-[4-(2,3-dihydroxy-2-methyl-butoxyloic) phenyl]ethyl{r_brace}benzamide, N-benzoyl-O-(4-acetoxyl-6,7-epoxy)-geranyltyramine, N-benzoyl-O-(4-acetoxyl-6,7-dihydroxy)-geranyltyramine and N-benzoyl-O-(6-acetoxyl-4,7-dihydroxy)-geranyltyramine. The isolated compounds clearly point to Swinglea phytochemical affinities with other Aurantioideae species. (author)

  6. NEW COHORT OF OPTICALLY ACTIVE NANOSTRUCTURE POLY(AMIDEIMIDE)S: PRODUCTION AND PROPERTIES

    Institute of Scientific and Technical Information of China (English)

    Shadpour Mallakpour; Mehdi Hatami

    2011-01-01

    Novel aromatic-aliphatic poly(amide-imide)s containing chiral units in the main chain and hydroxyl benzamide units in the side chain have been obtained from the step-growth polymerization of 3,5-diamino-N-(4-hydroxyphenyl) benzamide (2) with different chiral diacid chlorides (1a-1e).Theoretical calculations were done by means of computational chemistry methods to narrate the stable conformation and orientation of each diacid chloride monomers under reaction conditions.These polymers were characterized by conventional techniques.The resulting polymers show good thermal stability.Other physical properties of polymers including crystallinity,inherent viscosity and morphological characteristics were also studied.

  7. H-Y-zeolites induced heterocyclization: Highly efficient synthesis of substituted-quinazolin-4(3H)ones under microwave irradiation

    Institute of Scientific and Technical Information of China (English)

    M. Bakavoli; O. Sabzevari; M. Rahimizadeh

    2007-01-01

    A highly efficient synthesis of 2-amino-N-substituted-benzamides was performed by the condensation of isatoic anhydride with several amines in solvent-free conditions under microwave irradiation. H-Y-zeolites induced heterocyclization of these products with ortho-esters under similar conditions afforded the relevant substituted-quinazolin-4(3H)ones in high yields.

  8. Rapid and convenient semi-automated microwave-assisted solid-phase synthesis of arylopeptoids

    DEFF Research Database (Denmark)

    Rasmussen, Jakob Ewald; Boccia, Marcello Massimo; Nielsen, John;

    2014-01-01

    A facile and expedient route to the synthesis of arylopeptoid oligomers (N-alkylated aminomethyl benz-amides) using semi-automated microwave-assisted solid-phase synthesis is presented. The synthesis was optimized for the incorporation of side chains derived from sterically hindered or unreactive...

  9. C-Terminally modified peptides via cleavage of the HMBA linker by O-, i>N>- or S-nucleophiles

    DEFF Research Database (Denmark)

    Hansen, Jonas; Diness, Frederik; Meldal, Morten Peter

    2016-01-01

    A large variety of C-terminally modified peptides was obtained by nucleophilic cleavage of the ester bond in solid phase linked peptide esters of 4-hydroxymethyl benzamide (HMBA). The developed methods provided peptides, C-terminally functionalized as esters, amides and thioesters, with high puri...

  10. Cp*Co(III)-Catalyzed Dehydrative C-H Allylation of 6-Arylpurines and Aromatic Amides Using Allyl Alcohols in Fluorinated Alcohols.

    Science.gov (United States)

    Bunno, Youka; Murakami, Nanami; Suzuki, Yudai; Kanai, Motomu; Yoshino, Tatsuhiko; Matsunaga, Shigeki

    2016-05-01

    Cp*Co(III)-catalyzed C-H allylation of various aromatic C-H bonds using allyl alcohols as allylating reagents is described. Improved reaction conditions using fluorinated alcohol solvents afforded efficient directed C-H allylation of 6-arylpurines, benzamides, and a synthetically useful Weinreb amide with good functional group compatibility.

  11. The first X-ray crystal structure of the glucocorticoid receptor bound to a non-steroidal agonist

    Energy Technology Data Exchange (ETDEWEB)

    Madauss, Kevin P.; Bledsoe, Randy K.; Mclay, Iain; Stewart, Eugene L.; Uings, Iain J.; Weingarten, Gordon; Williams, Shawn P. (GSKNC); (GSK)

    2009-07-23

    The amino-pyrazole 2,6-dichloro-N-ethyl benzamide 1 is a selective GR agonist with dexamethasone-like in vitro potency. Its X-ray crystal structure in the GR LBD (Glucocorticoid ligand-binding domain) is described and compared to other reported structures of steroidal GR agonists in the GR LBD (3E7C).

  12. Aromatic oligoamides with a rare ortho-connectivity

    DEFF Research Database (Denmark)

    Hjelmgaard, T.; Nielsen, John

    2013-01-01

    Even though aromatic oligoamides composed of aromatic amino acids in a "one-way sequence" attract ever increasing research interest, backbones connected through ortho-linked aromatics remain rare. Herein, we present the first synthesis and study of N-alkylated ortho-aminomethyl- benzamides termed...

  13. Drug: D07310 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D07310 Drug Amisulpride (INN); Deniban (TN); Solian (TN) C17H27N3O4S 369.1722 369.4...n [BR:br08303] N NERVOUS SYSTEM N05 PSYCHOLEPTICS N05A ANTIPSYCHOTICS N05AL Benzamides N05AL05 Amisulpride D07310 Amisulpride

  14. Drug: D07311 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D07311 Drug Veralipride (INN); Agreal (TN) C17H25N3O5S 383.1515 383.4625 D07311.gif...N NERVOUS SYSTEM N05 PSYCHOLEPTICS N05A ANTIPSYCHOTICS N05AL Benzamides N05AL06 Veralipride D07311 Veralipride

  15. Multiway calibration in 3D QSAR

    NARCIS (Netherlands)

    Nilsson, J; de Jong, Sietse; Smilde, A

    1997-01-01

    We have introduced multilinear PLS in 3D QSAR and applied it to GRID descriptors from a set of benzamides with affinity to the dopamine D-3 receptor subtype, synthesized as potential drugs against schizophrenia. The key issue in 3D QSAR modelling is to obtain a predictive model that is easy to inter

  16. 4-Acylamino-and 4-ureidobenzamides as melanin-concentrating hormone (MCH) receptor 1 antagonists

    DEFF Research Database (Denmark)

    Receveur, Jean-Marie; Bjurling, Emelie; Ulven, Trond;

    2004-01-01

    Synthesis, in vitro biological evaluation and structure-activity relationships of 4-acylamino-and 4-ureidobenzamides as novel hMCH1R-antagonists are disclosed. The nature of the amine side chains could be varied considerably in contrast to the central benzamide scaffold and aromatic substituents....

  17. Analysis of Pyrolysates for Polysulphoneamide Fiber by Py-GC/MS

    Institute of Scientific and Technical Information of China (English)

    QIAN He-sheng; LIN Dan-li

    2006-01-01

    Pyrolysis of polysulphoneamide fiber has been investigated using pyrolysis gas chromatography-mass spectroscopy at the different temperatures from 420℃ to 750℃. Its compositions of pyrolysates have been analyzed. At 420 ℃,pyrolysis of molecular chain could not completely take place, 12 compounds of pyrolysis have only been identified.When the temperature increases, the compositions of pyrolysate increase sharply. Several compounds, especially sulfur dioxide, benzene, aniline, benzoic acid, 1,4-benzene dicaronitrile, N-phenyl-acetamide, diphenylamine, benzo[g]isoquinoline, N-phenyl-benzamide, N-( 4-cyanophenyl )benzamide, could be formed. The degradation mechanisms which are determined by structure and amount of the thermal decomposition products are described. During pyrolysis, for polysulphoneamide, polymeric chain scissions take place as a successive removal of the monomer units from the polymeric chain. The chain scissions are followed by secondary reactions, which lead to a variety of compounds.Additional reactions can also take place during pyrolysis.

  18. SYNTHESIS AND BIOLOGICAL EVALUATION OF SOME NOVEL 2-CHLORO-4- (METHYLSULFONYL PHENYL CONTAINING ACYLTHIOUREA AND 1,3- THIAZOLIDIN-4-ONE AS PROMISING ANTIMICROBIAL AGENTS. Synthese und biologische Bewertung einiger NEUE 2-Chlor-4- (Methylsulfonyl phenyl MIT Acylthioharnstoff und 1,3 - THIAZOLIDIN-4-ONE als aussichtsreiche ANTIMIKROBIELLE MITTEL.

    Directory of Open Access Journals (Sweden)

    Chandra Kant Belwal, Kaushik A. Joshi

    2013-07-01

    Full Text Available A series of acylthiourea derivatives, 2-chloro-4-(methylsulfonyl-N-(arylcarbamothioyl benzamides were synthesized by reaction of 2-chloro-4-(methylsulfonyl benzoyl chloride with ammonium thiocyanate and substituted aromatic amines. Cyclocondensation of acylthiourea derivatives, 2-chloro-4-(methylsulfonyl-N-(arylcarbamothioyl benzamides with tert-butyl chloroacetate yielded thiazolidinone derivatives, 3-{[2-chloro-4-(methylsulfonyl phenyl]carbonyl}-2-(imino-1,3-thiazolidin-4-one. Structure elucidation of the synthesized compounds has been accomplished on the basis of elemental analysis, mass, IR, 1H-NMR and 13C-NMR data. Synthesized compounds were screened for their antimicrobial activity against gram-positive, gram-negative bacteria and some selected fungal stains.

  19. Revision of the Crystal Structure of the First Molecular Polymorph in History

    DEFF Research Database (Denmark)

    Johansson, Kristoffer E.; van de Streek, Jacco

    2016-01-01

    Despite being the earliest reported case of polymorphism in a molecular crystal, the unstable form II of benzamide has thus far evaded thorough structural characterization because collection of experimental data at atomic resolution has proven extremely challenging. Using a highly validated...... computational crystal structure prediction (CSP) method based on dispersion-corrected density functional theory, we correctly predict the stable form I with the lowest energy among all sampled structures and its polytypic form III with slightly higher energy. From Rietveld refinement of selected CSP models...... against synchrotron X-ray powder diffraction data of the historical polymorph, we are able to identify a subtle weakness in the available experimental data and arrive at a revised structure of form II. The revised crystal structure is the first benzamide structure to form catemers rather than dimers...

  20. Preparation and Application of Perchloric Acid Supported on Alumina (Al2O3-HCIO4) to the Synthesis of α-(α-Amidobenzyl)-β-naphthols

    Institute of Scientific and Technical Information of China (English)

    SHATERIAN,Hamid Reza; KHORAMI,Fahimeh; AMIRZADEH,Azita; GHASHANG,Majid

    2009-01-01

    Preparation of perchloric acid supported on alumina and its primary application as a solid supported heterogeneous catalyst to the synthesis of α-(α-amidobenzyl)-β-naphthols by a one-pot,three-component condensation of benzaldehydes,β-naphthol and acetamide or benzamide under thermal solvent-free conditions were described.The present methodology offers several advantages such as simple procedure,shorter reaction time,and excellent yields.

  1. A Convenient Method for the Synthesis of 1,3,2-Oxazaphospholidin-[3,2-a]-8-oxo-10-thio(or seleno)-[1,3,2]-benzodiazaphosphorines

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    A Convenient method for the synthesis of fused phosphorusheterocycle 1,3,2-oxazaphosphorin-[3,2-a]-8-oxo-10-thio(or seleno)-[1,3,2]-benzodiazaphosphorines was carried out in one pot by the reaction of Tris(diethylamino)phosphine with multifunctional compounds 2-(N-(βor γ-hydroxyl) alkylene) amino-benzamides 1.When PCL3 was used, only chlorinated product was obtained.

  2. Carboxylate-Assisted Iridium-Catalyzed C-H Amination of Arenes with Biologically Relevant Alkyl Azides.

    Science.gov (United States)

    Zhang, Tao; Hu, Xuejiao; Wang, Zhen; Yang, Tiantian; Sun, Hao; Li, Guigen; Lu, Hongjian

    2016-02-24

    An iridium-catalyzed C-H amination of arenes with a wide substrate scope is reported. Benzamides with electron-donating and -withdrawing groups and linear, branched, and cyclic alkyl azides are all applicable. Cesium carboxylate is crucial for both reactivity and regioselectivity of the reactions. Many biologically relevant molecules, such as amino acid, peptide, steroid, sugar, and thymidine derivatives can be introduced to arenes with high yields and 100 % chiral retention. PMID:26712274

  3. Characterization of the 5-HT4 receptor mediating tachycardia in piglet isolated right atrium.

    OpenAIRE

    Medhurst, A. D.; Kaumann, A J

    1993-01-01

    1. In order to explore whether 5-HT4 receptor subtypes exist, we have characterized further the 5-HT4 receptor that mediates tachycardia in the piglet isolated right atrium. All experiments were carried out in the presence of propranolol (400 nM) and cocaine (6 microM). We used tryptamine derivatives, substituted benzamides and benzimidazolone derivatives as pharmacological tools. 2. Tachycardia responses to 5-hydroxytryptamine (5-HT) were mimicked by other tryptamine derivatives with the fol...

  4. 40 CFR 180.649 - Saflufenacil; tolerances for residues.

    Science.gov (United States)

    2010-07-01

    ...]benzamide, in or on the commodities. Commodity Parts per million Cattle, fat 0.01 Cattle, liver 0.80 Cattle, meat 0.01 Cattle, meat byproducts, except liver 0.02 Goat, fat 0.01 Goat, liver 0.80 Goat, meat 0.01..., except liver 0.02 Milk 0.01 Sheep, fat 0.01 Sheep, liver 0.80 Sheep, meat 0.01 Sheep, meat...

  5. Regulation of dopamine D2 receptors by sodium and pH

    International Nuclear Information System (INIS)

    The role of Na+ and H+ in the regulation of D2 receptor affinity for ligands was studied to determine the molecular mechanisms of this phenomenon. The potency of substituted benzamide derivatives and agonists at D2 receptors depended on the concentration of Na+ and H+, whereas the potency of other antagonists was relatively unaltered by changes in pH or Na+ concentration. The potency of agonists was generally decreased in the presence of NaCl or lowered pH. For example, in the absence of sodium the affinity of D2 receptors for dopamine was decreased 17-fold by lowering of the pH from 8.0 to pH 6.8. Addition of NaCl caused 2-4-fold decreases in affinity for most agonists. The affinity of the receptors for two substituted benzamide derivatives, on the other hand, was reduced 6-44-fold by elevated concentrations of H+ but was enhanced 7-24-fold in the presence of Na+. The regulation by H+ of the potency of dopamine was selective for D2 receptors, because binding of dopamine to neostriatal D1 receptors was unaffected by changes in pH. Decreasing of the pH from 8.0 or 7.3 to 6.8 facilitated the dissociation of the substituted benzamide ligand 125I epidepride from D2 receptors but inhibited dissociation of 3H spiperone. Furthermore, the presence of NaCl or lowered pH slowed inactivation of D2 receptors by N-ethylmaleimide. Together, these data suggest that the conformation of D2 receptors is regulated by both Na+ and H+. The affinity of D2 receptors for agonists and substituted benzamide antagonists varies according to the conformational state of the receptors, whereas other antagonists bind to both forms with approximately equal potency. Amiloride is a compound that interacts with many sodium-binding macromolecules

  6. Regulation of dopamine D2 receptors by sodium and pH

    Energy Technology Data Exchange (ETDEWEB)

    Neve, K.A. (VA Medical Center, Portland, OR (USA))

    1991-04-01

    The role of Na+ and H+ in the regulation of D2 receptor affinity for ligands was studied to determine the molecular mechanisms of this phenomenon. The potency of substituted benzamide derivatives and agonists at D2 receptors depended on the concentration of Na+ and H+, whereas the potency of other antagonists was relatively unaltered by changes in pH or Na+ concentration. The potency of agonists was generally decreased in the presence of NaCl or lowered pH. For example, in the absence of sodium the affinity of D2 receptors for dopamine was decreased 17-fold by lowering of the pH from 8.0 to pH 6.8. Addition of NaCl caused 2-4-fold decreases in affinity for most agonists. The affinity of the receptors for two substituted benzamide derivatives, on the other hand, was reduced 6-44-fold by elevated concentrations of H+ but was enhanced 7-24-fold in the presence of Na+. The regulation by H+ of the potency of dopamine was selective for D2 receptors, because binding of dopamine to neostriatal D1 receptors was unaffected by changes in pH. Decreasing of the pH from 8.0 or 7.3 to 6.8 facilitated the dissociation of the substituted benzamide ligand {sup 125}I epidepride from D2 receptors but inhibited dissociation of {sup 3}H spiperone. Furthermore, the presence of NaCl or lowered pH slowed inactivation of D2 receptors by N-ethylmaleimide. Together, these data suggest that the conformation of D2 receptors is regulated by both Na+ and H+. The affinity of D2 receptors for agonists and substituted benzamide antagonists varies according to the conformational state of the receptors, whereas other antagonists bind to both forms with approximately equal potency. Amiloride is a compound that interacts with many sodium-binding macromolecules.

  7. Drug: D08549 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D08549 Drug Sultopride (INN) C17H26N2O4S 354.1613 354.4643 D08549.gif Neuroleptic S...:br08303] N NERVOUS SYSTEM N05 PSYCHOLEPTICS N05A ANTIPSYCHOTICS N05AL Benzamides N05AL02 Sultopride D08549 Sultopride...ily Dopamine dopamine D2-receptor [HSA:1813] [KO:K04145] Sultopride [ATC:N05AL02] D08549 Sultopride

  8. Radioiodinated N-(alkylaminoalkyl)-substituted 4-methoxy-, 4-hydroxy-, and 4-aminobenzamides: Biological investigations for the improvement of melanoma-imaging agents

    International Nuclear Information System (INIS)

    The synthesis and radiolabeling of 27 new N-(alkylaminoalkyl)-4-methoxy-, 4-hydroxy-, and -4-aminobenzamides are described and evaluated in C57Bl/6 mice with subcutaneously transplanted B16 melanoma in order to screen the optimal chemical structure for melanoma scintigraphy. Using Tl(TFA)3 for 131I- labeling, a series of radioiodinated 4-methoxy benzamide derivatives proved to exhibit superior melanoma uptake with outstanding melanoma/non-target-tissue ratios. From the benzamide derivatives tested, N-(2-(1'-piperidinyl)ethyl)-3-[131I]iodo-4-methoxybenzamide (1) and N-(2-diethylaminoethyl)-3-[131I]iodo-4-methoxybenzamide (2) demonstrated best results. The introduction of 4-hydroxy and 4-amino groups led to less favourable benzamides. While the former compounds showed little melanoma uptake, the latter revealed unfavourable melanoma/non-target-tissue ratios. Additionally, it could be shown that an amino group was inevitably necessary for melanoma uptake, and that dialkylation of the amide nitrogen and replacing CONH by CH2NH revealed less advantageous results

  9. Intramolecular Homolytic Substitution with Amidyl Radicals: A Free-Radical Synthesis of Ebselen and Related Analogues.

    Science.gov (United States)

    Fong, Mei C.; Schiesser, Carl H.

    1997-05-16

    Irradiation of a water-cooled benzene solution of pyridine-2-thioneoxycarbonyl (PTOC) imidate esters 9 derived from N-butyl-2-(benzylseleno)benzamide (6, R = Bu), 2-(benzylseleno)-N-hexylbenzamide (6, R = Hex), N-benzyl-2-(benzylseleno)benzamide (6, R = Bn), and 2-(benzylseleno)-N-cyclohexylbenzamide (6, R = c-Hex) with a 250-W low-pressure mercury lamp affords the corresponding 1,2-benzisoselenazol-3(2H)-ones (1) in yields of 81-91% (R = primary alkyl) and 45% (R = c-Hex). Presumably, these transformations involve formation of amidyl radicals 2 which undergo subsequent intramolecular homolytic substitution at the selenium atom with expulsion of a benzyl radical. PTOC imidate esters derived from 2-(benzylseleno)benzanilide (6, R = Ph) and 2-(benzylseleno)-N-tert-butylbenzamide (6, R = t-Bu) were unable to be prepared in this manner. 1,2-Benzisoselenazol-3(2H)-ones (1, R = Ph, Hex, i-Pr, t-Bu) could also be prepared in 76-85% yield by reaction of the corresponding 2,2'-diselenobis(benzamide) (15) with benzoyl or tert-butyl peroxide. The mechanisms of these transformations are discussed.

  10. (S)-amisulpride as a discriminative stimulus in C57BL/6 mice and its comparison to the stimulus effects of typical and atypical antipsychotics.

    Science.gov (United States)

    Donahue, Timothy J; Hillhouse, Todd M; Webster, Kevin A; Young, Richard; De Oliveira, Eliseu O; Porter, Joseph H

    2014-07-01

    Amisulpride, a substituted benzamide derivative, exerts atypical antipsychotic and antidepressant clinical effects and its (S)-stereoisomer is thought to underlie these actions. In the present study, male C57BL/6 mice were trained to discriminate (S)-amisulpride (10mg/kg, s.c.) from vehicle in a two-lever drug discrimination task for food reward. The (S)-amisulpride stimulus was rapidly acquired and was shown to be dose-related, time dependent (effective between 30 and 120min) and stereoselective: (S)-amisulpride (ED50=1.77mg/kg; 4.2µmol/kg) was about three times more potent than rac-amisulpride (ED50=4.94mg/kg; 13.4µmol/kg) and ten times more potent than (R)-amisulpride (ED50=15.84mg/kg; 42.9µmol/kg). In tests of stimulus generalization, the (S)-amisulpride stimulus generalized completely to sulpiride (ED50=12.67mg/kg; 37.1µmol/kg), a benzamide analog that also is purported to be an atypical antipsychotic, but did not fully generalize to the typical antipsychotic drug haloperidol (maximum of 45% drug-lever responding) nor to the atypical antipsychotic drugs clozapine (partial substitution of 65% drug-lever responding) or aripiprazole (~30% drug-lever responding). These results demonstrated that (S)-amisulpride appears to exert a unique discriminative stimulus effect that is similar to other benzamides, but which differs from other structural classes of antipsychotic drugs.

  11. Peptide backbone cleavage by α-amidation is enhanced at methionine residues.

    Science.gov (United States)

    Hellwig, Michael; Löbmann, Katja; Orywol, Tom

    2015-01-01

    Cleavage reactions at backbone loci are one of the consequences of oxidation of proteins and peptides. During α-amidation, the Cα -N bond in the backbone is cleaved under formation of an N-terminal peptide amide and a C-terminal keto acyl peptide. On the basis of earlier works, a facilitation of α-amidation by the thioether group of adjacent methionine side chains was proposed. This reaction was characterized by using benzoyl methionine and benzoyl alanyl methionine as peptide models. The decomposition of benzoylated amino acids (benzoyl-methionine, benzoyl-alanine, and benzoyl-methionine sulfoxide) to benzamide in the presence of different carbohydrate compounds (reducing sugars, Amadori products, and reductones) was studied during incubation for up to 48 h at 80 °C in acetate-buffered solution (pH 6.0). Small amounts of benzamide (0.3-1.5 mol%) were formed in the presence of all sugars and from all benzoylated species. However, benzamide formation was strongly enhanced, when benzoyl methionine was incubated in the presence of reductones and Amadori compounds (3.5-4.2 mol%). The reaction was found to be intramolecular, because α-amidation of a similar 4-methylbenzoylated amino acid was not enhanced in the presence of benzoyl-methionine and carbohydrate compounds. In the peptide benzoyl-alanyl-methionine, α-amidation at the methionine residue is preferred over α-amidation at the benzoyl peptide bond. We propose here a mechanism for the enhancement of α-amidation at methionine residues.

  12. Effect of cyclosporin A on the uptake of D{sub 3}-selective PET radiotracers in rat brain

    Energy Technology Data Exchange (ETDEWEB)

    Tu Zhude; Li Shihong; Xu Jinbin; Chu Wenhua; Jones, Lynne A. [Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110 (United States); Luedtke, Robert R. [Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107 (United States); Mach, Robert H., E-mail: rhmach@mir.wustl.edu [Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110 (United States); Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110 (United States); Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110 (United States)

    2011-07-15

    Introduction: Four benzamide analogs having a high affinity and selectivity for D{sub 3} versus D{sub 2} receptors were radiolabeled with {sup 11}C or {sup 18}F for in vivo evaluation. Methods: Precursors were synthesized, and the four D{sub 3} selective benzamide analogs were radiolabeled. The tissue distribution and brain uptake of the four compounds were evaluated in control rats and rats pretreated with cyclosporin A, a modulator of P-glycoprotein and an inhibitor of other ABC efflux transporters that contribute to the blood brain barrier. Micro-positron emission tomographic (PET) imaging was carried out for [{sup 11}C]6 in a control and a cyclosporin A pretreated rat. Results: All four compounds showed low brain uptake in control rats at 5 and 30 min post-injection; despite recently reported rat behavioral studies conducted on analogs 6 (WC-10) and 7 (WC-44). Following administration of cyclosporin A, increased brain uptake was observed with all four PET radiotracers at both 5 and 30 min post-intravenous injection. An increase in brain uptake following modulation/inhibition of the ABC transporters was also observed in the microPET study. Conclusions: These data suggest that D3 selective conformationally-flexible benzamide analogs which contain a N-2-methoxyphenylpiperazine moiety are substrates for P-glycoprotein or other adenosine triphosphate (ATP)-binding cassette transporters expressed at the blood-brain barrier, and that PET radiotracers containing this pharmacophore may display low brain uptake in rodents due to the action of these efflux transporters.

  13. Copper-Catalyzed Intramolecular Benzylic C-H Amination for the Synthesis of Isoindolinones.

    Science.gov (United States)

    Yamamoto, Chiaki; Takamatsu, Kazutaka; Hirano, Koji; Miura, Masahiro

    2016-09-01

    A copper-catalyzed intramolecular amination occurs at the benzylic C-H of 2-methylbenzamides to deliver the corresponding isoindolinones of great interest in medicinal chemistry. The mild and abundant MnO2 works well as a terminal oxidant, and the reaction proceeds smoothly under potentially explosive organic peroxide-free conditions. Additionally, the directing-group-dependent divergent mechanisms are proposed: 8-aminoquinoline-containing benzamides include a Cu-mediated organometallic pathway whereas an aminyl radical-promoted Hofmann-Loffler-Freytag (HLF)-type mechanism can be operative in the case of N-naphthyl-substituted substrates. PMID:27504671

  14. Neonaucline, a New Indole Alkaloid from the Leaves of Ochreinauclea maingayii (Hook. f. Ridsd. (Rubiaceae

    Directory of Open Access Journals (Sweden)

    Marc Litaudon

    2011-12-01

    Full Text Available A new indole alkaloid; neonaucline (1, along with six known compounds–Cadamine (2, naucledine (3, harmane, benzamide, cinnamide and blumenol A–were isolated from the leaves of Ochreinauclea maingayii (Rubiaceae. In addition to that of compound 1, 13C-NMR data of cadamine (2 and naucledine (3 were also reported. Structural elucidations of these alkaloids were performed using spectroscopic methods especially 1D- and 2D-NMR, IR, UV and LCMS-IT-TOF. The excellent vasorelaxant activity on isolated rat aorta was observed for the alkaloids 1–3 after injection of each sample at 1 × 10−5 M.

  15. Nuclear medicine and imaging research (quantitative studies in radiopharmaceutical science)

    Energy Technology Data Exchange (ETDEWEB)

    Cooper, M.; Beck, R.N.

    1992-06-01

    This report describes three studies aimed at using radiolabeled pharmaceuticals to explore brain function and anatomy. The first section describes the chemical preparation of (F18)fluorinated benzamides (dopamine D-2 receptor tracers), (F18)fluorinated benzazepines (dopamine D-1 receptor tracers), and tissue distribution of (F18)-fluoxetine (serotonin reuptake site tracer). The second section relates pharmacological and behavioral studies of amphetamines. The third section reports on progress made with processing of brain images from CT, MRI and PET/SPECT with regards to brain metabolism of glucose during mental tasks.

  16. (E)-N′-[1-(Thiophen-2-yl)ethylidene]benzohydrazide

    OpenAIRE

    Shang Shan; Yan-Lan Huang; Han-Qi Guo; Deng-Feng Li; Jian Sun

    2011-01-01

    The title compound, C13H12N2OS, was obtained from the condensation reaction of 2-acetylthiophene and benzohydrazide. In the molecule, the formohydrazide fragment is approximately planar (r.m.s deviation = 0.0146 Å) and the mean plane is oriented at dihedral angles of 24.47 (11) and 28.86 (13)°, respectively, to the phenyl and thiophene rings. The thiophene and phenyl rings make a dihedral angle of 53.21 (8)°. The benzamide fra...

  17. Nuevas aplicaciones del cloral en la síntesis de compuestos heterocíclicos nitrogenados

    OpenAIRE

    Alarcón Belmonte, Enrique

    2015-01-01

    Se han desarrollado nuevos métodos de síntesis para varias clases de compuestos heterocíclicos nitrogenados partiendo de derivados del cloral: pirimidinas, imidazo[1,5-b]pirazoles, imidazo[1,5-b][1,2,4]triazoles, 1,2,4-triazinas y 1,2,4-triazoles. Se efectuaron reacciones entre cloral y acetofenonas que dieron lugar a cloralacetofenonas con elevados rendimientos, las cuales fueron eficazmente deshidratadas para dar 2,2,2-tricloroetilidenacetofenonas, que se hicieron reaccionar con benzamid...

  18. Formation of a Six-Coordinate fac-[Re(Co)3]+ Complex by the N-C bond cleavage of a potentially tetradentate ligand

    International Nuclear Information System (INIS)

    The rhenium(I) compound fac-[Re(CO)3(daa)]. Hpab.H2O (Hpab N,N'-(l,2-phenylene)bis(2'-aminobenzamide); Hdaa 2-amino-N-(2-aminophenyl)benzamide) was synthesized from the reaction of [Re(CO)5,Br] with two equivalent of Hpab in toluene. The monoanionic tridentate ligand daa was formed by the rhenium-mediated cleavage of an amido N-C bond of the potentially tetradentate ligand Hpab. The compound was characterized by IR spectroscopy and X-ray crystallography, and daa is coordinated as a diamino amide via three nitrogen-donor atoms

  19. Nuclear medicine and imaging research (quantitative studies in radiopharmaceutical science). Progress report, January 1, 1992--December 31, 1992

    Energy Technology Data Exchange (ETDEWEB)

    Cooper, M.; Beck, R.N.

    1992-06-01

    This report describes three studies aimed at using radiolabeled pharmaceuticals to explore brain function and anatomy. The first section describes the chemical preparation of [F18]fluorinated benzamides (dopamine D-2 receptor tracers), [F18]fluorinated benzazepines (dopamine D-1 receptor tracers), and tissue distribution of [F18]-fluoxetine (serotonin reuptake site tracer). The second section relates pharmacological and behavioral studies of amphetamines. The third section reports on progress made with processing of brain images from CT, MRI and PET/SPECT with regards to brain metabolism of glucose during mental tasks.

  20. Phase Behavior of the Ternary Solution Involving Rodlike and Random Coil Polymers

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    The present paper covers the phase behavior of poly(p-benzamide)(PBA)/Nylon 6/H2SO4 and poly(p-phenylene terephthalamide) (PPTA)/Nylon 6/H2SO4 systems. The transition temperatures detected by the Depolarized Light Intensity measurements were used to construct the phase diagram in which the influence of temperature was shown. The enhanced depolarized light intensity observed in the ternary system suggests that the coil polymer chains may tend to be extended and contribute to the overall anisotropy of the liquid crystal phase.

  1. Copper-promoted synthesis of 1,4-benzodiazepinones via alkene diamination

    Science.gov (United States)

    Karyakarte, Shuklendu D.; Sequeira, Fatima C.; Zibreg, Garrick H.; Huang, Guoqing; Matthew, Josiah P.; Ferreira, Marina M. M.

    2015-01-01

    A new method for the synthesis of 2-aminomethyl functionalized 1,4-benzodiazepin-5-ones is presented. The benzodiazepine core is well-known to interact with biological receptors and many pharmaceutical drugs are derived from this structure. The alkene diamination strategy is employed for the first time for the synthesis of 1,4-benzodiazepinones. In this reaction, copper(2-ethylhexanoate)2 serves as promoter and a range of external amines can be coupled with 2-sulfonamido-N-allyl benzamides to generate the 1,4-benzodiazepinones in good yields. PMID:26034340

  2. Nuclear medicine and imaging research (quantitative studies in radiopharmaceutical science)

    International Nuclear Information System (INIS)

    This report describes three studies aimed at using radiolabeled pharmaceuticals to explore brain function and anatomy. The first section describes the chemical preparation of [F18]fluorinated benzamides (dopamine D-2 receptor tracers), [F18]fluorinated benzazepines (dopamine D-1 receptor tracers), and tissue distribution of [F18]-fluoxetine (serotonin reuptake site tracer). The second section relates pharmacological and behavioral studies of amphetamines. The third section reports on progress made with processing of brain images from CT, MRI and PET/SPECT with regards to brain metabolism of glucose during mental tasks

  3. Drug: D02208 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D02208 Drug Sultopride hydrochloride (JAN); Sultopride monohydrochloride; Barnetil ...(TN) C17H26N2O4S. HCl 390.138 390.9253 D02208.gif Neuroleptic Therapeutic category: 1179 ATC code: N05AL02 B...sensory organs 11 Agents affecting central nervous system 117 Psychotropics 1179 Others D02208 Sultopride hy...3] N NERVOUS SYSTEM N05 PSYCHOLEPTICS N05A ANTIPSYCHOTICS N05AL Benzamides N05AL02 Sultopride D02208 Sultopr...sin family Dopamine dopamine D2-receptor [HSA:1813] [KO:K04145] Sultopride [ATC:N05AL02] D0220

  4. Drug: D08590 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D08590 Drug Tiapride (INN); Tiapridal (TN) C15H24N2O4S 328.1457 328.4271 D08590.gif...ANTIPSYCHOTICS N05AL Benzamides N05AL03 Tiapride D08590 Tiapride (INN) Target-based classification of drugs ...[BR:br08310] G Protein-coupled receptors Rhodopsin family Dopamine dopamine D2-receptor [HSA:1813] [KO:K04145] Tiapride... [ATC:N05AL03] D08590 Tiapride (INN) CAS: 51012-32-9 PubChem: 96025274

  5. Drug: D01522 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D01522 Drug Tiapride hydrochloride (JP16); Gramalil (TN) C15H24N2O4S. HCl 364.1224 ...eous 1190 Miscellaneous D01522 Tiapride hydrochloride (JP16) Anatomical Therapeutic Chemical (ATC) classific...ation [BR:br08303] N NERVOUS SYSTEM N05 PSYCHOLEPTICS N05A ANTIPSYCHOTICS N05AL Benzamides N05AL03 Tiaprid...e D01522 Tiapride hydrochloride (JP16) Target-based classification of drugs [BR:br0...8310] G Protein-coupled receptors Rhodopsin family Dopamine dopamine D2-receptor [HSA:1813] [KO:K04145] Tiapride

  6. Drug: D02682 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D02682 Drug Remoxipride (USAN) C16H23BrN2O3 370.0892 371.2694 D02682.gif Antipsycho...TICS N05A ANTIPSYCHOTICS N05AL Benzamides N05AL04 Remoxipride D02682 Remoxipride (USAN) Target-based classif...A:1813] [KO:K04145] Remoxipride [ATC:N05AL04] D02682 Remoxipride (USAN) Opioid si...gma1-opioid receptor [HSA:10280] Remoxipride [ATC:N05AL04] D02682 Remoxipride (USAN) CAS: 80125-14-0 PubChem

  7. Drug: D02683 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D02683 Drug Remoxipride hydrochloride (USAN) C16H23BrN2O3. HCl. H2O 424.0764 425.74...OUS SYSTEM N05 PSYCHOLEPTICS N05A ANTIPSYCHOTICS N05AL Benzamides N05AL04 Remoxipride D02683 Remoxipride hyd...mily Dopamine dopamine D2-receptor [HSA:1813] [KO:K04145] Remoxipride [ATC:N05AL04] D02683 Remoxipride... hydrochloride (USAN) Opioid sigma1-opioid receptor [HSA:10280] Remoxipride [ATC:N05AL04] D02683 Remoxipride

  8. Non-hinge-binding pyrazolo[1,5-a]pyrimidines as potent B-Raf kinase inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Berger, Dan M.; Torres, Nancy; Dutia, Minu; Powell, Dennis; Ciszewski, Greg; Gopalsamy, Ariamala; Levin, Jeremy I.; Kim, Kyung-Hee; Xu, Weixin; Wilhelm, James; Hu, YongBo; Collins, Karen; Feldberg, Larry; Kim, Steven; Frommer, Eileen; Wojciechowicz, Donald; Mallon, Robert; (Wyeth)

    2010-11-19

    As part of our research effort to discover B-Raf kinase inhibitors, we prepared a series of C-3 substituted N-(3-(pyrazolo[1,5-a]pyrimidin-7-yl)phenyl)-3-(trifluoromethyl)benzamides. X-ray crystallography studies revealed that one of the more potent inhibitors (10n) bound to B-Raf kinase without forming a hinge-binding hydrogen bond. With basic amine residues appended to C-3 aryl residues, cellular activity and solubility were enhanced over previously described compounds of this class.

  9. Thermolysis of some N-arylbenzamidoximes: Mechanistic studies for formation of anilide, oxazole and imidazole derivatives

    Indian Academy of Sciences (India)

    ABDEL-AAL GABER; LAYLA TAIB

    2016-05-01

    The thermolysis of N-2-pyridylbenzamidoxime I under nitrogen atmosphere for 5 hours givesrise to 2-phenyl-1H-imidazo[4,5-b]pyridine and N-(pyridin-2-yl)benzamide as the major products (52.4and 18.11%, respectively), in addition to 2-hydroxy pyridine, benzonitrile, benzoic acid, 2-aminopyridine,2-phenyloxazolo[4,5-b]pyridine, 9H-pyrrolo[2,3-b:5,4-b']dipyridine and 2,4,6-triphenyl-1,3,5-triazine. Also,heating N-Α-naphthylbenzamidoxime II under the same conditions gave N-(Α-Naphthyl)benzamide, 2-Phenyl-3H-naphtho[2,1-d] imidazole as the major products besides benzonitrile, benzoic acid, Α-naphthylamine and2-phenylnaphtho[1,2-d]oxazole. In the presence of tetralin, I gave 1-hydroxytetralin, Α-tetralone and 1,1'-bitetrayl besides the previous products. The reaction and isolated products have been interpreted in terms of afree radical mechanism involving the homolysis of N-O and/or C-N bonds.

  10. Nonaqueous capillary electrophoresis of imatinib mesylate and related substances.

    Science.gov (United States)

    Ye, Lei; Huang, Yifei; Li, Jian; Xiang, Guangya; Xu, Li

    2012-08-01

    In the present study, nonaqueous capillary electrophoretic separation of imatinib mesylate (IM) and related substances, N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidinamine (PYA), N-(4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)-4-((piperazin-1-yl)methyl) benzamide (NDI) and 4-chloromethyl-N-(4-methyl-3-((4-(pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide (CPB) was developed. The influential factors affecting separation, including type and concentration of the electrolyte, applied voltage, and buffer modifier were investigated. Baseline separation of the studied analytes was obtained using a buffer of 50 mM Tris and 50 mM methanesulfonic acid in methanol at a apparent pH (pH*) of 1.65. To enhance the sensitivity, large-volume sample stacking was employed for online concentration. The strongest analytical signal with a suitable separation was achieved when the injection time was 100 s. The linearity ranges of PYA and NDI were 0.100-2.50 μg mL(-1), and that of CPB was 0.125-2.50 μg mL(-1), with good coefficients (r(2) > 0.9948). The relative standard deviations of intra- and interday were satisfactory. Under the optimized conditions, seven batches of the synthesized samples were analyzed and CPB was detected in two batches. Owing to its simplicity, effectiveness, and low price, the developed method is promising for quality control of IM.

  11. Structure-Based Optimization of a Small Molecule Antagonist of the Interaction Between WD Repeat-Containing Protein 5 (WDR5) and Mixed-Lineage Leukemia 1 (MLL1).

    Science.gov (United States)

    Getlik, Matthäus; Smil, David; Zepeda-Velázquez, Carlos; Bolshan, Yuri; Poda, Gennady; Wu, Hong; Dong, Aiping; Kuznetsova, Ekaterina; Marcellus, Richard; Senisterra, Guillermo; Dombrovski, Ludmila; Hajian, Taraneh; Kiyota, Taira; Schapira, Matthieu; Arrowsmith, Cheryl H; Brown, Peter J; Vedadi, Masoud; Al-Awar, Rima

    2016-03-24

    WD repeat-containing protein 5 (WDR5) is an important component of the multiprotein complex essential for activating mixed-lineage leukemia 1 (MLL1). Rearrangement of the MLL1 gene is associated with onset and progression of acute myeloid and lymphoblastic leukemias, and targeting the WDR5-MLL1 interaction may result in new cancer therapeutics. Our previous work showed that binding of small molecule ligands to WDR5 can modulate its interaction with MLL1, suppressing MLL1 methyltransferase activity. Initial structure-activity relationship studies identified N-(2-(4-methylpiperazin-1-yl)-5-substituted-phenyl) benzamides as potent and selective antagonists of this protein-protein interaction. Guided by crystal structure data and supported by in silico library design, we optimized the scaffold by varying the C-1 benzamide and C-5 substituents. This allowed us to develop the first highly potent (Kdisp < 100 nM) small molecule antagonists of the WDR5-MLL1 interaction and demonstrate that N-(4-(4-methylpiperazin-1-yl)-3'-(morpholinomethyl)-[1,1'-biphenyl]-3-yl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide 16d (OICR-9429) is a potent and selective chemical probe suitable to help dissect the biological role of WDR5.

  12. New SPECT tracers: Example of tracers of proteoglycans and melanin; Nouveaux traceurs TEMP: exemple des traceurs des proteoglycanes et de la melanine

    Energy Technology Data Exchange (ETDEWEB)

    Cachin, F.; Mestas, D.; Kelly, A.; Merlin, C.; Veyre, A.; Maublant, J. [CRLCC Jean-Perrin, Service de Medecine Nucleaire, 63 - Clermont-Ferrand (France); Cachin, F.; Chezal, J.M.; Miot-Noirault, E.; Moins, N.; Auzeloux, P.; Vidal, A.; Bonnet-Duquennoy, M.; Boisgard, S.; D' Incan, M.; Madelmont, J.C.; Maublant, J. [Universite d' Auvergne, EA 4231, 63 - Clermont-Ferrand (France); Boisgard, S. [CHRU Gabriel-Montpied, Service d' Orthopedie, 63 - Clermont-Ferrand (France); D' Incan, M. [CHRU Gabriel-Montpied, Service de Dermatologie, 63 - Clermont-Ferrand (France); Redini, F. [Inserm, U957-EA3822, Faculte de Medecine, 44 - Nantes (France); Filaire, M. [Universite d' Auvergne, Lab. d' Anatomie, 63 - Clermont-Ferrand (France)

    2009-02-15

    The majority of research program on new radiopharmaceuticals turn to tracers used for positron emission tomography (PET). Only a few teams work on new non fluorine labeled tracers. However, the coming of SPECT/CT gamma cameras, the arrival of semi-conductors gamma cameras should boost the development of non-PET tracers. We exhibit in this article the experience acquired by our laboratory in the conception and design of two new non fluorine labelled compounds. The {sup 99m}Tc-N.T.P. 15-5 (N.T.P. 15-5 for N-[tri-ethyl-ammonium]-3-propyl-[15]ane-N5) which binds to proteoglycans could be used for the diagnosis and staging of osteoarthritis and chondrosarcoma. The iodo benzamides, specific to the melanin, are nowadays compared to {sup 18}F-fluorodeoxyglucose in a phase III clinical trial for the diagnosis and detection of melanoma metastasis. Our last development focus on N-[2-(diethyl-amino)ethyl]-4 and 2-iodo benzamides respectively B.Z.A. and B.Z.A.2 hetero-aromatic analogues usable for melanoma treatment. (authors)

  13. Synthesis and in vivo brain distribution of carbon-11-labeled {delta}-opioid receptor agonists

    Energy Technology Data Exchange (ETDEWEB)

    Pichika, Rama, E-mail: rpichika@ucsd.ed [Department of Radiology, University of California, San Diego, CA (United States); Jewett, Douglas M.; Sherman, Philip S. [Division of Nuclear Medicine, Department of Radiology, University of Michigan Medical School, Ann Arbor, MI 48109 (United States); Traynor, John R. [Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109 (United States); Husbands, Stephen M. [Department of Pharmacy and Pharmacology, University of Bath, Bath (United Kingdom); Woods, James H. [Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109 (United States); Kilbourn, Michael R. [Division of Nuclear Medicine, Department of Radiology, University of Michigan Medical School, Ann Arbor, MI 48109 (United States)

    2010-11-15

    Three new radiolabeled compounds, [{sup 11}C]SNC80 ((+)-4-[({alpha}R)-{alpha}-{l_brace}(2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl{r_brace}-3-[{sup 11}C] methoxybenzyl-N,N-diethylbenzamide), N,N-diethyl-4-[3-methoxyphenyl-1-[{sup 11}C]methylpiperidin-4-ylidenemethyl) benzamide and N,N-diethyl-4-[(1-[{sup 11}C]methylpiperidin-4-ylidene)phenylmethyl]benzamide, were prepared as potential in vivo radiotracers for the {delta}-opioid receptor. Each compound was synthesized by alkylation of the appropriate desmethyl compounds using [{sup 11}C]methyl triflate. In vivo biodistribution studies in mice showed very low initial brain uptake of all three compounds and no regional specific binding for [{sup 11}C]SNC80. A monkey positron emission tomography study of [{sup 11}C]SNC80 confirmed low brain permeability and uniform regional distribution of this class of opioid agonists in a higher species. Opioid receptor ligands of this structural class are thus unlikely to succeed as in vivo radiotracers, likely due to efficient exclusion from the brain by the P-glycoprotein efflux transporter.

  14. An Efficient Synthesis of 1-Alkyl-2-phenyl-4-quinolones from 2-Halobenzoic Acids

    Energy Technology Data Exchange (ETDEWEB)

    Song, Yoon Ju; Choi, Jin Sun; Lee, Jae In [Duksung Women' s Univ., Seoul (Korea, Republic of)

    2013-10-15

    The present method offers an efficient synthesis of 1-alkyl-2-phenyl-4-quinolones from 2-haloben-zoic acids. It has the advantages with respect to (i) synthesis of 2 equiv of alkynones 5 from 1 equiv of 4,6-pyrimidyl di(2-halobenzoates) 3, (ii) synthesis of versatile 1-alkyl-2-phenyl-4-quinolones in high overall yields, and (iii) use of readily available and cheap starting materials. Therefore, this method could be utilized as a practical synthesis of 1-alkyl-2-phenyl-4-quinolones. Several methods have been developed to synthesize 1-alkyl-2-phenyl-4-quinolones from 2'-substituted acetophenones, anilines, and 2-halobenzoyl chlorides as starting materials. The reaction of N-methylisatoic anhydride with the lithium enolate of an 4'-methoxyacetophenone afforded the 1-methyl-2-phenyl-4-quinolone in a short sequence, but the yield was low. N-(2-Acetylphenyl)benzamides, prepared by Friedel-Crafts acylation of N-phenyl benzamides with acetyl chloride or benzoylation of 2'-aminoacetophenones with benzoyl chlorides,8 were cyclized with potassium t-butoxide to yield 2-aryl-4-quinolones, which were further alkylated with alkyl iodides to give 1-alkyl-2-aryl-4-quinolones.

  15. Quinuclidine compounds differently act as agonists of Kenyon cell nicotinic acetylcholine receptors and induced distinct effect on insect ganglionic depolarizations.

    Science.gov (United States)

    Mathé-Allainmat, Monique; Swale, Daniel; Leray, Xavier; Benzidane, Yassine; Lebreton, Jacques; Bloomquist, Jeffrey R; Thany, Steeve H

    2013-12-01

    We have recently demonstrated that a new quinuclidine benzamide compound named LMA10203 acted as an agonist of insect nicotinic acetylcholine receptors. Its specific pharmacological profile on cockroach dorsal unpaired median neurons (DUM) helped to identify alpha-bungarotoxin-insensitive nAChR2 receptors. In the present study, we tested its effect on cockroach Kenyon cells. We found that it induced an inward current demonstrating that it bounds to nicotinic acetylcholine receptors expressed on Kenyon cells. Interestingly, LMA10203-induced currents were completely blocked by the nicotinic antagonist α-bungarotoxin. We suggested that LMA10203 effect occurred through the activation of α-bungarotoxin-sensitive receptors and did not involve α-bungarotoxin-insensitive nAChR2, previously identified in DUM neurons. In addition, we have synthesized two new compounds, LMA10210 and LMA10211, and compared their effects on Kenyon cells. These compounds were members of the 3-quinuclidinyl benzamide or benzoate families. Interestingly, 1 mM LMA10210 was not able to induce an inward current on Kenyon cells compared to LMA10211. Similarly, we did not find any significant effect of LMA10210 on cockroach ganglionic depolarization, whereas these three compounds were able to induce an effect on the central nervous system of the third instar M. domestica larvae. Our data suggested that these three compounds could bind to distinct cockroach nicotinic acetylcholine receptors. PMID:23884575

  16. Synthesis and antileishmanial activity of C7- and C12-functionalized dehydroabietylamine derivatives.

    Science.gov (United States)

    Dea-Ayuela, M Auxiliadora; Bilbao-Ramos, Pablo; Bolás-Fernández, Francisco; González-Cardenete, Miguel A

    2016-10-01

    Abietane-type diterpenoids, either naturally occurring or synthetic, have shown a wide range of pharmacological actions, including antiprotozoal properties. In this study, we report on the antileishmanial evaluation of a series of (+)-dehydroabietylamine derivatives functionalized at C7 and/or C12. Thus, the activity in vitro against Leishmania infantum, Leishmania donovani, Leishmania amazonensis and Leishmania guyanensis, was studied. Most of the benzamide derivatives showed activities at low micromolar concentration against cultured promastigotes of Leishmania spp. (IC50 = 2.2-46.8 μM), without cytotoxicity on J774 macrophage cells. Compound 15, an acetamide, was found to be the most active leishmanicidal agent, though it presented some cytotoxicity on J774 cells. Among the benzamide derivatives, compounds 8 and 10, were also active against L. infantum intracellular amastigotes, being 18- and 23-fold more potent than the reference compound miltefosine, respectively. Some structure-activity relationships have been identified for the antileishmanial activity in these dehydroabietylamine derivatives. PMID:27318121

  17. Two dodecanuclear heterometallic [Zn6Ln6] clusters constructed by a multidentate salicylamide salen-like ligand: synthesis, structure, luminescence and magnetic properties.

    Science.gov (United States)

    Song, Xue-Qin; Liu, Pan-Pan; Liu, Yuan-Ang; Zhou, Jing-Jing; Wang, Xiao-Long

    2016-05-10

    The employment of a multidentate salicylamide salen-like ligand, 2-hydroxy-N-(2-(2-hydroxybenzylidene)amino)ethyl)benzamide (H3L), in aid of NO3(-) anions under weak basic conditions in Zn(II)-Ln(III) chemistry (Ln = Eu, and Dy, ) led to the isolation of two novel butterfly heterometallic dodecanuclear clusters with six Ln(III) ions occupying the body position and six Zn(II) ions the outer wing-tip sites. All of them are fully characterized by elemental analysis, FT-IR spectroscopy, TG analysis, single-crystal X-ray diffraction, and X-ray powder diffraction (XRPD) techniques. Luminescence studies indicate that exhibits dual emission, while exhibits a bright blue emission under visible light excitation. Furthermore, magnetic susceptibility studies carried out for indicate that the magnetic exchange between Dy(III) ions revealed ferromagnetic interactions with interesting slow relaxation of magnetization of the SMM behavior. PMID:27092471

  18. Research into aroma changes in irradiated foodstuffs. I.- Studies on Fish

    International Nuclear Information System (INIS)

    Radiolytic formation of volatile compounds have been investigated in fillets of hake, codfish and bonito gamma-irradiated at a dose range of 0.1-5 Mrads. Analytical methods have been developed by gas chromatography of functional group derivatives: carbonyls as 2,4,-dinitrophenyl hydrazones, primary and secondary amines as N-alkyl benzamides, and thiols as 2,4-dinitrophenyl alkyl thioethers. The main results are as follows: increasing with the integral dose of the whole carbonyls, the most significant components being acetaldehyde, propional dehyde and formaldehyde; no significant variations with the integral dose od the traces of ammonia, methylamine, trimethylamine, ethylamine, diethylamine, propylamine, butylamine and pentylamine found in unirradiated samples; and radiolytic formation of methanethiol and dimethyl disulfide. (Author) 98 refs

  19. Fluorescence enhancement of Er3+ ion by Glibenclamide: A practical probe

    International Nuclear Information System (INIS)

    Glibenclamide, 5-chloro-N-[2-[4-(cyclohexylcarbamoyl-sulfamoyl) phenyl]ethyl]-2-methoxy-benzamide, is an important anti-diabetic drug that can enhance the erbium (Er) intrinsic fluorescence intensity. Based on that fact, Glibenclamide can be monitored using simple and sensitive fluorimetric probes. For this research, an interest arose in using lanthanides as probing biochemical reactions, and to study the interactions between Ca2+ and biologically important molecules. Methodologies employed are based on the unique fluorescence properties of lanthanides due to their unfilled 4fn electronic orbital, and formation of a complex between Er3+ and Glibenclamide. The proposed method was found to be simple, accurate and precise, thus allowing it to be used as a detector for high performance liquid chromatography in the future.

  20. Chemical constituents from red algae Bostrychia radicans (Rhodomelaceae): new amides and phenolic compounds

    Energy Technology Data Exchange (ETDEWEB)

    Oliveira, Ana Ligia Leandrini de; Silva, Denise B. da; Lopes, Norberto P.; Debonsi, Hosana M. [Universidade de Sao Paulo (FCFRP/USP), Ribeirao Preto, SP (Brazil). Fac. de Ciencias Farmaceuticas de Ribeirao Preto. Dept. de Quimica e Fisica; Yokoya, Nair S., E-mail: hosana@fcfrp.usp.br [Instituto de Botanica, Sao Paulo, SP (Brazil). Secao de Ficologia

    2012-07-01

    This study describes the isolation and structural determination of two amides, isolated for the first time: N,4-dihydroxy-N-(2'-hydroxyethyl)-benzamide (0.019%) and N,4-dihydroxy-N-(2'-hydroxyethyl)-benzeneacetamide (0.023%). These amides, produced by the red macroalgae Bostrychia radicans, had their structures assigned by NMR spectral data and MS analyses. In addition, this chemical study led to the isolation of cholesterol, heptadecane, squalene, trans-phytol, neophytadiene, tetradecanoic and hexadecanoic acids, methyl hexadecanoate and methyl 9-octadecenoate, 4-(methoxymethyl)-phenol, 4-hydroxybenzaldehyde, methyl 4-hydroxybenzeneacetate, methyl 2-hydroxy-3-(4-hydroxyphenyl)-propanoate, hydroquinone, methyl 4-hydroxymandelate, methyl 4-hydroxybenzoate, 4-hydroxybenzeneacetic acid and (4-hydroxyphenyl)-oxo-acetaldehyde. This is the first report concerning these compounds in B. radicans, contributing by illustrating the chemical diversity within the Rhodomelaceae family. (author)

  1. Synthesis and characterization of novel dopamine-derivative:Application of modified multi-wall carbon nanotubes paste electrode for electrochemical investigation

    Institute of Scientific and Technical Information of China (English)

    Shadpour Mallakpour; Mehdi Hatami; Ali A. Ensafi; Hassan Karimi-Maleh

    2011-01-01

    Novel dopamine-derivative compound, 3,5-diamino-N-(3,4-dihydroxyphenethyl)benzamide (3,5-DAB) was prepared in two steps. In the first step dopamine hydrochloride was reacted with 3,5-dinitrobenzoyl chloride in the presence of propylene oxide. In the second step reduction of nitro groups resulted in preparation of 3,5-DAB in quantitative yield. This material was characterized using conventional spectroscopic methods such as FT-IR and 1H NMR. In addition, the redox response of a modified carbon nanotubes paste electrode of 3,5-DAB was investigated in aqueous solution at a neutral pH. The result showed that the electrode process has a guasi-reversible response, with △Ep, greater than the (59/n) mV expected for a reversible system. Finally, the diffusion coefficient for redox process in paraffin oil matrix obtained using chronoamperometry methods.

  2. (E)-N′-[1-(Thio­phen-2-yl)ethyl­idene]benzohydrazide

    OpenAIRE

    Shan, Shang; Huang, Yan-Lan; Guo, Han-Qi; Li, Deng-feng; Sun, Jian

    2011-01-01

    The title compound, C13H12N2OS, was obtained from the condensation reaction of 2-acetyl­thio­phene and benzohydrazide. In the mol­ecule, the formohydrazide fragment is approximately planar (r.m.s deviation = 0.0146 Å) and the mean plane is oriented at dihedral angles of 24.47 (11) and 28.86 (13)°, respectively, to the phenyl and thio­phene rings. The thio­phene and phenyl rings make a dihedral angle of 53.21 (8)°. The benzamide fragment and thio­phene ring are located on the opposite sides of...

  3. Synthesis and biological evaluation of some new amide moiety bearing quinoxaline derivatives as antimicrobial agents.

    Science.gov (United States)

    Abu Mohsen, U; Yurttaş, L; Acar, U; Özkay, Y; Kaplacikli, Z A; Karaca Gencer, H; Cantürk, Z

    2015-05-01

    In this study, we aimed to synthesize some new quinoxaline derivatives bearing amide moiety and to evaluate their antimicrobial activity. A set of 16 novel compounds of N-[2,3-bis(4-methoxy/methylphenyl)quinoxalin-6-yl]-substituted benzamide derivatives were synthesized by reacting 2,3-bis(4-methoxyphenyl)-6-aminoquinoxaline or 2,3-bis(4-methylphenyl)-6-aminoquinoxaline with benzoyl chloride derivatives in tetrahydrofuran and investigated for their antimicrobial activity. The structures of the obtained final compounds were confirmed by spectral data (IR, (1)H-NMR, (13)C-NMR and MS). The antimicrobial activity of the compounds were determined by using the microbroth dilution method. Antimicrobial activity results revealed that synthesized compounds exhibited remarkable activity against Candida krusei (ATCC 6258) and Candida parapsilosis (ATCC 22019).

  4. Synthesis, Optimization, and Evaluation of Novel Small Molecules as Antagonists of WDR5-MLL Interaction.

    Science.gov (United States)

    Bolshan, Yuri; Getlik, Matthäus; Kuznetsova, Ekaterina; Wasney, Gregory A; Hajian, Taraneh; Poda, Gennadiy; Nguyen, Kong T; Wu, Hong; Dombrovski, Ludmila; Dong, Aiping; Senisterra, Guillermo; Schapira, Matthieu; Arrowsmith, Cheryl H; Brown, Peter J; Al-Awar, Rima; Vedadi, Masoud; Smil, David

    2013-03-14

    The WD40-repeat protein WDR5 plays a critical role in maintaining the integrity of MLL complexes and fully activating their methyltransferase function. MLL complexes, the trithorax-like family of SET1 methyltransferases, catalyze trimethylation of lysine 4 on histone 3, and they have been widely implicated in various cancers. Antagonism of WDR5 and MLL subunit interaction by small molecules has recently been presented as a practical way to inhibit activity of the MLL1 complex, and N-(2-(4-methylpiperazin-1-yl)-5-substituted-phenyl) benzamides were reported as potent and selective antagonists of such an interaction. Here, we describe the protein crystal structure guided optimization of prototypic compound 2 (K dis = 7 μM), leading to identification of more potent antagonist 47 (K dis = 0.3 μM).

  5. Derivatives of (phenylsulfonamido-methyl)nicotine and (phenylsulfonamido-methyl)thiazole as novel 11β-hydroxysteroid dehydrogenase type 1 inhibitors: synthesis and biological activities in vitro

    Institute of Scientific and Technical Information of China (English)

    Xu ZHANG; Yang ZHOU; Yu SHEN; Li-li DU; Jun-hua CHEN; Ying LENG; Jian-hua SHEN

    2009-01-01

    Aim: To design and synthese a novel class of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitors, featuring the (phenylsul-fonamido-methyl)pyridine and (phenyisulfonamido-methyl)thiazole framework. Methods: Our initial lead 4-(phenylsulfonamido-methyl)benzamides were modified. Inhibition of human and mouse 11β-HSD1 enzy-matic activities by the new compounds was determined by a scintillation proximity assay (SPA) using microsomes containing 11β-HSD1.Results: Sixteen new compounds (6a-6h, 7a-7h) were designed, synthesized and bioassayed. In dose-response studies, several com-pounds showed strong inhibitory activities with IC_(50) values at nanomolar or low nanomolar concentrations. Structure-activity relation-ships are also discussed with respect to molecular docking results. Conclusion: This study provides two promising new templates for 11β-HSD1 inhibitors.

  6. 3-(Benzodioxan-2-ylmethoxy)-2,6-difluorobenzamides bearing hydrophobic substituents at the 7-position of the benzodioxane nucleus potently inhibit methicillin-resistant Sa and Mtb cell division.

    Science.gov (United States)

    Straniero, Valentina; Pallavicini, Marco; Chiodini, Giuseppe; Zanotto, Carlo; Volontè, Luca; Radaelli, Antonia; Bolchi, Cristiano; Fumagalli, Laura; Sanguinetti, Maurizio; Menchinelli, Giulia; Delogu, Giovanni; Battah, Basem; De Giuli Morghen, Carlo; Valoti, Ermanno

    2016-09-14

    Lipophilic substituents at benzodioxane C (7) of 3-(benzodioxan-2-ylmethoxy)-2,6-difluorobenzamide improve the antibacterial activity against methicillin-resistant Staphylococcus aureus strains to MIC values in the range of 0.2-2.5 μg/mL, whereas hydrophilic substituents at the same position and modifications at the benzodioxane substructure, excepting for replacement with 2-cromanyl, are deleterious. Some of the lead compounds also exhibit good activity against Mtb. Parallel SARs to those of 3-(2-benzothiazol-2-ylmethoxy)-2,6-difluorobenzamide, well known FtsZ inhibitor, and cells alterations typical of FtsZ inhibition indicate such a protein as the target of these potent antibacterial benzodioxane-benzamides. PMID:27191617

  7. Cytotoxic T lymphocyte control during ectromelia (mousepox) virus infection: Interaction between MHC-restricted cells analyzed by non-radioactive-fluorimetry

    International Nuclear Information System (INIS)

    Cytotoxic T lymphocyte activity of draining lymph node cells isolated from BALB/c mice infected with ectromelia virus (EV) was examined using a fluorometric cell-mediated cytotoxicity (CMC) assay. Specific lysis of target cells A20 and EMT-6 primed with EV was demonstrated. The classical CD8+ cytolytic pathway (72.7%) as compared to that of CD4+ (27.3%) in the cellular response during acute infection. Also an alternative method for determining CMC, employing a bis-benzamide dye for labelling target cells, is described. Coefficient variations of relative fluorescence were below 6%, that makes the method sensitive and reliable. Comparison of the assay demonstrated with to that of the 51Cr-release assay is discussed

  8. Electrostatic assembly/disassembly of nanoscaled colloidosomes for light-triggered cargo release

    KAUST Repository

    Li, Song

    2015-04-27

    Colloidosome capsules possess the potential for the encapsulation and release of molecular and macromolecular cargos. However, the stabilization of the colloidosome shell usually requires an additional covalent crosslinking which irreversibly seals the capsules, and greatly limits their applications in large-cargos release. Herein we report nanoscaled colloidosomes designed by the electrostatic assembly of organosilica nanoparticles (NPs) with oppositely charged surfaces (rather than covalent bonds), arising from different contents of a bridged nitrophenylene-alkoxysilane [NB; 3-nitro-N-(3-(triethoxysilyl)propyl)-4-(((3-(triethoxysilyl)propyl)-amino)methyl)benzamid] derivative in the silica. The surface charge of the positively charged NPs was reversed by light irradiation because of a photoreaction in the NB moieties, which impacted the electrostatic interactions between NPs and disassembled the colloidosome nanosystems. This design was successfully applied for the encapsulation and light-triggered release of cargos. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  9. Selective solar photodegradation of organopollutant mixtures in water

    Energy Technology Data Exchange (ETDEWEB)

    Robert, D.; Piscopo, A.; Weber, J.V. [Metz Univ., Saint-Avold (France). Lab. de Chimie et Applications

    2004-11-01

    Heterogeneous photocatalysis in a water solution is recognised as a method of totally eliminating most recalcitrant organic pollutants found in such solutions. Our current work has tried to show that the heterogeneous photocatalysis process can also be a selective elimination method in the case of the mixture: 4-hydroxybenzoic acid (4-HBz) and benzamide (Bz) at semi-pilot plant scale (190 dm{sup 3}) under conditions of solar irradiation. The photocatalysis experiments performed by us were done at the 'Plataforma Solar de Almeria' and were carried out in the compound parabolic collectors' CPC system. We investigated in particular the influence of TiO{sub 2} loading, the effect of 4-HBz concentration and the effect of the presence of chloride anions and pH on the selectivity of the reaction process. (Author)

  10. Field evaluation of commercial repellents against the floodwater mosquito Psorophora columbiae (Diptera: Culicidae) in St. Johns County, Florida.

    Science.gov (United States)

    Qualls, Whitney A; Xue, Rui-De; Holt, J Adam; Smith, Mike L; Moeller, Jeanne J

    2011-11-01

    Three plant-based repellents-REPEL LEMON Eucalyptus Insect Repellent Lotion (active ingredient [AI] 30% oil of eucalyptus), Bite Blocker Xtreme Sportsman Organic Insect Repellent ([AI] 3% soybean oil, 6% geranium oil, and 8% castor oil), and Bite Blocker BioUD Insect Repellent ([AI] 7.75% 2-undecanone)--were evaluated against OFF! ([AI] 15% N,N-diethyl-m-toluamide or N,N-diethyl-3-methyl-benzamide, also called DEET) at a field site in Elkton, FL, to determine the mean protection time provided against Psorophora columbiae (Dyar & Knab). These products provided different protection times against biting Ps. columbiae. REPEL provided the longest protection time (330 min) followed by Bite Blocker Xtreme Sportsman (163 min), Bite Blocker BioUD (140 min), and OFF! (130 min). This study provides the first information about plant-based insect repellent protection times against Ps. columbiae. PMID:22238886

  11. Nickel-Catalyzed Oxidative C-H/N-H Isocyanide Insertion: An Efficient Synthesis of Iminoisoindolinone Derivatives.

    Science.gov (United States)

    Hao, Wenyan; Tian, Jun; Li, Wu; Shi, Renyi; Huang, Zhiliang; Lei, Aiwen

    2016-06-01

    Transition metal-catalyzed isocyanide insertion has served as a fundamental and important chemical transformation. Classical isocyanide insertion usually occurs between organohalides and nucleophiles, which normally involves tedious and non-atom-economical prefunctionalization processes. However, oxidative C-H/N-H isocyanide insertion offers an efficient and green alternative. Herein, a nickel-catayzed oxidative C-H/N-H isocyanide insertion of aminoquinoline benzamides has been developed. Different kinds of iminoisoindolinone derivatives could be synthesized in good yields by utilizing Ni(acac)2 as the catalyst. In this transformation, isocyanide serves as an efficient C1 connector, which further inserted into two simple nucleophiles (C-H/N-H), representing an effective way to construct heterocycles.

  12. Dopamine D(2) receptor quantification in extrastriatal brain regions using [(123)I]epidepride with bolus/infusion

    DEFF Research Database (Denmark)

    Pinborg, L H; Videbaek, C; Knudsen, G M;

    2000-01-01

    The iodinated benzamide epidepride, which shows a picomolar affinity binding to dopamine D(2) receptors, has been designed for in vivo studies using SPECT. The aim of the present study was to apply a steady-state condition by the bolus/infusion approach with [(123)I]epidepride for the...... bolus/infusion (B/I) experiment was applied. It was predicted that a B/I protocol with infusion of one-third of the initial bolus per hour would be appropriate. Steady-state conditions were attained in extrastriatal regions within 3-4 h but the infusion continued up to 7 h in order to minimize the...... has a unique signal-to-noise ratio compared to [(123)I]IBZM but present difficulties for steady-state measurements of striatal regions. The bolus/infusion approach is particularly feasible for quantification of the binding potential in extrastriatal regions....

  13. Autoradiographic comparison of [125I]epidepride and [125I]NCQ 298 binding to human brain extrastriated dopamine receptors.

    Science.gov (United States)

    Hall, H; Halldin, C; Jerning, E; Osterlund, M; Farde, L; Sedvall, G

    1997-07-01

    Extrastriatal D2-dopamine receptors can be visualised in the monkey and human brain using the benzamides [11C]- and [76Br]FLB 457 in PET and [123I]epidepride in SPECT but not with the salicylamide analogues [76Br]FLB 463 and [123I]NCQ 298. To clarify the background for the differences in binding seen in vivo, we have compared the in vitro binding of [125I]epidepride and [123I]NCQ 298, using human whole hemisphere autoradiography. The images obtained with any radioligand showed detailed distribution with very dense binding in the putamen and the caudate nucleus and with the same detailed extrastriatal distribution. Thus, the divergent results obtained in vivo cannot be explained by different binding properties of the extrastriatal receptors. PMID:9290072

  14. Autoradiographic comparison of [125I]epidepride and [125I]NCQ 298 binding to human brain extrastriated dopamine receptors

    International Nuclear Information System (INIS)

    Extrastriatal D2-dopamine receptors can be visualized in the monkey and human brain using the benzamides [11C]- and [76Br]FLB 457 in PET and [123I]epidepride in SPECT but not with the salicylamide analogues [76Br]FLB 463 and [123I]NCQ 298. To clarify the background for the differences in binding seen in vivo, we have compared the in vitro binding of [125I]epidepride and [125I]NCQ 298, using human whole hemisphere autoradiography. The images obtained with any radioligand showed detailed distribution with very dense binding in the putamen and the caudate nucleus and with the same detailed extrastriatal distribution. Thus, the divergent results obtained in vivo cannot be explained by different binding properties of the extrastriatal receptors

  15. Autoradiographic comparison of [{sup 125}I]epidepride and [{sup 125}I]NCQ 298 binding to human brain extrastriated dopamine receptors

    Energy Technology Data Exchange (ETDEWEB)

    Hall, Haakan; Halldin, Christer; Jerning, Eva; Oesterlund, Marie; Farde, Lars; Sedvall, Goeran

    1997-07-01

    Extrastriatal D{sub 2}-dopamine receptors can be visualized in the monkey and human brain using the benzamides [{sup 11}C]- and [{sup 76}Br]FLB 457 in PET and [{sup 123}I]epidepride in SPECT but not with the salicylamide analogues [{sup 76}Br]FLB 463 and [{sup 123}I]NCQ 298. To clarify the background for the differences in binding seen in vivo, we have compared the in vitro binding of [{sup 125}I]epidepride and [{sup 125}I]NCQ 298, using human whole hemisphere autoradiography. The images obtained with any radioligand showed detailed distribution with very dense binding in the putamen and the caudate nucleus and with the same detailed extrastriatal distribution. Thus, the divergent results obtained in vivo cannot be explained by different binding properties of the extrastriatal receptors.

  16. Research into aroma changes in irradiated foodstuffs. I.- Studies on Fish; Investigacion de Alteraciones de Aroma en alimentos irradiados. I Estudio sobre Pescado

    Energy Technology Data Exchange (ETDEWEB)

    Barreiro Pinero, R.; Gasco Sanchez, L.; Valverde Garcia, F.

    1972-07-01

    Radiolytic formation of volatile compounds have been investigated in fillets of hake, codfish and bonito gamma-irradiated at a dose range of 0.1-5 Mrads. Analytical methods have been developed by gas chromatography of functional group derivatives: carbonyls as 2,4,-dinitrophenyl hydrazones, primary and secondary amines as N-alkyl benzamides, and thiols as 2,4-dinitrophenyl alkyl thioethers. The main results are as follows: increasing with the integral dose of the whole carbonyls, the most significant components being acetaldehyde, propional dehyde and formaldehyde; no significant variations with the integral dose od the traces of ammonia, methylamine, trimethylamine, ethylamine, diethylamine, propylamine, butylamine and pentylamine found in unirradiated samples; and radiolytic formation of methanethiol and dimethyl disulfide. (Author) 98 refs.

  17. Difference in volatiles of poplar induced by various damages

    Institute of Scientific and Technical Information of China (English)

    HUZeng-hui; YANGDi; SHENYing-bai

    2004-01-01

    Three treatments including mechanical damage, Lymantria dispar attacking and daubing oral secretions of the insects on mechanically damaged cut were conducted on Populus simoniixPopulus pyramibalis c.v. in order to find the genuine reason leading to effective resistance response of tree to insects attacking. The release situation of the induced volatiles of the plant was analyzed by TCT-GC/MS at 24 hours after damages. The results indicated that some of the volatiles such as (Z)-3-hexenyl acetate, decanal, 3-hexenyl isovalerate, nonanal, ocimene, and 2-cyanobutane can be induced by both insects attacking and mechanical damage, while 2,6-dimethyl-1,3,5,7-octatetraene, 2-methyl-6-methylene-1,7-octadien-3-one, caryophyllene,Isovaleronitrile, diethyl-methyl-benzamide, and dicapryl phthalate were only induced by insects attacking. Such difference in volatiles was attributed to that there existed active components in oral sections of the larvae of Lymantria dispar

  18. Preparation and characterization of monosubstituted porphyrins immobilized on nanosilica

    Indian Academy of Sciences (India)

    Ebrahim Ahmadi; Ali Ramazani; Asemeh Mashhadi-Malekzadeh; Zahra Hamdi; Zahra Mohamadnia

    2014-08-01

    Three kinds of heteroaldehydes, -(3-triethoxysilylpropyl)-4-formyl benzamide (TPHA/SiO2), were prepared by the reaction of terephthalaldehydic acid with different silica supports such as hexagonal SBA-15, spherical SBA-15 and amorphous SiO2 for comparison purposes. Anchoring of this aldehyde to different supports allows the synthesis of mono-substituted porphyrins without the production of di-, tri- and tetra-substituted porphyrin side products. The exclusion of the aforementioned side products during the synthesis of monosubstituted porphyrins greatly reduced the complexity during purification of the product. Absorption spectrophotometry was performed on silica gel immobilizing porphyrin (CPTTP), free base tetraphenylporphyrin (H2TPP) and heteroaldehydes (TPHA/SiO2) using UV–Visible instrument and confirmed the presence of porphyrin on the structure of CPTTP.

  19. Synthesis and reactions with a midines of derivates cycles and of open chain of 2-bromo-3, 4-dioxobutanoic; Sintesis y reacciones con amidinas de derivados ciclicos y de cadena abierta del acido 2-bromo-3, 4-dioxobutanoico

    Energy Technology Data Exchange (ETDEWEB)

    Ancos, B. de; Delgado, F.; Martin, M.R. [Departamento de Quimica Organica, Facultad de Ciencias, Universidad Autonoma, Madrid (Spain)

    1995-12-31

    Bromination of enaminoesters 1 and 5, in appropriate conditions, affords in good yield enamines of the corresponding 2-bromo-3.4-dioxobutanoic acid derivatives 2-3 and 6 or dibromocompounds 4 and 6. The open chain enaminoesters (1-3) are more easily hydrolyzed that enaminofuranones 5 and 6. Prolongated treatment of 6 with hydrochloric acid affords the chlorinated enamine 11. The synthesis of 3-Bromo-4-hydroxy-5-methoxyfuran-2(5H)-one 10 can be achieved by bromination of 12, obtained by hydrolysis of 5. The reaction of methyl 3-bromo-4, 4-dimethoxy-3-oxobutanoate with amidines is a good method for the synthesis of 5-bromo-6-(dimethoxymethyl) pyrimidine-4(3H)-ones substituted at 2 position. Under the same conditions the reaction of furanone 10 with benzamide does not lead to the corresponding imidazoline. (Author) 12 refs.

  20. Synthetic studies on axial chiral biaryls and functional materials utilizing arene-metal complexes; aren kinzokusakutai no tokusei wo riyo shita jikufusai biariru, oyobi shinki kinosei zairyo no gosei kenkyu

    Energy Technology Data Exchange (ETDEWEB)

    Uemura, Motokazu [Osaka Prefecture University, Osaka (Japan). Faculty of Integrated Arts and Sceinces

    1999-12-16

    Axially chiral biaryls compounds are of importance not only as chiral ligands for asymmetric reactions but also as biologically active natural products, e. g., korupensamine, michellamine and vancomycin. (Arene) chromium complex exists in two enantiomeric forms based on a planar chirality. Axially chiral biaryls were stereoselectively prepared by palladium(0)-catalyzed cross-coupling of (aryl halide)Cr(CO){sub 3} complexes with arylboronic acids. This method was applied for the total synthesis of antimaralial agent korupensamine A, naphthyltetrahydro-isoquinoline alkaloid. Furthermore, chiral 1,2-diols and diamines are important compounds for asymmetric reactions. These enantionerically pure 1,2-diols and 1,2-diamines were stereoselectively prepared by pinacol coupling of planar chiral chromium complexes of benzaldehydes and benzaldimines with samarium iodide. Moreover, non-biaryl axial compounds, N,N-dialkyl 2,6-disubstituted benzamides were synthesized in enantiomerically pure form utilizing planar chiral arene chromium complex. (author)

  1. Grafting of 4-(2,4,6-Trimethylphenoxybenzoyl onto Single-Walled Carbon Nanotubes in Poly(phosphoric acid via Amide Function

    Directory of Open Access Journals (Sweden)

    Tan Loon-Seng

    2009-01-01

    Full Text Available Abstract Single-walled carbon nanotubes (SWCNTs, which were commercial grade containing 60–70 wt% impurity, were treated in a mild poly(phosphoric acid (PPA. The purity of PPA treated SWCNTs was greatly improved with or without little damage to SWCNTs framework and stable crystalline carbon particles. An amide model compound, 4-(2,4,6-trimethylphenoxybenzamide (TMPBA, was reacted with SWCNTs in PPA with additional phosphorous pentoxide as “direct” Friedel–Crafts acylation reaction to afford TMPBA functionalized SWCNTs. All evidences obtained from Fourier-transform infrared spectroscopy, Raman spectroscopy, thermogravimetric analysis, scanning electron microcopy, and transmission electron microscopy strongly supported that the functionalization of SWCNTs with benzamide was indeed feasible.

  2. Preliminary biological evaluation of acridinic compounds for a targeted combined chemo and internal radionuclide therapy for melanoma

    International Nuclear Information System (INIS)

    The increasing incidence of melanoma and a lack of effective therapy on the disseminated form induces the development of selective tissue-targeted therapies. The aim of the present work was a targeting approach combining a bimodality therapy with the same compound exhibiting both chemo and internal radionuclide therapeutic properties. Benzamides are known to present a specific affinity for melanoma tissue. Former studies have shown that with aromatic and hetero-aromatic analogues of N-(2-diethylaminoethyl)- 4-iodo benzamide (B.Z.A.), the affinity for melanoma was maintained. In this context, new compounds have been designed and synthesized conjugating a cytotoxic hetero-aromatic moiety, an amino-alkyl amidic side chain for melanoma targeting and a radioiodine for internal radionuclide therapy. Acridinic derivatives known as cytotoxic DNA-intercalating agents have been chosen for this study. The cytotoxic activity of fifteen new compounds has been tested in vitro on a panel of cell lines and the I.C.50 values were determined. The three first selected compounds have been further evaluated: in vivo, on B 16 F0 melanoma bearing C 57 B.L.6 mice to determine the pharmacological kinetic and namely the tumoral affinity. Two compounds exhibited a high, specific and long lasting concentration in melanoma tumor giving them a kinetic profile favourable for an application to radionuclide therapy; in vitro, using the 'colony forming' test on melanoma cells, for a first approach of association of chemo toxicity and radiotoxicity. Assessed on the ability of cells to form colonies, the inhibition observed with the association for a same molecule of chemo toxic and radio toxic doses was quite exactly the sum of the two separate effects, a result providing a first validation of the radio chemotherapy concept; in vitro, by a preliminary determination of molecular mechanisms. Compared to parent compounds, results confirmed a maintain of DNA-intercalating properties. These first results

  3. Synthesis and in Vitro and in Vivo Anticoagulant and Antiplatelet Activities of Amidino- and Non-Amidinobenzamides

    Directory of Open Access Journals (Sweden)

    Soo Hyun Lee

    2016-05-01

    Full Text Available Three amidino- and ten non-amidinobenzamides were synthesized as 3-aminobenzoic acid scaffold-based anticoagulant and antiplatelet compounds. The anticoagulant activities of thirteen synthesized compounds 1–13, and 2b and 3b as prodrugs were preliminary evaluated by screening the prolongation of activated partial thromboplastin time (aPTT and prothrombin time (PT in vitro. From the aPTT results obtained, two amidinobenzamides, N-(3′-amidinophenyl-3-(thiophen-2′′-ylcarbonylamino benzamide (1, 33.2 ± 0.7 s and N-(4′-amidinophenyl-3-(thiophen-2′′-ylcarbonylamino benzamide (2, 43.5 ± 0.6 s were selected to investigate the further anticoagulant and antiplatelet activities. The aPTT results of 1 (33.2 ± 0.7 s and 2 (43.5 ± 0.6 s were compared with heparin (62.5 ± 0.8 s in vitro at 30 μM. We investigated the effect of 1 and 2 on blood anticoagulant activity (ex vivo and on tail bleeding time (in vivo on mice. A tail cutting/bleeding time assay revealed that both 1 and 2 prolonged bleeding time in mice at a dose of 24.1 g/mouse and above. Compounds 1 and 2 dose-dependently inhibited thrombin-catalyzed fibrin polymerization and platelet aggregation. In addition, 1 and 2 were evaluated on the inhibitory activities of thrombin and FXa as well as the generation of thrombin and FXa in human umbilical vein endothelial cells (HUVECs. Collectively, 1 and 2 possess some antiplatelet and anticoagulant activities and offer a basis for development of a novel antithrombotic product.

  4. Architecture of Chiral Poly(phenylacetylene)s: From Compressed/Highly Dynamic to Stretched/Quasi-Static Helices.

    Science.gov (United States)

    Rodríguez, Rafael; Quiñoá, Emilio; Riguera, Ricardo; Freire, Félix

    2016-08-01

    The remarkable consequences in elongation, dynamic character, response to external stimuli (e.g., solvent effects, metal cations), and aggregation observed in helical poly(phenylacetylene)s (PPAs) when either the type of linkage with the pendant groups (i.e., anilide, benzamide) or the aromatic substitution pattern (i.e., ortho, meta, para) of the parent phenylacetylene monomer undergo modification are analyzed in depth. Two series of PPAs substituted at the phenyl ring in ortho, meta, and para with either (S)-α-methoxy-α-phenylacetic acid (MPA) or (S)-phenylglycine methyl ester (PGME) linked through anilide or benzamide bonds were prepared (i.e., o-, m-, p-poly-1 and poly-2 series) and characterized both in solution and in the solid state (CD, UV-vis, Raman, NMR, DSC, TGA, X-ray, AFM, SEM). Para-substituted polymers (p-poly-1 and p-poly-2) present the most compressed and dynamic helices, which respond easily to external stimuli. Meta-substituted PPAs (m-poly-1 and m-poly-2) exist as a mixture in equilibrium of two different helices (compressed and stretched), both less dynamic than the para counterparts and with a weak response to external stimuli. Moreover, in the solid state, m-poly-1 and m-poly-2 show separate fields for the compressed and for the stretched helices. For its part, the ortho-substituted PPA (o-poly-1) presents a highly stretched, almost planar and practically rigid helical structure, inert to external stimuli and prone to aggregate. These structural changes (elongation/dynamic behavior) are rationalized on the basis of the increasing difficulties imposed by the meta- and ortho-substitution on the accommodation of the pendants within the helical structure.

  5. Preparation and characterization of a novel Al(18)F-NOTA-BZA conjugate for melanin-targeted imaging of malignant melanoma.

    Science.gov (United States)

    Chang, Chih-Chao; Chang, Chih-Hsien; Lo, Yi-Hsuan; Lin, Ming-Hsien; Shen, Chih-Chieh; Liu, Ren-Shyan; Wang, Hsin-Ell; Chen, Chuan-Lin

    2016-08-15

    Melanin is an attractive target for the diagnosis and treatment of malignant melanoma. Previous studies have demonstrated the specific binding ability of benzamide moiety to melanin. In this study, we developed a novel (18)F-labeled NOTA-benzamide conjugate, Al(18)F-NOTA-BZA, which can be synthesized in 30min with a radiochemical yield of 20-35% and a radiochemical purity of >95%. Al(18)F-NOTA-BZA is highly hydrophilic (logP=-1.96) and shows good in vitro stability. Intravenous administration of Al(18)F-NOTA-BZA in two melanoma-bearing mouse models revealed highly specific uptake in B16F0 melanotic melanoma (6.67±0.91 and 1.50±0.26%ID/g at 15 and 120min p.i., respectively), but not in A375 amelanotic melanoma (0.87±0.21 and 0.24±0.09%ID/g at 15 and 120min p.i., respectively). The clearance from most normal tissues was fast. A microPET scan of Al(18)F-NOTA-BZA-injected mice also displayed high-contrast tumor images as compared with normal organs. Owing to the favorable in vivo distribution of Al(18)F-NOTA-BZA after intravenous administration, the estimated absorption dose was low in all normal organs and tissues. The melanin-specific binding ability, sustained tumor retention, fast normal tissues clearance and thelow projected human dosimetry supported that Al(18)F-NOTA-BZA is a very promising melanin-specific PET probe for melanin-positive melanoma. PMID:27445169

  6. In vivo and in vitro detection of dopamine d2 receptors in uveal melanomas.

    Science.gov (United States)

    Bodei, Lisa; Hofland, Leo J; Ferone, Diego; Mooy, Cornelia M; Kros, Johan M; Paridaens, Dion A; Baarsma, Seerp G; Ferdeghini, Marco; Van Hagen, Martin P; Krenning, Eric P; Kwekkeboom, Dik J

    2003-12-01

    Scintigraphy with radiolabeled benzamides was used in melanoma patients. Studies with a newer benzamide called 123I-epidepride, a high-affinity D2 receptor (D2R) antagonist, showed high sensitivity in D2R-positive pituitary adenomas. We evaluated the presence of D2R in patients with uveal melanomas in vivo with 123I-epidepride, and in vitro in melanomas, using immunohistochemistry (IHC) and 125I-epidepride autoradiography. We studied the in vivo tumor-to-background (TB) ratios in six patients with posterior uveal melanoma (one previously enucleated). IHC was performed in 3 of 6 tumors after enucleation and in another 20 uveal melanomas, 7 metastatic lymph nodes from skin melanoma, and 2 normal specimens. 125I-epidepride autoradiography was performed in 10 uveal melanomas (3 of which were studied in vivo), 7 metastases, and 2 normal samples. Radioligand uptake was present in the affected eye of 5 patients with uveal melanoma (TB = 3.1-6.1) and absent in the operated one (TB = 1). Eight uveal tumors were positive at IHC (35%), 14 weakly positive (61%), and 1 negative (4%). Two metastases were positive (29%), 2 weakly positive (29%), and 3 negative (42%). Two uveal tumors were positive at autoradiography (20%), 7 had nonspecific binding (70%), and 1 was negative (10%). One metastasis was positive (14%), while 6 were negative (86%). 123I-epidepride scintigraphy in uveal melanomas seems promising for sensitivity and image quality. D2R was demonstrated in a significant proportion of the melanomas, although 123I-epidepride uptake might also be nonspecific and unrelated to D2R binding. Although further studies on larger series are needed, 123I-epidepride could represent a future tool to study the expression of D2R in other classes of neuroendocrine tumors. PMID:14969602

  7. Radiation sensitizations at DNA-level by chemical and biological agents. Coordinated programme on improvement of radiotherapy of cancer using modifiers of radiosensitivity of cells

    International Nuclear Information System (INIS)

    Radiation sensitization by chemical agents at DNA level is discussed. Procaine, Halothan and Metronidazole showed no significant effect on unscheduled DNA synthesis (UDS) in mouse spleen cells, investigated by autoradiography and no effect on rejoining of DNA single strand breaks after gamma or UV irradiation. Oxyphenbutazon and prednisolone reduced the replicative DNA synthesis in vitro and in vivo but there was only little effect on DNA repair in the in vivo experiments. These two substances showed also a small reduction in poly(ADP-ribose) synthesis (PAR synthesis). 5-methoxypsoralen (5-MOP) and 8-methoxypsoralen (8-MOP) in combination with UV irradiation showed that 5-MOP was more toxic than mutagen, but induced much less DNA crosslinks than 8-MOP. Autoradiographic studies of radiation sensitization by biological agents showed significant inhibition of UDS in Yoshida tumor cells after acute mycoplasma infection in rats. Nucleoid sedimentation studies showed only in the case of Yoshida tumor cells after mycoplasma infection a dramatic effect in the sedimentation behaviour. Sensitization of cells by changing chromatin structure was also studied. Benzamide, 3-NH2-benzamide, 3-Methoxybenzamide, Spermine, Theophyllin and Caffeine were tested in different concentrations on replicative DNA synthesis, UDS after UV irradiation and PAR synthesis Chinese hamster ovary cells. 5-Methoxybenzamide was the strongest sensitizer and inhibitor of the PAR synthesis, and was used in further experiments. Results of KFA Juelich on sensitization of a mamma-adenocarcinoma EO 771 on C57 B1 mice are given. Replicative DNA synthesis, DNA repair and PAR synthesis were compared in spleen cells and adenocarcinoma cells after treatment with 5-Methoxybenzamide. An inhibitory effect on UDS could be shown only in adenocarcinoma cells but not in the mice spleen cells

  8. A novel radioligand for glycine transporter 1: characterization and use in autoradiographic and in vivo brain occupancy studies

    Energy Technology Data Exchange (ETDEWEB)

    Zeng Zhizhen [Imaging, Merck Research Laboratories, West Point, PA 19486 (United States)], E-mail: zhizhen_zeng@merck.com; O' Brien, Julie A. [Sleep and Psychiatric Disorders, Merck Research Laboratories, West Point, PA 19486 (United States); Lemaire, Wei [Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486 (United States); O' Malley, Stacey S.; Miller, Patricia J. [Imaging, Merck Research Laboratories, West Point, PA 19486 (United States); Zhao Zhijian [Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486 (United States); Wallace, Michael A. [Drug Metabolism, Merck Research Laboratories, Rahway, NJ 07065 (United States); Raab, Conrad [Drug Metabolism, Merck Research Laboratories, West Point, PA 19486 (United States); Lindsley, Craig W. [Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486 (United States); Departments of Pharmacology and Chemistry, Vanderbilt University, Nashville, TN 37232 (United States); Sur, Cyrille; Williams, David L. [Imaging, Merck Research Laboratories, West Point, PA 19486 (United States)

    2008-04-15

    Introduction: In an effort to develop agents to test the NMDA hypofunction hypothesis of schizophrenia, benchmark compounds from a program to discover potent, selective, competitive glycine transporter 1 (GlyT1) inhibitors were radiolabeled in order to further study the detailed pharmacology of these inhibitors and the distribution of GlyT1 in brain. We here report the in vitro characterization of [{sup 35}S](S)-2-amino-4-chloro-N-(1-(4-phenyl-1-(propylsulfonyl)piperidin-4-yl) ethyl)benzamide ([{sup 35}S]ACPPB), a radiotracer developed from a potent and selective non-sarcosine-derived GlyT1 inhibitor, its use in autoradiographic studies to localize (S)-2-amino-6-chloro-N-(1-(4-phenyl-1-(propylsulfonyl)piperidin-4-yl)ethyl) benzamide (ACPPB) binding sites in rat and rhesus brain and for in vivo occupancy assays of competitive GlyT1 inhibitors. Methods: Functional potencies of unlabeled compounds were characterized by [{sup 14}C]glycine uptake into JAR (human placental choriocarcinoma) cells and synaptosomes. Radioligand binding studies were performed with tissue homogenates. Autoradiographic studies were performed on tissue slices. Results: ACPPB is a potent (K{sub d}=1.9 nM), selective, GlyT1 inhibitor that, when radiolabeled with [{sup 35}S], is a well-behaved radioligand with low nondisplaceable binding. Autoradiographic studies of rat and rhesus brain slices with this ligand showed that specific binding sites were plentiful and nonhomogeneously distributed, with high levels of binding in the brainstem, cerebellar white matter, thalamus, cortical white matter and spinal cord gray matter. In vivo studies demonstrate displaceable binding of [{sup 35}S]ACPPB in rat brain tissues following iv administration of this radioligand. Conclusions: This is the first report of detailed anatomical localization of GlyT1 using direct radioligand binding, and the first demonstration that an in vivo occupancy assay is feasible, suggesting that it may also be feasible to develop

  9. Preliminary biological evaluation of acridinic compounds for a targeted combined chemo and internal radionuclide therapy for melanoma

    Energy Technology Data Exchange (ETDEWEB)

    Gardette, M.; Papon, J.; Desbois, N.; Labarre, P.; Maisonial, A.; Maublant, J.; Madelmont, J.C.; Moins, N.; Chezal, J.M. [Centre Jean Perrin, Inserm-Universite d' Auvergne, 63 - Clermont Ferrand (France)

    2008-02-15

    The increasing incidence of melanoma and a lack of effective therapy on the disseminated form induces the development of selective tissue-targeted therapies. The aim of the present work was a targeting approach combining a bimodality therapy with the same compound exhibiting both chemo and internal radionuclide therapeutic properties. Benzamides are known to present a specific affinity for melanoma tissue. Former studies have shown that with aromatic and hetero-aromatic analogues of N-(2-diethylaminoethyl)- 4-iodo benzamide (B.Z.A.), the affinity for melanoma was maintained. In this context, new compounds have been designed and synthesized conjugating a cytotoxic hetero-aromatic moiety, an amino-alkyl amidic side chain for melanoma targeting and a radioiodine for internal radionuclide therapy. Acridinic derivatives known as cytotoxic DNA-intercalating agents have been chosen for this study. The cytotoxic activity of fifteen new compounds has been tested in vitro on a panel of cell lines and the I.C.50 values were determined. The three first selected compounds have been further evaluated: in vivo, on B 16 F0 melanoma bearing C 57 B.L.6 mice to determine the pharmacological kinetic and namely the tumoral affinity. Two compounds exhibited a high, specific and long lasting concentration in melanoma tumor giving them a kinetic profile favourable for an application to radionuclide therapy; in vitro, using the 'colony forming' test on melanoma cells, for a first approach of association of chemo toxicity and radiotoxicity. Assessed on the ability of cells to form colonies, the inhibition observed with the association for a same molecule of chemo toxic and radio toxic doses was quite exactly the sum of the two separate effects, a result providing a first validation of the radio chemotherapy concept; in vitro, by a preliminary determination of molecular mechanisms. Compared to parent compounds, results confirmed a maintain of DNA-intercalating properties. These

  10. Characterization of novel MPS1 inhibitors with preclinical anticancer activity.

    Science.gov (United States)

    Jemaà, M; Galluzzi, L; Kepp, O; Senovilla, L; Brands, M; Boemer, U; Koppitz, M; Lienau, P; Prechtl, S; Schulze, V; Siemeister, G; Wengner, A M; Mumberg, D; Ziegelbauer, K; Abrieu, A; Castedo, M; Vitale, I; Kroemer, G

    2013-11-01

    Monopolar spindle 1 (MPS1), a mitotic kinase that is overexpressed in several human cancers, contributes to the alignment of chromosomes to the metaphase plate as well as to the execution of the spindle assembly checkpoint (SAC). Here, we report the identification and functional characterization of three novel inhibitors of MPS1 of two independent structural classes, N-(4-{2-[(2-cyanophenyl)amino][1,2,4]triazolo[1,5-a]pyridin-6-yl}phenyl)-2-phenylacetamide (Mps-BAY1) (a triazolopyridine), N-cyclopropyl-4-{8-[(2-methylpropyl)amino]-6-(quinolin-5-yl)imidazo[1,2-a]pyrazin-3-yl}benzamide (Mps-BAY2a) and N-cyclopropyl-4-{8-(isobutylamino)imidazo[1,2-a]pyrazin-3-yl}benzamide (Mps-BAY2b) (two imidazopyrazines). By selectively inactivating MPS1, these small inhibitors can arrest the proliferation of cancer cells, causing their polyploidization and/or their demise. Cancer cells treated with Mps-BAY1 or Mps-BAY2a manifested multiple signs of mitotic perturbation including inefficient chromosomal congression during metaphase, unscheduled SAC inactivation and severe anaphase defects. Videomicroscopic cell fate profiling of histone 2B-green fluorescent protein-expressing cells revealed the capacity of MPS1 inhibitors to subvert the correct timing of mitosis as they induce a premature anaphase entry in the context of misaligned metaphase plates. Hence, in the presence of MPS1 inhibitors, cells either divided in a bipolar (but often asymmetric) manner or entered one or more rounds of abortive mitoses, generating gross aneuploidy and polyploidy, respectively. In both cases, cells ultimately succumbed to the mitotic catastrophe-induced activation of the mitochondrial pathway of apoptosis. Of note, low doses of MPS1 inhibitors and paclitaxel (a microtubular poison) synergized at increasing the frequency of chromosome misalignments and missegregations in the context of SAC inactivation. This resulted in massive polyploidization followed by the activation of mitotic catastrophe. A

  11. Radiation damages in chemical components of organic scintillator detectors; Danos de radiacao em componentes quimicos de detectores cintiladores organicos

    Energy Technology Data Exchange (ETDEWEB)

    Fernandes Neto, Jose Maria

    2003-07-01

    Samples containing PPO (1%, g/ml), diluted in toluene, they were irradiated in a {sup 60}Co irradiator (6.46 kGy/h) at different doses. The PPO concentration decay bi-exponentially with the dose, generating the degradation products: benzoic acid, benzamide and benzilic alcohol. The liquid scintillator system was not sensitive to the radiation damage until 20 kGy. Otherwise, the pulse height analysis showed that dose among 30 to 40 kGy generate significant loss of quality of the sensor (liquid scintillating) and the light yield was reduced in half with the dose of (34.04 {+-} 0.80) kGy. This value practically was confirmed by the photo peak position analysis that resulted D{sub 1/2} = (31.7 {+-} 1,4) kGy, The transmittance, at 360 nm, of the irradiated solution decreased exponentially. The compartmental model using five compartments (fast decay PPO, slow decay PPO, benzamide, benzoic acid and benzilic alcohol) it was satisfactory to explain the decay of the PPO in its degradation products in function of the dose. The explanation coefficient r{sup 2} = 0.985636 assures that the model was capable to explain 98.6% of the experimental variations. The Target Theory together with the Compartmental Analysis showed that PPO irradiated in toluene solution presents two sensitive molecular diameters both of them larger than the true PPO diameter. >From this analysis it showed that the radiolytic are generated, comparatively, at four toluene molecules diameter far from PPO molecules. For each one PPO-target it was calculated the G parameter (damage/100 eV). For the target expressed by the fast decay the G value was (418.4 {+-} 54.1) damages/100 eV, and for the slow decay target the G value was (54.5 {+-} 8.9) damages/100 eV. The energies involved in the chemical reactions were w (0.239 {+-} 0.031) eV/damage (fast decay) and w = (1 834 {+-} 0.301) eV/damage (slow decay). (author)

  12. Evaluating cis-2,6-dimethylpiperidide (cis-DMP) as a base component in lithium-mediated zincation chemistry.

    Science.gov (United States)

    Armstrong, David R; Garden, Jennifer A; Kennedy, Alan R; Leenhouts, Sarah M; Mulvey, Robert E; O'Keefe, Philip; O'Hara, Charles T; Steven, Alan

    2013-09-27

    Most recent advances in metallation chemistry have centred on the bulky secondary amide 2,2,6,6-tetramethylpiperidide (TMP) within mixed metal, often ate, compositions. However, the precursor amine TMP(H) is rather expensive so a cheaper substitute would be welcome. Thus this study was aimed towards developing cheaper non-TMP based mixed-metal bases and, as cis-2,6-dimethylpiperidide (cis-DMP) was chosen as the alternative amide, developing cis-DMP zincate chemistry which has received meagre attention compared to that of its methyl-rich counterpart TMP. A new lithium diethylzincate, [(TMEDA)LiZn(cis-DMP)Et2] (TMEDA=N,N,N',N'-tetramethylethylenediamine) has been synthesised by co-complexation of Li(cis-DMP), Et2Zn and TMEDA, and characterised by NMR (including DOSY) spectroscopy and X-ray crystallography, which revealed a dinuclear contact ion pair arrangement. By using N,N-diisopropylbenzamide as a test aromatic substrate, the deprotonative reactivity of [(TMEDA)LiZn(cis-DMP)Et2] has been probed and contrasted with that of the known but previously uninvestigated di-tert-butylzincate, [(TMEDA)LiZn(cis-DMP)tBu2]. The former was found to be the superior base (for example, producing the ortho-deuteriated product in respective yields of 78% and 48% following D2O quenching of zincated benzamide intermediates). An 88% yield of 2-iodo-N,N-diisopropylbenzamide was obtained on reaction of two equivalents of the diethylzincate with the benzamide followed by iodination. Comparisons are also drawn using 1,1,1,3,3,3-hexamethyldisilazide (HMDS), diisopropylamide and TMP as the amide component in the lithium amide, Et2Zn and TMEDA system. Under certain conditions, the cis-DMP base system was found to give improved results in comparison to HMDS and diisopropylamide (DA), and comparable results to a TMP system. Two novel complexes isolated from reactions of the di-tert-butylzincate and crystallographically characterised, namely the pre-metallation complex [{(iPr)2N

  13. Imaging malignant melanoma with {sup 18}F-5-FPN

    Energy Technology Data Exchange (ETDEWEB)

    Feng, Hongyan; Xia, Xiaotian; Li, Chongjiao; Song, Yiling; Qin, Chunxia; Liu, Qingyao; Zhang, Yongxue; Lan, Xiaoli [Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology (China); Hubei Key Laboratory of Molecular Imaging (China)

    2016-01-15

    Radiolabelled benzamides are attractive candidates for targeting melanoma because they bind to melanin and exhibit high tumour uptake and retention. {sup 18}F-5-Fluoro-N-(2-[diethylamino]ethyl)picolinamide ({sup 18}F-5-FPN), a benzamide analogue, was prepared and its pharmacokinetics and binding affinity evaluated both in vitro and in vivo to assess its clinical potential in the diagnosis and staging of melanoma. {sup 18}F-5-FPN was prepared and purified. Its binding specificity was measured in vitro in two different melanoma cell lines, one pigmented (B16F10 cells) and one nonpigmented (A375m cells), and in vivo in mice xenografted with the same cell lines. Dynamic and static PET images using {sup 18}F-5-FPN were obtained in the tumour-bearing mice, and the static images were also compared with those acquired with {sup 18}F-FDG. PET imaging with {sup 18}F-5-FPN was also performed in B16F10 tumour-bearing mice with lung metastases. {sup 18}F-5-FPN was successfully prepared with radiochemical yields of 5 - 10 %. Binding of {sup 18}F-5-FPN to B16F10 cells was much higher than to A375m cells. On dynamic PET imaging B16F10 tumours were visible about 1 min after injection of the tracer, and the uptake gradually increased over time. {sup 18}F-5-FPN was rapidly excreted via the kidneys. B16F10 tumours were clearly visible on static images acquired 1 and 2 h after injection, with high uptake values of 24.34 ± 6.32 %ID/g and 16.63 ± 5.41 %ID/g, respectively, in the biodistribution study (five mice). However, there was no visible uptake by A375m tumours. {sup 18}F-5-FPN and {sup 18}F-FDG PET imaging were compared in B16F10 tumour xenografts, and the tumour-to-background ratio of {sup 18}F-5-FPN was ten times higher than that of {sup 18}F-FDG (35.22 ± 7.02 vs. 3.29 ± 0.53, five mice). {sup 18}F-5-FPN PET imaging also detected simulated lung metastases measuring 1 - 2 mm. {sup 18}F-5-FPN specifically targeted melanin in vitro and in vivo with high retention and affinity

  14. 抗痴呆药物CPI-1189的合成工艺改进%Improved synthesis of anti-dementia drug CPI-1189

    Institute of Scientific and Technical Information of China (English)

    赵金会; 王亚楼; 魏臻

    2013-01-01

    4-Acetamide-N-(tert-butyl)benzamide(CPI-1189) treatment of dementia,associated with AIDS virus(HIV-l) infection was synthesized from 4-nitrobenzoic acid via 4-step reactions, including chlorina-tion, amidation, reduction and N-acylation. The 4-nitrobenzoic acid reacted with thionyl chloride to give 4-ni-trobenzoyl chloride, which was condensed with tert-butyl amine to give N-( tert-butyl) 4-nitrobenzamide (2). The nitro group of compound2 was then reduced to amino group[4-amino-N(tert-butyl)benzamide, 3] by transfer hydrogenation with hydrazine and 5% Pd/C. Finally, acylation of amino group compound 3 with acetyl chloride provided the title compound. The overall yield of the target compound was 67. 9% ,and its structure was confirmed by elemental analysis,MS,and 'H-NMR. In comparison with the reported procedure , the improved process has the advantage of low cost, simple operation, short reaction time and aptness for industrial production.%目的 合成抗痴呆药物4-乙酰氨基-N-(叔丁基)苯甲酰胺(CPI-1189)并优化其合成工艺.方法 以4-硝基苯甲酸为起始原料,经过酰氯化、酰胺化、催化转移氢化和N-乙酰化4步反应合成目标化合物.结果 目标化合物的总收率为67.9%,其化学结构经元素分析、1H-NMR、MS谱确证.结论 与文献报道的方法相比较,本工艺以氯化亚砜为氯化剂,降低了成本,并改进了硝基还原反应工艺,缩短了反应时间,使操作条件更为简单、实用.

  15. Radiosynthesis, evaluation and preclinical studies of a new 5HT2A radioligand

    International Nuclear Information System (INIS)

    123I-5-I-R91150, a radioiodinated analogue of R91150 (a ligand (antagonist) of Janssen Research Foundation), showing high affinity and selectivity for 5HT2A receptors, was developed as a potential in vivo 5HT2A receptor tracer for SPECT. The applied radiochemistry, whereby the radioiodine was substituted on the 5 - position of the benzamide ring, allowed to obtain the tracer with high specific activity and high purity. In vitro and in vivo rat studies revealed that the new tracer bound reversibly with the required high affinity (Kd=0.1 nM) and high selectivity (a factor ranging from 10000 to at least 50 vis a vis other receptors) to 5HT2A receptors. In young normal subjects the major part of the 123I-5-I-R91150 radioactivity in the brain is present in cortical areas. Cortical area to cerebellum activity ratio reaches an equilibrium value of about 1.8 around 90 min. till 4 hours p.i.. This binding was specific and reversible. The cortical activity reflects a distribution in the brain similar to that of the mapping of 5HT2A receptors from post mortem studies. These findings suggested that 123I-5-I-R91150 allows imaging and quantitative estimation with SPECT and could be used for further clinical studies. The radiobromine analogue was synthetised as a potential PET tracer. (author)

  16. Synthesis and Biological Evaluation of Novel Urea- and Guanidine-Based Derivatives for the Treatment of Obesity-Related Hepatic Steatosis

    Directory of Open Access Journals (Sweden)

    Xiaolin Liang

    2014-05-01

    Full Text Available Leptin, the product of the obese gene, is an adipocyte-secreted protein hormone playing a key role in the progression of obesity and hepatic steatosis. In this study, 28 novel (thiourea and guanidine-based analogues have been synthesized and N-(1-(4-(3-(2-chloroethylureidobenzylpiperidin-4-yl-3-(trifluoromethyl benzamide (7i was found to be a potent regulator of leptin expression in 3T3-L1 adipocytes. Treatment with 7i at a dose of 50 mg/kg/day for 35 days reduced the body weight and liver weight of diet-induced obesity mice by 13.5% and 18.4%, respectively, while also improving the serum levels of triglyceride, total cholesterol, leptin, adiponectin, LDL-c, HDL-c. Hematoxylin-eosin (H&E and Oil Red O staining also confirmed that 7i ameliorated fat deposition in liver tissue and restricted the size of adipocytes in obesity-related fatty liver disease.

  17. On the clinical impact of cerebral dopamine D2 receptor scintigraphy

    International Nuclear Information System (INIS)

    The present review describes findings and clinical indications for the dopamine D2 receptor scintigraphy. Methods for the examination of D2 receptors are positron emission tomography (PET) using 11C- or 18F-labelled butyrophenones or benzamides or single photon emission tomography (SPECT) using 123I-iodobenzamide (IBZM) respectively. The most important indication in neurology is the differential diagnosis of Parkinsonism: Patients with early Parkinson's disease show an increased D2 receptor binding (D2-RB) compared to control subjects. However, patients suffering from Steele-Richardson-Olszewski-Syndrome or Multiple System Atrophy show a decreased D2-RB and are generally non-responsive to treatment. Postsynaptic blockade of D2 receptors results in a drug induced Parkinsonian syndrome, which can be diagnosed by D2 scintigraphy. Further possible indications occur in psychiatry: The assessment of receptor occupancy is useful in schizophrenic patients treated with neuroleptics. Additionally, D2 receptor scintigraphy might help to clarify the differential diagnosis between neuroleptic malignant syndrome and lethal catatonia. The method might be useful for supervising neurobiochemical changes in drug dependency and during withdrawal. Assessment of dopamine D2 receptor binding can simplify the choice of therapy in depressive disorder: Patients showing a low D2 binding are likely to improve following an antidepressive drug treatment whereas sleep deprivation is promising in patients with high D2 binding. (orig.)

  18. Microwave assisted synthesis of novel acridine-acetazolamide conjugates and investigation of their inhibition effects on human carbonic anhydrase isoforms hCA I, II, IV and VII.

    Science.gov (United States)

    Ulus, Ramazan; Aday, Burak; Tanç, Muhammet; Supuran, Claudiu T; Kaya, Muharrem

    2016-08-15

    4-Amino-N-(5-sulfamoyl-1,3,4-thiadiazol-2-yl)benzamide was condensed with cyclic-1,3-diketones (dimedone and cyclohexane-1,3-dione) and aromatic aldehydes under microwave irradiation, leading to a series of acridine-acetazolamide conjugates. The new compounds were investigated as inhibitors of carbonic anhydrases (CA, EC 4.2.1.1), and more precisely cytosolic isoforms hCA I, II, VII and membrane-bound one hCA IV. All investigated isoforms were inhibited in low micromolar and nanomolar range by the new compounds. hCA IV and VII were inhibited with KIs in the range of 29.7-708.8nM (hCA IV), and of 1.3-90.7nM (hCA VII). For hCA I and II the KIs were in the range of 6.7-335.2nM (hCA I) and of 0.5-55.4nM (hCA II). The structure-activity relationships (SAR) for the inhibition of these isoforms with the acridine-acetazolamide conjugates reported here were delineated. PMID:27298005

  19. FORMULATION AND EVALUATION OF AMISULPRIDE ORODISPERSIBLE TABLET

    Directory of Open Access Journals (Sweden)

    Dr. Hitesh P. Dalvadi

    2016-03-01

    Full Text Available Orodispersible dosage forms have lured the market for a certain section of the patient population which includes dysphagia, bed ridden, psychic, and geriatric patients. Moreover Orodispersible tablets shows increased bioavailability as compared to conventional dosage forms. Amisulpride is a psychotropic agent belonging to the chemical class of benzamide derivatives. At low doses, it enhances dopaminergic neurotransmission by preferentially blocking presynaptic dopamine D2/D3 auto receptors. The tablets were prepared by using direct compression method, and drug solubility is enhanced by solid dispersion. Formulation were prepared by using different superdisintegrant, combination of different superdisintegrant and effect of hydrophilic lubricant was studied and evaluated pre and post compression parameters. Tablets were evaluated for content uniformity, Disintegration time, wetting time, hardness, friability and In-vitro dissolution studies. More than 90% of drug was released from almost all the formulations within 10 min. Formulation C4 containing Sodium starch glycolate (4.5%, Crospovidone (2.5% and crosscarmellose sodium (3.5%, was having disintegration time 24 seconds, wetting time 18 seconds, hardness 3.4Kg/cm2 and in vitro drug release of 99.96% in pH 6.8. Based on this data C4 was found to be the best formulation. Further formulations were subjected to accelerated stability studies. Tablets showed no appreciable changes with respect to disintegration and dissolution profiles. Results of this study indicate among the superdisintegrants tried, combination of superdisintegrant gave the best result.

  20. Synthesis and characterization of dopamine substitue tripodal trinuclear [(salen/salophen/salpropen)M] (Mdbnd Cr(III), Mn(III), Fe(III) ions) capped s-triazine complexes: Investigation of their thermal and magnetic properties

    Science.gov (United States)

    Uysal, Şaban; Koç, Ziya Erdem

    2016-04-01

    In this work, we aimed to synthesize and characterize a novel tridirectional ligand including three catechol groups and its novel tridirectional-trinuclear triazine core complexes. For this purpose, we used melamine (2,4,6-triamino-1,3,5-triazine) (MA) as starting material. 2,4,6-tris(4-carboxybenzimino)-1,3,5-triazine (II) was synthesized by the reaction of an equivalent melamine (I) and three equivalent 4-carboxybenzaldehyde. 4,4‧,4″-((1E,1‧E,1″E)-((1,3,5-triazine-2,4,6-triyl)tris(azanylylidene))tris(methanylylidene))tris(N-(3,4-dihydroxyphenethyl)benzamide) L (IV) was synthesized by the reaction of one equivalent (II) and three equivalent dopamine (3,4-dihydroxyphenethylamine) (DA) by using two different methods. (II, III, IV) and nine novel trinuclear Cr(III), Mn(III) and Fe(III) complexes of (IV) were characterized by means of elemental analyses, 1H NMR, FT-IR spectrometry, LC-MS (ESI+) and thermal analyses. The metal ratios of the prepared complexes were performed using Atomic Absorption Spectrophotometry (AAS). We also synthesized novel tridirectional-trinuclear systems and investigated their effects on magnetic behaviors of [salen, salophen, salpropen Cr(III)/Mn(III)/Fe(III)] capped complexes. The complexes were determined to be low-spin distorted octahedral Mn(III) and Fe(III), and distorted octahedral Cr(III) all bridged by catechol group.

  1. EFFECT OF NANOSILICA ON THE KINETICS OF CURE REACTION AND THERMAL DEGRADATION OF EPOXY RESIN

    Institute of Scientific and Technical Information of China (English)

    M. Ghaemy; M. Bazzar; H. Mighani

    2011-01-01

    Nanocomposites from nanoscale silica particles (NS), diglycidylether of bisphenol-A based epoxy (DGEBA), and 3,5-diamino-N-(4-(quinolin-8-yloxy) phenyl) benzamide (DQPB) as curing agent were obtained from direct blending of these materials. The effect of nanosilica (NS) particles as catalyst on the cure reaction of DGEBA/DQPB system was studied by using non-isothermal DSC technique. The activation energy (Ea) was obtained by using Kissinger and Ozawa equations.The Ea value of curing of DGEBA/DQPB/10% NS system showed a decrease of about 10 KJ/mol indicating the catalytic effect of NS particles on the cure reaction. The Ea values of thermal degradation of the cured samples of both systems were 148 KJ/mol and 160 KJ/mol, respectively. The addition of 10% of NS to the curing mixture did not have much effect on the initial decomposition temperature (Ti) but increased the char residues from 20% to 28% at 650℃.

  2. Borneol Is a TRPM8 Agonist that Increases Ocular Surface Wetness

    Science.gov (United States)

    Chen, Gui-Lan; Lei, Ming; Zhou, Lu-Ping; Zou, Fangdong

    2016-01-01

    Borneol is a compound widely used in ophthalmic preparations in China. Little is known about its exact role in treating eye diseases. Here we report that transient receptor potential melastatin 8 (TRPM8) channel is a pharmacological target of borneol and mediates its therapeutic effect in the eyes. Ca2+ measurement and electrophysiological recordings revealed that borneol activated TRPM8 channel in a temperature- and dose-dependent manner, which was similar to but less effective than the action of menthol, an established TRPM8 agonist. Borneol significantly increased tear production in guinea pigs without evoking nociceptive responses at 25°C, but failed to induce tear secretion at 35°C. In contrast, menthol evoked tearing response at both 25 and 35°C. TRPM8 channel blockers N-(3-Aminopropyl)-2-[(3-methylphenyl)methoxy]-N-(2-thienylmethyl)benzamide hydrochloride (AMTB) and N-(4-tert-butylphenyl)-4-(3-chloropyridin-2-yl)piperazine-1-carboxamide (BCTC) abolished borneol- and menthol-induced tear secretion. Borneol at micromolar concentrations did not affect the viability of human corneal epithelial cells. We conclude that borneol can activate the cold-sensing TRPM8 channel and modestly increase ocular surface wetness, which suggests it is an active compound in ophthalmic preparations and particularly useful in treating dry eye syndrome. PMID:27448228

  3. (18)F-FBHGal for asialoglycoprotein receptor imaging in a hepatic fibrosis mouse model.

    Science.gov (United States)

    Kao, Hao-Wen; Chen, Chuan-Lin; Chang, Wen-Yi; Chen, Jenn-Tzong; Lin, Wuu-Jyh; Liu, Ren-Shyan; Wang, Hsin-Ell

    2013-02-15

    Quantification of the expression of asialoglycoprotein receptor (ASGPR), which is located on the hepatocyte membrane with high-affinity for galactose residues, can help assess ASGPR-related liver diseases. A hepatic fibrosis mouse model with lower asialoglycoprotein receptor expression was established by dimethylnitrosamine (DMN) administration. This study developed and demonstrated that 4-(18)F-fluoro-N-(6-((3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)hexyl)benzamide ((18)F-FBHGal), a new (18)F-labeled monovalent galactose derivative, is an asialoglycoprotein receptor (ASGPR)-specific PET probe in a normal and a hepatic fibrosis mouse models. Immunoassay exhibited a linear correlation between the accumulation of GalH-FITC, a fluorescent surrogate of FBHGal, and the amount of ASGPR. A significant reduction in HepG2 cellular uptake (P ASGPR blocking agent. Animal studies showed the accumulation of (18)F-FBHGal in fibrosis liver (14.84±1.10 %ID/g) was appreciably decreased compared with that in normal liver (20.50±1.51 %ID/g, P ASGPR-related liver dysfunction.

  4. Bcl-2/MDM2 Dual Inhibitors Based on Universal Pyramid-Like α-Helical Mimetics.

    Science.gov (United States)

    Wang, Ziqian; Song, Ting; Feng, Yingang; Guo, Zongwei; Fan, Yudan; Xu, Wenjie; Liu, Lu; Wang, Anhui; Zhang, Zhichao

    2016-04-14

    No α-helical mimetic that exhibits Bcl-2/MDM2 dual inhibition has been rationally designed due to the different helicities of the α-helixes at their binding interfaces. Herein, we extracted a one-turn α-helix-mimicking ortho-triarene unit from o-phenylene foldamers. Linking benzamide substrates with a rotatable C-N bond, we constructed a novel semirigid pyramid-like scaffold that could support its two-turn α-helix mimicry without aromatic stacking interactions and could adopt the different dihedral angles of the key residues of p53 and BH3-only peptides. On the basis of this universal scaffold, a series of substituent groups were installed to capture the key residues of both p53TAD and BimBH3 and balance the differences of the bulks between them. Identified by FP, ITC, and NMR spectroscopy, a compound 6e (zq-1) that directly binds to Mcl-1, Bcl-2, and MDM2 with balanced submicromolar affinities was obtained. Cell-based experiments demonstrated its antitumor ability through Bcl-2/MDM2 dual inhibition simultaneously.

  5. Effects of cisapride on ulcer formation and gastric secretion in rats: comparison with ranitidine and omeprazol.

    Science.gov (United States)

    Alarcón de la Lastra, C; Martin, M J; La Casa, M; López, A; Motilva, V

    1996-12-01

    1. The antiulcerogenic effects of cisapride, a potent benzamide-stimulating gastrointestinal motility agent, were studied on cold-resistant and pylorus-ligated gastric ulcers. Acidity, composition of gastric secretion, and quantitative and qualitative changes on mucus glycoprotein content were also determined. These effects were compared with those of ranitidine (50 mg/kg) and omeprazol (10 mg/kg). 2. Oral cisapride (10-100 mg/kg) dose-relatedly and significantly (P < 0.01, P < 0.05) decreased the severity of the lesions induced by cold-resistant stress. In stressed rats, cisapride increased the amount of mucus secretion and markedly enhanced the glycoprotein content. Morphometric evaluation of mucus secretion revealed a significant increase in both the PAS area (neutral glycoproteins) and Alcian blue area (sulfated glycoproteins). 3. In 4 h pyloric-ligated animals, cisapride (10-100 mg/kg) showed a significant reduction in the number and severity of ulcers (P < 0.01) and histamine concentration (P < 0.01, P < 0.001). In addition, at the highest doses (50-100 mg/kg), cisapride produced a significant decreases in acidity; however, it did not alter the gastric volume secretion or pepsin concentrations. 4. These results suggest that cisapride shows antiulcerogenic effects which could possibly be explained through antisecretory and cytoprotective mechanisms involving an enhancement of cuality and production of gastric mucus. PMID:9304418

  6. Bis(2-{2-[2-(benzylcarbamoylphenoxy]acetamido}ethylammonium nitrate ethanol disolvate

    Directory of Open Access Journals (Sweden)

    Weisheng Liu

    2011-01-01

    Full Text Available In the title compound, C36H40N5O6+·NO3−·2C2H5OH, the nitrate anion is disordered over the two orientations of equal occupancy while the solvent molecule reveals large displacement parameters. The cation is formed by protonation of the N atom of a secondary amine in the middle of the flexible chain and the whole compound has crystallographically imposed C-2 symmetry with the crystallographic b axis. An O atom of the nitrate anion links the acidic H atoms of the cation via N—H...O hydrogen bonding. In addition, neighbouring cations are connected by intermolecular N—H...O hydrogen bonds and π–π interactions between the benzamide groups of the cations [centroid–centroid distance = 4.000 (3 Å], forming a chain along [001]. The ethanol solvent molecules are arranged on the side of the chain through O—H...O hydrogen bonds.

  7. Evaluation of Hexane Extract of Tuber of Root of Cyperus rotundus Linn (Cyperaceae for Repellency against Mosquito Vectors

    Directory of Open Access Journals (Sweden)

    S. P. Singh

    2009-01-01

    Full Text Available Hexane extract of tuber of plant Cyperus rotundus (Cyperaceae was screened under laboratory conditions for repellent activity against mosquito vector Anopheles culicifacies Giles species A (Diptera: Culicidae, Anopheles stephensi Liston (Diptera: Culicidae, and Culex quinquefasciatus Say (Diptera: Culicidae. The Cyperus rotundus tuber extract was used to determine their effect on mosquito vector, and comparison with the DEET (NN Diethyl 1-3 methyl Benzamide, formerly known as diethyl 1-m-toluamide. The tuber extracts showed more effective at all the dose. Result obtained from the laboratory experiment showed that the tuber extracts are more effective for repellency of allthe mosquito vector even at low dose. Clear dose response relationships were established with the highest dose of 10% tuber extract evoking 100% repellency. Percent protection obtained against An. culicifacies Giles species A 100% repellency in 4 hours, 6 hours, An. stephensi 100% repellency in 6 hours and Cx. quinquefasciatus was 100% repellency in 6 hours at the 10% concentration. Against DEET- 2.5% An. culicifacies A 100% repellency in 1 hour, 2 hours, 6 hours, An. stephensi have shown 100% repellency in 6 hours, and Culex quinquefasciatus have shown 100% repellency in 1 hour, 2 hours, 6 hours. The consolidated data of the repellency observed in different species is given and it is evident that the over all repellency rates varied between 80 and 100% for different repellents concentrations (2.5%, 5%, and 10%. The extract can be applied as an effective personal protective measure against mosquito bites.

  8. Synthesis and electron paramagnetic resonance study of a nitroxide free radical covalently bonded on aminopropyl-silica gel

    Energy Technology Data Exchange (ETDEWEB)

    Tudose, Madalina; Constantinescu, Titus [Institute of Physical Chemistry, Spl. Independentei 202, 060021 Bucharest (Romania); Balaban, Alexandru T. [Texas A and M University at Galveston, Marine Sciences Department, Galveston, TX 77551 (United States); Ionita, Petre [Institute of Physical Chemistry, Spl. Independentei 202, 060021 Bucharest (Romania)], E-mail: pionita@icf.ro

    2008-01-30

    A solid spin-labeled material was obtained starting from 2-chloro-3,5-dinitro-N-(4-(2,2,6,6-tetramethyl-piperidine-1-oxyl) -benzamide) and aminopropyl-silica gel. Stability tests showed that even after several months the spin-labeled material had the same properties as immediately after synthesis. EPR properties of the TEMPO-derivatized silica were studied as a function of solvent polarity and temperature. Rotational correlation times were calculated from EPR spectra and correlated with solvent characteristics and temperature. Polar solvents induce a fast motion of the spin-label, clearly seen in the EPR spectra by the apparition of the well-known TEMPO radical triplet. The solid spin-labeled (dry) sample showed a high interspin interaction, which can be disrupted not only by different (liquid) solvents, but also by absorption of different solids, like cyclodextrins, dendrimers or polyethyleneglycols. Also, changes induced by the temperature were studied in the case of toluene wet sample. From 150 to 370 K, the spectrum is changing from a slow motion spectrum type to a fast motion regime. The preparative procedures to obtain the spin-labeled silica as well as some of its parameters are described.

  9. Biology and control of swamp dodder (Cuscuta gronovii)

    International Nuclear Information System (INIS)

    A simple model predicting swamp dodder (Cuscuta gronovii Willd.) emergence was developed. The model states that 0.1% of the cranberry seedlings will emerge after 150 to 170 GDD have accumulated after the winter ice has melted on the cranberry beds, using 0 C as the low temperature threshold. Experiments in cranberry showed that pronamide [3,5-dichloro-(N-1,1-dimethyl-2-propynyl)benzamide] was effective in controlling swamp dodder when applied preemergence. Rates below 2.4 kg ai/ha appeared to be safe for cranberry plants and fruit. Experiments with 14C glyphosate showed that the herbicide moved out of carrot leaves to the physiological sinks in the plant. In carrots parasitized by swamp dodder the dodder acted as one of the strongest sinks for photosynthates from the host. In cranberry glyphosate moved out of the leaves, but most remained in the stem to which the treated leaves were attached. The only physiological sinks that accumulated significant amounts of label were the stem apices. The concentration of the herbicide in this sink decreased with time. Swamp dodder stems were able to absorb glyphosate directly from solution

  10. Rational prescription of drugs within similar therapeutic or structural class for gastrointestinal disease treatment: Drug metabolism and its related interactions

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    AIM: To review and summarize drug metabolism and its related interactions in prescribing drugs within the similar therapeutic or structural class for gastrointestinal disease treatment so as to promote rational use of medicines in clinical practice.METHODS: Relevant literature was identified by performing MEDLINE/Pubmed searches covering the period from 1988 to 2006. RESULTS: Seven classes of drugs were chosen, including gastric proton pump inhibitors, histamine H2-receptor antagonists, benzamide-type gastroprokinetic agents, selective 5-HT3 receptor antagonists, fluoroquinolones, macrolide antibiotics and azole antifungals. They showed significant differences in metabolic profile (I.e., the fraction of drug metabolized by cytochrome P450 (CYP), CYP reaction phenotype, impact of CYP genotype on interindividual pharmacokinetics variability and CYP-mediated drug-drug interaction potential). Many events of severe adverse drug reactions and treatment failures were closely related to the ignorance of the above issues. CONCLUSION: Clinicians should acquaint themselves with what kind of drug has less interpatient variability in clearance and whether to perform CYP genotyping prior to initiation of therapy. The relevant CYP knowledge helps clinicians to enhance the management of patients with gastrointestinal disease who may require treatment with polytherapeutic regimens.

  11. Effect of heparin addition on expansion of cord blood hematopoietic progenitor cells in three-dimensional coculture with stromal cells in nonwoven fabrics.

    Science.gov (United States)

    Okamoto, Toru; Takagi, Mutsumi; Soma, Toshihiro; Ogawa, Hiroyasu; Kawakami, Manabu; Mukubo, Masaaki; Kubo, Kazusuke; Sato, Reiko; Toma, Kazunori; Yoshida, Toshiomi

    2004-01-01

    Primary human cord blood mononuclear cells (CB MNCs) were inoculated into layers of primary human bone marrow stromal cells prepared in a nonwoven fabric porous carrier [three dimensional (3-D)] or on a dish [two dimensional (2-D)] using a cytokine-free medium and were cultured for 7 days with or without the addition of heparin. The number of progenitor cells increased threefold during the 3-D coculture, whereas it decreased in the 2-D culture. Heparin addition to the 3-D coculture further increased the number of progenitors twofold, whereas the addition of desulfated heparin had no effect. The heparin effect was also observed in a 3-D culture of CB MNCs without stromal cells when conditioned medium was employed. The coating of the carrier with N-(O-beta-(6-O-sulfogalactopyranosyl)-6-oxyhexyl)-3,5-bis (dodecyloxy)-benzamide instead of heparin addition also increased the number of progenitor cells in the 3-D culture of CB MNCs without stromal cells when the conditioned medium was employed. The 3-D coculture constructed with nonwoven fabrics and stromal cells was clearly superior to the 2-D culture because of the expansion of CB hematopoietic progenitor cells without cytokine addition. Heparin addition to the 3-D coculture further increased the number of progenitor cells, which may result from a synergistic effect of soluble cytokines produced by stromal cells with the sulfur group of heparin. PMID:15739052

  12. Computer-aided identification of potential TYK2 inhibitors from drug database

    Science.gov (United States)

    Zhang, Wei; Li, Jianzong; Huang, Zhixin; Wang, Haiyang; Luo, Hao; Wang, Xin; Zhou, Nan; Wu, Chuanfang; Bao, Jinku

    2016-10-01

    TYK2 is a member of JAKs family protein tyrosine kinase activated in response to various cytokines. It plays a crucial role in transducing signals downstream of various cytokine receptors, which are involved in proinflammatory responses associated with immunological diseases. Thus, the study of selective TYK2 inhibitors is one of the most popular fields in anti-inflammation drug development. Herein, we adopted molecular docking, molecular dynamics simulation and MM-PBSA binding free energy calculation to screen potential TYK2-selective inhibitors from ZINC Drug Database. Finally, three small molecule drugs ZINC12503271 (Gemifloxacin), ZINC05844792 (Nebivolol) and ZINC00537805 (Glyburide) were selected as potential TYK2-selective inhibitors. Compared to known inhibitor 2,6-dichloro-N-{2-[(cyclopropylcarbonyl)amino]pyridin-4-yl}benzamide, these three candidates had better Grid score and Amber score from molecular docking and preferable results from binding free energy calculation as well. What's more, the ATP-binding site and A-loop motif had been identified to play key roles in TYK2-targeted inhibitor discovery. It is expected that our study will pave the way for the design of potent TYK2 inhibitors of new drugs to treat a wide variety of immunological diseases such as inflammatory diseases, multiple sclerosis, psoriasis inflammatory bowel disease (IBD) and so on.

  13. Electrochemical Sensor for the Selective Determination of Prindopril Based on Phosphotungestic Acid Plastic Membrane

    International Nuclear Information System (INIS)

    A novel PVC membrane sensor for perindopril based on perindopril-phosphotungstate ion pair complex was prepared. The influence of membrane composition (i.e. percent of PVC, plasticizer, ion-pair complex, and kind of plasticizer), inner solution, pH of test solution and foreign cations on the electrode performance was investigated. The optimized membrane demonstrates Nernstian response (30.9 ± 1.0 mV per decade) for perindopril cations over a wide linear range from 9.0 Χ 10-7 to 1 Χ 10-2 M at 25 .deg. C. The potentiometric response is independent of the pH in the range of 4.0-9.5. The proposed sensor has the advantages of easy preparation, fast response time. The selectivity coefficients indicate excellent selectivity for perindopril over many common cations (e. g., Na+, K+, Mg2+, Cu2+, Ni2+, rhamnose, maltose, glycine and benzamide). The practical applications of this electrode was demonstrated by measuring the concentrations of perindopril in pure solutions and pharmaceutical preparations with satisfactory results

  14. Disposable microcolumns with welded metal frits.

    Science.gov (United States)

    Hong, Sung Hoon; Cheong, Won Jo

    2016-01-01

    This study reports the preparation of disposable microcolumns with welded metal frits for the first time. First, the bottom of glass-lined stainless-steel tubing of 30 cm length, 1.6 mm od, and 0.5 mm id was welded with a stainless-steel screen frit of 1.6 mm diameter. A micro-welding machine was used for this. Next, the column was connected to a slurry packer and packed with porous silica particles. Then, the inlet of the column was carefully welded with another frit. The column was tested for separation of a test mix composed of phenol, 2-nitrophenol, acetophenone, aceanilide, and benzamide. Another column of the same physical dimension was also prepared with frits that were not welded to the column. The chromatographic performances of the two groups of columns (welded frits versus non-welded frits) were examined. The columns of welded frits showed ca. 18% better separation efficiency (number of theoretical plates) than those of non-welded frits. PMID:26614222

  15. A cyclohexanecarboxamide derivative with inhibitory effects on Schistosoma mansoni cercarial serine protease and penetration of mice skin by the parasite.

    Science.gov (United States)

    Bahgat, Mahmoud; Aboul-Enein, Mohamed N; El Azzouny, Aida A; Maghraby, Amany; Ruppel, Andreas; Soliman, Wael M

    2009-01-01

    A cyclohexanecarboxamide derivative, N-phenyl-N-[1-(piperidine-1-carbonyl)cyclohexyl] benzamide (MNRC-5), was evaluated for its inhibitory effects on Schistosoma mansoni cercarial serine protease activity and cercarial penetration. MNRC-5 exerted an inhibitory effect on S. mansoni cercarial serine protease at serial concentrations of the specific chromogenic substrate Boc-Val-Leu-Gly-Arg-PNA for such enzyme family and the inhibitory coefficient (Ki) value was deduced. Moreover, topical treatment of mice tails with the most potent inhibitory concentration of MNRC-5 formulated in jojoba oil successfully blocked cercarial penetration as demonstrated by a significant reduction (75%; p jojoba oil base containing no MNRC-5. In addition, the IgM and IgG reactivities to crude S. mansoni cercarial, worm and egg antigens were generally lower in sera from treated infected mice than untreated infected mice. In conclusion, we report on a new serine protease inhibitor capable for blocking penetration of host skin by S. mansoni cercariae as measured by lowering worm burden and decrease in the levels of both IgM and IgG towards different bilharzial antigens upon topical treatment.

  16. Cinitapride protects against ethanol-induced gastric mucosal injury in rats: role of 5-hydroxytryptamine, prostaglandins and sulfhydryl compounds.

    Science.gov (United States)

    Alarcón-de-la-Lastra Romero, C; López, A; Martín, M J; la Casa, C; Motilva, V

    1997-04-01

    This study was designed to determine the gastroprotective properties of cinitapride (CNT), a novel prokinetic benzamide derivative agonist of 5-HT4 and 5-HT1 receptors and 5-HT2 antagonist, on mucosal injury produced by 50% (v/v) ethanol. Results were compared with those for 5-hydroxytryptamine (5-HT: 10 mg kg-1). The possible involvements of gastric mucus secretion, endogenous prostaglandins (PGs) and sulfhydryl compounds (SH) in the protection mediated by CNT were also examined. Intraperitoneal administration of CNT (0.50 and 1 mg kg-1), 30 min before ethanol, significantly prevented gastric ulceration and increased the hexosamine content of gastric mucus. CNT (1 mg kg-1) also produced a significant increase in gastric mucosal levels of PGE2, but did not induce any significant changes in SH values. On the contrary, pretreatment with 5-HT worsened ethanol-induced erosions, however, did not affect gastric mucus secretion, glycoprotein content or PGE2 levels, although the non-protein SH fraction was significantly decreased. The present results demonstrate that the gastroprotective effects of CNT could be partly explained by a complex PG dependent mechanism. We suggest that 5-HT dependent mechanisms through 5-HT2 receptor blockade and 5-HT1 receptor activation could be also involved. PMID:9211565

  17. 6,7-Dimethoxy-2-{2-[4-(1H-1,2,3-triazol-1-yl)phenyl]ethyl}-1,2,3,4-tetrahydroisoquinolines as superior reversal agents for P-glycoprotein-mediated multidrug resistance.

    Science.gov (United States)

    Liu, Baomin; Qiu, Qianqian; Zhao, Tianxiao; Jiao, Lei; Li, Yunman; Huang, Wenlong; Qian, Hai

    2015-02-01

    P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) is a major obstacle for successful cancer chemotherapy. Based on our previous study, 17 novel compounds with the 6,7-dimethoxy-2-{2-[4-(1H-1,2,3-triazol-1-yl)phenyl]ethyl}-1,2,3,4-tetrahydroisoquinoline scaffold were designed and synthesized. Among them, 2-[(1-{4-[2-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)ethyl]phenyl}-1H-1,2,3-triazol-4-yl)methoxy]-N-(p-tolyl)benzamide (compound 7 h) was identified as a potent modulator of P-gp-mediated MDR, with high potency (EC50 =127.5 ± 9.1 nM), low cytotoxicity (TI>784.3), and long duration (>24 h) in reversing doxorubicin (DOX) resistance in K562/A02 cells. Compound 7 h also enhanced the effects of other MDR-related cytotoxic agents (paclitaxel, vinblastine, and daunorubicin), increased the accumulation of DOX and blocked P-gp-mediated rhodamine 123 efflux function in K562/A02 MDR cells. Moreover, 7 h did not have any effect on cytochrome (CYP3A4) activity. These results indicate that 7 h is a relatively safe modulator of P-gp-mediated MDR that has good potential for further development. PMID:25470220

  18. [Chemotherapies of negative schizophrenia].

    Science.gov (United States)

    Petit, M; Dollfus, S

    1991-01-01

    Five years ago, Goldberg claimed that negative symptoms of schizophrenia do respond to neuroleptics. This apparent discovery is, in fact, a very common way of thinking for European schools of psychiatry, specially the French one guided by Delay and Deniker. Initially focused on reserpine and some alerting phenothiazines such as thioproperazine, this opinion has been extended to benzamides in the 1970s. The analysis of the publications devoted to this point indicates that several drugs are actually considered as potent disinhibitors (i.e. active on negative symptoms of schizophrenia): Phenothiazines: As shown in the controlled studies by Itil (1971), Poirier-Littré (1988), fluphenazine and pipotiazine improve the BPRS anergia factor and the SANS score. Butyrophenones: The first description of the "imipramine like" effect of trifluperidol by Janssen (1959) initiated the studies by Gallant (1960), Fox (1963). They compared trifluperidol at low doses versus haloperidol and chlorpromazine at medium and high doses, BPRS anergia factor improved only at low doses. Diphenylbutylpiperidines (DPBP): Meltzer's review (1986) concluded to the efficacy of such drugs on negative symptoms appearing as a specific biochemical relationship effect. A definite analysis about doses leads to a very different interpretation: DPBP low doses and only low doses improved negative symptoms as much as some low doses of phenothiazines. On the opposite, DPBP, phenothiazines and butyrophenones high doses are inefficient.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1683624

  19. Single photon emission tomography (SPET) imaging of dopamine D2 receptors in the course of dopamine replacement therapy in patients with nocturnal myoclonus syndrome (NMS)

    International Nuclear Information System (INIS)

    Single photon emission tomography (SPET) permits the in vivo measurements of regional cerebral radioactivity in the human brain following the administration of compounds labeled with photon-emitting isotopes. According to our SPET findings of a reduced binding of [123I]labeled (S)-2-hydroxy-3-iodo-6-methoxy-([1-ethyl-2-pyrrolidinyl]methyl) benzamide (IBZM) (a highly selective CNS D2 dopamine receptor ligand) to D2 dopamine receptors in striatal structures in untreated patients with nocturnal myoclonus syndrome (NMS) it seemed to be of interest to investigate whether there are changes in D2 receptor binding under dopamine replacement therapy or not. We studied the uptake and distribution of [123I]IBZM before and in the course of dopamine replacement therapy in four patients with severe insomnia caused by nocturnal myoclonus syndrome (NMS). We found an increase of the IBZM binding to D2 receptors in the course of treatment, which was associated with an improvement of sleep quality. Reasons for this are discussed. The [123I]IBZM SPET technique in conclusion offers an interesting tool for in vivo investigations of functional changes in the dopaminergic neurotransmitter system in longitudinal studies. (author)

  20. Synthesis and antimicrobial activity of some novel cross-linked chitosan hydrogels.

    Science.gov (United States)

    Mohamed, Nadia Ahmed; Fahmy, Mona Mohamed

    2012-01-01

    Four novel hydrogels based on chitosan were synthesized via a cross-linking reaction of chitosan with different concentrations of oxalyl bis 4-(2,5-dioxo-2H-pyrrol- 1(5H)-yl)benzamide. Their structures were confirmed by fourier transform infrared X-ray (FTIR), scanning electron microscopy (SEM) and X-ray diffraction. The antimicrobial activities of the hydrogels against two crop-threatening pathogenic fungi namely: Aspergillus fumigatus (A. fumigatus, RCMBA 06002), and Aspergillus niger (A. niger, RCMBA 06106), and five bacterial species namely: Bacillis subtilis (B. subtilis, RCMBA 6005), Staphylococcus aureus (S. aureus, RCMBA 2004), Streptococcus pneumoniae (S. pneumonia, RCMB 000101) as Gram positive bacteria, and Salmonella typhimurium (S. typhimurium, RCMB 000104), and Escherichia coli (E. coli, RCMBA 5003) as Gram negative bacteria have been investigated. The prepared hydrogels showed much higher antimicrobial activities than that of the parent chitosan. The hydrogels were more potent in case of Gram-positive bacteria than Gram-negative bacteria. Increasing the degree of cross-linking in the hydrogels resulted in a weaker antimicrobial activity.

  1. Pharmacotherapy of gastroparesis.

    LENUS (Irish Health Repository)

    Quigley, E M

    2012-02-03

    The evaluation and management of gastric motor dysfunction continues to represent a significant clinical challenge. The very definition of what constitutes a clinically relevant disturbance of gastric motility remains unclear. The spectrum of gastroparesis extends from those with classical symptoms and severe delay of gastric emptying to those with dyspepsia and a mild delay in emptying rate. Indeed, for many patients with dyspepsia, the role of gastric emptying delay in the pathogenesis of symptoms, remains unclear. Any assessment of the efficacy of any therapeutic class in gastroparesis must be mindful, therefore, of these variations in definition. For those individuals with severe established gastroparesis, therapeutic success often remains elusive and i.v. erythromycin and oral dopamine antagonists, or substituted benzamides, remain the best options for acute severe exacerbations and chronic maintenance therapy, respectively. Alternatives, currently under investigation, include a number of 5-HT4 agonists, macrolides devoid of antibiotic activity, CCK antagonists and gastric electrical stimulation. Other novel approaches include strategies to address some of the regional abnormalities in gastric motor function that have been identified in some patients with dyspepsia.

  2. Radiopharmaceuticals for SPECT exploration of dopaminergic systems. Diagnosis and surveillance of neuro-degenerative diseases; Les radiopharmaceutiques pour l`exploration des system dopaminergique en TEMP. Interet pour le diagnostic et le suivi des maladies neurodegeneratives

    Energy Technology Data Exchange (ETDEWEB)

    Gouilloteau, D.; Prunier-Levallon, C.; Zimmer, L.; Autret, A.; Besnard, J-Cl.; Baulieu, J-L. [CHU TOURS (France)

    1997-12-31

    New radiopharmaceuticals were developed to explore the pre- or post-synaptic slopes of the dopaminergic terminations. At present, their interest is recognized for the differential diagnosis of the extra-pyramidal syndromes. Other various applications in neurology and psychiatry are in view. On the pre-synaptic slope, implied in the Parkinson`s disease, the dopamine carrier, able to be visualized due to its iodine derivatives of cocaine, is localized. The {beta}CIT, which is presently the best known specificity-free derivative, has actually an equivalent affinity for the dopamine carrier and the serotonin carrier. Besides, its kinetic does not allow its imaging in the day of injection. We have developed and validated another derivative, the PE2I: N-(3-Iodoprop-(2E)-enyl) -2{beta}-carbometoxy -3{beta}-(4`-methyl-phenyl) nortropane which displays the properties required by kinetic and specificity. On the post-synaptic slope the type-D2 dopaminergic receptors were localized, which can be explored by means of (iodolisuride) ergolenes and benzamide derivatives (IBZM). These ligands have not an AMM yet, therefore their utilization may be approached by magistral preparation. The scintigraphy of the D2 receptors and dopamine carrier could be useful for the earlier diagnosis and the therapeutic surveillance of the neuro-degenerative decease. The coupling of the pre- and post-synaptic scintigraphies may be taken into consideration to augment diagnosis potentiality

  3. Biomimetic anchors applied to the host-guest antifouling functionalization of titanium substrates.

    Science.gov (United States)

    Cai, Xiao Yan; Li, Ning Ning; Chen, Jiu Cun; Kang, En-Tang; Xu, Li Qun

    2016-08-01

    A biomimetic strategy was developed for the construction of antifouling titanium oxide (Ti(oxide)) surfaces based on host-guest interactions. Two catecholic derivatives, dopamine 4-(phenylazo)benzamide (AZODopa) and dopamine 1-adamantanecarboxamide (AdaDopa) were synthesized and immobilized onto the Ti(oxide) surfaces. The guest molecules-anchored Ti(oxide) surfaces were further functionalized with zwitterionic heptakis[6-deoxy-6-(N-3-sulfopropyl-N,N-dimethylammonium ethyl sulfanyl)]-β-cyclodextrin (SBCD) and hydrophilic β-CD polymer (CDP). The surface elemental compositions and hydrophobic/hydrophilic properties of the Ti(oxide) surfaces before and after modification were characterized by X-ray photoelectron spectroscopy (XPS) and static water contact angle measurements, respectively. The antifouling properties of the modified Ti(oxide) surfaces were evaluated by the protein adsorption and bacterial adhesion assays. The zwitterionic SBCD- and hydrophilic CDP-functionalized Ti(oxide) surfaces can reduce the adsorption of bovine plasma fibrinogen and adhesion of Escherichia coli, as compared to the pristine and guest molecules-anchored Ti(oxide) surfaces. PMID:27135943

  4. Synthesis of New Congeners of 1-methyl-3-aminoisoquinolines, Evaluation of Their Cytotoxic Activity, In Silico and In Vitro Study of Their Molecular Targets as PDE4B.

    Science.gov (United States)

    Lapa, Gennady B; Tsunoda, Toshiyuki; Shirasawa, Senji; Baryshnikova, Maria A; Evseev, Gregory G; Afanasyeva, Daria A; Chigorina, Elena A

    2016-04-01

    To examine the cytotoxic activity of congeners of 3-amino-isoquinoline, we performed the phenotypic screening using panel of 60 cell lines and found that (N-(6,7-dimethoxy-1-methyl-isoquinolin-3-yl)-4-{[(1-ethyl-4-methyl-1H-pyrazol-3-yl)methyl]amino}benzamide (4d)) exhibited the significant effect against different tumor cell lines while showing the high activity toward human colorectal cancer HCT-116 cells (IC50 = 18 μm) and human breast cancer T-47D cells (GI50 = 1.9 μm). Virtual screening indicated that these compounds target protein kinases and phosphodiesterases (PDE). However, wet screening among panel of protein kinases did not show any significant activity. By contrast, 50 μm of 4c and 4d inhibited the growth of HKe3-mtKRAS spheroids in the 3D floating (3DF) culture suggesting that 4c and 4d target PDE4B which is selectively upregulated by mtKRAS in 3DF culture. PMID:26613238

  5. Human sterol 14α-demethylase as a target for anticancer chemotherapy: towards structure-aided drug design.

    Science.gov (United States)

    Hargrove, Tatiana Y; Friggeri, Laura; Wawrzak, Zdzislaw; Sivakumaran, Suneethi; Yazlovitskaya, Eugenia M; Hiebert, Scott W; Guengerich, F Peter; Waterman, Michael R; Lepesheva, Galina I

    2016-08-01

    Rapidly multiplying cancer cells synthesize greater amounts of cholesterol to build their membranes. Cholesterol-lowering drugs (statins) are currently in clinical trials for anticancer chemotherapy. However, given at higher doses, statins cause serious side effects by inhibiting the formation of other biologically important molecules derived from mevalonate. Sterol 14α-demethylase (CYP51), which acts 10 steps downstream, is potentially a more specific drug target because this portion of the pathway is fully committed to cholesterol production. However, screening a variety of commercial and experimental inhibitors of microbial CYP51 orthologs revealed that most of them (including all clinical antifungals) weakly inhibit human CYP51 activity, even if they display high apparent spectral binding affinity. Only one relatively potent compound, (R)-N-(1-(3,4'-difluorobiphenyl-4-yl)-2-(1H-imidazol-1-yl)ethyl)-4-(5-phenyl-1,3,4-oxadiazol-2-yl)benzamide (VFV), was identified. VFV has been further tested in cellular experiments and found to decrease proliferation of different cancer cell types. The crystal structures of human CYP51-VFV complexes (2.0 and 2.5 Å) both display a 2:1 inhibitor/enzyme stoichiometry, provide molecular insights regarding a broader substrate profile, faster catalysis, and weaker susceptibility of human CYP51 to inhibition, and outline directions for the development of more potent inhibitors. PMID:27313059

  6. VFV as a New Effective CYP51 Structure-Derived Drug Candidate for Chagas Disease and Visceral Leishmaniasis.

    Science.gov (United States)

    Lepesheva, Galina I; Hargrove, Tatiana Y; Rachakonda, Girish; Wawrzak, Zdzislaw; Pomel, Sébastien; Cojean, Sandrine; Nde, Pius N; Nes, W David; Locuson, Charles W; Calcutt, M Wade; Waterman, Michael R; Daniels, J Scott; Loiseau, Philippe M; Villalta, Fernando

    2015-11-01

    Sterol 14α-demethylases (CYP51) are the enzymes essential for sterol biosynthesis. They serve as clinical targets for antifungal azoles and are considered as targets for treatment of human Trypanosomatidae infections. Recently, we have shown that VNI, a potent and selective inhibitor of trypanosomal CYP51 that we identified and structurally characterized in complex with the enzyme, can cure the acute and chronic forms of Chagas disease. The purpose of this work was to apply the CYP51 structure/function for further development of the VNI scaffold. As anticipated, VFV (R)-N-(1-(3,4'-difluorobiphenyl-4-yl)-2-(1H-imidazol-1-yl)ethyl)-4-(5-phenyl-1,3,4-oxadiazol-2-yl)benzamide, the derivative designed to fill the deepest portion of the CYP51 substrate-binding cavity, reveals a broader antiprotozoan spectrum of action. It has stronger antiparasitic activity in cellular experiments, cures the experimental Chagas disease with 100% efficacy, and suppresses visceral leishmaniasis by 89% (vs 60% for VNI). Oral bioavailability, low off-target activity, favorable pharmacokinetics and tissue distribution characterize VFV as a promising new drug candidate. PMID:25883390

  7. Synthesis, radiolabeling, and preliminary evaluation in mice of some (N-diethylaminoethyl)-4-iodobenzamide derivatives as melanoma imaging agents

    International Nuclear Information System (INIS)

    N-(2-Diethylaminoethyl)-4-iodobenzamide (BZA) is a radiopharmaceutical recently developed in our laboratory for the scintigraphic detection of melanoma and metastases. Optimal time for imaging was between 18-24 h p.i. of [123I] BZA. With a view to selecting compounds able to provide quality images shortly after the injection, synthesis of an initial series of BZA derivatives and their evaluation in B16 melanoma bearing mice have been carried out. The [125I] radiolabeled products were obtained by a simple isotopic exchange procedure with high radiochemical yields (85-95%). After i.v. administration of the compounds we observed a good tumoral targeting ability. Tumoral activity peaked at 2.6 to 7.7% injected dose per g within 1 h post-injection. One of the benzamides with a blood clearance faster than that of BZA--0.06 vs. 0.2% I D/g--6 h p.i. gave the same tumor to blood and to organ ratios as BZA at 12-18 h p.i. Based on these preclinical data we hope to obtain good tumoral images 6 h p.i. in scintigraphic studies in man

  8. Synthesis of novel nanostructured chiral poly(amide-imide)s containing dopamine and natural amino acids

    Indian Academy of Sciences (India)

    Shadpour Mallakpour; Amin Zadehnazari

    2013-01-01

    Four new thermally stable and optically active poly(amide-imide)s (PAI)s with good inherent viscosities were synthesized from the direct polycondensation reaction of N,N'-(pyromellitoyl)-bis-L--amino acids with 3,5-diamino-N-(3,4-dihydroxy-phen-ethyl)benzamide in a medium consisting of a molten salt, tetrabutylammonium bromide, and triphenyl phosphite as the activator. The polymerization reactions produced a series of novel PAIs containing dopamine segment in the side chain in high yield with inherent viscosities between 0.33 and 0.49 dL/g. The obtained polymers were typically characterized by means of FT-IR, 1HNMR spectroscopy, elemental analyses, powder X-ray diffraction, field emission scanning electronmicroscopy, inherent viscosity, and solubility tests. Thermal properties and flame retardant behaviour of the PAIs were also investigated using thermal gravimetric analysis (TGA and DTG) and limiting oxygen index (LOI). Data obtained by thermal analysis revealed that these polymers showed good thermal stability. Furthermore, high char yield in TGA and good LOI values indicated that the obtained polymers were capable of exhibiting good flame retardant properties.

  9. Chidamide, a novel histone deacetylase inhibitor, inhibits the viability of MDS and AML cells by suppressing JAK2/STAT3 signaling

    Science.gov (United States)

    Zhao, Sida; Guo, Juan; Zhao, Youshan; Fei, Chengming; Zheng, Qingqing; Li, Xiao; Chang, Chunkang

    2016-01-01

    Many studies have indicated that histone deacetylase (HDAC) activity is always increased in a lot of human tumors, and inhibition of HDAC activity is a promising new strategy in the treatment of cancers. Chidamide, a novel HDAC inhibitor of the benzamide class, is currently under clinical trials. In this study, we aimed to investigate the antitumor activity of Chidamide on myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) cell lines and explore the possible mechanism. Chidamide exhibited efficient anti-proliferative activity on MDS and AML cells in a time- and dose-dependent manner, accompanied by cell cycle arrest at G0/G1 phase and cell apoptosis. Importantly, Chidamide possessed potent HDAC inhibition property, as evaluated by HDAC activity analysis and acetylation of histone H3 and H4. Moreover, Chidamide significantly increased the expression of Suppressors of cytokine signaling 3 (SOCS3), reduced the expression of Janus activated kinases 2 (JAK2) and Signal transducer and activator of transcription 3 (STAT3), and inhibited STAT3 downstream genes, including c-Myc, Bcl-xL, and Mcl-1, which are involved in cell cycle progression and anti-apoptosis. Therefore, we demonstrate that Chidamide exhibits potent inhibitory effect on cell viability of MDS and AML cells, and the possible mechanism may lie in the downregulation of JAK2/STAT3 signaling through SOCS3 upregulation. Our data provide rationale for clinical investigations of Chidamide in MDS and AML. PMID:27508038

  10. Repellency of oils of lemon eucalyptus, geranium, and lavender and the mosquito repellent MyggA natural to Ixodes ricinus (Acari: Ixodidae) in the laboratory and field.

    Science.gov (United States)

    Jaenson, Thomas G T; Garboui, Samira; Palsson, Katinka

    2006-07-01

    MyggA Natural (Bioglan, Lund, Sweden) is a commercially available repellent against blood-feeding arthropods. It contains 30% of lemon-scented eucalyptus, Corymbia citriodora (Hook.) K. D. Hill & L. A. S. Johnson (Myrtaceae), oil with a minimum of 50% p-menthane-3,8-diol. MyggA Natural also contains small amounts of the essential oils of lavender, Lavandula angustifolia Mill. (Lamiaceae), and geranium, Pelargonium graveolens L'Her. (Geraniaceae). In laboratory bioassays, MyggA Natural and C. citriodora oil exhibited 100% repellency against host-seeking nymphs of Ixodes ricinus (L.) (Acari: Ixodidae). Lavender oil and geranium oil, when diluted to 1% in 1,2-propanediol, had weak repellent activities on I. ricinus nymphs, but when diluted to 30% in 1,2-propanediol had 100% repellencies. 1,2-Propanediol (100%) had no significant repellent activity in comparison with that of the control. In field tests in tick-infested areas in central Sweden, tick repellency of MyggA Natural and C. citriodora oil was tested by the blanket-dragging technique for 4 d during a 6-d period. The repellencies (74 and 85%, respectively) on day 1 are similar (89%) to that of blankets treated in a similar manner with 19% diethyl-methyl-benzamide, based on previous work. Repellencies declined significantly from day 1 to day 6 (74 to 45% for MyggA Natural; 85 to 42% for C. citriodora oil). PMID:16892632

  11. Evaluation of DEET and eight essential oils for repellency against nymphs of the lone star tick, Amblyomma americanum (Acari: Ixodidae).

    Science.gov (United States)

    Meng, Hao; Li, Andrew Y; Costa Junior, Livio M; Castro-Arellano, Ivan; Liu, Jingze

    2016-02-01

    DEET and Eight commercially available essential oils (oregano, clove, thyme, vetiver, sandalwood, cinnamon, cedarwood, and peppermint) were evaluated for repellency against host-seeking nymphs of the lone star tick, Amblyomma americanum. Concentration-repellency response was established using the vertical paper bioassay technique for each essential oil and compared with that of N,N-diethyl-3-methyl benzamide (DEET), a standard repellent compound present in many commercial repellent formulations. The effective concentration of DEET that repels 50% of ticks (EC50) was estimated at 0.02 mg/cm(2), while EC50s of the essential oils fall between 0.113 and 0.297 mg/cm(2). Based on EC50 estimates, oregano essential oil was the most effective among all essential oils tested, followed by clove, thyme, vetiver, sandalwood, cinnamon, cedarwood, and peppermint oils. None of the tested essential oils demonstrated a level of tick repellency found with DEET. Results from this study illustrated the challenge in search for more effective natural tick repellents. PMID:26590930

  12. Autoradiographic localization of extrastriatal D2-dopamine receptors in the human brain using [125I]epidepride.

    Science.gov (United States)

    Hall, H; Farde, L; Halldin, C; Hurd, Y L; Pauli, S; Sedvall, G

    1996-06-01

    Epidepride is a benzamide with high affinity for central D2- and D3-dopamine receptors. The anatomical distribution of [125I]epidepride binding was examined by autoradiography, using postmortem human whole-hemisphere cryosections. The density of [125I]epidepride binding sites was high in caudate nucleus and putamen. [125I]epidepride also labeled receptors in extrastriatal region such as in the pallidum, some thalamic nuclei, the neocortex, and the substantia nigra. The neocortical binding was heterogeneously distributed. In most cortical regions, binding sites were located in superficial layers (I-II). However, in basal levels of the occipital cortex, [125I]epidepride binding was located in a deeper layer, probably corresponding to layer V. Competition studies indicated that most of the [125I]epidepride binding represented predominantly D2-dopamine receptors, in striatal as well as in extrastriatal regions. The presence of extrastriatal D2-dopamine receptor populations is of particular interest for research on schizophrenia and antipsychotic drug action. PMID:8723716

  13. Striatal and extrastriatal imaging of dopamine D{sub 2}receptors in the living human brain with [ {sup 123}I]epidepride single-photon emission tomography

    Energy Technology Data Exchange (ETDEWEB)

    Kuikka, J.T. [Department of Clinical Physiology, Kuopio University Hospital, Kuopio (Finland); Aakerman, K.K. [Department of Clinical Physiology, Kuopio University Hospital, Kuopio (Finland); Hiltunen, J. [MAP Medical Technologies Inc., Tikkakoski (Finland); Bergstroem, K.A. [Department of Clinical Physiology, Kuopio University Hospital, Kuopio (Finland); Raesaenen, P. [Department of Forensic Psychiatry, University of Kuopio and Niuvanniemi Hospital, Kuopio (Finland); Vanninen, E. [Department of Clinical Physiology, Kuopio University Hospital, Kuopio (Finland); Halldin, C. [Karolinska Institutet, Department of Clinical Neuroscience, Karolinska Hospital, Stockholm (Sweden); Tiihonen, J. [Department of Forensic Psychiatry, University of Kuopio and Niuvanniemi Hospital, Kuopio (Finland)

    1997-05-01

    The iodine-123 labelled ligand benzamide epidepride was evaluated as a probe for in vivo imaging of striatal and extrastriatal dopamine D{sub 2}receptor sites in the human brain. Four healthy males were imaged with a high-resolution single-photon emission tomography scanner. Striatal radioactivity peaked at 3 h after injection. The specific binding in the striatum was 0.91 {+-}0.03 at 3 h and this ratio steadily increased with time. Extrastriatal radioactivity was highest in the thalamus, in the midbrain and in the temporal cortex, and peaked at 45-60 min after injection of tracer. A smaller amount of radioactivity was found in the parietal, frontal and occipital cortices. Two radioactive metabolites were observed, of which one was more lipophilic than the parent compound. The radiation burden to the patient was 0.035 mSv/MBq (effective dose equivalent). The preliminary results showed that [ {sup 123}I]epidepride can be used for imaging striatal and extrastriatal dopamine D {sub 2}receptor sites in the living human brain. (orig.). With 5 figs., 1 tab.

  14. Striatal and extrastriatal imaging of dopamine D2 receptors in the living human brain with [123I]epidepride single-photon emission tomography.

    Science.gov (United States)

    Kuikka, J T; Akerman, K K; Hiltunen, J; Bergström, K A; Räsänen, P; Vanninen, E; Halldin, C; Tiihonen, J

    1997-05-01

    The iodine-123 labelled ligand benzamide epidepride was evaluated as a probe for in vivo imaging of striatal and extrastriatal dopamine D2 receptor sites in the human brain. Four healthy males were imaged with a high-resolution single-photon emission tomography scanner. Striatal radioactivity peaked at 3 h after injection. The specific binding in the striatum was 0.91+/-0.03 at 3 h and this ratio steadily increased with time. Extrastriatal radioactivity was highest in the thalamus, in the midbrain and in the temporal cortex, and peaked at 45-60 min after injection of tracer. A smaller amount of radioactivity was found in the parietal, frontal and occipital cortices. Two radioactive metabolites were observed, of which one was more lipophilic than the parent compound. The radiation burden to the patient was 0.035 mSv/MBq (effective dose equivalent). The preliminary results showed that [123I]epidepride can be used for imaging striatal and extrastriatal dopamine D2 receptor sites in the living human brain. PMID:9142727

  15. Striatal and extrastriatal imaging of dopamine D2receptors in the living human brain with [ 123I[epidepride single-photon emission tomography

    International Nuclear Information System (INIS)

    The iodine-123 labelled ligand benzamide epidepride was evaluated as a probe for in vivo imaging of striatal and extrastriatal dopamine D2receptor sites in the human brain. Four healthy males were imaged with a high-resolution single-photon emission tomography scanner. Striatal radioactivity peaked at 3 h after injection. The specific binding in the striatum was 0.91 ±0.03 at 3 h and this ratio steadily increased with time. Extrastriatal radioactivity was highest in the thalamus, in the midbrain and in the temporal cortex, and peaked at 45-60 min after injection of tracer. A smaller amount of radioactivity was found in the parietal, frontal and occipital cortices. Two radioactive metabolites were observed, of which one was more lipophilic than the parent compound. The radiation burden to the patient was 0.035 mSv/MBq (effective dose equivalent). The preliminary results showed that [ 123I[epidepride can be used for imaging striatal and extrastriatal dopamine D 2receptor sites in the living human brain. (orig.). With 5 figs., 1 tab

  16. Fluorine-18 radiofluorination of (S)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(3-fluoropropyl)-2,3-dimethoxybenzamide

    International Nuclear Information System (INIS)

    Substituted benzamides are selective ligands for the dopamine D2 receptors in the mammalian brain. The 5-(3-fluoropropyl) analogue of the very potent SPECT agent [123I]epidepride was shown to have the properties of a potential PET agent. Cyclotron produced H18F was delivered in 400 μL H218O into a vessel containing 1 mL of K2CO3/Kryptofix [222] in 96:4 acetonitrile/water. The H218O was removed by azeotropic distillations with acetonitrile to give K+/[K222]18F as an oil. [18F]Fluoropropylepidepride 2 was prepared by adding 5 mg of the corresponding tosylate 1 in 1 mL of acetonitrile. The reaction was allowed to proceed at 88 degree C for 24 min. Unreacted 18F was removed by eluting the reaction mixture through a silica Sep-Pak with ether. The ether was evaporated and the crude product was dissolved in 100 μL of 50:50 acetonitrile/ethanol. HPLC purification gave radiochemically pure 2

  17. Research Perspective: Potential Role of Nitazoxanide in Ovarian Cancer Treatment. Old Drug, New Purpose?

    Energy Technology Data Exchange (ETDEWEB)

    Di Santo, Nicola, E-mail: nico.disanto@duke.edu; Ehrisman, Jessie [Division of Gynecologic Oncology, Duke University Medical Center, Durham, NC 27710 (United States)

    2013-09-10

    Among gynecological malignancies epithelial ovarian cancer (EOC) is the leading cause of death. Despite improvements in conventional chemotherapy combinations, the overall cure rate has remained mostly stable over the years, and only 10%–15% of patients maintain a complete response following first-line therapy. To improve the efficacy of ovarian cancer chemotherapy it is essential to develop drugs with new mechanisms of action. Compared to normal tissues, protein disulfide isomerase (PDI) is overexpressed in ovarian tumors. PDI is a cellular enzyme in the lumen of the endoplasmic reticulum (ER) of eukaryotes or the periplasmic region of prokaryotes. This protein catalyzes the formation and breakage of disulphide bonds between cysteine residues in proteins, which affects protein folding. Selective inhibition of PDI activity has been exhibited both in vitro and in vivo anticancer activity in human ovarian cancer models. PDI inhibition caused accumulation of unfolded or misfolded proteins, which led to ER stress and the unfolded protein response (UPR), and in turn resulted in cell death. Nitazoxanide [NTZ: 2-acetyloxy-N-(5-nitro-2-thiazolyl)benzamide] is a thiazolide antiparasitic agent with excellent activity against a wide variety of protozoa and helminths. In this article, we propose that NTZ, acting as PDI inhibitor, may be a new and potent addition to the chemotherapeutic strategy against ovarian cancer.

  18. Coordination behavior of tetraaza [N4] ligand towards Co(II), Ni(II), Cu(II), Cu(I) and Pd(II) complexes: Synthesis, spectroscopic characterization and anticancer activity

    Science.gov (United States)

    El-Boraey, Hanaa A.

    2012-11-01

    Novel eight Co(II), Ni(II), Cu(II), Cu(I) and Pd(II) complexes with [N4] ligand (L) i.e. 2-amino-N-{2-[(2-aminobenzoyl)amino]ethyl}benzamide have been synthesized and structurally characterized by elemental analysis, spectral, thermal (TG/DTG), magnetic, and molar conductivity measurements. On the basis of IR, mass, electronic and EPR spectral studies an octahedral geometry has been proposed for Co(II), Ni(II) complexes and Cu(II) chloride complex, square-pyramidal for Cu(I) bromide complex. For Cu(II) nitrate complex (6), Pd(II) complex (8) square planar geometry was proposed. The EPR data of Cu(II) complexes in powdered form indicate dx2-y2 ground state of Cu(II) ion. The antitumor activity of the synthesized ligand and some selected metal complexes has been studied. The palladium(II) complex (8) was found to display cytotoxicity (IC50 = 25.6 and 41 μM) against human breast cancer cell line MCF-7 and human hepatocarcinoma HEPG2 cell line.

  19. Bio-Inspired Nitrile Hydration by Peptidic Ligands Based on L-Cysteine, L-Methionine or L-Penicillamine and Pyridine-2,6-dicarboxylic Acid

    Directory of Open Access Journals (Sweden)

    Cillian Byrne

    2014-12-01

    Full Text Available Nitrile hydratase (NHase, EC 4.2.1.84 is a metalloenzyme which catalyses the conversion of nitriles to amides. The high efficiency and broad substrate range of NHase have led to the successful application of this enzyme as a biocatalyst in the industrial syntheses of acrylamide and nicotinamide and in the bioremediation of nitrile waste. Crystal structures of both cobalt(III- and iron(III-dependent NHases reveal an unusual metal binding motif made up from six sequential amino acids and comprising two amide nitrogens from the peptide backbone and three cysteine-derived sulfur ligands, each at a different oxidation state (thiolate, sulfenate and sulfinate. Based on the active site geometry revealed by these crystal structures, we have designed a series of small-molecule ligands which integrate essential features of the NHase metal binding motif into a readily accessible peptide environment. We report the synthesis of ligands based on a pyridine-2,6-dicarboxylic acid scaffold and L-cysteine, L-S-methylcysteine, L-methionine or L-penicillamine. These ligands have been combined with cobalt(III and iron(III and tested as catalysts for biomimetic nitrile hydration. The highest levels of activity are observed with the L-penicillamine ligand which, in combination with cobalt(III, converts acetonitrile to acetamide at 1.25 turnovers and benzonitrile to benzamide at 1.20 turnovers.

  20. Nitazoxanide Use as Part of an Empiric Multi-Drug Regimen in Treating Children with Suspected Helicobacter pylori Infection

    Directory of Open Access Journals (Sweden)

    Asuncion G. Ramos-Soriano

    2015-01-01

    Full Text Available Helicobacter pylori, a Gram-negative bacterium found in the human stomach, is often present in patients with chronic gastritis. Traditional treatment for H. pylori infection includes metronidazole or clarithromycin, both being associated with development of resistance. In this retrospective report, we describe our clinical experience using a multi-drug treatment regimen for pediatric H. pylori that included nitazoxanide, a newer nitrothiazole benzamide compound used in treating intestinal protozoa infections. Charts were identified for patients who were treated between January 1, 2008 and December 31, 2013 with an ICD-9-CM code 041.86 (H. pylori and who underwent elective endoscopy. All patients were exposed to nitazoxanide for 3 days plus azithromycin, and cefixime (or another 3rd-generation oral cephalosporin for 7-10 days, plus a proton pump inhibitor for 30 days. The clinical cure criteria were predefined. There were 127 individual occurrences or cases identified for inclusion in the review, with 111 occurrences meeting the inclusion criteria. The success rate or clinical cure for the new therapy combination prescribed as defined prior to the chart review was 99 out of 111 cases (89.2%. There were no serious adverse events observed or reported during the treatment of any patient. Approximately 10% of patient charts reflected minor complaints of nausea, vomiting or abdominal cramps during the time of active drug therapy. Nitazoxanide appears to be an effective and well-tolerated option for use in combination with other agents to treat H. pylori-induced gastritis.

  1. Effects of Side Chains with Similar Lengths and Different Structures of Polyimides on Liquid Crystal Alignment Behavior

    Institute of Scientific and Technical Information of China (English)

    Jia-hao Xia; Ying Jiang; Shi-ming Gong; Zhen Sun; Ying-han Wang

    2014-01-01

    Polyimides (PI) with different side chains in structure were synthesized by copolycondensation of pyromelliticmdianhydride (PMDA) with 3,5-diamino-(4'-methane acid hexyl ester) phenyl-benzamide (C6-PDA),(4-butoxybiphenol)-3',5'-diaminobenzoate (C4-BBDA) and 3,5-diamino-benzoic acid decyl ester (C 10-DA) named PI-PDA,PI-C4,PI-DA,respectively.The lengths of side chains of PI-PDA and PI-DA are as similar as that of PI-C4.Through the pretilt angle tests it is demonstrated that neither the structure of side chains nor the rubbing process could make an obvious difference on vertical alignment property when the lengths of the side chains are similar,standing at around 1.6 nm.The measurement of surface energy of PI surfaces further proved this result.The result of the X-ray photo-electron spectroscope measurement indicated that the side chains of PIs stretched out from the polymer bulk phase and accumulated on the surface.

  2. In vitro efficacy of nitro- and halogeno-thiazolide/thiadiazolide derivatives against Sarcocystis neurona.

    Science.gov (United States)

    Gargala, G; Le Goff, L; Ballet, J J; Favennec, L; Stachulski, A V; Rossignol, J F

    2009-06-10

    Sarcocystis neurona is an obligate intracellular parasite that causes equine protozoal myeloencephalitis (EPM). The aim of this work was to document inhibitory activities of nitazoxanide (NTZ, [2-acetolyloxy-N-(5-nitro 2-thiazolyl) benzamide]) and new thiazolides/thiadiazolides on S. neurona in vitro development, and investigate their structure-activity relationships. S. neurona was grown in bovine turbinate cell cultures. At concentrations varying from 1.0 to 5.0mg/L, nitazoxanide and 21 of 32 second generation thiazolide/thiadiazolide agents exerted a > or =95% maximum inhibition on S. neurona development. Most active agents were either NO(2) or halogen substituted in position 5 of their thiazole moiety. In contrast, other 5-substitutions such as hydrogen, methyl, SO(2)CH(3), and CH(3) negatively impacted activity. Compared with derivatives with an acetylated benzene moiety, deacetylated compounds which most probably represent primary metabolites exhibited similar inhibitory activities. Present data provide the first evidence of in vitro inhibitory activities of nitazoxanide and new thiazolides/thiadiazolides on S. neurona development. Active halogeno-thiazolide/thiadiazolides may provide a valuable nitro-free alternative to nitazoxanide for EPM treatment depending on further evaluation of their in vivo activities. PMID:19369006

  3. Raman and surface enhanced Raman spectroscopic studies of specific, small molecule activator of histone acetyltransferase p300

    Science.gov (United States)

    Kundu, Partha P.; Pavan Kumar, G. V.; Mantelingu, Kempegowda; Kundu, Tapas K.; Narayana, Chandrabhas

    2011-07-01

    We report for the first time, the Raman and surface enhanced Raman scattering (SERS) studies of N-(4-chloro-3-trifluoromethyl-phenyl)-2-ethoxy-benzamide (CTB). This molecule is specific activator of human histone acetyltransferase (HAT), p300, and serves as lead molecule to design anti-neoplastic therapeutics. A detailed Raman and SERS band assignments have been performed for CTB, which are compared with the density functional theory calculations. The observed red shift of N sbnd H stretching frequency from the computed wavenumber indicates the weakening of N sbnd H bond resulting from proton transfer to the neighboring oxygen atom. We observe Ag sbnd N vibrational mode at 234 cm -1 in SERS of CTB. This indicates there is a metal-molecule bond leading to chemical enhancement in SERS. We also observe, enhancement in the modes pertaining to substituted benzene rings and methyl groups. Based on SERS analysis we propose the adsorption sites and the orientation of CTB on silver surface.

  4. Physicochemical properties of new amide-based protic ionic liquids and their use as materials for anhydrous proton conductors

    Energy Technology Data Exchange (ETDEWEB)

    Xiang Jin [School of Chemical Engineering and Environment, Beijing Institute of Technology, Beijing Key Laboratory of Environmental Science and Engineering, Beijing 100081 (China); Chen Renjie, E-mail: chenrj@bit.edu.cn [School of Chemical Engineering and Environment, Beijing Institute of Technology, Beijing Key Laboratory of Environmental Science and Engineering, Beijing 100081 (China); National Development Center of High Technology Green Materials, Beijing 100081 (China); Wu Feng, E-mail: wufeng863@vip.sina.com [School of Chemical Engineering and Environment, Beijing Institute of Technology, Beijing Key Laboratory of Environmental Science and Engineering, Beijing 100081 (China); National Development Center of High Technology Green Materials, Beijing 100081 (China); Li Li; Chen Shi [School of Chemical Engineering and Environment, Beijing Institute of Technology, Beijing Key Laboratory of Environmental Science and Engineering, Beijing 100081 (China); National Development Center of High Technology Green Materials, Beijing 100081 (China); Zou Qinqin [School of Chemical Engineering and Environment, Beijing Institute of Technology, Beijing Key Laboratory of Environmental Science and Engineering, Beijing 100081 (China)

    2011-09-01

    We prepared 3 protic ionic liquids based on trifluoromethanesulfonic acid and an amide, namely isobutyramide (ITSA), n-butyramide(NTSA), and benzamide(BTSA). All of the protic ionic liquids exhibit excellent thermal stability (above 200 deg. C). ITSA has the highest ionic conductivity, which is 32.6 mS/cm at 150 deg. C. ITSA was used to prepare anhydrous, conducting composite membranes based on polymers of polyvinylidene-fluoride (PVDF) to serve as intermediate temperature proton exchange membrane fuel cells. This type of composite membrane possesses good thermal stability, high ionic conductivity and good mechanical properties. Increasing the polymer content leads to the improvement of mechanical properties, but is accompanied by a reduction in ionic conductivity. We made efforts to eliminate the trade-off between strength and conductivity of the ITSA/PVDF composite membrane by adding polyamide imide, which resulted in a simultaneous increase in strength and conductivity. A conductivity of 7.5 mS/cm is achieved in a membrane containing 60 wt.% ITSA and 5 wt.% PAI in PVDF at 150 deg. C.

  5. The contribution of delta subunit-containing GABAA receptors to phasic and tonic conductance changes in cerebellum, thalamus and neocortex.

    Directory of Open Access Journals (Sweden)

    Stephen G Brickley

    2013-12-01

    Full Text Available We have made use of the delta subunit-selective allosteric modulator DS2 (4-chloro-N-[2-(2-thienylimidazo[1,2-a]pyridine-3-yl benzamide to assay the contribution of delta-GABAARs to tonic and phasic conductance changes in the cerebellum, thalamus and neocortex. In cerebellar granule cells, an enhancement of the tonic conductance was observed for DS2 and the orthosteric agonist THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol. As expected, DS2 did not alter the properties of GABAA receptor-mediated inhibitory postsynaptic synaptic currents (IPSCs supporting a purely extrasynaptic role for delta-GABAARs in cerebellar granule cells. DS2 also enhanced the tonic conductance recorded from thalamic relay neurons of the visual thalamus with no alteration in IPSC properties. However, in addition to enhancing the tonic conductance DS2 also slowed the decay of IPSCs recorded from layer II/III neocortical neurons. A slowing of the IPSC decay also occurred in the presence of the voltage-gated sodium channel blocker TTX. Moreover, under conditions of reduced GABA release the ability of DS2 to enhance the tonic conductance was attenuated. These results indicate that delta-GABAARs can be activated following vesicular GABA release onto neocortical neurons and that the actions of DS2 on the tonic conductance may be influenced by the ambient GABA levels present in particular brain regions.

  6. Electrochemical Sensor for the Selective Determination of Prindopril Based on Phosphotungestic Acid Plastic Membrane

    Energy Technology Data Exchange (ETDEWEB)

    Zareh, Mohsen M. [Univ. of Tabuk, Tabuk (Saudi Arabia); Wasel, Anower M. [Association of Drug Agency, Cairo (Egypt); Abd Alkreem, Yasser M. [Zagazig Univ., Zagazig (Egypt)

    2013-10-15

    A novel PVC membrane sensor for perindopril based on perindopril-phosphotungstate ion pair complex was prepared. The influence of membrane composition (i.e. percent of PVC, plasticizer, ion-pair complex, and kind of plasticizer), inner solution, pH of test solution and foreign cations on the electrode performance was investigated. The optimized membrane demonstrates Nernstian response (30.9 ± 1.0 mV per decade) for perindopril cations over a wide linear range from 9.0 Χ 10{sup -7} to 1 Χ 10{sup -2} M at 25 .deg. C. The potentiometric response is independent of the pH in the range of 4.0-9.5. The proposed sensor has the advantages of easy preparation, fast response time. The selectivity coefficients indicate excellent selectivity for perindopril over many common cations (e. g., Na{sup +}, K{sup +}, Mg{sup 2+}, Cu{sup 2+}, Ni{sup 2+}, rhamnose, maltose, glycine and benzamide). The practical applications of this electrode was demonstrated by measuring the concentrations of perindopril in pure solutions and pharmaceutical preparations with satisfactory results.

  7. Biodegradation of acrylamide by Enterobacter aerogenes isolated from wastewater in Thailand

    Institute of Scientific and Technical Information of China (English)

    Kanokhathai Buranasilp; Jittima Charoenpanich

    2011-01-01

    A widespread use of acrylamide, probably a neurotoxicant and carcinogen, in various industrial processes has led to environmental contamination. Fortunately, some microorganisms are able to derive energy from acrylamide. In the present work, we reported the isolation and characterization of a novel acrylamide-degrading bacterium from domestic wastewater in Chonburi, Thailand. The strain grew well in the presence of acrylamide as 0.5% (W/V), at pH 6.0 to 9.0 and 25℃. Identification based on biochemical characteristics and 16S rRNA gene sequence identified the strain as Enterobacter aerogenes. Degradation of acrylamide to acrylic acid started in the late logarithmic growth phase as a biomass-dependent pattern. Specificity of cell-free supernatant towards amides completely degraded butyramide and urea and 86% of lactamide. Moderate degradation took place in other amides with that by formamide > benzamide > acetamide > cyanoacetamide > propionamide. No degradation was detected in the reactions of N,N-methylene bisacrylamide, sodium azide, thioacetamide, and iodoacetamide. These results highlighted the potential of this bacterium in the cleanup of acrylamide/amide in the environment.

  8. First synthesis and anticancer activity of novel naphthoquinone amides.

    Science.gov (United States)

    Pradidphol, Narathip; Kongkathip, Ngampong; Sittikul, Pichamon; Boonyalai, Nonlawat; Kongkathip, Boonsong

    2012-03-01

    Sixteen novel naphthoquinone aromatic amides were synthesized by a new route starting from 1-hydroxy-2-naphthoic acid in nine or ten steps with good to excellent yield. Amide formation reaction was carried out by using 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM) as an efficient condensing agent leading to carboxamides in high yield. The key step for converting naphthol to 3-hydroxynaphthoquinone was the Fremy's salt oxidation followed by hydroxylation with tert-butyl hydroperoxide and triton B. Anticancer activity of these new naphthoquinone amides were evaluated and benzamide 22 showed potent inhibition against NCI-H187 cell lines while naphthamides 23 and 43 were the most potent inhibition against KB cells. The decatenation assay revealed that compounds 24 and 43 at 20 μM can inhibit hTopoIIα activity while three other compounds, namely compounds 22, 23, and 45, exhibited hTopoIIα inhibitory activity at final concentration of 50 μM. Docking experiment revealed the same trend as the cytotoxicity and decatenation assay. Therefore, naphthamides 24 and 43 can be promising target molecules for anticancer drug development. PMID:22280818

  9. Metabolic and Dynamic Profiling for Risk Assessment of Fluopyram, a Typical Phenylamide Fungicide Widely Applied in Vegetable Ecosystem

    Science.gov (United States)

    Wei, Peng; Liu, Yanan; Li, Wenzhuo; Qian, Yuan; Nie, Yanxia; Kim, Dongyeop; Wang, Mengcen

    2016-09-01

    Fluopyram, a typical phenylamide fungicide, was widely applied to protect fruit vegetables from fungal pathogens-responsible yield loss. Highly linked to the ecological and dietary risks, its residual and metabolic profiles in the fruit vegetable ecosystem still remained obscure. Here, an approach using modified QuEChERS (Quick, Easy, Cheap, Effective, Rugged and Safe) extraction combined with GC-MS/MS analysis was developed to investigate fluopyram fate in the typical fruit vegetables including tomato, cucumber, pepper under the greenhouse environment. Fluopyram dissipated in accordance with the first-order rate dynamics equation with the maximum half-life of 5.7 d. Cleveage of fluopyram into 2-trifluoromethyl benzamide and subsequent formation of 3-chloro-5-(trifluoromethyl) pyridine-2-acetic acid and 3-chloro-5-(trifluoromethyl) picolinic acid was elucidated to be its ubiquitous metabolic pathway. Moreover, the incurrence of fluopyram at the pre-harvest interval (PHI) of 7–21 d was between 0.0108 and 0.1603 mg/kg, and the Hazard Quotients (HQs) were calculated to be less than 1, indicating temporary safety on consumption of the fruit vegetables incurred with fluopyram, irrespective of the uncertain toxicity of the metabolites. Taken together, our findings reveal the residual essential of fluopyram in the typical agricultural ecosystem, and would advance the further insight into ecological risk posed by this fungicide associated with its metabolites.

  10. A soluble and fluorescent new type thienylpyrrole based conjugated polymer: optical, electrical and electrochemical properties.

    Science.gov (United States)

    Soganci, Tugba; Soyleyici, Hakan Can; Ak, Metin

    2016-06-01

    Recently, increased attention has been focused on the synthesis of soluble and processable conducting polymers due to interest in their potential application. For this purpose a new type electroactive 2,5-di(2-thienyl)pyrrole derivative was synthesized and its novel solution-processable and fluorescent polymer, namely poly(N-(2,5-di(thiophen-2-yl)-1H-pyrrol-1-yl)-3,4,5-tris(dodecyloxy)benzamide) (P(TPDOB)), was electrochemically synthesized. Characterization of the monomer and the polymer was performed by (1)H-NMR, (13)C-NMR, cyclic voltammetry, and UV-vis and fluorescence spectroscopy. This soluble polymer has very well-defined and reversible redox processes in the acetonitrile-lithium perchlorate (ACN/LiClO4) couple. Moreover, P(TPDOB) shows multielectrochromic behavior: blue in the oxidized state, caesious in the intermediate state and greenish in the neutral state. Also the copolymer consists of EDOT and TPDOB was synthesized by cyclic voltammetry. A copolymer film has superior electrochromic and electrical properties when compared with a homopolymer. Furthermore, the fluorescence features of the monomer and the polymer were investigated. Although the monomer is a violet light emitter, its polymer is a yellow light emitter. Synthesis of this new type solution-processable and fluorescent conducting polymer is an alternative to the conventional synthesis of soluble conducting polymers which allows the direct application of the conductive polymer to any desired surface for potential technological applications. PMID:27171850

  11. The novel NF-κB inhibitor IMD-0354 induces apoptosis in chronic lymphocytic leukemia.

    Science.gov (United States)

    Kanduri, M; Tobin, G; Aleskog, A; Nilsson, K; Rosenquist, R

    2011-03-01

    Nuclear factor-κB (NF-κB) is an important regulator of cell survival and has been shown to be constitutively active in chronic lymphocytic leukemia (CLL) cells. Recently, a novel NF-κB inhibitor, IMD-0354 (N-(3, 5-bis-trifluoromethyl-phenyl)-5-chloro-2-hydroxy-benzamide), was shown to specifically inhibit the phosphorylation of IκBα by IkB kinases, thus preventing NF-κB release. In this study, we investigated if IMD-0354 can inhibit NF-κB activation and induce apoptosis in CLL cells in vitro. The rate of increase in apoptosis, drug sensitivity and DNA-binding activity of NF-κB were studied using Annexin V stainings, the fluorometric microculture cytotoxicity assay and electrophoretic mobility shift assay, respectively. Finally, the impact of IMD-0354 treatment on the expression of a set of apoptosis-related genes was investigated. The results clearly show that IMD-0354 induced apoptosis (mean 26%, range 8-48%) in CLL cells, independent of immunoglobulin heavy variable (IGHV) gene mutational status, and showed a dose-dependent cytotoxic effect. IMD-0354 treatment also significantly lowered the DNA-binding activity of NF-κB in CLL cells. In addition, we identified differences in expression levels of pro- and antiapoptotic genes following IMD-0354 treatment. In summary, our novel findings show that IMD-0354 can induce apoptosis in CLL cells, and thus merits further investigation as an anticancer agent in vivo. PMID:22829125

  12. The discovery of epidepride and its analogs as high-affinity radioligands for imaging extrastriatal dopamine D(2) receptors in human brain.

    Science.gov (United States)

    de Paulis, Tomas

    2003-01-01

    [(123)I]Epidepride, [(18)F]fallypride, and [(76)Br]isoremoxipride (FLB-457) and their corresponding [(11)C]labeled derivatives belong to a class of high-affinity radioligands for SPECT or PET imaging of dopamine D(2) receptors in the human brain. In contrast to previously used imaging agents, these ligands are capable of identifying extrastriatal dopamine D(2) receptors. The design of these substituted benzamides derive its origin from the atypical antipsychotic agent, remoxipride. Starting in the late 1970's, halogenated analogs of (S)-sulpiride were evaluated in binding assays and behavioral studies, leading to the discovery of remoxipride. Remoxipride was 10 times weaker than sulpiride in vitro but 50 times more potent in vivo. Search for a putative active metabolite of remoxipride led to the discovery of raclopride and eticlopride, the former becoming a useful radioligand as tritium or carbon-11 labeled form for receptor binding and PET studies, respectively. In the US, the mono-iodine analog of raclopride, [(123)I]iodobenzamide (IBZM), was found to have moderate putamen-to-cerebellum ratio in rat and human brain. Continued search for metabolites of remoxipride led to the discovery of its 3,6-dihydroxy derivative, NCQ-344, with an extremely potent in vivo activity in the rat. SAR studies of the metabolites of remoxipride led to the discovery of the 3-methoxy isomer, isoremoxipride (FLB-457) and its corresponding 6-hydroxy analog, FLB-463, both having affinities for the dopamine D(2) receptor in the 20-30 pM range. Later, the 5-[(123)I]iodo analog of FLB-463, [(123)I]ioxipride ([(123)I]NCQ-298), became a potential SPECT imaging agent. In the mean time, the deshydroxy analog of IBZM, [(125)I]iodopride, showed binding potential in the rat similar to [(125)I]IBZM. Epidepride was designed by combining the structure of isoremoxipride with that of iodopride. In 1988, epidepride was independently prepared and radiolabeled in three separate laboratories in Stockholm

  13. Synthesis, in vitro pharmacologic characterization, and preclinical evaluation of N-[2-(1'-piperidinyl)ethyl]-3-[125I]iodo-4-methoxybenzamide (P[125I]MBA) for imaging breast cancer.

    Science.gov (United States)

    John, C S; Bowen, W D; Fisher, S J; Lim, B B; Geyer, B C; Vilner, B J; Wahl, R L

    1999-05-01

    The goal of this study was to investigate the potential use of a radioiodinated benzamide, N-[2-(1'-piperidinyl)ethyl]-3-iodo[125I]-4-methoxybenzamide (P[125I]MBA), a sigma receptor binding radioligand for imaging breast cancer. The chemical and radiochemical syntheses of PIMBA are described. The pharmacological evaluation of PIMBA was carried out for sigma-1 and sigma-2 receptor sites. The in vivo pharmacokinetics of the radioiodinated benzamide were determined in rats and comparison of P[125I]MBA with Tc-99m sestamibi were made in a rat mammary tumor model. Sigma-1 affinity (Ki) for PIMBA in guinea pig brain membranes using [3H](+)pentazocine was found to be 11.82 +/- 0.68 nM, whereas sigma-2 affinity in rat liver using [3H]DTG (1,3-o-di-tolylguanidine) was 206 +/- 11 nM. Sites in guinea pig brain membranes labeled by P[125I]MBA showed high affinity for haloperidol, (+)-pentazocine, BD1008, and PIMBA (Ki = 4.87 +/- 1.49, 8.81 +/- 1.97, 0.057 +/- 0.005, 46.9 +/- 1.8 nM, respectively). Competition binding studies were carried out in human ductal breast carcinoma cells (T47D). A dose-dependent inhibition of specific binding was observed with several sigma ligands. Ki values for the inhibition of P[125I]MBA binding in T47D cells for haloperidol, N-[2-(1'-piperidinyl)]ethyl]4-iodobenzamide (IPAB), N-(N-benzylpiperidin-4-yl)-4-iodobenzamide (4-IBP), and PIMBA were found to be 1.30 +/- 0.07, 13 +/- 1.5, 5.19 +/- 2.3, 1.06 +/- 0.5 nM, respectively. The in vitro binding data in guinea pig brain membranes and breast cancer cells confirmed binding to sigma sites. The saturation binding of P[125I]MBA in T47D cells as studied by Scatchard analysis showed saturable binding, with a Kd = 94 +/- 7 nM and a Bmax = 2035 +/- 305 fmol/mg of proteins. Biodistribution studies in Sprague-Dawley rats showed a rapid clearance of P[125I]MBA from the normal organs. The potential of PIMBA in imaging breast cancer was evaluated in Lewis rats bearing syngeneic RMT breast cancers, a cancer that

  14. 5-HT1A receptors are involved in the modulation of respiratory rhythmical discharge activity in the medulla oblongata slice preparation of neonatal rats%5-HT1A受体对新生大鼠离体延髓脑片呼吸节律性放电的调制

    Institute of Scientific and Technical Information of China (English)

    秦峥; 吴中海; 王晓锋

    2007-01-01

    本研究探讨5-HT1A受体在延髓基本节律性呼吸放电发生和调节中的作用.以改良Kreb's液恒温灌流新生Sprague-Dawley大鼠离体延髓脑片标本,稳定记录与之相连的舌下神经根的呼吸节律性放电活动(respiratory rhythmical discharge activity,RRDA)后,第一组在灌流液中分别单独给予5-HT1A受体的特异性激动剂8-羟四氢萘[(+/-)-8-hydroxy-2-(di-N-propylamino)tetralin hydrobromide,8-OHDPAT]和特异性拮抗剂多次甲基多苯基多异氰酸酯[4-iodo-N-[2-[4-methoxyphenyl]-1-piperazinyl]ethyl]-N-2-pyridynyl-benzamide hydrochloride,PMPPI];第二组分别先后给予8-OHDPAT和8-OHDPAT+PMPPI,观察舌下神经根RRDA的变化,探讨5-HT1A受体对其调节作用.结果显示,给予8-OHDPAT后,呼吸周期(respiratory cycle,RC)和呼气时程(expiratory time,TE)显著延长,放电的积分幅度(integral amplitude,IA)持续降低,吸气时程(inspiratory time,TI)无明显变化;给予PMPPI后RC、TI和TE明显缩短,舌下神经根IA无明显变化,且8-OHDPAT的作用可部分被PMPPI逆转.结果提示,5-HT1A受体参与了哺乳动物基本呼吸节律的产生和调节.

  15. Amisulpride vs. fluoxetine treatment of chronic fatigue syndrome: a pilot study.

    Science.gov (United States)

    Pardini, Matteo; Guida, Silvia; Primavera, Alberto; Krueger, Frank; Cocito, Leonardo; Gialloreti, Leonardo Emberti

    2011-03-01

    Different pharmacologic agents have been evaluated in the treatment of Chronic Fatigue Syndrome (CFS), albeit with moderate efficacy. Among the compounds thought to present with potential to be efficacious in CFS patients stands out low-dose amisulpride, a substituted benzamide that has been shown to be an useful treatment for conditions which exhibit some overlap with CFS such as dysthymia and somatoform disorders. We thus recruited forty non-depressed CFS patients that were randomized to receive either amisulpride 25mg bid, or fluoxetine 20mg uid; all subjects were un-blinded to the treatment regimen. At the time of enrollment in the study and after twelve weeks of treatment, enrolled subjects completed the Krupp Fatigue Severity Scale, the Hospital Anxiety and Depression Scale and a visual analog scale focused on pain and bodily discomfort. Moreover, all subjects were evaluated by a clinician, blinded to the treatment regimen, using the Clinical Global Impression Severity Scale. Our data revealed a significant improvement both in self-report, and observer-based measures for the amisulpride-treated, but not for the fluoxetine-treated patients. Amisulpride-treated subjects also presented with a significant reduction of somatic complaints, while the amisulpride effect on anxiety and mood levels was not significant. Both drugs were equally well tolerated. Summing up, we showed a positive symptomatic effect of amisulpride, compared to SSRI treatment, in a group of non-depressed CSF patients on self-report and on observer-based measures of fatigue and somatic complaints. If confirmed by larger, blinded studies, amisulpride thus could represent an effective approach to this difficult-to-treat condition.

  16. Prandial effect on the systemic exposure of amisulpride.

    Science.gov (United States)

    Jang, Yoo-Jung; Jeong, Tae Cheon; Noh, Keumhan; Baek, In-Whan; Kwon, Kwang-il; Kim, Eunyoung; Yoon, Young-Ran; Kang, Wonku

    2014-10-01

    A substituted benzamide, amisulpride is an atypical antipsychotic and a specific antagonist for dopamine D2 and D3 receptors. The prandial effect on amisulpride absorption remains unclear, therefore, this study was designed to investigate the effect of food on the systemic exposure to amisulpride in healthy volunteers. The study was a randomized, two-way crossed trial in which a single oral dose of amisulpride was administered on two occasions, with 7-days washout period between each drug administration. The volunteers were randomly divided into two groups and received amisulpride (50 mg) with Korean traditional food or under fasting state. Blood was serially taken, and the plasma amisulpride concentrations were measured by LC/MS/MS. At fasting state, amisulpride reached the first peak (37.1 ± 13.3 ng/ml) at ~2.3 h, and decreased down to 19.4 ± 4.3 ng/ml until 3.5 h, and then again went up to the second peak (25.3 ± 5.8 ng/ml) at 5 h followed by a slow decay with 10.6 h of half-life. In contrast, no double peaks were shown when the drug was given with meal. The maximum concentration of amisulpride (56.0 ± 12.7 ng/ml) was increased by a 1.5-fold compared with that under fasting (p > 0.05), and the time to peak shortened a little (1.7 ± 0.6 h).

  17. Imaging brain gene expression profiles by antipsychotics: region-specific action of amisulpride on postsynaptic density transcripts compared to haloperidol.

    Science.gov (United States)

    de Bartolomeis, Andrea; Marmo, Federica; Buonaguro, Elisabetta Filomena; Rossi, Rodolfo; Tomasetti, Carmine; Iasevoli, Felice

    2013-11-01

    Induction of motor disorders is considered the clinical landmark differentiating typical from atypical antipsychotics, and has been mainly correlated to dopamine D2 receptors blockade in striatum. This view is challenged by benzamides, such as amisulpride, which display low liability for motor side effects despite being D2/D3 receptors high-affinity blocking agents. These effects have been explained with the prominent presynaptic action of amisulpride or with the fast dissociation at D2 receptors, but there is scarce information on the effects of amisulpride on postsynaptic signaling. We carried out a molecular imaging study of gene expression after acute administration of haloperidol (0.8 mg/kg), amisulpride (10 or 35 mg/kg), or vehicle, focusing on postsynaptic genes that are key regulators of synaptic plasticity, such as Arc, c-fos, Zif-268, Norbin, Homer. The last one has been associated to schizophrenia both in clinical and preclinical studies, and is differentially induced by antipsychotics with different D2 receptors affinity. Topography of gene expression revealed that amisulpride, unlike haloperidol, triggers transcripts expression peak in medial striatal regions. Correlation analysis of gene expression revealed a prevalent correlated gene induction within motor corticostriatal regions by haloperidol and a more balanced gene induction within limbic and motor corticostriatal regions by amisulpride. Despite the selective dopaminergic profile of both compounds, our results demonstrated a differential modulation of postsynaptic molecules by amisulpride and haloperidol, the former impacting preferentially medial regions of striatum whereas the latter inducing strong gene expression in lateral regions. Thus, we provided a possible molecular profile of amisulpride, putatively explaining its "atypical atypicality".

  18. GPR139, an Orphan Receptor Highly Enriched in the Habenula and Septum, Is Activated by the Essential Amino Acids L-Tryptophan and L-Phenylalanine.

    Science.gov (United States)

    Liu, Changlu; Bonaventure, Pascal; Lee, Grace; Nepomuceno, Diane; Kuei, Chester; Wu, Jiejun; Li, Qingqin; Joseph, Victory; Sutton, Steven W; Eckert, William; Yao, Xiang; Yieh, Lynn; Dvorak, Curt; Carruthers, Nicholas; Coate, Heather; Yun, Sujin; Dugovic, Christine; Harrington, Anthony; Lovenberg, Timothy W

    2015-11-01

    GPR139 is an orphan G-protein-coupled receptor expressed in the central nervous system. To identify its physiologic ligand, we measured GPR139 receptor activity from recombinant cells after treatment with amino acids, orphan ligands, serum, and tissue extracts. GPR139 activity was measured using guanosine 5'-O-(3-[(35)S]thio)-triphosphate binding, calcium mobilization, and extracellular signal-regulated kinases phosphorylation assays. Amino acids L-tryptophan (L-Trp) and L-phenylalanine (L-Phe) activated GPR139, with EC50 values in the 30- to 300-μM range, consistent with the physiologic concentrations of L-Trp and L-Phe in tissues. Chromatography of rat brain, rat serum, and human serum extracts revealed two peaks of GPR139 activity, which corresponded to the elution peaks of L-Trp and L-Phe. With the purpose of identifying novel tools to study GPR139 function, a high-throughput screening campaign led to the identification of a selective small-molecule agonist [JNJ-63533054, (S)-3-chloro-N-(2-oxo-2-((1-phenylethyl)amino)ethyl) benzamide]. The tritium-labeled JNJ-63533054 bound to cell membranes expressing GPR139 and could be specifically displaced by L-Trp and L-Phe. Sequence alignment revealed that GPR139 is highly conserved across species, and RNA sequencing studies of rat and human tissues indicated its exclusive expression in the brain and pituitary gland. Immunohistochemical analysis showed specific expression of the receptor in circumventricular regions of the habenula and septum in mice. Together, these findings suggest that L-Trp and L-Phe are candidate physiologic ligands for GPR139, and we hypothesize that this receptor may act as a sensor to detect dynamic changes of L-Trp and L-Phe in the brain.

  19. Food restriction alters N'-propyl-4,5,6,7-tetrahydrobenzothiazole-2,6-diamine dihydrochloride (pramipexole)-induced yawning, hypothermia, and locomotor activity in rats: evidence for sensitization of dopamine D2 receptor-mediated effects.

    Science.gov (United States)

    Collins, Gregory T; Calinski, Diane M; Newman, Amy Hauck; Grundt, Peter; Woods, James H

    2008-05-01

    Food restriction enhances sensitivity to the reinforcing effects of a variety of drugs of abuse including opiates, nicotine, and psychostimulants. Food restriction has also been shown to alter a variety of behavioral and pharmacological responses to dopaminergic agonists, including an increased sensitivity to the locomotor stimulatory effects of direct- and indirect-dopamine agonists, elevated extracellular dopamine levels in responses to psychostimulants, as well as suppression of agonist-induced yawning. Behavioral and molecular studies suggest that augmented dopaminergic responses observed in food-restricted animals result from a sensitization of the dopamine D2 receptor; however, little is known about how food restriction affects dopamine D3 receptor function. The current studies were aimed at better defining the effects of food restriction on D2 and D3 receptor function by assessing the capacity of N'-propyl-4,5,6,7-tetrahydrobenzothiazole-2,6-diamine dihydrochloride (pramipexole) to induce yawning, penile erection (PE), hypothermia, and locomotor activity in free-fed and food-restricted rats. Food restriction resulted in a suppression of pramipexole-induced yawning, a sensitized hypothermic response, and an enhanced locomotor response to pramipexole, effects that are suggestive of an enhanced D2 receptor activity; no effect on pramipexole-induced PE was observed. Antagonist studies further supported a food restriction-induced enhancement of the D2 receptor activity because the D2 antagonist 3-[4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl]methyl-1H-indole (L741,626) recovered pramipexole-induced yawning to free-fed levels, whereas yawning and PE were suppressed following pretreatment with the D3 antagonist N-{4-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-trans-but-2-enyl}-4-pyridine-2-yl-benzamide hydrochloride (PG01037). The results of the current studies suggest that food restriction sensitized rats to the D2-mediated effects of pramipexole while having no effect

  20. International Union of Basic and Clinical Pharmacology. XCV. Recent Advances in the Understanding of the Pharmacology and Biological Roles of Relaxin Family Peptide Receptors 1–4, the Receptors for Relaxin Family Peptides

    Science.gov (United States)

    Halls, Michelle L.; Bathgate, Ross A. D.; Sutton, Steve W.; Dschietzig, Thomas B.

    2015-01-01

    Relaxin, insulin-like peptide 3 (INSL3), relaxin-3, and INSL5 are the cognate ligands for the relaxin family peptide (RXFP) receptors 1–4, respectively. RXFP1 activates pleiotropic signaling pathways including the signalosome protein complex that facilitates high-sensitivity signaling; coupling to Gαs, Gαi, and Gαo proteins; interaction with glucocorticoid receptors; and the formation of hetero-oligomers with distinctive pharmacological properties. In addition to relaxin-related ligands, RXFP1 is activated by Clq-tumor necrosis factor-related protein 8 and by small-molecular-weight agonists, such as ML290 [2-isopropoxy-N-(2-(3-(trifluoromethylsulfonyl)phenylcarbamoyl)phenyl)benzamide], that act allosterically. RXFP2 activates only the Gαs- and Gαo-coupled pathways. Relaxin-3 is primarily a neuropeptide, and its cognate receptor RXFP3 is a target for the treatment of depression, anxiety, and autism. A variety of peptide agonists, antagonists, biased agonists, and an allosteric modulator target RXFP3. Both RXFP3 and the related RXFP4 couple to Gαi/Gαo proteins. INSL5 has the properties of an incretin; it is secreted from the gut and is orexigenic. The expression of RXFP4 in gut, adipose tissue, and β-islets together with compromised glucose tolerance in INSL5 or RXFP4 knockout mice suggests a metabolic role. This review focuses on the many advances in our understanding of RXFP receptors in the last 5 years, their signal transduction mechanisms, the development of novel compounds that target RXFP1–4, the challenges facing the field, and current prospects for new therapeutics. PMID:25761609

  1. International Union of Basic and Clinical Pharmacology. XCV. Recent advances in the understanding of the pharmacology and biological roles of relaxin family peptide receptors 1-4, the receptors for relaxin family peptides.

    Science.gov (United States)

    Halls, Michelle L; Bathgate, Ross A D; Sutton, Steve W; Dschietzig, Thomas B; Summers, Roger J

    2015-01-01

    Relaxin, insulin-like peptide 3 (INSL3), relaxin-3, and INSL5 are the cognate ligands for the relaxin family peptide (RXFP) receptors 1-4, respectively. RXFP1 activates pleiotropic signaling pathways including the signalosome protein complex that facilitates high-sensitivity signaling; coupling to Gα(s), Gα(i), and Gα(o) proteins; interaction with glucocorticoid receptors; and the formation of hetero-oligomers with distinctive pharmacological properties. In addition to relaxin-related ligands, RXFP1 is activated by Clq-tumor necrosis factor-related protein 8 and by small-molecular-weight agonists, such as ML290 [2-isopropoxy-N-(2-(3-(trifluoromethylsulfonyl)phenylcarbamoyl)phenyl)benzamide], that act allosterically. RXFP2 activates only the Gα(s)- and Gα(o)-coupled pathways. Relaxin-3 is primarily a neuropeptide, and its cognate receptor RXFP3 is a target for the treatment of depression, anxiety, and autism. A variety of peptide agonists, antagonists, biased agonists, and an allosteric modulator target RXFP3. Both RXFP3 and the related RXFP4 couple to Gα(i)/Gα(o) proteins. INSL5 has the properties of an incretin; it is secreted from the gut and is orexigenic. The expression of RXFP4 in gut, adipose tissue, and β-islets together with compromised glucose tolerance in INSL5 or RXFP4 knockout mice suggests a metabolic role. This review focuses on the many advances in our understanding of RXFP receptors in the last 5 years, their signal transduction mechanisms, the development of novel compounds that target RXFP1-4, the challenges facing the field, and current prospects for new therapeutics. PMID:25761609

  2. Effect of a novel synthesized sulfonamido-based gallate-SZNTC on chondrocytes metabolism in vitro.

    Science.gov (United States)

    Liu, Qin; Li, Mu-Yan; Lin, Xiao; Lin, Cui-Wu; Liu, Bu-Ming; Zheng, Li; Zhao, Jin-Min

    2014-09-25

    The ideal therapeutic agent for treatment of osteoarthritis (OA) should have not only potent anti-inflammatory effect but also favorable biological properties to restore cartilage function. Gallic acid (GA) and its derivatives are anti-inflammatory agents reported to have an effect on OA (Singh et al., 2003) [1]. However, GA has much weaker antioxidant effects and inferior bioactivity compared with its derivatives. We modified GA with the introduction of sulfonamide to synthesize a novel sulfonamido-based gallate named sodium salt of 3,4,5-trihydroxy-N-[4-(thiazol-2-ylsulfamoyl)-phenyl]-benzamide (SZNTC) and analyzed its chondro-protective and pharmacological effects. Comparison of SZNTC with GA and sulfathiazole sodium (ST-Na) was also performed. Results showed that SZNTC could effectively inhibit the Interleukin-1 (IL-1)-mediated induction of metalloproteinase-1 (MMP-1) and MMP-3 and could induce the expression of tissue inhibitor of metalloproteinase-1 (TIMP-1), which demonstrated ability to reduce the progression of OA. SZNTC can also exert chondro-protective effects by promoting cell proliferation and maintaining the phenotype of articular chondrocytes, as evidenced by improved cell growth, enhanced synthesis of cartilage specific markers such as aggrecan, collagen II and Sox9. Expression of the collagen I gene was effectively down-regulated, revealing the inhibition of chondrocytes dedifferentiation by SZNTC. Hypertrophy that may lead to chondrocyte ossification was also undetectable in SZNTC groups. The recommended dose of SZNTC ranges from 3.91μg/ml to 15.64μg/ml, among which the most profound response was observed with 7.82μg/ml. In contrast, its source products of GA and ST-Na have a weak effect in the bioactivity of chondrocytes, which indicated the significance of this modification. This study revealed SZNTC as a promising novel agent in the treatment of chondral and osteochondral lesions. PMID:25130855

  3. Loss of dysbindin-1, a risk gene for schizophrenia, leads to impaired group 1 metabotropic glutamate receptor function in mice.

    Directory of Open Access Journals (Sweden)

    Sanjeev K Bhardwaj

    2015-03-01

    Full Text Available The expression of dysbindin-1, a protein coded by the risk gene dtnbp1, is reduced in the brains of schizophrenia patients. Evidence indicates a role of dysbindin-1 in dopaminergic and glutamatergic transmission. Glutamatergic transmission and plasticity at excitatory synapses is critically regulated by G-protein coupled metabotropic glutamate receptor (mGluR family members, that have been implicated in schizophrenia. Here, we report a role of dysbindin-1 in hippocampal group 1 mGluR (mGluRI function in mice. In hippocampal synaptoneurosomal preparations from sandy (sdy mice, that have a loss of function mutation in dysbindin-1 gene, we observed a striking reduction in mGluRI agonist [(S-3,5-dihydroxyphenylglycine] (DHPG-induced phosphorylation of extracellular signal regulated kinase 1/2 (ERK1/2. This mGluR-ERK1/2 deficit occurred in the absence of significant changes in protein levels of the two members of the mGluRI family (i.e., mGluR1 and mGluR5 or in another mGluRI signaling pathway, i.e., protein kinase C (PKC. Aberrant mGluRI-ERK1/2 signaling affected hippocampal synaptic plasticity in the sdy mutants as DHPG-induced long-term depression (LTD at CA1 excitatory synapses was significantly reduced. Behavioral data suggest that the mGluRI hypofunction may underlie some of the cognitive abnormalities described in sdy mice as the administration of CDPPB (3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl benzamide, a positive allosteric modulator of mGluR5, rescued short-term object recognition and spatial learning and memory deficits in these mice. Taken together, our data suggest a novel role of dysbindin-1 in regulating mGluRI functions.

  4. Study of polymorphism in imatinib mesylate: A quantum chemical approach using electronic and vibrational spectra

    Science.gov (United States)

    Srivastava, Anubha; Joshi, B. D.; Tandon, Poonam; Ayala, A. P.; Bansal, A. K.; Grillo, Damián

    2013-02-01

    Imatinib mesylate, 4-(4-methyl-piperazin-1-ylmethyl)-N-u[4-methyl-3-(4-pyridin-3-yl)pyrimidine-2-ylamino)phenyl]benzamide methanesulfonate is a therapeutic drug that is approved for the treatment of chronic myelogeneous leukemia (CML) and gastrointestinal stromal tumors (GIST). It is known that imatinib mesylate exists in two polymorphic forms α and β. However, β-form is more stable than the α-form. In this work, we present a detailed vibrational spectroscopic investigation of β-form by using FT-IR and FT-Raman spectra. These data are supported by quantum mechanical calculations using DFT employing 6-311G(d,p) basis set, which allow us to characterize completely the vibrational spectra of this compound. The FT-IR spectrum of α-form has also been discussed. The importance of hydrogen-bond formation in the molecular packing arrangements of both forms has been examined with the vibrational shifts observed due to polymorphic changes. The red shift of the NH stretching bands in the infrared spectrum from the computed wavenumber indicates the weakening of the NH bond. The UV-vis spectroscopic studies along with the HOMO-LUMO analysis of both polymorphs (α and β) were performed and their chemical activity has been discussed. The TD-DFT method was used to calculate the electronic absorption spectra in the gas phase as well as in the solvent environment using IEF-PCM model and 6-31G basis set. Finally, the results obtained complements to the experimental findings.

  5. Photophysical study of a polyoxo ethylene linked naphthalene-based fluorescent chemosensor for Mg2+ and Ca2+ detection.

    Science.gov (United States)

    Xiang, Xiaoyan; Wang, Dan; Guo, Yali; Liu, Weisheng; Qin, Wenwu

    2013-07-01

    A naphthalene-based bichromophoric fluorescent sensor 2,2'-[oxy-bis(2-oxatetramethyleneoxy)]-bis[N-(2-naphthyl)-benzamide)] (1) was synthesized and characterized. Fluorescence decay for 1 in alcoholic solvents in the region of 415-460 nm revealed bi-exponential behavior. The faster component of the decay can be attributed to the formation of dimers. Above 480 nm, besides the dimer, there is also a little excimer formation and this excimer emits at longer wavelengths than the dimer. The observation of the change of the fluorescence emission spectra upon addition of water in EtOH-water mixtures is in line with the formation of water-bridged complexes preventing excimer formation. The sensor shows an increase in fluorescence intensity upon increasing Mg(2+) or Ca(2+) concentration in EtOH because the formation of the excimer can be hindered upon complexation with Mg(2+) or Ca(2+) ions. Because of the competition between hydrated metal ions and the water-bridged complex, spectral changes by complexation with Mg(2+) or Ca(2+) in EtOH-H2O (9 : 1 v/v) are quite different from those in neat ethanol. The ground-state dissociation constant K(d) estimated for the complex with Mg(2+) or Ca(2+) was found to be around 2.0 mM in EtOH-H2O (9 : 1 v/v), which makes it suitable for the measurement of the concentrations of these ions in physiologically relevant concentration ranges.

  6. Characterization of the biological effects of a novel protein kinase D inhibitor in endothelial cells.

    Science.gov (United States)

    Evans, Ian M; Bagherzadeh, Azadeh; Charles, Mark; Raynham, Tony; Ireson, Chris; Boakes, Alexandra; Kelland, Lloyd; Zachary, Ian C

    2010-08-01

    VEGF (vascular endothelial growth factor) plays an essential role in angiogenesis during development and in disease largely mediated by signalling events initiated by binding of VEGF to its receptor, VEGFR2 (VEGF receptor 2)/KDR (kinase insert domain receptor). Recent studies indicate that VEGF activates PKD (protein kinase D) in endothelial cells to regulate a variety of cellular functions, including signalling events, proliferation, migration and angiogenesis. To better understand the role of PKD in VEGF-mediated endothelial function, we characterized the effects of a novel pyrazine benzamide PKD inhibitor CRT5 in HUVECs (human umbilical vein endothelial cells). The activity of the isoforms PKD1 and PKD2 were blocked by this inhibitor as indicated by reduced phosphorylation, at Ser916 and Ser876 respectively, after VEGF stimulation. The VEGF-induced phosphorylation of three PKD substrates, histone deacetylase 5, CREB (cAMP-response-element-binding protein) and HSP27 (heat-shock protein 27) at Ser82, was also inhibited by CRT5. In contrast, CRT6, an inactive analogue of CRT5, had no effect on PKD or HSP27 Ser82 phosphorylation. Furthermore, phosphorylation of HSP27 at Ser78, which occurs solely via the p38 MAPK (mitogen-activated protein kinase) pathway, was also unaffected by CRT5. In vitro kinase assays show that CRT5 did not significantly inhibit several PKC isoforms expressed in endothelial cells. CRT5 also decreased VEGF-induced endothelial migration, proliferation and tubulogenesis, similar to effects seen when the cells were transfected with PKD siRNA (small interfering RNA). CRT5, a novel specific PKD inhibitor, will greatly facilitate the study of the role of PKD signalling mechanisms in angiogenesis. PMID:20497126

  7. CX717 as a positive allosteric modulator of α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionic acid receptor: research advances%AMPA受体正向变构调节剂CX717研究进展

    Institute of Scientific and Technical Information of China (English)

    贺艺超; 肖典; 齐倩倩; 赵国明; 周辛波

    2013-01-01

    α-氨基-3-羟基-5-甲基-4-异噁唑丙酸(AMPA)受体是离子型谷氨酸受体的一种亚型,分布于中枢神经系统的突触后膜,介导大多数快速兴奋性神经传递.CX717是由美国Cortex制药公司研制的苯甲酰胺类AMPA受体正向调节剂,能够降低AMPA受体失活或降敏的速度从而提高突触的活性,与阿尔茨海默病、帕金森病、抑郁症和注意力缺陷多动症等疾病的治疗密切相关.本文主要综述CX717在化学结构、药代动力学、毒理学和药效学方面的研究进展.%α-Amino-3-hydroxyl-5-methyl-4-isoxazole-propionic acid (AMPA) receptor,a subtype of ionotropic glutamate receptors in the postsynaptic membrane of the central nervous system (CNS),mediates most of the fast excitatory neurotransmission.CX717 developed by Cortex Pharmaceuticals Company of the USA belongs to the benzamide series of AMPA receptor positive modulators.It can reduce the speed of AMPA receptor inactivation or desensitization,thereby enhancing synaptic activity,and is closely related to the treatment of Alzheimer's disease,Parkinson's disease,depression and attention deficit hyperactivity disorder(ADHD).This article reviews the latest research of CX717 regarding its structure,pharmacokinetics,toxicology and pharmacodynamics.

  8. Novel Cholinesterase Inhibitors Based on O-Aromatic N,N-Disubstituted Carbamates and Thiocarbamates

    Directory of Open Access Journals (Sweden)

    Martin Krátký

    2016-02-01

    Full Text Available Based on the presence of carbamoyl moiety, twenty salicylanilide N,N-disubstituted (thiocarbamates were investigated using Ellman’s method for their ability to inhibit acetylcholinesterase (AChE and butyrylcholinesterase (BChE. O-Aromatic (thiocarbamates exhibited weak to moderate inhibition of both cholinesterases with IC50 values within the range of 1.60 to 311.0 µM. IC50 values for BChE were mostly lower than those obtained for AChE; four derivatives showed distinct selectivity for BChE. All of the (thiocarbamates produced a stronger inhibition of AChE than rivastigmine, and five of them inhibited BChE more effectively than both established drugs rivastigmine and galantamine. In general, 5-chloro-2-hydroxy-N-[4-(trifluoromethyl-phenyl]benzamide, 2-hydroxy-N-phenylbenzamide as well as N-methyl-N-phenyl carbamate derivatives led to the more potent inhibition. O-{4-Chloro-2-[(4-chlorophenylcarbamoyl]phenyl} dimethylcarbamothioate was identified as the most effective AChE inhibitor (IC50 = 38.98 µM, while 2-(phenylcarbamoylphenyl diphenylcarbamate produced the lowest IC50 value for BChE (1.60 µM. Results from molecular docking studies suggest that carbamate compounds, especially N,N-diphenyl substituted representatives with considerable portion of aromatic moieties may work as non-covalent inhibitors displaying many interactions at peripheral anionic sites of both enzymes. Mild cytotoxicity for HepG2 cells and consequent satisfactory calculated selectivity indexes qualify several derivatives for further optimization.

  9. Evaluation of new iodinated acridine derivatives for targeted radionuclide therapy of melanoma using 125I, an Auger electron emitter

    International Nuclear Information System (INIS)

    The full text of the publication follows. The increasing incidence of melanoma and the lack of effective therapy on the disseminated form have led to an urgent need for new specific therapies. Several iodo-benzamides or analogs are known to possess specific affinity for melanoma tissue. New hetero-aromatic derivatives have been designed with a cytotoxic moiety and termed DNA intercalating agents. These compounds could be applied in targeted radionuclide therapy using 125I, Auger electrons emitter which gives high-energetic localized irradiation. Two iodinated acridine derivatives have been reported to present an in vivo kinetic profile conducive to application in targeted radionuclide therapy. The aim of the present study was to perform a preclinical evaluation of these compounds. The DNA intercalating property was confirmed for both compounds. After radiolabeling with 125I, the two compounds induced in vitro a significant radiotoxicity on B16F0 melanoma cells. The acridine compound, ICF01040, appeared more radio toxic than the acridone compound, ICF01035. While cellular uptake was similar for both compounds, SIMS analysis and in vitro protocol showed a stronger affinity for melanin with ICF01035, which was able to induce a predominant scavenging process in the melanosome and restrict access to the nucleus. Nevertheless, an important radiotoxicity was measured for the two compounds while the nuclear accumulation was low. Indeed, even if nuclear localization remains the main target sensitive to Auger electrons, the cell membrane remains sensitive to 125I decays. So, these compounds may induce secondary toxic effects of irradiation, such as membrane lipid damage. Conducted to current experiments are evaluate such hypothesis. Taken together, these results suggest that ICF01040 is a better candidate for application in targeted radionuclide therapy using 125I. The next step will be in vivo evaluation, where high tumoral vectorization gives promising perspectives

  10. On-line solid phase extraction-high performance liquid chromatography-isotope dilution-tandem mass spectrometry approach to quantify N,N-diethyl-m-toluamide and oxidative metabolites in urine.

    Science.gov (United States)

    Kuklenyik, Peter; Baker, Samuel E; Bishop, Amanda M; Morales-A, Pilar; Calafat, Antonia M

    2013-07-17

    Human exposure to N,N-diethyl-m-toluamide (DEET) occurs because of the widespread use of DEET as an active ingredient in insect repellents. However, information on the extent of such exposure is rather limited. Therefore, we developed a fast on-line solid phase extraction-high performance liquid chromatography-isotope dilution tandem mass spectrometry (HPLC-MS/MS) method to measure in urine the concentrations of DEET and two of its oxidative metabolites: N,N-diethyl-3-(hydroxymethyl)benzamide and 3-(diethylcarbamoyl)benzoic acid (DCBA). To the best of our knowledge, this is the first HPLC-MS/MS method for the simultaneous quantification of DEET and its select metabolites in human urine. After enzymatic hydrolysis of the conjugated species in 0.1 mL of urine, the target analytes were retained and pre-concentrated on a monolithic column, separated from each other and from other urinary biomolecules on a reversed-phase analytical column, and detected by atmospheric pressure chemical ionization in positive ion mode. The limits of detection ranged from 0.1 ng mL(-1) to 1.0 ng mL(-1), depending on the analyte. Accuracy ranged between 90.4 and 104.9%, and precision ranged between 5.5 and 13.1% RSD, depending on the analyte and the concentration. We tested the usefulness of this method by analyzing 75 urine samples collected anonymously in the Southeastern United States in June 2012 from adults with no known exposure to DEET. Thirty eight samples (51%) tested positive for at least one of the analytes. We detected DCBA most frequently and at the highest concentrations. Our results suggest that this method can be used for the analysis of a large number of samples for epidemiological studies to assess human exposure to DEET. PMID:23830449

  11. mGluR5 Positive and Negative Allosteric Modulators Differentially Affect Dendritic Spine Density and Morphology in the Prefrontal Cortex.

    Science.gov (United States)

    LaCrosse, Amber L; Taylor, Sara B; Nemirovsky, Natali E; Gass, Justin T; Olive, Michael F

    2015-01-01

    Positive and negative allosteric modulators (PAMs and NAMs, respectively) of type 5 metabotropic glutamate receptors (mGluR5) are currently being investigated as novel treatments for neuropsychiatric diseases including drug addiction, schizophrenia, and Fragile X syndrome. However, only a handful of studies have examined the effects of mGluR5 PAMs or NAMs on the structural plasticity of dendritic spines in otherwise naïve animals, particularly in brain regions mediating executive function. In the present study, we assessed dendritic spine density and morphology in pyramidal cells of the medial prefrontal cortex (mPFC) after repeated administration of either the prototypical mGluR5 PAM 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5- yl)benzamide (CDPPB, 20 mg/kg), the clinically utilized mGluR5 NAM 1-(3-chlorophenyl)-3-(3-methyl-5-oxo-4Himidazol- 2-yl)urea (fenobam, 20 mg/kg), or vehicle in male Sprague-Dawley rats. Following once daily treatment for 10 consecutive days, coronal brain sections containing the mPFC underwent diolistic labeling and 3D image analysis of dendritic spines. Compared to vehicle treated animals, rats administered fenobam exhibited significant increases in dendritic spine density and the overall frequency of spines with small (0.4 μm). Administration of CDPPB had no discernable effects on dendritic spine density or morphology, and neither CDPPB nor fenobam had any effect on spine length or volume. We conclude that mGluR5 PAMs and NAMs differentially affect mPFC dendritic spine structural plasticity in otherwise naïve animals, and additional studies assessing their effects in combination with cognitive or behavioral tasks are needed. PMID:25921744

  12. Comparison of kinetic properties of amine oxidases from sainfoin and lentil and immunochemical characterization of copper/quinoprotein amine oxidases.

    Science.gov (United States)

    Zajoncová, L; Frébort, I; Luhová, L; Sebela, M; Galuszka, P; Pec, P

    1999-01-01

    Kinetic properties of novel amine oxidase isolated from sainfoin (Onobrychis viciifolia) were compared to those of typical plant amine oxidase (EC 1.4.3.6) from lentil (Lens culinaris). The amine oxidase from sainfoin was active toward substrates, such as 1,5-diaminopentane (cadaverine) with K(m) of 0.09 mM and 1,4-diaminobutane (putrescine) with K(m) of 0.24 mM. The maximum rate of oxidation for cadaverine at saturating concentration was 2.7 fold higher than that of putrescine. The amine oxidase from lentil had the maximum rate for putrescine comparable to the rate of sainfoin amine oxidase with the same substrate. Both amine oxidases, like other plant Cu-amine oxidases, were inhibited by substrate analogs (1,5-diamino-3-pentanone, 1,4-diamino-2-butanone and aminoguanidine), Cu2+ chelating agents (diethyltriamine, 1,10-phenanthroline, 8-hydroxyquinoline, 2,2'-bipyridyl, imidazole, sodium cyanide and sodium azide), some alkaloids (L-lobeline and cinchonine), some lathyrogens (beta-aminopropionitrile and aminoacetonitrile) and other inhibitors (benzamide oxime, acetone oxime, hydroxylamine and pargyline). Tested by Ouchterlony's double diffusion in agarose gel, polyclonal antibodies against the amine oxidase from sainfoin, pea and grass pea cross-reacted with amine oxidases from several other Fabaceae and from barley (Hordeum vulgare) of Poaceae, while amine oxidase from the filamentous fungus Aspergillus niger did not cross-react at all. However, using Western blotting after SDS-PAGE with rabbit polyclonal antibodies against the amine oxidase from Aspergillus niger, some degree of similarity of plant amine oxidases from sainfoin, pea, field pea, grass pea, fenugreek, common melilot, white sweetclover and Vicia panonica with the A. niger amine oxidase was confirmed. PMID:10092944

  13. Pharmacological Characterization of the Edema Caused by Vitalius dubius (Theraphosidae, Mygalomorphae) Spider Venom in Rats.

    Science.gov (United States)

    Rocha-E-Silva, Thomaz A A; Linardi, Alessandra; Antunes, Edson; Hyslop, Stephen

    2016-01-01

    Bites by tarantulas (Theraphosidae, Mygalomorphae) in humans can result in mild clinical manifestations such as local pain, erythema, and edema. Vitalius dubius is a medium-sized, nonaggressive theraphosid found in southeastern Brazil. In this work, we investigated the mediators involved in the plasma extravasation caused by V. dubius venom in rats. The venom caused dose-dependent (0.1-100 μg/site) edema in rat dorsal skin. This edema was significantly inhibited by ((S)1-{2-[3(3-4-dichlorophenyl)-1-(3-iso-propoxyphenylacetyl)piperidine-3-yl]ethyl}-4-phenyl-1-azoniabicyclo[2.2.2]octone, chloride) (SR140333, a neurokinin NK1 receptor antagonist), indomethacin [a nonselective cyclooxygenase (COX) inhibitor], cyproheptadine (a serotonin 5-hydroxytryptamine1/2 and histamine H1 receptor antagonist), and N(ω)-nitro-L-arginine methyl ester (a nitric oxide synthase inhibitor). In contrast, mepyramine (a histamine H1 receptor antagonist), D-Arg-[Hyp(3),Thi(5),D-Tic(7),Oic(8)-]-BK (JE 049, a bradykinin B2 receptor antagonist), and ((S)-N-methyl-N-[4-(4-acetylamino-4-phenylpiperidino)-2-(3,4-di-chlorophenyl)butyl]benzamide) (SR48968, a neurokinin NK2 receptor antagonist) had no effect on the venom-induced increase in vascular permeability. In rat hind paws, the venom-induced edema was attenuated by ketoprofen (a nonselective COX inhibitor) administered 15 minutes postvenom. Preincubation of venom with commercial antiarachnid antivenom attenuated the venom-induced edema. These results suggest that the enhanced vascular permeability evoked by V. dubius venom involves serotonin, COX products, neurokinin NK1 receptors, and nitric oxide formation. The attenuation of hind paw edema by ketoprofen suggests that COX inhibitors could be useful in treating the local inflammatory response to bites by these spiders.

  14. Meta-diamide insecticides acting on distinct sites of RDL GABA receptor from those for conventional noncompetitive antagonists.

    Science.gov (United States)

    Nakao, Toshifumi; Banba, Shinich; Nomura, Michikazu; Hirase, Kangetsu

    2013-04-01

    The RDL GABA receptor is an attractive target of insecticides. Here we demonstrate that meta-diamides [3-benzamido-N-(4-(perfluoropropan-2-yl)phenyl)benzamides] are a distinct class of RDL GABA receptor antagonists showing high insecticidal activity against Spodoptera litura. We also suggest that the mode of action of the meta-diamides is distinct from that of conventional noncompetitive antagonists (NCAs), such as fipronil, picrotoxin, lindane, dieldrin, and α-endosulfan. Using a membrane potential assay, we examined the effects of the meta-diamide 3-benzamido-N-(2-bromo-4-(perfluoropropan-2-yl)-6-(trifluoromethyl)phenyl)-2-fluorobenzamide (meta-diamide 7) and NCAs on mutant Drosophila RDL GABA receptors expressed in Drosophila Mel-2 cells. NCAs had little or no inhibitory activity against at least one of the three mutant receptors (A2'S, A2'G, and A2'N), which were reported to confer resistance to NCAs. In contrast, meta-diamide 7 inhibited all three A2' mutant receptors, at levels comparable to its activity with the wild-type receptor. Furthermore, the A2'S·T6'V mutation almost abolished the inhibitory effects of all NCAs. However, meta-diamide 7 inhibited the A2'S・T6'S mutant receptor at the same level as its activity with the wild-type receptor. In contrast, a G336M mutation in the third transmembrane domain of the RDL GABA receptor abolished the inhibitory activities of meta-diamide 7, although the G336M mutation had little effect on the inhibitory activities of conventional NCAs. Molecular modeling studies also suggested that the binding site of meta-diamides was different from those of NCAs. Meta-diamide insecticides are expected to be prominent insecticides effective against A2' mutant RDL GABA receptors with a different mode of action.

  15. Metabolic consequences of DNA damage: The role of poly (ADP-ribose) polymerase as mediator of the suicide response

    International Nuclear Information System (INIS)

    Recent studies show that DNA damage can produce rapid alterations in steady state levels of deoxynucleoside triphosphate pools, for example, MNNG or uv-irradiation cause rapid increases in dATP and dTTP pools without significant changes in dGTP or dCTP pools. In vitro, studies with purified eukaryotic DNA polymerases show that the frequency of nucleotide misincorporation was affected by alterations in relative concentrations of the deoxynucleoside triphosphates. Thus the alterations in dNTP pool sizes that occur consequent to DNA damage may contribute to an increased mutagenic frequency. Poly(ADP-ribose) polymerase mediated suicide mechanism may participate in the toxicity of adenosine deaminase deficiency and severe combined immune deficiency disease in humans. Individuals with this disease suffer severe lymphopenia due to the toxic effects of deoxyadenosine. The lymphocytotoxic effect of adenosine deaminase deficiency can be simulated in lymphocyte cell lines from normal individuals by incubating them with the adenosine deaminase inhibitor, deoxycoformycin. Incubation of such leukocytes with deoxycoformycin and deoxyadenosine results in the gradual accumulation of DNA strand breaks and the depletion of NAD+ leading to cell death over a period of several days. This depletion of NAD and loss of cell viability were effectively blocked by nicotinamide or 3-amino benzamide. Thus, persistent activation of poly(ADP-ribose) polymerase by unrepaired or recurrent DNA strand breaks may activate the suicide mechanism of cell death. This study provides a basis for the interesting suggestion that treatment with nicotinamide could block the persistent activity of poly(ADP-ribose) polymerase and may help preserve lymphocyte function in patients with adenosine deaminase deficiency. 16 refs., 3 figs., 2 tabs

  16. Laboratory and field trial of developing medicinal local Thai plant products against four species of mosquito vectors.

    Science.gov (United States)

    Trongtokit, Yuwadee; Rongsriyam, Yupha; Komalamisra, Narumon; Krisadaphong, Panvipa; Apiwathnasorn, Chamnarn

    2004-06-01

    Oils of Syzygium aromaticum (clove) and Zanthoxylum limonella (makaen), widely used essential oils for dental caries or flavoring of food in Thailand, were prepared as 10 experimental repellent products in gel or cream form against Aedes aegypti, Culex quinquefasciatus, and Anopheles dirus under laboratory conditions, using the human-arm-in-cage method. Two products that gave the longest-lasting complete protection were selected to examine their repellency against a variety of mosquito species under field conditions. In laboratory tests, 0.1 g of each product was applied to 3x10 cm of exposed area on a volunteer's forearm, while in field trials, 1.0 g was applied to each volunteer's leg (from knee to ankle). In the laboratory, the gel dosage form contained 20% clove oil (Gel B) or 10% clove plus 10% makaen oil mixture (Gel E) were promising plant-based repellents against three mosquito species and gave significantly longer complete protection times of 4-5 hours than all other developing products. Therefore, their efficacy in the field was evaluated. Under field conditions, Gel E showed complete protection for 4 hours and gave 95.7% repellency after 5 hours application, whereas Gel B and 20% deet (di-methyl benzamide) provided only 86.8 and 82.7% repellency after treatment, respectively against Ae. aegypti, daytime-biting mosquitos. For nighttime-biting, the 3 repellents under development yielded equally excellent (average 97.1%) repellency for 5 hours against the predominant Cx. quinquefasciatus and Mansonia uniformis, but they gave 89.0% repellency against Cx. tritaeniorhynchus and Cx. gelidus. This finding demonstrated the effectiveness of Gel B and Gel E products for possible use by low-income rural communities against various mosquito species. PMID:15691131

  17. Structure-Functional Characterization of Cytochrome P450 Sterol 14α-Demethylase (CYP51B) from Aspergillus fumigatus and Molecular Basis for the Development of Antifungal Drugs.

    Science.gov (United States)

    Hargrove, Tatiana Y; Wawrzak, Zdzislaw; Lamb, David C; Guengerich, F Peter; Lepesheva, Galina I

    2015-09-25

    Aspergillus fumigatus is the opportunistic fungal pathogen that predominantly affects the immunocompromised population and causes 600,000 deaths/year. The cytochrome P450 51 (CYP51) inhibitor voriconazole is currently the drug of choice, yet the treatment efficiency remains low, calling for rational development of more efficient agents. A. fumigatus has two CYP51 genes, CYP51A and CYP51B, which share 59% amino acid sequence identity. CYP51B is expressed constitutively, whereas gene CYP51A is reported to be inducible. We expressed, purified, and characterized A. fumigatus CYP51B, including determination of its substrate preferences, catalytic parameters, inhibition, and x-ray structure in complexes with voriconazole and the experimental inhibitor (R)-N-(1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethyl)-4-(5-phenyl-1,3,4-oxadiazol-2-yl)benzamide (VNI). The enzyme demethylated its natural substrate eburicol and the plant CYP51 substrate obtusifoliol at steady-state rates of 17 and 16 min(-1), respectively, but did not metabolize lanosterol, and the topical antifungal drug miconazole was the strongest inhibitor that we identified. The x-ray crystal structures displayed high overall similarity of A. fumigatus CYP51B to CYP51 orthologs from other biological kingdoms but revealed phylum-specific differences relevant to enzyme catalysis and inhibition. The complex with voriconazole provides an explanation for the potency of this relatively small molecule, whereas the complex with VNI outlines a direction for further enhancement of the efficiency of this new inhibitory scaffold to treat humans afflicted with filamentous fungal infections. PMID:26269599

  18. Metabolic characterization of AH-7921, a synthetic opioid designer drug: in vitro metabolic stability assessment and metabolite identification, evaluation of in silico prediction, and in vivo confirmation.

    Science.gov (United States)

    Wohlfarth, Ariane; Scheidweiler, Karl B; Pang, Shaokun; Zhu, Mingshe; Castaneto, Marisol; Kronstrand, Robert; Huestis, Marilyn A

    2016-08-01

    AH-7921 (3,4-dichloro-N-[(1-dimethylamino)cyclohexylmethyl]benzamide) is a new synthetic opioid and has led to multiple non-fatal and fatal intoxications. To comprehensively study AH-7921 metabolism, we assessed human liver microsome (HLM) metabolic stability, determined AH-7921's metabolic profile after human hepatocytes incubation, confirmed our findings in a urine case specimen, and compared results to in silico predictions. For metabolic stability, 1 µmol/L AH-7921 was incubated with HLM for up to 1 h; for metabolite profiling, 10 µmol/L was incubated with pooled human hepatocytes for up to 3 h. Hepatocyte samples were analyzed by liquid chromatography quadrupole/time-of-flight high-resolution mass spectrometry (MS). High-resolution full scan MS and information-dependent acquisition MS/MS data were analyzed with MetabolitePilot™ (SCIEX) using multiple data processing algorithms. The presence of AH-7921 and metabolites was confirmed in the urine case specimen. In silico prediction of metabolite structures was performed with MetaSite™ (Molecular Discovery). AH-7921 in vitro half-life was 13.5 ± 0.4 min. We identified 12 AH-7921 metabolites after hepatocyte incubation, predominantly generated by demethylation, less dominantly by hydroxylation, and combinations of different biotransformations. Eleven of 12 metabolites identified in hepatocytes were found in the urine case specimen. One metabolite, proposed to be di-demethylated, N-hydroxylated and glucuronidated, eluted after AH-7921 and was the most abundant metabolite in non-hydrolyzed urine. MetaSite™ correctly predicted the two most abundant metabolites and the majority of observed biotransformations. The two most dominant metabolites after hepatocyte incubation (also identified in the urine case specimen) were desmethyl and di-desmethyl AH-7921. Together with the glucuronidated metabolites, these are likely suitable analytical targets for documenting AH-7921 intake. Copyright © 2015

  19. Nitric oxide interacts with oxygen free radicals to evoke the release of adenosine and adenine nucleotides from rat hippocampal slices.

    Science.gov (United States)

    Broad, R M; Fallahi, N; Fredholm, B B

    2000-07-01

    The present study examined some possible mechanisms underlying the previously demonstrated release of adenosine by nitric oxide (NO) donors. Perfusion with the NO-donor S-nitroso-N-acetyl penicillamine (SNAP; 300 microM) led to a significant increase in the release of [3H]purines from both unstimulated and electrically stimulated hippocampal slices prelabeled with [3H]adenine. The NO-donor also evoked the release of endogenous ATP and ADP from unstimulated slices and, when combined with electrical stimulation, the release of ATP, AMP and adenosine. The SNAP-induced [3H]purine release was calcium-dependent, but not affected by the glutamate receptor antagonists MK-801 ((+)-5-methyl-10,11-dihydro-5H-dibenzo[a, d]-cyclohepten-5,10-imine;100 nM) and CNQX (6-cyano-7-nitroquinoxaline-2,3-dione; 10 microM). Zaprinast (5 microM), an inhibitor of the cyclic GMP-dependent phosphodiesterase and 8-Br-cyclic GMP (0.01-1 mM) failed to evoke the release of purines, whereas generation of oxygen free radicals by xanthine plus xanthine oxidase did evoke purine release. Coperfusion of SNAP with the free radical scavengers superoxide dismutase (SOD; 60 microg/ml) and catalase (50 microg/ml) reduced or eliminated the ability of the NO-donor to enhance [3H]purine release, but the poly (ADP-ribosyl) synthetase (PARS) inhibitor benzamide (500 microM) did not affect it. These data indicate that NO interacts with superoxide, likely forming peroxynitrite, which subsequently acts to release adenosine and adenine nucleotides from hippocampal tissue.

  20. Slow DNA rejoining in ultraviolet-irradiated human diploid fibroblasts treated with the mitogens trypsin and insulin

    International Nuclear Information System (INIS)

    Normally in mammalian cells the postincision steps of UV-induced excision repair are much more rapid than the recognition of damage and incision. This means that at any one time the level of repair-generated single-stranded DNA breaks is very low. Here we report that detectable levels of DNA breaks accumulate in quiescent human fibroblasts which are UV irradiated a few hours after replating in conditions that stimulate progress through the cell cycle. Most DNA breaks accumulate in cultures trypsinized and seeded in medium supplemented with insulin, and irradiated in early G1. Because trypsin and insulin have no effect on UV-induced incision rates, as measured by DNA break accumulation in the presence of DNA synthesis inhibitors, we argue that our ability to detect incomplete repair-sites is due to a significant reduction in the rate of gap sealing indicative of a shift in the steady state of excision repair. Provision of DNA precursors prevents the enhancing effect of trypsin and insulin on the accumulation of DNA breaks, implying that these agents affect DNA precursor metabolism. Perturbation of the repair process, which leads to the accumulation of 1500-2000 DNA breaks/genome, is also associated with other effects including increased lethality, the appearance of double-strand breaks and the loss of NAD, the last effect presumably arising as a consequence of break-stimulated poly(ADPR) transferase activity. Addition of 3-amino-benzamide, an inhibitor of poly(ADPR) synthesis, completely blocks the decline in NAD levels, but does not change the rate of sealing of the accumulated DNA breaks. These results strongly suggest that ligation is largely, if not entirely, independent of ADP ribosylation in this system

  1. mGluR5 positive modulators both potentiate activation and restore inhibition in NMDA receptors by PKC dependent pathway

    Directory of Open Access Journals (Sweden)

    Liao Pei-Fei

    2011-02-01

    Full Text Available Abstract Background In order to understand the interaction between the metabotropic glutamate subtype 5 (mGluR5 and N-methyl-D-aspartate (NMDA receptors, the influence of mGluR5 positive modulators in the inhibition of NMDA receptors by the noncompetitive antagonist ketamine, the competitive antagonist D-APV and the selective NR2B inhibitor ifenprodil was investigated. Methods This study used the multi-electrode dish (MED system to observe field potentials in hippocampal slices of mice. Results Data showed that the mGluR5 agonist (RS-2-chloro-5-hydroxyphenylglycine (CHPG, as well as the positive allosteric modulators 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl benzamide (CDPPB and 3,3'-difluorobenzaldazine (DFB alone did not alter the basal field potentials, but enhanced the amplitude of field potentials induced by NMDA. The inhibitory action of ketamine on NMDA-induced response was reversed by CHPG, DFB, and CDPPB, whereas the blockade of NMDA receptor by D-APV was restored by CHPG and CDPPB, but not by DFB. Alternatively, activation of NMDA receptors prior to the application of mGluR5 modulators, CHPG was able to enhance NMDA-induced field potentials and reverse the suppressive effect of ketamine and D-APV, but not ifenprodil. In addition, chelerythrine chloride (CTC, a protein kinase C (PKC inhibitor, blocked the regulation of mGluR5 positive modulators in enhancing NMDA receptor activation and recovering NMDA receptor inhibition. The PKC activator (PMA mimicked the effects of mGluR5 positive modulators on enhancing NMDA receptor activation and reversing NMDA antagonist-evoked NMDA receptor suppression. Conclusion Our results demonstrate that the PKC-dependent pathway may be involved in the positive modulation of mGluR5 resulting in potentiating NMDA receptor activation and reversing NMDA receptor suppression induced by NMDA antagonists.

  2. Uncharged isocoumarin-based inhibitors of urokinase-type plasminogen activator

    Directory of Open Access Journals (Sweden)

    Deck Lorraine M

    2006-02-01

    Full Text Available Abstract Background Urokinase-type plasminogen activator (uPA plays a major role in extracellular proteolytic events associated with tumor cell growth, migration and angiogenesis. Consequently, uPA is an attractive target for the development of small molecule active site inhibitors. Most of the recent drug development programs aimed at nonpeptidic inhibitors targeted at uPA have focused on arginino mimetics containing amidine or guanidine functional groups attached to aromatic or heterocyclic scaffolds. There is a general problem of limited bioavailability of these charged inhibitors. In the present study, uPA inhibitors were designed on an isocoumarin scaffold containing uncharged substituents. Results 4-Chloro-3-alkoxyisocoumarins were synthesized in which the 3-alkoxy group contained a terminal bromine; these were compared with similar inhibitors that contained a charged terminal functional group. Additional variations included functional groups attached to the seven position of the isocoumarin scaffold. N- [3-(3-Bromopropoxy-4-chloro-1-oxo-1H-isochromen-7-yl]benzamide was identified as an uncharged lead inhibitor of uPA, Ki = 0.034 μM. Molecular modeling of human uPA with these uncharged inhibitors suggests that the bromine occupies the same position as positively charged arginino mimetic groups. Conclusion This study demonstrates that potent uncharged inhibitors of uPA can be developed based upon the isocoumarin scaffold. A tethered bromine in the three position and an aromatic group in the seven position are important contributors to binding. Although the aim was to develop compounds that act as mechanism-based inactivators, these inhibitors are competitive reversible inhibitors.

  3. Clinical study of dopamine transporter imaging with 131I-epidepride for Parkinson's disease

    International Nuclear Information System (INIS)

    Objective: Epidepride is a novel benzamide derivative with high affinity for dopaminergic D2 receptors. It has been used to study striatal and extrastriatal D2 receptor abnormalities in humans. The aim of this study was to evaluate the level of D2 receptors in dopaminergic nitrostriatal pathway and its correlation with clinical severity in Parkinson's disease (PD). Methods: Thirty-eight patients with idiopathic PD [graded according to Hoehn and Yahr (H/Y) stage: n(I)=13, n(II)=11, n(III)=8, n (IV)=6] and 12 healthy volunteers as control were included in this study. SPECT brain imaging was performed 3 h after 18.5 MBq 131I-epidepride administration. Regions of interest (ROIs) were drawn over the striatum (ST) and occipital cortex (OC). The ratios of ST to OC ROI counts (ST/OC) were calculated and correlated with clinical severity H/Y stage. SPSS 10.0 was used for data analysis, the t test and Spearman correlation analysis were used. Results: ST showed intense uptake of 131I-eplaepnde, whereas frontal, parietal, temporal, occipital lobes and cerebellum showed low uptake in control group. Increased 131I-epidepride uptake was observed in PD patients when compared with normal control group but without statistically significant difference. Early stage patients (hemi-PD with H/Y I) showed increased 131I-epidepride uptake intensity and size in contralateral ST (especially caudate nucleus) significantly more than unilateral ST (t= 7.89, P0.05). Conclusions: This study suggested that 131I-epidepride SPECT was useful in qualitative and quantitative evaluation of D2 receptor status in dopaminergic nigrostriatal neurons, which were over-expressed in PD patients. However, no statistically significant correlation was found between ST 131I-epidepride binding ratios and disease severity. (authors)

  4. Characterization and distribution of [125I]epidepride binding to dopamine D2 receptors in basal ganglia and cortex of human brain

    International Nuclear Information System (INIS)

    The distribution and pharmacology of the binding of 125I-epidepride, a substituted benzamide with high affinity and selectivity for dopamine (DA) D2 receptors in rat brain is described in human brain. Saturation analysis of the binding of 125I-epidepride to membranes derived from striatum and regions of cortex demonstrated similar Kd values (34 and 28-33 pM, respectively) but differing maximum density of binding site values (152 and 3-8 fmol/mg of protein, respectively). The pharmacological profile of binding in cortex was also similar to striatum (epidepride greater than spiperone greater than butaclamol = flupenthixol greater than clozapine) except that an additional low-affinity site, blocked by the alpha-2 adrenergic antagonist idazoxan, was present in cortex. Quantification by autoradiography also demonstrated the greatest binding in the basal ganglia, with the striatum exhibiting greater binding than the pallidal complex or midbrain regions. For the pallidum, binding in the external segment was higher than the internal segment. Within the midbrain the binding of 125I-epidepride correlated well with the known distribution of DA-containing cell bodies, with the substantia nigra (pars compacta and pars lateralis) and ventral tegmental area (A10) higher than area A8 and central gray. Binding in frontal and parietal cortex was highest in the internal layers (layers V and VI). Temporal cortex showed a 2-fold higher density of binding than other cortical regions and a trilaminar pattern; binding was greater in the external (layers I and II) and internal layers than in the middle layers (III and IV). This pattern changed in the parahippocampal complex. Within the lateral occipitotemporal cortex, binding was densest in layers I to III and very low in layers IV to VI, but binding was almost nonexistent in the adjacent entorhinal cortex

  5. Characterization and distribution of (125I)epidepride binding to dopamine D2 receptors in basal ganglia and cortex of human brain

    Energy Technology Data Exchange (ETDEWEB)

    Joyce, J.N.; Janowsky, A.; Neve, K.A. (Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia (USA))

    1991-06-01

    The distribution and pharmacology of the binding of {sup 125}I-epidepride, a substituted benzamide with high affinity and selectivity for dopamine (DA) D2 receptors in rat brain is described in human brain. Saturation analysis of the binding of {sup 125}I-epidepride to membranes derived from striatum and regions of cortex demonstrated similar Kd values (34 and 28-33 pM, respectively) but differing maximum density of binding site values (152 and 3-8 fmol/mg of protein, respectively). The pharmacological profile of binding in cortex was also similar to striatum (epidepride greater than spiperone greater than butaclamol = flupenthixol greater than clozapine) except that an additional low-affinity site, blocked by the alpha-2 adrenergic antagonist idazoxan, was present in cortex. Quantification by autoradiography also demonstrated the greatest binding in the basal ganglia, with the striatum exhibiting greater binding than the pallidal complex or midbrain regions. For the pallidum, binding in the external segment was higher than the internal segment. Within the midbrain the binding of {sup 125}I-epidepride correlated well with the known distribution of DA-containing cell bodies, with the substantia nigra (pars compacta and pars lateralis) and ventral tegmental area (A10) higher than area A8 and central gray. Binding in frontal and parietal cortex was highest in the internal layers (layers V and VI). Temporal cortex showed a 2-fold higher density of binding than other cortical regions and a trilaminar pattern; binding was greater in the external (layers I and II) and internal layers than in the middle layers (III and IV). This pattern changed in the parahippocampal complex. Within the lateral occipitotemporal cortex, binding was densest in layers I to III and very low in layers IV to VI, but binding was almost nonexistent in the adjacent entorhinal cortex.

  6. Dopamine D(2) receptor quantification in extrastriatal brain regions using [(123)I]epidepride with bolus/infusion.

    Science.gov (United States)

    Pinborg, L H; Videbaek, C; Knudsen, G M; Swahn, C G; Halldin, C; Friberg, L; Paulson, O B; Lassen, N A

    2000-06-15

    The iodinated benzamide epidepride, which shows a picomolar affinity binding to dopamine D(2) receptors, has been designed for in vivo studies using SPECT. The aim of the present study was to apply a steady-state condition by the bolus/infusion approach with [(123)I]epidepride for the quantification of striatal and extrastriatal dopamine D(2) receptors in humans. In this way the distribution volume of the tracer can be determined from a single SPECT image and one blood sample. Based on bolus experiments, an algorithm using conventional convolution arguments for prediction of the outcome of a bolus/infusion (B/I) experiment was applied. It was predicted that a B/I protocol with infusion of one-third of the initial bolus per hour would be appropriate. Steady-state conditions were attained in extrastriatal regions within 3-4 h but the infusion continued up to 7 h in order to minimize the significance of individual differences in plasma clearance and binding parameters. A steady-state condition, however, could not be attained in striatal brain regions using a B/I protocol of 20 h, even after 11 h. Under near steady-state conditions a striatal:cerebellar ratio of 23 was demonstrated. Epidepride has a unique signal-to-noise ratio compared to [(123)I]IBZM but present difficulties for steady-state measurements of striatal regions. The bolus/infusion approach is particularly feasible for quantification of the binding potential in extrastriatal regions. PMID:10819910

  7. The Effects of Pharmacological Inhibition of Histone Deacetylase 3 (HDAC3 in Huntington's Disease Mice.

    Directory of Open Access Journals (Sweden)

    Haiqun Jia

    Full Text Available An important epigenetic modification in Huntington's disease (HD research is histone acetylation, which is regulated by histone acetyltransferase and histone deacetylase (HDAC enzymes. HDAC inhibitors have proven effective in HD model systems, and recent work is now focused on functional dissection of the individual HDAC enzymes in these effects. Histone deacetylase 3 (HDAC3, a member of the class I subfamily of HDACs, has previously been implicated in neuronal toxicity and huntingtin-induced cell death. Hence, we tested the effects of RGFP966 ((E-N-(2-amino-4-fluorophenyl-3-(1-cinnamyl-1H-pyrazol-4-ylacrylamide, a benzamide-type HDAC inhibitor that selectively targets HDAC3, in the N171-82Q transgenic mouse model of HD. We found that RGFP966 at doses of 10 and 25 mg/kg improves motor deficits on rotarod and in open field exploration, accompanied by neuroprotective effects on striatal volume. In light of previous studies implicating HDAC3 in immune function, we measured gene expression changes for 84 immune-related genes elicited by RGFP966 using quantitative PCR arrays. RGFP966 treatment did not cause widespread changes in cytokine/chemokine gene expression patterns, but did significantly alter the striatal expression of macrophage migration inhibitory factor (Mif, a hormone immune modulator associated with glial cell activation, in N171-82Q transgenic mice, but not WT mice. Accordingly, RGFP966-treated mice showed decreased glial fibrillary acidic protein (GFAP immunoreactivity, a marker of astrocyte activation, in the striatum of N171-82Q transgenic mice compared to vehicle-treated mice. These findings suggest that the beneficial actions of HDAC3 inhibition could be related, in part, with lowered Mif levels and its associated downstream effects.

  8. Crystal Structures of Trypanosoma brucei Sterol 14[alpha]-Demethylase and Implications for Selective Treatment of Human Infections

    Energy Technology Data Exchange (ETDEWEB)

    Lepesheva, Galina I.; Park, Hee-Won; Hargrove, Tatiana Y.; Vanhollebeke, Benoit; Wawrzak, Zdzislaw; Harp, Joel M.; Sundaramoorthy, Munirathinam; Nes, W. David; Pays, Etienne; Chaudhuri, Minu; Villalta, Fernando; Waterman, Michael R. (ULdB); (Vanderbilt); (TTU); (Toronto); (NWU); (Meharry)

    2010-01-25

    Sterol 14{alpha}-demethylase (14DM, the CYP51 family of cytochrome P450) is an essential enzyme in sterol biosynthesis in eukaryotes. It serves as a major drug target for fungal diseases and can potentially become a target for treatment of human infections with protozoa. Here we present 1.9 {angstrom} resolution crystal structures of 14DM from the protozoan pathogen Trypanosoma brucei, ligand-free and complexed with a strong chemically selected inhibitor N-1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethyl-4-(5-phenyl-1,3,4-oxadi-azol-2-yl)benzamide that we previously found to produce potent antiparasitic effects in Trypanosomatidae. This is the first structure of a eukaryotic microsomal 14DM that acts on sterol biosynthesis, and it differs profoundly from that of the water-soluble CYP51 family member from Mycobacterium tuberculosis, both in organization of the active site cavity and in the substrate access channel location. Inhibitor binding does not cause large scale conformational rearrangements, yet induces unanticipated local alterations in the active site, including formation of a hydrogen bond network that connects, via the inhibitor amide group fragment, two remote functionally essential protein segments and alters the heme environment. The inhibitor binding mode provides a possible explanation for both its functionally irreversible effect on the enzyme activity and its selectivity toward the 14DM from human pathogens versus the human 14DM ortholog. The structures shed new light on 14DM functional conservation and open an excellent opportunity for directed design of novel antiparasitic drugs.

  9. HDAC inhibitors, MS-275 and salermide, potentiates the anticancer effect of EF24 in human pancreatic cancer cells

    Science.gov (United States)

    Yar Saglam, Atiye Seda; Yilmaz, Akin; Onen, Hacer Ilke; Alp, Ebru; Kayhan, Handan; Ekmekci, Abdullah

    2016-01-01

    Histone deacetylases (HDACs) play a major role in the regulation of chromatin structure and gene expression by changing acetylation status of histone and non-histone proteins. MS-275 (entinostat, MS) is a well-known benzamide-based HDACI and Salermide (SAL), a reverse amide compound HDACI, have antiproliferative effects on several human cancer cells. In this study, we aimed to investigate the effects of HDACIs (MS and SAL) alone and/or combined use with EF24 (EF), a novel synthetic curcumin analog, on human pancreatic cancer cell line (BxPC-3). In vitro, BxPC-3 cells were exposed to varying concentrations of MS, SAL with or without EF, and their effects on cell viability, acetylated Histone H3 and H4 levels, cytotoxicity, and cleaved caspase 3 levels, and cell cycle distribution were measured. The viability of BxPC-3 cells decreased significantly after treatment with EF, MS and SAL treatments. MS and SAL treatment increased the acetylation of histone H3 and H4 in a dose dependent manner. MS and SAL alone or combined with EF were increased the number of cells in G1 phase. In addition, treatment with agents significantly decreased the ratio of cell in G2/M phase. There were significant dose-dependent increases at cleaved Caspase 3 levels after MS treatment but not after SAL treatment. Our results showed that HDAC inhibitors (MS and SAL), when combined with EF, may effectively reduce pancreatic cancer cell (BxPC-3) progression and stop the cell cycle at G1 phase. Further molecular analyses are needed to understand the fundamental molecular consequences of HDAC inhibition in pancreas cancer cells. PMID:27330528

  10. DEET mosquito repellent provides personal protection against malaria: a household randomized trial in an Afghan refugee camp in Pakistan.

    Science.gov (United States)

    Rowland, Mark; Downey, Gerald; Rab, Abdur; Freeman, Tim; Mohammad, Nasir; Rehman, Hamid; Durrani, Naeem; Reyburn, Hugh; Curtis, Chris; Lines, Jo; Fayaz, Mohammad

    2004-03-01

    Synthetic repellents based on di-ethyl 3-methyl benzamide (DEET) are a popular method of obtaining protection from mosquitoes and yet clear evidence for a protective effect against malaria has hitherto never been convincingly demonstrated. A household randomized trial was undertaken among a study population of 127 families (25%) in an Afghan refugee village in Pakistan to compare the efficacy of repellent soap (Mosbar containing 20% DEET and 0.5% permethrin) vs. a placebo lotion. Cases of falciparum and vivax malaria were detected by passive case detection at the camp's clinic. At the end of the 6 month trial 3.7% (23 of 618) of individuals in the Mosbar group had presented with one or more episodes of falciparum malaria compared with 8.9% (47 of 530) of the placebo group (odds ratio 0.44, 95% CI 0.25-0.76). 16.7% of the Mosbar group (103 of 618) presented with vivax malaria compared with 11.7% (62 of 530) of the placebo group, and thus no effect was shown against vivax malaria (odds ratio 1.29, 95% CI 0.86-1.94). A considerable proportion of individuals (22%) had presented with vivax malaria during the 7 months leading up to the trial and thus any intervention effect would be partially masked by relapsed infections. The distribution of mosquitoes among households was broadly similar between Mosbar and placebo groups. The repellent was popularly received and very few side-effects were reported. There is a case for giving repellents more prominence in public health as a preventive measure in regions where vectors bite in the early evening or in emergency situations such as epidemics or newly established refugee camps. PMID:14996362

  11. Spectroscopic, thermal and X-ray structural study of the antiparasitic and antiviral drug nitazoxanide

    Science.gov (United States)

    Bruno, Flavia P.; Caira, Mino R.; Monti, Gustavo A.; Kassuha, Diego E.; Sperandeo, Norma R.

    2010-12-01

    Nitazoxanide [2-(acetyloxy)- N-(5-nitro-2-thiazolyl)benzamide, NTZ] is a potent antiparasitic and antiviral agent recently approved. The anti-protozoal activity of NTZ is believed to be due to interference with the pyruvate:ferredoxin oxidoreductase (PFOR) enzyme dependent electron transfer reaction. As drug-enzyme interactions are governed by the three-dimensional stereochemistry of both participants, the crystal structure of NTZ was determined for the first time to identify the conformational preferences that may be related to biological activity. NTZ crystallizes as the carboxamide tautomer in the orthorhombic system, space group Pna2 1 with the following parameters at 100(2) K: a = 14.302(2) Å, b = 5.2800(8) Å, c = 33.183(5) Å, V = 2505.8(6) Å 3, Z = 8, D x = 1.629 g cm -3, R = 0.0319, wR2 = 0.0799 for 5121 reflections. In addition, the spectroscopic and thermal properties were determined and related to the molecular structure. The 13C CPMAS NMR spectra showed resolved signals for each carbon of NTZ, some signals being broad due to residual dipolar interaction with quadrupolar 14N nuclei. In particular, the resonance at about 127 ppm showed multiplicity, indicating more than one molecule in the asymmetric unit and this is consistent with the crystallographic data. The DSC and TG data revealed that NTZ shows a single DSC melting peak with extrapolated onset at 201 °C which is accompanied by a TG weight loss, indicating that NTZ melts with decomposition.

  12. On-line solid phase extraction-high performance liquid chromatography–isotope dilution–tandem mass spectrometry approach to quantify N,N-diethyl-m-toluamide and oxidative metabolites in urine

    Energy Technology Data Exchange (ETDEWEB)

    Kuklenyik, Peter; Baker, Samuel E.; Bishop, Amanda M.; Morales-A, Pilar; Calafat, Antonia M., E-mail: aic7@cdc.gov

    2013-07-17

    Graphical abstract: -- Highlights: •A fast assay to quantify the concentrations of N,N-Diethyl-m-Toluamide and two urinary metabolites was developed •It uses online SPE, reversed phase HPLC and tandem mass spectrometry •The method is precise and accurate with limits of detection ≤1 ng mL{sup −1} -- Abstract: Human exposure to N,N-diethyl-m-toluamide (DEET) occurs because of the widespread use of DEET as an active ingredient in insect repellents. However, information on the extent of such exposure is rather limited. Therefore, we developed a fast on-line solid phase extraction–high performance liquid chromatography–isotope dilution tandem mass spectrometry (HPLC-MS/MS) method to measure in urine the concentrations of DEET and two of its oxidative metabolites: N,N-diethyl-3-(hydroxymethyl)benzamide and 3-(diethylcarbamoyl)benzoic acid (DCBA). To the best of our knowledge, this is the first HPLC-MS/MS method for the simultaneous quantification of DEET and its select metabolites in human urine. After enzymatic hydrolysis of the conjugated species in 0.1 mL of urine, the target analytes were retained and pre-concentrated on a monolithic column, separated from each other and from other urinary biomolecules on a reversed-phase analytical column, and detected by atmospheric pressure chemical ionization in positive ion mode. The limits of detection ranged from 0.1 ng mL{sup −1} to 1.0 ng mL{sup −1}, depending on the analyte. Accuracy ranged between 90.4 and 104.9%, and precision ranged between 5.5 and 13.1% RSD, depending on the analyte and the concentration. We tested the usefulness of this method by analyzing 75 urine samples collected anonymously in the Southeastern United States in June 2012 from adults with no known exposure to DEET. Thirty eight samples (51%) tested positive for at least one of the analytes. We detected DCBA most frequently and at the highest concentrations. Our results suggest that this method can be used for the analysis of a large

  13. Proerectile effects of dopamine D2-like agonists are mediated by the D3 receptor in rats and mice.

    Science.gov (United States)

    Collins, Gregory T; Truccone, Andrew; Haji-Abdi, Faiza; Newman, Amy Hauck; Grundt, Peter; Rice, Kenner C; Husbands, Stephen M; Greedy, Benjamin M; Enguehard-Gueiffier, Cecile; Gueiffier, Alain; Chen, Jianyong; Wang, Shaomeng; Katz, Jonathan L; Grandy, David K; Sunahara, Roger K; Woods, James H

    2009-04-01

    Dopamine D(2)-like agonists induce penile erection (PE) and yawning in a variety of species, effects that have been suggested recently to be specifically mediated by the D(4) and D(3) receptors, respectively. The current studies were aimed at characterizing a series of D(2), D(3), and D(4) agonists with respect to their capacity to induce PE and yawning in the rat and the proerectile effects of apomorphine [(R)-(-)-5,6,6a,7-tetrahydro-6-methyl-4H-dibenzo-[de,g]quinoline-10,11-diol hydrochloride] in wild-type and D(4) receptor (R) knockout (KO) mice. All D(3) agonists induced dose-dependent increases in PE and yawning over a similar range of doses, whereas significant increases in PE or yawning were not observed with any of the D(4) agonists. Likewise, D(2), D(3), and D(4) antagonists were assessed for their capacity to alter apomorphine- and pramipexole (N'-propyl-4,5,6,7-tetrahydrobenzothiazole-2,6-diamine dihydrochloride)-induced PE and yawning. The D(3) antagonist, PG01037 [N-{4-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-trans-but-2-enyl}-4-pyridine-2-yl-benzamide hydrochloride], inhibited the induction of PE and yawning, whereas the D(2) antagonist, L-741,626 [3-[4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl]methyl-1H-indole], reversed the inhibition of PE and yawning observed at higher doses. The D(4) antagonist, L-745,870 [3-(4-[4-chlorophenyl]piperazin-1-yl)-methyl-1H-pyrrolo[2,3-b]pyridine trihydrochloride], did not alter apomorphine- or pramipexole-induced PE or yawning. A role for the D(3) receptor was further supported because apomorphine was equipotent at inducing PE in wild-type and D(4)RKO mice, effects that were inhibited by the D(3) antagonist, PG01037, in both wild-type and D(4)R KO mice. Together, these studies provide strong support that D(2)-like agonist-induced PE and yawning are differentially mediated by the D(3) (induction) and D(2) (inhibition) receptors. These studies fail to support a role for the D(4) receptor in the regulation of PE or

  14. Synthesis and positron emission tomography studies of carbon-11-labeled imatinib (Gleevec)

    Energy Technology Data Exchange (ETDEWEB)

    Kil, Kun-Eek [Medical Department, Brookhaven National Laboratory, Upton, NY 11973 (United States); Department of Chemistry, State University of New York at Stony Brook, Stony Brook, NY 11794-3400 (United States); Ding Yushin [Department of Radiology, Yale University School of Medicine, New Haven, CT 06520-8048 (United States); Lin Kuoshyan [Department of Radiology, University of Pittsburgh, Pittsburgh, PA 15213 (United States); Alexoff, David [Medical Department, Brookhaven National Laboratory, Upton, NY 11973 (United States); Kim, Sung Won [Medical Department, Brookhaven National Laboratory, Upton, NY 11973 (United States); Department of Chemistry, State University of New York at Stony Brook, Stony Brook, NY 11794-3400 (United States); Shea, Colleen [Medical Department, Brookhaven National Laboratory, Upton, NY 11973 (United States); Xu Youwen [Medical Department, Brookhaven National Laboratory, Upton, NY 11973 (United States); Muench, Lisa [Medical Department, Brookhaven National Laboratory, Upton, NY 11973 (United States); Fowler, Joanna S. [Medical Department, Brookhaven National Laboratory, Upton, NY 11973 (United States) and Department of Chemistry, State University of New York at Stony Brook, Stony Brook, NY 11794-3400 (United States)]. E-mail: fowler@bnl.gov

    2007-02-15

    Introduction: Imatinib mesylate (Gleevec) is a well known drug for treating chronic myeloid leukemia and gastrointestinal stromal tumors. Its active ingredient, imatinib ([4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridyl) -2-pyrimidinyl]amino]phenyl]benzamide), blocks the activity of several tyrosine kinases. Here we labeled imatinib with carbon-11 as a tool for determining the drug distribution and pharmacokinetics of imatinib, and we carried out positron emission tomography (PET) studies in baboons. Methods: [N-{sup 11}C-methyl]imatinib was synthesized from [{sup 11}C]methyl iodide and norimatinib was synthesized by the demethylation of imatinib (isolated from Gleevec tablets) according to a patent procedure [Collins JM, Klecker RW Jr, Anderson LW. Imaging of drug accumulation as a guide to antitumor therapy. US Patent 20030198594A1, 2003]. Norimatinib was also synthesized from the corresponding amine and acid. PET studies were carried out in three baboons to measure pharmacokinetics in the brain and peripheral organs and to determine the effect of a therapeutic dose of imatinib. Log D and plasma protein binding were also measured. Results: [N-{sup 11}C-methyl]imatinib uptake in the brain is negligible (consistent with P-glycoprotein-mediated efflux); it peaks and clears rapidly from the heart, lungs and spleen. Peak uptake and clearance occur more slowly in the liver and kidneys, followed by accumulation in the gallbladder and urinary bladder. Pretreatment with imatinib did not change uptake in the heart, lungs, kidneys and spleen, and increased uptake in the liver and gallbladder. Conclusions: [N-{sup 11}C-methyl]imatinib has potential for assessing the regional distribution and kinetics of imatinib in the human body to determine whether the drug targets tumors and to identify other organs to which the drug or its labeled metabolites distribute. Paired with tracers such as 2'deoxy-2'-[{sup 18}F]fluoro-D-glucose ({sup 18}FDG) and 3&apos

  15. SIRT1 inactivation induces inflammation through the dysregulation of autophagy in human THP-1 cells

    Energy Technology Data Exchange (ETDEWEB)

    Takeda-Watanabe, Ai; Kitada, Munehiro; Kanasaki, Keizo [Diabetology and Endocrinology, Kanazawa Medical University, Kahoku-Gun, Ishikawa (Japan); Koya, Daisuke, E-mail: koya0516@kanazawa-med.ac.jp [Diabetology and Endocrinology, Kanazawa Medical University, Kahoku-Gun, Ishikawa (Japan)

    2012-10-12

    Highlights: Black-Right-Pointing-Pointer SIRT1 inactivation decreases autophagy in THP-1 cell. Black-Right-Pointing-Pointer Inhibition of autophagy induces inflammation. Black-Right-Pointing-Pointer SIRT1 inactivation induces inflammation through NF-{kappa}B activation. Black-Right-Pointing-Pointer The p62/Sqstm1 accumulation by impairment of autophagy is related to NF-{kappa}B activation. Black-Right-Pointing-Pointer SIRT1 inactivation is involved in the activation of mTOR and decreased AMPK activation. -- Abstract: Inflammation plays a crucial role in atherosclerosis. Monocytes/macrophages are some of the cells involved in the inflammatory process in atherogenesis. Autophagy exerts a protective effect against cellular stresses like inflammation, and it is regulated by nutrient-sensing pathways. The nutrient-sensing pathway includes SIRT1, a NAD{sup +}-dependent histone deacetylase, which is implicated in the regulation of a variety of cellular processes including inflammation and autophagy. The mechanism through which the dysfunction of SIRT1 contributes to the regulation of inflammation in relation to autophagy in monocytes/macrophages is unclear. In the present study, we demonstrate that treatment with 2-[(2-Hydroxynaphthalen-1-ylmethylene)amino]-N-(1-phenethyl)benzamide (Sirtinol), a chemical inhibitor of SIRT1, induces the overexpression of inflammation-related genes such as tumor necrosis factor (TNF)-{alpha} and interleukin (IL)-6 through nuclear factor (NF)-{kappa}B signaling activation, which is associated with autophagy dysfunction, as shown through p62/Sqstm1 accumulation and decreased expression of light chain (LC) 3 II in THP-1 cells. The autophagy inhibitor, 3-methyladenine, also induces inflammation-related NF-{kappa}B activation. In p62/Sqstm1 knockdown cells, Sirtinol-induced inflammation through NF-{kappa}B activation is blocked. In addition, inhibition of SIRT1 is involved in the activation of the mammalian target of rapamycin (mTOR) pathway and

  16. Avaliação de xaropes contendo cloridrato de metoclopramida, pelo método de Bratton-Marshall Evaluation of metoclopramide syrups by Bratton-Marshall method

    Directory of Open Access Journals (Sweden)

    Beatriz Resende Freitas

    2005-06-01

    Full Text Available Atualmente, a maioria dos fármacos apresenta grupamento amínico. Estes quando associados a açúcares redutores ou a outros adjuvantes farmacêuticos contendo carbonila, freqüentemente produzem problemas de estabilidade, comprometendo a idoneidade do produto. A Reação de Maillard pode explicar tal ocorrência. Neste trabalho estudou-se o comportamento de xarope contendo amina aromática, tendo em vista a associação de açúcares e aminas, a Reação de Maillard e problemas de estabilidade. O protótipo escolhido foi o cloridrato de metoclopramida, benzamida com atividade farmacológica antiemética. Amostras dos xaropes de cloridrato de metoclopramida foram mantidas em estufa a 40 °C por seis meses. Em intervalos regulares de tempo alíquotas foram retiradas e submetidas à análise pelo método de Bratton-Marshall, seguida de leitura espectrofotométrica. Não houve grande variação no teor do cloridrato de metoclopramida em relação ao teor de açúcar, sendo que foram preparadas amostras padronizadas dos xaropes de cloridrato de metoclopramida em diferentes concentrações de açúcar. Houve diminuição do teor do cloridrato de metoclopramida, da ordem de 50%, tanto para amostras padronizadas como para amostra comercial.Nowadays, most of the drugs have amine group in their structure. These drugs, when associated to sugar reducers, or other carbonyl excipients frequently produce dark stains or fading. The Maillard reaction can explain such occurrence. In this work, we have studied the behavior of syrups containing aromatic amines. It is known that association of sugars and amines can generate problems of stability. The chosen prototype was the metoclopramide hydrochloride, a benzamide, with anti-emetic pharmacological activity. Samples of the metoclopramide syrups were maintained in stove at 40 °C for six months. In regular time intervals aliquots were removed and submitted to quantitative determination by the Bratton

  17. A comparison of the stimulatory effects of metoclopramide and cinitapride in the guinea-pig isolated ileum.

    Science.gov (United States)

    Massingham, R; Bou, J; Roberts, D J

    1985-03-01

    The pharmacological effects of a new benzamide derivative cinitapride, have been compared to those of metoclopramide in guinea-pig isolated ileum and longitudinal smooth muscle-myenteric plexus preparations treated with propranolol (3 microM). Cinitapride (EC50 = 0.74 microM) was 6 times more potent than metoclopramide (EC50 = 4.69 microM) in enhancing the twitch response of co-axially stimulated preparations and 11 times more potent in eliciting contractions in non-stimulated tissues, their respective EC50 values being 0.58 microM and 6.52 microM. These contractile effects of cinitapride and metoclopramide amounted to approximately 25% of the maximum response of the tissues to acetylcholine (1 microM). Neither cinitapride nor metoclopramide, in concentrations up to 10 microM, significantly affected concentration-response curves to exogenous acetylcholine or 5-hydroxytryptamine but both drugs elicited a concentration-dependent potentiation of the ileum responses to a fixed concentration (10 microM) of the ganglion stimulant dimethylphenylpiperazinium (DMPP). Analysis of the twitch-enhancing and contractile effects of cinitapride using a variety of drugs suggested that a common, prejunctional locus of action upon the cell bodies or axons of postganglionic, parasympathetic neurones of the myenteric plexus is involved in both of these responses. In hexamethonium (100 microM) and methysergide (0.1 microM)-treated longitudinal smooth muscle preparations desensitization or blockade of 5-hydroxytryptamine receptors using high concentrations of the same agonist (30 microM) or quipazine (10 microM) or the putative antagonists cocaine (30 microM) or tubocurarine (10 microM) produced small inhibitions (congruent to 20%) of the contractile responses to metoclopramide and cinitapride but did not affect twitch responses to these drugs. It is concluded that cinitapride is a more potent stimulant of guinea-pig intestinal smooth muscle than metoclopramide in vitro although the

  18. On-line solid phase extraction-high performance liquid chromatography–isotope dilution–tandem mass spectrometry approach to quantify N,N-diethyl-m-toluamide and oxidative metabolites in urine

    International Nuclear Information System (INIS)

    Graphical abstract: -- Highlights: •A fast assay to quantify the concentrations of N,N-Diethyl-m-Toluamide and two urinary metabolites was developed •It uses online SPE, reversed phase HPLC and tandem mass spectrometry •The method is precise and accurate with limits of detection ≤1 ng mL−1 -- Abstract: Human exposure to N,N-diethyl-m-toluamide (DEET) occurs because of the widespread use of DEET as an active ingredient in insect repellents. However, information on the extent of such exposure is rather limited. Therefore, we developed a fast on-line solid phase extraction–high performance liquid chromatography–isotope dilution tandem mass spectrometry (HPLC-MS/MS) method to measure in urine the concentrations of DEET and two of its oxidative metabolites: N,N-diethyl-3-(hydroxymethyl)benzamide and 3-(diethylcarbamoyl)benzoic acid (DCBA). To the best of our knowledge, this is the first HPLC-MS/MS method for the simultaneous quantification of DEET and its select metabolites in human urine. After enzymatic hydrolysis of the conjugated species in 0.1 mL of urine, the target analytes were retained and pre-concentrated on a monolithic column, separated from each other and from other urinary biomolecules on a reversed-phase analytical column, and detected by atmospheric pressure chemical ionization in positive ion mode. The limits of detection ranged from 0.1 ng mL−1 to 1.0 ng mL−1, depending on the analyte. Accuracy ranged between 90.4 and 104.9%, and precision ranged between 5.5 and 13.1% RSD, depending on the analyte and the concentration. We tested the usefulness of this method by analyzing 75 urine samples collected anonymously in the Southeastern United States in June 2012 from adults with no known exposure to DEET. Thirty eight samples (51%) tested positive for at least one of the analytes. We detected DCBA most frequently and at the highest concentrations. Our results suggest that this method can be used for the analysis of a large number of samples

  19. Tuning of EAG K(+) channel inactivation: molecular determinants of amplification by mutations and a small molecule.

    Science.gov (United States)

    Garg, Vivek; Sachse, Frank B; Sanguinetti, Michael C

    2012-09-01

    Ether-à-go-go (EAG) and EAG-related gene (ERG) K(+) channels are close homologues but differ markedly in their gating properties. ERG1 channels are characterized by rapid and extensive C-type inactivation, whereas mammalian EAG1 channels were previously considered noninactivating. Here, we show that human EAG1 channels exhibit an intrinsic voltage-dependent slow inactivation that is markedly enhanced in rate and extent by 1-10 µM 3-nitro-N-(4-phenoxyphenyl) benzamide, or ICA105574 (ICA). This compound was previously reported to have the opposite effect on ERG1 channels, causing an increase in current magnitude by inhibition of C-type inactivation. The voltage dependence of 2 µM ICA-induced inhibition of EAG1 current was half-maximal at -73 mV, 62 mV negative to the half-point for channel activation. This finding suggests that current inhibition by the drug is mediated by enhanced inactivation and not open-channel block, where the voltage half-points for current inhibition and channel activation are predicted to overlap, as we demonstrate for clofilium and astemizole. The mutation Y464A in the S6 segment also induced inactivation of EAG1, with a time course and voltage dependence similar to that caused by 2 µM ICA. Several Markov models were investigated to describe gating effects induced by multiple concentrations of the drug and the Y464A mutation. Models with the smallest fit error required both closed- and open-state inactivation. Unlike typical C-type inactivation, the rate of Y464A- and ICA-induced inactivation was not decreased by external tetraethylammonium or elevated [K(+)](e). EAG1 channel inactivation introduced by Y464A was prevented by additional mutation of a nearby residue located in the S5 segment (F359A) or pore helix (L434A), suggesting a tripartite molecular model where interactions between single residues in S5, S6, and the pore helix modulate inactivation of EAG1 channels. PMID:22930803

  20. Ultra-structural cell distribution of the melanoma marker iodobenzamide: improved potentiality of SIMS imaging in life sciences

    Directory of Open Access Journals (Sweden)

    Papon Janine

    2004-04-01

    Full Text Available Abstract Background Analytical imaging by secondary ion mass spectrometry (SIMS provides images representative of the distribution of a specific ion within a sample surface. For the last fifteen years, concerted collaborative research to design a new ion microprobe with high technical standards in both mass and lateral resolution as well as in sensitivity has led to the CAMECA NanoSims 50, recently introduced onto the market. This instrument has decisive capabilities, which allow biological applications of SIMS microscopy at a level previously inaccessible. Its potential is illustrated here by the demonstration of the specific affinity of a melanoma marker for melanin. This finding is of great importance for the diagnosis and/or treatment of malignant melanoma, a tumour whose worldwide incidence is continuously growing. Methods The characteristics of the instrument are briefly described and an example of application is given. This example deals with the intracellular localization of an iodo-benzamide used as a diagnostic tool for the scintigraphic detection of melanic cells (e.g. metastasis of malignant melanoma. B16 melanoma cells were injected intravenously to C57BL6/J1/co mice. Multiple B16 melanoma colonies developed in the lungs of treated animals within three weeks. Iodobenzamide was injected intravenously in tumour bearing mice six hours before sacrifice. Small pieces of lung were prepared for SIMS analysis. Results Mouse lung B16 melanoma colonies were observed with high lateral resolution. Cyanide ions gave "histological" images of the cell, representative of the distribution of C and N containing molecules (e.g. proteins, nucleic acids, melanin, etc. while phosphorus ions are mainly produced by nucleic acids. Iodine was detected only in melanosomes, confirming the specific affinity of the drug for melanin. No drug was found in normal lung tissue. Conclusion This study demonstrates the potential of SIMS microscopy, which allows the

  1. Design and preclinical evaluation of melanoma targeting agents for internal radionuclide therapy

    Energy Technology Data Exchange (ETDEWEB)

    Chezal, J.M.; Papon, J.; Labarre, P.; Denoyer, D.; Bonnet-Duquennoy, M.; Miot-Noirault, E.; Bayle, M.; Chavignon, O.; Teulade, J.C.; Maublant, J.; Madelmont, J.C.; Moins, N. [Centre Jean Perrin, Inserm-Univ. d' Auvergne, UMR 484, 63 - Clermont Ferrand (France)

    2008-02-15

    Targeted internal radionuclide therapy would be an effective alternative to current therapies for disseminated melanoma treatment. N-(2-diethylaminoethyl)-4-iodo benzamide (B.Z.A.) and compounds of this series exhibit a specific affinity for melanoma tissue giving them a potent application for gamma imaging ({sup 123}I) or radionuclide therapy ({sup 131}I or {sup 125}I).With the aim of internal radionuclide therapy, a pharmaco-chemical study has been carried out in order to select new derivatives with a longer retention time in the tumor of melanoma bearing mice and suitable dosimetry. New molecules synthesized are B.Z.A. analogs differing by (1) the aliphatic side chain, (2) aromatic ring. After the design of compounds, the synthesis, and the labelling with {sup 125}I, a study of their biodistribution was performed in B 16 F0 melanoma bearing C.57 B.L.6 mice after i.v. injection. The radioactivity biodistribution was analysed using an A.M.B.I.S.4000 detector on whole body slices of mice obtained by cryo section. The radioactivity was quantified in different organs including tumor and expressed as percentage of injected dose/g of tissue (% I.D./g). Dosimetry parameters for a {sup 131}I utilization were extrapolated using the M.I.R.D. program. The first selected compound has been further evaluated on different models. S.I.M.S. imaging, metabolism and in vivo anti tumoral activity after {sup 131}I labelling were assessed. For number of the studied molecules, a tumor uptake was observed and at least four compounds exhibited an original pharmacokinetic profile: high, specific and durable tumour concentration with a rapid clearance from non-target organs. The tumour concentration after 72 h was increased up to 16- fold compared to B.Z.A. and in term of dosimetry, for a {sup 131}I labelling, the tumor absorbed dose was increased by more than 6-fold. Such profiles made these compounds promising for an application to internal radionuclide therapy. The first selected

  2. Enhancement of social novelty discrimination by positive allosteric modulators at metabotropic glutamate 5 receptors: adolescent administration prevents adult-onset deficits induced by neonatal treatment with phencyclidine.

    Science.gov (United States)

    Clifton, Nicholas E; Morisot, Nadège; Girardon, Sylvie; Millan, Mark J; Loiseau, Florence

    2013-02-01

    Metabotropic glutamate-5 receptors (mGluR5), which physically and functionally interact with N-methyl-D-Aspartate (NMDA) receptors, likewise control cognitive processes and have been proposed as targets for novel classes of antipsychotic agent. Since social cognition is impaired in schizophrenia and disrupted by NMDA receptor antagonists like dizocilpine, we evaluated its potential modulation by mGluR5. Acute administration (0.63-40 mg/kg) of the mGluR5 positive allosteric modulators (PAMs), 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) and ADX47273, reversed a delay-induced impairment in social novelty discrimination (SND) in adult rats. The action of CDPPB was blocked by the mGluR5 antagonist, 2-methyl-6-(phenylethynyl)-pyridine (2.5-10 mg/kg), and was also expressed upon microinjection into frontal cortex (0.63-10 μg/side), but not striatum. Supporting an interrelationship between mGluR5 and NMDA receptors, enhancement of SND by CDPPB was blocked by dizocilpine (0.08 mg/kg) while, reciprocally, dizocilpine-induced impairment in SND was attenuated by CDPPB (10 mg/kg). The SND deficit elicited by post-natal administration of phencyclidine (10 mg/kg, days 7-11) was reversed by CDPPB or ADX47273 in adults at week 8. This phencyclidine-induced impairment in cognition emerged in adult rats from week 7 on, and chronic, pre-symptomatic treatment of adolescent rats with CDPPB over weeks 5-6 (10 mg/kg per day) prevented the appearance of SND deficits in adults until at least week 13. In conclusion, as evaluated by a SND procedure, mGluR5 PAMs promote social cognition via actions expressed in interaction with NMDA receptors and exerted in frontal cortex. MGluR5 PAMs not only reverse but also (when given during adolescence) prevent the emergence of cognitive impairment associated with a developmental model of schizophrenia.

  3. Targeting Lysine Deacetylases (KDACs in Parasites.

    Directory of Open Access Journals (Sweden)

    Qi Wang

    Full Text Available Due to an increasing problem of drug resistance among almost all parasites species ranging from protists to worms, there is an urgent need to explore new drug targets and their inhibitors to provide new and effective parasitic therapeutics. In this regard, there is growing interest in exploring known drug leads of human epigenetic enzymes as potential starting points to develop novel treatments for parasitic diseases. This approach of repurposing (starting with validated targets and inhibitors is quite attractive since it has the potential to reduce the expense of drug development and accelerate the process of developing novel drug candidates for parasite control. Lysine deacetylases (KDACs are among the most studied epigenetic drug targets of humans, and a broad range of small-molecule inhibitors for these enzymes have been reported. In this work, we identify the KDAC protein families in representative species across important classes of parasites, screen a compound library of 23 hydroxamate- or benzamide-based small molecules KDAC inhibitors, and report their activities against a range of parasitic species, including the pathogen of malaria (Plasmodium falciparum, kinetoplastids (Trypanosoma brucei and Leishmania donovani, and nematodes (Brugia malayi, Dirofilaria immitis and Haemonchus contortus. Compound activity against parasites is compared to that observed against the mammalian cell line (L929 mouse fibroblast in order to determine potential parasite-versus-host selectivity. The compounds showed nanomolar to sub-nanomolar potency against various parasites, and some selectivity was observed within the small panel of compounds tested. The possible binding modes of the active compounds at the different protein target sites within different species were explored by docking to homology models to help guide the discovery of more selective, parasite-specific inhibitors. This current work supports previous studies that explored the use of KDAC

  4. Targeting Lysine Deacetylases (KDACs) in Parasites.

    Science.gov (United States)

    Wang, Qi; Rosa, Bruce A; Nare, Bakela; Powell, Kerrie; Valente, Sergio; Rotili, Dante; Mai, Antonello; Marshall, Garland R; Mitreva, Makedonka

    2015-01-01

    Due to an increasing problem of drug resistance among almost all parasites species ranging from protists to worms, there is an urgent need to explore new drug targets and their inhibitors to provide new and effective parasitic therapeutics. In this regard, there is growing interest in exploring known drug leads of human epigenetic enzymes as potential starting points to develop novel treatments for parasitic diseases. This approach of repurposing (starting with validated targets and inhibitors) is quite attractive since it has the potential to reduce the expense of drug development and accelerate the process of developing novel drug candidates for parasite control. Lysine deacetylases (KDACs) are among the most studied epigenetic drug targets of humans, and a broad range of small-molecule inhibitors for these enzymes have been reported. In this work, we identify the KDAC protein families in representative species across important classes of parasites, screen a compound library of 23 hydroxamate- or benzamide-based small molecules KDAC inhibitors, and report their activities against a range of parasitic species, including the pathogen of malaria (Plasmodium falciparum), kinetoplastids (Trypanosoma brucei and Leishmania donovani), and nematodes (Brugia malayi, Dirofilaria immitis and Haemonchus contortus). Compound activity against parasites is compared to that observed against the mammalian cell line (L929 mouse fibroblast) in order to determine potential parasite-versus-host selectivity). The compounds showed nanomolar to sub-nanomolar potency against various parasites, and some selectivity was observed within the small panel of compounds tested. The possible binding modes of the active compounds at the different protein target sites within different species were explored by docking to homology models to help guide the discovery of more selective, parasite-specific inhibitors. This current work supports previous studies that explored the use of KDAC inhibitors in

  5. Involvement of the 5-HT(1A) receptor in the anti-immobility effects of fluvoxamine in the forced swimming test and mouse strain differences in 5-HT(1A) receptor binding.

    Science.gov (United States)

    Sugimoto, Yumi; Furutani, Sachiko; Kajiwara, Yoshinobu; Hirano, Kazufumi; Yamada, Shizuo; Tagawa, Noriko; Kobayashi, Yoshiharu; Hotta, Yoshihiro; Yamada, Jun

    2010-03-10

    We previously demonstrated the presence of strain differences in baseline immobility time and sensitivity to the selective serotonin reuptake inhibitor (SSRI) fluvoxamine in five strains of mice (ICR, ddY, C57BL, DBA/2 and BALB/c mice). Furthermore, variations in serotonin (5-HT) transporter binding in the brain were strongly related to strain differences in baseline immobility and sensitivity to fluvoxamine. In the present study, we examined the involvement of the 5-HT(1A) receptor in anti-immobility effects in DBA/2 mice, which show high sensitivity to fluvoxamine. The anti-immobility effects of fluvoxamine in DBA/2 mice were inhibited by the 5-HT(1A) receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide (WAY 100635). However, the 5-HT(1B) receptor antagonist 3-[3-(dimethylamino)propyl]-4-hydroxy-N-[4-(4-pyridinyl)phenyl]benzamide (GR55562), the 5-HT(2) receptor antagonist 6-methyl-1-(methylethyl)-ergoline-8beta-carboxylic acid 2-hydroxy-1-methylpropyl ester (LY 53857), the 5-HT(3) receptor antagonist ondansetron and the 5-HT(4) receptor antagonist 4-amino-5-chloro-2-methoxy-benzoic acid 2-(diethylamino)ethyl ester (SDZ 205,557) did not influence the anti-immobility effects of fluvoxamine in DBA/2 mice. These results suggest that fluvoxamine-induced antidepressant-like effects in DBA/2 mice are mediated by the 5-HT(1A) receptor. We analyzed 5-HT(1A) receptor binding in the brains of five strains of mice. Strain differences in 5-HT(1A) receptor binding were observed. 5-HT(1A) receptor binding in brain was not correlated with baseline immobility time in the five strains of mice examined. These results suggest that, although the anti-immobility effects of fluvoxamine in DBA/2 mice are mediated by the 5-HT(1A) receptor, strain differences in 5-HT(1A) receptor binding are not related to variation in immobility time and responses to fluvoxamine.

  6. Exploration of dopamine transporter and D2 receptors in morphine dependent rats through 125I-β-CTT, 125I-IBZM cerebral autoradiography and the biodistribution study

    International Nuclear Information System (INIS)

    Objective: To explore the variation of cerebral dopamine (DA) transmitting system in morphine dependent (MD) rats using dopamine transporter (DAT) and D2 receptors imaging agent. Methods: MD model rats were established by using a two-compartment (C1 and C2-morphine conditioned compartment) apparatus for assessing morphine conditioned place preferences in rats. 125I-2β-carbomethoxy-3β-(4-iodophenyl) tropane (125I-β-CIT) and 125I-3-iodo-2-hydroxy-6-methoxy-N[(1-ethyl-2-pyrrolidinyl) methyl] benzamide (125I-IBZM) cerebral DAT and D2 receptor autoradiography and biodistribution study were used to evaluate the variation of DAT and D2 receptors in morphine dependent rats. Results: The mean time of MD rats entering from C1 to C2 was (0.84 +- 0.50) min after 6 days' conditioned place preference training, shorter than that of the control group [(2.40 +- 1.10) min, P 125I-β-CIT uptake ratio of striatum (ST)/cerebellum (CB) and nucleus acumens (NAC)/CB in MD group were 4.76 +- 0.92 and 2.72 +- 0.96, significantly lower than that of control group (5.92 +- 0.67 and 4.16 +- 0.56, P 125I-IBZM uptake ratio in MD group were 4.11 +- 0.56 and 2.64 +- 0.25, lower than that in control group (5.43 +- 0.74 and 3.49 +- 0.65, P 125I-β-CIT, 125I-IBZM biodistribution study also showed that the DAT and D2 binding sites were reduced in ST of MD group by (21.68 +- 11.11)% and (18.69 +- 9.97)% comparing to the controls, respectively. Conclusions: The DAT and D2 receptors in both ST and NAC were all involved and reduced to some extent in morphine dependent model rats, the DAT and D2 receptor imaging agent could reflect the variation of DAT and D2receptors, this would afford the theoretical basis for D2 receptors and DAT imaging in study on preventing drug addiction and on its abstinence

  7. Searching for combinations of small-molecule correctors to restore f508del-cystic fibrosis transmembrane conductance regulator function and processing.

    Science.gov (United States)

    Boinot, Clément; Jollivet Souchet, Mathilde; Ferru-Clément, Romain; Becq, Frédéric

    2014-09-01

    The mutated protein F508del-cystic fibrosis transmembrane conductance regulator (CFTR) failed to traffic properly as a result of its retention in the endoplasmic reticulum and functions as a chloride (Cl(-)) channel with abnormal gating and endocytosis. Small chemicals (called correctors) individually restore F508del-CFTR trafficking and Cl(-) transport function, but recent findings indicate that synergistic pharmacology should be considered to address CFTR defects more clearly. We studied the function and maturation of F508del-CFTR expressed in HeLa cells using a combination of five correctors [miglustat, IsoLAB (1,4-dideoxy-2-hydroxymethyl-1,4-imino-l-threitol), Corr4a (N-[2-(5-chloro-2-methoxy-phenylamino)-4'-methyl-[4,5']bithiazolyl-2'-yl]-benzamide), VX-809 [3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid], and suberoylamilide hydroxamic acid (SAHA)]. Using the whole-cell patch-clamp technique, the current density recorded in response to CFTR activators (forskolin + genistein) was significantly increased in the presence of the following combinations: VX-809 + IsoLAB; VX-809 + miglustat + SAHA; VX-809 + miglustat + IsoLAB; VX-809 + IsoLAB + SAHA; VX-809 + miglustat + IsoLAB + SAHA. These combinations restored the activity of F508del-CFTR but with a differential effect on the appearance of mature c-band of F508del-CFTR proteins. Focusing on the VX-809 + IsoLAB cocktail, we recorded a level of correction higher at 37°C versus room temperature, but without amelioration of the thermal instability of CFTR. The level of functional rescue with VX-809 + IsoLAB after 4 hours of incubation was maximal and similar to that obtained in optimal conditions of use for each compound (i.e., 24 hours for VX-809 + 4 hours for IsoLAB). Finally, we compared the stimulation of F508del-CFTR by forskolin or forskolin + VX-770 [N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide] with cells corrected by

  8. Ethanol, not metabolized in brain, significantly reduces brain metabolism, probably via specific GABA(A) receptors

    Science.gov (United States)

    Rae, Caroline D.; Davidson, Joanne E.; Maher, Anthony D.; Rowlands, Benjamin D.; Kashem, Mohammed A.; Nasrallah, Fatima A.; Rallapalli, Sundari K.; Cook, James M; Balcar, Vladimir J.

    2014-01-01

    Ethanol is a known neuromodulatory agent with reported actions at a range of neurotransmitter receptors. Here, we used an indirect approach, measuring the effect of alcohol on metabolism of [3-13C]pyruvate in the adult Guinea pig brain cortical tissue slice and comparing the outcomes to those from a library of ligands active in the GABAergic system as well as studying the metabolic fate of [1,2-13C]ethanol. Ethanol (10, 30 and 60 mM) significantly reduced metabolic flux into all measured isotopomers and reduced all metabolic pool sizes. The metabolic profiles of these three concentrations of ethanol were similar and clustered with that of the α4β3δ positive allosteric modulator DS2 (4-Chloro-N-[2-(2-thienyl)imidazo[1,2a]-pyridin-3-yl]benzamide). Ethanol at a very low concentration (0.1 mM) produced a metabolic profile which clustered with those from inhibitors of GABA uptake, and ligands showing affinity for α5, and to a lesser extent, α1-containing GABA(A)R. There was no measureable metabolism of [1,2-13C]ethanol with no significant incorporation of 13C from [1,2-13C]ethanol into any measured metabolite above natural abundance, although there were measurable effects on total metabolite sizes similar to those seen with unlabeled ethanol. The reduction in metabolism seen in the presence of ethanol is therefore likely to be due to its actions at neurotransmitter receptors, particularly α4β3δ receptors, and not because ethanol is substituting as a substrate or because of the effects of ethanol catabolites acetaldehyde or acetate. We suggest that the stimulatory effects of very low concentrations of ethanol are due to release of GABA via GAT1 and the subsequent interaction of this GABA with local α5-containing, and to a lesser extent, α1-containing GABA(A)R. PMID:24313287

  9. Pharmacological profile of DA-6886, a novel 5-HT4 receptor agonist to accelerate colonic motor activity in mice.

    Science.gov (United States)

    Lee, Min Jung; Cho, Kang Hun; Park, Hyun Min; Sung, Hyun Jung; Choi, Sunghak; Im, Weonbin

    2014-07-15

    DA-6886, the gastrointestinal prokinetic benzamide derivative is a novel 5-HT4 receptor agonist being developed for the treatment of constipation-predominant irritable bowel syndrome (IBS-C). The purpose of this study was to characterize in vitro and in vivo pharmacological profile of DA-6886. We used various receptor binding assay, cAMP accumulation assay, organ bath experiment and colonic transit assay in normal and chemically constipated mice. DA-6886 exhibited high affinity and selectivity to human 5-HT4 receptor splice variants, with mean pKi of 7.1, 7.5, 7.9 for the human 5-HT4a, 5-HT4b and 5-HT4d, respectively. By contrast, DA-6886 did not show significant affinity for several receptors including dopamine D2 receptor, other 5-HT receptors except for 5-HT2B receptor (pKi value of 6.2). The affinity for 5-HT4 receptor was translated into functional agonist activity in Cos-7 cells expressing 5-HT4 receptor splice variants. Furthermore, DA-6886 induced relaxation of the rat oesophagus preparation (pEC50 value of 7.4) in a 5-HT4 receptor antagonist-sensitive manner. The evaluation of DA-6886 in CHO cells expressing hERG channels revealed that it inhibited hERG channel current with an pIC50 value of 4.3, indicating that the compound was 1000-fold more selective for the 5-HT4 receptor over hERG channels. In the normal ICR mice, oral administration of DA-6886 (0.4 and 2mg/kg) resulted in marked stimulation of colonic transit. Furthermore, in the loperamide-induced constipation mouse model, 2mg/kg of DA-6886 significantly improved the delay of colonic transit, similar to 10mg/kg of tegaserod. Taken together, DA-6886 is a highly potent and selective 5-HT4 receptor agonist to accelerate colonic transit in mice, which might be therapeutic agent having a favorable safety profile in the treatment of gastrointestinal motor disorders such as IBS-C and chronic constipation.

  10. Human umbilical cord blood mesenchymal stem cell transplantation for the treatment of hepatic cirrhosis in rats%人脐血间充质干细胞移植治疗大鼠肝硬化模型*

    Institute of Scientific and Technical Information of China (English)

    詹三华; 张鲁峰; 姚卫民; 杨明辉; 宋晓玲; 焦红亮

    2013-01-01

    BACKGROUND:Studies have shown that cord blood mesenchymal stem cel s can be induced into hepatocyte-like cel s in a specific environment, and the transplanted cel s can exercise the normal function of liver cel s. OBJECTIVE:To establish the rat model of hepatic cirrhosis induced with carbon tetrachloride, and to observe the therapeutic effect of umbilical cord blood mesenchymal stem cel transplantation on a rat model of hepatic cirrhosis. METHODS:Hepatic cirrhosis models were established through carbon tetrachloride inducing, then 20 rat models of hepatic cirrhosis were randomly divided into two groups. The control group was injected with 0.5 mL normal saline via the tail vein;the treatment group was injected with chloromethyl benzamide labeled umbilical cord blood mesenchymal stem cel suspension, and the number of the stem cel s was 1×106. After 2 weeks, al animals were sacrificed. Liver tissues were obtained for the histological observation and the venous blood was col ected to detected the liver function indicators. RESULTS AND CONCLUSION:The liver cel s of the hepatic cirrhosis models were loose and cloudy swel ing, part of the cel s were degenerated and necrosis, the structure of the hepatic lobule was vague, and several pseudolobules with different sizes were formed which meet the diagnostic criteria of hepatic cirrhosis. Compared with the control group, the level of serum albumin in the treatment group was significantly increased (P<0.05), while the levels of bilirubin and transaminases in the treatment group were significantly decreased (P<0.05). There were lots of red chloromethyl benzamide labeled umbilical cord blood mesenchymal stem cel s in the liver tissue of the treatment group. Human umbilical cord blood mesenchymal stem cel s can effectively improve the physiological function of hepatic cirrhosis through tail vein.%  背景:研究表明,脐血间充质干细胞可在特定环境下诱导为肝样细胞,移植入体内能行使正常肝

  11. Novel 99mTc labeled

    Institute of Scientific and Technical Information of China (English)

    FAN; Caiyun

    2006-01-01

    [1]Quirion,R.,Bowen,W.D.,Itzhak,Y.et al.,A proposal for the classification of sigma binding sites,Trends Pharmacol.Sci.,1992,13:85-86.[2]Su,T.P.,Sigma receptors:Putative links between nervous,endocrine and immune systems,Eur.J.Biochem.,1991,200:633-642.[3]Guitart,X.,Codony,X.,Monroy,X.,Sigma receptors:Biology and therapeutic potential,Psychopharmacology,2004,174:301-319.[4]Vilner,B.J.,John,C.S.,Bowen,W.D.,Sigma-1 and sigma-2 receptors are expressed in a wide variety of human and rodent tumor cell lines,Cancer Res.,1995,55:408-413.[5]Mach,R.H.,Smith,C.R.,al-Nabulsi,I.et al.,σ2 receptors as potential biomarkers of proliferation in breast cancer,Cancer Res.,1997,57:156-161.[6]Shiue,C.Y.,Shiue,G.G.,Zhang,S.X.et al.,N-(N-benzylpi-peridin-4-yl)-2-[18F]fluorobenzamide:A potential ligand for PET imaging of σ receptors,Nucl.Med.Biol.,1997,24:671-676.[7]Dence,C.S.,John,C.S.,Bowen,W.D.et al.,Synthesis and evaluation of [18F] labeled benzamides:High affinity sigma receptor ligands for PET imaging,Nucl.Med.Biol.,1997,24:333-340.[8]Shiue,C.Y.,Shiue,G.G.,Benard,F.et al.,N-(N-benzylpi-peridin-4-yl)-2-[18F]fluorobenzamide:A potential ligand for PET imaging of breast cancer,Nucl.Med.Biol.,2000,27:763-767.[9]Rowland,D.J.,Tu,Z.,Mach,R.H.et al.,Investigation of a new sigma-2 receptor ligand for detection of breast cancer,J.Labelled Cpd.Radiopharm.,2003,46:S6.[10]Everaert,H.,Flamen,P.,Franken,P.R.et al.,Sigma receptor imaging by means of 123-IDAB scintigraphy;clinical application in melanoma and non-small cell lung cancer,Anticancer Res.,1997,17:1577-1582.[11]John,C.S.,Gulden,M.E.,Li,J.et al.,Synthesis,in vitro binding,and tissue distribution of radioiodinated 2-[125I]N-(N-benzylpip-eridin-4-yl)-2-iodobenzamide,2-[125I]BP:A potential σ receptor marker for human prostate tumors,Nucl.Med.Biol.,1998,25:189-194.[12]Staelens,L.,Oltenfreiter,R.,Dumont,F.et al.,In vivo evaluation of [123I]-4-iodo-N-(4-(4-(2-me-thoxyphenyl)-piperazin-1-yl)butyl)-benzamide:A potential sigma receptor ligand

  12. 5-HT1A receptors are involved in the modulation of discharge activities of biphasic expiratory neurons and inspiratory neurons%5-HT1A受体对双相呼气和吸气神经元电活动的调制

    Institute of Scientific and Technical Information of China (English)

    秦峥; 王晓锋; 郭谦; 吴中海

    2007-01-01

    目的 探讨5-HT1A受体对延髓脑片双相呼气神经元和吸气神经元电活动的影响.方法 在新生大鼠延髓脑片上同步记录舌下神经根和双相呼气神经元/吸气神经元单位的放电活动,并在灌流的改良Kreb'S液中先后加以5-HT1A受体的特异性激动剂(+/-)-8-hydroxy-2-(di-N-propylamino)tetralin hydrobromide(8-OH-DPAT)和特异性拮抗剂多次甲基多苯基多异氰酸酯[4-iodo-N-[2-[4-(methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridynyl-benzamide hydrochloride](PMPPI)观察对神经元单位放电的影响.结果 给予5-HT1A受体激动剂8-OH-DPAT后,双相呼气神经元/吸气神经元的呼吸周期和呼气时程明显延长,积分幅度降低,单位放电峰频率显著性降低;给予特异性拮抗剂PMPPI后,对呼吸周期,呼气时程的作用相反,而积分幅度和单位放电峰频率无明显变化.结论 5-HT1A受体可能通过影响双相呼气神经元的电活动参与了呼吸时相的转换,同时也可能介导了吸气神经元的抑制性突触输入.%Objective To determine whether 5-HT1A receptors could modulate the discharge activities of biphasic expiratory neurons(BE-neurons)and inspiratory neurons (I-neurons).Methods Brainstem slices from newborn SD rats(0~3d)were made according to the method of Suzue,et al.These preparations included the medial region of the nucleus retrofacialis (mNRF)with the hypoglossal nerve rootlets retained.Respiratory rhythmical discharge activities (RRDA)of BE-neurons/I-neurons in mNRF and activities of the hypoglossal nerve(Ⅻ nerve)were simultaneously recorded by using extracellular microelectrodes and suction electrode,respectively.The effects of 5-HT1A receptors on the respiratory rhythm were investigated by application of 5-HT1A receptor specific agonist 8-OH-DPAT and its specific antagonist PMPPI in the perfusion solution.Results 8-OHDPAT induced a significant increase in the respiratory cycles(RC)and the expiratory time (TE) as well as a decrease

  13. On the clinical impact of cerebral dopamine D{sub 2} receptor scintigraphy; Zur klinischen Wertigkeit der zerebralen Dopamin-D{sub 2}-Rezeptorszintigraphie

    Energy Technology Data Exchange (ETDEWEB)

    Larisch, R. [Duesseldorf Univ. (Germany). Klinik fuer Nuklearmedizin; Klimke, A. [Duesseldorf Univ. (Germany). Psychiatrische Klinik

    1998-12-31

    The present review describes findings and clinical indications for the dopamine D{sub 2} receptor scintigraphy. Methods for the examination of D{sub 2} receptors are positron emission tomography (PET) using {sup 11}C- or {sup 18}F-labelled butyrophenones or benzamides or single photon emission tomography (SPECT) using {sup 123}I-iodobenzamide (IBZM) respectively. The most important indication in neurology is the differential diagnosis of Parkinsonism: Patients with early Parkinson`s disease show an increased D{sub 2} receptor binding (D{sub 2}-RB) compared to control subjects. However, patients suffering from Steele-Richardson-Olszewski-Syndrome or Multiple System Atrophy show a decreased D{sub 2}-RB and are generally non-responsive to treatment. Postsynaptic blockade of D{sub 2} receptors results in a drug induced Parkinsonian syndrome, which can be diagnosed by D{sub 2} scintigraphy. Further possible indications occur in psychiatry: The assessment of receptor occupancy is useful in schizophrenic patients treated with neuroleptics. Additionally, D{sub 2} receptor scintigraphy might help to clarify the differential diagnosis between neuroleptic malignant syndrome and lethal catatonia. The method might be useful for supervising neurobiochemical changes in drug dependency and during withdrawal. Assessment of dopamine D{sub 2} receptor binding can simplify the choice of therapy in depressive disorder: Patients showing a low D{sub 2} binding are likely to improve following an antidepressive drug treatment whereas sleep deprivation is promising in patients with high D{sub 2} binding. (orig.) [Deutsch] Die vorliegende Arbeit gibt eine Uebersicht ueber Befunde und klinische Indikationen zur Dopamin-D{sub 2}-Rezeptorszintigraphie. Methoden zur Untersuchung der D{sub 2}-Rezeptoren sind die Positronen-Emissions-Tomographie (PET) mit {sup 11}C- oder {sup 18}F-markierten Butyrophenonen oder Benzamiden oder die Einzelphotonen-Emissions-Tomographie (SPECT) mit {sup 123}I

  14. The carcinogenicity of certain derivatives of p-dimethylaminozobenz in the rat.

    Science.gov (United States)

    MILLER, J A; MILLER, E C

    1948-02-01

    , since the 3'-nitro derivative was incompletely absorbed its real activity appears to be about 1(1/2) times that of 4-dimethylaminoazobenzene. 2'-Nitro- and 2'-chloro-4-dimethylaminoazobenzene were about one-half to one-third as active and 4'-chloro-4-dimethylaminoazobenzene was approximately one-fourth as active as the parent dye. 3'-Ethoxy-4-dimethylaminoazobenzene and 3-methyl-4-monomethylaminoazobenzene exhibited only slight carcinogenic activity. The following compounds proved inactive: the benzamide of N,N-dimethyl-p-phenylenediamine; the diethyl, monoethyl, benzylmethyl, beta-hydroxyethylmethyl, and formyl derivatives of 4-aminoazobenzene on the amino group; and the 3-methyl, 3', 5'-dimethyl, 2',5'-dimethyl, and 2',4'-dimethyl derivatives of 4-dimethylaminoazobenzene. From the available data two conditions appear to be essential if a dye is to possess high activity: (1) at least one methyl group must be attached to the amino group together with the proper second substituent, and (2) the rings must bear either no substituents or carry only certain substituents, preferably in the 3' position. 3. The data on the carcinogenicity of the 2'-, 3'-, or 4'-methyl, chloro, and nitro derivatives of 4-dimethylaminoazobenzene show that the position of these groups determines the carcinogenicity of these compounds to a greater extent than does the type of group. The activity relationship was 3' > 2' > 4'. 4. Primary, secondary, and tertiary aminoazo dyes were determined in the livers and blood of rats fed aminoazo dyes which differed in the substituents on the amino group. The data show that deethylation of 4-diethyl-, 4-monoethyl-, and 4-ethylmethylaminoazobenzene occurs in vivo just as 4-dimethyl- and 4-monomethylaminoazobenzene are demethylated in vivo. However, 4-benzylmethylaminoazobenzene and 4-beta-hydroxyethylmethylaminoazobenzene were dealkylated only slightly under similar conditions. 5. The following new compounds are described: 4-ethylmethyl-, 4-monoethyl-, 4

  15. 一株除草剂氰氟草酯降解菌的分离鉴定与降解特性%Isolation of a Cyhalofop-butyl-degrading Bacterium and Its Degradation Characteristics

    Institute of Scientific and Technical Information of China (English)

    聂志娟; 顾谢军; 蔡舒; 谢香婷; 何健; 郑金伟; 李顺鹏

    2011-01-01

    Stenotrophomonas sp. The degradation rate was about 88.2% when the strain with an inoculum size of 5% (V/V) was incubated at the concentration of 100 mg/L cyhalofop-butyl for 5 d. And large initial inoculum size could promote the degradation in the range of 5%. The optimal pH and temperature for cyhalofop-butyl degradation were 7.0 and 30 ℃, respectively. Three metabolites of cyhalofop-butyl degradation by strain QDZ-B were identified as cyhalofop acid, cyhalofop amide and 2-fluoro-(3-p-ethoxy-phenoxy) benzamide by HPLC/MS analysis. Fig 11, Ref 21

  16. 查尔酮类似化合物的合成及其抑菌活性研究%Study on Synthesis and Antifungal Activity of Chalcone Analogues

    Institute of Scientific and Technical Information of China (English)

    田珈源; 罗青春; 梁华忠; 谌晓洪

    2011-01-01

    [目的]合成查尔酮类似化合物,并研究其抑菌活性,以寻找高效、安全的抑菌活性化合物.[方法]以苯甲酰氯类化合物和胺类化合物为原料,通过酰氯的胺解反应设计并合成了16种查尔酮类似化合物,对其分子结构经红外光谱(IR)和氢核磁共振波谱(1H NMR)进行确认.[结果]该类化合物具有一定的抑菌活性,当浓度为100 mg/L时,化合物A2(2-氯-N-苯基苯甲酰胺)对水稻纹枯病(Rhizoctonia solani)和油菜菌核病菌(Sclerotiua sclerotiorum的抑制率分别达90.27%和92.56%.[结论]产物A2为查尔酮的类似化合物,且属于天然产物,在自然界中能够自然降解,不会引起环境污染;而且其化学结构简单,人工合成也比较容易,可以以此为先导化合物对其结构进行优化和改造;研究其结构和活性之间的关系,开发出高效、低毒、对非靶标生物安全的新型抑菌剂.%[Objective] To synthesize chalcone analogues and study their antifungal activity so as to find high-efficient and safe compounds with antifungal activity. [Method] With benzoyl chloride compounds and amines as the materials, 16 chalcone analogues were designed and synthe sized through the aminolysis reaction of acyl chloride, and their molecular structures were determined by IR and ' H NMR. [ Result ] The chal cone analogues had certain antifungal activity. The antifungal rate of 100 mg/L compound A2 (2-chloro-N-phenyl benzamide) against Rhizoctonia solani and Sclerotiua sclerotiorum reached 90. 27% and 92.56% , respectively. [Conclusion] Product A2 was an analogue of the natural product chalcone that could naturally degrade without causing environmental pollution. What's more, its chemical structure was simple and easy to pre pare. Using A2 as a lead compound, new high-efficient and low-toxic antifungal agents which were safe to the non-target organisms could be de veloped through optimizing its chemical structure and studying the relationship

  17. Clinical study of dopamine transporter imaging with 131I-epidepride for Parkinson's disease%多巴胺D2受体乃131I-epidepride显像对帕金森病的临床研究

    Institute of Scientific and Technical Information of China (English)

    武婕; 王峰; 杨敏; 王自正; 孟庆乐; 过燕萍

    2008-01-01

    Objective Epidepride is a novel benzamide derivative with high affinity for dopaminergic D2 receptors.It has been used to study striatal and extrastriatal D2 receptor abnormalities in humans.The aim of this study was to evaluate the level of D2 receptors in dopaminergic nitrostriatal pathway and its correlation with clinical severity in Parkinson's disease(PD).Methods Thirty-eight patients with idio-pathic PD[graded according to Hoehn and Yahr(H/Y)stage:n(Ⅰ)=13,n(Ⅱ)=11,n(Ⅲ)=8,n(Ⅳ)=6]and 12 healthy volunteers as control were included in this study.SPECT brain imaging was performed 3 h after 18.5 MBq 131I-epidepride administration.Regions of interest(ROIs)were drawn over the striatum(ST)and occipital cortex(OC).The ratios of ST to OC ROI counts(ST/OC)were calculated and correlated with clinical severity H/Y stage.SPSS 10.0 was used for data analysis,the t test and Spearman correlation analysis were used.Results ST showed intense uptake of 131I-epidepride,whereas frontal,parietal,temporal,occipital lobes and cerebellum showed low uptake in control group.Increased 131I-epide-pride uptake was observed in PD patients when compared with normal control group but without statistically significant difference.Early stage patients(hemi-PD with H/Y I)showed increased [131]I-epidepride uptake intensity and size in contralateral ST(especially caudate nucleus)significantly more than unilateral ST(t=7.89.P<0.05).ST/OC ratio was not found to be statistically significant when correlated with the clinical severity H/Y stage(r=0.1 2,P>0.05).Conclusions This study suggested that 131I-epidepride SPECT was useful in qualitative and quantitative evaluation of D2 receptor status in dopaminergic nigrostriatal neurons,which were over-expressed in PD patients.However,no statistically significant correlation was,found between ST 131I-epidepride binding ratios and disease severity.%目的 评价多巴胺D2受体显像剂131I-(s)-(-)-N-[(1-乙基-2-吡咯烷基)甲基]-5-碘-2,3-二