5-Chloro-5′′-[4-(dimethylaminobenzylidene]-4′-[4-(dimethylaminophenyl]-1′,1′′-dimethyldispiro[indoline-3,2′-pyrrolidine-3′,3′′-piperidine]-2,4′′-dione

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I. S. Ahmed Farag

2014-01-01

Full Text Available The title compound, C34H38ClN5O2, has spiro links connecting the pyrrolidine ring and indole residue, as well as the piperidine and pyrrolidine rings. A half-chair conformation is found for the piperidine ring with the C atom connected to the spiro-C atom lying 0.738 (4 Å out of the plane of the remaining five atoms (r.m.s. deviation = 0.0407 Å. The methylene C atom is the flap in the envelope conformation for the pyrrolidine ring. In the crystal, supramolecular chains are sustained by alternating eight-membered {...HNCO}2 and 14-membered {...HC5O}2 synthons. Chains are connected into a three-dimensional network by (pyrrolidine-bound phenyl-methylC—H...π(pyrrolidine-bound phenyl edge-to-face interactions.

Facile access to unnatural dipeptide-alcohols based on cis-2,5-disubstituted pyrrolidines.

Science.gov (United States)

Jia, Yan-Yan; Li, Xiao-Ye; Wang, Ping-An; Wen, Ai-Dong

2015-02-11

Well-defined unnatural dipeptide-alcohols based on a cis-2,5-disubstitued pyrrolidine backbone were synthesized from commercially available starting materials meso-diethyl-2,5-dibromoadipate, (S)-(-)-1-phenylethylamine, and phenylalaninol. The structures of these unnatural dipeptide-alcohols are supported by HRMS, 1H- and 13C-NMR spectroscopy. These unnatural dipeptide-alcohols can act as building blocks for peptidomimetics.

Synthesis and biological evaluation of pyrrolidine derivatives as novel and potent sodium channel blockers for the treatment of ischemic stroke.

Science.gov (United States)

Seki, Maki; Tsuruta, Osamu; Tatsumi, Ryo; Soejima, Aki

2013-07-15

A novel series of pyrrolidine derivatives as Na(+) channel blockers was synthesized and evaluated for their inhibitory effects on neuronal Na(+) channels. Structure-activity relationship (SAR) studies of a pyrrolidine analogue 2 led to the discovery of 5e as a potent Na(+) channel blocker with a low inhibitory action against human ether-a-go-go-related gene (hERG) channels. Compound 5e showed remarkably neuroprotective activity in a rat transient middle cerebral artery occlusion (MCAO) model, suggesting that 5e would act as a neuroprotectant for ischemic stroke. Copyright © 2013 Elsevier Ltd. All rights reserved.

Practical Synthesis of Pachastrissamine (Jaspine B), 2-epi-Pachastrissamine, and the 2-epi-Pyrrolidine Analogue.

Science.gov (United States)

Fujiwara, Tomoya; Liu, Bo; Niu, Wenqi; Hashimoto, Kazuki; Nambu, Hisanori; Yakura, Takayuki

2016-01-01

The practical syntheses of pachastrissamine (jaspine B), 2-epi-pachastrissamine, and the 2-epimer of the pyrrolidine analogue were accomplished via the stereoselective reduction of an allylketone derived from commercially available diethyl D-tartrate and the cross-metathesis of an allyltetrahydrofuran or allypyrrolidine with 1-tridecene as key steps.

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

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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.

N,3,4-Trisubstituted pyrrolidines by electron transfer-induced oxidative cyclizations of N-allylic beta-amino ester enolates

Czech Academy of Sciences Publication Activity Database

Jahn, Ullrich; Kafka, František; Pohl, Radek; Jones, P.G.

2009-01-01

Roč. 65, č. 52 (2009), s. 10917-10929 ISSN 0040-4020 Institutional research plan: CEZ:AV0Z40550506 Keywords : electron transfer * pyrrolidines * oxidation Subject RIV: CC - Organic Chemistry Impact factor: 3.219, year: 2009

Crystal structure of methyl 3′-benzamido-4′-(4-methoxyphenyl-1′-methylspiro[indeno[1,2-b]quinoxaline-11,2′-pyrrolidine]-3′-carboxylate

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Kuppan Chandralekha

2016-09-01

Full Text Available In the title compound, C35H30N4O3, the spiro C atom connects the five-membered pyrrolidine ring and the indenoquinoxaline ring system. The pyrrolidine ring adopts a twist conformation. An intramolecular N—H...N interaction between the amino group and the pyrazine ring is observed. In the crystal, molecules are linked by a pairs of C—H...O hydrogen bonds, forming inversion dimers.

Theoretical and NMR conformational studies of β-proline oligopeptides with alternating chirality of pyrrolidine units

Science.gov (United States)

Mantsyzov, Alexey B.; Savelyev, Oleg Y.; Ivantcova, Polina M.; Bräse, Stefan; Kudryavtsev, Konstantin V.; Polshakov, Vladimir I.

2018-03-01

Synthetic β-peptides are potential functional mimetics of native α-proteins. A recently developed, novel, synthetic approach provides an effective route to the broad group of β-proline oligomers with alternating patterns of stereogenic centers. Conformation of the pyrrolidine ring, Z/E isomerism of β-peptide bonds, and hindered rotation of the neighboring monomers determine the spatial structure of this group of β-proline oligopeptides. Preferences in structural organization and corresponding thermodynamic properties are determined by NMR spectroscopy, restrained molecular dynamics and quantum mechanics. The studied β-proline oligopeptides exist in dimethyl sulfoxide solution in a limited number of conformers, with compatible energy of formation and different spatial organization. In the β-proline tetrapeptide with alternating chirality of composing pyrrolidine units, one of three peptide bonds may exist in an E configuration. For the alternating β-proline pentapeptide, the presence of an E configuration for at least of one β-peptide bond is mandatory. In this case, three peptide bonds synchronously change their configurations. Larger polypeptides may only exist in the presence of several E configurations of β-peptide bonds forming a wave-like extended structure.

Theoretical and NMR Conformational Studies of β-Proline Oligopeptides With Alternating Chirality of Pyrrolidine Units

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Alexey B. Mantsyzov

2018-03-01

Full Text Available Synthetic β-peptides are potential functional mimetics of native α-proteins. A recently developed, novel, synthetic approach provides an effective route to the broad group of β-proline oligomers with alternating patterns of stereogenic centers. Conformation of the pyrrolidine ring, Z/E isomerism of β-peptide bonds, and hindered rotation of the neighboring monomers determine the spatial structure of this group of β-proline oligopeptides. Preferences in their structural organization and corresponding thermodynamic properties are determined by NMR spectroscopy, restrained molecular dynamics and quantum mechanics. The studied β-proline oligopeptides exist in dimethyl sulfoxide solution in a limited number of conformers, with compatible energy of formation and different spatial organization. In the β-proline tetrapeptide with alternating chirality of composing pyrrolidine units, one of three peptide bonds may exist in an E configuration. For the alternating β-proline pentapeptide, the presence of an E configuration for at least of one β-peptide bond is mandatory. In this case, three peptide bonds synchronously change their configurations. Larger polypeptides may only exist in the presence of several E configurations of β-peptide bonds forming a wave-like extended structure.

Diastereomerically and enantiomerically pure 2,3-disubstituted pyrrolidines from 2,3-aziridin-1-ols using a sulfoxonium ylide: a one-carbon homologative relay ring expansion.

Science.gov (United States)

Schomaker, Jennifer M; Bhattacharjee, Somnath; Yan, Jun; Borhan, Babak

2007-02-21

An ylide-based aza-Payne rearrangement of 2,3-aziridin-1-ols leads to an efficient process for the preparation of pyrrolidines. The aza-Payne rearrangement under basic reaction conditions favors the formation of epoxy amines. Subsequent nucleophilic attack of the epoxide by the ylide yields a bis-anion, which upon a 5-exo-tet ring-closure yields the desired pyrrolidine, thus completing the relay of the three-membered to the five-membered nitrogen-containing ring system. This process takes place with complete transfer of stereochemical fidelity and can be applied to sterically hindered aziridinols.

Synthesis of a drug-like focused library of trisubstituted pyrrolidines using integrated flow chemistry and batch methods.

Science.gov (United States)

Baumann, Marcus; Baxendale, Ian R; Kuratli, Christoph; Ley, Steven V; Martin, Rainer E; Schneider, Josef

2011-07-11

A combination of flow and batch chemistries has been successfully applied to the assembly of a series of trisubstituted drug-like pyrrolidines. This study demonstrates the efficient preparation of a focused library of these pharmaceutically important structures using microreactor technologies, as well as classical parallel synthesis techniques, and thus exemplifies the impact of integrating innovative enabling tools within the drug discovery process.

1-Benzyl-3′-[(1H-indol-3-ylcarbonyl]-1′-methyl-2-oxo-4′-(pyridin-3-ylspiro[indoline-3,2′-pyrrolidine]-3′-carbonitrile

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P. Seethalakshmi

2016-11-01

Full Text Available In the title compound, C34H27N5O2, the central pyrrolidine ring adopts an envelope conformation, with the N atom as the flap. The mean planes of the two indoline ring systems are inclined to the mean plane of the central pyrrolidine ring by 86.26 (9 and 69.30 (9°, respectively. The dihedral angle between the benzene and pyridine rings is 75.09 (11°. In the crystal, molecules are linked by N—H...N and C—H...N hydrogen bonds, forming sheets parallel to the ab plane.

Ethyl 3-hydroxy-13-methyl-4′-phenyl-2′-(3,4,5-trimethoxyphenyl-6,7,8,9,11,12,13,14,15,16-decahydrospiro[cyclopenta[a]phenanthrene-16,3′-pyrrolidine]-5′-carboxylate

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R. Murugan

2008-11-01

Full Text Available In the title compound, C39H45NO7,the pyrrolidine ring is connected to an estrone group, a trimethoxy benzene and a phenyl ring. The pyrrolidine ring exhibits a twist conformation and the other five-membered ring an envelope conformation. Molecules are linked by N—H...O hydrogen bonds, C—H...π interactions and C—H...O hydrogen bonds.

Ligand-Enabled γ-C(sp(3))-H Olefination of Amines: En Route to Pyrrolidines.

Science.gov (United States)

Jiang, Heng; He, Jian; Liu, Tao; Yu, Jin-Quan

2016-02-17

Pd(II)-catalyzed olefination of γ-C(sp(3))-H bonds of triflyl (Tf) and 4-nitrobenzenesulfonyl (Ns) protected amines is achieved. Subsequent aza-Wacker oxidative cyclization or conjugate addition of the olefinated intermediates provides a variety of C-2 alkylated pyrrolidines. Three pyridine- and quinoline-based ligands are developed to match different classes of amine substrates, demonstrating a rare example of ligand-enabled C(sp(3))-H olefination reactions. The use of Ns protecting group to direct C(sp(3))-H activation of alkyl amines is also a significant step toward practical C-H functionalizations of alkyl amines.

Design and synthesis of new of 3-(benzo[d]isoxazol-3-yl)-1-substituted pyrrolidine-2, 5-dione derivatives as anticonvulsants.

Science.gov (United States)

Malik, Sachin; Ahuja, Priya; Sahu, Kapendra; Khan, Suroor Ahmad

2014-09-12

A series of 3-(benzo[d]isoxazol-3-yl)-N-substituted pyrrolidine-2, 5-dione (7a-7d, 8a-8d, 9a-9c) have been prepared and evaluated for their anticonvulsant activities. Preliminary anticonvulsant activity was performed using maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) tests after intraperitoneal (ip) injection into mice, which are the most widely employed models for early identification of anticonvulsant candidate. The acute neurological toxicity (NT) was determined applying rotorod test. The quantitative evaluation after oral administration in rats showed that the most active was 3-(benzo[d]isoxazol-3-yl)-1-(4-fluorophenyl) pyrrolidine-2, 5-dione (8a) with ED50 values of 14.90 mg/kg. Similarly the most potent in scPTZ was 3-(benzo[d]isoxazol-3-yl)-1-cyclohexylpyrrolidine-2, 5-dione (7d) with ED50 values of 42.30 mg/kg. These molecules were more potent and less neurotoxic than phenytoin and ethosuximide which were used as reference antiepileptic drugs. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Structure-Activity Relationship Study of Ionotropic Glutamate Receptor Antagonist (2S,3R)-3-(3-Carboxyphenyl)pyrrolidine-2-carboxylic Acid

DEFF Research Database (Denmark)

Krogsgaard-Larsen, Niels; Storgaard, Morten; Møller, Charlotte

2015-01-01

Herein we describe the first structure-activity relationship study of the broad-range iGluR antagonist (2S,3R)-3-(3-carboxyphenyl)pyrrolidine-2-carboxylic acid (1) by exploring the pharmacological effect of substituents in the 4, 4', or 5' positions and the bioisosteric substitution of the distal...... carboxylic acid for a phosphonic acid moiety. Of particular interest is a hydroxyl group in the 4' position 2a which induced a preference in binding affinity for homomeric GluK3 over GluK1 (Ki = 0.87 and 4.8 μM, respectively). Two X-ray structures of ligand binding domains were obtained: 2e in GluA2-LBD...... and 2f in GluK1-LBD, both at 1.9 Å resolution. Compound 2e induces a D1-D2 domain opening in GluA2-LBD of 17.3-18.8° and 2f a domain opening in GluK1-LBD of 17.0-17.5° relative to the structures with glutamate. The pyrrolidine-2-carboxylate moiety of 2e and 2f shows a similar binding mode as kainate...

Crystal structure of 1-[(2S*,4R*-6-fluoro-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]pyrrolidin-2-one

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P. S. Pradeep

2014-09-01

Full Text Available In the title compound, C14H17FN2O, the 1,2,3,4-tetrahydropyridine ring of the quinoline moiety adopts a half-chair conformation, while the pyrrolidine ring has an envelope conformation with the central methylene C atom as the flap. The pyrrolidine ring lies in the equatorial plane and its mean plane is normal to the mean plane of the quinoline ring system, with a dihedral angle value of 88.37 (9°. The bridging N—C bond distance [1.349 (3 Å] is substantially shorter than the sum of the covalent radii (dcov: C—N = 1.47 Å and C=N = 1.27 Å, which indicates partial double-bond character for this bond, resulting in a certain degree of charge delocalization. In the crystal, molecules are linked by N—H...O and C—H...O hydrogen bonds, forming sheets lying parallel to (10-1. These two-dimensional networks are linked via C—H...F hydrogen bonds and C—H...π interactions, forming a three-dimensional structure.

Ligand-Enabled γ-C(sp3)–H Olefination of Amines: En Route to Pyrrolidines

Science.gov (United States)

Jiang, Heng; He, Jian; Liu, Tao

2016-01-01

Pd(II)-catalyzed olefination of γ-C(sp3)–H bonds of triflyl (Tf) and 4-nitrobenzenesulfonyl (Ns) protected amines is achieved. Subsequent aza-Wacker oxidative cyclization or conjugate addition of the olefinated intermediates provides a variety of C-2 alkylated pyrrolidines. Three pyridine- and quinoline-based ligands are developed to match different classes of amine substrates, demonstrating a rare example of ligand-enabled C(sp3)–H olefination reaction. The use of Ns protecting group to direct C(sp3)–H activation of alkyl amine is also a significant step towards practical C–H functionalizations of alkyl amines. PMID:26796676

Time-resolved fluorescence study of exciplex formation in diastereomeric naproxen-pyrrolidine dyads.

Science.gov (United States)

Khramtsova, Ekaterina A; Plyusnin, Viktor F; Magin, Ilya M; Kruppa, Alexander I; Polyakov, Nikolay E; Leshina, Tatyana V; Nuin, Edurne; Marin, M Luisa; Miranda, Miguel A

2013-12-19

The influence of chirality on the elementary processes triggered by excitation of the (S,S)- and (R,S)- diastereoisomers of naproxen-pyrrolidine (NPX-Pyr) dyads has been studied by time-resolved fluorescence in acetonitrile-benzene mixtures. In these systems, the quenching of the (1)NPX*-Pyr singlet excited state occurs through electron transfer and exciplex formation. Fluorescence lifetimes and quantum yields revealed a significant difference (around 20%) between the (S,S)- and (R,S)- diastereomers. In addition, the quantum yields of exciplexes differed by a factor of 2 regardless of solvent polarity. This allows us to suggest a similar influence of the chiral centers on the local charge transfer resulting in exciplex and full charge separation that leads to ion-biradicals. A simplified scheme is proposed to estimate a set of rate constant values (k1-k5) for the elementary stages in each solvent system.

Evaluation of the influence of proline, hydroxyproline or pyrrolidine in the presence of sodium nitrite on N-nitrosamine formation when heating cured meat.

Science.gov (United States)

Drabik-Markiewicz, G; Dejaegher, B; De Mey, E; Impens, S; Kowalska, T; Paelinck, H; Vander Heyden, Y

2010-01-11

N-nitrosamines are meant to be probable or possible carcinogenic components, possibly formed out of a reaction between nitrite and N-containing substances such as amino acids and secondary amines. Nitrite is often used for processing meat products because of its colouring and antimicrobial properties. During this experimental setup, the influence of proline, hydroxyproline or pyrrolidine on N-nitrosamine formation in meat samples was evaluated. The N-nitrosamines concentrations were measured with gas chromatography-thermal energy analyzer. Only the concentrations of N-nitrosodimethylamine and N-nitrosopyrrolidine were found above the limit of detection in a number of tested experimental conditions. The concentration of these two N-nitrosamines was modelled as a function of temperature and nitrite concentration for different situations (presence or absence of added natural N-containing meat components). It could be concluded that proline and pyrrolidine promoted the formation of N-nitrosopyrrolidine. It could also be confirmed that the higher the temperature of the meat processing procedure and the higher the sodium nitrite amounts added, the higher were the yields of the respective N-nitrosamines.

Preconcentration of metallic elements by complexation with ammonium pyrrolidine dithiocarbamate (APDC) for atomic absorption analysis

International Nuclear Information System (INIS)

Santos Coelho, Ricardo dos; Dantas, Elizabeth S.K.

1997-01-01

Ammonium pyrrolidine dithiocarbamate (APDC) forms stable chelates with many metals being therefore, used in systems of preconcentration for determination of heavy metals in water. In this work, the metals were complexed with APDC and extracted with methyl isobutyl ketone (MIBK). The results showed that the studied metals (Co, Cu, Fe, Ni, Pb, Cr and Cd), in the range of 2 to 5 μg, in 100 ml of sample, were quantitatively extracted in only one stage using 10 ml of MIBK and 5 ml of 4% APDC. The pH must be between 4 and 5. The complexes stability was also studied. The proposed method can be applied to pre concentrate heavy metals in natural waters. (author). 4 refs., 1 fig., 3 tabs

Determination of Acid Dissociation Constants (pKa) of Bicyclic Thiohydantoin-Pyrrolidine Compounds in 20% Ethanol-Water Hydroorganic Solvent

Science.gov (United States)

Nural, Yahya; Döndaş, H. Ali; Sarı, Hayati; Atabey, Hasan; Belveren, Samet; Gemili, Müge

2014-01-01

The acid dissociation constants of potential bioactive fused ring thiohydantoin-pyrrolidine compounds were determined by potentiometric titration in 20% (v/v) ethanol-water mixed at 25 ± 0.1°C, at an ionic background of 0.1 mol/L of NaCl using the HYPERQUAD computer program. Proton affinities of potential donor atoms of the ligands were calculated by AM1 and PM3 semiempiric methods. We found, potentiometrically, three different acid dissociation constants for 1a–f. We suggest that these acid dissociation constants are related to the carboxyl, enol, and amino groups. PMID:24799905

Impact of pyrrolidine-bispyrrole DNA minor groove binding agents and chirality on global proteomic profile in Escherichia Coli.

Science.gov (United States)

Yang, Ya-Ting; Lin, Chun-Yu; Jeng, Jingyueh; Ong, Chi-Wi

2013-05-23

There is great interest in the design of small molecules that selectively target minor grooves of duplex DNA for controlling specific gene expression implicated in a disease. The design of chiral small molecules for rational drug design has attracted increasing attention due to the chirality of DNA. Yet, there is limited research on the chirality effect of minor groove binders on DNA interaction, especially at the protein expression level. This paper is an attempt to illustrate that DNA binding affinity might not provide a full picture on the biological activities. Drug interacting at the genomic level can be translated to the proteomic level. Here we have illustrated that although the chiral bispyrrole-pyrrolidine-oligoamides, PySSPy and PyRSPy, showed low binding affinity to DNA, their influence at the proteomic level is significant. More importantly, the chirality also plays a role. Two-dimensional proteomic profile to identify the differentially expressed protein in Escherichia coli DH5α (E coli DH5α) were investigated. E coli DH5α incubated with the chiral PySSPy and PyRSPy, diastereomeric at the pyrrolidine ring, showed differential expression of eighteen proteins as observed through two dimensional proteomic profiling. These eighteen proteins identified by MALDI_TOF/TOF MS include antioxidant defense, DNA protection, protein synthesis, chaperone, and stress response proteins. No statistically significant toxicity was observed at the tested drug concentrations as measured via MTT assay. The current results showed that the chiral PySSPy and PyRSPy impact on the proteomic profiling of E coli DH5α, implicating the importance of drug chirality on biological activities at the molecular level.

3,3,4,4-Tetrafluoro-1-[2-(3,3,4,4-tetrafluoropyrrolidin-1-ylphenyl]pyrrolidine

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Jin Wang

2011-09-01

Full Text Available The asymmetric unit of the title compound, C14H12F8N2, contains one tetrafluoropyrrolidine system and one half-molecule of benzene; the latter, together with a second heterocyclic unit, are completed by symmetry, with a twofold crystallographic axis crossing through both the middle of the bond between the C atoms bearing the heterocyclic rings and the opposite C—C bonds of the whole benzene molecule. The pyrrolidine ring shows an envelope conformation with the apex at the N atom. The dihedral angle between the least-squares plane of this ring and the benzene ring is 36.9 (5°. There are intramolecular C—H...N interactions generating S(6 ring motifs. In the crystal structure, the molecules are linked by C—H...F interactions, forming chains parallel to [010].

N-methyl-3-pyrrolidines preparation by means of [3+2] dipoles cycloaddition reactions; Preparacion de N-metil-3-arilpirrolidinas mediante reacciones de cicloadicion dipolares [3+2

Energy Technology Data Exchange (ETDEWEB)

Negron, Guillermo [Universidad Autonoma Metropolitana-Azcapotzalco, Mexico, D.F. (Mexico); Fuentes, Aydee; Romero, Moises [Universidad Autonoma del Estado de Mexico, Toluca, Estado de Mexico (Mexico); Madrid, Gustavo; Cruz, Raymundo [Universidad Nacional Autonoma de Mexico, Mexico, D.F. (Mexico)

1999-08-01

The [3+2] cycloaddition reaction between azomethine ylide generated by deprotonation of trimethylamine N-oxide with LDA and various {alpha}-asarone derivatives to afford the corresponding pyrrolidines is described. [Spanish] Las reacciones de cicloadicion [3+2] entre iluros de azometino generados por accion del LDA sobre el N-oxido de trimetilamina y varios derivados de la {alpha}-asarona, permite la obtencion de las pirrolidinas correspondientes.

A new class of potential chloroquine-resistance reversal agents for Plasmodia: syntheses and biological evaluation of 1-(3'-diethylaminopropyl)-3-(substituted phenylmethylene)pyrrolidines.

Science.gov (United States)

Batra, S; Srivastava, P; Roy, K; Pandey, V C; Bhaduri, A P

2000-09-07

1-(3'-Diethylaminopropyl)-3-(substituted phenylmethylene)pyrrolidines were synthesized and evaluated for CQ-resistant reversal activity. In general the compounds of the series elicit better biological response than their phenylmethyl analogues. The most active compound 4b has been evaluated in vivo in detail, and the results are presented. The possible mode of action of the compounds of this series is by inhibition of the enzyme heme oxygenase, thereby increasing the levels of heme and hemozoin, which are lethal to the parasite.

Ethyl 4′-ethenyl-2′-oxo-4-phenyl-2-(3,4,5-trimethoxyphenylspiro[pyrrolidine-3,3′-indoline]-5-carboxylate monohydrate

Directory of Open Access Journals (Sweden)

P. Ramesh

2008-11-01

Full Text Available In the title compound, C31H32N2O6·H2O, the pyrrolidine ring adopts an envelope conformation. The ethyl C atoms of the ethoxycabonyl group are disordered over two positions with occupancies of ca 0.80 and 0.20. Intramolecular N—H...O hydrogen bonds form S(5 and S(6 ring motifs. Molecules are linked into a three-dimensional framework by O—H...O, N—H...O and C—H...O hydrogen bonds, and by C—H...π interactions.

Pyrrolidine dithiocarbamate activates the Nrf2 pathway in astrocytes.

Science.gov (United States)

Liddell, Jeffrey R; Lehtonen, Sarka; Duncan, Clare; Keksa-Goldsteine, Velta; Levonen, Anna-Liisa; Goldsteins, Gundars; Malm, Tarja; White, Anthony R; Koistinaho, Jari; Kanninen, Katja M

2016-02-26

Endogenous defense against oxidative stress is controlled by nuclear factor erythroid 2-related factor 2 (Nrf2). The normal compensatory mechanisms to combat oxidative stress appear to be insufficient to protect against the prolonged exposure to reactive oxygen species during disease. Counterbalancing the effects of oxidative stress by up-regulation of Nrf2 signaling has been shown to be effective in various disease models where oxidative stress is implicated, including Alzheimer's disease. Stimulation of Nrf2 signaling by small-molecule activators is an appealing strategy to up-regulate the endogenous defense mechanisms of cells. Here, we investigate Nrf2 induction by the metal chelator and known nuclear factor-κB inhibitor pyrrolidine dithiocarbamate (PDTC) in cultured astrocytes and neurons, and mouse brain. Nrf2 induction is further examined in cultures co-treated with PDTC and kinase inhibitors or amyloid-beta, and in Nrf2-deficient cultures. We show that PDTC is a potent inducer of Nrf2 signaling specifically in astrocytes and demonstrate the critical role of Nrf2 in PDTC-mediated protection against oxidative stress. This induction appears to be regulated by both Keap1 and glycogen synthase kinase 3β. Furthermore, the presence of amyloid-beta magnifies PDTC-mediated induction of endogenous protective mechanisms, therefore suggesting that PDTC may be an effective Nrf2 inducer in the context of Alzheimer's disease. Finally, we show that PDTC increases brain copper content and glial expression of heme oxygenase-1, and decreases lipid peroxidation in vivo, promoting a more antioxidative environment. PDTC activates Nrf2 and its antioxidative targets in astrocytes but not neurons. These effects may contribute to the neuroprotection observed for PDTC in models of Alzheimer's disease.

Syntheses and study of pyrrolidinic nitroxide free radicals. Preparation of a nitroxide-type stable bi-radical; Synthese et etudes de radicaux libres nitroxydes pyrrolidiniques. Preparation d'un biradical stable du type nitroxyde

Energy Technology Data Exchange (ETDEWEB)

Dupeyre, R M [Commissariat a l' Energie Atomique, Grenoble (France). Centre d' Etudes Nucleaires, Laboratoire de chimie organique physique

1967-12-01

Syntheses and study of pyrrolidinic nitroxide free radicals: These radicals are obtained by oxidation, with hydrogen peroxide, of pyrrolidinic amines prepared from triacetonamine by ring contraction. The U. V,, I. R, and E.P.R. spectral characteristics have been determined. The oxidation of these amines with hydrogen peroxide has led also to rupture of the pentagonal ring; some of the decomposition products have been identified. The high chemical stability of the nitroxide group has made it possible to synthesize and study a stable bi-radical. (author) [French] Syntheses et etudes de radicaux libres nitroxydes pyrrolidiniques: Ces radicaux sont obtenus par oxydation l'eau oxygenee d'amines pyrrolidiniques preparees a partir de la triacetonamine par contraction de cycle. Les caracteristiques spectroscopiques ultra-violettes, infra-rouge et resonance paramagnetique sont determinees. Cependant, 1'oxydation de ces amines a l'eau oxygenee a entraine la coupure du cycle pentagonal et identification de certaines substances de decomposition obtenues. La grande stabilite chimique de groupement nitroxyde a permis la synthese et l'etude d'un biradical stable. (auteur)

Protective effects of the nuclear factor kappa B inhibitor pyrrolidine dithiocarbamate in bladder ischemia-reperfusion injury in rats.

Science.gov (United States)

Yucel, Mehmet; Kucuk, Aysegul; Bayraktar, Aslihan Cavunt; Tosun, Murat; Yalcinkaya, Soner; Hatipoglu, Namik Kemal; Erkasap, Nilufer; Kavutcu, Mustafa

2013-10-01

The aim of the present study was to evaluate the protective effects of the NF-кB inhibition with pyrrolidine-dithiocarbamate (PDTC) in ischemia-reperfusion (I/R) injury in the rat bladder. Twenty-four Sprague-Dawley male rats were divided into three groups. Group I; (n = 8) control, group II; (n = 8) I/R group; group III (n = 8) I/R and PDTC treatment. Superoxide dismutase (SOD), catalase (CAT), and gluatathione-S-transferase (GST) enzymes was studied in bladder tissue. Lipid peroxidation (as TBARS) levels in tissue homogenate were measured with thiobarbituric acid reaction. All the slides were stained with NF-кB, p53 and HSP60 immunohistochemistry for detection genome destruction and tissue stress, respectively. Our results show that the mean TBARS levels were significantly higher in group II (p effects on ischemia/reperfusion stress related bladder tissue destruction.

Discovery of a New Class of Ionotropic Glutamate Receptor Antagonists by the Rational Design of (2S,3R)-3-(3-Carboxyphenyl)-pyrrolidine-2-carboxylic Acid

DEFF Research Database (Denmark)

Larsen, Ann Møller; Venskutonyte, Raminta; Valadés, Elena Antón

2011-01-01

The kainic acid (KA) receptors belong to the class of glutamate (Glu) receptors in the brain and constitute a promising target for the treatment of neurological and/ or psychiatric diseases such as schizophrenia, major depression, and epilepsy. Five KA subtypes have been identified and named GluK1......-5. In this article, we present the discovery of (2S,3R)-3-(3-carboxyphenyl)-pyrrolidine-2-carboxylic acid (1) based on a rational design process. Target compound 1 was synthesized by a stereoselective strategy in 10 steps from commercially available starting materials. Binding affinities of 1 at native ionotropic...

Pyrrolidine Dithiocarbamate (PDTC Attenuates Cancer Cachexia by Affecting Muscle Atrophy and Fat Lipolysis

Directory of Open Access Journals (Sweden)

Chunxiao Miao

2017-12-01

Full Text Available Cancer cachexia is a kind of whole body metabolic disorder syndrome accompanied with severe wasting of muscle and adipose tissue. NF-κB signaling plays an important role during skeletal muscle atrophy and fat lipolysis. As an inhibitor of NF-κB signaling, Pyrrolidine dithiocarbamate (PDTC was reported to relieve cancer cachexia; however, its mechanism remains largely unknown. In our study, we showed that PDTC attenuated cancer cachexia symptom in C26 tumor bearing mice models in vivo without influencing tumor volume. What’s more, PDTC inhibited muscle atrophy and lipolysis in cells models in vitro induced by TNFα and C26 tumor medium. PDTC suppressed atrophy of myotubes differentiated from C2C12 by reducing MyoD and upregulating MuRF1, and preserving the expression of perilipin as well as blocking the activation of HSL in 3T3-L1 mature adipocytes. Meaningfully, we observed that PDTC also inhibited p38 MAPK signaling besides the NF-κB signaling in cancer cachexia in vitro models. In addition, PDTC also influenced the protein synthesis of skeletal muscle by activating AKT signaling and regulated fat energy metabolism by inhibiting AMPK signaling. Therefore, PDTC primarily influenced different pathways in different tissues. The study not only established a simple and reliable screening drugs model of cancer cachexia in vitro but also provided new theoretical basis for future treatment of cancer cachexia.

Self-assembled monolayer of ammonium pyrrolidine dithiocarbamate on copper detected using electrochemical methods, surface enhanced Raman scattering and quantum chemistry calculations

Energy Technology Data Exchange (ETDEWEB)

Liao, Q.-Q., E-mail: liaoqq1971@yahoo.com.cn [Key Lab of Shanghai Colleges and Universities for Electric Power Corrosion Control and Applied Electrochemistry, Shanghai Engineering Research Center of Energy-Saving in Heat Exchange Systems, Shanghai University of Electric Power, Shanghai 200090 (China); Yue, Z.-W.; Yang, D. [Key Lab of Shanghai Colleges and Universities for Electric Power Corrosion Control and Applied Electrochemistry, Shanghai Engineering Research Center of Energy-Saving in Heat Exchange Systems, Shanghai University of Electric Power, Shanghai 200090 (China); Wang, Z.-H. [Department of Chemistry, Tongji University, Shanghai 200092 (China); Li, Z.-H. [Department of Chemistry, Fudan University, Shanghai 200433 (China); Ge, H.-H. [Key Lab of Shanghai Colleges and Universities for Electric Power Corrosion Control and Applied Electrochemistry, Shanghai Engineering Research Center of Energy-Saving in Heat Exchange Systems, Shanghai University of Electric Power, Shanghai 200090 (China); Li, Y.-J. [Department of Chemistry, Tongji University, Shanghai 200092 (China)

2011-07-29

Ammonium pyrrolidine dithiocarbamate (APDTC) monolayer was self-assembled on fresh copper surface obtained after oxidation-reduction cycle treatment in 0.1 mol L{sup -1} potassium chloride solution at ambient temperature. The APDTC self-assembled monolayer (SAM) on copper surface was investigated by surface enhanced Raman scattering spectroscopy and the results show that APDTC SAM is chemisorbed on copper surface by its sulfur atoms with perpendicular orientation. The optimum immersing period for SAM formation is 4 h at 0.01 mol L{sup -1} concentration of APDTC. The impedance results indicate that APDTC SAM has good corrosion inhibition effects for copper in 0.5 mol L{sup -1} hydrochloric acid solution and its maximum inhibition efficiency could reach 95%. Quantum chemical calculations show that APDTC has relatively small {Delta}E between the highest occupied molecular orbital and the lowest unoccupied molecular orbital and large negative charge in its two sulfur atoms, which facilitate formation of an insulating Cu/APDTC film on copper surface.

Design and Synthesis of a Series of L-trans-4-Substituted Prolines as Selective Antagonists for the Ionotropic Glutamate Receptors Including Functional and X-ray Crystallographic Studies of New Subtype Selective Kainic Acid Receptor Subtype 1 (GluK1) Antagonist (2S,4R)-4-(2-Carboxyphenoxy)pyrrolidine

DEFF Research Database (Denmark)

Krogsgaard-Larsen, Niels; Delgar, Claudia; Koch, Karina

2017-01-01

Ionotropic glutamate receptor antagonists are valuable tool compounds for studies of neurological pathways in the central nervous system. On the basis of rational ligand design, a new class of selective antagonists, represented by (2S,4R)-4-(2-carboxy-phenoxy)pyrrolidine-2-carboxylic acid (1b...... to the structure with glutamate, consistent with 1b being an antagonist. A structure-activity relationship study showed that the chemical nature of the tethering atom (C,O, or S) linking the pyrrolidine ring and the phenyl ring plays a key role in the receptor selectivity profile and that substituents......), for cloned homomeric kainic acid receptor subtype 1 (GluK1) was attained (Ki = 4 µM). In a functional assay, 1b displayed full antagonist activity with IC50 = 6 ± 2 µM. A crystal structure was obtained of 1b when bound in the ligand binding domain of GluK1. A domain opening of 13-14° was seen compared...

Evaluation of Stability of Complexes of Inner Transition Metal Ions with 2-Oxo-1-pyrrolidine Acetamide and Role of Systematic Errors

Directory of Open Access Journals (Sweden)

Sangita Sharma

2011-01-01

Full Text Available BEST FIT models were used to study the complexation of inner transition metal ions like Y(III, La(III, Ce(III, Pr(III, Nd(III, Sm(III, Gd(III, Dy(III and Th(IV with 2-oxo-1-pyrrolidine acetamide at 30 °C in 10%, 20, 30, 40, 50% and 60% v/v dioxane-water mixture at 0.2 M ionic strength. Irving Rossotti titration method was used to get titration data. Calculations were carried out with PKAS and BEST Fortran IV computer programs. The expected species like L, LH+, ML, ML2 and ML(OH3, were obtained with SPEPLOT. Stability of complexes has increased with increasing the dioxane content. The observed change in stability can be explained on the basis of electrostatic effects, non electrostatic effects, solvating power of solvent mixture, interaction between ions and interaction of ions with solvents. Effect of systematic errors like effect of dissolved carbon dioxide, concentration of alkali, concentration of acid, concentration of ligand and concentration of metal have also been explained here.

Novel Hybrid Anticonvulsants Derived from Pyrrolidine-2,5-dione Scaffold with Broad Spectrum of Activity in the Preclinical Studies.

Science.gov (United States)

Kaminski, Krzysztof

2017-01-01

The multifunctional ligands application is an emerging approach in drug delivery, mainly in the treatment of diseases with complex pathology, such as Alzheimer's, cancer, and epilepsy. Using this method many biomolecules with different properties are combined to form a single unit that can provide a complex broad spectrum activity. Thus, a new type of hybrid anticonvulsants based on the pyrrolidine-2,5-dione frame are detailed with the aim of acquiring more effective antiepileptic drugs (AED) that could suppress various human convulsions. These hybrid molecules attach to the chemical particles of clinically relevant AEDs such as ethosuximide, levetiracetam, and lacosamide. As a result of this hybridization process the compounds obtained were effective in three most important animal epilepsy models, namely the maximal electroshock seizure (MES) test, the subcutaneous pentylenetetrazole (scPTZ) test, and the six-Hertz (6 Hz) model in mice. These substances displayed wider spectrum of protection, more potent efficacy, and better safety profile than the aforementioned AEDs. Several compounds were also active in the formalin model of persistent pain in mice. The in vitro ligand binding studies have proved that the most conceivable molecular mechanism of anticonvulsant and antinociceptive action was the influence on the neuronal voltage-sensitive sodium and L-type calcium channels. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Gefitinib and pyrrolidine dithiocarbamate decrease viral replication and cytokine production in dengue virus infected human monocyte cultures.

Science.gov (United States)

Duran, Anyelo; Valero, Nereida; Mosquera, Jesús; Fuenmayor, Edgard; Alvarez-Mon, Melchor

2017-12-15

The epidermal growth factor receptor (EGFR) and nucleotide-binding and oligomerization-domain containing 2 (NOD2) are important in cancer and in microbial recognition, respectively. These molecules trigger intracellular signaling pathways inducing the expression of inflammatory genes by NF-kB translocation. Gefitinib (GBTC) and pyrrolidine dithiocarbamate (PDTC) are capable of inhibiting EGFR/NOD2 and NF-kB, respectively. In earlier stages of dengue virus (DENV) infection, monocytes are capable of sustaining viral replication and increasing cytokine production, suggesting that monocyte/macrophages play an important role in early DENV replication. GBTC and PDTC have not been used to modify the pathogenesis of DENV in infected cells. This study was aimed to determine the effect of GBTC and PDTC on viral replication and cytokine production in DENV serotype 2 (DENV2)-infected human monocyte cultures. GBTC and PDTC were used to inhibit EGFR/NOD2 and NF-kB, respectively. Cytokine production was measured by ELISA and viral replication by plaque forming unit assay. Increased DENV2 replication and anti-viral cytokine production (IFN-α/β, TNF-α, IL-12 and IL-18) in infected cultures were found. These parameters were decreased after EGFR/NOD2 or NF-kB inhibitions. The inhibitory effects of GBTC and PDTC on viral replication and cytokine production can be beneficial in the treatment of patients infected by dengue and suggest a possible role of EGFR/NOD2 receptors and NF-kB in dengue pathogenesis. Copyright © 2017 Elsevier Inc. All rights reserved.

Pyrrolidine dithiocarbamate inhibits superoxide anion-induced pain and inflammation in the paw skin and spinal cord by targeting NF-κB and oxidative stress.

Science.gov (United States)

Pinho-Ribeiro, Felipe A; Fattori, Victor; Zarpelon, Ana C; Borghi, Sergio M; Staurengo-Ferrari, Larissa; Carvalho, Thacyana T; Alves-Filho, Jose C; Cunha, Fernando Q; Cunha, Thiago M; Casagrande, Rubia; Verri, Waldiceu A

2016-06-01

We evaluated the effect of pyrrolidine dithiocarbamate (PDTC) in superoxide anion-induced inflammatory pain. Male Swiss mice were treated with PDTC and stimulated with an intraplantar or intraperitoneal injection of potassium superoxide, a superoxide anion donor. Subcutaneous PDTC treatment attenuated mechanical hyperalgesia, thermal hyperalgesia, paw oedema and leukocyte recruitment (neutrophils and macrophages). Intraplantar injection of superoxide anion activated NF-κB and increased cytokine production (IL-1β, TNF-α and IL-10) and oxidative stress (nitrite and lipid peroxidation levels) at the primary inflammatory foci and in the spinal cord (L4-L6). PDTC treatment inhibited superoxide anion-induced NF-κB activation, cytokine production and oxidative stress in the paw and spinal cord. Furthermore, intrathecal administration of PDTC successfully inhibited superoxide anion-induced mechanical hyperalgesia, thermal hyperalgesia and inflammatory response in peripheral foci (paw). These results suggest that peripheral stimulus with superoxide anion activates the local and spinal cord oxidative- and NF-κB-dependent inflammatory nociceptive mechanisms. PDTC targets these events, therefore, inhibiting superoxide anion-induced inflammatory pain in mice.

Speciation analysis of tellurium by solid-phase extraction in the presence of ammonium pyrrolidine dithiocarbamate and inductively coupled plasma mass spectrometry

Energy Technology Data Exchange (ETDEWEB)

Yu, Chunhai; Cai, Qiantao; Guo, Zhong-Xian; Yang, Zhaoguang [Centre for Advanced Water Technology, Innovation Centre (NTU), Singapore (Singapore); Khoo, Soo Beng [Department of Chemistry, National University of Singapore (Singapore)

2003-05-01

Under acidic conditions tellurium(IV) formed a complex with ammonium pyrrolidine dithiocarbamate (APDC). The tellurium(IV) complex was completely retained on a non-polar Isolute silica-based octadecyl (C{sub 18}) sorbent-containing solid-phase extraction (SPE) cartridge, while the uncomplexed Te(VI) passed through the cartridge and remained as a free species in the solution. Only partial Te(IV) was retained on the SPE cartridge for samples without addition of APDC. On the basis of different retention behaviours of the complexed Te(IV) and uncomplexed Te(VI), a simple and highly sensitive method is proposed for the determination of total tellurium and Te(VI) by SPE separation and inductively coupled plasma mass spectrometry (ICP-MS) detection. The Te(IV) concentration was calculated as the difference between total tellurium and Te(VI) concentrations. The detection limit (3{sigma}) is 3 ng L{sup -1} tellurium. Factors affecting the separation and detection of tellurium species were investigated. Coexisting ions did not show significant interferences with the Te(IV)-APDC complex retention and the subsequent ICP-MS detection of Te. The method has been successfully applied to the tellurium speciation analysis in waters with spiked recoveries for Te(IV) and Te(VI) of 86.0-108% and 87.1-97.4%, respectively. (orig.)

Biotransformation of Daclatasvir In Vitro and in Nonclinical Species: Formation of the Main Metabolite by Pyrrolidine δ-Oxidation and Rearrangement.

Science.gov (United States)

Li, Wenying; Zhao, Weiping; Liu, Xiaohong; Huang, Xiaohua; Lopez, Omar D; Leet, John E; Fancher, R Marcus; Nguyen, Van; Goodrich, Jason; Easter, John; Hong, Yang; Caceres-Cortes, Janet; Chang, Shu Y; Ma, Li; Belema, Makonen; Hamann, Lawrence G; Gao, Min; Zhu, Mingshe; Shu, Yue-Zhong; Humphreys, W Griffith; Johnson, Benjamin M

2016-06-01

Daclatasvir is a first-in-class, potent, and selective inhibitor of the hepatitis C virus nonstructural protein 5A replication complex. In support of nonclinical studies during discovery and exploratory development, liquid chromatography-tandem mass spectrometry and nuclear magnetic resonance were used in connection with synthetic and radiosynthetic approaches to investigate the biotransformation of daclatasvir in vitro and in cynomolgus monkeys, dogs, mice, and rats. The results of these studies indicated that disposition of daclatasvir was accomplished mainly by the release of unchanged daclatasvir into bile and feces and, secondarily, by oxidative metabolism. Cytochrome P450s were the main enzymes involved in the metabolism of daclatasvir. Oxidative pathways included δ-oxidation of the pyrrolidine moiety, resulting in ring opening to an aminoaldehyde intermediate followed by an intramolecular reaction between the aldehyde and the proximal imidazole nitrogen atom. Despite robust formation of the resulting metabolite in multiple systems, rates of covalent binding to protein associated with metabolism of daclatasvir were modest (55.2-67.8 pmol/mg/h) in nicotinamide adenine dinucleotide phosphate (reduced form)-supplemented liver microsomes (human, monkey, rat), suggesting that intramolecular rearrangement was favored over intermolecular binding in the formation of this metabolite. This biotransformation profile supported the continued development of daclatasvir, which is now marketed for the treatment of chronic hepatitis C virus infection. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

An evaluation of the performance and mechanistic action of the costabiliser N-phenyl-3-acetyl pyrrolidine-2,4-dione and its derivatives in poly(vinyl chloride)

International Nuclear Information System (INIS)

Chaudhry, H.I.

1999-10-01

N-phenyl-3-acetyl pyrrolidine-2,4-dione (F6) and its derivatives (F6c and F6d) have been investigated as costabilisers for PVC at processing temperatures, along with the commercial costabilisers: dehydroacetic acid (DHA) and Rhodiostab-83 (R83). Spectroscopic (fluorescence, Fourier-transform infrared and nuclear magnetic resonance) studies on PVC itself, and model compounds of PVC impurities (e.g. 4-chloro-2-hexene) have shown two distinct modes of action: in which a metal complex between the costabiliser and a metal soap stabiliser (zinc stearate and calcium stearate is the active entity, one in which costabiliser action is facilitated by release of zinc chloride. F6 was shown to substitute for allylic chloride by a C-alkylation reaction so inhibiting polyene formation and giving very good initial colour. It was demonstrated that F6 formed a complex with the zinc stearate at room temperature to give a chelate in which the zinc ion is tetracoordinated. Because the costabiliser is able to co-ordinate readily to zinc stearate, this leads to good initial colour, but a more rapid evolution of HCl ('short-term' costabilisation). When the -C=O substituent in the 3-position was replaced by a '-C=N-alkyl' (F6d), or a '-C=N-phenyl' (F6c) group, the behaviour was changed markedly. FTIR and HCl evolution showed that F6d was unstable at 180 deg. C and reacted with HCl evolved from the degraded PVC, decomposing into a basic gas and a structure similar to F6. F6d being more basic formed a complex with the Lewis acid ZnCI 2 instead of zinc stearate. F6c did not interact with the ZnCl 2 or ZnSt 2 , despite the fact that it has an extra nitrogen atom. The reason for this is that the π orbital system of the N-substituted phenyl ring in the 3-position in the pyrrolidine ring is conjugated with the C=N double bond. DHA also interacted with the zinc stearate, but this interaction was significant only at higher temperatures, i.e. after heating to processing temperatures. The

Short-term pyrrolidine dithiocarbamate administration attenuates cachexia-induced alterations to muscle and liver in ApcMin/+ mice.

Science.gov (United States)

Narsale, Aditi A; Puppa, Melissa J; Hardee, Justin P; VanderVeen, Brandon N; Enos, Reilly T; Murphy, E Angela; Carson, James A

2016-09-13

Cancer cachexia is a complex wasting condition characterized by chronic inflammation, disrupted energy metabolism, and severe muscle wasting. While evidence in pre-clinical cancer cachexia models have determined that different systemic inflammatory inhibitors can attenuate several characteristics of cachexia, there is a limited understanding of their effects after cachexia has developed, and whether short-term administration is sufficient to reverse cachexia-induced signaling in distinctive target tissues. Pyrrolidine dithiocarbamate (PDTC) is a thiol compound having anti-inflammatory and antioxidant properties which can inhibit STAT3 and nuclear factor κB (NF-κB) signaling in mice. This study examined the effect of short-term PDTC administration to ApcMin/+ mice on cachexia-induced disruption of skeletal muscle protein turnover and liver metabolic function. At 16 weeks of age ApcMin/+ mice initiating cachexia (7% BW loss) were administered PDTC (10mg/kg bw/d) for 2 weeks. Control ApcMin/+ mice continued to lose body weight during the treatment period, while mice receiving PDTC had no further body weight decrease. PDTC had no effect on either intestinal tumor burden or circulating IL-6. In muscle, PDTC rescued signaling disrupting protein turnover regulation. PDTC suppressed the cachexia induction of STAT3, increased mTORC1 signaling and protein synthesis, and suppressed the induction of Atrogin-1 protein expression. Related to cachectic liver metabolic function, PDTC treatment attenuated glycogen and lipid content depletion independent to the activation of STAT3 and mTORC1 signaling. Overall, these results demonstrate short-term PDTC treatment to cachectic mice attenuated cancer-induced disruptions to muscle and liver signaling, and these changes were independent to altered tumor burden and circulating IL-6.

Short-term pyrrolidine dithiocarbamate administration attenuates cachexia-induced alterations to muscle and liver in ApcMin/+ mice

Science.gov (United States)

VanderVeen, Brandon N.; Enos, Reilly T.; Murphy, E. Angela; Carson, James A.

2016-01-01

Cancer cachexia is a complex wasting condition characterized by chronic inflammation, disrupted energy metabolism, and severe muscle wasting. While evidence in pre-clinical cancer cachexia models have determined that different systemic inflammatory inhibitors can attenuate several characteristics of cachexia, there is a limited understanding of their effects after cachexia has developed, and whether short-term administration is sufficient to reverse cachexia-induced signaling in distinctive target tissues. Pyrrolidine dithiocarbamate (PDTC) is a thiol compound having anti-inflammatory and antioxidant properties which can inhibit STAT3 and nuclear factor κB (NF-κB) signaling in mice. This study examined the effect of short-term PDTC administration to ApcMin/+ mice on cachexia-induced disruption of skeletal muscle protein turnover and liver metabolic function. At 16 weeks of age ApcMin/+ mice initiating cachexia (7% BW loss) were administered PDTC (10mg/kg bw/d) for 2 weeks. Control ApcMin/+ mice continued to lose body weight during the treatment period, while mice receiving PDTC had no further body weight decrease. PDTC had no effect on either intestinal tumor burden or circulating IL-6. In muscle, PDTC rescued signaling disrupting protein turnover regulation. PDTC suppressed the cachexia induction of STAT3, increased mTORC1 signaling and protein synthesis, and suppressed the induction of Atrogin-1 protein expression. Related to cachectic liver metabolic function, PDTC treatment attenuated glycogen and lipid content depletion independent to the activation of STAT3 and mTORC1 signaling. Overall, these results demonstrate short-term PDTC treatment to cachectic mice attenuated cancer-induced disruptions to muscle and liver signaling, and these changes were independent to altered tumor burden and circulating IL-6. PMID:27449092

Preconcentration of metallic elements by complexation with ammonium pyrrolidine dithiocarbamate (APDC) for atomic absorption analysis; Pre concentracao de elementos metalicos por complexacao com ditiocarbamato de amonioe prirrolidina (APDC) para analise por absorcao atomica

Energy Technology Data Exchange (ETDEWEB)

Santos Coelho, Ricardo dos; Dantas, Elizabeth S.K. [Instituto de Pesquisas Energeticas e Nucleares (IPEN), Sao Paulo, SP (Brazil)

1997-10-01

Ammonium pyrrolidine dithiocarbamate (APDC) forms stable chelates with many metals being therefore, used in systems of preconcentration for determination of heavy metals in water. In this work, the metals were complexed with APDC and extracted with methyl isobutyl ketone (MIBK). The results showed that the studied metals (Co, Cu, Fe, Ni, Pb, Cr and Cd), in the range of 2 to 5 {mu}g, in 100 ml of sample, were quantitatively extracted in only one stage using 10 ml of MIBK and 5 ml of 4% APDC. The pH must be between 4 and 5. The complexes stability was also studied. The proposed method can be applied to pre concentrate heavy metals in natural waters. (author). 4 refs., 1 fig., 3 tabs.

Ligand-conjugated mesoporous silica nanorattles based on enzyme targeted prodrug delivery system for effective lung cancer therapy

Energy Technology Data Exchange (ETDEWEB)

Sundarraj, Shenbagamoorthy, E-mail: sundarrajbu09@gmail.com [Proteomics and Molecular Cell Physiology Laboratory, Department of Zoology, Bharathiar University, Coimbatore 641 046, TN (India); Thangam, Ramar [Proteomics and Molecular Cell Physiology Laboratory, Department of Zoology, Bharathiar University, Coimbatore 641 046, TN (India); Department of Virology, King Institute of Preventive Medicine and Research, Guindy, Chennai 600 032, TN (India); Sujitha, Mohanan V.; Vimala, Karuppaiya [Proteomics and Molecular Cell Physiology Laboratory, Department of Zoology, Bharathiar University, Coimbatore 641 046, TN (India); Kannan, Soundarapandian, E-mail: skperiyaruniv@gmail.com [Proteomics and Molecular Cell Physiology Laboratory, Department of Zoology, Bharathiar University, Coimbatore 641 046, TN (India); Department of Zoology, Periyar University, Salem 636 011, TN (India)

2014-03-15

Epidermal growth factor receptor antibody (EGFRAb) conjugated silica nanorattles (SNs) were synthesized and used to develop receptor mediated endocytosis for targeted drug delivery strategies for cancer therapy. The present study determined that the rate of internalization of silica nanorattles was found to be high in lung cancer cells when compared with the normal lung cells. EGFRAb can specifically bind to EGFR, a receptor that is highly expressed in lung cancer cells, but is expressed at low levels in other normal cells. Furthermore, in vitro studies clearly substantiated that the cPLA{sub 2}α activity, arachidonic acid release and cell proliferation were considerably reduced by pyrrolidine-2 loaded EGFRAb-SN in H460 cells. The cytotoxicity, cell cycle arrest and apoptosis were significantly induced by the treatment of pyrrolidine-2 loaded EGFRAb-SN when compared with free pyrrolidine-2 and pyrrolidine-2 loaded SNs in human non-small cell lung cancer cells. An in vivo toxicity assessment showed that silica nanorattles and EGFRAb-SN-pyrrolidine-2 exhibited low systemic toxicity in healthy Balb/c mice. The EGFRAb-SN-pyrrolidine-2 showed a much better antitumor activity (38%) with enhanced tumor inhibition rate than the pyrrolidine-2 on the non-small cell lung carcinoma subcutaneous model. Thus, the present findings validated the low toxicity and high therapeutic potentials of EGFRAb-SN-pyrrolidine-2, which may provide a convincing evidence of the silica nanorattles as new potential carriers for targeted drug delivery systems. - Highlights: • EGFRAb-SN developed for receptor-mediated Drug delivery system (DDS). • EGFRAb-SN-pyrrolidine-2 targeted DDS for cPLA2α inhibition in NSLC. • Study indicates EGFRAb-SN-pyrrolidine-2 as an efficient in target dug delivery carrier. • Study explains entire efficiency of EGFRAb-SN-pyrrolidine-2 in vitro and in vivo models.

Ligand-conjugated mesoporous silica nanorattles based on enzyme targeted prodrug delivery system for effective lung cancer therapy

International Nuclear Information System (INIS)

Sundarraj, Shenbagamoorthy; Thangam, Ramar; Sujitha, Mohanan V.; Vimala, Karuppaiya; Kannan, Soundarapandian

2014-01-01

Epidermal growth factor receptor antibody (EGFRAb) conjugated silica nanorattles (SNs) were synthesized and used to develop receptor mediated endocytosis for targeted drug delivery strategies for cancer therapy. The present study determined that the rate of internalization of silica nanorattles was found to be high in lung cancer cells when compared with the normal lung cells. EGFRAb can specifically bind to EGFR, a receptor that is highly expressed in lung cancer cells, but is expressed at low levels in other normal cells. Furthermore, in vitro studies clearly substantiated that the cPLA 2 α activity, arachidonic acid release and cell proliferation were considerably reduced by pyrrolidine-2 loaded EGFRAb-SN in H460 cells. The cytotoxicity, cell cycle arrest and apoptosis were significantly induced by the treatment of pyrrolidine-2 loaded EGFRAb-SN when compared with free pyrrolidine-2 and pyrrolidine-2 loaded SNs in human non-small cell lung cancer cells. An in vivo toxicity assessment showed that silica nanorattles and EGFRAb-SN-pyrrolidine-2 exhibited low systemic toxicity in healthy Balb/c mice. The EGFRAb-SN-pyrrolidine-2 showed a much better antitumor activity (38%) with enhanced tumor inhibition rate than the pyrrolidine-2 on the non-small cell lung carcinoma subcutaneous model. Thus, the present findings validated the low toxicity and high therapeutic potentials of EGFRAb-SN-pyrrolidine-2, which may provide a convincing evidence of the silica nanorattles as new potential carriers for targeted drug delivery systems. - Highlights: • EGFRAb-SN developed for receptor-mediated Drug delivery system (DDS). • EGFRAb-SN-pyrrolidine-2 targeted DDS for cPLA2α inhibition in NSLC. • Study indicates EGFRAb-SN-pyrrolidine-2 as an efficient in target dug delivery carrier. • Study explains entire efficiency of EGFRAb-SN-pyrrolidine-2 in vitro and in vivo models

Synthesis, and anticonvulsant activity of new amides derived from 3-methyl- or 3-ethyl-3-methyl-2,5-dioxo-pyrrolidin-1-yl-acetic acids.

Science.gov (United States)

Obniska, Jolanta; Rapacz, Anna; Rybka, Sabina; Góra, Małgorzata; Kamiński, Krzysztof; Sałat, Kinga; Żmudzki, Paweł

2016-04-15

This paper describes the synthesis of the library of 22 new 3-methyl- and 3-ethyl-3-methyl-2,5-dioxo-pyrrolidin-1-yl-acetamides as potential anticonvulsant agents. The maximal electroshock (MES) and the subcutaneous pentylenetetrazole (scPTZ) seizure models were used for screening all the compounds. The 6 Hz model of pharmacoresistant limbic seizures was applied for studying selected derivatives. Six amides were chosen for pharmacological characterization of their antinociceptive activity in the formalin model of tonic pain as well as local anesthetic activity was assessed in mice. The pharmacological data indicate on the broad spectra of activity across the preclinical seizure models. Compounds 10 (ED50=32.08 mg/kg, MES test) and 9 (ED50=40.34 mg/kg, scPTZ test) demonstrated the highest potency. These compounds displayed considerably better safety profiles than clinically relevant antiepileptic drugs phenytoin, ethosuximide, or valproic acid. Several molecules showed antinociceptive and local anesthetic properties. The in vitro radioligand binding studies demonstrated that the influence on the sodium and calcium channels may be one of the essential mechanisms of action. Copyright © 2016. Published by Elsevier Ltd.

Passivating ZnO Surface States by C60 Pyrrolidine Tris-Acid for Hybrid Solar Cells Based on Poly(3-hexylthiophene/ZnO Nanorod Arrays

Directory of Open Access Journals (Sweden)

Peng Zhong

2017-12-01

Full Text Available Construction of ordered electron acceptors is a feasible way to solve the issue of phase separation in polymer solar cells by using vertically-aligned ZnO nanorod arrays (NRAs. However, the inert charge transfer between conducting polymer and ZnO limits the performance enhancement of this type of hybrid solar cells. In this work, a fullerene derivative named C60 pyrrolidine tris-acid is used to modify the interface of ZnO/poly(3-hexylthiophene (P3HT. Results indicate that the C60 modification passivates the surface defects of ZnO and improves its intrinsic fluorescence. The quenching efficiency of P3HT photoluminescence is enhanced upon C60 functionalization, suggesting a more efficient charge transfer occurs across the modified P3HT/ZnO interface. Furthermore, the fullerene modified hybrid solar cell based on P3HT/ZnO NRAs displays substantially-enhanced performance as compared to the unmodified one and the devices with other modifiers, which is contributed to retarded recombination and enhanced exciton separation as evidenced by electrochemical impedance spectra. Therefore, fullerene passivation is a promising method to ameliorate the connection between conjugated polymers and metal oxides, and is applicable in diverse areas, such as solar cells, transistors, and light-emitting dioxides.

Study of magnetization switching for MRAM based memory technologies

Science.gov (United States)

Pham, Huy

Amphibian alkaloids are attractive targets for synthesis due to their biological activity. An important class of amphibian alkaloids is the 2,5-disubstituted pyrrolidine-based family of compounds. There are many synthetic approaches for the preparation of the trans-2,5-disubstituted pyrrolidines, but methods for the construction of the cis-2,5-pyrrolidines are limited. Therefore, it was desired to develop an enantioselective approach for the preparation of cis-2,5-disubsituted pyrrolidines. (+)-Tropin-2-one derived from cocaine was used as starting material to exploit the inherent stereochemistry for construction of the cis-pyrrolidine ring. This permitted the unequivocal assignment of the absolute configuration of the target pyrrolidine. The structurally simple pyrrolidine alkaloid, 225H, was selected as a target to develop a general synthetic approach. The enantioselective synthesis of 225H was achieved in nine steps and good overall yield. The search for potent cannabinoid receptor partial agonist ligands as potential marijuana addiction therapeutic agents has led to an investigation of the synthesis of diaryl ether hybrid analogues of BAY 59-3074. A series of 2-(3-alkyl-5-hydroxyphenoxy)-6-(trifluoromethyl)benzonitriles, 3-(2-cyano-3-(trifluoromethyl)phenoxy)phenylalkanoates, and (3-(benzyloxy)phenoxy)-6-(trifluoromethyl)benzonitriles were synthesized and evaluated in vitro for CB1 affinity. The olivetol diaryl ether analogue was the most potent ligand of the alkyl series, but the diaryl ester analogues exhibited modest affinity for CB1 receptors. The most potent compound of the series was the 2-(3-(benzyloxy)phenoxy)-6-(trifluoromethyl)benzonitrile. Keywords. amphibian alkaloids, enantioselective synthesis, pyrrolidine, cannabinoid receptor, marijuana.

Carbonate binding to copper(II) in solution: mixed-ligand complex formation and its application to the isolation and separation of the three isomers of [Cu(bpp)(H₂O)][ClO₄]₂ [bpp = 2,6-bis(pyrrolidin-2-yl)pyridine

OpenAIRE

Bernauer, Klaus; Godefroy, Isabelle; Cabort, Amel; Guicher, Nathalie; Stoeckli-Evans, Helen; Süss-Fink, Georg

2006-01-01

The binding of the carbonate anion to [Cu(meso-bpp)(H2O)]2+ and rac-[Cu(bpp)(H2O)]2+ [bpp = 2,6-bis(pyrrolidin-2-yl)pyridine] in aqueous solution has been investigated. Formation constants of the carbonato complexes [Cu(meso-bpp)(CO3)] and rac-[Cu(bpp)(CO3)] (1.02 × 103 M–1 and 1.77 × 103 M–1, respectively, µ= 0.70 M) have been calculated from spectrophotometric measurements. The formation of these Cu2+ complexes can also be used for an improved synthesis and an easy isolation of the three di...

Pyrrolidine dithiocarbamate administered during ex-vivo lung perfusion promotes rehabilitation of injured donor rat lungs obtained after prolonged warm ischemia.

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Cyril Francioli

Full Text Available Damaged lung grafts obtained after circulatory death (DCD lungs and warm ischemia may be at high risk of reperfusion injury after transplantation. Such lungs could be pharmacologically reconditioned using ex-vivo lung perfusion (EVLP. Since acute inflammation related to the activation of nuclear factor kappaB (NF-κB is instrumental in lung reperfusion injury, we hypothesized that DCD lungs might be treated during EVLP by pyrrolidine dithiocarbamate (PDTC, an inhibitor of NF-κB. Rat lungs exposed to 1h warm ischemia and 2 h cold ischemia were subjected to EVLP during 4h, in absence (CTRL group, N = 6 or in presence of PDTC (2.5g/L, PDTC group, N = 6. Static pulmonary compliance (SPC, peak airway pressure (PAWP, pulmonary vascular resistance (PVR, and oxygenation capacity were determined during EVLP. After EVLP, we measured the weight gain of the heart-lung block (edema, and the concentration of LDH (cell damage, proteins (permeability edema and of the cytokines IL-6, TNF-α and CINC-1 in bronchoalveolar lavage (BAL, and we evaluated NF-κB activation by the degree of phosphorylation and degradation of its inhibitor IκBα in lung tissue. In CTRL, we found significant NF-κB activation, lung edema, and a massive release of LDH, proteins and cytokines. SPC significantly decreased, PAWP and PVR increased, while oxygenation tended to decrease. Treatment with PDTC during EVLP inhibited NF-κB activation, did not influence LDH release, but markedly reduced lung edema and protein concentration in BAL, suppressed TNFα and IL-6 release, and abrogated the changes in SPC, PAWP and PVR, with unchanged oxygenation. In conclusion, suppression of innate immune activation during EVLP using the NF-κB inhibitor PDTC promotes significant improvement of damaged rat DCD lungs. Future studies will determine if such rehabilitated lungs are suitable for in vivo transplantation.

1-[2-Oxo-1′-phenyl-2′,3′,5′,6′,7′,7a'-hexahydroindoline-3-spiro-3′-1′H-pyrrolizin-2′-yl]-3-phenylprop-2-en-1-one

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S. Sriman Narayanan

2008-09-01

Full Text Available In the title compound, C29H26N2O2, one of the pyrrolidine rings in the pyrrolizine system is disordered, with site occupancies of ca 0.55 and 0.45. Both components of the disordered pyrrolidine ring adopt envelope conformations, whereas the other pyrrolidine ring adopts a twist conformation. The molecules are linked into centrosymmetric dimers by N—H...O hydrogen bonds and the dimers are connected via C—H...π interactions.

Phase equilibrium measurements and the tuning behavior of new sII clathrate hydrates

Energy Technology Data Exchange (ETDEWEB)

Shin, Woongchul; Park, Seongmin; Ro, Hyeyoon; Koh, Dong-Yeun; Seol, Jiwoong [Department of Chemical and Biomolecular Engineering (BK21 Program), KAIST, Daejeon 305-701 (Korea, Republic of); Lee, Huen, E-mail: h_lee@kaist.ac.kr [Department of Chemical and Biomolecular Engineering (BK21 Program), KAIST, Daejeon 305-701 (Korea, Republic of); Graduate School of EEWS, KAIST, Daejeon 305-701 (Korea, Republic of)

2012-01-15

Graphical abstract: Pyrrolidine and piperidine act as sII clathrate hydrate formers under methane gas. Highlights: > New sII clathrate hydrate formers were proposed: pyrrolidine and piperidine. > Formation of gas hydrate with methane as help gas was confirmed. > NMR, Raman, and XRD patterns were analyzed to identify the hydrate structures. > We measured (L + H + V) phase equilibrium with proposed hydrate formers. > Tuning phenomena increase gas storage in (pyrrolidine + CH{sub 4}) clathrate hydrates. - Abstract: We suggest two types of new amine-type sII formers: pyrrolidine and piperidine. These guest compounds fail to form clathrate hydrate structures with host water, but instead have to combine with light gaseous guest molecules (methane) for enclathration. First, two binary clathrate hydrates of (pyrrolidine + methane) and (piperidine + methane) were synthesized at various amine concentrations. {sup 13}C NMR and Raman analysis were done to identify the clathrate hydrate structure and guest distribution over sII-S and sII-L cages. XRD was also used to find the exact structure and corresponding cell parameters. At a dilute pyrrolidine concentration of less than 5.56 mol%, the tuning phenomenon is observed such that methane molecules surprisingly occupy sII-L cages. At the critical guest concentration of about 0.1 mol%, the cage occupancy ratio reaches the maximum of approximately 0.5. At very dilute guest concentration below 0.1 mol%, the methane molecules fail to occupy large cages on account of their rarefied distribution in the network. Direct-release experiments were performed to determine the actual guest compositions in the clathrate hydrate phases. Finally, we measured the clathrate hydrate phase equilibria of (pyrrolidine + methane) and (piperidine + methane).

Phase equilibrium measurements and the tuning behavior of new sII clathrate hydrates

International Nuclear Information System (INIS)

Shin, Woongchul; Park, Seongmin; Ro, Hyeyoon; Koh, Dong-Yeun; Seol, Jiwoong; Lee, Huen

2012-01-01

Graphical abstract: Pyrrolidine and piperidine act as sII clathrate hydrate formers under methane gas. Highlights: → New sII clathrate hydrate formers were proposed: pyrrolidine and piperidine. → Formation of gas hydrate with methane as help gas was confirmed. → NMR, Raman, and XRD patterns were analyzed to identify the hydrate structures. → We measured (L + H + V) phase equilibrium with proposed hydrate formers. → Tuning phenomena increase gas storage in (pyrrolidine + CH 4 ) clathrate hydrates. - Abstract: We suggest two types of new amine-type sII formers: pyrrolidine and piperidine. These guest compounds fail to form clathrate hydrate structures with host water, but instead have to combine with light gaseous guest molecules (methane) for enclathration. First, two binary clathrate hydrates of (pyrrolidine + methane) and (piperidine + methane) were synthesized at various amine concentrations. 13 C NMR and Raman analysis were done to identify the clathrate hydrate structure and guest distribution over sII-S and sII-L cages. XRD was also used to find the exact structure and corresponding cell parameters. At a dilute pyrrolidine concentration of less than 5.56 mol%, the tuning phenomenon is observed such that methane molecules surprisingly occupy sII-L cages. At the critical guest concentration of about 0.1 mol%, the cage occupancy ratio reaches the maximum of approximately 0.5. At very dilute guest concentration below 0.1 mol%, the methane molecules fail to occupy large cages on account of their rarefied distribution in the network. Direct-release experiments were performed to determine the actual guest compositions in the clathrate hydrate phases. Finally, we measured the clathrate hydrate phase equilibria of (pyrrolidine + methane) and (piperidine + methane).

3-(4-Fluorophenyl-1-[1′-(4-fluorophenyl-2-oxo-5′,6′,7′,7a′-tetrahydro-1H-indole-3(2H-spiro-3′(2′H-1H′-pyrrolizin-2′-yl]prop-2-en-1-one

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S. Sriman Narayanan

2008-09-01

Full Text Available In the title compound, C29H24F2N2O2, one of the pyrrolidine rings of the pyrrolizine system is disordered over two sites, with occupancy factors 0.734:0.266 (12. Both components of the disordered pyrrolidine ring adopt envelope conformations, whereas the other pyrrolidine ring adopts a twist conformation. The molecules are linked into centrosymmetric dimers by N—H...O hydrogen bonds and the dimers are connected via C—H...π interactions. The crystal structure is also stabilized by intermolecular C—H...F hydrogen bonds.

Neutral and stereospecific Tc-99m complexes: [99mTc]N-benzyl-3,4-di-(N-2-mercaptoethyl)-amino-pyrrolidines (P-BAT)

International Nuclear Information System (INIS)

Zhuang Zhiping; Ploessl, Karl; Kung Meiping; Mu Mu; Kung, Hank F.

1999-01-01

Technetium-99m-labeled radiopharmaceuticals are currently the most commonly used agents in nuclear medicine. To prepare binding site-specific small molecules containing a Tc-99m complexing core, it is important to consider a ligand system, which selectively forms only one stereoisomer. A novel series of bisaminoethanethiol (BAT) derivatives as a model system were prepared. Stereoisomers of N-benzyl-3,4-di-(N-2-mercaptoethyl)-amino pyrrolidines (P-BAT): (3R,4R)-P-BAT (R,R-4) and (3,4)meso-P-BAT (8), the trans and meso isomer, respectively, as a chelating group were prepared successfully. The desired Tc-99m P-BAT complexes were obtained by using Sn(II)/glucoheptonate as the reducing agent for [ 99m Tc]pertechnetate. As predicted, after complexation with [ 99m Tc]Tc v O, the trans isomer, (3R,4R)-P-BAT (R,R-4), showed only one isomer; whereas the corresponding meso isomer, (3,4)meso-P-BAT (8), produced two distinctive complexes isolated readily by high performance liquid chromatography (HPLC). The [ 99m Tc](R,S)meso-P-BAT (8) isomers showed a different lipophilicity (partition coefficient [P.C.]=54.3 and 55.4 for peak A and peak B, respectively), as compared with that of the corresponding [ 99m Tc](3R,4R)-P-BAT (R,R-4), trans isomer ( P.C.=163). Results of the biodistribution study in rats of these isomers show different heart and brain uptake, suggesting that the intrinsic differences in biodistribution are due to structural and stereospecific factors. Examples in this report confirm that it is possible to design stereospecific Tc-99m complexes based on the bisaminoethanethiol (N 2 S 2 , BAT) ligand system. Consideration on stereoselectivity of site-specific agents labeled with Tc-99m is likely an essential requirement on developing binding-site specific radiopharmaceuticals

Aggregation behavior of gemini pyrrolidine-based ionic liquids 1,1'-(butane-1,4-diyl)bis(1-alkylpyrrolidinium) bromide ([C(n)py-4-C(n)py][Br2]) in aqueous solution.

Science.gov (United States)

Zhang, Shaohua; Yan, Han; Zhao, Mingwei; Zheng, Liqiang

2012-04-15

Three gemini pyrrolidine-based ionic liquids, 1,1'-(butane-1,4-diyl)bis(1-alkylpyrrolidinium) bromide ([C(n)py-4-C(n)py][Br(2)], n=10, 12, 14), were synthesized. Their aggregation behavior in aqueous solution was systematically investigated by surface tension, electrical conductivity, and steady-state fluorescence. Compared with their corresponding monomers, N-alkyl-N-methylpyrrolidinium bromide (C(n)MPB), [C(n)py-4-C(n)py][Br(2)], have higher surface activity. The special structure of [C(n)py-4-C(n)py][Br(2)] that has a spacer in their hydrophilic head groups results in a lower surface excess concentration (Γ(max)) and a larger molecular cross-sectional area (A(min)). Electrical conductivity studies show a lower degree of counter-ion binding to the aggregates. A smaller aggregation number (N(agg)) is observed by the pyrene fluorescence quenching method. A series of thermodynamic parameters (ΔG(agg)(0),ΔH(agg)(0),-TΔS(agg)(0)) of aggregation derived from electrical conductivity indicate that the aggregation of [C(n)py-4-C(n)py][Br(2)] is enthalpy-driven, while aggregation of C(n)MPB is entropy-driven at low temperatures but enthalpy-driven at high temperatures. Copyright © 2012 Elsevier Inc. All rights reserved.

Isomers and conformational barriers of gas phase nicotine, nornicotine and their protonated forms

Energy Technology Data Exchange (ETDEWEB)

Yoshida, Tomoki; Farone, William A.; Xantheas, Sotiris S.

2014-07-17

We report extensive conformational searches of the neutral nicotine, nornicotine and their protonated analogs that are based on ab-initio second order Møller-Plesset perturbation (MP2) electronic structure calculations. Initial searches were performed with the 6-31G(d,p) and the energetics of the most important structures were further refined from geometry optimizations with the aug-cc-pVTZ basis set. Based on the calculated free energies at T=298 K for the gas phase molecules, neutral nicotine has two dominant trans conformers, whereas neutral nornicotine is a mixture of several conformers. For nicotine, the protonation on both the pyridine and the pyrrolidine sites is energetically competitive, whereas nornicotine prefers protonation on the pyridine nitrogen. The protonated form of nicotine is mainly a mixture of two pyridine-protonated trans conformers and two pyrrolidine-protonated trans conformers, whereas the protonated form of nornicotine is a mixture of four pyridine-protonated trans conformers. Nornicotine is conformationally more flexible than nicotine, however it is less protonated at the biologically important pyrrolidine nitrogen site. The lowest energy isomers for each case were found to interconvert via low (< 6 kcal/mol) rotational barriers around the pyridine-pyrrolidine bond.

Multicomponent synthesis, biological evaluation and molecular docking of new spiro-oxindole derivatives

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M. Sapnakumari

2017-11-01

Full Text Available A new series of spiro-oxindoles that were identified based upon their ability to inhibit methionine tRNA synthase (PDB ID: 1PFV and glucosamine-6-phosphate synthase (PDB ID: 1JXA enzymes in virtual screening was synthesized by a three-component 1,3-dipolar cycloaddition method. The reaction proceeds through the formation of azomethine ylides generated in situ by the decarboxylative condensation of isatin and amino acids with dipolarophile chalcones. These compounds are active against Staphylococcus aureus, Escherichia coli, Aspergillus niger and Aspergillus flavus, supporting the in silico screening. In addition, their antitubercular activity was assessed using the MABA method. The compounds 3′-[(4-fluorophenylcarbonyl]-4′-phenylspiro[indole-3,2′-pyrrolidin]-2(1H-one 3a, 4′-(4-bromophenyl-3′-[(4-fluorophenylcarbonyl]-5′-(hydroxymethyl spiro[indole-3,2′-pyrrolidin]-2(1H-one 3e and 4′-(4-chlorophenyl-3′-[(4-fluorophenylcarbonyl]-5′-(2-methylpropylspiro[indole-3,2′-pyrrolidin]-2(1H-one 3g are potent molecules with MIC of 0.8 μg/mL. In the DPPH radical scavenging assay, compounds 4′-(4-chlorophenyl-3′-[(4-fluorophenylcarbonyl]spiro[indole-3,2′-pyrrolidin]-2(1H-one 3b, 4′-(4-chlorophenyl-3′-[(4-fluorophenylcarbonyl]-5′-(hydroxymethylspiro[indole-3,2′-pyrrolidin]-2(1H-one 3d and 4′-(4-bromophenyl-3′-[(4-fluorophenylcarbonyl]-5′-(hydroxymethylspiro[indole-3,2′-pyrrolidin]-2(1H-one 3e exhibited significant radical scavenging capacity. Keywords: Chalcone, Spiro-oxindole, Azomethine ylide, Antimicrobial activity, Molecular docking

In vitro Dissolution Studies on Solid Dispersions of Mefenamic Acid.

Science.gov (United States)

Rao, K R S Sambasiva; Nagabhushanam, M V; Chowdary, K P R

2011-03-01

Solid dispersions of mefanamic acid with a water-soluble polymer polyvinyl pyrrolidine and a super disintegrant, primojel were prepared by common solvent and solvent evaporation methods employing methanol as the solvent. The dissolution rate and dissolution efficiency of the prepared solid dispersions were evaluated in comparison to the corresponding pure drug. Solid dispersions of mefenamic acid showed a marked enhancement in dissolution rate and dissolution efficiency. At 1:4 ratio of mefenamic acid-primojel a 2.61 fold increase in the dissolution rate of mefenamic acid was observed with solid dispersion. The solid dispersions in combined carriers gave much higher rates of dissolution than super disintegrants alone. Mefanamic acid-primojel-polyvinyl pyrrolidine (1:3.2:0.8) solid dispersion gave a 4.11 fold increase in the dissolution rate of mefenamic acid. Super disintegrants alone or in combination with polyvinyl pyrrolidine could be used to enhance the dissolution rate of mefenamic acid.

Deoxyiminoalditols from Aldonic Acids - VI. - Preparation of the Four Stereoisomeric 4-Amino-3-hydroxypyrrolidines from Bromodeoxytetronic Acids. Discovery of a New alfa-Mannosidase Inhibitor

DEFF Research Database (Denmark)

Lundt, Inge; Limberg, Gerrit; Zavilla, John

1999-01-01

A convenient four step synthesis of amino hydroxy pyrrolidines is presented. From the readily available D- and L-tetronic acids the four possible stereoisomeric 4-amino-3-hydroxy pyrrolidines 14, 15, 17 and 19 could be accessed as crystalline compounds, avoiding any chromatographic purification....... The key step in the reactions was the regioselective formation of either the 2,4-diamino-2,4-dideoxy-D-threono-1,4-lactam (5) or the 3,4-diamino-3,4-dideoxy-L-erythrono-1,4-lactam (10) by treatment of the methyl 4-bromo-4-deoxy-2,3-cis- 3 or 2,3-trans- 9 epoxy tetronates, respectively, with liquid ammonia....... Thus, opposite regioselectivity for opening of the cis-configurated epoxide 3 (4 : 1, C-2 : C-3) and the trans-configurated epoxide 9 (3 : 7, C-2 : C-3) by ammonia was observed. - Initial testing as glycosidase inhibitors of the amino hydroxy pyrrolidines formed by reduction of the lactams showed...

Structural and sensory characterization of key pungent and tingling compounds from black pepper (Piper nigrum L.).

Science.gov (United States)

Dawid, Corinna; Henze, Andrea; Frank, Oliver; Glabasnia, Anneke; Rupp, Mathias; Büning, Kirsten; Orlikowski, Diana; Bader, Matthias; Hofmann, Thomas

2012-03-21

To gain a more comprehensive knowledge on whether, besides the well-known piperine, other compounds are responsible for the pungent and tingling oral impression imparted by black pepper, an ethanol extract prepared from black pepper (Piper nigrum L.) was screened for its key sensory-active nonvolatiles by application of taste dilution analysis (TDA). Purification of the compounds perceived with the highest sensory impact, followed by LC-MS and 1D/2D NMR experiments as well as synthesis, led to the structure determination of 25 key pungent and tingling phytochemicals, among which the eight amides 1-(octadeca-2E,4E,13Z-trienyl)piperidine, 1-(octadeca-2E,4E,13Z-trienyl)pyrrolidine, (2E,4E,13Z)-N-isobutyl-octadeca-2,4,13-trienamide, 1-(octadeca-2E,4E,12Z-trienoyl)-pyrrolidine, 1-(eicosa-2E,4E,15Z-trienyl)piperidine, 1-(eicosa-2E,4E,15Z-trienyl)pyrrolidine, (2E,4E,15Z)-N-isobutyl-eicosa-2,4,15-trienamide, and 1-(eicosa-2E,4E,14Z-trienoyl)-pyrrolidine were not yet reported in literature. Sensory studies by means of a modified half-tongue test revealed recognition thresholds ranging from 3.0 to 1150.2 nmol/cm² for pungency and from 520.6 to 2162.1 nmol/cm² for the tingling orosensation depending on their chemical structure.

Ethyl 27-oxo-15-oxa-2,20-diazahexacyclo[18.6.1.01,8.02,6.09,14.021,26]heptacosa-9,11,13,21,23,25-hexaene-7-carboxylate

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Devadasan Velmurugan

2013-01-01

Full Text Available In the title compound, C27H30N2O4, the pyrrolidine ring adopts a twisted conformation. The indoline ring system is almost perpendicular to the mean plane of the pyrrolidine ring, making a dihedral angle of 81.7 (8°. In the crystal, molecules are linked into centrosymmetric dimers with graph-set motif R22(16 via pairs of C—H...O hydrogen bonds. The terminal ethyl group of the ester group is disordered over two sets of sites, with a site-occupancy ratio of 0.587 (11:0.413 (11.

(1′S-4-(3,4-Dichlorophenyl-1′-(3,5-dimethoxyphenyl-1,2,3,4-tetrahydronaphthalene-2-spiro-2′-pyrrolizidine-3′-spiro-3′′-indoline-1,2′′-dione

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S. Sriman Narayanan

2008-10-01

Full Text Available In the title compound C37H32Cl2N2O4, the unsubstituted pyrrolidine ring shows a twist conformation whereas the substituted pyrrolidine ring shows an envelope conformation. The dimethoxy benzene ring is perpendicular to the tetralone ring, making a dihedral angle of 89.94 (5°. Molecules are linked into centrosymmetric dimers by N—H...O hydrogen bonds and the crystal structure is stabilized by C—H...π interactions and C—H...O hydrogen bonds. One methoxy group is disordered over two positions with the site occupancy factors of 0.84 (2 and 0.16 (2.

Current Status on Biochemistry and Molecular Biology of Microbial Degradation of Nicotine

Science.gov (United States)

Gurusamy, Raman; Natarajan, Sakthivel

2013-01-01

Bioremediation is one of the most promising methods to clean up polluted environments using highly efficient potent microbes. Microbes with specific enzymes and biochemical pathways are capable of degrading the tobacco alkaloids including highly toxic heterocyclic compound, nicotine. After the metabolic conversion, these nicotinophilic microbes use nicotine as the sole carbon, nitrogen, and energy source for their growth. Various nicotine degradation pathways such as demethylation pathway in fungi, pyridine pathway in Gram-positive bacteria, pyrrolidine pathway, and variant of pyridine and pyrrolidine pathways in Gram-negative bacteria have been reported. In this review, we discussed the nicotine-degrading pathways of microbes and their enzymes and biotechnological applications of nicotine intermediate metabolites. PMID:24470788

Studies on the Red Sea Sponge Haliclona sp. for its Chemical and Cytotoxic Properties.

Science.gov (United States)

Al-Massarani, Shaza Mohamed; El-Gamal, Ali Ali; Al-Said, Mansour Sulaiman; Abdel-Kader, Maged S; Ashour, Abdelkader E; Kumar, Ashok; Abdel-Mageed, Wael M; Al-Rehaily, Adnan Jathlan; Ghabbour, Hazem A; Fun, Hoong-Kun

2016-01-01

A great number of novel compounds with rich chemical diversity and significant bioactivity have been reported from Red Sea sponges. To isolate, identify, and evaluate the cytotoxic activity of the chemical constituents of a sponge belonging to genus Haliclona collected from the Eastern coast of the Red Sea. The total ethanolic extract of the titled sponge was subjected to intensive chromatographic fractionation and purification guided by cytotoxic bioassay toward various cancer cell lines. The structures of the isolated compounds were elucidated using spectroscopic techniques including one-dimension and two-dimension nuclear magnetic resonance, mass spectrometry, ultraviolet, and infrared data, as well as comparison with the reported spectral data for the known compounds. X-ray single-crystal structure determination was performed to determine the absolute configuration of compound 4. The screening of antiproliferative activity of the compounds was carried on three tumor cell lines, namely the human cervical cancer (HeLa), human hepatocellular carcinoma (HepG2), and human medulloblastoma (Daoy) cells using MTT assay. This investigation resulted in the isolation of a new indole alkaloid, 1-(1H-indol-3-yloxy) propan-2-ol (1), with the previously synthesized pyrrolidine alkaloid, (2R, 3S, 4R, 5R) pyrrolidine-(1-hydroxyethyl)-3,4-diol hydrochloride (4), isolated here from a natural source for the first time. In addition, six known compounds tetillapyrone (2), nortetillapyrone (3), 2-methyl maleimide-5-oxime (5), maleimide-5-oxime (6), 5-(hydroxymethyl) dihydrofuran-2 (3H)-one (7), and ergosta-5,24 (28)-dien-3-ol (8) were also identified. Most of the isolated compounds exhibited weak cytotoxic activity against HepG-2, Daoy, and HeLa cancer cell lines. This is the first report of the occurrence of the indole and pyrrolidine alkaloids, 1-(1H-indol-2-yloxy) propan-2-ol (1), and the - (1-hydroxyethyl)-3,4-diol hydrochloride (4), in the Red Sea Haliclona sp. From the Red Sea

11-[(E-Benzylidene]-14-hydroxy-8-phenyl-6-thia-3,13-diazaheptacyclo[13.7.1.19,13.02,9.02,14.03,7.019,23]tetracosa-1(22,15(23,16,18,20-pentaen-10-one

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Raju Suresh Kumar

2012-07-01

Full Text Available In the title compound, C34H28N2O2S, the piperidine ring adopts a chair conformation. One of the pyrrolidine rings adopts an envelope conformation with the methylene C atom at the flap whereas the other pyrrolidine ring and the thiazolidine ring adopt half-chair conformations. The mean plane of the dihydroacenaphthylene ring system [maximum deviation = 0.067 (1 Å] makes dihedral angles of 28.31 (5 and 31.32 (6° with the two terminal benzene rings. An intramolecular O—H...N hydrogen bond forms an S(5 ring motif. In the crystal, molecules are linked by C—H...O and C—H...S hydrogen bonds into layers lying parallel to the ac plane.

Synthesis of cefepime-d3 and cefepime-d8

International Nuclear Information System (INIS)

Kamachi, Hajime; Okita, Takaaki; Tsuno, Takashi; Naito, Takayuki

1990-01-01

Synthesis of cefepime-d 3 (6a) and cefepime-d 8 (6b) is described. Diphenylmethyl 7-benzylideneamino-3-chloromethyl-3-cephem-4-carboxylate (2) was treated with sodium iodide to afford the iodide 3, which was without isolation, allowed to react with N-methyl-d 3 -pyrrolidine to give the quaternary salt 4a. Deblocking of 4a with HCO 2 H and HCl gave 7-amino-3-(N-methyl-d3-pyrrolidinio)methyl-3-cephem-4-carboxylate hydrochloride (5a). Acylation of 5a with benzotriazol-1-yl (Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetate followed by treatment with dil. H 2 SO 4 afforded 6a sulfate. In the same way, 6b was synthesized using N-methyl-pyrrolidine-d 8 . (author)

Ring Expansion of Vinylaziridines through the Strain-Release Pericyclic Reaction: Recent Developments and Applications

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Yu Mi Heo

2013-08-01

Full Text Available Recent syntheses of azetidines, pyrrolidines, piperidines and azepines through cycloaddition or sigmatropic rearrangements of vinylaziridines are described. Applications to natural product synthesis and mechanistic investigations are also summarized.

[Intervention of pyrrolidine dithiocarbamate on expressions of connective tissue growth factor, type I collagen, and type III collage in acute paraquat poisoned rats].

Science.gov (United States)

Huang, Min; Yang, Hui-fang; Zhang, Ping; Chang, Xiu-li; Zhou, Zhi-jun

2013-01-01

To observe the changes in the expression of connective tissue growth factor (CTGF), type I collagen (Col I), and type III collagen (Col III) among the rats with acute paraquat (PQ) poisoning and the intervention effect of pyrrolidine dithiocarbamate (PDTC) on their expression, and to investigate the mechanism of PQ-induced pulmonary fibrosis and the intervention effect of PDTC on the disease. Sprague-Dawley rats were randomly divided into control group (n = 6), PQ group (n = 36), and PQ + PDTC group (n = 36). The PQ group and PQ + PDTC group were given a single dose of saline-diluted PQ (80 mg/kg) by gavage; 2 h later, the PQ + PDTC group was intraperitoneally injected with a single dose of PDTC (100 mg/kg), and the PQ group was intraperitoneally injected with the same amount of saline. The control group was given saline (1 ml/kg) by gavage and was intraperitoneally injected with the same amount of saline 2h later. At 1, 3, 7, 14, 25, and 56 days after operation, the protein expression of CTGF was evaluated by Western blot; the mRNA expression of CTGF, Col I, and Col III was analyzed by real-time quantitative PCR; the content of hydroxyproline in lung tissue was measured, and the pathological changes of lung tissue of the poisoned rats were observed. The protein expression of CTGF in the PQ group increased as the time went on, slowly from the 3rd to the 14th day and rapidly from the 28th to the 56th day, significantly higher than that in the control group at each time point (P < 0.05 or P < 0.01). The mRNA expression of CTGF in the PQ group began to rise markedly on the 1st day, increased rapidly from the 3rd to the 14th day, and remained at a relatively high level from the 28th to the 56th day, significantly higher than that in the control group at each time point (P < 0.01). The mRNA expression of Col I in the PQ group changed little on the 1st and 3rd day, increased slightly on the 7th day, and increased greatly from the 14th to the 56th day, significantly

4′-Methyl-14′,19′-dioxa-4′-azaspiro[acenaphthylene-1,5′-tetracyclo[18.4.0.02,6.08,13]tetracosane]-1′(24′,8′,10′,12′,20′,22′-hexaene-2,7′(1H-dione

Directory of Open Access Journals (Sweden)

Sibi Narayanan

2012-12-01

Full Text Available In the title compound, C33H29NO4, the acenaphthylene ring system is essentially planar (r.m.s. deviation = 0.0290 Å. The pyrrolidine ring adopts a C-envelope conformation with a C atom displaced by 0.671 (2 Å from the mean-plane formed by the remaining ring atoms. The pyrrolidine ring is fused to acenaphthylene ring system making a dihedral angle of 88.0 (7°. In the crystal, molecules are linked into R22(9 dimers via C—H...N and C—H...O hydrogen bonds. Two C atoms act as donors to the same O atom acceptor, resulting in the formation of R21(7 ring motifs. These two motifs combine to form hydrogen-bonded sheets running along the a- and b-axis directions.

Human Acid β-Glucosidase Inhibition by Carbohydrate Derived Iminosugars: Towards New Pharmacological Chaperones for Gaucher Disease.

Science.gov (United States)

Parmeggiani, Camilla; Catarzi, Serena; Matassini, Camilla; D'Adamio, Giampiero; Morrone, Amelia; Goti, Andrea; Paoli, Paolo; Cardona, Francesca

2015-09-21

A collection of carbohydrate-derived iminosugars belonging to three structurally diversified sub-classes (polyhydroxylated pyrrolidines, piperidines, and pyrrolizidines) was evaluated for inhibition of human acid β-glucosidase (glucocerebrosidase, GCase), the deficient enzyme in Gaucher disease. The synthesis of several new pyrrolidine analogues substituted at the nitrogen or α-carbon atom with alkyl chains of different lengths suggested an interpretation of the inhibition data and led to the discovery of two new GCase inhibitors at sub-micromolar concentration. In the piperidine iminosugar series, two N-alkylated derivatives were found to rescue the residual GCase activity in N370S/RecNcil mutated human fibroblasts (among which one up to 1.5-fold). This study provides the starting point for the identification of new compounds in the treatment of Gaucher disease. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Crystal structure of 2′-[(2′,4′-difluorobiphenyl-4-ylcarbonyl]-1′-phenyl-1′,2′,5′,6′,7′,7a'-hexahydrospiro[indole-3,3′-pyrrolizin]-2(1H-one

Directory of Open Access Journals (Sweden)

M. Fathimunnisa

2015-08-01

Full Text Available In the title pyrrolizidine derivative, C33H26F2N2O2, both pyrrolidine rings of the pyrrolizidine moiety adopt an envelope conformation. The difluorophenyl group is oriented at an angle of 54.3 (1° with respect to the oxindole moiety. The crystal packing features an N—H...O hydrogen bond, which forms an R22(8 motif, and a C—H...O interaction, which generates a C(8 chain along [010]. In addition, this chain structure is stabilized by C—H...π interactions. In one of the pyrrolidine rings, the methylene group forming the flap of an envelope and the H atoms of the adjacent methylene groups are disordered over two sets of sites, with site-occupancy factors of 0.571 (4 and 0.429 (4

An Ugi Reaction Incorporating a Redox-Neutral Amine C-H Functionalization Step.

Science.gov (United States)

Zhu, Zhengbo; Seidel, Daniel

2016-02-19

Pyrrolidine and 1,2,3,4-tetrahydroisoquinoline (THIQ) undergo redox-neutral α-amidation with concurrent N-alkylation upon reaction with aromatic aldehydes and isocyanides. Reactions are promoted by acetic acid and represent a new variant of the Ugi reaction.

Study of Serum Drug Levels in Calves Following Intramuscular Administration of Three Tetracycline Drug Preparations

OpenAIRE

Black, W. D.; Claxton, J.; Robinson, G. A.

1982-01-01

Three antibiotic formulations, oxytetracycline (A) in propylene glycol and oxytetracycline (B) in polyvinyl pyrrolidine and pyrrolidino-methyltetracycline in an oil suspension were given to calves by the intramuscular route. Only oxytetracycline (A) appeared to cause much pain after injection.

Stabilization of colloidal palladium particles by a block copolymer of polystyrene and a block containing amide sidegroups

NARCIS (Netherlands)

Roescher, G.A.; Roescher, A.; Hempenius, Mark A.; Klok, H.A.; Moller, M.; Möller, M.

1996-01-01

A block copolymer of polystyrene and poly(tert-butylmethacrylate) was prepared by anionic polymerization. The ester groups of the poly(tert-butylmethacrylate) were hydrolyzed, after wich the remaining carboxyl groups were reacted with pyrrolidine. The resulting block copolymer with amide sidegroups

Biological activity of the alkaloids of Erythroxylum coca and Erythroxylum novogranatense

NARCIS (Netherlands)

Salemink, C.A.; Novák, M.; Khan, I.

1984-01-01

The cultivated Erythroxylum varieties E. coca var. coca, E. coca var. ipadu, E. novogranatense var. novogranatense and E. novogranatense var. truxillense contain 18 alkaloids, identified so far, belonging to the tropanes, pyrrolidines and pyridines, with cocaine as the main alkaloid. The biological

Tying up Nicotine: New Selective Competitive Antagonist of the Neuronal Nicotinic Acetylcholine Receptors

DEFF Research Database (Denmark)

Petersen, Ida Nymann; Crestey, François; Jensen, Anders A

2015-01-01

Conformational restriction of the pyrrolidine nitrogen in nicotine by the introduction of an ethylene bridge provided a potent and selective antagonist of the α4β2-subtype of the nicotinic acetylcholine receptors. Resolution by chiral SFC, pharmacological characterization of the two enantiomers...

Fullerene-based Anchoring Groups for Molecular Electronics

DEFF Research Database (Denmark)

Martin, Christian A.; Ding, Dapeng; Sørensen, Jakob Kryger

2008-01-01

We present results on a new fullerene-based anchoring group for molecular electronics. Using lithographic mechanically controllable break junctions in vacuum we have determined the conductance and stability of single-molecule junctions of 1,4-bis(fullero[c]pyrrolidin-1-yl)benzene. The compound can...

Asymmetric synthesis of synthetic alkaloids by a tandem biocatalysis/Ugi/Pictet-Spengler-type

NARCIS (Netherlands)

Znabet, A.; Zonneveld, J.; Janssen, E.; de Kanter, F.J.J.; Helliwell, M.; Turner, N.J.; Ruijter, E.; Orru, R.V.A.

2010-01-01

We have combined the biocatalytic desymmetrization of 3,4-cis-substituted meso-pyrrolidines with an Ugi-type multicomponent reaction followed in situ by a Pictet-Spengler-type cyclization reaction sequence for the rapid asymmetric synthesis of alkaloid-like polycyclic compounds. © The Royal Society

Expedient Access to an N -phenylpyrrolidin-2-yl Heterocycle via a ...

African Journals Online (AJOL)

Expedient Access to an N -phenylpyrrolidin-2-yl Heterocycle via a Base-Induced Intramolecular aza -Michael Reaction. ... in good overall yield when employing a stoichiometric amount of base to facilitate the intramolecular aza-Michael reaction. Keywords: aza Michael, intramolecular, catalysed, piperidine, pyrrolidine, base ...

Aggregation behavior of fullerenes in aqueous solutions: a capillary electrophoresis and asymmetric flow field-flow fractionation study

NARCIS (Netherlands)

Astefanei, A.; Núñez, O.; Galceran, M.T.; Kok, W.Th.; Schoenmakers, P.J.

2015-01-01

In this work, the electrophoretic behavior of hydrophobic fullerenes [buckminsterfullerene (C-60), C-70, and N-methyl-fulleropyrrolidine (C-60-pyrr)] and water-soluble fullerenes [fullerol (C-60(OH)(24)); polyhydroxy small gap fullerene, hydrated (C-120(OH)(30)); C-60 pyrrolidine tris acid

The Development of an Aza-C-Glycoside Library Based on a Tandem Staudinger/Aza-Wittig/Ugi Three-Component Reaction

NARCIS (Netherlands)

Wennekes, T.; Bonger, K.M.; Vogel, K.; Berg, van den S.A.; Strijland, A.; Donker-Koopman, W.E.; Aerts, J.; Marel, van der A.; Overkleeft, H.S.

2012-01-01

We report the tandem Staudinger/aza-Wittig/Ugi three-component reaction mediated synthesis of a 64-member compound library of aza-C-glycosides. The library is composed of four pyrrolidine and three piperidine scaffolds, onto which a number of functional groups is grafted to form seven sublibraries.

Regulatory mechanisms of viral hepatitis B and C

Indian Academy of Sciences (India)

Unknown

NS5A, nonstructural protein 5A; PDTC, pyrrolidine dithiocarbamate; PKR, double stranded RNA-dependent protein kinase; ROS, reactive oxygen ... unifying and simplifying generalization, rather than in the description of isolated situation-in the visualization of simple ... of work has focused on liver-specific aspects of HBV.

4′-Methyl-1H-14′,19′-dioxa-4′-azaspiro[indole-3,5′-tetracyclo[18.4.0.02,6.08,13]tetracosane]-1′(24′,8′,10′,12′,20′,22′-hexaene-2,7′(3H-dione

Directory of Open Access Journals (Sweden)

Sibi Narayanan

2012-12-01

Full Text Available In the title compound, C29H28N2O4, the indoline ring system is essentially planar, with a maximum deviation of 0.027 (2 Å; the carbonyl O atom lies 0.102 (1 Å out of the least-squares plane of the indole ring. The pyrrolidine ring adopts a C-envelope conformation, with a C atom displaced by 0.643 (2 Å from the mean plane formed by the remaining ring atoms. The pyrrolidine ring makes a dihedral angle of 86.1 (8° with the indoline ring system. In the crystal, N—H...O hydrogen bonds result in the formation of cyclic centrosymmetric dimers [R22(8]. C—H...π interactions also occur, leading to a chain along the b-axis direction. There is a rather weak π–π electron interaction between the pyrrazole and benzene rings, with a centroid–centroid distance of 3.765 (1 Å.

Comment on "An unexpected formation of the novel 7-oxa-2-azabicyclo[2.2.1]hept-5-ene skeleton during the reaction of furfurylamine with maleimides and their bioprospection using a zebrafish embryo model" by C. E. Puerto Galvis and V. V. Kouznetsov, Org. Biomol. Chem., 2013, 11, 407.

Science.gov (United States)

Zubkov, F I; Kvyatkovskaya, E A; Nikitina, E V; Amoyaw, P N-A; Kouznetsov, V V; Lazarenko, V A; Khrustalev, V N

2017-08-02

It has been proved that the reaction between furfuryl amines and N-R-maleimides leads to the formation of aza-Michael addition products - 3-(furylmethylamino)-N-R-pyrrolidine-2,5-diones, instead of 7-oxa-2-azabicyclo[2.2.1]hept-5-enes, as this journal reported previously.

ALKALOIDS OF SOME EUROPEAN AND MACARONESIAN SEDOIDEAE AND SEMPERVIVOIDEAE (CRASSULACEAE)

NARCIS (Netherlands)

STEVENS, JF; THART, H; HENDRIKS, H; MALINGRE, TM

1992-01-01

Some 22 pyrrolidine and piperdine alkaloids were detected in the leafy parts of Sedum acre, S. aetnense, S. anglicum, S. brissemoreti, S. farinosum, S. fusiforme, S. lancerottense, S. melanantherum, and S. nudum. In addition to the alkaloids known from S. acre, 1-(2-pyrrolidyl)-propan-2-one and

Non-Heme Iron Catalysts with a Rigid Bis-Isoindoline Backbone and Their Use in Selective Aliphatic C−H Oxidation

NARCIS (Netherlands)

Chen, Jianming; Lutz, Martin; Milan, Michela; Costas, Miquel; Otte, Matthias; Klein Gebbink, Bert

2017-01-01

Iron complexes derived from a bis-isoindoline-bis-pyridine ligand platform based on the BPBP ligand (BPBP=N,N′-bis(2-picolyl)-2,2′-bis-pyrrolidine) have been synthesized and applied in selective aliphatic C−H oxidation with hydrogen peroxide under mild conditions. The introduction of benzene

IBX-mediated oxidation of unactivated cyclic amines: application in highly diastereoselective oxidative Ugi-type and aza-Friedel-Crafts reactions.

Science.gov (United States)

de Graaff, C; Bensch, L; van Lint, Matthijs J; Ruijter, E; Orru, R V A

2015-10-28

The first o-iodoxybenzoic acid (IBX) mediated oxidation of unactivated amines to imines is described. A range of meso-pyrrolidines were shown to be suitable substrates. The chemical space was further explored with one-pot oxidative Ugi-type and aza-Friedel-Crafts reactions, which proved to be highly diastereoselective.

Identification and analytical characterization of nine synthetic cathinone derivatives N-ethylhexedrone, 4-Cl-pentedrone, 4-Cl-α-EAPP, propylone, N-ethylnorpentylone, 6-MeO-bk-MDMA, α-PiHP, 4-Cl-α-PHP, and 4-F-α-PHP.

Science.gov (United States)

Liu, Cuimei; Jia, Wei; Li, Tao; Hua, Zhendong; Qian, Zhenhua

2017-08-01

Clinical and forensic toxicology laboratories are continuously confronted by analytical challenges when dealing with the new psychoactive substances (NPS) phenomenon. In this study, the analytical characterization of nine synthetic cathinones is described: 2-(ethylamino)-1-phenylhexan-1-one (N-ethylhexedrone 1), 1-(4-chlorophenyl)-2-(methylamino)pentan-1-one (4-Cl-pentedrone 2), 1-(4-chlorophenyl)-2-(ethylamino)pentan-1-one (4-Cl-α-EAPP 3), 1-(3,4-methylenedioxyphenyl)-2-propylaminopropan-1-one (propylone 4), 1-(3,4-methylenedioxyphenyl)-2-ethylaminopentan-1-one (N-ethylnorpentylone 5), 1-(6-methoxy-3,4-methylenedioxyphenyl)-2-methylaminopropan-1-one (6-MeO-bk-MDMA 6), 4-methyl-1-phenyl-2-(pyrrolidin-1-yl)pentan-1-one (α-PiHP 7), 1-(4-chlorophenyl)-2-(pyrrolidin-1-yl)hexan-1-one (4-Cl-α-PHP 8), and 1-(4-fluorophenyl)-2-(pyrrolidin-1-yl)hexan-1-one (4-F-α-PHP 9). The identification was based on ultra-high-performance liquid chromatography-quadrupole time-of-flight-mass spectrometry (UHPLC-QTOF-MS), gas chromatography-mass spectrometry (GC-MS), and nuclear magnetic resonance (NMR) spectroscopy. The mass-spectral fragmentations of these compounds following collision-induced dissociation (CID) and electron ionization (EI) were studied to assist forensic laboratories in identifying these compounds or other substances with similar structure in their case work. To our knowledge, no analytical data about the compounds 1-4, 7, and 8 have appeared until now, making this the first report on these compounds. The GC-MS data of 5, 6 and 9 has been reported, but this study added the LC-MS, Fourier Transform Infrared (FTIR) and NMR data for additional characterization. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Proline-Based Carbamates as Cholinesterase Inhibitors

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Hana Pizova

2017-11-01

Full Text Available Series of twenty-five benzyl (2S-2-(arylcarbamoylpyrrolidine-1-carboxylates was prepared and completely characterized. All the compounds were tested for their in vitro ability to inhibit acetylcholinesterase (AChE and butyrylcholinesterase (BChE, and the selectivity of compounds to individual cholinesterases was determined. Screening of the cytotoxicity of all the compounds was performed using a human monocytic leukaemia THP-1 cell line, and the compounds demonstrated insignificant toxicity. All the compounds showed rather moderate inhibitory effect against AChE; benzyl (2S-2-[(2-chlorophenylcarbamoyl]pyrrolidine-1-carboxylate (IC50 = 46.35 μM was the most potent agent. On the other hand, benzyl (2S-2-[(4-bromophenyl-] and benzyl (2S-2-[(2-bromophenylcarbamoyl]pyrrolidine-1-carboxylates expressed anti-BChE activity (IC50 = 28.21 and 27.38 μM, respectively comparable with that of rivastigmine. The ortho-brominated compound as well as benzyl (2S-2-[(2-hydroxyphenylcarbamoyl]pyrrolidine-1-carboxylate demonstrated greater selectivity to BChE. The in silico characterization of the structure–inhibitory potency for the set of proline-based carbamates considering electronic, steric and lipophilic properties was provided using comparative molecular surface analysis (CoMSA and principal component analysis (PCA. Moreover, the systematic space inspection with splitting data into the training/test subset was performed to monitor the statistical estimators performance in the effort to map the probability-guided pharmacophore pattern. The comprehensive screening of the AChE/BChE profile revealed potentially relevant structural and physicochemical features that might be essential for mapping of the carbamates inhibition efficiency indicating qualitative variations exerted on the reaction site by the substituent in the 3′-/4′-position of the phenyl ring. In addition, the investigation was completed by a molecular docking study of recombinant human AChE.

Synthesis of some glycoside analogs and related compounds from 9-amino-6-(methylthio)-9H-purine.

Science.gov (United States)

Temple, C; Kussner, C L; Montgomery, J A

1975-12-01

Additional information on the anticancer activity of 9-amino-9H-purine-6(1H)-thione and its derivatives was sought by the synthesis of some 9-(substituted amino)-6-(methylthio)-9H-purines in which the 9-substituent contained functional groups capable of either reversible or irreversible binding with an enzymatic site. Condensation of 9-amino-6-(methylthio)-9H-purine (1) with some carbonyl compounds followed by hydride reduction of the azomethine linkage in the intermediates leads to the 2-pyrrolylmethyl (8), 2,3,4-trihydroxybutyl (10), and the 1,5-dihydroxy-2- and 3-pentyl (11 and 12) compounds. A 4-hydroxybutyl derivative (13) was obtained by alkylation of 18, the 9-acetyl derivative of 1, with 4-chlorobutyl acetate followed by saponification. The cyclization of 13 and 11 with a sulfonyl chloride gave the 9-pyrrolidin-1-yl (27) and the 9-[2-(tosyloxymethyl)pyrrolidin-1-yl] (28), respectively. Acylation of 1 with ethyl L-2-pyrrolidine-5-carboxylate and ethyl 1-methyl-5-pyrrolidone-3-carboxylate, respectively, in Me2SO containing NaH gave the corresponding amides 15 and 17. Alkylation of 18 with 1-bromo-2-chloroethane and epichlorohydrin gave the N-(2-chloroethyl) and N-(1,2-epoxy-3-propyl) derivatives 19 and 20. The chloro group of the chlorobutyl derivative of 18 was displaced with KSCN and NaN3, respectively, to give the thiocyanate and azido derivatives 23 and 24. Hydrogenation of the latter gave the amine (25), which was acylated with ethyl chloroformate to give the (ethoxycarbonyl)amino compound 26. None of these compounds showed activity against L1210 leukemia cells implanted ip in mice on a single-dose schedule, suggesting that the activity observed in the simpler 9-aminopurines resulted from cleavage of the hydrazino linkage to give pH-purine-6(1H)-thione.

1-Benzyl-2-(1H-indol-3-yl-5-oxopyrrolidine-2-carbonitrile

Directory of Open Access Journals (Sweden)

Raymond Schinazi

2008-02-01

Full Text Available In the title compound, C20H17N3O, a potential anti-human immunodeficiency virus type 1 (HIV-1 non-nucleoside reverse-transcriptase inhibitor, the pyrrolidine ring has an envelope conformation. In the crystal structure, adjacent molecules are connected into infinite chains via an N—H...O hydrogen bond.

Design of Plasmodium vivax Hypoxanthine-Guanine Phosphoribosyltransferase Inhibitors as Potential Antimalarial Therapeutics

Czech Academy of Sciences Publication Activity Database

Keough, D. T.; Rejman, Dominik; Pohl, Radek; Zborníková, Eva; Hocková, Dana; Croll, T.; Edstein, M. D.; Birrell, G. W.; Chavchich, M.; Naesens, L. M. J.; Pierens, G. K.; Brereton, I. M.; Guddat, L. W.

2018-01-01

Roč. 13, č. 1 (2018), s. 82-90 ISSN 1554-8929 R&D Projects: GA ČR(CZ) GA16-06049S; GA ČR GA15-11711S Institutional support: RVO:61388963 Keywords : plasmodium vivax * inhibitor * pyrrolidine nucleotide bisphosphonate * HXGPRT Subject RIV: CC - Organic Chemistry OBOR OECD: Organic chemistry Impact factor: 4.995, year: 2016

1-(4-Bromobenzoyl-2-phenylpyrrolidine-2-carboxamide

Directory of Open Access Journals (Sweden)

Vahan Martirosyan

2008-03-01

Full Text Available In the title compound, C18H17BrN2O2, which is a potential human immunodeficiency virus type 1 (HIV-1 non-nucleoside reverse transcriptase inhibitor, the pyrrolidine ring exhibits an envelope conformation. In the crystal structure, intermolecular N—H...O hydrogen bonds [N...O = 2.861 (3 Å] link the molecules into centrosymmetric dimers.

7-Chloro-11a-phenyl-2,3,5,10,11,11a-hexahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine-5,11-dione

Directory of Open Access Journals (Sweden)

Vahan Martirosyan

2008-03-01

Full Text Available The title compound, C18H15ClN2O2, is a potential human immunodeficiency virus type-1 (HIV-1 non-nucleoside reverse transcriptase inhibitor. The pyrrolidine ring adopts an envelope and the diazepine ring a boat conformation. In the crystal structure, two isomers (R and S form centrosymmetric dimers via N—H...O hydrogen bonds.

N-Iodosuccinimide-Promoted Hofmann-Löffler Reactions of Sulfonimides under Visible Light.

Science.gov (United States)

O'Broin, Calvin Q; Fernández, Patricia; Martínez, Claudio; Muñiz, Kilian

2016-02-05

Conditions for an attractive and productive protocol for the position-selective intramolecular C-H amination of aliphatic groups (Hofmann-Löffler reaction) are reported employing sulfonimides as nitrogen sources. N-Iodosuccinimide is the only required promoter for this transformation, which is conveniently initiated by visible light. The overall transformation provides pyrrolidines under mild and selective conditions as demonstrated for 17 different substrates.

Discovery and optimization of adamantyl carbamate inhibitors of 11β-HSD1.

Science.gov (United States)

Tice, Colin M; Zhao, Wei; Krosky, Paula M; Kruk, Barbara A; Berbaum, Jennifer; Johnson, Judith A; Bukhtiyarov, Yuri; Panemangalore, Reshma; Scott, Boyd B; Zhao, Yi; Bruno, Joseph G; Howard, Lamont; Togias, Jennifer; Ye, Yuan-Jie; Singh, Suresh B; McKeever, Brian M; Lindblom, Peter R; Guo, Joan; Guo, Rong; Nar, Herbert; Schuler-Metz, Annette; Gregg, Richard E; Leftheris, Katerina; Harrison, Richard K; McGeehan, Gerard M; Zhuang, Linghang; Claremon, David A

2010-11-15

Synthesis of 2-adamantyl carbamate derivatives of piperidines and pyrrolidines led to the discovery of 9a with an IC(50) of 15.2 nM against human 11β-HSD1 in adipocytes. Optimization for increased adipocyte potency, metabolic stability and selectivity afforded 11k and 11l, both of which were >25% orally bioavailable in rat. Copyright © 2010 Elsevier Ltd. All rights reserved.

Vacuum ultraviolet photochemistry of tetrahydrothiophene and sulfolane

International Nuclear Information System (INIS)

Scala, A.A.; Colon, I.

1979-01-01

The vacuum uv photolysis of tetrahydrothiophene (THT) involves the breaking of the S to α-C bond. Besides ethylene, C 3 H 6 and 1,3-butadiene are also formed. Photolyses of THT, tetrahydrofuran, and pyrrolidine are similar. The vacuum uv photolysis of tetramethylene sulfone (sulfolane) was also studied; products are SO 2 , cyclobutane, 1-butene, and ethylene. No cis-2-butene was observed

Piracetam and TRH analogues antagonise inhibition by barbiturates, diazepam, melatonin and galanin of human erythrocyte D-glucose transport

OpenAIRE

Naftalin, Richard J; Cunningham, Philip; Afzal-Ahmed, Iram

2004-01-01

Nootropic drugs increase glucose uptake into anaesthetised brain and into Alzheimer's diseased brain. Thyrotropin-releasing hormone, TRH, which has a chemical structure similar to nootropics increases cerebellar uptake of glucose in murine rolling ataxia. This paper shows that nootropic drugs like piracetam (2-oxo 1 pyrrolidine acetamide) and levetiracetam and neuropeptides like TRH antagonise the inhibition of glucose transport by barbiturates, diazepam, melatonin and endogenous neuropeptide...

A new feruloyl amide derivative from the fruits of Tribulus terrestris.

Science.gov (United States)

Zhang, Xiaopo; Wei, Na; Huang, Jian; Tan, Yinfeng; Jin, Dejun

2012-01-01

A new feruloyl amide derivative, named tribulusamide C, was isolated from the fruits of Tribulus terrestris. Its structure was determined on the basis of spectroscopic analysis including IR, 1-D-, 2-D-NMR and HR-ESI-MS. The structure of tribulusamide C was characterised by a unit of pyrrolidine-2,5-dione, which distinguished it from other lignanamides previously isolated from the fruits of T. terrestris.

Diclofenac salts, part 6: release from lipid microspheres.

Science.gov (United States)

Fini, Adamo; Cavallari, Cristina; Rabasco Alvarez, Antonio M; Rodriguez, Marisa Gonzalez

2011-08-01

The release of diclofenac (20%, w/w) was studied from lipidic solid dispersions using three different chemical forms (acid, sodium salt, and pyrrolidine ethanol salt) and two different lipid carriers (Compritol 888 ATO or Carnauba wax) either free or together with varying amounts (10%-30%, w/w) of stearic acid. Microspheres were prepared by ultrasound-assisted atomization of the molten dispersions and analyzed by scanning electron microscopy, differential scanning calorimetry, and hot stage microscopy. The effects of different formulations on the resulting drug release profiles as a function of pH were studied and the results were discussed. The formulation of the 18 systems and the chemical form of the drug were found to strongly affect the mode of the drug release. The solubility of the chemical forms in the lipid mixture is in the following order: pyrrolidine ethanol salt ≫ acid > sodium salt (according to the solubility parameters), and the nature of the systems thus obtained ranges from a matrix, for mutually soluble drug/carrier pairs, to a microcapsule, for pairs wherein mutual solubility is poor. Drug release from microspheres prepared by pure lipids was primarily controlled by diffusion, whereas the release from microspheres containing stearic acid was diffusion/erosion controlled at pH 7.4. Copyright © 2011 Wiley-Liss, Inc.

Electroencephalographic, behavioral and receptor binding correlates of phencyclinoids in the rat

International Nuclear Information System (INIS)

Mattia, A.; Marquis, K.L.; Leccese, A.P.; el-Fakahany, E.E.; Moreton, J.E.

1988-01-01

The pharmacology and structure-activity relationship of phencyclidine (PCP)-like drugs (phencyclinoids) were studied using electroencephalographic (EEG), behavioral and receptor binding techniques. The effects of PCP, 1-phenylcyclohexylamine HCl, N-methyl-1-phenycyclohexylamine HCl, N-ethyl-1-phenylcyclohexylamine HCl, N-(s-butyl)-1-phenylcyclohexylamine HCL, 1-(1-phenylcyclo-hexyl)-pyrrolidine HCl, 1-[1-(2-thienyl)cyclohexyl] piperidine HCl, 1-[1-(2-thienyl)cyclohexyl]-pyrrolidine HCl, ketamine and (+/-)-SKF 10047 were evaluated on the direct EEG and EEG spectra after acute i.v. injections (0.1-17.8 mg/kg). Similarities and differences were noted in the EEG dose-response curves. At lower doses of PCP and its analogs, low-amplitude theta waves predominated; however, at higher doses, high-amplitude, lower-frequency waves predominated. Qualitatively, the N-piperidine derivatives were similar to PCP and differed primarily in potency. The benzomorphan (+/-)-SKF 10047 produced only theta activity at doses up to 12.8 mg/kg. These EEG effects occurred in conjunction with overt behaviors including locomotion, stereotypy and ataxia, concurrently assessed via observer-based rating scales. A strong correlation (r = 0.98) was obtained between the EEG and behavioral effects and the IC50 values from [ 3 H]PCP displacement experiments using crude rat brain homogenates

Density functional study of the electronic structure of dye-functionalized fullerenes and their model donor-acceptor complexes containing P3HT

International Nuclear Information System (INIS)

Baruah, Tunna; Garnica, Amanda; Paggen, Marina; Basurto, Luis; Zope, Rajendra R.

2016-01-01

We study the electronic structure of C 60 fullerenes functionalized with a thiophene-diketo-pyrrolopyrrole-thiophene based chromophore using density functional theory combined with large polarized basis sets. As the attached chromophore has electron donor character, the functionalization of the fullerene leads to a donor-acceptor (DA) system. We examine in detail the effect of the linker and the addition site on the electronic structure of the functionalized fullerenes. We further study the electronic structure of these DA complexes with a focus on the charge transfer excitations. Finally, we examine the interface of the functionalized fullerenes with the widely used poly(3-hexylthiophene-2,5-diyl) (P3HT) donor. Our results show that all functionalized fullerenes with an exception of the C 60 -pyrrolidine [6,6], where the pyrrolidine is attached at a [6,6] site, have larger electron affinities relative to the pristine C 60 fullerene. We also estimate the quasi-particle gap, lowest charge transfer excitation energy, and the exciton binding energies of the functionalized fullerene-P3MT model systems. Results show that the exciton binding energies in these model complexes are slightly smaller compared to a similarly prepared phenyl-C 61 -butyric acid methyl ester (PCBM)-P3MT complex.

Supported L-pyrrolidine-2-carboxylic acid-4-hydrogen sulphate on ...

Indian Academy of Sciences (India)

pounds.2 Furthermore, a field of increasing interest is the synthesis of useful ... MCRs is of interest.3–5 β-Acetamido ketones .... we decide to introduce a new, simple, mild and effective .... Financial support for this study by the Research Affairs.

The inhibition of NF-kappaB activation pathways and the induction of apoptosis by dithiocarbamates in T cells are blocked by the glutathione precursor N-acetyl-L-cysteine

OpenAIRE

Fernandez, P C; Machado, J; Heussler, Volker; Botteron, C; Palmer, G H; Dobbelaere, D A

1999-01-01

Nuclear factor-kappaB regulates genes that control immune and inflammatory responses and are involved in the pathogenesis of several diseases, including AIDS and cancer. It has been proposed that reactive oxygen intermediates participate in NF-kappaB activation pathways, and compounds with putative antioxidant activity such as N-acetyl-L-cysteine (NAC) and pyrrolidine dithiocarbamate (PDTC) have been used interchangeably to demonstrate this point. We examined their effects, separately and com...

The 5-Endo-trig Cyclization of D-Glucose Derived γ-Alkenylamines with Mercury (II Salts: Synthesis of 1-Deoxycastanospermine and its 8a-epi-Analogueâ€

Directory of Open Access Journals (Sweden)

S. Jachak

2005-08-01

Full Text Available The intramolecular aminomercuration of γ-alkenylamines 1a, 1b and 4 was shown to afford the 5-endo-trig cyclized product exclusively in good yield. The utility of pyrrolidine derivatives thus obtained from D-glucose derived γ-alkenylamines 1a and 1b was demonstrated in the synthesis of 1-deoxycastanospermine (3a and 1-deoxy-8a-epi- castanospermine (3b.

Facile and Green Synthesis of Saturated Cyclic Amines

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Arruje Hameed

2017-10-01

Full Text Available Single-nitrogen containing saturated cyclic amines are an important part of both natural and synthetic bioactive compounds. A number of methodologies have been developed for the synthesis of aziridines, azetidines, pyrrolidines, piperidines, azepanes and azocanes. This review highlights some facile and green synthetic routes for the synthesis of unsubstituted, multisubstituted and highly functionalized saturated cyclic amines including one-pot, microwave assisted, metal-free, solvent-free and in aqueous media.

Catalytic enantioselective alkene aminohalogenation/cyclization involving atom transfer.

Science.gov (United States)

Bovino, Michael T; Chemler, Sherry R

2012-04-16

Problem solved: the title reaction was used for the synthesis of chiral 2-bromo, chloro, and iodomethyl indolines and 2-iodomethyl pyrrolidines. Stereocenter formation is believed to occur by enantioselective cis aminocupration and C-X bond formation is believed to occur by atom transfer. The ultility of the products as versatile synthetic intermediates was demonstrated, as was a radical cascade cyclization sequence. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The unexpected product of Diels-Alder reaction between "indanocyclon" and maleimide

Science.gov (United States)

Dobrowolski, Michał A.; Roszkowski, Piotr; Struga, Marta; Szulczyk, Daniel

2017-02-01

A heterocyclic compound commonly known as "indanocyclon" undergoes an unexpected Diels-Alder addition with maleimide. The resulting product has been isolated and characterized in order to get an information about its structure and possible mechanism of the reaction. Extensive comparison of single crystal properties of 3-(2,8-dioxo-1,3-diphenyl-2,8-dihydrocyclopenta[a]inden-8a(1H)-yl)pyrrolidine-2,5-dione and favorable product of the reaction has been also performed.

Unusual reactions of diazocarbonyl compounds with α,β-unsaturated δ-amino esters: Rh(II-catalyzed Wolff rearrangement and oxidative cleavage of N–H-insertion products

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Valerij A. Nikolaev

2016-08-01

Full Text Available Rh(II-сatalyzed reactions of aroyldiazomethanes, diazoketoesters and diazodiketones with α,β-unsaturated δ-aminoesters, in contrast to reactions of diazomalonates and other diazoesters, give rise to the Wolff rearrangement and/or oxidative cleavage of the initially formed N–H-insertion products. These oxidation processes are mediated by Rh(II catalysts possessing perfluorinated ligands. The formation of pyrrolidine structures, characteristic for catalytic reactions of diazoesters, was not observed in these processes at all.

Synthesis, Characterization and Biological Activities of Novel (E)-3-(1-(Alkyloxyamino)ethylidene)-1-alkylpyrrolidine-2,4-dione Derivatives

Energy Technology Data Exchange (ETDEWEB)

Zhu, Zhao Yong; Shi, Qing Ming; Han, Bao Feng; Wang, Xian Feng; Qiang, Sheng; Yang, Chun Long [Nanjing Agricultural University, Nanjing (China)

2010-09-15

Twenty novel tetramic acid derivatives (E)-3-(1-(alkyloxyamino)ethylidene)-1-alkylpyrrolidine-2,4-diones were synthesized by the reaction of 3-(1-hydroxyethylidene)pyrrolidine-2,4-diones with O-alkyl hydroxylamines. The title compounds were confirmed by IR, {sup 1}H NMR, MS and elemental analysis. The structure of compound 6r was further verified by X-ray diffraction crystallography. The bioassays showed that most of the title compounds exhibited noticeable herbicidal and fungicidal activities.

Determination of trace amounts of selenium in minerals and rocks by flame less atomic-absorption spectrometry

International Nuclear Information System (INIS)

Alduan, F. A.; Capdevilla, C.

1980-01-01

The determination of trace amounts of selenium In silicate rocks and feldspar by solvent extraction and graphite furnace atomic-absorption spectrometry has been stu- died. Sodium diethyl-ditio carbamate and ammonium pyrrolidine dithiocarbamate have been tried as chelating agents. The best results are achieved when selenium is extracted Into carbon tetrachloride as the sodium diethyldithiocarbamate complex. The method allows to detect 0,75 ppm of selenium in the sample. Recoveries are about 100%. (Author) 7 refs

Determination of trace amounts of selenium in minerals and rocks by flame less atomic-absorption spectrometry; Determinacion de selinio en minerales y rocas por espectrometria de absorcion atomica

Energy Technology Data Exchange (ETDEWEB)

Alduan, F. A.; Capdevilla, C.

1980-07-01

The determination of trace amounts of selenium In silicate rocks and feldspar by solvent extraction and graphite furnace atomic-absorption spectrometry has been stu- died. Sodium diethyl-ditio carbamate and ammonium pyrrolidine dithiocarbamate have been tried as chelating agents. The best results are achieved when selenium is extracted Into carbon tetrachloride as the sodium diethyldithiocarbamate complex. The method allows to detect 0,75 ppm of selenium in the sample. Recoveries are about 100%. (Author) 7 refs.

Radical cascades using enantioenriched 7-azabenzonorbornenes and their applications in synthesis

Directory of Open Access Journals (Sweden)

2008-10-01

Full Text Available Tandem deoxygenation–neophyl-type radical rearrangement–electrophile trapping using xanthates from 7-azabenzonorbornadienes gives 3-exo-substituted 2-aza-5,6-benzonorbornenes, which in some cases undergo isomerisation to (aminomethylindenes. The starting xanthates are accessible in good yields and high enantiomeric ratios via asymmetric hydroboration of (aryne/pyrrole-derived 7-azabenzonorbornadienes. Oxidation (using RuO4 and Birch reduction of the 2-aza-5,6-benzonorbornenes provide access to substituted pyrrolidines and tetrahydroindenes, respectively.

Recent developments in the synthesis of five- and six-membered heterocycles using molecular iodine

Digital Repository Service at National Institute of Oceanography (India)

Parvatkar, P.T.; Parameswaran, P.S.; Tilve, S.G.

obtained from reaction of 2-vinyl phenyl lithium with carbonyl compounds (Scheme 4). In case of electron donating group (R 2 = OMe) on the aryl ring, the yield was found to decrease. The resulting (1-iodomethyl)-1,3- dihydroisobenzofurans... and 18. Functional group manipulations with AgOAc proceeds via the corresponding aziridinium ion. Further deprotection gave access to polyhydroxylated pyrrolidines. Interestingly, iodocyclization of (3R)-configured β-amino esters (3R,αS)-19 and (3R...

The effect of nucleotides and adenosine on stimulus-evoked glutamate release from rat brain cortical slices

OpenAIRE

Bennett, Gillian C; Boarder, Michael R

2000-01-01

Evidence has previously been presented that P1 receptors for adenosine, and P2 receptors for nucleotides such as ATP, regulate stimulus-evoked release of biogenic amines from nerve terminals in the brain. Here we investigated whether adenosine and nucleotides exert presynaptic control over depolarisation-elicited glutamate release.Slices of rat brain cortex were perfused and stimulated with pulses of 46 mM K+ in the presence of the glutamate uptake inhibitor L-trans-pyrrolidine-2,4-dicarboxyl...

2′-Methyl-2′-nitro-1′-phenyl-2′,3′,5′,6′,7′,7a'-hexahydrospiro[indoline-3,3′-1′H-pyrrolizin]-2-one

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Yaghoub Sarrafi

2008-08-01

Full Text Available The title compound, C21H21N3O3, was synthesized by a multi-component 1,3-dipolar cycloaddition of azomethine ylide, derived from isatin and proline by a decarboxylative route, and (E-1-phenyl-2-nitropropene. In the molecule, the spiro junction links a planar oxindole ring and a pyrrolidine ring in an envelope conformation. The molecular packing is stabilized by an intermolecular N—H...N interaction of the oxindole and pyrrolizidine rings.

Identification of phase I and II metabolites of the new designer drug α-pyrrolidinohexiophenone (α-PHP) in human urine by liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QTOF-MS).

Science.gov (United States)

Paul, Michael; Bleicher, Sergej; Guber, Susanne; Ippisch, Josef; Polettini, Aldo; Schultis, Wolfgang

2015-11-01

Pyrrolidinophenones represent one emerging class of newly encountered drugs of abuse, also known as 'new psychoactive substances', with stimulating psychoactive effects. In this work, we report on the detection of the new designer drug α-pyrrolidinohexiophenone (α-PHP) and its phase I and II metabolites in a human urine sample of a drug abuser. Determination and structural elucidation of these metabolites have been achieved by liquid chromatography electrospray ionisation quadrupole time-of-flight mass spectrometry (LC-ESI-QTOF-MS). By tentative identification, the exact and approximate structures of 19 phase I metabolites and nine phase II glucuronides were elucidated. Major metabolic pathways revealed the reduction of the ß-keto moieties to their corresponding alcohols, didesalkylation of the pyrrolidine ring, hydroxylation and oxidation of the aliphatic side chain leading to n-hydroxy, aldehyde and carboxylate metabolites, and oxidation of the pyrrolidine ring to its lactam followed by ring cleavage and additional hydroxylation, reduction and oxidation steps and combinations thereof. The most abundant phase II metabolites were glucuronidated ß-keto-reduced alcohols. Besides the great number of metabolites detected in this sample, α-PHP is still one of the most abundant ions together with its ß-keto-reduced alcoholic dihydro metabolite. Monitoring of these metabolites in clinical and forensic toxicology may unambiguously prove the abuse of the new designer drug α-PHP. Copyright © 2015 John Wiley & Sons, Ltd.

Why does anatabine, but not nicotine, accumulate in jasmonate-elicited cultured tobacco BY-2 cells?

Science.gov (United States)

Shoji, Tsubasa; Hashimoto, Takashi

2008-08-01

Suspension-cultured cells of Nicotiana tabacum cv. Bright Yellow-2 (BY-2) grow rapidly in a highly homogenous population and still exhibit the general behavior of plant cells, and thus are often used as model systems in several areas of plant molecular and cellular biology, including secondary metabolism. While the parental tobacco variety synthesizes nicotine as a major alkaloid, the cultured tobacco cells mainly produce a related alkaloid anatabine, instead of nicotine, when elicited with jasmonates. We report here that cultured BY-2 cells scarcely express N-methylputrescine oxidase (MPO) genes even after jasmonate elicitation. MPO is the second enzyme in the biosynthetic pathway that supplies the pyrrolidine moiety of nicotine and nornicotine, but is predicted to be dispensable for the biosynthesis of anatabine, anabasine and anatalline, which do not contain the pyrrolidine moiety. When MPO was overexpressed in tobacco BY-2 cells, nicotine synthesis was dramatically enhanced while anatabine formation was effectively suppressed. As a complementary approach, we suppressed MPO expression by RNA interference in tobacco hairy roots that normally accumulate nicotine. In the MPO-suppressed roots, the contents of anatabine, anabasine and anatalline, as well as N-methylputrescine and putrescine, markedly increased to compensate for suppressed formation of nicotine and nornicotine. These results identify the transcriptional regulation of MPO as a critical rate-limiting step that restricts nicotine formation in cultured tobacco BY-2 cells.

Ruthenium-bipyridine complexes bearing fullerene or carbon nanotubes: synthesis and impact of different carbon-based ligands on the resulting products.

Science.gov (United States)

Wu, Zhen-yi; Huang, Rong-bin; Xie, Su-yuan; Zheng, Lan-sun

2011-09-07

This paper discusses the synthesis of two carbon-based pyridine ligands of fullerene pyrrolidine pyridine (C(60)-py) and multi-walled carbon nanotube pyrrolidine pyridine (MWCNT-py) via 1,3-dipolar cycloaddition. The two complexes, C(60)-Ru and MWCNT-Ru, were synthesized by ligand substitution in the presence of NH(4)PF(6), and Ru(II)(bpy)(2)Cl(2) was used as a reaction precursor. Both complexes were characterized by mass spectroscopy (MS), elemental analysis, nuclear magnetic resonance (NMR) spectroscopy, infrared spectroscopy (IR), ultraviolet/visible spectroscopy (UV-VIS) spectrometry, Raman spectroscopy, X-ray photoelectron spectroscopy (XPS), thermogravimetric analysis (TGA), and cyclic voltammetry (CV). The results showed that the substitution way of C(60)-py is different from that of MWCNT-py. The C(60)-py and a NH(3) replaced a Cl(-) and a bipyridine in Ru(II)(bpy)(2)Cl(2) to produce a five-coordinate complex of [Ru(bpy)(NH(3))(C(60)-py)Cl]PF(6), whereas MWCNT-py replaced a Cl(-) to generate a six-coordinate complex of [Ru(bpy)(2)(MWCNT-py)Cl]PF(6). The cyclic voltammetry study showed that the electron-withdrawing ability was different for C(60) and MWCNT. The C(60) showed a relatively stronger electron-withdrawing effect with respect to MWCNT. This journal is © The Royal Society of Chemistry 2011

Intramolecular Redox-Mannich Reactions: Facile Access to the Tetrahydroprotoberberine Core.

Science.gov (United States)

Ma, Longle; Seidel, Daniel

2015-09-07

Cyclic amines such as pyrrolidine undergo redox-annulations with 2-formylaryl malonates. Concurrent oxidative amine α-CH bond functionalization and reductive N-alkylation render this transformation redox-neutral. This redox-Mannich process provides regioisomers of classic Reinhoudt reaction products as an entry to the tetrahydroprotoberberine core, enabling the synthesis of (±)-thalictricavine and its epimer. An unusually mild amine-promoted dealkoxycarbonylation was discovered in the course of these studies. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

(S-2-(2-Pyrrolidinio-1H-benzimidazol-3-ium dichloride monohydrate

Directory of Open Access Journals (Sweden)

Dai Jing

2009-06-01

Full Text Available In the title compound, C11H15N32+·2Cl−·H2O, one N atom of the imidazole ring and the N atom of the pyrrolidine ring are protonated. The crystal structure is stabilized by aromatic π–π interactions between the benzene rings of neighbouring benzimidazole systems [centroid–centroid duistance = 3.712 (2 Å]. The crystal structure is further stabilized by intermolecular N—H...Cl, O—H...Cl and N—H...O hydrogen bonds.

Fluorinated Amine Stereotriads via Allene Amination.

Science.gov (United States)

Liu, Lu; Gerstner, Nels C; Oxtoby, Lucas J; Guzei, Ilia A; Schomaker, Jennifer M

2017-06-16

The incorporation of fluorine into organic scaffolds often improves the bioactivity of pharmaceutically relevant compounds. C-F/C-N/C-O stereotriad motifs are prevalent in antivirals, neuraminidase inhibitors, and modulators of androgen receptors, but are challenging to install. An oxidative allene amination strategy using Selectfluor rapidly delivers triply functionalized triads of the form C-F/C-N/C-O, exhibiting good scope and diastereoselectivity for all syn products. The resulting stereotriads are readily transformed into fluorinated pyrrolidines and protected α-, β-, and γ-amino acids.

A short synthesis and its application to the preparation of radio labelled leukotriene inhibitor Sch 37224

International Nuclear Information System (INIS)

Duelfer, T.; Gala, D.

1991-01-01

A new, short synthesis of 1-(1,2-dihydro-4-hydroxyl-1-phenyl-2-oxo-1,8-naphthyridin-3-yl)-pyrrolidinium hydroxide, inner salt, 1, was achieved by condensing methyl 2-phenylamino-3-pyridine carboxylate 2 with ethyl 1-pyrrolidine acetate 4. This gave highly pure product in 60% yield. This synthesis was applied to the preparation of 14 C labelled 1. Radiolabelled 1 was synthesized from u-[ 14 C]-aniline in three steps at 97% radiochemical purity and 27.3% radiochemical yield. (author)

Facile synthesis of some novel 2-substituted-4,6-diarylpyrimidines using 4 ' -hydroxy-3 ' ,5 ' -dinitrochalcones and S-benzylthiouronium chloride

Directory of Open Access Journals (Sweden)

K. L. Ameta

2012-01-01

Full Text Available Various 4'-hydroxy-3',5'-dinitro substituted chalcones 1 and S-benzylthiouronium chloride (SBT 2 in the presence of DMF-organic bases (morpholine/ pyrrolidine/ piperidine gave 4,6-diaryl-2-(4-morpholinyl / 1-pyrrolidinyl /1-piperidinyl- pyrimidines 4, 5 and 6 in a facile one-pot conversion. In an another attempt reactants 1 and 2 yielded intermediate 2-benzylthiopyrimidines 3, in presence of DMF, which on treatment with heterocyclic secondary amines gave products 4, 5 and 6 in an alternate two-step process.

Spectroscopic studies on the interactions of 5-ethyl-6-phenyl-3,8-bis((3-aminoalkyl)propanamido)phenanthridin-5-ium derivatives with G-quadruplex DNA

Science.gov (United States)

Yalçın, Ergin; Duyar, Halil; Ihmels, Heiko; Seferoğlu, Zeynel

2018-05-01

An improved microwave-induced synthesis of five ethidium derivatives (Ethidium derivatives, 2a-d) is presented. As the derivatives 2a-d have been proposed previously to be telomerase inhibitors, the binding interactions of these ethidium derivatives with G-quadruplex DNA were evaluated by means of photometric and fluorimetric titration, thermal DNA denaturation, CD and 1H NMR spectroscopy. In particular, the compound bearing 3,8-bis(pyrrolidin-1-yl)propanamido substituent 2a exhibits high selectivity for G-quadruplex DNA relative to duplex DNA.

13-Hydroxy-4,16-dimethyl-4,16-diazapentacyclo[12.3.1.01,5.05,13.07,12]octadeca-7(12,8,10-triene-6,18-dione

Directory of Open Access Journals (Sweden)

K. Gurunathan

2009-05-01

Full Text Available In the title compound, C18H20N2O3, the N-methylpiperidone ring adopts a chair conformation. The pyrrolidine ring and the five-membered cyclopentane rings adopt envelope conformations. The five-membered ring of the ninhydrin system adopts an envelope conformation with the central C atom deviating by 0.217 (1Å from the mean plane through the other atoms. The molecular packing is characterized by intermolecular C—H...O and intramolecular C—H...O and O—H...N interactions.

Interaction of serum amyloid P component with hexanoyl bis(d-proline) (CPHPC)

Energy Technology Data Exchange (ETDEWEB)

Kolstoe, Simon E. [University College London, Rowland Hill Street, London NW3 2PF (United Kingdom); Jenvey, Michelle C. [University of Southampton, Southampton SO17 1BJ (United Kingdom); Purvis, Alan [Imperial College London, London SW7 2AZ (United Kingdom); Light, Mark E. [University of Southampton, Southampton SO17 1BJ (United Kingdom); Thompson, Darren [University of Sussex, Falmer, Brighton BN1 9RQ (United Kingdom); Hughes, Peter; Pepys, Mark B.; Wood, Stephen P., E-mail: s.wood@ucl.ac.uk [University College London, Rowland Hill Street, London NW3 2PF (United Kingdom)

2014-08-01

Serum amyloid P component is a pentameric plasma glycoprotein that recognizes and binds to amyloid fibres in a calcium-dependent fashion and is likely to contribute to their deposition and persistence in vivo. Five molecules of the drug CPHPC avidly cross-link pairs of protein pentamers and the decameric complex is rapidly cleared in vivo. Crystal structures of the protein in complex with a bivalent drug and cadmium ions, which improve crystal quality, allow the definition of the preferred bound drug isomers. Under physiological conditions, the pentameric human plasma protein serum amyloid P component (SAP) binds hexanoyl bis(d-proline) (R-1-(6-[R-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl) pyrrolidine-2-carboxylic acid; CPHPC) through its d-proline head groups in a calcium-dependent interaction. Cooperative effects in binding lead to a substantial enhancement of affinity. Five molecules of the bivalent ligand cross-link and stabilize pairs of SAP molecules, forming a decameric complex that is rapidly cleared from the circulation by the liver. Here, it is reported that X-ray analysis of the SAP complex with CPHPC and cadmium ions provides higher resolution detail of the interaction than is observed with calcium ions. Conformational isomers of CPHPC observed in solution by HPLC and by X-ray analysis are compared with the protein-bound form. These are discussed in relation to the development of CPHPC to provide SAP depletion for the treatment of amyloidosis and other indications.

Lewis acid catalyzed [3 + 2] annulation of ketenimines with donor-acceptor cyclopropanes: an approach to 2-alkylidenepyrrolidine derivatives.

Science.gov (United States)

Alajarin, Mateo; Egea, Adrian; Orenes, Raul-Angel; Vidal, Angel

2016-11-02

The [3 + 2] annulation reaction of C,C,N-trisubstituted ketenimines with donor-acceptor cyclopropanes bearing aryl, styryl and vinyl substituents at the C2 position, triggered by the Lewis acid Sc(OTf) 3 , supplies highly substituted pyrrolidines. Activated cyclopropanes fused to naphthalene and [1]benzopyrane nuclei are also suitable substrates in similar transformations, yielding partially saturated benz[g]indoles and [1]benzopyran[4,3-b]pyrroles. An intramolecular version of this ketenimine/cyclopropane [3 + 2] annulation has also been developed leading to the pyrrolo[2,1-a]isoindole framework.

Stereodivergent Synthesis of N-Heterocycles by Catalyst-Controlled, Activity-Directed Tandem Annulation of Diazo Compounds with Amino Alkynes.

Science.gov (United States)

Liu, Kai; Zhu, Chenghao; Min, Junxiang; Peng, Shiyong; Xu, Guangyang; Sun, Jiangtao

2015-10-26

A stereodivergent synthesis of five-membered N-heterocycles, such as 2,3-dihydropyrroles, and 2-methylene and 3-methylene pyrrolidines, has been developed through a tandem annulation of amino alkynes with diazo compounds and involves the trapping of in situ formed intermediates. Mechanistic investigations indicate that the copper-catalyzed tandem annulations proceed by allenoate formation and subsequent intramolecular hydroamination. In contrast, the rhodium-catalyzed protocol features a carbenoid insertion into the NH bond and subsequent Conia-ene cyclization. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

2-[4-(2-Chloroacetylphenyl]-2-methyl-1-(pyrrolidin-1-ylpropan-1-one

Directory of Open Access Journals (Sweden)

Dong-mei Ren

2013-08-01

Full Text Available The asymmetric unit of the title compound, C16H20ClNO2, contains two molecules in which the dihedral angles between the benzene ring and the plane of the amide unit are 77.4 (1 and 81.1 (1°. In both molecules, the five-membered ring adopts an envelope conformation with one of the β-C atoms as the flap. In the crystal, molecules are connected via C—H...O hydrogen bonds, forming chains along the b-axis direction. These chains are further linked by C—H...π interactions, forming a three-dimensional network.

Discovery of a potent, dual serotonin and norepinephrine reuptake inhibitor.

Science.gov (United States)

Dreyfus, Nicolas; Myers, Jason K; Badescu, Valentina O; de Frutos, Oscar; de la Puente, Maria Luz; Ding, Chunjin; Filla, Sandra A; Fynboe, Karsten; Gernert, Douglas L; Heinz, Beverly A; Hemrick-Luecke, Susan K; Johnson, Kirk W; Johnson, Michael P; López, Pilar; Love, Patrick L; Martin, Laura J; Masquelin, Thierry; McCoy, Michael J; Mendiola, Javier; Morrow, Denise; Muhlhauser, Mark; Pascual, Gustavo; Perun, Thomas J; Pfeifer, Lance A; Phebus, Lee A; Richards, Simon J; Rincón, Juan Antonio; Seest, Eric P; Shah, Jikesh; Shaojuan, Jia; Simmons, Rosa Maria A; Stephenson, Gregory A; Tromiczak, Eric G; Thompson, Linda K; Walter, Magnus W; Weber, Wayne W; Zarrinmayeh, Hamideh; Thomas, Craig E; Joshi, Elizabeth; Iyengar, Smriti; Johansson, Anette M

2013-06-13

The objective of the described research effort was to identify a novel serotonin and norepinephrine reuptake inhibitor (SNRI) with improved norepinephrine transporter activity and acceptable metabolic stability and exhibiting minimal drug-drug interaction. We describe herein the discovery of a series of 3-substituted pyrrolidines, exemplified by compound 1. Compound 1 is a selective SNRI in vitro and in vivo, has favorable ADME properties, and retains inhibitory activity in the formalin model of pain behavior. Compound 1 thus represents a potential new probe to explore utility of SNRIs in central nervous system disorders, including chronic pain conditions.

Opportunities and challenges for direct C–H functionalization of piperazines

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Zhishi Ye

2016-04-01

Full Text Available Piperazine ranks within the top three most utilized N-heterocyclic moieties in FDA-approved small-molecule pharmaceuticals. Herein we summarize the current synthetic methods available to perform C–H functionalization on piperazines in order to lend structural diversity to this privileged drug scaffold. Multiple approaches such as those involving α-lithiation trapping, transition-metal-catalyzed α-C–H functionalizations, and photoredox catalysis are discussed. We also highlight the difficulties experienced when successful methods for α-C–H functionalization of acyclic amines and saturated mono-nitrogen heterocyclic compounds (such as piperidines and pyrrolidines were applied to piperazine substrates.

4-Hydroxy-5-(4-methoxyphenylpyrrolidin-2-one

Directory of Open Access Journals (Sweden)

Suchada Chantrapromma

2008-03-01

Full Text Available In the title compound, C11H13NO3, the pyrrolidin-2-one ring is in an envelope conformation with the hydroxyl and 4-methoxyphenyl substituents mutually cis. The methoxy group is slighty twisted away from the mean plane of the attached benzene ring. The molecules are arranged into screw chains along the c axis. These chains are interconnected via intermolecular O—H...O and N—H...O hydrogen bonds into sheets parallel to the ac plane. The crystal structure is further stabilized by weak intermolecular C—H...O and C—H...π interactions.

Rhodium-Catalyzed Denitrogenative [3+2] Cycloaddition: Access to Functionalized Hydroindolones and the Framework of Montanine-Type Amaryllidaceae Alkaloids.

Science.gov (United States)

Yang, Hongjian; Hou, Shengtai; Tao, Cheng; Liu, Zhao; Wang, Chao; Cheng, Bin; Li, Yun; Zhai, Hongbin

2017-09-18

Rhodium-catalyzed denitrogenative [3+2] cycloaddition of 1-sulfonyl-1,2,3-triazoles with cyclic silyl dienol ethers has been developed for the synthesis of functionalized hydroindolones or their corresponding silyl ethers. The present method has been employed to construct synthetically valuable bicyclo[3.3.1]alkenone derivatives and pyrrolidine-ring-containing bicyclic indole compounds. As a further synthetic application, a stereoselective synthesis of 5,11-methanomorphanthridin-3-one, which shares a key skeleton with montanine-type Amaryllidaceae alkaloids has been achieved by using this chemistry. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

New enamine derivatives of lapachol and biological activity

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OLIVEIRA MAILCAR F.

2002-01-01

Full Text Available A convenient synthesis of the new enamine derivatives 2-(4-morpholinyl-3-(3-methyl-2-butenyl-1,4-naphthalenedione, 2-(1-piperidinyl-3-(3-methyl-2-butenyl-1,4-naphtalenedione and 2-(1-pyrrolidinyl-3-(3-methyl-2-butenyl-1,4-naphthalenedione was carried out from natural 2-hydroxy-3-(3-methyl-2-butenyl-1,4-naphthalenedione (lapachol and morpholine, piperidine and pyrrolidine. The structures of the products were established mainly by NMR analysis, including 2D experiments. Biological activities of these products were evaluated against Artemia salina, Aedes aegypti and cytotoxicity using A549 human breast cells.

Selective Flow-Injection Quantification of Ultra-trace Amounts of Cr(VI) via On-line Complexation and Preconcentration with APDC Followed by Determination by Electrothermal Atomic Absorption Spectrometry

DEFF Research Database (Denmark)

Nielsen, Steffen; Hansen, Elo Harald

1998-01-01

A rapid, sensitive and selective time-based flow injection (FI) preconcentration procedure is described for the determination of ultra-trace amounts of Cr(VI) via on-line reaction with ammonium pyrrolidine dithiocarbamate (APDC) and formation of the Cr(VI)-PDC complex. The preconcentration...... to direct introduction of 55 mu l samples, yielding a detection limit (3 sigma) of 4.2 ng l(-1). The sample frequency was 21.2 samples per hour. The proposed method was evaluated by analyzing drinking water, a NIST Cr(VI)-reference material and synthetic sea water. A major contribution to successful...

Determination of traces of silver in waters by anion exchange and atomic absorption spectrophotometry

Science.gov (United States)

Chao, T.T.; Fishman, M. J.; Ball, J.W.

1969-01-01

A method has been developed for the accurate determination of 0.1-1 ??g of silver per liter of water. The method permits stabilization of silver in water without loss to container walls. Optimum conditions have been established for the complete recovery of silver from water with an anion-exchange column, for quantitative elution of silver from the resin, and for measurement of silver by atomic absorption spectrophotometry after chelation with ammonium pyrrolidine dithiocarbamate and extraction of the chelate with MIBK. Silver in the 1-10 ??g 1 range can be determined by extraction without pre-concentration on an ion-exchange resin. ?? 1969.

Discovery and Optimization of Imidazopyridine-Based Inhibitors of Diacylglycerol Acyltransferase 2 (DGAT2).

Science.gov (United States)

Futatsugi, Kentaro; Kung, Daniel W; Orr, Suvi T M; Cabral, Shawn; Hepworth, David; Aspnes, Gary; Bader, Scott; Bian, Jianwei; Boehm, Markus; Carpino, Philip A; Coffey, Steven B; Dowling, Matthew S; Herr, Michael; Jiao, Wenhua; Lavergne, Sophie Y; Li, Qifang; Clark, Ronald W; Erion, Derek M; Kou, Kou; Lee, Kyuha; Pabst, Brandon A; Perez, Sylvie M; Purkal, Julie; Jorgensen, Csilla C; Goosen, Theunis C; Gosset, James R; Niosi, Mark; Pettersen, John C; Pfefferkorn, Jeffrey A; Ahn, Kay; Goodwin, Bryan

2015-09-24

The medicinal chemistry and preclinical biology of imidazopyridine-based inhibitors of diacylglycerol acyltransferase 2 (DGAT2) is described. A screening hit 1 with low lipophilic efficiency (LipE) was optimized through two key structural modifications: (1) identification of the pyrrolidine amide group for a significant LipE improvement, and (2) insertion of a sp(3)-hybridized carbon center in the core of the molecule for simultaneous improvement of N-glucuronidation metabolic liability and off-target pharmacology. The preclinical candidate 9 (PF-06424439) demonstrated excellent ADMET properties and decreased circulating and hepatic lipids when orally administered to dyslipidemic rodent models.

The Influence of pH and Temperature on the Stability of N-[(Piperidinemethylene]daunorubicin Hydrochloride and a Comparison of the Stability of Daunorubicin and Its Four New Amidine Derivatives in Aqueous Solutions

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Mikołaj Piekarski

2014-01-01

Full Text Available The influence of pH and temperature on the stability of N-[(piperidinemethylene]daunorubicin hydrochloride (PPD was investigated. Degradation was studied using an HPLC method. Specific acid-base catalysis of PPD involves hydrolysis of protonated molecules of PPD catalyzed by hydrogen ions and spontaneous hydrolysis under the influence of water zwitterions, unprotonated molecules, and monoanions of PPD. The thermodynamic parameters of these reactions, energy, enthalpy, and entropy, were calculated. Also, the stability of daunorubicin and its new amidine derivatives (piperidine, morpholine, pyrrolidine, and hexahydroazepin-1-yl in aqueous solutions was compared and discussed.

Towards the chiral metabolomics: Liquid chromatography–mass spectrometry based DL-amino acid analysis after labeling with a new chiral reagent, (S)-2,5-dioxopyrrolidin-1-yl-1-(4,6-dimethoxy-1,3,5-triazin-2-yl) pyrrolidine-2-carboxylate, and the application to saliva of healthy volunteers

Energy Technology Data Exchange (ETDEWEB)

Mochizuki, Toshiki; Takayama, Takahiro; Todoroki, Kenichiro; Inoue, Koichi; Min, Jun Zhe; Toyo’oka, Toshimasa, E-mail: toyooka@u-shizuoka-ken.ac.jp

2015-05-22

Highlights: • A novel chiral labeling reagent was synthesized. • Analysis of DL-amino acids was performed by UPLC–ESI-MS/MS. • Efficient enantioseparation and detection of DL-amino acids were performed. • DL-Amino acid in saliva was successfully determined under mild conditions. - Abstract: A novel triazine-type chiral derivatization reagent, i.e., (S)-2,5-dioxopyrrolidin-1-yl-1-(4,6-dimethoxy-1,3,5-triazin-2-yl) pyrrolidine-2-carboxylate (DMT-(S)-Pro-OSu), was developed for the highly sensitive and selective detection of chiral amines and amino acids by UPLC–MS/MS analysis. The enantiomers of amino acids were easily labeled with the reagents at room temperature within 40 min in an alkaline medium containing triethylamine. The diastereomers derived from proteolytic amino acids, except serine, were well separated under isocratic elution conditions by reversed-phase chromatography using an ODS column (R{sub s} = 1.2–9.0). DL-Serine was separated by use of an ADME column which has relatively higher polar surface than the conventional ODS column. The characteristic product ions, i.e., m/z 195.3 and m/z 209.3, were detected from all the diastereomers by the collision-induced dissociation of the protonated molecule. A highly sensitive detection on the amol–fmol level was obtained from the selected reaction monitoring (SRM) chromatogram. The chiral amines (e.g., adrenaline and noradrenaline) labeled with DMT-(S)-Pro-OSu were also well separated and sensitively detected by the present procedure. The method using DMT-(S)-Pro-OSu was used for the determination of DL-amino acids in the human saliva from healthy volunteers. Various L-amino acids were identified in the saliva. Furthermore, D-alanine (D-Ala) and D-proline (D-Pro) were also detected in relatively high concentrations (>5%). The ratio was higher in male saliva than in female saliva. However, the difference in the ratio of D-Ala for one day was not very high and the effect of foods and beverage

Search for new potential anticonvulsants with anxiolytic and antidepressant properties among derivatives of 4,4-diphenylpyrrolidin-2-one.

Science.gov (United States)

Malawska, Katarzyna; Rak, Aleksandra; Gryzło, Beata; Sałat, Kinga; Michałowska, Małgorzata; Żmudzka, Elżbieta; Lodarski, Krzysztof; Malawska, Barbara; Kulig, Katarzyna

2017-02-01

The aim of this study was to synthesize a series of new N-Mannich bases derived from 4,4-diphenylpyrrolidin-2-one having differently substituted 4-phenylpiperazines as potential anticonvulsant agents with additional (beneficial) pharmacological properties. The target compounds 8-12 were prepared in one step from the 4-substituted phenylpiperazines, paraformaldehyde, and synthesized 4,4-diphenylpyrrolodin-2-one (7) by a Mannich-type reaction. The obtained compounds were assessed and tested for their anticonvulsant activity in two screening mouse models of seizures, i.e., the maximal electroshock (MES) test and in the subcutaneous pentylenetetrazole (scPTZ) test. The effect of these compounds on animals' motor coordination was measured in the rotarod test. A selected 4,4-diphenyl-1-((4-phenylpiperazin-1-yl)methyl)pyrrolidin-2-one (8) was evaluated in vivo for its anxiolytic- and antidepressant-like properties. Its impact on animals' locomotor activity was also evaluated. Compound 8 showed protection (25%) in the MES and in the scPTZ tests at the dose of 100mg/kg and was not neurotoxic. In the four-plate test, compound 8 at the dose of 30mg/kg showed a statistically significant (p<0.05) anxiolytic-like activity. In the forced swim test, it reduced the immobility time by 24.3% (significant at p<0.05), which indicates its potential antidepressant-like properties. In the locomotor activity test, compound 8 significantly reduced animals' locomotor activity by 79.9%. The results obtained make a new derivative of 4,4-diphenyl-1-((4-phenylpiperazin-1-yl)methyl)pyrrolidin-2-one (8) a promising lead structure for further development. Copyright © 2016. Published by Elsevier Urban & Partner Sp. z o.o.

Asymmetric Michael Addition Mediated by Chiral Ionic Liquids.

Science.gov (United States)

Suzuki, Yumiko

2018-06-01

Chiral ionic liquids with a focus on their applications in asymmetric Michael additions and related reactions were reviewed. The examples were classified on the basis of the mode of asymmetric induction (e.g., external induction/non-covalent interaction or internal induction/covalent bond formation), the roles in reactions (as a solvent or catalyst), and their structural features (e.g., imidazolium-based chiral cations, other chiral oniums; proline derivatives). Most of the reactions with high chiral induction are Michael addition of ketones or aldehydes to chalcones or nitrostyrenes where proline-derived chiral ionic liquids catalyze the reaction through enamine/ iminium formation. Many reports demonstrate the recyclability of ionic liquid-tagged pyrrolidines.

Rhodium(III)-catalyzed [3+2] annulation of 5-aryl-2,3-dihydro-1H-pyrroles with internal alkynes through C(sp²)-H/alkene functionalization.

Science.gov (United States)

Zhou, Ming-Bo; Pi, Rui; Hu, Ming; Yang, Yuan; Song, Ren-Jie; Xia, Yuanzhi; Li, Jin-Heng

2014-10-13

This study describes a new rhodium(III)-catalyzed [3+2] annulation of 5-aryl-2,3-dihydro-1H-pyrroles with internal alkynes using a Cu(OAc)2 oxidant for building a spirocyclic ring system, which includes the functionalization of an aryl C(sp(2))-H bond and addition/protonolysis of an alkene C=C bond. This method is applicable to a wide range of 5-aryl-2,3-dihydro-1H-pyrroles and internal alkynes, and results in the assembly of the spiro[indene-1,2'-pyrrolidine] architectures in good yields with excellent regioselectivities. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Simultaneous separation of copper, cadmium and cobalt from sea-water by co-flotation with octadecylamine and ferric hydroxide as collectors.

Science.gov (United States)

Cabezon, L M; Caballero, M; Cela, R; Perez-Bustamante, J A

1984-08-01

A method is proposed for the simultaneous quantitative separation of traces ofCu(II), Cd(II) and Co(II) from sea-water samples by means of the co-flotation (adsorbing colloid flotation) technique with ferric hydroxide as co-precipitant and octadecylamine as collector. The experimental parameters have been studied and optimized. The drawbacks arising from the low solubility of octadecylamine and the corresponding sublates in water have been avoided by use of a 6M hydrochloric acid-MIBK-ethanol (1:2:2 v v ) mixture. The results obtained by means of the proposed method have been compared with those given by the usual ammonium pyrrolidine dithiocarbamate/MIBK extraction method.

2-Hydroxy-16-[(E-4-methylbenzylidene]-13-(4-methylphenyl-12-phenyl-1,11-diazapentacyclo[12.3.1.02,10.03,8.010,14]octadeca-3(8,4,6-triene-9,15-dione

Directory of Open Access Journals (Sweden)

Raju Suresh Kumar

2010-08-01

Full Text Available In the title compound, C37H32N2O3, an intramolecular O—H...N hydrogen bond generates a five-membered ring, producing an S(5 motif. The piperidone ring adopts a half-chair conformation. The two fused pyrrolidine rings have similar envelope conformations. The interplanar angles between the benzene rings A/B and C/D are 75.68 (7 and 30.22 (6°, respectively. In the crystal structure, adjacent molecules are interconnected into chains propagating along the [010] direction via intermolecular C—H...O hydrogen bonds. Further stabilization is provided by weak C—H...π interactions.

Selective Flow Injection Analysis of Ultra-trace Amounts of Cr(VI), Preconcentration of It by Solvent Extraction, and Determination by Electrothermal Atomic Absorption Spectrometry (ETAAS)

DEFF Research Database (Denmark)

Nielsen, Steffen; Sturup, Stefan; Spliid, Henrik

1999-01-01

(IBMK). The Cr(VI) is complexed by reaction with ammonium pyrrolidine dithiocarbamate (APDC), and the non-charged Cr(VI)-PDC chelate formed is extracted into IBMK in a knotted reactor made from PTFE tubing. The organic extractant is separated from the aqueous phase by a gravity phase separator......(VI) was achieved after preconcentration for 99 s at a sample flow rate of 5.5 ml min-1, as compared to direct introduction of 55 mul of sample, yielding a detection limit (3sigma) of 3.3 ng l-1. The sampling frequency was 24.2 samples h-1. The proposed method was successfully evaluated by analyzing a NIST Cr...

[1+1+3] Annulation of Diazoenals and Vinyl Azides: Direct Synthesis of Functionalized 1-Pyrrolines through Olefination.

Science.gov (United States)

Kanchupalli, Vinaykumar; Katukojvala, Sreenivas

2018-05-04

A dirhodium carboxylate catalyzed [1+1+3] annulation reaction of diazoenals and vinyl azides that gives synthetically important enal-functionalized 1-pyrroline derivatives was developed. The reaction involves a novel rhodium-catalyzed olefination of diazoenals with vinyl azides via electrophilic enal carbenoids, resulting in a new class of enal acrylates. The annulation reaction was used for the direct synthesis of valuable deuterated 1-pyrrolines. Structural diversification of the enal-functionalized 1-pyrrolines resulted in the biologically important pyrrolidine-fused oxaziridine, amino acid derivatives, and a 6-azabicyclo[3.2.1]octane motif present in polycyclic alkaloids. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Crystal structures of two triazola-dioxola-benzenacyclononaphanes

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Vijayan Viswanathan

2015-07-01

Full Text Available In the title compounds, C25H29BrN5O7, (I [systematic name: (Z-15-bromo-32,32-dimethyl-21-nitro-22,23,25,26,27,27a,33a,35,36,36a-decahydro-21H,61H-4,9-dioxa-2(3,2-pyrrolizina-6(4,1-triazola-3(5,6-furo[2,3-d][1,3]dioxola-1(1,2-benzenacyclononaphane], and C24H29N5O7S, (II [systematic name: (Z-32,32-dimethyl-27-nitro-25,26,27,27a,33a,35,36,36a-octahydro-21H,23H,61H-4,9-dioxa-2(5,6-pyrrolo[1,2-c]thiazola-6(4,1-triazola-3(5,6-furo[2,3-d][1,3]dioxola-1(1,2-benzenacyclononaphane], the triazole rings adopt almost planar conformations. In (I, the fused pyrrolidine rings adopt envelope conformations with the C atoms opposite the fused N—C bond as the flap in each ring, and their mean planes are inclined to one another by 52.8 (3°. In (II, the pyrrolidine and thiazole rings are both twisted on the fused N—C bond, and their mean planes are inclined to one another by 70.8 (2°. In both (I and (II, the furan ring adopts an envelope conformation with the adjacent C atom of the macrocycle as the flap. In the crystal of (I, molecules are linked via C—H...N and C—H...O hydrogen bonds, forming sheets parallel to (10-1, while in (II, molecules are linked via C—H...N and C—H...O hydrogen bonds, forming helical chains propagating along [010], which are linked via C—H...S hydrogen bonds, forming slabs parallel to (001.

Asymmetric Michael Addition Mediated by Chiral Ionic Liquids

Science.gov (United States)

Suzuki, Yumiko

2018-01-01

Chiral ionic liquids with a focus on their applications in asymmetric Michael additions and related reactions were reviewed. The examples were classified on the basis of the mode of asymmetric induction (e.g., external induction/non-covalent interaction or internal induction/covalent bond formation), the roles in reactions (as a solvent or catalyst), and their structural features (e.g., imidazolium-based chiral cations, other chiral oniums; proline derivatives). Most of the reactions with high chiral induction are Michael addition of ketones or aldehydes to chalcones or nitrostyrenes where proline-derived chiral ionic liquids catalyze the reaction through enamine/ iminium formation. Many reports demonstrate the recyclability of ionic liquid-tagged pyrrolidines. PMID:29861702

Modification of indole by electron-rich atoms and their application in novel electron donor materials

Science.gov (United States)

Zhang, Maolin; Qin, Guangjiong; Liu, Jialei; Zhen, Zhen; Fedorchuk, A. A.; Lakshminarayana, G.; Albassam, A. A.; El-Naggar, A. M.; Ozga, Katarzyna; Kityk, I. V.

2017-08-01

Novel nonlinear optical (NLO) chromophore based on 6-(pyrrolidin-1-yl)-1H-indole as the electron donor group was designed and synthesized. The molecular structure of this chromophore was characterized by 1H NMR spectra, 13C NMR spectra, and MS spectra. The delocalized energy level was estimated by UV-Vis. spectra. The thermal property was studied by thermogravimetric analysis (TGA). The poled films containing chromophores ZML-1 with a loading density of 10 wt% in amorphous polycarbonate (APC) afford an average electro-optic (EO) coefficient (r33) of 19 pm/V at 1310 nm. Compared to the reported aniline-based chromophore (r33 = 12 pm/V) analogues, chromophore ZML-1 exhibits enhanced electro-optical activity.

Determination of heavy metals at traces level in leached samples by energy dispersive x-ray fluorescence technique

International Nuclear Information System (INIS)

Simabuco, Silvana M.; Nascimento Filho, Virgilio F. do; Inacio, Graziela R.; Navarro, Angela N.

1996-01-01

In landfill solid residues are disposed in the soil. When made based on technical criteria and specifically operation patterns a safe confinement is warranted according to environmental and public health protection. However, when the disposal is made by a random and unsuitable way serious problems can be caused as groundwater and superficial water contamination through leach action, indicating the usefulness of monitoring landfills. In this way energy dispersive X-ray fluorescence analysis with radioisotopic excitation was applied to evaluate the concentrations of heavy metals at trace levels in leached samples from the Americana City Landfill with pre-concentration of the elements by a non-specific precipitating agent, called ammonium pyrrolidine dithiocarbamate (APDC). (author)

Determination of heavy metals at traces level in leached samples by energy dispersive x-ray fluorescence technique; Determinacao de metais pesados a nivel de tracos em amostras de chorume pela tecnica de fluorescencia de raios X por dispersao de energia

Energy Technology Data Exchange (ETDEWEB)

Simabuco, Silvana M. [Universidade Estadual de Campinas, SP (Brazil). Faculdade de Engenharia Civil; Nascimento Filho, Virgilio F. do; Inacio, Graziela R.; Navarro, Angela N. [Centro de Energia Nuclear na Agricultura (CENA), Piracicaba, SP (Brazil). Secao de Metodologia de Radioisotopos

1996-07-01

In landfill solid residues are disposed in the soil. When made based on technical criteria and specifically operation patterns a safe confinement is warranted according to environmental and public health protection. However, when the disposal is made by a random and unsuitable way serious problems can be caused as groundwater and superficial water contamination through leach action, indicating the usefulness of monitoring landfills. In this way energy dispersive X-ray fluorescence analysis with radioisotopic excitation was applied to evaluate the concentrations of heavy metals at trace levels in leached samples from the Americana City Landfill with pre-concentration of the elements by a non-specific precipitating agent, called ammonium pyrrolidine dithiocarbamate (APDC). (author)

A rapid screening method for heavy metals in biological materials by emission spectroscopy.

Science.gov (United States)

Blacklock, E C; Sadler, P A

1981-06-02

A semi-quantitative screening method for heavy metals in biological material is described. The metals are complexed with ammonium pyrrolidine dithiocarbamate, sodium diethyl dithiocarbamate and potassium sodium tartrate. The solutions are adjusted to pH 4 and then extracted into chloroform. The chloroform phase is evaporated onto a matrix mixture of lithium fluoride and graphite. The sample is analysed by direct current arc emission spectroscopy using a 3 metre grating spectrograph. The spectra are recorded on a photographic plate. The method is developed on aqueous and spiked samples and then applied to in vivo samples containing toxic levels of heavy metals. Atomic absorption spectroscopy is used to check standard concentrations and to monitor the efficiency of the extraction procedure.

Neutron spectroscopic and Raman studies of interaction between water and proline

Energy Technology Data Exchange (ETDEWEB)

Zhang Peng [Department of Space Science and Applied Physics, Shandong University at Weihai, Weihai 264209 (China); State Key Laboratory of Magnetism, Institute of Physics, Chinese Academy of Sciences, Beijing 100080 (China); Han Shenghao [Department of Space Science and Applied Physics, Shandong University at Weihai, Weihai 264209 (China); Zhang Ying [State Key Laboratory of Magnetism, Institute of Physics, Chinese Academy of Sciences, Beijing 100080 (China); Ford, Robert C. [MIB, University of Manchester, Manchester M60 1QD (United Kingdom); Li Jichen [Department of Physics and Astronomy, University of Manchester, Manchester M60 1QD (United Kingdom)], E-mail: j.c.li@manchester.ac.uk

2008-04-18

A series of measurements for the vibrational dynamics of water around proline were made by using inelastic neutron scattering and Raman spectroscopy techniques. Comparing the spectra at different hydrations, we found that proline has very different hydrophilic property compared with other amino acids we have studied [Y. Zhang et al., J. Phys. Chem. B 109 (2005) 17784]. We interpret these differences in terms of the unique structure of proline with an imino group which is fixed rigidly in the pyrrolidine ring. As result, we may observe a non-ionic form of proline solid transformed to an ionic state after hydration. This phenomenon was not seen in other amino acids we have studied so far.

Synthesis of Unsymmetrical Annulated 2,2’-Bipyridine Analogues with Attached Cycloalkene and Piperidine Rings via Sequential Diels-Alder Reaction of 5,5’-bi-1,2,4-triazinesâ€

Directory of Open Access Journals (Sweden)

D. Branowska

2005-12-01

Full Text Available Synthesis of bisfunctionalized unsymmetrical 2,2’-bipyridines 8 or their sulfonyl derivatives 12a,b are described. They were prepared via the Diels-Alder reaction of 1-methyl-4-pyrrolidin-1-yl-1,2,3,6-tetrahydropyridine (6 with 3,3’-bis(methyl- sulfanyl-5,5’-bi-1,2,4-triazine (1. The reaction leads to the single cycloaddition product 7 which undergoes Diels-Alder reaction with cyclic enamines 2a,b to give unsymmetrical 2,2’-bipyridine derivatives 8, consisting of the two different heterocyclic units: cycloalkeno[c]pyridine and 2,6-naphthyridine.

Design of novel HIV-1 protease inhibitors incorporating isophthalamide-derived P2-P3 ligands: Synthesis, biological evaluation and X-ray structural studies of inhibitor-HIV-1 protease complex

Energy Technology Data Exchange (ETDEWEB)

Ghosh, Arun K.; Brindisi, Margherita; Nyalapatla, Prasanth R.; Takayama, Jun; Ella-Menye, Jean-Rene; Yashchuk, Sofiya; Agniswamy, Johnson; Wang, Yuan-Fang; Aoki, Manabu; Amano, Masayuki; Weber, Irene T.; Mitsuya, Hiroaki

2017-10-01

Based upon molecular insights from the X-ray structures of inhibitor-bound HIV-1 protease complexes, we have designed a series of isophthalamide-derived inhibitors incorporating substituted pyrrolidines, piperidines and thiazolidines as P2-P3 ligands for specific interactions in the S2-S3 extended site. Compound 4b has shown an enzyme Ki of 0.025 nM and antiviral IC50 of 69 nM. An X-ray crystal structure of inhibitor 4b-HIV-1 protease complex was determined at 1.33 Å resolution. We have also determined X-ray structure of 3b-bound HIV-1 protease at 1.27 Å resolution. These structures revealed important molecular insight into the inhibitor–HIV-1 protease interactions in the active site.

Unusual NHC-Iridium(I) Complexes and Their Use in the Intramolecular Hydroamination of Unactivated Aminoalkenes

KAUST Repository

Sipos, Gellé rt; Ou, Arnold; Skelton, Brian W.; Falivene, Laura; Cavallo, Luigi; Dorta, Reto

2016-01-01

N-heterocyclic carbene (NHC) ligands with naphthyl side chains were employed for the synthesis of unsaturated, yet isolable [(NHC)Ir(cod)]+ (cod=1,5-cyclooctadiene) complexes. These compounds are stabilised by an interaction of the aromatic wingtip that leads to a sideways tilt of the NHC-Ir bond. Detailed studies show how the tilting of such N-heterocyclic carbenes affects the electronic shielding properties of the carbene carbon atom and how this is reflected by significant upfield shifts in the 13CNMR signals. When employed in the intramolecular hydroamination, these [(NHC)Ir(cod)]+ species show very high catalytic activity under mild reaction conditions. An enantiopure version of the catalyst system produces pyrrolidines with excellent enantioselectivities. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

A new furofuran lignan from Piper terminaliflorum Tseng.

Science.gov (United States)

Liu, Tie; Liang, Qian; Zhang, Xin-Min; Huang, Shen-Yang; Xu, Wen-Hui

2018-02-01

The chemical investigation of whole plants Piper terminaliflorum Tseng led to the isolation of one new furofuran lignan, 7-methoxyasarinin (1), along with three known amide alkaloids (2-4) as N-3,5-dimethoxy-4-hydroxycinnamoylpyrrole (2), dihydropipercide (3) and 1-[(2E,4E,9E)-10-(3,4-Methylenedioxyphenyl)-2,4,9-undecatrienoyl]pyrrolidine (4). Their structures were elucidated by extensive spectroscopic analyses, including 1D, 2D NMR and HR-ESI-MS, and by comparison with the literature. Compounds (2-4) were isolated from Piper terminaliflorum Tseng for the first time. All isolated compounds (1-4) were evaluated for their cytotoxic activities against five human cancer cell lines (including A-549, SMMC-7721, HL-60, MCF-7 and SW-480).

Hydrogen-bonded co-crystal structure of benzoic acid and zwitterionic l-proline

Directory of Open Access Journals (Sweden)

Aaron M. Chesna

2017-03-01

Full Text Available The title compound [systematic name: benzoic acid–pyrrolidin-1-ium-2-carboxylate (1/1], C7H6O2·C5H9NO2, is an example of the application of non-centrosymmetric co-crystallization for the growth of a crystal containing a typically centrosymmetric component in a chiral space group. It co-crystallizes in the space group P212121 and contains benzoic acid and l-proline in equal proportions. The crystal structure exhibits chains of l-proline zwitterions capped by benzoic acid molecules which form a C(5[R33(11] hydrogen-bonded network along [100]. The crystal structure is examined and compared to that of a similar co-crystal containing l-proline zwitterions and 4-aminobenzoic acid.

N-Butoxycarbonyl-5-oxo-l-proline ethyl ester

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P. Rajalakshmi

2013-04-01

Full Text Available The molecular structure of the title compound, C12H19NO5, may be visualized as made up of two nearly perpendicular planes [dihedral angle = 87.39 (12°] and its crystal structure is a good example of C—H...O interactions assuming significance in optimizing supramolecular aggregation in crystals in a molecule which is severely imbalanced in terms of donors to acceptor atoms. The pyrrolidine ring adopts a (3T2 twist conformation with puckering parameters Q = 0.2630 (4 Å and ϕ = 59 (9°. The crystal structure features R24(10 and R34(26 ring motifs formed by four weak C—H...O interactions, leading to supramolecular sheets lying parallel to the bc plane.

2,3-Di­phenyl­male­imide 1-methyl­pyrrol­idin-2-one monosolvate

Science.gov (United States)

Bulatov, Evgeny; Boyarskaya, Dina; Chulkova, Tatiana; Haukka, Matti

2014-01-01

In the title compound, C16H11NO2·C5H9NO, the dihedral angles between the male­imide and phenyl rings are 34.7 (2) and 64.8 (2)°. In the crystal, the 2,3-di­phenyl­male­imide and 1-methyl­pyrrolidin-2-one mol­ecules form centrosymmetrical dimers via pairs of strong N—H⋯O hydrogen bonds and π–π stacking inter­actions between the two neighboring male­imide rings [centroid–centroid distance = 3.495 (2) Å]. The dimers are further linked by weak C—H⋯O and C—H⋯π hydrogen bonds into a three-dimensional framework. PMID:24764976

Unusual NHC-Iridium(I) Complexes and Their Use in the Intramolecular Hydroamination of Unactivated Aminoalkenes

KAUST Repository

Sipos, Gellért

2016-04-10

N-heterocyclic carbene (NHC) ligands with naphthyl side chains were employed for the synthesis of unsaturated, yet isolable [(NHC)Ir(cod)]+ (cod=1,5-cyclooctadiene) complexes. These compounds are stabilised by an interaction of the aromatic wingtip that leads to a sideways tilt of the NHC-Ir bond. Detailed studies show how the tilting of such N-heterocyclic carbenes affects the electronic shielding properties of the carbene carbon atom and how this is reflected by significant upfield shifts in the 13CNMR signals. When employed in the intramolecular hydroamination, these [(NHC)Ir(cod)]+ species show very high catalytic activity under mild reaction conditions. An enantiopure version of the catalyst system produces pyrrolidines with excellent enantioselectivities. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Synthesis of carbon-14 and tritium labeled cis-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzamidehydrochloride, an anticonvulsant agent

International Nuclear Information System (INIS)

Hsi, R.S.P.; Stolle, W.T.; Ayer, D.E.

1992-01-01

The title compound, U-54494A, is an anticonvulsant agent with clinical potential for treating epilepsy and a broad spectrum of seizure disorders. Structurally it is related to kappa opiod agonists and shares their anticonvulsant properties, but appears to be devoid of analgesic, sedative, and diuretic side effects. It also has been shown to inhibit neuronal damage and seizures induced by excitatory amino acids. This report describes the synthesis of the racemic U-54494A labeled with carbon-14 at the carboxamide carbon and with tritium in the pyrrolidine ring at C-3 and C-4. These radioisotope labeled versions of U-54494A were prepared for conducting drug disposition studies of this compound in test animals and human subjects

A conformational study of proline derivatives

Directory of Open Access Journals (Sweden)

M.E. Kamwaya

2002-12-01

Full Text Available From the study of the structures and molecular conformations of a number of proline derivatives, some conclusions were drawn. The widening effect of angle Cα-C'-N' is caused by steric repulsion between a hydrogen atom at Cα of the preceding prolyl residue with any other at either Cα or Cδ of the pyrrolidine ring cis to it. This effect is influenced by the distance between the said hydrogen atoms: the nearer this distance is, the greater is the steric repulsion and the wider is the angle of steric repulsion. The ratio of the angle of steric repulsion to the distance between Cα and the following Cα (or Cδ cis to it is approximately 40 and 41 for peptides with trans and cis configurations, respectively. The torsion angle ranges for χ1, χ3, χ 4, θ and φ in these derivatives are widened more than usual. The highest vibration, which more often takes place at either the Cβ or Cγ of the pyrrolidine ring, does so not necessarily at the one that is puckered. A Δ&psi -relationship is established, for the determination of α-helixity or collageneity, also in small peptides and amino acids that contain proline. The Δ&psi-relationship is versatile and gives about +180o and –180o for the two categories, respectively. The distance between the carbonyl and hydroxyl (or otherwise terminal end atoms is minimal (2.2 Å and constant, for all peptides. The ratios of the angles at the carbonyl carbons (O'-C'-N' or (O'-C'-O' to this distance is also constant: 56 and 57 for the cis and trans confirgurations, respectively; i.e. a proline O'-C'-N'- (or O'-C'-O'-test, hereinafter called the CT-test, has been established for the determination of cis and trans configurations. It is also established in these proline derivatives, that whereas puckering takes place at Cβ for the CS form, it does so at Cγ for the C2 form.

Simultaneous determination of piracetam and its four impurities by RP-HPLC with UV detection.

Science.gov (United States)

Arayne, M Saeed; Sultana, Najma; Siddiqui, Farhan Ahmed; Mirza, Agha Zeeshan; Qureshi, Faiza; Zuberi, M Hashim

2010-08-01

A simple and rapid high-performance liquid chromatographic method for the separation and determination of piracetam and its four impurities, 2-oxopyrrolidin-1-yl)acetic acid, pyrrolidin-2-one, methyl (2-oxopyrrolidin-1-yl)acetate, and ethyl (2-oxopyrrolidin-1-yl)acetate, was developed. The separation was achieved on a reversed-phase C(18) Nucleosil column (25 cm x 0.46 cm, 10 microm). The mobile phase is composed of an aqueous solution containing 0.2 g/L of triethyl amine-acetonitrile (85:15, v/v). The pH of the mobile phase was adjusted to 6.5 with phosphoric acid at a flow rate of 1 mL/min at ambient temperature and UV detection at 205 nm. The developed method was found to give good separation between the pure drug and its four related substance. The polynomial regression data for the calibration plots showed good linear relationship in the concentration range of 50-10,000 ng/mL, 25-10,000 ng/mL, 45-10,000 ng/mL, 34-10,000 ng/mL, and 55-10,000 ng/mL, respectively, with r(2) = 0.9999. The method was validated for precision, accuracy, ruggedness, and recovery. The minimum quantifiable amounts were found to be 50 ng/mL of piracetam, 25 ng/mL of 2-oxopyrrolidin-1-yl)acetic acid, 45 ng/mL of pyrrolidin-2-one, 34 ng/mL of methyl (2-oxopyrrolidin-1-yl)acetate, and 55 ng/mL of ethyl (2-oxopyrrolidin-1-yl)acetate. Statistical analysis proves that the method is reproducible and selective for the estimation of piracetam as well as its related substance. As the method could effectively separate the drug from the related substances, it can be employed as a stability-indicating one. The proposed method shows high efficiency, allowing the separation of the main component piracetam from other impurities.

DFT studies of the substituent effects of dimethylamino on non-heme active oxidizing species: iron(V)-oxo species or iron(IV)-oxo acetate aminopyridine cation radical species?

Science.gov (United States)

Wang, Fang; Sun, Wei; Xia, Chungu; Wang, Yong

2017-10-01

Through the introduction of dimethylamino (Me 2 N) substituent at the pyridine ring of 2-((R)-2-[(R)-1-(pyridine-2-ylmethyl)pyrrolidin-2-yl]pyrrolidin-1-ylmethyl)pyridine (PDP) ligand, the non-heme Fe II ( Me2N PDP)/H 2 O 2 /AcOH catalyst system was found to exhibit significant higher catalytic activity and enantioselectivity than the non-substituent one in the asymmetric epoxidation experiments. The mechanistic origin of the remarkable substituent effects in these oxidation reactions has not been well established. To ascertain the potent oxidant and the related reaction mechanism, a detailed DFT calculation was performed. Interestingly, a novel Fe(IV)-oxo Me2N PDP cation radical species, [( Me2N PDP) + · Fe IV (O)(OAc)] 2+ ( Me2N 5), with about one spin spreading over the non-heme Me2N PDP ligand was formed via a carboxylic-acid-assisted O-O bond heterolysis, which is reminiscent of Compound I (an Fe(IV)(O)(porphyrin cation radical) species) in cytochrome P450 chemistry. Me2N 5 is energetically comparable with the cyclic ferric peracetate species Me2N 6, while in the pristine Fe(PDP) catalyst system, H 6 is more stable than H 5. Comparison of the activation energy for the ethylene epoxidation promoted by Me2N 5 and Me2N 6, Me2N 5 is supposed as the true oxidant triggering the epoxidation of olefins. In addition, a systematic research on the substituent effects varied from the electron-donating substituent (dMM, the substituents at sites 3, 4, and 5 of the pyridine ring: methyl, methoxyl, and methyl) to the electron-withdrawing one (CF 3 , 2,6-bis(trifluoromethyl)phenyl) on the electronic structure of the reaction intermediates has also been investigated. An alternative cyclic ferric peracetate complex is obtained, indicating that the substituents at the pyridine ring of PDP ligands have significant impacts on the electronic structure of the oxidants.

Dispersive liquid-liquid microextraction combined with graphite furnace atomic absorption spectrometry

International Nuclear Information System (INIS)

Zeini Jahromi, Elham; Bidari, Araz; Assadi, Yaghoub; Milani Hosseini, Mohammad Reza; Jamali, Mohammad Reza

2007-01-01

Dispersive liquid-liquid microextraction (DLLME) technique was successfully used as a sample preparation method for graphite furnace atomic absorption spectrometry (GF AAS). In this extraction method, 500 μL methanol (disperser solvent) containing 34 μL carbon tetrachloride (extraction solvent) and 0.00010 g ammonium pyrrolidine dithiocarbamate (chelating agent) was rapidly injected by syringe into the water sample containing cadmium ions (interest analyte). Thereby, a cloudy solution formed. The cloudy state resulted from the formation of fine droplets of carbon tetrachloride, which have been dispersed, in bulk aqueous sample. At this stage, cadmium reacts with ammonium pyrrolidine dithiocarbamate, and therefore, hydrophobic complex forms which is extracted into the fine droplets of carbon tetrachloride. After centrifugation (2 min at 5000 rpm), these droplets were sedimented at the bottom of the conical test tube (25 ± 1 μL). Then a 20 μL of sedimented phase containing enriched analyte was determined by GF AAS. Some effective parameters on extraction and complex formation, such as extraction and disperser solvent type and their volume, extraction time, salt effect, pH and concentration of the chelating agent have been optimized. Under the optimum conditions, the enrichment factor 125 was obtained from only 5.00 mL of water sample. The calibration graph was linear in the rage of 2-20 ng L -1 with detection limit of 0.6 ng L -1 . The relative standard deviation (R.S.D.s) for ten replicate measurements of 20 ng L -1 of cadmium was 3.5%. The relative recoveries of cadmium in tap, sea and rivers water samples at spiking level of 5 and 10 ng L -1 are 108, 95, 87 and 98%, respectively. The characteristics of the proposed method have been compared with cloud point extraction (CPE), on-line liquid-liquid extraction, single drop microextraction (SDME), on-line solid phase extraction (SPE) and co-precipitation based on bibliographic data. Therefore, DLLME combined with

New One-Pot Methodologies for the Modification or Synthesis of Alkaloid Scaffolds

Directory of Open Access Journals (Sweden)

Amir E. Wahba

2010-08-01

Full Text Available There are several avenues by which promising bioactive natural products can be produced in sufficient quantities to enable lead optimization and medicinal chemistry studies. The total synthesis of natural products is an important, but sometimes difficult, approach and requires the development of innovative synthetic methodologies to simplify the synthesis of complex molecules. Various classes of natural product alkaloids are both common and widely distributed in plants, bacteria, fungi, insects and marine organisms. This mini-review will discuss the scope, mechanistic insights and enantioselectivity aspects of selected examples of recently developed one-pot methods that have been published in 2009 for the synthesis of substituted piperidines, quinolizidines, pyrrolidines, hexahydropyrrolizines, octahydroindolizines and g-lactams. In addition, progress on the synthesis of b-carboline (manzamine alkaloids will also be discussed.

Penicillenols from a deep-sea fungus Aspergillus restrictus inhibit Candida albicans biofilm formation and hyphal growth.

Science.gov (United States)

Wang, Jie; Yao, Qi-Feng; Amin, Muhammad; Nong, Xu-Hua; Zhang, Xiao-Yong; Qi, Shu-Hua

2017-06-01

Penicillenols (A1, A2, B1, B2, C1 and C2) were isolated from Aspergillus restrictus DFFSCS006, and could differentially inhibit biofilm formation and eradicate pre-developed biofilms of Candida albicans. Their structure-bioactivity relationships suggested that the saturation of hydrocarbon chain at C-8, R-configuration of C-5 and trans-configuration of the double bond between C-5 and C-6 of pyrrolidine-2,4-dione unit were important for their anti-biofilm activities. Penicillenols A2 and B1 slowed the hyphal growth and suppressed the transcripts of hypha specific genes HWP1, ALS1, ALS3, ECE1 and SAP4. Moreover, penicillenols A2 and B1 were found to act synergistically with amphotericin B against C. albicans biofilm formation.

Determination of Lead in Blood by Atomic Absorption Spectrophotometry1

Science.gov (United States)

Selander, Stig; Cramér, Kim

1968-01-01

Lead in blood was determined by atomic absorption spectrophotometry, using a wet ashing procedure and a procedure in which the proteins were precipitated with trichloroacetic acid. In both methods the lead was extracted into isobutylmethylketone before measurement, using ammonium pyrrolidine dithiocarbamate as chelator. The simpler precipitation procedure was shown to give results identical with those obtained with the ashing technique. In addition, blood specimens were examined by the precipitation method and by spectral analysis, which method includes wet ashing of the samples, with good agreement. All analyses were done on blood samples from `normal' persons or from lead-exposed workers, and no additions of inorganic lead were made. The relatively simple protein precipitation technique gave accurate results and is suitable for the large-scale control of lead-exposed workers. PMID:5663425

New and Efficient Synthesis of Amides from Acid Chlorides Using Diisobutyl(amino)aluminum

Energy Technology Data Exchange (ETDEWEB)

Park, Jae Kyo; Shin, Won Kyu; An, Duk Keun [Kangwon National Univ., Chuncheon (Korea, Republic of)

2013-05-15

In conclusion, we have developed a facile, alternative method for the formation of secondary and tertiary amides including morpholine amides from acid chlorides by using diisobutyl(amino)aluminum under mild reaction conditions. The advantages of the present method include the high product yields, simple experimental procedure, short reaction time (10 min), and the fact that an excess amount of amine is not required. This result suggests that our new method can provide an alternative method for the synthesis of useful amides from acid chlorides. Amides are valuable functional groups in biological, agrochemical, and pharmaceutical molecules. Several amides such as Weinreb amides, morpholine amides, and pyrrolidine amides are useful intermediates for the synthesis of aldehydes or ketones. Among them, morpholine amides are a cheap and good substitute for Weinreb amides.

The stereochemistry of the addition of chlorotitanium enolates of N-acyl oxazolidin-2-ones to 5- and 6- membered N-acyliminium ions

Directory of Open Access Journals (Sweden)

Pilli Ronaldo A.

2001-01-01

Full Text Available The stereoselective addition of chiral and achiral titanium enolates derived from the corresponding N-acyl oxazolidin-2-ones to 5- and 6- membered N-acyliminium ions afforded 2-substituted pyrrolidines in moderate to good diastereoisomeric ratio (5:1 to 14:1 while lower diastereoselection was generally observed in the formation of the corresponding 2-substituted piperidines. The stereochemical outcome was found to be modulated by the nature of the cyclic N-acyliminium ion (5- or 6-membered and of its carbamate and by the N-acyl group in the enolate precursor. The preferential lk approach seems to be dictated mainly by the minimization of non-bonding interactions between the N-acyl group in the chlorotitanium (IV enolate and the carbamate and methylene groups in the cyclic N-acyliminium ion.

Fulleropyrrolidine end-capped molecular wires for molecular electronics--synthesis, spectroscopic, electrochemical, and theoretical characterization

DEFF Research Database (Denmark)

Sørensen, Jakob Kryger; Fock, Jeppe; Pedersen, Anders Holmen

2011-01-01

In continuation of previous studies showing promising metal-molecule contact properties a variety of C(60) end-capped "molecular wires" for molecular electronics were prepared by variants of the Prato 1,3-dipolar cycloaddition reaction. Either benzene or fluorene was chosen as the central wire...... state. However, the fluorescence of C(60) was quenched by charge transfer from the wire to C(60). Quantum chemical calculations predict and explain the collapse of coherent electronic transmission through one of the fulleropyrrolidine-terminated molecular wires......., and synthetic protocols for derivatives terminated with one or two fullero[c]pyrrolidine "electrode anchoring" groups were developed. An aryl-substituted aziridine could in some cases be employed directly as the azomethine ylide precursor for the Prato reaction without the need of having an electron...

New and Efficient Synthesis of Amides from Acid Chlorides Using Diisobutyl(amino)aluminum

International Nuclear Information System (INIS)

Park, Jae Kyo; Shin, Won Kyu; An, Duk Keun

2013-01-01

In conclusion, we have developed a facile, alternative method for the formation of secondary and tertiary amides including morpholine amides from acid chlorides by using diisobutyl(amino)aluminum under mild reaction conditions. The advantages of the present method include the high product yields, simple experimental procedure, short reaction time (10 min), and the fact that an excess amount of amine is not required. This result suggests that our new method can provide an alternative method for the synthesis of useful amides from acid chlorides. Amides are valuable functional groups in biological, agrochemical, and pharmaceutical molecules. Several amides such as Weinreb amides, morpholine amides, and pyrrolidine amides are useful intermediates for the synthesis of aldehydes or ketones. Among them, morpholine amides are a cheap and good substitute for Weinreb amides

Gas phase radiolysis and vacuum ultraviolet photolysis of heterocyclic organic compounds. Progress report, February 1, 1974--February 1, 1975

International Nuclear Information System (INIS)

Scala, A.A.; Salomon, D.; Colon, I.; D'Angona, J.

1975-01-01

In the γ radiolysis of tetrahydrofuran there are pronounced density effects in the pressure range from 0 to 50 Torr with the most important ion-pair yields decreasing as the pressure increases. The relative product yields of the radiolysis is compared with that of xenon photolysis. Possible mechanisms to explain the results obtained are discussed. The ion-pair yields from the γ radiolysis of the heterocyclic amines, ethylenimine, azetidine, pyrrolidine, and piperidine, are determined, and the pressure effects are evaluated. Reactions mechanisms are discussed. The vacuum ultraviolet photolysis products of thietane and tetrahydrothiophene are studied and compared with the γ radiolysis products. Reaction mechanisms are discussed. The status of the construction of a photoionization mass spectrometer and the measurement of the ionization efficiencies and extinction coefficients of organic compounds is reported. (U.S.)

Ultra-bright and highly efficient inorganic based perovskite light-emitting diodes

Science.gov (United States)

Zhang, Liuqi; Yang, Xiaolei; Jiang, Qi; Wang, Pengyang; Yin, Zhigang; Zhang, Xingwang; Tan, Hairen; Yang, Yang (Michael); Wei, Mingyang; Sutherland, Brandon R.; Sargent, Edward H.; You, Jingbi

2017-06-01

Inorganic perovskites such as CsPbX3 (X=Cl, Br, I) have attracted attention due to their excellent thermal stability and high photoluminescence quantum efficiency. However, the electroluminescence quantum efficiency of their light-emitting diodes was CsPbBr3 lattice and by depositing a hydrophilic and insulating polyvinyl pyrrolidine polymer atop the ZnO electron-injection layer to overcome these issues. As a result, we obtained light-emitting diodes exhibiting a high brightness of 91,000 cd m-2 and a high external quantum efficiency of 10.4% using a mixed-cation perovskite Cs0.87MA0.13PbBr3 as the emitting layer. To the best of our knowledge, this is the brightest and most-efficient green perovskite light-emitting diodes reported to date.

N,2,3,4-Tetrasubstituted Pyrrolidines through Tandem Lithium Amide Conjugate Addition/Radical Cyclization/Oxygenation Reactions

Czech Academy of Sciences Publication Activity Database

Kafka, František; Pohl, Radek; Císařová, I.; Mackman, R.; Bahador, G.; Jahn, Ullrich

2016-01-01

Roč. 2016, č. 22 (2016), s. 3862-3871 ISSN 1434-193X R&D Projects: GA ČR GA13-40188S Grant - others:COST(XE) CM1201 Institutional support: RVO:61388963 Keywords : tandem reactions * nitrogen heterocycles * Michael addition * radical reactions * cyclization * enolates Subject RIV: CC - Organic Chemistry Impact factor: 2.834, year: 2016

Synthesis and discovery of highly functionalized mono- and bis-spiro-pyrrolidines as potent cholinesterase enzyme inhibitors.

Science.gov (United States)

Kia, Yalda; Osman, Hasnah; Suresh Kumar, Raju; Basiri, Alireza; Murugaiyah, Vikneswaran

2014-04-01

Novel mono and bis spiropyrrolidine derivatives were synthesized via an efficient ionic liquid mediated, 1,3-dipolar cycloaddition methodology and evaluated in vitro for their AChE and BChE inhibitory activities in search for potent cholinesterase enzyme inhibitors. Most of the synthesized compounds displayed remarkable AChE inhibitory activities with IC50 values ranging from 1.68 to 21.85 μM, wherein compounds 8d and 8j were found to be most active inhibitors against AChE and BChE with IC50 values of 1.68 and 2.75 μM, respectively. Molecular modeling simulation on Torpedo californica AChE and human BChE receptors, showed good correlation between IC50 values and binding interaction template of the most active inhibitors docked into the active site of their relevant enzymes. Copyright © 2014 Elsevier Ltd. All rights reserved.

P53 status influences regulation of HSPs and ribosomal proteins by PDTC and radiation

International Nuclear Information System (INIS)

Thompson, John S.; Asmis, Reto; Glass, Judith; Liu Hua; Wilson, Colin; Nelson, Brandy; Brown, Stephen A.; Stromberg, Arnold J.

2006-01-01

Pyrrolidine dithiocarbamate (PDTC) is a thiol-containing compound that can act under varying conditions as an anti-oxidant or pro-oxidant. Utilizing microarrays, we determined the effect of PDTC +/- ionizing radiation (IR) on the expression of heat shock protein (HSP) genes in isolated B6/129 wild-type (WT) and p53-/- spleen cells. Extremely significant microarrays demonstrated that PDTC, but not IR, markedly up-regulated the expression of the majority of detectable HSP genes in WT and many to a significantly greater degree in p53-/- deficient cells. Determination of the glutathione/glutathione disulfide ratio indicated that PDTC was acting as a pro-oxidant under these conditions. From these data we conclude that the clinical use of 'antioxidants' with radiotherapy or chemotherapy must be very carefully based on knowledge of the p53 status of their intended normal and tumor target cells

Differential Rapid Screening of Phytochemicals by Leaf Spray Mass Spectrometry

International Nuclear Information System (INIS)

Mueller, Thomas; Graham Cooks, R.

2014-01-01

Ambient ionization can be achieved by generating an electrospray directly from plant tissue ('leaf spray'). The resulting mass spectra are characteristic of ionizable phytochemicals in the plant material. By subtracting the leaf spray spectra recorded from the petals of two hibiscus species H. moscheutos and H. syriacus one gains rapid access to the metabolites that differ most in the two petals. One such compound was identified as the sambubioside of quercitin (or delphinidin) while others are known flavones. Major interest centered on a C 19 H 29 NO 5 compound that occurs only in the large H. moscheutos bloom. Attempts were made to characterize this compound by mass spectrometry alone as a test of such an approach. This showed that the compound is an alkaloid, assigned to the polyhydroxylated pyrrolidine class, and bound via a C 3 hydrocarbon unit to a monoterpene

Calculations of optical rotation: Influence of molecular structure

Directory of Open Access Journals (Sweden)

Yu Jia

2012-01-01

Full Text Available Ab initio Hartree-Fock (HF method and Density Functional Theory (DFT were used to calculate the optical rotation of 26 chiral compounds. The effects of theory and basis sets used for calculation, solvents influence on the geometry and values of calculated optical rotation were all discussed. The polarizable continuum model, included in the calculation, did not improve the accuracy effectively, but it was superior to γs. Optical rotation of five or sixmembered of cyclic compound has been calculated and 17 pyrrolidine or piperidine derivatives which were calculated by HF and DFT methods gave acceptable predictions. The nitrogen atom affects the calculation results dramatically, and it is necessary in the molecular structure in order to get an accurate computation result. Namely, when the nitrogen atom was substituted by oxygen atom in the ring, the calculation result deteriorated.

Autoradiographic studies on the distribution of 14C-piracetam in the primate brain

International Nuclear Information System (INIS)

Ostrowski, J.; Keil, M.

1978-01-01

Autoradiography of the brain of the monkey Callithrix jacchus 2 and 6h after oral application of 200 mg 14 C-piracetam/kg (2-oxo-pyrrolidine-l-acetamide-2- 14 C) shows that the drug is preferably concentrated in the cortex of cerebrum and cerebellum. This specific affinity of piracetam which was observed earlier in dog and rats is thus confirmed in the primate and seems to be species independent. Besides the dominant cortical concentration there is a characteristic storage of piracetam in many nuclei of other brain areas, for instance, nucleus caudatus, hippocampus, n, anteriores thalami, n. dorsales thalami, corpus geniculatum laterale and mediale, corpora mamillaria, nucleus supraopticus, substantia grisea centralis, colliculi superiores and inferiores. Furthermore piracetam is stored in the blood vessel wall of the brain over 6h. The hypophysis and pineal body take up radioactivity intensively. (orig.) [de

Crystallographic investigations of select cathinones: emerging illicit street drugs known as `bath salts'.

Science.gov (United States)

Wood, Matthew R; Lalancette, Roger A; Bernal, Ivan

2015-01-01

The name `bath salts', for an emerging class of synthetic cathinones, is derived from an attempt to evade prosecution and law enforcement. These are truly illicit drugs that have psychoactive CNS (central nervous system) stimulant effects and they have seen a rise in abuse as recreational drugs in the last few years since first having been seen in Japan in 2006. The ease of synthesis and modification of specific functional groups of the parent cathinone make these drugs particularly difficult to regulate. MDPV (3,4-methylenedioxypyrovalerone) is commonly encountered as its hydrochloride salt (C16H21NO3·HCl), in either the hydrated or the anhydrous forms. This `bath salt' has various names in the US, e.g. `Super Coke', `Cloud Nine', and `Ivory Wave', to name just a few. We report here the structures of two forms of the HCl salt, one as a mixed bromide/chloride salt, C16H22NO3(+)·0.343Br(-)·0.657Cl(-) [systematic name: 1-(benzo[d][1,3]dioxol-5-yl)-2-(pyrrolidin-1-ium-1-yl)pentan-1-one bromide/chloride (0.343/0.657)], and the other with the H7O3(+) cation, as well as the HCl counter-ion [systematic name: hydroxonium 1-(benzo[d][1,3]dioxol-5-yl)-2-(pyrrolidin-1-ium-1-yl)pentan-1-one dichloride, H7O3(+)·C16H22NO3(+)·2Cl(-)]. This is one of a very few structures (11 to be exact) in which we have a new example of a precisely determined hydroxonium cation. During the course of researching the clandestine manufacture of MDPV, we were surprised by the fact that a common precursor of this illicit stimulant is known to be the fragrant species piperonal, which is present in the fragrances of orchids, most particularly in the case of the vanilla orchid. We found that MDPV can be made by a Grignard reaction of this heliotropin. This may also explain the unexpected appearance of the bromide counter-ion in some of the salts we encountered (C16H21NO3·HBr), one of which is presented here [systematic name: 1-(benzo[d][1,3]dioxol-5-yl)-2-(pyrrolidin-1-ium-1-yl)pentan-1-one

Hepatoselective Nitric Oxide (NO) Donors, V-PYRRO/NO and V-PROLI/NO, in Nonalcoholic Fatty Liver Disease: A Comparison of Antisteatotic Effects with the Biotransformation and Pharmacokinetics.

Science.gov (United States)

Kus, Kamil; Walczak, Maria; Maslak, Edyta; Zakrzewska, Agnieszka; Gonciarz-Dytman, Anna; Zabielski, Piotr; Sitek, Barbara; Wandzel, Krystyna; Kij, Agnieszka; Chabowski, Adrian; Holland, Ryan J; Saavedra, Joseph E; Keefer, Larry K; Chlopicki, Stefan

2015-07-01

V-PYRRO/NO [O(2)-vinyl-1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate] and V-PROLI/NO (O2-vinyl-[2-(carboxylato)pyrrolidin-1-yl]diazen-1-ium-1,2-diolate), two structurally similar diazeniumdiolate derivatives, were designed as liver-selective prodrugs that are metabolized by cytochrome P450 isoenzymes, with subsequent release of nitric oxide (NO). Yet, their efficacy in the treatment of nonalcoholic fatty liver disease (NAFLD) and their comparative pharmacokinetic and metabolic profiles have not been characterized. The aim of the present work was to compare the effects of V-PYRRO/NO and V-PROLI/NO on liver steatosis, glucose tolerance, and liver fatty acid composition in C57BL/6J mice fed a high-fat diet, as well as to comprehensively characterize the ADME (absorption, distribution, metabolism and excretion) profiles of both NO donors. Despite their similar structure, V-PYRRO/NO and V-PROLI/NO showed differences in pharmacological efficacy in the murine model of NAFLD. V-PYRRO/NO, but not V-PROLI/NO, attenuated liver steatosis, improved glucose tolerance, and favorably modified fatty acid composition in the liver. Both compounds were characterized by rapid absorption following i.p. administration, rapid elimination from the body, and incomplete bioavailability. However, V-PYRRO/NO was eliminated mainly by the liver, whereas V-PROLI/NO was excreted mostly in unchanged form by the kidney. V-PYRRO/NO was metabolized by CYP2E1, CYP2C9, CYP1A2, and CYP3A4, whereas V-PROLI/NO was metabolized mainly by CYP1A2. Importantly, V-PYRRO/NO was a better NO releaser in vivo and in the isolated, perfused liver than V-PROLI/NO, an effect compatible with the superior antisteatotic activity of V-PYRRO/NO. In conclusion, V-PYRRO/NO displayed a pronounced antisteatotic effect associated with liver-targeted NO release, whereas V-PROLI/NO showed low effectiveness, was not taken up by the liver, and was eliminated mostly in unchanged form by the kidney. U.S. Government work not protected by

Differential Rapid Screening of Phytochemicals by Leaf Spray Mass Spectrometry

Energy Technology Data Exchange (ETDEWEB)

Mueller, Thomas; Graham Cooks, R. [Univ. of Innsbruck, Innsbruck (Austria)

2014-03-15

Ambient ionization can be achieved by generating an electrospray directly from plant tissue ('leaf spray'). The resulting mass spectra are characteristic of ionizable phytochemicals in the plant material. By subtracting the leaf spray spectra recorded from the petals of two hibiscus species H. moscheutos and H. syriacus one gains rapid access to the metabolites that differ most in the two petals. One such compound was identified as the sambubioside of quercitin (or delphinidin) while others are known flavones. Major interest centered on a C{sub 19}H{sub 29}NO{sub 5} compound that occurs only in the large H. moscheutos bloom. Attempts were made to characterize this compound by mass spectrometry alone as a test of such an approach. This showed that the compound is an alkaloid, assigned to the polyhydroxylated pyrrolidine class, and bound via a C{sub 3} hydrocarbon unit to a monoterpene.

Inhibitors of nuclear factor kappa B cause apoptosis in cultured macrophages

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E. E. Mannick

1997-01-01

Full Text Available The precise role of the transcription factor nuclear factor kappa B (NF- κB in the regulation of cell survival and cell death is still unresolved and may depend on cell type and position in the cell cycle. The aim of this study was to determine if three pharmacologic inhibitors of NF-κB, pyrrolidine dithiocarbamate, N-tosyl-L-lysl chloromethyl ketone and calpain I inhibitor, induce apoptosis in a murine macrophage cell line (RAW 264.7 at doses similar to those required for NF-κB inhibition. We found that each of the three inhibitors resulted in a dose- and time-dependent increase in morphologic indices of apoptosis in unstimulated, LPS-stimulated and TNF-stimulated cells. Lethal doses were consistent with those required for NF- κB inhibition. We conclude that nuclear NF-κB activation may represent an important survival mechanism in macrophages.

Separation/preconcentration of silver(I) and lead(II) in environmental samples on cellulose nitrate membrane filter prior to their flame atomic absorption spectrometric determinations

International Nuclear Information System (INIS)

Soylak, Mustafa; Cay, Rukiye Sungur

2007-01-01

An enrichment method for trace amounts of Ag(I) and Pb(II) has been established prior to their flame atomic absorption spectrometric determinations. The preconcentration/separation procedure is based on chelate formation of Ag(I) and Pb(II) with ammonium pyrrolidine dithiocarbamate (APDC) and on retention of the chelates on cellulose nitrate membrane filter. The influences of some analytical parameters including pH and amounts of reagent, etc. on the recoveries of analytes were investigated. The effects of interferic ions on the quantitative recoveries of analytes were also examined. The detection limits (k = 3, N = 11) were 4.6 μg L -1 for silver(I) and 15.3 μg L -1 for lead(II). The relative standard deviations (R.S.D.) of the determinations for analyte ions were below 3%. The method was applied to environmental samples for the determination of analyte ions with satisfactory results (recoveries >95%)

Evidence for a role of GABA- and glutamate-gated chloride channels in olfactory memory.

Science.gov (United States)

Boumghar, Katia; Couret-Fauvel, Thomas; Garcia, Mikael; Armengaud, Catherine

2012-11-01

In the honeybee, we investigated the role of transmissions mediated by GABA-gated chloride channels and glutamate-gated chloride channels (GluCls) of the mushroom bodies (MBs) on olfactory learning using a single-trial olfactory conditioning paradigm. The GABAergic antagonist picrotoxin (PTX) or the GluCl antagonist L-trans-pyrrolidine-2,4-dicarboxylic acid (L-trans-PDC) was injected alone or in combination into the α-lobes of MBs. PTX impaired early long-term olfactory memory when injected before conditioning or before testing. L-trans-PDC alone induced no significant effect on learning and memory but induced a less specific response to the conditioned odor. When injected before PTX, L-trans-PDC was able to modulate PTX effects. These results emphasize the role of MB GABA-gated chloride channels in consolidation processes and strongly support that GluCls are involved in the perception of the conditioned stimulus.

Molecular interaction of a potent nonpeptide agonist with the chemokine receptor CCR8

DEFF Research Database (Denmark)

Jensen, Pia C; Nygaard, Rie; Thiele, Stefanie

2007-01-01

Most nonpeptide antagonists for CC-chemokine receptors share a common pharmacophore with a centrally located, positively charged amine that interacts with the highly conserved glutamic acid (Glu) located in position 6 of transmembrane helix VII (VII:06). We present a novel CCR8 nonpeptide agonist......, 8-[3-(2-methoxyphenoxy)benzyl]-1-phenethyl-1,3,8-triaza-spiro[4.5]decan-4-one (LMD-009), that also contains a centrally located, positively charged amine. LMD-009 selectively stimulated CCR8 among the 20 identified human chemokine receptors. It mediated chemotaxis, inositol phosphate accumulation......-binding pockets of CCR8 uncovered that the binding of LMD-009 and of four analogs [2-(1-(3-(2-methoxyphenoxy)benzyl)-4-hydroxypiperidin-4-yl)benzoic acid (LMD-584), N-ethyl-2-4-methoxybenzenesulfonamide (LMD-902), N-(1-(3-(2-methoxyphenoxy)benzyl)piperidin-4-yl)-2-phenyl-4-(pyrrolidin-1yl)butanamide (LMD-268...

Atomic absorption spectrophotometric determination of microgram levels of Co, Ni, Cu, Pb, and Zn in soil and sediment extracts containing large amounts of Mn and Fe

Science.gov (United States)

Chao, T.T.; Sanzolone, R.F.

1973-01-01

An atomic absorption spectrophotometric method has been developed for the determination of seven metal ions in the hydroxylamine extract of soils and sediments. Mn, Fe, and Zn are directly determined in the aqueous extract upon dilution. Co, Ni, Cu, and Pb in a separate aliquot of the extract are chelated with APDC (ammonium pyrrolidine dithiocarbamate) and extracted into MIBK (methyl isobutyl ketone) before determination. Data are presented to show the quantitative recovery of microgram levels of Co, Ni, Cu, and Pb by APDC-MIBK chelation-extraction from synthetic solutions containing as much as 2,000 ug/ml (micrograms per milliliter) Mn or 50 ug/ml Fe. Recovery of known amounts of the metal ions from sample solutions is equally satisfactory. Reproducible results are obtained by replicate analyses of two sediment samples for the seven metals.

Analytical characterization of three cathinone derivatives, 4-MPD, 4F-PHP and bk-EPDP, purchased as bulk powder from online vendors.

Science.gov (United States)

Apirakkan, Orapan; Frinculescu, Anca; Shine, Trevor; Parkin, Mark C; Cilibrizzi, Agostino; Frascione, Nunzianda; Abbate, Vincenzo

2018-02-01

Novel emerging drugs of abuse, also referred as new psychoactive substances, constitute an ever-changing mixture of chemical compounds designed to circumvent legislative controls by means of chemical modifications of previously banned recreational drugs. One such class, synthetic cathinones, namely β-keto derivatives of amphetamines, has been largely abused over the past decade. A number of new synthetic cathinones are detected each year, either in bulk powders/crystals or in biological matrices. It is therefore important to continuously monitor the supply of new synthetic derivatives and promptly report them. By using complementary analytical techniques (i.e. one- and two-dimensional NMR, FT-IR, GC-MS, HRMS and HPLC-UV), this study investigates the detection, identification and full characterization of 1-(4-methylphenyl)-2-(methylamino)pentanone (4-methylpentedrone, 4-MPD), 1-(4-fluorophenyl)-2-(pyrrolidin-1-yl)hexanone (4F-PHP) and 1-(1,3-benzodioxol-5-yl)-2-(ethylamino)-1-pentanone (bk-EPDP), three emerging cathinone derivatives. Copyright © 2017 John Wiley & Sons, Ltd.

Structure-Based Design of an Iminoheterocyclic β-Site Amyloid Precursor Protein Cleaving Enzyme (BACE) Inhibitor that Lowers Central Aβ in Nonhuman Primates

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Mandal, Mihirbaran; Wu, Yusheng; Misiaszek, Jeffrey; Li, Guoqing; Buevich, Alexei; Caldwell, John P.; Liu, Xiaoxiang; Mazzola, Robert D.; Orth, Peter; Strickland, Corey; Voigt, Johannes; Wang, Hongwu; Zhu, Zhaoning; Chen, Xia; Grzelak, Michael; Hyde, Lynn A.; Kuvelkar, Reshma; Leach, Prescott T.; Terracina, Giuseppe; Zhang, Lili; Zhang, Qi; Michener, Maria S.; Smith, Brad; Cox, Kathleen; Grotz, Diane; Favreau, Leonard; Mitra, Kaushik; Kazakevich, Irina; McKittrick, Brian A.; Greenlee, William; Kennedy, Matthew E.; Parker, Eric M.; Cumming, Jared N.; Stamford, Andrew W. (Merck)

2016-04-14

We describe successful efforts to optimize the in vivo profile and address off-target liabilities of a series of BACE1 inhibitors represented by 6 that embodies the recently validated fused pyrrolidine iminopyrimidinone scaffold. Employing structure-based design, truncation of the cyanophenyl group of 6 that binds in the S3 pocket of BACE1 followed by modification of the thienyl group in S1 was pursued. Optimization of the pyrimidine substituent that binds in the S2'–S2'' pocket of BACE1 remediated time-dependent CYP3A4 inhibition of earlier analogues in this series and imparted high BACE1 affinity. These efforts resulted in the discovery of difluorophenyl analogue 9 (MBi-4), which robustly lowered CSF and cortex Aβ40 in both rats and cynomolgus monkeys following a single oral dose. Compound 9 represents a unique molecular shape among BACE inhibitors reported to potently lower central Aβ in nonrodent preclinical species.

Investigating the Spectrum of Biological Activity of Substituted Quinoline-2-Carboxamides and Their Isosteres

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Ales Imramovsky

2012-01-01

Full Text Available In this study, a series of thirty-five substituted quinoline-2-carboxamides and thirty-three substituted naphthalene-2-carboxamides were prepared and characterized. They were tested for their activity related to the inhibition of photosynthetic electron transport (PET in spinach (Spinacia oleracea L. chloroplasts. Primary in vitro screening of the synthesized compounds was also performed against four mycobacterial species. N-Cycloheptylquinoline-2-carboxamide, N-cyclohexylquinoline-2-carboxamide and N-(2-phenylethylquinoline-2-carboxamide showed higher activity against M. tuberculosis than the standards isoniazid or pyrazinamide and 2-(pyrrolidin-1-ylcarbonylquinoline and 1-(2-naphthoylpyrrolidine expressed higher activity against M. kansasii and M. avium paratuberculosis than the standards isoniazid or pyrazinamide. The most effective antimycobacterial compounds demonstrated insignificant toxicity against the human monocytic leukemia THP-1 cell line. The PET-inhibiting activity expressed by IC50 value of the most active compound N-benzyl-2-naphthamide was 7.5 μmol/L. For all compounds, the structure-activity relationships are discussed.

Kinetics of nitrosamine and amine reactions with NO3 radical and ozone related to aqueous particle and cloud droplet chemistry

Science.gov (United States)

Weller, Christian; Herrmann, Hartmut

2015-01-01

Aqueous phase reactivity experiments with the amines dimethylamine (DMA), diethanolamine (DEA) and pyrrolidine (PYL) and their corresponding nitrosamines nitrosodimethylamine (NDMA), nitrosodiethanolamine (NDEA) and nitrosopyrrolidine (NPYL) have been performed. NO3 radical reaction rate coefficients for DMA, DEA and PYL were measured for the first time and are 3.7 × 105, 8.2 × 105 and 8.7 × 105 M-1 s-1, respectively. Rate coefficients for NO3 + NDMA, NDEA and NPYL are 1.2 × 108, 2.3 × 108 and 2.4 × 108 M-1 s-1. Compared to OH radical rate coefficients for reactions with amines, the NO3 radical will most likely not be an important oxidant but it is a potential nighttime oxidant for nitrosamines in cloud droplets or deliquescent particles. Ozone is unreactive towards amines and nitrosamines and upper limits of rate coefficients suggest that aqueous ozone reactions are not important in atmospheric waters.

Sb(III) and Sb(V) separation and analytical speciation by a continuous tandem on-line separation device in connection with inductively coupled plasma atomic emission spectrometry

Energy Technology Data Exchange (ETDEWEB)

Menendez Garcia, A. [Oviedo Univ. (Spain). Dept. of Phys. and Anal. Chem.; Perez Rodriguez, M.C. [Oviedo Univ. (Spain). Dept. of Phys. and Anal. Chem.; Sanchez Uria, J.F. [Oviedo Univ. (Spain). Dept. of Phys. and Anal. Chem.; Sanz-Medel, A. [Oviedo Univ. (Spain). Dept. of Phys. and Anal. Chem.

1995-09-01

A sensitive, precise and automated non-chromatographic method for Sb(III) and Sb(V) analytical speciation based on a continuous tandem on-line separation device in connection with inductively coupled plasma-atomic emission (ICP-AES) detection is proposed. Two on-line successive separation steps are included into this method: a continuous liquid-liquid extraction of Sb(III) with ammonium pyrrolidine dithiocarbamate (APDC) into methylisobuthylketone (MIBK), followed by direct stibine generation from the organic phase. Both separation steps are carried out in a continuous mode and on-line with the ICP-AES detector. Optimization of experimental conditions for the tandem separation and ICP-AES detection are investigated in detail. Detection limits for Sb(III) were 3 ng.mL{sup -1} and for Sb(V) 8 ng.mL{sup -1}. Precisions observed are in the range {+-} 5%. The proposed methodology has been applied to Sb(III) and Sb(V) speciation in sea-water samples. (orig.)

Characterization of Small Molecule Scaffolds that Bind to the Shigella Type III Secretion System Protein IpaD

Science.gov (United States)

Dey, Supratim; Anbanandam, Asokan; Mumford, Ben E.; De Guzman, Roberto N.

2017-01-01

Many pathogens such as Shigella and other bacteria assemble the type III secretion system (T3SS) nanoinjector to inject virulence proteins into their target cells to cause infectious diseases in humans. The rise of drug resistance among pathogens that rely on the T3SS for infectivity, plus the dearth of new antibiotics require alternative strategies in developing new antibiotics. The Shigella T3SS tip protein IpaD is an attractive target for developing anti-infectives because of its essential role in virulence and its exposure on the bacterial surface. Currently, the only known small molecules that bind to IpaD are bile salts sterols. Here, we identified four new small molecule scaffolds that bind to IpaD based on the methylquinoline, pyrrolidin-aniline, hydroxyindole, and morpholinoaniline scaffolds. NMR mapping revealed potential hotspots in IpaD for binding small molecules. These scaffolds can be used as building blocks in developing small molecule inhibitors of IpaD that could lead to new anti-infectives. PMID:28750143

Design, synthesis, and evaluation of nonretinoid retinol binding protein 4 antagonists for the potential treatment of atrophic age-related macular degeneration and Stargardt disease.

Science.gov (United States)

Cioffi, Christopher L; Dobri, Nicoleta; Freeman, Emily E; Conlon, Michael P; Chen, Ping; Stafford, Douglas G; Schwarz, Daniel M C; Golden, Kathy C; Zhu, Lei; Kitchen, Douglas B; Barnes, Keith D; Racz, Boglarka; Qin, Qiong; Michelotti, Enrique; Cywin, Charles L; Martin, William H; Pearson, Paul G; Johnson, Graham; Petrukhin, Konstantin

2014-09-25

Accumulation of lipofuscin in the retina is associated with pathogenesis of atrophic age-related macular degeneration and Stargardt disease. Lipofuscin bisretinoids (exemplified by N-retinylidene-N-retinylethanolamine) seem to mediate lipofuscin toxicity. Synthesis of lipofuscin bisretinoids depends on the influx of retinol from serum to the retina. Compounds antagonizing the retinol-dependent interaction of retinol-binding protein 4 (RBP4) with transthyretin in the serum would reduce serum RBP4 and retinol and inhibit bisretinoid formation. We recently showed that A1120 (3), a potent carboxylic acid based RBP4 antagonist, can significantly reduce lipofuscin bisretinoid formation in the retinas of Abca4(-/-) mice. As part of the NIH Blueprint Neurotherapeutics Network project we undertook the in vitro exploration to identify novel conformationally flexible and constrained RBP4 antagonists with improved potency and metabolic stability. We also demonstrate that upon acute and chronic dosing in rats, 43, a potent cyclopentyl fused pyrrolidine antagonist, reduced circulating plasma RBP4 protein levels by approximately 60%.

Icotinib inhibits the invasion of Tca8113 cells via downregulation of nuclear factor κB-mediated matrix metalloproteinase expression.

Science.gov (United States)

Yang, Cailing; Yan, Jianguo; Yuan, Guoyan; Zhang, Yinghua; Lu, Derong; Ren, Mingxin; Cui, Weigang

2014-09-01

Icotinib is an epidermal growth factor receptor tyrosine kinase inhibitor, which has been revealed to inhibit proliferation in tumor cells. However, the effect of icotinib on cancer cell metastasis remains to be explained. This study examines the effect of icotinib on the migration and invasion of squamous cells of tongue carcinoma (Tca8113 cells) in vitro . The results of the Boyden chamber invasion assay demonstrated that icotinib reduced cell invasion, suppressed the protein levels of matrix metalloproteinases (MMPs), MMP-2 and MMP-9, and increased the expression of tissue inhibitor of metalloproteinase-1. In addition, icotinib was found to significantly decrease the protein levels of nuclear factor κB (NF-κB) p65, which suggested that icotinib inhibits NF-κB activity. Furthermore, treatment with the NF-κB inhibitor, pyrrolidine dithiocarbamate, suppressed cell invasion and MMP-2 expression. These results suggested that icotinib inhibits the invasion of Tca8113 cells by downregulating MMP via the inactivation of the NF-κB signaling pathways.

Control of media browning in micropropagation of guava (Psidium guajava L.)

International Nuclear Information System (INIS)

Ahmad, I.; Nafees, M.; Ashraf, I.

2016-01-01

Guava (Psidium guajava L.) is a highly valuable fruit of the tropical regions of the world. This species faces browning or blackening of culture medium during In vitro culture due to leaching of phenolic, microbial contagion and tissue recalcitrance. A study therefore designed to evaluate the effects of antioxidants in reduction of phenolic exudation which hampers In vitro regeneration. The nodal explants of the plant were cultured on MS media after pre-soaking in antioxidant solutions of citric acid, ascorbic acid, poly vinyl pyrrolidine (PVP) and charcoal. After culturing explants, the amount of phenolic exude was determined periodically on spectrophotometer at 750 nm absorbance. Phenolic exudation from guava was significantly reduced in nodes treated with charcoal as compared to control and rest of the treatments. Moreover, guava nodes survival percentage was also significantly increased in charcoal treated nodes. It is concluded that pre-soaking in different antioxidants significantly reduced the media browning and thus micro-propagation of guava could be achieved on commercial basis. (author)

A model for evolution and regulation of nicotine biosynthesis regulon in tobacco.

Science.gov (United States)

Kajikawa, Masataka; Sierro, Nicolas; Hashimoto, Takashi; Shoji, Tsubasa

2017-06-03

In tobacco, the defense alkaloid nicotine is produced in roots and accumulates mainly in leaves. Signaling mediated by jasmonates (JAs) induces the formation of nicotine via a series of structural genes that constitute a regulon and are coordinated by JA-responsive transcription factors of the ethylene response factor (ERF) family. Early steps in the pyrrolidine and pyridine biosynthesis pathways likely arose through duplication of the polyamine and nicotinamide adenine dinucleotide (NAD) biosynthetic pathways, respectively, followed by recruitment of duplicated primary metabolic genes into the nicotine biosynthesis regulon. Transcriptional regulation of nicotine biosynthesis by ERF and cooperatively-acting MYC2 transcription factors is implied by the frequency of cognate cis-regulatory elements for these factors in the promoter regions of the downstream structural genes. Indeed, a mutant tobacco with low nicotine content was found to have a large chromosomal deletion in a cluster of closely related ERF genes at the nicotine-controlling NICOTINE2 (NIC2) locus.

An unexpected reaction pathway in the synthesis of the ABCE framework of strychnine-type alkaloids - A multidisciplinary study

Science.gov (United States)

Šoral, Michal; Markus, Jozef; Doháňošová, Jana; Šoralová, Stanislava; Dvoranová, Dana; Chyba, Andrej; Moncol, Ján; Berkeš, Dušan; Liptaj, Tibor

2017-01-01

Acid-catalyzed cyclization of spirocyclic 1‧-benzyl-2‧-(prop-2-en-1-yl)spiro[indole-3,3‧-pyrrolidine]-5‧-one (1) was performed. The pentacyclic product of Povarov-like imino-Diels-Alder reaction was isolated in high yield instead of expected tetracyclic aza-Prins intermediate. The unusual exotic alkaloid-type structure of the resulting molecule 2 was unambiguously confirmed by a detailed NMR analysis using a set of 2D NMR spectra including an INADEQUATE experiment. The relative configuration of 2 was predicted from the synthesis mechanism and DFT geometry calculations and independently confirmed using NOESY and residual dipolar coupling (RDC) assisted NMR analysis in stretched crosslinked polystyrene gels. The reversibility of the cycloaddition in aprotic solvents was observed. A new reaction pathway yielding a rare 6-5-5-5 tetracyclic spiroindoline 3 was suggested. The relative configuration within the tetracyclic framework was ultimately proved using Single-crystal X-ray diffraction analysis of compound 4.

Ultratrace Determination of Cr(VI and Pb(II by Microsample Injection System Flame Atomic Spectroscopy in Drinking Water and Treated and Untreated Industrial Effluents

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Jameel Ahmed Baig

2013-01-01

Full Text Available Simple and robust analytical procedures were developed for hexavalent chromium (Cr(VI and lead (Pb(II by dispersive liquid-liquid microextraction (DLLME using microsample injection system coupled with flame atomic absorption spectrophotometry (MIS-FAAS. For the current study, ammonium pyrrolidine dithiocarbamate (APDC, carbon tetrachloride, and ethanol were used as chelating agent, extraction solvent, and disperser solvent, respectively. The effective variables of developed method have been optimized and studied in detail. The limit of detection of Cr(VI and Pb(II were 0.037 and 0.054 µg/L, respectively. The enrichment factors in both cases were 400 with 40 mL of initial volumes. The relative standard deviations (RSDs, were 96%. The proposed method was successfully applied to the determination of Cr(VI and Pb(II at ultratrace levels in natural drinking water and industrial effluents wastewater of Denizli. Moreover, the proposed method was compared with the literature reported method.

Determination of cadmium in seawater by chelate vapor generation atomic fluorescence spectrometry

Science.gov (United States)

Sun, Rui; Ma, Guopeng; Duan, Xuchuan; Sun, Jinsheng

2018-03-01

A method for the determination of cadmium in seawater by chelate vapor generation (Che-VG) atomic fluorescence spectrometry is described. Several commercially available chelating agents, including ammonium pyrrolidine dithiocarbamate (APDC), sodium dimethyl dithiocarbamate (DMDTC), ammonium dibutyl dithiophosphate (DBDTP) and sodium O,O-diethyl dithiophosphate (DEDTP), are compared with sodium diethyldithiocarbamate (DDTC) for the Che-VG of cadmium, and results showed that DDTC and DEDTP had very good cadmium signal intensity. The effect of the conditions of Che-VG with DDTC on the intensity of cadmium signal was investigated. Under the optimal conditions, 85 ± 3% Che-VG efficiency is obtained for cadmium. The detection limit (3σ) obtained in the optimal conditions was 0.19 ng ml- 1. The relative standard deviation (RSD, %) for ten replicate determinations at 2 ng ml- 1 Cd was 3.42%. The proposed method was successfully applied to the ultratrace determination of cadmium in seawater samples by the standard addition method.

Novel small molecule induces p53-dependent apoptosis in human colon cancer cells

International Nuclear Information System (INIS)

Park, Sang Eun; Min, Yong Ki; Ha, Jae Du; Kim, Bum Tae; Lee, Woo Ghil

2007-01-01

Using high-throughput screening with small-molecule libraries, we identified a compound, KCG165 [(2-(3-(2-(pyrrolidin-1-yl)ethoxy)-1,10b-dihydro-[1,2,4]triazolo[1,5-c] quinazolin-5(6H)-one)], which strongly activated p53-mediated transcriptional activity. KCG165-induced phosphorylations of p53 at Ser 6 , Ser 15 , and Ser 20 , which are all key residues involved in the activation and stabilization of p53. Consistent with these findings, KCG165 increased level of p53 protein and led to the accumulation of transcriptionally active p53 in the nucleus with the increased occupancy of p53 in the endogenous promoter region of its downstream target gene, p21 WAF1/CIP . Notably, KCG165-induced p53-dependent apoptosis in cancer cells. Furthermore, we suggested topoisomerase II as the molecular target of KCG165. Together, these results indicate that KCG165 may have potential applications as an antitumor agent

Diffusion studies on permeable nitroxyl spin probe through lipid bilayer membrane

International Nuclear Information System (INIS)

Benial, A. Milton Franklin; Meenakumari, V.; Ichikawa, Kazuhiro; Yamada, Ken-ichi; Utsumi, Hideo; Hyodo, Fuminori; Jawahar, A.

2014-01-01

Electron spin resonance (ESR) studies were carried out for 2mM 14 N labeled deutrated permeable 3- methoxycarbonyl-2,2,5,5-tetramethyl-pyrrolidine-1-oxyl (MC-PROXYL) in pure water, 1 mM, 2 mM, 3 mM and 4 mM concentration of MC-PROXYL in 300 mM concentration of liposomal solution by using a L-band ESR spectrometer. The ESR parameters such as linewidth, hyperfine coupling constant, g-factor, partition parameter and permeability were reported. The partition parameter and permeability values indicate the maximum spin distribution in the lipid phase at 2 mM concentration. This study illustrates that ESR can be used to differentiate between the intra and extra-membrane water by loading the liposome vesicles with a lipid-permeable nitroxyl spin probe. From the ESR results, the radical concentration was optimized as 2 mM in liposomal solution for ESR phantom studies and experiments

Concise Total Synthesis of (-)-Affinisine Oxindole, (+)-Isoalstonisine, (+)-Alstofoline, (-)-Macrogentine, (+)-Na -Demethylalstonisine, (-)-Alstonoxine A, and (+)-Alstonisine.

Science.gov (United States)

Stephen, Michael Rajesh; Rahman, M Toufiqur; Tiruveedhula, V V N Phani Babu; Fonseca, German O; Deschamps, Jeffrey R; Cook, James M

2017-11-07

A highly enantio- and diastereoselective strategy to access any member of the sarpagine/macroline family of oxindole alkaloids via internal asymmetric induction was developed from readily available d-(+)-tryptophan. At the center of this approach was the diastereospecific generation of the spiro[pyrrolidine-3,3'-oxindole] moiety at an early stage via a tert-butyl hypochlorite-promoted oxidative rearrangement of a chiral tetrahydro-β-carboline derivative. This key branching point determined the spatial configuration at the C-7 spiro center to be entirely 7R or 7S. Other key stereospecific processes were the asymmetric Pictet-Spengler reaction and Dieckmann cyclization, which were scalable to the 600 and 150 gram levels, respectively. Execution of this approach resulted in first enantiospecific total synthesis of (+)-isoalstonisine and (-)-macrogentine from the chitosenine series (7R), as well as (+)-alstonisine, (+)-alstofoline, (-)-alstonoxine A and (+)-N a -demethylalstonisine from the alstonisine series (7S). © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Biotransformation and bioactivation reactions of alicyclic amines in drug molecules.

Science.gov (United States)

Bolleddula, Jayaprakasam; DeMent, Kevin; Driscoll, James P; Worboys, Philip; Brassil, Patrick J; Bourdet, David L

2014-08-01

Aliphatic nitrogen heterocycles such as piperazine, piperidine, pyrrolidine, morpholine, aziridine, azetidine, and azepane are well known building blocks in drug design and important core structures in approved drug therapies. These core units have been targets for metabolic attack by P450s and other drug metabolizing enzymes such as aldehyde oxidase and monoamine oxidase (MAOs). The electron rich nitrogen and/or α-carbons are often major sites of metabolism of alicyclic amines. The most common biotransformations include N-oxidation, N-conjugation, oxidative N-dealkylation, ring oxidation, and ring opening. In some instances, the metabolic pathways generate electrophilic reactive intermediates and cause bioactivation. However, potential bioactivation related adverse events can be attenuated by structural modifications. Hence it is important to understand the biotransformation pathways to design stable drug candidates that are devoid of metabolic liabilities early in the discovery stage. The current review provides a comprehensive summary of biotransformation and bioactivation pathways of aliphatic nitrogen containing heterocycles and strategies to mitigate metabolic liabilities.

Methyl 11-hydroxy-9-[1-(4-methoxyphenyl-4-oxo-3-phenoxyazetidin-2-yl]-18-oxo-10-oxa-2-azapentacyclo[9.7.0.01,8.02,6.012,17]octadeca-12(17,13,15-triene-8-carboxylate

Directory of Open Access Journals (Sweden)

S. Sundaramoorthy

2012-07-01

Full Text Available In the title compound, C34H32N2O8, one of the pyrrolidine rings in the pyrrolizidine ring system adopts a twist conformation, whereas the other ring adopts an envelope conformation (C atom as flap. The five-membered ring in the indene ring system and the fused furan ring also adopt envelope conformations (C and O atoms as flaps, respectively. The β-lactam ring makes dihedral angles of 23.41 (2 and 25.98 (2°, respectively, with the attached methoxyphenyl and phenoxy rings. The molecular conformation is stabilized by an intramolecular O—H...N hydrogen bond, generating an S(5 motif. In the crystal, molecules are linked into C(12 chains running along the a axis by C—H...O hydrogen bonds. The structure is further consolidated by weak intermolecular C—H...π and π–π interactions [centroid–centroid distance = 3.7987 (14 Å].

Anti-nociceptive, anti-hyperalgesic and anti-arthritic activity of amides and extract obtained from Piper amalago in rodents.

Science.gov (United States)

da Silva Arrigo, Jucicléia; Balen, Eloise; Júnior, Ubirajara Lanza; da Silva Mota, Jonas; Iwamoto, Renan Donomae; Barison, Andersson; Sugizaki, Mario Mateus; Leite Kassuya, Cândida Aparecida

2016-02-17

Piper amalago (Piperaceae) has been used in folk medicine as an analgesic. This study aimed to evaluate the pharmacological effects of extract and pure amides obtained from P. amalago on pain to provide a pharmacological basis for their use in traditional medicine. This study evaluated the anti-nociceptive, anti-hyperalgesic, anti-arthritic and anti-depressive activities of the ethanolic extract of P. amalago (EEPA) and the amides N-[7-(3',4'-methylenedioxyphenyl)-2(Z),4(Z)-heptadienoyl] pyrrolidine (1) and N-[7-(3',4'-methylenedioxyphenyl)-2(E),4(E)-heptadienoyl] pyrrolidine (2) obtained from P. amalago in animal models. Mice treated daily with EEPA (100mg/kg, p.o.) were assayed for 20 days for knee edema (micrometer measurement), mechanical hyperalgesia (analgesiometer analysis), heat sensitivity and immobility (forced swim test) in the Complete Freund's Adjuvant (CFA) model. Cold (acetone test) and mechanical hyperalgesia (electronic von Frey analysis) responses were evaluated for 15 days in rats treated with oral EEPA (100mg/kg) in the spared nerve injury (SNI) model. Meanwhile, mice were evaluated for carrageenan-induced edema and mechanical hyperalgesia and for nociception using the formalin model after a single administration of EEPA (100mg/kg) or amides 1 and 2 (1mg/kg). Amides (1) and (2) were detected and isolated from the EEPA. The EEPA inhibited mechanical hyperalgesia, knee edema, and heat hyperalgesia, but not depressive-like behavior, induced by the intraplantar injection of CFA. When evaluated in the SNI model, the EEPA inhibited mechanical and cold hyperalgesia. The EEPA, 1 and 2 prevented the mechanical hyperalgesia induced by carrageenan and the anti-nociceptive effects in both phases of formalin nociception. The EEPA did not induce alterations in the open field test. The EEPA was effective for inhibition of pain and arthritic parameters but was not effective against depressive-like behavior; additionally, it did not alter locomotor activity. The

Characterization of Volatile Compounds with HS-SPME from Oxidized n-3 PUFA Rich Oils via Rancimat Tests.

Science.gov (United States)

Yang, Kai-Min; Cheng, Ming-Ching; Chen, Chih-Wei; Tseng, Chin-Yin; Lin, Li-Yun; Chiang, Po-Yuan

2017-02-01

Algae oil and fish oil are n-3 PUFA mainstream commercial products. The various sources for the stability of n-3 PUFA oxidation are influenced by the fatty acid composition, extraction and refined processing. In this study, the oil stability index (OSI) occurs within 2.3 to 7.6 hours with three different n-3 PUFA rich oil. To set the OSI in the Rancimat test as the oil stability limit and observed various degrees of oxidation (0, 25, 50, 75, 100 and 125%). The volatile oxidation compounds were analyzed via headspace-solid phase microextraction (HS-SPME) and GC/MS. We detected 51 volatile compound variations during the oxidation, which were composed of aldehydes, hydrocarbons, cyclic compounds, alcohols, benzene compounds, ketones, furans, ester and pyrrolidine. The off-flavor characteristics can be strongly influenced by the synergy effects of volatile oxidation compounds. Chemometric analysis (PCA and AHC) was applied to identify the sensitive oxidation marker compounds, which included a (E,E)-2,4-heptadienal appropriate marker, via lipid oxidation in the n-3 PUFA rich oil.

Permeability studies of redox-sensitive nitroxyl spin probes in corn oil using an L-band ESR spectrometer

Energy Technology Data Exchange (ETDEWEB)

Jebaraj, D. David [Department of Physics, The American College, Madurai-625 002, Tamilnadu (India); Utsumi, Hideo [Innovation Center for Medical Redox Navigation, Kyushu University, Fukuoka 812-8582 (Japan); Asath, R. Mohamed; Benial, A. Milton Franklin, E-mail: miltonfranklin@yahoo.com [Department of Physics, NMSSVN College, Madurai-625 019, Tamilnadu (India)

2016-05-23

Electron spin resonance (ESR) studies were carried out for 2mM {sup 14}N labeled {sup 2}H enriched 3-methoxycarbonyl-2,2,5,5-tetramethyl-pyrrolidine-1-oxyl (MC-PROXYL) and 3–carboxy-2,2,5,5,-tetramethyl-1-pyrrolidinyloxy (carboxy-PROXYL) in pure water and various concentrations of corn oil. The ESR parameters, such as the line width, hyperfine coupling constant, g-factor, rotational correlation time, partition parameter and permeability were reported for the samples. The line width broadening was observed for both nitroxyl radicals in corn oil solutions. The partition parameter for permeable MC-PROXYL in corn oil increases with increasing concentration of corn oil, which reveals that the nitroxyl spin probe permeates into the oil phase. From the results, the corn oil concentration was optimized as 50 % for phantom studies. The rotational correlation time also increases with increasing concentration of corn oil. The permeable and impermeable nature of nitroxyl spin probes was demonstrated. These results will be useful for the development of ESR/OMR imaging modalities in in vivo and in vitro studies.

Nuclear magnetic resonance at 310 MHz in a superconducting solenoid; Resonance magnetique nucleaire a 310 MHz dans un solenoide supra-conducteur

Energy Technology Data Exchange (ETDEWEB)

Dunand, J J [Commissariat a l' Energie Atomique, Grenoble (France). Centre d' Etudes Nucleaires

1970-07-01

The realisation of an NMR spectrometer with a superconducting magnet is presented in the first section. The methods to attain the best possible homogeneity of the magnetic field and to minimize the error in the spectrometer are described. The second section is devoted to the study of elastomers and nitr-oxides free radicals. A shift of the transition temperature with the magnetic field appears for the elastomers. The increasing paramagnetic shift has allowed a complete study by NMR of piperidinic and pyrrolidinic nitroxide free radicals. (author) [French] Dans la premiere partie est exposee la realisation d'un spectrometre de RMN utilisant un solenoide supraconducteur. Des solutions sont donnees pour obtenir la meilleure homogeneite possible du champ magnetique et pour minimiser les sources d'erreur apportees par le spectrometre. La deuxieme partie est consacree a l'etude d'elastomeres et de radicaux libres nitroxydes. Une variation de la temperature de transition avec le champ magnetique est mise en evidence pour les elastomeres. L'accroissement du deplacement paramagnetique a permis une etude complete par RMN des radicaux libres nitroxydes piperidiniques et pyrrolidiniques. (auteur)

Study of the nitration of poly(4,4'-diphenylether-1,3,4-oxadiazole) to gas permeation

International Nuclear Information System (INIS)

Carneiro, Candida da C.; Sena, Maria Eugenia R. de; Borges, Cristiano P.

2001-01-01

This work is a systematic modification of the poly(4,4'-diphenylether-1,3,4-oxadiazole), POD-DPE, through of the substitution of atoms of hydrogen for NO 2 groups, in aromatic rings. The presence of these groups increases the spacing among the polymer chains and decreases the packing, that promotes a larger free volume for diffusion of the permeable molecules. The nitration of POD-DPE was accomplished using N-methyl-pyrrolidine as solvent, ammonium nitrate and trifluor acetic anhydride as nitrating agent and triethylamine to finish the reaction. The influence of reaction conditions was investigated by characterization of the modified polymer. The characterization was carried out by thermal analysis (TMA and TGA), viscosity, conductivity, NMR and permeability. The viscosity analysis showed that the chemical stability of the nitrate material decreased. The results also indicated that the nitration of the aromatic rings takes to a significant reduction in Tg and little affects the polymer degradation temperature. The characterization by gas permeation also presented an increase in the permeability and selectivity of the polymer. (author)

Fluorescent molecularly imprinted polymer thin films for specific protein detection prepared with dansyl ethylenediamine-conjugated O-acryloyl L-hydroxyproline.

Science.gov (United States)

Inoue, Yuki; Kuwahara, Atsushi; Ohmori, Kohei; Sunayama, Hirobumi; Ooya, Tooru; Takeuchi, Toshifumi

2013-10-15

Protein-imprinted polymers, capable of specific transduction of protein binding events into fluorescent signal change, were designed and synthesized by using dansyl ethylenediamine-conjugated O-acryloyl L-hydroxyproline (Hyp-En-Dans). Human serum albumin (HSA) was used as a model target protein and HSA-imprinted polymers (HSA-IP) were prepared on glass substrates. Specific fluorescence change was observed for HSA binding on the imprinted polymer thin film, whereas a weaker response was observed for other proteins, including bovine serum albumin, chymotrypsin, lysozyme, and avidin. The binding specificity was found to derive from the rigid structure of the hydrogen-bondable pyrrolidine moiety. Compared with SPR measurements, the non-specific binding caused by the polymer matrix and/or randomly located fluorescent monomer residues that did not compose specific binding sites did not contribute to the observed fluorescence change. These results revealed that the proposed protein-imprinting technique using Hyp-En-Dans could provide a highly selective protein-sensing platform, in which only specific binding events would be detected by fluorescent measurements. Copyright © 2013 Elsevier B.V. All rights reserved.

Characterization of Small-Molecule Scaffolds That Bind to the Shigella Type III Secretion System Protein IpaD.

Science.gov (United States)

Dey, Supratim; Anbanandam, Asokan; Mumford, Ben E; De Guzman, Roberto N

2017-09-21

Many pathogens such as Shigella and other bacteria assemble the type III secretion system (T3SS) nanoinjector to inject virulence proteins into their target cells to cause infectious diseases in humans. The rise of drug resistance among pathogens that rely on the T3SS for infectivity, plus the dearth of new antibiotics require alternative strategies in developing new antibiotics. The Shigella T3SS tip protein IpaD is an attractive target for developing anti-infectives because of its essential role in virulence and its exposure on the bacterial surface. Currently, the only known small molecules that bind to IpaD are bile salt sterols. In this study we identified four new small-molecule scaffolds that bind to IpaD, based on the methylquinoline, pyrrolidine-aniline, hydroxyindole, and morpholinoaniline scaffolds. NMR mapping revealed potential hotspots in IpaD for binding small molecules. These scaffolds can be used as building blocks in developing small-molecule inhibitors of IpaD that could lead to new anti-infectives. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

In vitro schistosomicidal effects of aqueous and dichloromethane fractions from leaves and stems of Piper species and the isolation of an active amide from P. amalago L. (Piperaceae).

Science.gov (United States)

Carrara, V S; Vieira, S C H; de Paula, R G; Rodrigues, V; Magalhães, L G; Cortez, D A G; Da Silva Filho, A A

2014-09-01

Dichloromethane and aqueous fractions from leaves and stems of Piper arboreum Aubl., P. aduncum L., P. amalago L., P. crassinervium H.B. & K., P. diospyrifolium Kunth, P. hispidum Sw. and P. xylosteoides (Kunth) Steud. were tested against adult worms of Schistosoma mansoni. The in vitro activity was evaluated in terms of mortality, number of separated worms and number of worms with reduced motor activity. Most dichloromethane fractions from all Piper species showed moderate schistosomicidal activity, but aqueous fractions were not active. The dichloromethane fraction of P. amalago leaves (at 100 μg/ml) showed the highest activity, resulting in worm mortality, the separation of worm pairs and reduced motor activity. Chromatographic fractionation of the dichloromethane fraction of P. amalago leaves led to the isolation of its major compound, which was also tested against adults of S. mansoni. The isolated piperamide N-[7-(3',4'-methylenedioxyphenyl)-2(Z),4(Z)-heptadienoyl] pyrrolidine, at 100 μ m, resulted in the mortality of all adult worms after 24 h of incubation. The findings suggest that species of Piper are potential sources of schistosomicidal compounds.

Piracetam defines a new binding site for allosteric modulators of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors.

Science.gov (United States)

Ahmed, Ahmed H; Oswald, Robert E

2010-03-11

Glutamate receptors are the most prevalent excitatory neurotransmitter receptors in the vertebrate central nervous system and are important potential drug targets for cognitive enhancement and the treatment of schizophrenia. Allosteric modulators of AMPA receptors promote dimerization by binding to a dimer interface and reducing desensitization and deactivation. The pyrrolidine allosteric modulators, piracetam and aniracetam, were among the first of this class of drugs to be discovered. We have determined the structure of the ligand binding domain of the AMPA receptor subtypes GluA2 and GluA3 with piracetam and a corresponding structure of GluA3 with aniracetam. Both drugs bind to GluA2 and GluA3 in a very similar manner, suggesting little subunit specificity. However, the binding sites for piracetam and aniracetam differ considerably. Aniracetam binds to a symmetrical site at the center of the dimer interface. Piracetam binds to multiple sites along the dimer interface with low occupation, one of which is a unique binding site for potential allosteric modulators. This new site may be of importance in the design of new allosteric regulators.

Kinetics of rapid covalent bond formation of aniline with humic acid: ESR investigations with nitroxide spin labels

Science.gov (United States)

Glinka, Kevin; Matthies, Michael; Theiling, Marius; Hideg, Kalman; Steinhoff, Heinz-Jürgen

2016-04-01

Sulfonamide antibiotics used in livestock farming are distributed to farmland by application of slurry as fertilizer. Previous work suggests rapid covalent binding of the aniline moiety to humic acids found in soil. In the current work, kinetics of this binding were measured in X-band EPR spectroscopy by incubating Leonardite humic acid (LHA) with a paramagnetic aniline spin label (anilino-NO (2,5,5-Trimethyl-2-(3-aminophenyl)pyrrolidin-1-oxyl)). Binding was detected by a pronounced broadening of the spectral lines after incubation of LHA with anilino-NO. The time evolution of the amplitude of this feature was used for determining the reaction kinetics. Single- and double-exponential models were fitted to the data obtained for modelling one or two first-order reactions. Reaction rates of 0.16 min-1 and 0.012 min-1, were found respectively. Addition of laccase peroxidase did not change the kinetics but significantly enhanced the reacting fraction of anilino-NO. This EPR-based method provides a technically simple and effective method for following rapid binding processes of a xenobiotic substance to humic acids.

Synthesis, Crystal Structure and Anti-Fatigue Effects of Some Benzamide Derivatives

Directory of Open Access Journals (Sweden)

Xianglong Wu

2014-01-01

Full Text Available A series of benzamide derivatives such as 1-(1,3-benzodioxol-5-ylcarbonyl piperidine (1-BCP were synthesized by the reaction of substituted benzoic acids with piperidine, morpholine or pyrrolidine using a novel method. The crystals of these benzamide derivatives were obtained by recrystallization. Structures of target and intermediate compounds were determined via FT-IR, 1H-NMR and elemental analysis and X-ray crystallography of select examples. The crystal structures of these compounds have potential applications to identify the binding site for allosteric modulators of the α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA receptor. The anti-fatigue effects of the benzamide derivatives in weight-loaded forced swimming mice were investigated in a swimming endurance capacity test used as an indicator of fatigue. The swimming times to exhaustion were longer in the b3, d3, and e3 groups than in the caffeine group (p < 0.05. In conclusion, b3, d3 and e3 enhanced the forced swimming capacity of mice. The mechanism of the anti-fatigue effects will be studied in the future.

Permeability studies of redox-sensitive nitroxyl spin probes in corn oil using an L-band ESR spectrometer

International Nuclear Information System (INIS)

Jebaraj, D. David; Utsumi, Hideo; Asath, R. Mohamed; Benial, A. Milton Franklin

2016-01-01

Electron spin resonance (ESR) studies were carried out for 2mM 14 N labeled 2 H enriched 3-methoxycarbonyl-2,2,5,5-tetramethyl-pyrrolidine-1-oxyl (MC-PROXYL) and 3–carboxy-2,2,5,5,-tetramethyl-1-pyrrolidinyloxy (carboxy-PROXYL) in pure water and various concentrations of corn oil. The ESR parameters, such as the line width, hyperfine coupling constant, g-factor, rotational correlation time, partition parameter and permeability were reported for the samples. The line width broadening was observed for both nitroxyl radicals in corn oil solutions. The partition parameter for permeable MC-PROXYL in corn oil increases with increasing concentration of corn oil, which reveals that the nitroxyl spin probe permeates into the oil phase. From the results, the corn oil concentration was optimized as 50 % for phantom studies. The rotational correlation time also increases with increasing concentration of corn oil. The permeable and impermeable nature of nitroxyl spin probes was demonstrated. These results will be useful for the development of ESR/OMR imaging modalities in in vivo and in vitro studies.

Construction of green fluorescent protein-tagged recombinant iridovirus to assess viral replication.

Science.gov (United States)

Huang, Youhua; Huang, Xiaohong; Cai, Jia; Ye, Fuzhou; Guan, Liya; Liu, Hong; Qin, Qiwei

2011-09-01

Green fluorescent protein-tagged recombinant virus has been successfully applied to observing the infective dynamics and evaluating viral replication. Here, we identified soft-shelled turtle iridovirus (STIV) ORF55 as an envelope protein (VP55), and developed a recombinant STIV expressing an enhanced green fluorescent protein (EGFP) fused to VP55 (EGFP-STIV). Recombinant EGFP-STIV shared similar single-step growth curves and ultrastructural morphology with wild type STIV (wt-STIV). The green fluorescence distribution during EGFP-STIV infection was consistent with the intracellular distribution of VP55 which was mostly co-localized with virus assembly sites. Furthermore, EGFP-STIV could be used to evaluate viral replication conveniently under drug treatment, and the result showed that STIV replication was significantly inhibited after the addition of antioxidant pyrrolidine dithiocarbamate (PDTC). Thus, the EGFP-tagged recombinant iridovirus will not only be useful for further investigations on the viral replicative dynamics, but also provide an alternative simple strategy to screen for antiviral substances. Copyright © 2011 Elsevier B.V. All rights reserved.

Low-generation dendrimers with a calixarene core and based on a chiral C2-symmetric pyrrolidine as iminosugar mimics

Directory of Open Access Journals (Sweden)

Marco Marradi

2012-06-01

Full Text Available The preparation of low-generation dendrimers based on a simple calix[4]arene scaffold by insertion of the iminosugar-analogue C2-symmetric 3,4-dihydroxypyrrolidine is described. This methodology allows a rapid incorporation of a considerable number of iminosugar-like moieties in a reduced volume and in a well-defined geometry. The inclusion of alkali-metal ions (sodium and potassium in the polar cavity defined by the acetamide moieties at the lower rim of the calixarene was demonstrated, which allows also the rigidification of the dendrimer structure and the iminosugar presentation in the clusters. The combination of the supramolecular properties of calixarenes with the advantage of a dendrimeric presentation of repetitive units opens up the possibility of generating well-defined multivalent and multifaceted systems with more complex and/or biologically relevant iminosugars.

Synthesis, conformational studies, and biological properties of phosphonomethoxyethyl derivatives of nucleobases with a locked conformation via a pyrrolidine ring

Czech Academy of Sciences Publication Activity Database

Pohl, Radek; Poštová Slavětínská, Lenka; Eng, W. S.; Keough, D. T.; Guddat, L. W.; Rejman, Dominik

2015-01-01

Roč. 13, č. 16 (2015), s. 4693-4705 ISSN 1477-0520 R&D Projects: GA ČR GA13-24880S; GA ČR GAP207/11/0108 Institutional support: RVO:61388963 Keywords : nucleoside phosphonates * nucleotide analogs * inhibitors Subject RIV: CC - Organic Chemistry Impact factor: 3.559, year: 2015 http://pubs.rsc.org/en/content/articlepdf/2015/ob/c5ob00097a

Iminium-ion formation and deuterium exchange by acetone in the presence of pyrrolidine, pyrazolidine, isoxazolidine, and their acyclic analogues

International Nuclear Information System (INIS)

Hine, J.; Evangelista, R.A.

1980-01-01

Equilibrium constants for iminium-ion-formation in the reaction of in acetone in aqueous solution at 35 0 C with pyrazolidinium, isoxazolidinium, O,N-dimethylhydroxylammonium, and N,N'-dimethylhydrazinium ions were found to be 9.33, 8.96, 0.117, and 0.057 M -1 , respectively. The kinetics of hydrolysis of the iminium ions were studied in every case except that of the N-isopropylidene-O,N-dimethylhydroxylammonium ion, whose hydrolysis is too fast to follow by the techniques used with the other iminium ions. The rate of hydrolysis of the N-isopropylidenepyrazolidinium ion is independent of the pH from about pH 3 to 6; it is hydrogen ion catalyzed at lower pHs and hydroxide ion catalyzed at higher pHs. The rate of hydrolysis of N-isopropylidenisoxazolidinium ions is Ph independent from pH 0.5 to about 2, increases until about pH 4, remains pH independent until pH 6.5, and has become too fast to measure above pH 8. Both reactions are general base catalyzed in all the buffers studied. A mechanism is described to fit the kinetics of each of these reactions. The dedeuteration of acetone-d 6 was studied pyridine buffers in the presence of each of the four hydrazine and hydroxylamine derivatives and also in the presence of the dimethylammonium and pyrrolidinium ion. All six of these secondary ammonium ions catalyze the dedeuteration by transforming the acetone-d 6 to an iminium ion that is dedeuterated by pyridine more rapidly than the ketone is. The iminium-ion formation is a relatively rapid equilibrium in all cases except that of pyrrolidinium ions, where the intermediate iminium ion loses deuterium and hydrolyzes at comparable rates, and possibly the case of dimethylammonium ions, where the amount of catalysis via iminium-ion formation is too small to reveal mechanistic details. The effect of structure on the efficiency of catalysis of dedeuteration via iminium-ion formation is discussed. 3 figures, 7 tables

Transition metal complexes of oxazolinylboranes and cyclopentadienyl-bis(oxazolinyl)borates: Catalysts for asymmetric olefin hydroamination and acceptorless alcohol decarbonylation

Energy Technology Data Exchange (ETDEWEB)

Manna, Kuntal [Ames Lab., Ames, IA (United States)

2012-12-17

The research presented and discussed in this dissertation involves the synthesis of transition metal complexes of oxazolinylboranes and cyclopentadienyl-bis(oxazolinyl)borates, and their application in catalytic enantioselective olefin hydroamination and acceptorless alcohol decarbonylation. Neutral oxazolinylboranes are excellent synthetic intermediates for preparing new borate ligands and also developing organometallic complexes. Achiral and optically active bis(oxazolinyl)phenylboranes are synthesized by reaction of 2-lithio-2-oxazolide and 0.50 equiv of dichlorophenylborane. These bis(oxazolinyl)phenylboranes are oligomeric species in solid state resulting from the coordination of an oxazoline to the boron center of another borane monomer. The treatment of chiral bis(oxazolinyl)phenylboranes with sodium cyclopentadienide provide optically active cyclopentadienyl-bis(oxazolinyl)borates H[PhB(C₅H₅)(Ox^R)₂] [Ox^R = Ox^4S-iPr,Me2, Ox^4R-iPr,Me2, Ox^4S-tBu]. These optically active proligands react with an equivalent of M(NMe₂)₄ (M = Ti, Zr, Hf) to afford corresponding cyclopentadienyl-bis(oxazolinyl)borato group 4 complexes {PhB(C₅H₄)(Ox^R)₂}M(NMe₂)₂ in high yields. These group 4 compounds catalyze cyclization of aminoalkenes at room temperature or below, providing pyrrolidine, piperidine, and azepane with enantiomeric excesses up to 99%. Our mechanistic investigations suggest a non-insertive mechanism involving concerted C-N/C-H bond formation in the turnover limiting step of the catalytic cycle. Among cyclopentadienyl-bis(oxazolinyl)borato group 4 catalysts, the zirconium complex {PhB(C₅H₄)(Ox4^S-iPr,Me2)₂}Zr(NMe₂)₂ ({S-2}Zr(NMe₂)₂) displays highest activity and enantioselectivity. Interestingly, _S-2

In vitro study comparing the efficacy of the water-soluble HSP90 inhibitors, 17-AEPGA and 17-DMAG, with that of the non‑water-soluble HSP90 inhibitor, 17-AAG, in breast cancer cell lines.

Science.gov (United States)

Ghadban, Tarik; Jessen, André; Reeh, Matthias; Dibbern, Judith L; Mahner, Sven; Mueller, Volkmar; Wellner, Ulrich F; Güngör, Cenap; Izbicki, Jakob R; Vashist, Yogesh K

2016-10-01

Heat shock protein (HSP)90 has emerged as an important target in cancer therapeutics. Diverse HSP90 inhibitors are under evaluation. The aim of the present study was to investigate the growth inhibitory effects of the newly developed water-soluble HSP90 inhibitors, 17-[2-(Pyrrolidin-1-yl)ethyl]amino-17-demethoxygeldanamycin (17-AEPGA) and 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), compared to that of the non-water-soluble HSP90 inhibitor, 17-allylamino-17-demethoxygeldanamycin (17-AAG). The anti-proliferative effects of the 3 drugs on the human breast cancer cell lines, MCF-7, SKBR-3 and MDA-MB-231, were examined in vitro. In addition, tumor progression factors, including human epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor 1 (EGFR1) and insulin-like growth factor type 1 receptor (IGF1R), as well as apoptotic markers were analysed. We found a time- and dose-dependent effect in all the tested cell lines. The effects of 17-AEPGA and 17-DMAG were equal or superior to those of 17-AAG. The 50% growth inhibition concentration was AAG.

Photometric Characterization of the Reductive Amination Scope of the Imine Reductases from Streptomyces tsukubaensis and Streptomyces ipomoeae.

Science.gov (United States)

Matzel, Philipp; Krautschick, Lukas; Höhne, Matthias

2017-10-18

Imine reductases (IREDs) have emerged as promising enzymes for the asymmetric synthesis of secondary and tertiary amines starting from carbonyl substrates. Screening the substrate specificity of the reductive amination reaction is usually performed by time-consuming GC analytics. We found two highly active IREDs in our enzyme collection, IR-20 from Streptomyces tsukubaensis and IR-Sip from Streptomyces ipomoeae, that allowed a comprehensive substrate screening with a photometric NADPH assay. We screened 39 carbonyl substrates combined with 17 amines as nucleophiles. Activity data from 663 combinations provided a clear picture about substrate specificity and capabilities in the reductive amination of these enzymes. Besides aliphatic aldehydes, the IREDs accepted various cyclic (C 4 -C 8 ) and acyclic ketones, preferentially with methylamine. IR-Sip also accepted a range of primary and secondary amines as nucleophiles. In biocatalytic reactions, IR-Sip converted (R)-3-methylcyclohexanone with dimethylamine or pyrrolidine with high diastereoselectivity (>94-96 % de). The nucleophile acceptor spectrum depended on the carbonyl substrate employed. The conversion of well-accepted substrates could also be detected if crude lysates were employed as the enzyme source. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Bioactivity Studies of β-Lactam Derived Polycyclic Fused Pyrroli-Dine/Pyrrolizidine Derivatives in Dentistry: In Vitro, In Vivo and In Silico Studies

Science.gov (United States)

Winfred, Sofi Beaula; Mannivanan, Bhavani; Bhoopalan, Hemadev; Shankar, Venkatesh; Sekar, Sathiya; Venkatachalam, Deepa Parvathi; Pitani, Ravishankar; Nagendrababu, Venkateshbabu; Thaiman, Malini; Devivanayagam, Kandaswamy; Jayaraman, Jeyakanthan; Ragavachary, Raghunathan; Venkatraman, Ganesh

2015-01-01

The antibacterial activity of β-lactam derived polycyclic fused pyrrolidine/pyrrolizidine derivatives synthesized by 1, 3-dipolar cycloaddition reaction was evaluated against microbes involved in dental infection. Fifteen compounds were screened; among them compound 3 showed efficient antibacterial activity in an ex vivo dentinal tubule model and in vivo mice infectious model. In silico docking studies showed greater affinity to penicillin binding protein. Cell damage was observed under Scanning Electron Microscopy (SEM) which was further proved by Confocal Laser Scanning Microscope (CLSM) and quantified using Flow Cytometry by PI up-take. Compound 3 treated E. faecalis showed ROS generation and loss of membrane integrity was quantified by flow cytometry. Compound 3 was also found to be active against resistant E. faecalis strains isolated from failed root canal treatment cases. Further, compound 3 was found to be hemocompatible, not cytotoxic to normal mammalian NIH 3T3 cells and non mutagenic. It was concluded that β-lactam compound 3 exhibited promising antibacterial activity against E. faecalis involved in root canal infections and the mechanism of action was deciphered. The results of this research can be further implicated in the development of potent antibacterial medicaments with applications in dentistry. PMID:26185985

Untargeted LC-MS/MS Profiling of Cell Culture Media Formulations for Evaluation of High Temperature Short Time Treatment Effects.

Science.gov (United States)

Floris, Patrick; McGillicuddy, Nicola; Albrecht, Simone; Morrissey, Brian; Kaisermayer, Christian; Lindeberg, Anna; Bones, Jonathan

2017-09-19

An untargeted LC-MS/MS platform was implemented for monitoring variations in CHO cell culture media upon exposure to high temperature short time (HTST) treatment, a commonly used viral clearance upstream strategy. Chemically defined (CD) and hydrolysate-supplemented media formulations were not visibly altered by the treatment. The absence of solute precipitation effects during media treatment and very modest shifts in pH values observed indicated sufficient compatibility of the formulations evaluated with the HTST-processing conditions. Unsupervised chemometric analysis of LC-MS/MS data, however, revealed clear separation of HTST-treated samples from untreated counterparts as observed from analysis of principal components and hierarchical clustering sample grouping. An increased presence of Maillard products in HTST-treated formulations contributed to the observed differences which included organic acids, observed particularly in chemically defined formulations, and furans, pyridines, pyrazines, and pyrrolidines which were determined in hydrolysate-supplemented formulations. The presence of Maillard products in media did not affect cell culture performance with similar growth and viability profiles observed for CHO-K1 and CHO-DP12 cells when cultured using both HTST-treated and untreated media formulations.

Determination of Lead in Urine by Atomic Absorption Spectrophotometry1

Science.gov (United States)

Selander, Stig; Cramé, Kim

1968-01-01

A method for the determination of lead in urine by means of atomic absorption spectrophotometry (AAS) is described. A combination of wet ashing and extraction with ammonium pyrrolidine dithiocarbamate into isobutylmethylketone was used. The sensitivity was about 0·02 μg./ml. for 1% absorption, and the detection limit was about 0·02 μg./ml. with an instrumental setting convenient for routine analyses of urines. Using the scale expansion technique, the detection limit was below 0·01 μg./ml., but it was found easier to determine urinary lead concentrations below 0·05 μg./ml. by concentrating the lead in the organic solvent by increasing the volume of urine or decreasing that of the solvent. The method was applied to fresh urines, stored urines, and to urines, obtained during treatment with chelating agents, of patients with lead poisoning. Urines with added inorganic lead were not used. The results agreed well with those obtained with a colorimetric dithizone extraction method (r = 0·989). The AAS method is somewhat more simple and allows the determination of smaller lead concentrations. PMID:5647975

Multidrug resistance-selective antiproliferative activity of Piper amide alkaloids and synthetic analogues.

Science.gov (United States)

Wang, Yue-Hu; Goto, Masuo; Wang, Li-Ting; Hsieh, Kan-Yen; Morris-Natschke, Susan L; Tang, Gui-Hua; Long, Chun-Lin; Lee, Kuo-Hsiung

2014-10-15

Twenty-five amide alkaloids (1-25) from Piper boehmeriifolium and 10 synthetic amide alkaloid derivatives (39-48) were evaluated for antiproliferative activity against eight human tumor cell lines, including chemosensitive and multidrug-resistant (MDR) cell lines. The results suggested tumor type-selectivity. 1-[7-(3,4,5-Trimethoxyphenyl)heptanoyl]piperidine (46) exhibited the best inhibitory activity (IC50=4.94 μM) against the P-glycoprotein (P-gp)-overexpressing KBvin MDR sub-line, while it and all other tested compounds, except 9, were inactive (IC50 >40 μM) against MDA-MB-231 and SK-BR-3. Structure-activity relationships (SARs) indicated that (i) 3,4,5-trimethoxy phenyl substitution is critical for selectivity against KBvin, (ii) the 4-methoxy group in this pattern is crucial for antiproliferative activity, (iii) double bonds in the side chain are not needed for activity, and (iv), in arylalkenylacyl amide alkaloids, replacement of an isobutylamino group with pyrrolidin-1-yl or piperidin-1-yl significantly improved activity. Further study on Piper amides is warranted, particularly whether side chain length affects the ability to overcome the MDR cancer phenotype. Copyright © 2014 Elsevier Ltd. All rights reserved.

Piracetam Defines a New Binding Site for Allosteric Modulators of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors§

Science.gov (United States)

Ahmed, Ahmed H.; Oswald, Robert E.

2010-01-01

Glutamate receptors are the most prevalent excitatory neurotransmitter receptors in the vertebrate central nervous system and are important potential drug targets for cognitive enhancement and the treatment of schizophrenia. Allosteric modulators of AMPA receptors promote dimerization by binding to a dimer interface and reducing desensitization and deactivation. The pyrrolidine allosteric modulators, piracetam and aniracetam, were among the first of this class of drugs to be discovered. We have determined the structure of the ligand binding domain of the AMPA receptor subtypes GluA2 and GluA3 with piracetam and a corresponding structure of GluA3 with aniracetam. Both drugs bind to both GluA2 and GluA3 in a very similar manner, suggesting little subunit specificity. However, the binding sites for piracetam and aniracetam differ considerably. Aniracetam binds to a symmetrical site at the center of the dimer interface. Piracetam binds to multiple sites along the dimer interface with low occupation, one of which is a unique binding site for potential allosteric modulators. This new site may be of importance in the design of new allosteric regulators. PMID:20163115

Nicotine promotes cervical carcinoma cell line HeLa migration and invasion by activating PI3k/Akt/NF-κB pathway in vitro.

Science.gov (United States)

Wang, Chengze; Gu, Weiting; Zhang, Yunpeng; Ji, Yawen; Wen, Yong; Xu, Xin

2017-07-05

Cigarette smoking is one of highly risk factors of cervical cancer. Recently nicotine has been reported to increase proliferation and invasion in some smoking related cancers, like non-small cell lung cancer and esophageal squamous cell cancer. However, the effects and mechanisms of nicotine stimulation on cervical cancer cells are not clear. Here, we investigated the effects and mechanisms of nicotine stimulation on HeLa cells in vitro. In our study, we found that nicotine could accelerate HeLa cells migration and invasion, activate PI3K/Akt and NF-κB pathways and increase the expression of Vimentin in vitro. Moreover, we demonstrated that the specific PI3K inhibitor LY294002 could reverse nicotine-induced cell migration and invasion, NF-κB activation and up-regulation of Vimentin. Inhibition of NF-κB by Pyrrolidine dithiocarbamate (PDTC) also antagonized nicotine-induced cell migration, invasion and up-regulation of Vimentin. Simply put, these findings suggest that nicotine promotes cervical carcinoma cell line HeLa migration and invasion by activating PI3k/Akt/NF-κB pathway in vitro. Copyright © 2017 Elsevier GmbH. All rights reserved.

Nicotine demethylation in Nicotiana cell suspension cultures: N'-formylnornicotine is not involved.

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Bartholomeusz, Trixie Ann; Bhogal, Ramneek K; Molinié, Roland; Felpin, François-Xavier; Mathé-Allainmat, Monique; Meier, Anna-Carolin; Dräger, Birgit; Lebreton, Jacques; Roscher, Albrecht; Robins, Richard J; Mesnard, François

2005-10-01

Nicotine or nornicotine enriched with stable isotopes in either the N'-methyl group or the pyrrolidine-N were fed to Nicotiana plumbaginifolia suspension cell cultures that do not form endogenous nicotine. The metabolism of these compounds was investigated by analysing the incorporation of isotope into other alkaloids using gas chromatography-mass spectroscopy (GC-MS). Nicotine metabolism primarily resulted in the accumulation of nornicotine, the N'-demethylation product. In addition, six minor metabolites appeared during the course of nicotine metabolism, four of which were identified as cotinine, myosmine, N'-formylnornicotine and N'-carboethoxynornicotine. While cotinine was formed from [(13)C,(2)H(3)-methyl]nicotine without dilution of label, N'-formylnornicotine was labelled at only about 6% of the level of nicotine and N'-carboethoxynornicotine was unlabelled. Feeding with [1'-(15)N]nornicotine resulted in incorporation without dilution of label into both N'-formylnornicotine and N'-carboethoxynornicotine. This pattern strongly indicates that, while nornicotine and cotinine are derived directly from nicotine, N'-formylnornicotine and N'-carboethoxynornicotine are metabolites of nornicotine. Thus, it is directly demonstrated that N'-formylnornicotine is not an intermediate in nicotine demethylation.

High performance preconcentration of inorganic Se species by dispersive micro-solid phase extraction with a nanosilica-ionic liquid hybrid material

Science.gov (United States)

Llaver, Mauricio; Coronado, Eduardo A.; Wuilloud, Rodolfo G.

2017-12-01

A highly sensitive and efficient dispersive micro-solid phase extraction (D-μ-SPE) method was developed for inorganic Se speciation analysis. A novel ionic liquid (IL)-nanomaterial hybrid consisting of 1-dodecyl-3-methylimidazolium bromide-functionalized nanosilica was used for the efficient retention of Se(IV) complexed with ammonium pyrrolidine dithiocarbamate, followed by elution with an ethyl acetate/Triton X-114 mixture and determination by electrothermal atomic absorption spectroscopy. The Se(VI) species was selectively determined by difference between total inorganic Se and Se(IV) after pre-reduction. The IL-nanomaterial hybrid was characterized by Fourier transform infrared spectroscopy and transmission electronic microscopy. Likewise, Se(IV) sorption capacity of the retention material and maximum amount of IL loaded on its surface were determined. Several factors concerning the functionalization, extraction and elution steps were optimized, yielding a 100% extraction efficiency for Se(IV) under optimal conditions. A limit of detection of 1.1 ng L- 1, a relative standard deviation of 5.7% and a 110-fold enhancement factor were obtained. The D-μ-SPE method was successfully applied to several water samples from different origins and compositions, including rain, tap, underground, river and sea.

Simultaneous Pre-Concentration of Cadmium and Lead in Environmental Water Samples with Dispersive Liquid-Liquid Microextraction and Determination by Inductively Coupled Plasma-Atomic Emission Spectrometry

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M. Salahinejad

2013-06-01

Full Text Available The dispersive liquid–liquid microextraction (DLLME method for determination of Pb+2 and Cd+2 ions in the environmental water samples was combined with inductively coupled plasma-atomic emission spectrometry (ICP-AES. Ammonium pyrrolidine dithiocarbamate (APDC, chloroform and ethanol were used as chelating agent, extraction solvent and disperser solvent, respectively. Some effective parameters on the microextraction and the complex formation were selected and optimized. These parameters included extraction and disperser solvent type as well as their volume, extraction time, salt effect, pH, sample volume and amount of the chelating agent.   Under the optimum conditions, the enrichment factor of 75 and 105 for Cd+2 and Pb+2 ions respectively was obtained from only 5.00mL of water sample. The detection limit (S/N=3 was 12 and 0.8ngmL−1 for Pb and Cd respectively. The relative standard deviation (RSDs for five replicate measurements of 0.50 mgL−1 of lead and cadmium was 6.5 and 4.4 % respectively. Mineral, tap, river, sea, dam and spiked water samples were analyzed for Cd and Pb amount.

Identification and analytical characterization of four synthetic cathinone derivatives iso-4-BMC, β-TH-naphyrone, mexedrone, and 4-MDMC.

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Qian, Zhenhua; Jia, Wei; Li, Tao; Liu, Cuimei; Hua, Zhendong

2017-02-01

New psychoactive substances (NPS) have gained much popularity on the global market over the last number of years. The synthetic cathinone family is one of the most prominent groups and this paper reports on the analytical properties of four synthetic cathinone derivatives: (1) 1-(4-bromophenyl)-1-(methylamino)propan-2-one (iso-4-BMC or iso-brephedrone), (2) 2-(pyrrolidin-1-yl)-1-(5,6,7,8-tetrahydronaphthalen-2-yl)pentan-1-one (β-TH-naphyrone), (3) 3-methoxy-2-(methylamino)-1-(4-methylphenyl)propan-1-one (mexedrone), and (4) 2-(dimethylamino)-1-(4-methylphenyl)propan-1-one (4-MDMC). These identifications were based on liquid chromatography-quadrupole time-of-flight-mass spectrometry (LC-QTOF-MS), gas chromatography-mass spectrometry (GC-MS) and nuclear magnetic resonance (NMR) spectroscopy. To our knowledge, no chemical or pharmacological data about compounds 1-3 have appeared until now, making this the first report on these compounds. The Raman and GC-MS data of 4 have been reported, but this study added the LC-MS and NMR data for additional characterization. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Lead-oriented synthesis: Investigation of organolithium-mediated routes to 3-D scaffolds and 3-D shape analysis of a virtual lead-like library.

Science.gov (United States)

Lüthy, Monique; Wheldon, Mary C; Haji-Cheteh, Chehasnah; Atobe, Masakazu; Bond, Paul S; O'Brien, Peter; Hubbard, Roderick E; Fairlamb, Ian J S

2015-06-01

Synthetic routes to six 3-D scaffolds containing piperazine, pyrrolidine and piperidine cores have been developed. The synthetic methodology focused on the use of N-Boc α-lithiation-trapping chemistry. Notably, suitably protected and/or functionalised medicinal chemistry building blocks were synthesised via concise, connective methodology. This represents a rare example of lead-oriented synthesis. A virtual library of 190 compounds was then enumerated from the six scaffolds. Of these, 92 compounds (48%) fit the lead-like criteria of: (i) -1⩽AlogP⩽3; (ii) 14⩽number of heavy atoms⩽26; (iii) total polar surface area⩾50Å(2). The 3-D shapes of the 190 compounds were analysed using a triangular plot of normalised principal moments of inertia (PMI). From this, 46 compounds were identified which had lead-like properties and possessed 3-D shapes in under-represented areas of pharmaceutical space. Thus, the PMI analysis of the 190 member virtual library showed that whilst scaffolds which may appear on paper to be 3-D in shape, only 24% of the compounds actually had 3-D structures in the more interesting areas of 3-D drug space. Copyright © 2015 Elsevier Ltd. All rights reserved.

An automated flow injection system for metal determination by flame atomic absorption spectrometry involving on-line fabric disk sorptive extraction technique.

Science.gov (United States)

Anthemidis, A; Kazantzi, V; Samanidou, V; Kabir, A; Furton, K G

2016-08-15

A novel flow injection-fabric disk sorptive extraction (FI-FDSE) system was developed for automated determination of trace metals. The platform was based on a minicolumn packed with sol-gel coated fabric media in the form of disks, incorporated into an on-line solid-phase extraction system, coupled with flame atomic absorption spectrometry (FAAS). This configuration provides minor backpressure, resulting in high loading flow rates and shorter analytical cycles. The potentials of this technique were demonstrated for trace lead and cadmium determination in environmental water samples. The applicability of different sol-gel coated FPSE media was investigated. The on-line formed complex of metal with ammonium pyrrolidine dithiocarbamate (APDC) was retained onto the fabric surface and methyl isobutyl ketone (MIBK) was used to elute the analytes prior to atomization. For 90s preconcentration time, enrichment factors of 140 and 38 and detection limits (3σ) of 1.8 and 0.4μgL(-1) were achieved for lead and cadmium determination, respectively, with a sampling frequency of 30h(-1). The accuracy of the proposed method was estimated by analyzing standard reference materials and spiked water samples. Copyright © 2016 Elsevier B.V. All rights reserved.

Nuclear magnetic resonance at 310 MHz in a superconducting solenoid; Resonance magnetique nucleaire a 310 MHz dans un solenoide supra-conducteur

Energy Technology Data Exchange (ETDEWEB)

Dunand, J.J. [Commissariat a l' Energie Atomique, Grenoble (France). Centre d' Etudes Nucleaires

1970-07-01

The realisation of an NMR spectrometer with a superconducting magnet is presented in the first section. The methods to attain the best possible homogeneity of the magnetic field and to minimize the error in the spectrometer are described. The second section is devoted to the study of elastomers and nitr-oxides free radicals. A shift of the transition temperature with the magnetic field appears for the elastomers. The increasing paramagnetic shift has allowed a complete study by NMR of piperidinic and pyrrolidinic nitroxide free radicals. (author) [French] Dans la premiere partie est exposee la realisation d'un spectrometre de RMN utilisant un solenoide supraconducteur. Des solutions sont donnees pour obtenir la meilleure homogeneite possible du champ magnetique et pour minimiser les sources d'erreur apportees par le spectrometre. La deuxieme partie est consacree a l'etude d'elastomeres et de radicaux libres nitroxydes. Une variation de la temperature de transition avec le champ magnetique est mise en evidence pour les elastomeres. L'accroissement du deplacement paramagnetique a permis une etude complete par RMN des radicaux libres nitroxydes piperidiniques et pyrrolidiniques. (auteur)

[Synthetic transformations of higher terpenoids. XXX. Synthesis and cytotoxic activity of betulonic acid amides with a piperidine or pyrrolidine nitroxide moiety].

Science.gov (United States)

Antimonova, A N; Petrenko, N I; Shults, E E; Polienko, Iu F; Shakirov, M M; Irtegova, I G; Pokrovskiĭ, M A; Sherman, K M; Grigor'ev, I A; Pokrovskiĭ, A G; Tolstikov, G A

2013-01-01

The reaction of betulonic acid chloride with 4-amino-2,2,6,6-tetramethylpeperidine-1-oxyl, 3-amino-2,2,5,5-tetramethylpyrrolidine-1-oxyl and 3-aminomethyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl gave corresponding triterpenoid amides. It was found that new derivatives exhibit cytotoxic activity against tumor cells CEM-13, U-937, MT-4. CCID50 value for most activity compound--N-[3-oxolup-20(29)-en-30-yl]-(2,2,6,6-tetramethylpiperidine-4-yl)-1-oxyl--was 5.7-33.1 microM.

Autoantibodies Targeting AT1 Receptor from Patients with Acute Coronary Syndrome Upregulate Proinflammatory Cytokines Expression in Endothelial Cells Involving NF-κB Pathway

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Weijuan Li

2014-01-01

Full Text Available Our study intended to prove whether agonistic autoantibodies to angiotensin II type 1 receptor (AT1-AAs exist in patients with coronary heart disease (CHD and affect the human endothelial cell (HEC by upregulating proinflammatory cytokines expression involved in NF-κB pathway. Antibodies were determined by chronotropic responses of cultured neonatal rat cardiomyocytes coupled with receptor-specific antagonists (valsartan and AT1-EC2 as described previously. Interleukin-6 (IL-6, vascular cell adhesion molecule-1 (VCAM-1, and monocyte chemotactic protein-1 (MCP-1 expression were improved at both mRNA and protein levels in HEC, while NF-κB in the DNA level was improved detected by electrophoretic mobility shift assays (EMSA. These improvements could be inhibited by specific AT1 receptor blocker valsartan, NF-κB blocker pyrrolidine dithiocarbamate (PDTC, and specific short peptides from the second extracellular loop of AT1 receptor. These results suggested that AT1-AAs, via the AT1 receptor, induce expression of proinflammatory cytokines involved in the activation of NF-κB. AT1-AAs may play a great role in the pathogenesis of the acute coronary syndrome by mediating vascular inflammatory effects involved in the NF-κB pathway.

Bioactivity Studies of β-Lactam Derived Polycyclic Fused Pyrroli-Dine/Pyrrolizidine Derivatives in Dentistry: In Vitro, In Vivo and In Silico Studies.

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Gowri Meiyazhagan

Full Text Available The antibacterial activity of β-lactam derived polycyclic fused pyrrolidine/pyrrolizidine derivatives synthesized by 1, 3-dipolar cycloaddition reaction was evaluated against microbes involved in dental infection. Fifteen compounds were screened; among them compound 3 showed efficient antibacterial activity in an ex vivo dentinal tubule model and in vivo mice infectious model. In silico docking studies showed greater affinity to penicillin binding protein. Cell damage was observed under Scanning Electron Microscopy (SEM which was further proved by Confocal Laser Scanning Microscope (CLSM and quantified using Flow Cytometry by PI up-take. Compound 3 treated E. faecalis showed ROS generation and loss of membrane integrity was quantified by flow cytometry. Compound 3 was also found to be active against resistant E. faecalis strains isolated from failed root canal treatment cases. Further, compound 3 was found to be hemocompatible, not cytotoxic to normal mammalian NIH 3T3 cells and non mutagenic. It was concluded that β-lactam compound 3 exhibited promising antibacterial activity against E. faecalis involved in root canal infections and the mechanism of action was deciphered. The results of this research can be further implicated in the development of potent antibacterial medicaments with applications in dentistry.

Cloud point extraction combined with electrothermal atomic absorption spectrometry for the speciation of antimony(III) and antimony(V) in food packaging materials

International Nuclear Information System (INIS)

Jiang Xiuming; Wen Shengping; Xiang Guoqiang

2010-01-01

A simple, sensitive method for the speciation of inorganic antimony by cloud point extraction combined with electrothermal atomic absorption spectrometry (ETAAS) is presented and evaluated. The method based on the fact that formation of a hydrophobic complex of antimony(III) with ammonium pyrrolidine dithiocarbamate (APDC) at pH 5.0 and subsequently the hydrophobic complex enter into surfactant-rich phase, whereas antimony(V) remained in aqueous solutions. Antimony(III) in surfactant-rich phase was analyzed by ETAAS after dilution by 0.2 mL nitric acid in methanol (0.1 M), and antimony(V) was calculated by subtracting antimony(III) from the total antimony after reducing antimony(V) to antimony(III) by L-cysteine. The main factors affecting the cloud point extraction, such as pH, concentration of APDC and Triton X-114, equilibrium temperature and incubation time, sample volume were investigated in detail. Under the optimum conditions, the detection limit (3σ) of the proposed method was 0.02 ng mL -1 for antimony(III), and the relative standard deviation was 7.8% (c = 1.0 ng mL -1 , n = 7). The proposed method was successfully applied to speciation of inorganic antimony in the leaching solutions of different food packaging materials with satisfactory results.

Radiolytic Syntheses of Nanoparticles and Inorganic-Polymer Hybrid Microgels

International Nuclear Information System (INIS)

Chen, Q.; Shi, J.; Zhao, R.; Shen, X.

2010-01-01

In the second year of the project, we have gotten progress mainly in two directions. Firstly, for the first time, Prussian blue (PB) nanoparticles (NPs) were successfully synthesized by the partly radiolytic reduction of Fe3+ and Fe(CN)63 in the presence of poly(N-vinyl pyrrolidine) (PVP) under N2 atmospheres at room temperature. With the increase of the concentration of PVP, the size and the size distribution of the synthesized quasi-spherical PB NPs decreased obviously, leading to a hypsochromic shift on their peak position of the characteristic absorption. In the experiment, we further found that the smaller ones have a larger capacity to Cs+, suggesting that the application of PB NPs in curing thallotoxicosis may decrease the usage of PB for the patient to great extent. Secondly, through a series of preliminary experiments, we got a clear picture about the one-step radiolytic preparation of inorganic-poly(methacrylic acid-co-methyl methacrylate) hybrid microgels by surfactant-free emulsion polymerization. Besides, unpurified N-carbamothioylmethacrylamide was synthesized via the methacrylation of thiourea. These created favorable conditions for the one-step synthesis of metal sulfide-poly(methacrylic acid-co-methyl methacrylate) hybrid microgels by -irradiation and surfactant-free emulsion polymerization. (author)

Nitroxide free radical clearance in the live rat monitored by radio-frequency CW-EPR and PEDRI

International Nuclear Information System (INIS)

Alecci, Marcello; Seimenis, Ioannis; McCallum, Stephen J.; Lurie, David J.; Foster, Margaret A.

1998-01-01

The use of RF (100 to 300 MHz) PEDRI and CW-EPR techniques allows the in vivo study of large animals such as whole rats and rabbits. Recently a PEDRI instrument was modified to also allow CW-EPR spectroscopy with samples of similar size and under the same experimental conditions. In the present study, this CW-EPR and PEDRI apparatus was used to assess the feasibility of the detection of a pyrrolidine nitroxide free radical (2,2,5,5,-tetramethylpyrrolidine-1-oxyl-3-carboxylic acid, PCA) in the abdomen of rats. In particular, we have shown that after the PCA administration (4 mmol kg -1 b.w.): (i) the PCA EPR linewidth does not show line broadening due to concentration effects; (ii) a similar PCA up-take phase is observed by EPR and PEDRI; and (iii) the PCA half-lives in the whole abdomen of rats measured with the CW-EPR (T 1/2 =26±4 min, mean±sd, n=10) and PEDRI (T 1/2 =29±4 min, mean±sd, n=4) techniques were not significantly different (p>0.05). These results show, for the first time, that information about PCA pharmacokinetics obtained by CW-EPR is the same as that from PEDRI under the same experimental conditions. (author)

NF-κB is involved in the LPS-mediated proliferation and apoptosis of MAC-T epithelial cells as part of the subacute ruminal acidosis response in cows.

Science.gov (United States)

Fan, Wen-Jie; Li, He-Ping; Zhu, He-Shui; Sui, Shi-Ping; Chen, Pei-Ge; Deng, Yue; Sui, Tong-Ming; Wang, Yue-Ying

2016-11-01

To determine the effect of NF-κB on cell proliferation and apoptosis, we investigate the expression of inflammation and apoptosis-related factors in the bovine mammary epithelial cell line, MAC-T. MAC-T cells were cultured in vitro and MTT and LDH assays used to determine the effects of lipopolysaccharide (LPS) on proliferation and cytotoxicity respectively. RT-PCR and western blotting were used to evaluate the effect of LPS and NF-κB inhibition [pyrrolidine dithiocarbamate (PDTC) treatment] on the expression of inflammation and apoptosis-related factors. LPS significantly inhibited MAC-T cell proliferation in a dose- and time-dependent manner. Furthermore, LPS promoted apoptosis while the NF-кB inhibitor PDTC attenuated this effect. After LPS treatment, the NF-кB signaling pathway was activated, and the expression of inflammation and apoptosis-related factors increased. When PDTC blocked NF-кB signaling, the expression of inflammation and apoptosis-related factors were decreased in MAC-T cells. LPS activates the TLR4/NF-κB signaling pathway, inhibits proliferation and promotes apoptosis in MAC-T cells. NF-кB inhibition attenuates MAC-T cell apoptosis and TLR4/NF-κB signaling pathway. NF-кB inhibitor alleviating MAC-T cell apoptosis is presumably modulated by NF-кB.

A reduced-amide inhibitor of Pin1 binds in a conformation resembling a twisted-amide transition state.

Science.gov (United States)

Xu, Guoyan G; Zhang, Yan; Mercedes-Camacho, Ana Y; Etzkorn, Felicia A

2011-11-08

The mechanism of the cell cycle regulatory peptidyl prolyl isomerase (PPIase), Pin1, was investigated using reduced-amide inhibitors designed to mimic the twisted-amide transition state. Inhibitors, R-pSer-Ψ[CH(2)N]-Pro-2-(indol-3-yl)ethylamine, 1 [R = fluorenylmethoxycarbonyl (Fmoc)] and 2 (R = Ac), of Pin1 were synthesized and bioassayed. Inhibitor 1 had an IC(50) value of 6.3 μM, which is 4.5-fold better for Pin1 than our comparable ground-state analogue, a cis-amide alkene isostere-containing inhibitor. The change of Fmoc to Ac in 2 improved aqueous solubility for structural determination and resulted in an IC(50) value of 12 μM. The X-ray structure of the complex of 2 bound to Pin1 was determined to 1.76 Å resolution. The structure revealed that the reduced amide adopted a conformation similar to the proposed twisted-amide transition state of Pin1, with a trans-pyrrolidine conformation of the prolyl ring. A similar conformation of substrate would be destabilized relative to the planar amide conformation. Three additional reduced amides, with Thr replacing Ser and l- or d-pipecolate (Pip) replacing Pro, were slightly weaker inhibitors of Pin1.

Reduced-Amide Inhibitor of Pin1 Binds in a Conformation Resembling a Twisted-Amide Transition State†

Science.gov (United States)

Xu, Guoyan G.; Zhang, Yan; Mercedes-Camacho, Ana Y.; Etzkorn, Felicia A.

2011-01-01

The mechanism of the cell cycle regulatory peptidyl prolyl isomerase (PPIase), Pin1, was investigated using reduced-amide inhibitors designed to mimic the twisted-amide transition state. Inhibitors, R–pSer–Ψ[CH2N]–Pro–2-(indol-3-yl)-ethylamine, 1 (R = fluorenylmethoxycarbonyl, Fmoc), and 2 (R = Ac), of Pin1 were synthesized and bioassayed. Inhibitor 1 had an IC50 value of 6.3 μM, which is 4.5-fold better inhibition for Pin1 than our comparable ground state analogue, a cis-amide alkene isostere containing inhibitor. The change of Fmoc to Ac in 2 improved aqueous solubility for structural determination, and resulted in an IC50 value of 12 μM. The X-ray structure of the complex of 2 bound to Pin1 was determined to 1.76 Å resolution. The structure revealed that the reduced amide adopted a conformation similar to the proposed twisted-amide transition state of Pin1, with a trans-pyrrolidine conformation of the prolyl ring. A similar conformation of substrate would be destabilized relative to the planar amide conformation. Three additional reduced amides, with Thr replacing Ser, and l- or d-pipecolate (Pip) replacing Pro, were slightly weaker inhibitors of Pin1. PMID:21980916

Spinal NF-κB and chemokine ligand 5 expression during spinal glial cell activation in a neuropathic pain model.

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Qin Yin

Full Text Available BACKGROUND: The NF-κB pathway and chemokine (C-C motif ligand 5 (CCL5 are involved in pain modulation; however, the precise mechanisms of their interactions in chronic neuropathic pain have yet to be established. METHODS: The present study examined the roles of spinal NF-κB and CCL5 in a neuropathic pain model after chronic constriction injury (CCI surgery. CCI-induced pain facilitation was evaluated using the Plantar and von Frey tests. The changes in NF-κB and CCL5 expression were analyzed by immunohistochemistry and Western blot analyses. RESULTS: Spinal NF-κB and CCL5 expression increased after CCI surgery. Repeated intrathecal infusions of pyrrolidine dithiocarbamate (PDTC, a NF-κB inhibitor decreased CCL5 expression, inhibited the activation of microglia and astrocytes, and attenuated CCI-induced allodynia and hyperalgesia. Intrathecal injection of a CCL5-neutralizing antibody attenuated CCI-induced pain facilitation and also suppressed spinal glial cell activation after CCI surgery. However, the CCL5-neutralizing antibody did not affect NF-κB expression. Furthermore, selective glial inhibitors, minocycline and fluorocitrate, attenuated the hyperalgesia induced by intrathecal CCL5. CONCLUSIONS: The inhibition of spinal CCL5 expression may provide a new method to prevent and treat nerve injury-induced neuropathic pain.

Signal regulatory protein α associated with the progression of oral leukoplakia and oral squamous cell carcinoma regulates phenotype switch of macrophages.

Science.gov (United States)

Ye, Xiaojing; Zhang, Jing; Lu, Rui; Zhou, Gang

2016-12-06

Signal regulatory protein α (SIRPα) is a cell-surface protein expressed on macrophages that are regarded as an important component of the tumor microenvironment. The expression of SIRPα in oral leukoplakia (OLK) and oral squamous cell carcinoma (OSCC), and further explored the role of SIRPα on the phenotype, phagocytosis ability, migration, and invasion of macrophages in OSCC were investigated. The expression of SIRPα in OLK was higher than in OSCC, correlating with the expression of CD68 and CD163 on macrophages. After cultured with the conditioned media of oral cancer cells, the expression of SIRPα on THP-1 cells was decreased gradually. In co-culture system, macrophages were induced into M2 phenotype by oral cancer cells. Blockade of SIRPα inhibited phagocytosis ability and IL-6, TNF-α productions of macrophages. In addition, the proliferation, migration, and IL-10, TGF-β productions of macrophages were upregulated after blockade of SIRPα. Macrophages upregulated the expression of SIRPα and phagocytosis ability, and inhibited the migration and invasion when the activation of NF-κB was inhibited by pyrrolidine dithiocarbamate ammonium (PDTC). Hence, SIRPα might play an important role in the progression of OLK and oral cancer, and could be a pivotal therapeutic target in OSCC by regulating the phenotype of macrophages via targeting NF-κB.

Radiolytic Syntheses of Nanoparticles and Inorganic-Polymer Hybrid Microgels

Energy Technology Data Exchange (ETDEWEB)

Chen, Q.; Shi, J.; Zhao, R.; Shen, X., E-mail: qdchen@pku.edu.cn [Department of Applied Chemistry, College of Chemistry and Molecular Engineering, Peking University, No. 5, Yiheyuan Load, Haidian District Beijing 100871 (China)

2010-07-01

In the second year of the project, we have gotten progress mainly in two directions. Firstly, for the first time, Prussian blue (PB) nanoparticles (NPs) were successfully synthesized by the partly radiolytic reduction of Fe3+ and Fe(CN)63 in the presence of poly(N-vinyl pyrrolidine) (PVP) under N2 atmospheres at room temperature. With the increase of the concentration of PVP, the size and the size distribution of the synthesized quasi-spherical PB NPs decreased obviously, leading to a hypsochromic shift on their peak position of the characteristic absorption. In the experiment, we further found that the smaller ones have a larger capacity to Cs+, suggesting that the application of PB NPs in curing thallotoxicosis may decrease the usage of PB for the patient to great extent. Secondly, through a series of preliminary experiments, we got a clear picture about the one-step radiolytic preparation of inorganic-poly(methacrylic acid-co-methyl methacrylate) hybrid microgels by surfactant-free emulsion polymerization. Besides, unpurified N-carbamothioylmethacrylamide was synthesized via the methacrylation of thiourea. These created favorable conditions for the one-step synthesis of metal sulfide-poly(methacrylic acid-co-methyl methacrylate) hybrid microgels by -irradiation and surfactant-free emulsion polymerization. (author)

A novel separation/preconcentration technique based on ultrasonic dispersion liquid-liquid microextraction for determination of trace cobalt by flame atomic absorption spectrometry

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Jingci Li

2012-12-01

Full Text Available An improved method for the determination of trace cobalt in water samples has been developed using ultrasonic dispersion liquid-liquid microextraction (US-DLLME prior to flame atomic absorption spectrometry (FAAS analysis. In this method, cobalt was extracted into the fine droplets of carbon tetrachloride after chelate formation with the water soluble ligand, ammonium pyrrolidine dithiocarbamate (APDC. The fine droplets of carbon tetrachloride were formed and dispersed in the aqueous sample with the help of ultrasonic waves which accelerated the formation of the fine cloudy solution without using disperser solvents. Under optimum conditions, the calibration curve was linear in the range of 2.5-500 μg L-1, with a detection limit of 0.8 μg L-1. The relative standard deviation (RSD for ten replicate measurements of 20 and 500 μg L-1 of cobalt were 3.3 and 2.2%. This proposed method was successfully applied to tap water, river water, and sea water, and accuracy was assessed through the analysis of certified reference water or recovery experiments. Operation simplicity, low cost, high enrichment factor, and low consumption of the extraction solvent are the main advantages of the proposed method.DOI: http://dx.doi.org/10.4314/bcse.v26i1.2

RAPID AND SENSITIVE DETERMINATION OF PALLADIUM USING HOMOGENEOUS LIQUID-LIQUID MICROEXTRACTION VIA FLOTATION ASSISTANCE FOLLOWED BY GRAPHITE FURNACE ATOMIC ABSORPTION SPECTROMETRY

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Mohammad Rezaee

2015-05-01

Full Text Available A method for the determination of trace amounts of palladium was developed using homogeneous liquid-liquid microextraction via flotation assistance (HLLME-FA followed by graphite furnace atomic absorption spectrometry (GFAAS. Ammonium pyrrolidine dithiocarbamate (APDC was used as a complexing agent. This was applied to determine palladium in three types of water samples. In this study, a special extraction cell was designed to facilitate collection of the low-density solvent extraction. No centrifugation was required in this procedure. The water sample solution was added to the extraction cell which contained an appropriate mixture of extraction and homogeneous solvents. By using air flotation, the organic solvent was collected at the conical part of the designed cell. Parameters affecting extraction efficiency were investigated and optimized. Under the optimum conditions, the calibration graph was linear in the range of 1.0-200 µg L-1 with a limit of detection of 0.3 µg L-1. The performance of the method was evaluated for the extraction and determination of palladium in water samples and satisfactory results were obtained. In order to verify the accuracy of the approach, the standard addition method was applied for the determination of palladium in spiked synthetic samples and satisfactory results were obtained.

Diffusion studies on permeable nitroxyl spin probes through bilayer lipid membranes: A low frequency ESR study

International Nuclear Information System (INIS)

Meenakumari, V.; Benial, A. Milton Franklin; Utsumi, Hideo; Ichikawa, Kazuhiro; Yamada, Ken-ichi; Hyodo, Fuminori; Jawahar, A.

2015-01-01

Electron spin resonance (ESR) studies were carried out for permeable 2mM 14 N-labeled deutrated 3 Methoxy carbonyl-2,2,5,5-tetramethyl-pyrrolidine-1-oxyl (MC-PROXYL) in pure water and 1mM, 2mM, 3mM, 4mM concentration of 14N-labeled deutrated MC-PROXYL in 400mM concentration of liposomal solution by using a 300 MHz ESR spectrometer. The ESR parameters such as linewidth, hyperfine coupling constant, g-factor, partition parameter and permeability were reported for these samples. The line broadening was observed for the nitroxyl spin probe in the liposomal solution. The line broadening indicates that the high viscous nature of the liposomal solution. The partition parameter and permeability values indicate the maximum diffusion of nitroxyl spin probes in the bilayer lipid membranes at 2 mM concentration of nitroxyl radical. This study illustrates that ESR can be used to differentiate between the intra and extra- membrane water by loading the liposome vesicles with a lipid-permeable nitroxyl spin probe. From the ESR results, the spin probe concentration was optimized as 2mM in liposomal solution for ESR phantom studies/imaging, invivo and invitro experiments

Probing the Influence of Linker Length and Flexibility in the Design and Synthesis of New Trehalase Inhibitors

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Giampiero D’Adamio

2018-02-01

Full Text Available This work aims to synthesize new trehalase inhibitors selective towards the insect trehalase versus the porcine trehalase, in view of their application as potentially non-toxic insecticides and fungicides. The synthesis of a new pseudodisaccharide mimetic 8, by means of a stereoselective α-glucosylation of the key pyrrolizidine intermediate 13, was accomplished. The activity of compound 8 as trehalase inhibitor towards C. riparius trehalase was evaluated and the results showed that 8 was active in the μM range and showed a good selectivity towards the insect trehalase. To reduce the overall number of synthetic steps, simpler and more flexible disaccharide mimetics 9–11 bearing a pyrrolidine nucleus instead of the pyrrolizidine core were synthesized. The biological data showed the key role of the linker chain’s length in inducing inhibitory properties, since only compounds 9 (α,β-mixture, bearing a two-carbon atom linker chain, maintained activity as trehalase inhibitors. A proper change in the glucosyl donor-protecting groups allowed the stereoselective synthesis of the β-glucoside 9β, which was active in the low micromolar range (IC50 = 0.78 μM and 12-fold more potent (and more selective than 9α towards the insect trehalase.

Activation of NF-κB is involved in 6-hydroxydopamine-but not MPP+-induced dopaminergic neuronal cell death: its potential role as a survival determinant

International Nuclear Information System (INIS)

Park, Seong H.; Choi, Won-Seok; Yoon, So-Young; Ahn, Young Soo; Oh, Young J.

2004-01-01

The nuclear factor-kappaB (NF-κB) family plays an important role in the control of the apoptotic response. Its activation has been demonstrated in both neurons and glial cells in many neurological disorders. In the present study, we specifically examined whether and to what extent NF-κB activation is involved in culture models of Parkinson's disease following exposure of MN9D dopaminergic neuronal cells to 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenyl-4-phenylpyridinium ion (MPP + ). Both analysis by immunocytochemistry and of immunoblots revealed that NF-κB-p65 was translocated into the nuclei following 6-OHDA but not MPP + -treatment. A time-dependent activation of NF-κB induced by 6-OHDA but not MPP + was also demonstrated by an electrophoretic mobility shift assay. A competition assay indicated that not only NF-κB-p65 but also -p50 is involved in 6-OHDA-induced NF-κB activity. Co-treatment with an antioxidant, N-acetyl-L-cysteine, blocked 6-OHDA-induced activation of NF-κB signaling. In the presence of an NF-κB inhibitor, pyrrolidine dithiocarbamate (PDTC), 6-OHDA-induced cell death was accelerated while PDTC did not affect MPP + -induced cell death. Our data may point to a drug-specific activation of NF-κB as a survival determinant for dopaminergic neurons

Determination of mercury and copper in water samples by activation analysis using preconcentration on emission spectroscopic carbon powder

International Nuclear Information System (INIS)

Nagatsuka, Sumiko; Tanizaki, Yoshiyuki

1978-01-01

A simple preconcentration procedure for mercury and copper was examined in the activation analysis of water samples. The preconcentration using pure activated carbon has been reported in several papers. The authors found that the carbon powder for emission spectroscopic analysis showed the high purity equivalent to pure activated carbon. The influence of various parameters in adsorption conditions was studied by radioactive tracers 197 Hg and 64 Cu. It was confirmed that 100% of these elements were adsorbed on carbon powders as pyrrolidine dithiocarbonate complexes at an acidity of pH 6 - 8, the temperature of 50 0 C and the stirring time of 30 minutes. This method was applied to the activation analysis of the river water samples taken from the upper stream area of the Arakawa river and the ground water samples taken from the wells of the environs of Tokyo Megalopolis. The carbon powders which adsorbed these elements were filtered, dried and analyzed by instrumental neutron activation analysis. The Hg concentrations of 0.01 - 0.1 ppb in river water and 0.03 - 1.4 ppb in ground water were obtained as well as the Cu concentrations of 0.3 - 3.0 ppb in ground water. The limits of determination of this method are 0.01 ppb Hg and 0.2 ppb Cu in the case of 1.1 sample of fresh water. (auth.)

Importance of the Electron Correlation and Dispersion Corrections in Calculations Involving Enamines, Hemiaminals, and Aminals. Comparison of B3LYP, M06-2X, MP2, and CCSD Results with Experimental Data.

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Castro-Alvarez, Alejandro; Carneros, Héctor; Sánchez, Dani; Vilarrasa, Jaume

2015-12-18

While B3LYP, M06-2X, and MP2 calculations predict the ΔG° values for exchange equilibria between enamines and ketones with similar acceptable accuracy, the M06-2X/6-311+G(d,p) and MP2/6-311+G(d,p) methods are required for enamine formation reactions (for example, for enamine 5a, arising from 3-methylbutanal and pyrrolidine). Stronger disagreement was observed when calculated energies of hemiaminals (N,O-acetals) and aminals (N,N-acetals) were compared with experimental equilibrium constants, which are reported here for the first time. Although it is known that the B3LYP method does not provide a good description of the London dispersion forces, while M06-2X and MP2 may overestimate them, it is shown here how large the gaps are and that at least single-point calculations at the CCSD(T)/6-31+G(d) level should be used for these reaction intermediates; CCSD(T)/6-31+G(d) and CCSD(T)/6-311+G(d,p) calculations afford ΔG° values in some cases quite close to MP2/6-311+G(d,p) while in others closer to M06-2X/6-311+G(d,p). The effect of solvents is similarly predicted by the SMD, CPCM, and IEFPCM approaches (with energy differences below 1 kcal/mol).

The 'glial' glutamate transporter, EAAT2 (Glt-1) accounts for high affinity glutamate uptake into adult rodent nerve endings.

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Suchak, Sachin K; Baloyianni, Nicoletta V; Perkinton, Michael S; Williams, Robert J; Meldrum, Brian S; Rattray, Marcus

2003-02-01

The excitatory amino acid transporters (EAAT) removes neurotransmitters glutamate and aspartate from the synaptic cleft. Most CNS glutamate uptake is mediated by EAAT2 into glia, though nerve terminals show evidence for uptake, through an unknown transporter. Reverse-transcriptase PCR identified the expression of EAAT1, EAAT2, EAAT3 and EAAT4 mRNAs in primary cultures of mouse cortical or striatal neurones. We have used synaptosomes and glial plasmalemmal vesicles (GPV) from adult mouse and rat CNS to identify the nerve terminal transporter. Western blotting showed detectable levels of the transporters EAAT1 (GLAST) and EAAT2 (Glt-1) in both synaptosomes and GPVs. Uptake of [3H]D-aspartate or [3H]L-glutamate into these preparations revealed sodium-dependent uptake in GPV and synaptosomes which was inhibited by a range of EAAT blockers: dihydrokainate, serine-o-sulfate, l-trans-2,4-pyrrolidine dicarboxylate (PDC) (+/-)-threo-3-methylglutamate and (2S,4R )-4-methylglutamate. The IC50 values found for these compounds suggested functional expression of the 'glial, transporter, EAAT2 in nerve terminals. Additionally blockade of the majority EAAT2 uptake sites with 100 micro m dihydrokainate, failed to unmask any functional non-EAAT2 uptake sites. The data presented in this study indicate that EAAT2 is the predominant nerve terminal glutamate transporter in the adult rodent CNS.

IFN-γ regulates human dental pulp stem cells behavior via NF-κB and MAPK signaling

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He, Xinyao; Jiang, Wenkai; Luo, Zhirong; Qu, Tiejun; Wang, Zhihua; Liu, Ningning; Zhang, Yaqing; Cooper, Paul R.; He, Wenxi

2017-01-01

During caries, dental pulp expresses a range of pro-inflammatory cytokines in response to the infectious challenge. Interferon gamma (IFN-γ) is a dimerized soluble cytokine, which is critical for immune responses. Previous study has demonstrated that IFN-γ at relative high concentration (100 ng/mL) treatment improved the impaired dentinogenic and immunosuppressive regulatory functions of disease-derived dental pulp stem cells (DPSCs). However, little is known about the regulatory effects of IFN-γ at relative low concentration on healthy DPSC behavior (including proliferation, migration, and multiple-potential differentiation). Here we demonstrate that IFN-γ at relatively low concentrations (0.5 ng/mL) promoted the proliferation and migration of DPSCs, but abrogated odonto/osteogenic differentiation. Additionally, we identified that NF-κB and MAPK signaling pathways are both involved in the process of IFN-γ-regulated odonto/osteogenic differentiation of DPSCs. DPSCs treated with IFN-γ and supplemented with pyrrolidine dithiocarbamate (PDTC, an NF-κB inhibitor) or SB203580 (a MAPK inhibitor) showed significantly improved potential for odonto/osteogenic differentiation of DPSCs both in vivo and in vitro. These data provide important insight into the regulatory effects of IFN-γ on the biological behavior of DPSCs and indicate a promising therapeutic strategy for dentin/pulp tissue engineering in future endodontic treatment. PMID:28098169

An improved method to prepare an injectable microemulsion of the galanin-receptor 3 selective antagonist, SNAP 37889, using Kolliphor® HS 15

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Scheller, Karlene J.; Williams, Spencer J.; Lawrence, Andrew J.; Jarrott, Bevyn; Djouma, Elvan

2014-01-01

Research into the galanin-3 (GAL3) receptor has many challenges, including the lack of commercially available selective ligands. While the identification of non-peptidergic GAL3 receptor-selective antagonists, 1-phenyl-3-[3-(trifluoromethyl)phenyl]iminoindol-2-one (SNAP 37889) and 1-[3-(2-pyrrolidin-1-ylethoxy)phenyl]-3-[3-(trifluoromethyl)phenyl]iminoindol-2-one (SNAP 398299) have implicated a role for GAL3 receptors in anxiety, depression and drug-seeking behaviour, a major limitation of their use is poor aqueous solubility. Previously we have used 5% dimethylsulfoxide (DMSO) with 1% hydroxypropylmethyl cellulose in saline to dissolve SNAP 37889 for intraperitoneal (i.p.) injections of rats; however this produced a micro-suspension that was not ideal. The injectable formulation of SNAP 37889 was improved as follows:•30% (w/v) Kolliphor® HS 15 (Solutol HS® 15) and sodium phosphate buffer (0.01 M, pH 7.4) were used as vehicles.•A smooth glass mortar and pestle was used to triturate the Kolliphor® HS 15 and SNAP 37889 into a paste before addition to the sodium phosphate buffer at room temperature (RT).•The resulting mixture was vortexed until the paste was fully dissolved and the microemulsion was allowed to sit for 20 min to allow air bubbles to coalesce. PMID:26150955

Concentration, size distribution and dry deposition of amines in atmospheric particles of urban Guangzhou, China

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Liu, Fengxian; Bi, Xinhui; Zhang, Guohua; Peng, Long; Lian, Xiufeng; Lu, Huiying; Fu, Yuzhen; Wang, Xinming; Peng, Ping'an; Sheng, Guoying

2017-12-01

Size-segregated PM10 samples were collected in Guangzhou, China during autumn of 2014. Nine amines, including seven aliphatic amines and two heterocyclic amines, were detected using a gas chromatography-mass spectrometer after derivatization by benzenesulfonyl chloride. The total concentration of the nine amines (Ʃamines) was 79.6-140.9 ng m-3 in PM10. The most abundant species was methylamine (MA), which had a concentration of 29.2-70.1 ng m-3. MA, dimethylamine (DMA), diethylamine (DEA) and dibutylamine (DBA) were the predominant amines in the samples and accounted for approximately 80% of Ʃamines in each size segment. Two heterocyclic amines, pyrrolidine (PYR) and morpholine (MOR), were detected in all samples and had average concentrations of 1.14 ± 0.37 and 1.89 ± 0.64 ng m-3, respectively, in particles with aerodynamic diameters ammonium ranged from 0.0068 to 0.0107 in particles with diameters <1.5 μm, and the maximum ratio occurred in the smallest particles (diameter< 0.49 μm). The average dry deposition flux and velocity of Ʃamines in PM10 were 7.9 ± 1.6 μg m-2 d-1 and 0.084 ± 0.0021 cm s-1, respectively. The results of this study provide essential information on the contribution of amines to secondary organic aerosols and dry removal mechanisms in urban areas.

Reduced resting potentials in dystrophic (mdx) muscle fibers are secondary to NF-κB-dependent negative modulation of ouabain sensitive Na+-K+ pump activity.

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Miles, M T; Cottey, E; Cottey, A; Stefanski, C; Carlson, C G

2011-04-15

To examine potential mechanisms for the reduced resting membrane potentials (RPs) of mature dystrophic (mdx) muscle fibers, the Na(+)-K(+) pump inhibitor ouabain was added to freshly isolated nondystrophic and mdx fibers. Ouabain produced a 71% smaller depolarization in mdx fibers than in nondystrophic fibers, increased the [Na(+)](i) in nondystrophic fibers by 40%, but had no significant effect on the [Na(+)](i) of mdx fibers, which was approximately double that observed in untreated nondystrophic fibers. Western blots indicated no difference in total and phosphorylated Na(+)-K(+) ATPase catalytic α1 subunit between nondystrophic and mdx muscle. Examination of the effects of the NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC) indicated that direct application of the drug slowly hyperpolarized mdx fibers (7 mV in 90 min) but had no effect on nondystrophic fibers. Pretreatment with ouabain abolished this hyperpolarization, and pretreatment with PDTC restored ouabain-induced depolarization and reduced [Na(+)](i). Administration of an NF-κB inhibitor that utilizes a different mechanism for reducing nuclear NF-κB activation, ursodeoxycholic acid (UDCA), also hyperpolarized mdx fibers. These results suggest that in situ Na(+)-K(+) pump activity is depressed in mature dystrophic fibers by NF-κB dependent modulators, and that this reduced pump activity contributes to the weakness characteristic of dystrophic muscle. Copyright © 2011 Elsevier B.V. All rights reserved.

Amides from Piper as a Diuretic: Behind the Ethnopharmacological Uses of Piper glabratum Kunth

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Thiago Bruno Lima Prando

2014-01-01

Full Text Available Several species of the genus Piper are known in Brazilian folk medicine as having diuretic activity. So, we propose to investigate the acute diuretic activity and the possible toxic effects of Piper glabratum Kunth, popularly known as false Jaborandi. Additionally, we propose to check whether there is any correlation between the biological activities of the crude extract (MEPG and its 2-methoxy-4,5-methylenedioxy-trans-cinnamoyl-pyrrolidine (MMCP in Wistar rats. The MEPG was fractioned by chromatography column and the MMCP was identified by analyses of 1H and 13C RMN spectral data and correlations. Both MEPG and MMCP were assayed for diuretic activity. The preparations obtained were orally administered in a single dose to rats. The urine excretion, pH, density, conductivity, and content of Na+, K+, Cl−, and HCO3- were measured in the urine of saline-loaded animals. Additionally, acute toxicity of the extract was also evaluated. MMCP at doses of 30 mg/kg was able to increase the urine volume, pH, and HCO3- excretion. Moreover, high dosage of MEPG showed important liver toxicity and elevated mortality when injected intraperitoneally. The results indicate that the MMCP shows important diuretic properties when administered in Wistar rats. Additionally, MEPG can induce important acute toxicity if given in high doses.

Protection by the gross saponins of Tribulus terrestris against cerebral ischemic injury in rats involves the NF-κB pathway

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En-ping Jiang

2011-06-01

Full Text Available The aim of this study was to investigate whether the gross saponins of Tribulus terrestris (GSTT, a traditional Chinese herbal medicine, have neuroprotective effects on rats subjected to middle cerebral artery occlusion (MCAO, through nuclear factor-κB (NF-κB pathway and inflammatory mediators. Cerebral ischemia was produced by MCAO in either untreated (control or GSTT-pretreated rats, and the animals were examined for infarct volume, cerebral edema, neuro-behavioral abnormality and pathological changes. Meanwhile, the expression of NF-κB protein in brain tissue was analyzed on Western blots and the serum levels of TNF-α and IL-1 were determined by ELISA. The experimental results demonstrated that, compared with the control MCAO group, GSTT-pretreated MCAO group had significantly reduced infarct volume, brain edema and neuro-behavioral abnormality, and lesser degree of pathologic changes in the brain, as well as had lower levels of serum TNF-α and IL-1β, and higher levels of brain NF-κB (P<0.05. Furthermore, treatment with an NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC abolished the protective effects of GSTT against MCAO-induced cerebral ischemic injury. These results indicated that GSTT's ability to protect against cerebral ischemic injury was mediated through the NF-κB signaling pathway, and that GSTT may act through inhibition of the production of inflammatory mediators.

IFN-γ regulates human dental pulp stem cells behavior via NF-κB and MAPK signaling.

Science.gov (United States)

He, Xinyao; Jiang, Wenkai; Luo, Zhirong; Qu, Tiejun; Wang, Zhihua; Liu, Ningning; Zhang, Yaqing; Cooper, Paul R; He, Wenxi

2017-01-18

During caries, dental pulp expresses a range of pro-inflammatory cytokines in response to the infectious challenge. Interferon gamma (IFN-γ) is a dimerized soluble cytokine, which is critical for immune responses. Previous study has demonstrated that IFN-γ at relative high concentration (100 ng/mL) treatment improved the impaired dentinogenic and immunosuppressive regulatory functions of disease-derived dental pulp stem cells (DPSCs). However, little is known about the regulatory effects of IFN-γ at relative low concentration on healthy DPSC behavior (including proliferation, migration, and multiple-potential differentiation). Here we demonstrate that IFN-γ at relatively low concentrations (0.5 ng/mL) promoted the proliferation and migration of DPSCs, but abrogated odonto/osteogenic differentiation. Additionally, we identified that NF-κB and MAPK signaling pathways are both involved in the process of IFN-γ-regulated odonto/osteogenic differentiation of DPSCs. DPSCs treated with IFN-γ and supplemented with pyrrolidine dithiocarbamate (PDTC, an NF-κB inhibitor) or SB203580 (a MAPK inhibitor) showed significantly improved potential for odonto/osteogenic differentiation of DPSCs both in vivo and in vitro. These data provide important insight into the regulatory effects of IFN-γ on the biological behavior of DPSCs and indicate a promising therapeutic strategy for dentin/pulp tissue engineering in future endodontic treatment.

Surfactant-enhanced liquid-liquid microextraction coupled to micro-solid phase extraction onto highly hydrophobic magnetic nanoparticles

International Nuclear Information System (INIS)

Giannoulis, Kiriakos M.; Giokas, Dimosthenis L.; Tsogas, George Z.; Vlessidis, Athanasios G.; Zhu, Qing; Pan, Qinmin

2013-01-01

We are presenting a simplified alternative method for dispersive liquid-liquid microextraction (DLLME) by resorting to the use of surfactants as emulsifiers and micro solid-phase extraction (μ-SPE). In this combined procedure, DLLME of hydrophobic components is initially accomplished in a mixed micellar/microemulsion extractant phase that is prepared by rapidly mixing a non-ionic surfactant and 1-octanol in aqueous medium. Then, and in contrast to classic DLLME, the extractant phase is collected by highly hydrophobic polysiloxane-coated core-shell Fe 2 O 3 (at)C magnetic nanoparticles. Hence, the sample components are the target analyte in the DLLME which, in turn, becomes the target analyte of the μ-SPE step. This 2-step approach represents a new and simple DLLME procedure that lacks tedious steps such as centrifugation, thawing, or delicate collection of the extractant phase. As a result, the analytical process is accelerated and the volume of the collected phase does not depend on the volume of the extraction solvent. The method was applied to extract cadmium in the form of its pyrrolidine dithiocarbamate chelate from spiked water samples prior to its determination by FAAS. Detection limits were brought down to the low μg L −1 levels by preconcentrating 10 mL samples with satisfactory recoveries (96.0–108.0 %). (author)

Mitochondrial Reactive Oxygen Species Trigger Hypoxia-Induced Transcription

Science.gov (United States)

Chandel, N. S.; Maltepe, E.; Goldwasser, E.; Mathieu, C. E.; Simon, M. C.; Schumacker, P. T.

1998-09-01

Transcriptional activation of erythropoietin, glycolytic enzymes, and vascular endothelial growth factor occurs during hypoxia or in response to cobalt chloride (CoCl2) in Hep3B cells. However, neither the mechanism of cellular O2 sensing nor that of cobalt is fully understood. We tested whether mitochondria act as O2 sensors during hypoxia and whether hypoxia and cobalt activate transcription by increasing generation of reactive oxygen species (ROS). Results show (i) wild-type Hep3B cells increase ROS generation during hypoxia (1.5% O2) or CoCl2 incubation, (ii) Hep3B cells depleted of mitochondrial DNA (ρ 0 cells) fail to respire, fail to activate mRNA for erythropoietin, glycolytic enzymes, or vascular endothelial growth factor during hypoxia, and fail to increase ROS generation during hypoxia; (iii) ρ 0 cells increase ROS generation in response to CoCl2 and retain the ability to induce expression of these genes; and (iv) the antioxidants pyrrolidine dithiocarbamate and ebselen abolish transcriptional activation of these genes during hypoxia or CoCl2 in wild-type cells, and abolish the response to CoCl2 in ρ 0 cells. Thus, hypoxia activates transcription via a mitochondria-dependent signaling process involving increased ROS, whereas CoCl2 activates transcription by stimulating ROS generation via a mitochondria-independent mechanism.

Tumor Necrosis Factor-α Is Required for Mast Cell-Mediated Host Immunity Against Cutaneous Staphylococcus aureus Infection.

Science.gov (United States)

Liu, Chao; Ouyang, Wei; Xia, Jingyan; Sun, Xiaoru; Zhao, Liying; Xu, Feng

2018-05-08

Mast cells (MCs) play a key role in immune process response to invading pathogens. This study assessed the involvement of MCs in controlling Staphylococcus aureus infection in a cutaneous infection model of MC-deficient (KitW-sh/W-sh) mice. KitW-sh/W-sh mice developed significantly larger skin lesions after the cutaneous S. aureus challenge, when compared to wild-type (WT) mice, while MC dysfunction reduced the inflammation response to S. aureus. The levels of tumor necrosis factor (TNF)-α in skin tissues were significantly decreased in KitW-sh/W-sh mice upon infection. Moreover, the exogenous administration of MCs or recombinant TNF-α effectively restored the immune response against S. aureus in KitW-sh/W-sh mice via the recruitment of neutrophils to the infected site. These results indicate that the effects of MC deficiency are largely attributed to the decrease in production of TNF-α in cutaneous S. aureus infection. In addition, S. aureus-induced MC activation was dependent on the c-kit receptor-activated phosphoinositide 3-kinase (PI3K)/AKT/P65-nuclear factor (NF-κB) pathway, which was confirmed by treatment with Masitinib (a c-kit receptor inhibitor), Wortmannin (a PI3K inhibitor), and pyrrolidine dithiocarbamate (a NF-κB inhibitor), respectively. The present study identifies the critical role of MCs in the host defense against S. aureus infection.

Deleterious effect of salusin-β in paraventricular nucleus on sympathetic activity and blood pressure via NF-κB signaling in a rat model of obesity hypertension.

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Huang, Xiaodong; Wang, Yanchun; Ren, Kuang

2015-08-01

The paraventricular nucleus (PVN) has been shown to play a critical role in regulating blood pressure and sympathetic activity in obesity hypertension (OH). Salusin-β is a bioactive peptide with potential roles in mediating cardiovascular activity. The study was designed to test the hypothesis that salusin-β in the PVN can modulate sympathetic activity and blood pressure in OH. Male Sprague-Dawley rats were used to induce OH by a 12-week feeding of a high-fat diet (42% kcal as fat). Microinjection of salusin-β into the PVN increased the renal sympathetic nerve activity (RSNA), mean arterial pressure (MAP) and heart rate (HR) in a dose-dependent manner, whereas salusin-β antibody elicited significant decreases in RSNA, MAP and HR, and abolished the effects of salusin-β only in the OH rats. As expected, the OH rats had a higher norepinephrine level, which was further increased by salusin-β. Furthermore, salusin-β in the PVN accelerated the nuclear translocation of the p65 subunit of nuclear factor kappa B (NF-KB) and the degradation of IKB-α (an endogenous inhibitor of NF-KB). Pretreatment with pyrrolidine dithiocarbamate (an exogenous inhibitor of NF-KB) decreased RSNA, MAP and HR, and abolished the effects of salusin-β in the PVN in the OH rats. We concluded that salusin-β in the PVN markedly increased sympathetic outflow and blood pressure in diet-induced OH rats via NF-κB signaling.

Development of a method for multielemental determination in water by EDXRF with radioisotopic source of 238Pu

International Nuclear Information System (INIS)

Serrano, C.; Estévez, J.; Montero, A.; Pupo, I.; Herrero, Z.; Leyva, D.; Arteche, J.; Varcárcel, L.; Van Espen, P.; Santos Júnior, J. A. dos

2017-01-01

A method for determination of Cr, Fe, Co, Ni, Cu, Zn, Hg and Pb in waters by Energy Dispersive X Ray Fluorescence (EDXRF) was implemented, using a radioisotopic source of 238 Pu. For previous concentration was employed a procedure including a coprecipitation step with ammonium pyrrolidine dithiocarbamate (APDC) as quelant agent, the separation of the phases by filtration, the measurement of filter by EDXRF and quantification by a thin layer absolute method. Sensitivity curves for K and L lines were obtained respectively. The sensitivity for most elements was greater by an order of magnitude in the case of measurement with a source of 238 Pu instead of 109 Cd, which means a considerable decrease in measurement times. The influence of the concentration in the precipitation efficiency was evaluated for each element. In all cases the recoveries are close to 100%, for this reason it can be affirmed that the method of determination of the studied elements is quantitative. Metrological parameters of the method such as trueness, precision, detection limit and uncertainty were calculated. A procedure to calculate the uncertainty of the method was elaborated; the most significant source of uncertainty for the thin layer EDXRF method is associated with the determination of instrumental sensitivities. The error associated with the determination, expressed as expanded uncertainty (in %), varied from 15.4% for low element concentrations (2.5-5 μg/L) to 5.4% for the higher concentration range (20-25 μg/L). (author)

Determination of trace elements in ground water by two preconcentration methods using atomic absorption spectrometry

International Nuclear Information System (INIS)

Elhag, A. Y.

2004-01-01

This is a comparative study between two different methods of preconcentration done to separate the trace elements cadmium, nickel. chromium, manganese, copper, zinc, and lead in drinking (ground) water samples taken from different locations in Gezira State, central Sudan (the map); these methods are (coprecipitation) with aluminium hydroxide and by Ammonium Pyrrolidine Dithiocarbamate (APDC) using Methyl Isobutyl Ketone (MIBK) as an organic solvent; and subsequent analysis by Atomic Absorption Spectrometry (AAS) for both methods. The result of comparison showed the superiority of the (APDC) coprecipitation method over the aluminium hydroxide coprecipitation method in the total percentage recoveries of the studied trace elements in drinking (ground) water samples, such results confirm previous studies. This study also involves direct analysis of these water samples by atomic absorption spectrometry to determine the concentrations of trace elements Cadmium, Nickel, Chromium, Manganese, Copper, Zinc and Lead and compare it to the corresponding guide line values described by the World Health Organization and the maximum concentrations of trace elements in drinking water permitted by the Sudanese Standards and Metrology Organizations (SSMO), where the concentrations of some elements in some samples were found to be different than the described values by both of the organizations. The study includes a trial to throw light on the effect of the proximity of the water samples sources to the Blue Nile river on its trace elements concentrations; no relation was proved to exist in that respect.(Author)

SIRT1 induces resistance to apoptosis in human granulosa cells by activating the ERK pathway and inhibiting NF-κB signaling with anti-inflammatory functions.

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Han, Ying; Luo, Haining; Wang, Hui; Cai, Jun; Zhang, Yunshan

2017-10-01

SIRT1, a member of the sirtuin family, has recently emerged as a vital molecule in controlling ovarian function. The aims of the present study were to investigate SIRT1 expression and analyze SIRT1-mediated apoptosis in human granulosa cells (GCs). Human ovarian tissues were subjected to immunohistochemistry for localization of SIRT1 expression. SIRT1 knockdown in a human ovarian GC tumor line (COV434) was achieved by small interfering RNA, and the relationship between apoptosis and SIRT1 was assessed by quantitative reverse transcription polymerase chain reaction and western blotting. We further detected SIRT1 expression in human luteinized GCs. Associations among SIRT1 knockdown, SIRT1 stimulation (resveratrol) and expression of ERK1/2 and apoptotic regulatory proteins were analyzed in cell lines and luteinized GCs. Resveratrol downregulated the levels of nuclear factor (NF)-κB/p65, but this inhibitory effect was attenuated by suppressing SIRT1 activity. The NF-κB/p65 inhibitor pyrrolidine dithiocarbamate achieved similar anti-apoptosis effects. These results suggest that SIRT1 might play an anti-apoptotic role in apoptosis processes in GCs, possibly by sensing and regulating the ERK1/2 pathway, which has important clinical implications. Thus, our study provides a mechanistic link, whereby activation of SIRT1 function might help to sustain human reproduction by maintaining GCs as well as oocytes, offering a novel approach for developing a new class of therapeutic anti-inflammatory agents.

Nuclear Factor-Kappa B Activity Regulates Brain Expression of P-Glycoprotein in the Kainic Acid-Induced Seizure Rats

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Nian Yu

2011-01-01

Full Text Available This study was aimed to investigate the effect of NF-κB activity on the seizure susceptibility, brain damage, and P-gp expression in kainic acid- (KA- induced seizure rats. Male SD rats were divided into saline control group (NS group, KA induced epilepsy group (EP group, and epilepsy group intervened with NF-κB inhibitor-pyrrolidine dithiocarbamate salt (PDTC group or with dexamethasone (DEX group. No seizures were observed in the rats of NS group. Compared with NS group, increased P-gp expression and NF-κB activation in the rat brain of the EP group were observed after KA micro-injection. Both PDTC and DEX pre-treatment significantly increased the latency to grade III or V seizure onset compared to EP group but failed to show neuron-protective effect as the number of survival neurons didn't significantly differ from that in EP group. Furthermore, PDTC pre-treatment significantly decreased P-gp expression along with NF-κB activation in the hippocampus CA3 area and amygdala complex of rats compared with the EP group, implying that NF-κB activation involved in the seizure susceptibility and seizure induced brain P-gp over-expression. Additionally, DEX pre-treatment only decreased P-gp expression level without inhibition of NF-κB activation, suggesting NF-κB independent pathway may also participate in regulating seizure induced P-gp over-expression.

Quantitative analysis of 15N-labeled positional isomers of glutamine and citrulline via electrospray ionization tandem mass spectrometry of their dansyl derivatives.

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Marini, Juan C

2011-05-15

The enteral metabolisms of glutamine and citrulline are intertwined because, while glutamine is one of the main fuel sources for the enterocyte, citrulline is one of its products. It has been shown that the administration of (15)N-labeled glutamine results in the incorporation of the (15)N label into citrulline, but it is not clear which of the three nitrogen groups of citrulline is actually labeled. To determine the (15)N-enrichment of the positional isomers of glutamine and citrulline, a rapid liquid chromatography/tandem mass spectrometry (LC/MS/MS) method was developed. The amino acids were analyzed as their dansyl derivatives. The product ion resulting from the loss of NH(3) from the omega carbon allows for the determination of the enrichment of the ureido (citrulline) or amido groups (glutamine). The protonated pyrrolidine (citrulline) or 5-oxopyrrolidine (glutamine) product ion contains the 2-N (amino group) and is used to determine its enrichment. The method described showed no ion suppression and a wide dynamic range ranging from 1.3 picomoles to 2 nanomoles for citrulline. Background samples and standards resulted in enrichments not different from those theoretically expected. The enrichment curves for the different glutamine and citrulline isotopomers were linear (R(2)  > 0.998) over the range of enrichments studied. The method developed provides an additional insight into the metabolism of glutamine and citrulline tracing the precursor-product relationship between these two amino acids. Copyright © 2011 John Wiley & Sons, Ltd.

In vitro photostability and photoprotection studies of a novel 'multi-active' UV-absorber.

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Venditti, E; Spadoni, T; Tiano, L; Astolfi, P; Greci, L; Littarru, G P; Damiani, E

2008-08-01

This paper reports on the synthesis and properties of a new UV-absorber (OC-NO) based on the most popular UV filter worldwide, ethylhexyl methoxycinnamate (OMC) in which the methoxy group has been replaced with a pyrrolidine nitroxide bearing antioxidant activity. This sunscreen active has therefore both UV-absorbing and antioxidant properties which could ideally address both the UV-B and UV-A skin photo-damage. For broad-spectrum coverage, the combinations of OC-NO with two commonly used UV-A absorbers (BMDBM and DHHB) were also studied. The results obtained reveal that OC-NO: (a) is as photostable as OMC after UV-A exposure; (b) acts as free radical scavenger as demonstrated by EPR and chemical studies; (c) reduces UV-A and UV-A+BMDBM induced lipid peroxidation in liposomes and cells, measured as reduced TBARS levels and increased C11-BODIPY red fluorescence, respectively; (d) has comparable antioxidant activity to that of vitamin E and BHT commonly used in skin care formulations; (e) is non-cytotoxic to human skin fibroblasts as assessed with the MTT assay when exposed to increasing doses of UV-A; and (f) OC-NO+DHHB is a promising, photostable broad spectrum UV-filter combination that concomitantly reduces UV-induced free radical damage. These results suggest that nitroxide/antioxidant-based UV-absorbers may pave the way for the utilization of 'multi-active' ingredients in sunscreens thereby reducing the number of ingredients in these formulations.

[Gallic acid inhibits inflammatory response of RAW264.7 macrophages by blocking the activation of TLR4/NF-κB induced by LPS].

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Huang, Lihua; Hou, Lin; Xue, Hainan; Wang, Chunjie

2016-12-01

Objective To observe the influence of gallic acid on Toll-like receptor 4/nuclear factor-κB (TLR4/NF-κB) pathway in the RAW264.7 macrophages stimulated by lipopolysaccharide (LPS). Methods RAW264.7 macrophages were divided into the following groups: control group, LPS group, LPS combined with gallic acid group, LPS combined with pyrrolidine dithiocarbamate (PDTC) group and LPS combined with dexamethasone (DM) group. RAW264.7 cells were cultured for 24 hours after corresponding treatments. The levels of tumor necrosis factor α (TNF-α), interleukin-1 (IL-1) and IL-6 were detected by ELISA. The levels of TLR4 and NF-κB mRNAs were tested by real-time PCR. The levels of p-IκBα, p65, p-p65 and TLR4 proteins were examined by Western blotting. Results The expression levels of TNF-α, IL-1 and IL-6 were up-regulated in the RAW264.7 macrophages after stimulated by LPS. Gallic acid could reduce the elevated expression levels of TNF-α, IL-1 and IL-6 induced by LPS. The expression of TLR4 significantly increased after stimulated by LPS and NF-κB was activated. Gallic acid could reverse the above changes and prevent the activation of NF-κB. Conclusion Gallic acid could inhibit LPS-induced inflammatory response in RAW264.7 macrophages via TLR4/NF-κB pathway.

Anomalous H/D isotope effect on 35Cl NQR frequencies and H/D isotope effect on 1H MAS NMR spectra in pyrrolidinium p-chlorobenzoate

International Nuclear Information System (INIS)

Nakano, Ryo; Honda, Hisashi; Nakata, Eiichi; Takamizawa, Satoshi; Noro, Sumiko; Kimura, Taiki; Kyo, Shin-shin; Ishimaru, Shin'ichi; Miyake, Ryosuke

2010-01-01

An anomalous isotope effect was observed in the 35 Cl NQR frequency of pyrrolidinium p-chlorobenzoate (C 4 H 8 NH 2 + ·ClC 6 H 4 COO - ) by deuterium substitution of hydrogen atoms which form two kinds of N-H...O type hydrogen bonds. Large negative frequency shifts of the 35 Cl resonance lines, reaching 309 kHz at 77 K and 267 kHz at 293 K, were obtained upon deuteration, although the Cl atom in the molecule formed no hydrogen bonds in the crystal. 1 H MAS NMR lines showed significant changes by the deuterium substitution, while in contrast, small shifts of 13 C CP/MAS NMR signals were obtained. Our measurements of 1 H NMR spin-lattice relaxation times (T 1 ) suggested that the H/D isotope shifts detected from the 35 Cl NQR frequencies and 1 H NMR spectra are due to structural changes rather than molecular dynamics. Single-crystal X-ray diffraction measurements showed two remarkable H/D isotope differences in the molecular arrangements, (1) the N-H length along the crystallographic a axis became 1 pm shorter, and (2) the dihedral angle between benzene and the pyrrolidine ring changed by 1.1(2)deg upon deuteration. Using density functional theory estimations, the anomalous 35 Cl NQR frequency shifts and 1 H MAS NMR line-shape changes could be explained by the dihedral angle change rather than the N-H length difference. (author)

Piracetam and TRH analogues antagonise inhibition by barbiturates, diazepam, melatonin and galanin of human erythrocyte D-glucose transport

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Naftalin, Richard J; Cunningham, Philip; Afzal-Ahmed, Iram

2004-01-01

Nootropic drugs increase glucose uptake into anaesthetised brain and into Alzheimer's diseased brain. Thyrotropin-releasing hormone, TRH, which has a chemical structure similar to nootropics increases cerebellar uptake of glucose in murine rolling ataxia. This paper shows that nootropic drugs like piracetam (2-oxo 1 pyrrolidine acetamide) and levetiracetam and neuropeptides like TRH antagonise the inhibition of glucose transport by barbiturates, diazepam, melatonin and endogenous neuropeptide galanin in human erythrocytes in vitro. The potencies of nootropic drugs in opposing scopolamine-induced memory loss correlate with their potencies in antagonising pentobarbital inhibition of erythrocyte glucose transport in vitro (Pnootropics, D-levetiracetam and D-pyroglutamate, have higher antagonist Ki's against pentobarbital inhibition of glucose transport than more potent L-stereoisomers (Pnootropics, like aniracetam and levetiracetam, while antagonising pentobarbital action, also inhibit glucose transport. Analeptics like bemigride and methamphetamine are more potent inhibitors of glucose transport than antagonists of hypnotic action on glucose transport. There are similarities between amino-acid sequences in human glucose transport protein isoform 1 (GLUT1) and the benzodiazepine-binding domains of GABAA (gamma amino butyric acid) receptor subunits. Mapped on a 3D template of GLUT1, these homologies suggest that the site of diazepam and piracetam interaction is a pocket outside the central hydrophilic pore region. Nootropic pyrrolidone antagonism of hypnotic drug inhibition of glucose transport in vitro may be an analogue of TRH antagonism of galanin-induced narcosis. PMID:15148255

Synthesis of Novel 2-(Substituted aminoalkylthiopyrimidin-4(3H-ones as Potential Antimicrobial Agents

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Mohamed I. Attia

2013-12-01

Full Text Available 5-Alkyl-6-(substituted benzyl-2-thiouracils 3a,c were reacted with (2-chloroethyl diethylamine hydrochloride to afford the corresponding 2-(2-diethylaminoethylthiopyrimidin- 4(3H-ones 4a,b. Reaction of 3a–c with N-(2-chloroethylpyrrolidine hydrochloride and/or N-(2-chloroethylpiperidine hydrochloride gave the corresponding 2-[2-(pyrrolidin-1-ylethyl]-thiopyrimidin-4(3H-ones 5a–c and 2-[2-(piperidin-1-ylethyl]thiopyrimidin-4(3H-ones 6a,b, respectively. Treatment of 3a–d with N-(2-chloroethylmorpholine hydrochloride under the same reaction conditions formed the corresponding 2-[2-(morpholin-4-ylethyl]thiopyrimidines 6c–f. On the other hand, 3a,b were reacted with N-(2-bromoethylphthalimide and/or N-(3-bromopropylphthalimide to furnish the corresponding 2-[2-(N-phthalimidoethyl]-pyrimidines 7a,b and 2-[3-(N-phthalimido-propyl]pyrimidines 7c,d, respectively. Compounds 3a–d, 4a,b, 5a–c, 6a–f and 7a–d were screened against Gram-positive bacteria (Staphylococcus aureus ATCC 29213, Bacillus subtilis NRRL 4219 and Bacillus cereus, yeast-like pathogenic fungus (Candida albicans ATCC 10231 and a fungus (Aspergillusniger NRRL 599. The best antibacterial activity was displayed by compounds 3a, 3b, 4a, 5a, 5b, 6d, 6f, 7b and 7d, whereas compounds 4b, 5b, 5c, 6a, 6b and 6f exhibited the best antifungal activity.

Development of a method for multielemental determination in water by EDXRF with radioisotopic source of {sup 238}Pu

Energy Technology Data Exchange (ETDEWEB)

Serrano, C.; Estévez, J.; Montero, A.; Pupo, I.; Herrero, Z.; Leyva, D.; Arteche, J.; Varcárcel, L. [Centro de Aplicaciones Tecnológicas y Desarrollo Nuclear (CEADEN), (Cuba); Van Espen, P. [University of Amberes, (Belgium); Santos Júnior, J. A. dos, E-mail: cserrano@cedaen.edu.cu [Universidade Federal de Pernambuco (UFPE), Recife (Brazil)

2017-07-01

A method for determination of Cr, Fe, Co, Ni, Cu, Zn, Hg and Pb in waters by Energy Dispersive X Ray Fluorescence (EDXRF) was implemented, using a radioisotopic source of {sup 238}Pu. For previous concentration was employed a procedure including a coprecipitation step with ammonium pyrrolidine dithiocarbamate (APDC) as quelant agent, the separation of the phases by filtration, the measurement of filter by EDXRF and quantification by a thin layer absolute method. Sensitivity curves for K and L lines were obtained respectively. The sensitivity for most elements was greater by an order of magnitude in the case of measurement with a source of {sup 238}Pu instead of {sup 109}Cd, which means a considerable decrease in measurement times. The influence of the concentration in the precipitation efficiency was evaluated for each element. In all cases the recoveries are close to 100%, for this reason it can be affirmed that the method of determination of the studied elements is quantitative. Metrological parameters of the method such as trueness, precision, detection limit and uncertainty were calculated. A procedure to calculate the uncertainty of the method was elaborated; the most significant source of uncertainty for the thin layer EDXRF method is associated with the determination of instrumental sensitivities. The error associated with the determination, expressed as expanded uncertainty (in %), varied from 15.4% for low element concentrations (2.5-5 μg/L) to 5.4% for the higher concentration range (20-25 μg/L). (author)

Pharmacological Inhibition of Macrophage Toll-like Receptor 4/Nuclear Factor-kappa B Alleviates Rhabdomyolysis-induced Acute Kidney Injury.

Science.gov (United States)

Huang, Rong-Shuang; Zhou, Jiao-Jiao; Feng, Yu-Ying; Shi, Min; Guo, Fan; Gou, Shen-Ju; Salerno, Stephen; Ma, Liang; Fu, Ping

2017-09-20

Acute kidney injury (AKI) is the most common and life-threatening systemic complication of rhabdomyolysis. Inflammation plays an important role in the development of rhabdomyolysis-induced AKI. This study aimed to investigate the kidney model of AKI caused by rhabdomyolysis to verify the role of macrophage Toll-like receptor 4/nuclear factor-kappa B (TLR4/NF-κB) signaling pathway. C57BL/6 mice were injected with a 50% glycerin solution at bilateral back limbs to induce rhabdomyolysis, and CLI-095 or pyrrolidine dithiocarbamate (PDTC) was intraperitoneally injected at 0.5 h before molding. Serum creatinine levels, creatine kinase, the expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6, and hematoxylin and eosin stainings of kidney tissues were tested. The infiltration of macrophage, mRNA levels, and protein expression of TLR4 and NF-κB were investigated by immunofluorescence double-staining techniques, reverse transcriptase-quantitative polymerase chain reaction, and Western blotting, respectively. In vitro, macrophage RAW264.7 was stimulated by ferrous myoglobin; the cytokines, TLR4 and NF-κB expressions were also detected. In an in vivo study, using CLI-095 or PDTC to block TLR4/NF-κB, functional and histologic results showed that the inhibition of TLR4 or NF-κB alleviated glycerol-induced renal damages (P rhabdomyolysis-induced AKI by the regulation of proinflammatory cytokine production and macrophage infiltration.

Rates of proton transfer to Fe-S-based clusters: comparison of clusters containing {MFe(mu(2)-S)(2)}n+ and {MFe(3)(mu(3)-S)(4)}n+ (M = Fe, Mo, or W) cores.

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Bates, Katie; Garrett, Brendan; Henderson, Richard A

2007-12-24

The rates of proton transfer from [pyrH]+ (pyr = pyrrolidine) to the binuclear complexes [Fe2S2Cl4]2- and [S2MS2FeCl2]2- (M = Mo or W) are reported. The reactions were studied using stopped-flow spectrophotometry, and the rate constants for proton transfer were determined from analysis of the kinetics of the substitution reactions of these clusters with the nucleophiles Br- or PhS- in the presence of [pyrH]+. In general, Br- is a poor nucleophile for these clusters, and proton transfer occurs before Br- binds, allowing direct measure of the rate of proton transfer from [pyrH]+ to the cluster. In contrast, PhS- is a better nucleophile, and a pathway in which PhS- binds preferentially to the cluster prior to proton transfer from [pyrH]+ usually operates. For the reaction of [Fe2S2Cl4]2- with PhS- in the presence of [pyrH]+ both pathways are observed. Comparison of the results presented in this paper with analogous studies reported earlier on cuboidal Fe-S-based clusters allows discussion of the factors which affect the rates of proton transfer in synthetic clusters including the nuclearity of the cluster core, the metal composition, and the nature of the terminal ligands. The possible relevance of these findings to the protonation sites of natural Fe-S-based clusters, including FeMo-cofactor from nitrogenase, are presented.

Preliminary studies towards the preparation of reactive 3-pyrrolin-2-ones in conjugate addition reactions for the syntheses of potentially bioactive 2-pyrrolidinones and pyrrolidines

International Nuclear Information System (INIS)

Alves, Jose C.F.

2007-01-01

Pyrrolin-2-ones and 2-pyrrolidinones are moieties often found in the structure of several biologically active natural products and 3-pyrrolin-2-ones are valuable starting materials in organic synthesis due to their ability to react as acceptors in conjugate addition reactions. In this article we report the initial results about the performed study aiming at the syntheses of reactive 3-pyrrolin-2-ones in conjugate addition reactions and the preparation of a potential precursor for the synthesis of the nootropic (+/-)-nebracetam. (author)

Structure-antiproliferative activity studies on l-proline- and homoproline-4-N-pyrrolidine-3-thiosemicarbazone hybrids and their nickel(ii), palladium(ii) and copper(ii) complexes.

Science.gov (United States)

Dobrova, Aliona; Platzer, Sonja; Bacher, Felix; Milunovic, Miljan N M; Dobrov, Anatolie; Spengler, Gabriella; Enyedy, Éva A; Novitchi, Ghenadie; Arion, Vladimir B

2016-09-14

Two water-soluble thiosemicarbazone-proline (H2L(1)) and thiosemicarbazone-homoproline hybrids (H2L(2)) were synthesised. By reaction of H2L(1) with NiCl2·6H2O, PdCl2 and CuCl2·2H2O in ethanol, the series of square-planar complexes [Ni(H2L(1))Cl]Cl·1.3H2O (1·1.3H2O), [Pd(H2L(1))Cl]Cl·H2O (2·H2O) and [Cu(H2L(1))Cl]Cl·0.7H2O (3·0.7H2O) was prepared, and starting from H2L(2) and CuCl2·2H2O in methanol, the complex [Cu(H2L(2))Cl2]·H2O (4·H2O) was obtained. The compounds have been characterised by elemental analysis, spectroscopic methods (IR, UV-vis and NMR spectroscopy), ESI mass spectrometry and single crystal X-ray crystallography (H2L(1), 1, 2 and 4). As a solid, 1 is diamagnetic, while it is paramagnetic in methanolic solution. The effective magnetic moment of 3.26 B.M. at room temperature indicates the change in coordination geometry from square-planar to octahedral upon dissolution. The in vitro anticancer potency of ligand precursors H2L(1) and H2L(2) and metal complexes 1-4 was studied in three human cancer cell lines (A549, CH1 and SW480) and in noncancerous murine embryonal fibroblasts (NIH/3T3), and the mechanism of cell death was also assayed by flow cytometry. Clear-cut structure-activity relationships have been established. The metal ions exert marked effects in a divergent manner: copper(ii) increases, whereas nickel(ii) and palladium(ii) decrease the cytotoxicity of the hybrids. The antiproliferative activity of H2L(1) and metal complexes 1-3 decreases in all three tumour cell lines in the following rank order: 3 > H2L(1) > 1 > 2. The role of square-planar geometry in the underlying mechanism of cytotoxicity of the metal complexes studied seems to be negligible, while structural modifications at the terminal amino group of thiosemicarbazide and proline moieties are significant for enhancing the antiproliferative activity of both hybrids and copper(ii) complexes.

Radiosynthesis of [11C]SB-705498, a selective transient receptor potential Vanilloid 1 (TRPV1) receptor antagonist

International Nuclear Information System (INIS)

Dolle, F.; Bramoulle, Y.; Deverre, J.R.; Bottlaender, M.; Passchier, J.

2011-01-01

Complete text of publication follows: Objectives: The transient receptor potential vanilloid 1 (TRPV1) receptor, previously known as the vanilloid receptor 1 (VR1), is a non-selective cation channel activated by a range of noxious stimuli and highly expressed in nociceptive fibres. TRPV1 receptor is involved in pain and sensitisation associated with tissue injury and inflammation and therefore represents a pharmacological target of choice for the development of novel therapeutic agents for the treatment of chronic pain, migraine and gastrointestinal disorders. Among a novel series of pyrrolidinyl ureas recently discovered by GSK, SB-705498 (1, namely 1-(2-bromophenyl)-3-[(R)-1-(5- trifluoromethylpyridin-2-yl)pyrrolidin-3-yl]urea) has been identified as a potent, selective and orally bioavailable TRPV1 antagonist and considered for positron emission tomography studies. SB-705498 (1) has therefore been isotopically labelled with the short-lived positron-emitter carbon-11 (t1/2: 20.38 min) at its urea site using [ 11 C]phosgene in a one-pot two-step process, via the intermediate preparation of 2-bromophenyl [ 11 C]isocyanate. Methods: Carbon-11-labeling of SB-705498 comprises: (A) Trapping of [ 11 C]phosgene (radio-synthesized from cyclotron-produced [ 11 C]methane via [ 11 C]carbon tetrachloride using minor modifications of published processes) at room temperature for 1 to 2 minutes in 250 μL of acetonitrile containing 0.6 μmole of 2-bromoaniline (2) giving 2-bromophenyl [ 11 C]isocyanate ([ 11 C]-3), followed by (B) addition of an excess of chiral (R)-1-(5- trifluoromethylpyridin-2-yl)pyrrolidin-3-ylamine (4, 40 μmoles in 500 μL of acetonitrile) as the second amine and reaction at room temperature for an additional one minute giving the desired urea derivative ([ 11 C]SB-705498 ([ 11 C]-1)), (C) dilution of the crude reaction mixture with water (500 μL) containing 4% (v:v) of DEA, injection and purification on a semi-preparative Waters Symmetry R C18 HPLC

Determination of the concentrations of lead in raw milk in the Valley of Toluca

International Nuclear Information System (INIS)

Rosas Vilchis, E.

1991-01-01

The object of the present work, undertaken under the program of Regional and Cooperative Agreement for Nuclear Science and Technology in Latin America (ARCAL IV), was to determine the amounts of lead found in raw milk using the analytic techniques of Atomic Absorption Spectrophotometry (AAS), Inductively Coupled Plasma Atomic Emission Spectrometry (ICP-AES) and X-ray Fluorescence (FRX); so as to aid in solving problems of public health originating from elevated amounts of heavy metals in foods of animal origin. A total of thirty samples of raw milk were collected in the Valley of Toluca in Mexico, where heavy metal contaminants in the environment due to effects of rapid industrialization and urbanization, are known to have entered the food chain. The methodology, consisting in destroying organic matter in the samples by calcination, and included, in the case of AAS and ICP-AES, acid digestion. In the case of FRX, lead was extracted by ammonium 1-pyrrolidine carboditioate (APDC). The equipment to be used was calibrated and both blank and working solutions prepared in order to perform quantitative analysis. The concentrations of lead which were found in all the milk samples ranged from <0.03 to 0.31 μg/ml milk. These amounts within the maximum permissible limits, 0.5 μg/ml for all types of milk, established by the FDA. In the analysis ICP-AES gave best results as to sensitivity, precision and accuracy, followed by AAS which gave reliable results. FRX failed to detect lower limits and was, therefore, less reliable. (Author)

Modulating the Global Response Regulator, LuxO of V. cholerae Quorum Sensing System Using a Pyrazine Dicarboxylic Acid Derivative (PDCApy: An Antivirulence Approach

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M. Hema

2017-10-01

Full Text Available Vibrio cholerae is a Gram-negative pathogen which causes acute diarrhoeal disease, cholera by the expression of virulence genes through quorum sensing (QS mechanism. The QS circuit of V. cholerae is controlled by the global quorum regulator, LuxO, which at low cell density (LCD state produces major virulence factors such as, toxin co-regulated pilus (TCP and cholera toxin (CT to mediate infection. On the contrary, at the high cell density (HCD state the virulent genes are downregulated and the vibrios are detached from the host intestinal epithelial cells, promoted by HapA protease. Hence, targeting the global regulator LuxO would be a promising approach to modulate the QS to curtail V. cholerae pathogenesis. In our earlier studies, LuxO targeted ligand, 2,3 pyrazine dicarboxylic acid (PDCA and its derivatives having desired pharmacophore properties were chemically synthesized and were shown to have biofilm inhibition as well as synergistic activity with the conventionally used antibiotics. In the present study, the QS modulatory effect of the PDCA derivative with pyrrolidine moiety designated as PDCApy against the V. cholerae virulence gene expression was analyzed at various growth phases. The data significantly showed a several fold reduction in the expression of the genes, tcp and ct whereas the expression of hapR was upregulated at the LCD state. In addition, PDCApy reduced the adhesion and invasion of the vibrios onto the INT407 intestinal cell lines. Collectively, our data suggest that PDCApy could be a potential QS modulator (QSM for the antivirulence therapeutic approach.

Development of new portable miniaturize solid phase microextraction of silver-APDC complex using micropipette tip in-syringe system couple with electrothermal atomic absorption spectrometry

Science.gov (United States)

Naeemullah; Kazi, Tasneem Gul; Afridi, Hassan Imran; Shah, Faheem; Arain, Sadaf Sadia; Arain, Salma Aslam; Panhwar, Abdul Haleem; Arain, Mariam Shahzadi; Samoon, Muhammad Kashif

2016-02-01

An innovative and simple miniaturized solid phase microextraction (M-SPME) method, was developed for preconcentration and determination of silver(I) in the fresh and waste water samples. For M-SPME, a micropipette tip packed with activated carbon cloth (ACC) as sorbent, in a syringe system. The size, morphology and elemental composition of ACC before and after adsorption of analyte have been characterized by scanning electron microscopy and energy dispersive spectroscopy. The sample solution treated with a complexing reagent, ammonium pyrrolidine dithiocarbamate (APDC), was drawn into the syringe filled with ACC and dispensed manually for 2 to 10 aspirating/dispensing cycle. Then the Ag- complex sorbed on the ACC in micropipette was quantitatively eluted by drawing and dispensing of different concentrations of acids for 2 to 5 aspirating/dispensing cycles. The extracted Ag ions with modifier were injected directly into the electrothermal atomic absorption spectrometry for analysis. The influence of different variables on the extraction efficiency, including the concentration of ligand, pH, sample volume, eluent type, concentration and volume was investigated. Validity and accuracy of the developed method was checked by the standard addition method. Reliability of the proposed methodology was checked by the relative standard deviation (%RSD), which was found to be < 5%. Under the optimized experimental variables, the limits of detection (LOD) and enhancement factors (EF), were obtained to be 0.86 ng L- 1 and 120, respectively. The proposed method was successfully applied for the determination of trace levels of silver ions in fresh and waste water samples.

Lipopolysaccharide stimulates endogenous β-glucuronidase via PKC/NF-κB/c-myc signaling cascade: a possible factor in hepatolithiasis formation.

Science.gov (United States)

Yao, Dianbo; Dong, Qianze; Tian, Yu; Dai, Chaoliu; Wu, Shuodong

2017-11-29

Hepatolithiasis is commonly encountered in Southeastern and Eastern Asian countries, but the pathogenesis mechanism of stone formation is still not well understood. Now, the role of endogenous β-glucuronidase in pigment stones formation is being gradually recognized. In this study, the mechanism of increased expression and secretion of endogenous β-glucuronidase during hepatolithiasis formation was investigated. We assessed the endogenous β-glucuronidase, c-myc, p-p65, and p-PKC expression in liver specimens with hepatolithiasis by immunohistochemical staining, and found that compared with that in normal liver samples, the expression of endogenous β-glucuronidase, c-myc, p-p65, and p-PKC in liver specimens with hepatolithiasis significantly increased, and their expressions were positively correlated with each other. Lipopolysaccharide (LPS) induced increased expression of endogenous β-glucuronidase and c-myc in hepatocytes and intrahepatic biliary epithelial cells in a dose- and time-dependent manner, and endogenous β-glucuronidase secretion increased, correspondingly. C-myc siRNA transfection effectively inhibited the LPS-induced expression of endogenous β-glucuronidase. Furthermore, NF-κB inhibitor pyrrolidine dithiocarbamate or PKC inhibitor chelerythrine could effectively inhibit the LPS-induced expression of c-myc and endogenous β-glucuronidase, and the expression of p-p65 was also partly inhibited by chelerythrine. Our clinical observations and experimental data indicate that LPS could induce the increased expression and secretion of endogenous β-glucuronidase via a signaling cascade of PKC/NF-κB/c-myc in hepatocytes and intrahepatic biliary epithelial cells, and endogenous β-glucuronidase might play a possible role in the formation of hepatolithiasis.

Role of NFkappaB in an animal model of complex regional pain syndrome-type I (CRPS-I).

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de Mos, Marissa; Laferrière, André; Millecamps, Magali; Pilkington, Mercedes; Sturkenboom, Miriam C J M; Huygen, Frank J P M; Coderre, Terence J

2009-11-01

NFkappaB is involved in several pathogenic mechanisms that are believed to underlie the complex regional pain syndrome (CRPS), including ischemia, inflammation and sensitization. Chronic postischemia pain (CPIP) has been developed as an animal model that mimics the symptoms of CRPS-I. The possible involvement of NFkappaB in CRPS-I was studied using CPIP rats. Under sodium pentobarbital anesthesia, a tourniquet was placed around the rat left ankle joint, producing 3 hours of ischemia, followed by rapid reperfusion (IR injury). NFkappaB was measured in nuclear extracts of muscle and spinal cord tissue using ELISA. Moreover, the anti-allodynic (mechanical and cold) effect was tested for systemic, intrathecal, or intraplantar treatment with the NFkappaB inhibitor pyrrolidine dithiocarbamate (PDTC). At 2 and 48 hours after IR injury, NFkappaB was elevated in muscle and spinal cord of CPIP rats compared to shams. At 7 days, NFkappaB levels were normalized in muscle, but still elevated in spinal cord tissue. Systemic PDTC treatment relieved mechanical and cold allodynia in a dose-dependent manner, lasting for at least 3 hours. Intrathecal-but not intraplantar-administration also relieved mechanical allodynia. The results suggest that muscle and spinal NFkappaB plays a role in the pathogenesis of CPIP and potentially of human CRPS. Using the CPIP model, we demonstrate that NFkappaB is involved in the development of allodynia after a physical injury (ischemia and reperfusion) without direct nerve trauma. Since CPIP animals exhibit many features of human CRPS-I, this observation indicates a potential role for NFkappaB in human CRPS.

Neuronal uptake and intracellular superoxide scavenging of a fullerene (C60)-poly(2-oxazoline)s nanoformulation

KAUST Repository

Tong, Jing

2011-05-01

Fullerene, the third allotrope of carbon, has been referred to as a "radical sponge" because of its powerful radical scavenging activities. However, the hydrophobicity and toxicity associated with fullerene limits its application as a therapeutic antioxidant. In the present study, we sought to overcome these limitations by generating water-soluble nanoformulations of fullerene (C(60)). Fullerene (C(60)) was formulated with poly(N-vinyl pyrrolidine) (PVP) or poly(2-alkyl-2-oxazoline)s (POx) homopolymer and random copolymer to form nano-complexes. These C(60)-polymer complexes were characterized by UV-vis spectroscopy, infrared spectroscopy (IR), dynamic light scattering (DLS), atomic force microscopy (AFM) and transmission electron microscopy (TEM). Cellular uptake and intracellular distribution of the selected formulations in catecholaminergic (CATH.a) neurons were examined by UV-vis spectroscopy, immunofluorescence and immunogold labeling. Electron paramagnetic resonance (EPR) spectroscopy was used to determine the ability of these C(60)-polymer complexes to scavenge superoxide. Their cytotoxicity was evaluated in three different cell lines. C(60)-POx and C(60)-PVP complexes exhibited similar physicochemical properties and antioxidant activities. C(60)-poly(2-ethyl-2-oxazoline) (PEtOx) complex, but not C(60)-PVP complex, were efficiently taken up by CATH.a neurons and attenuated the increase in intra-neuronal superoxide induced by angiotensin II (Ang II) stimulation. These results show that C(60)-POx complexes are non-toxic, neuronal cell permeable, superoxide scavenging antioxidants that might be promising candidates for the treatment of brain-related diseases associated with increased levels of superoxide.

Low-frequency ESR studies on permeable and impermeable deuterated nitroxyl radicals in corn oil solution.

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David Jebaraj, D; Utsumi, Hideo; Milton Franklin Benial, A

2018-04-01

Low-frequency electron spin resonance studies were performed for 2 mM concentration of deuterated permeable and impermeable nitroxyl spin probes, 3-methoxycarbonyl-2,2,5,5-tetramethyl-pyrrolidine-1-oxyl and 3-carboxy-2,2,5,5,-tetramethyl-1-pyrrolidinyloxy in pure water and various concentrations of corn oil solution. The electron spin resonance parameters such as the line width, hyperfine coupling constant, g factor, rotational correlation time, permeability, and partition parameter were estimated. The broadening of line width was observed for nitroxyl radicals in corn oil mixture. The rotational correlation time increases with increasing concentration of corn oil, which indicates the less mobile nature of spin probe in corn oil mixture. The membrane permeability and partition parameter values were estimated as a function of corn oil concentration, which reveals that the nitroxyl radicals permeate equally into the aqueous phase and oil phase at the corn oil concentration of 50%. The electron spin resonance spectra demonstrate the permeable and impermeable nature of nitroxyl spin probes. From these results, the corn oil concentration was optimized as 50% for phantom studies. In this work, the corn oil and pure water mixture phantom models with various viscosities correspond to plasma membrane, and whole blood membrane with different hematocrit levels was studied for monitoring the biological characteristics and their interactions with permeable nitroxyl spin probe. These results will be useful for the development of electron spin resonance and Overhauser-enhanced magnetic resonance imaging modalities in biomedical applications. Copyright © 2017 John Wiley & Sons, Ltd.

Cytotoxicity and apoptotic inducibility of Vitex agnus-castus fruit extract in cultured human normal and cancer cells and effect on growth.

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Ohyama, Kunio; Akaike, Takenori; Hirobe, Chieko; Yamakawa, Toshio

2003-01-01

A crude extract was prepared with ethanol from dried ripened Vitex agnus-castus fruits growing in Israel (Vitex extract). Cytotoxicity of the extract against human uterine cervical canal fibroblast (HCF), human embryo fibroblast (HE-21), ovarian cancer (MCF-7), cervical carcinoma (SKG-3a), breast carcinoma (SKOV-3), gastric signet ring carcinoma (KATO-III), colon carcinoma (COLO 201), and small cell lung carcinoma (Lu-134-A-H) cells was examined. After culture for 24 h (logarithmic growth phase) or 72 h (stationary growth phase), the cells were treated with various concentrations of Vitex extract. In both growth phases, higher growth activity of cells and more cytotoxic activity of Vitex extract were seen. The cytotoxic activity against stationary growth-phase cells was less than that against logarithmic growth-phase cells. DNA fragmentation of Vitex extract-treated cells was seen in SKOV-3, KATO-III, COLO 201, and Lu-134-A-H cells. The DNA fragmentation in Vitex extract-treated KATO-III cells was inhibited by the presence of the antioxidative reagent pyrrolidine dithiocarbamate or N-acetyl-L-cysteine (NAC). Western blotting analysis showed that in Vitex extract-treated KATO-III cells, the presence of NAC also inhibited the expression of heme oxygenase-1 and the active forms of caspases-3, -8 and -9. It is concluded that the cytotoxic activity of Vitex extract may be attributed to the effect on cell growth, that cell death occurs through apoptosis, and that this apoptotic cell death may be attributed to increased intracellular oxidation by Vitex extract treatment.

Resveratrol Protects against TNF-α-Induced Injury in Human Umbilical Endothelial Cells through Promoting Sirtuin-1-Induced Repression of NF-KB and p38 MAPK

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Huang, Shujie; Zhu, Pengli

2016-01-01

Inflammation and reactive oxygen species (ROS) play important roles in the pathogenesis of atherosclerosis. Resveratrol has been shown to possess anti-inflammatory and antioxidative stress activities, but the underlying mechanisms are not fully understood. In the present study, we investigated the molecular basis associated with the protective effects of resveratrol on tumor necrosis factor-alpha (TNF-α)-induced injury in human umbilical endothelial cells (HUVECs) using a variety of approaches including a cell viability assay, reverse transcription and quantitative polymerase chain reaction, western blot, and immunofluorescence staining. We showed that TNF-α induced CD40 expression and ROS production in cultured HUVECs, which were attenuated by resveratrol treatment. Also, resveratrol increased the expression of sirtuin 1 (SIRT1); and repression of SIRT1 by small-interfering RNA (siRNA) and the SIRT1 inhibitor Ex527 reduced the inhibitory effects of resveratrol on CD40 expression and ROS generation. In addition, resveratrol downregulated the levels of p65 and phospho-p38 MAPK, but this inhibitory effect was attenuated by the suppression of SIRT1 activity. Moreover, the p38 MAPK inhibitor SD203580 and the nuclear factor (NF)-κB inhibitor pyrrolidine dithiocarbamate (PDTC) achieved similar repressive effects as resveratrol on TNF-α-induced ROS generation and CD40 expression. Thus, our study provides a mechanistic link between resveratrol and the activation of SIRT1, the latter of which is involved in resveratrol-mediated repression of the p38 MAPK/NF-κB pathway and ROS production in TNF-α-treated HUVECs. PMID:26799794

Collagen gel protects L929 cells from TNFα-induced death by activating NF-κB.

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Wang, Hong-Ju; Li, Meng-Qi; Liu, Wei-Wei; Hayashi, Toshihiko; Fujisaki, Hitomi; Hattori, Shunji; Tashiro, Shin-Ichi; Onodera, Satoshi; Ikejima, Takashi

2017-09-01

Type I collagen is one of the most abundant components of extracellular matrix. We previously illustrated that murine fibrosarcoma L929 cells grew well on type I collagen gel and escaped from TNFα-induced cell death. In this study, we investigated the mechanism underlying the protective effect of collagen gel. We used western blot, confocal microscopy, MTT assay and flow cytometry by introducing fluorescence staining to determine the expression levels of nuclear factor kappa B (NF-κB), inhibitory ratio and autophagy. L929 cells on collagen gel showed higher expression of NF-κB in the nucleus. Inhibition of NF-κB with pyrrolidine dithiocarbamate hydrochloride (PDTC) or knockdown by NF-κB-siRNA canceled the protective effect of collagen gel on L929 cells from TNFα-induced death, suggesting for the role of NF-κB in the protection from cell death. We found a new aspect of the effect of PDTC on L929 cells cultured on collagen gel. PDTC alone without TNFα induced apoptosis in the L929 cells cultured on collagen gel but not the cells on plastic dish. The apoptosis induction of the L929 cells cultured on collagen gel with PDTC was repressed by inhibiting autophagy with chloroquine, an autophagy inhibitor, suggesting that autophagy contributes to the death induced by the treatment with PDTC. Possible underlying mechanism of this finding is discussed. NF-κB played an important role in protecting the L929 cells cultured on collagen gel from TNFα-induced death.

On-line liquid phase micro-extraction based on drop-in-plug sequential injection lab-at-valve platform for metal determination

Energy Technology Data Exchange (ETDEWEB)

Mitani, Constantina [Laboratory of Analytical Chemistry, Department of Chemistry, Aristotle University, Thessaloniki 54124 (Greece); Anthemidis, Aristidis N., E-mail: anthemid@chem.auth.gr [Laboratory of Analytical Chemistry, Department of Chemistry, Aristotle University, Thessaloniki 54124 (Greece)

2013-04-10

Highlights: ► Drop-in-plug micro-extraction based on SI-LAV platform for metal preconcentration. ► Automatic liquid phase micro-extraction coupled with FAAS. ► Organic solvents with density higher than water are used. ► Lead determination in environmental water and urine samples. -- Abstract: A novel automatic on-line liquid phase micro-extraction method based on drop-in-plug sequential injection lab-at-valve (LAV) platform was proposed for metal preconcentration and determination. A flow-through micro-extraction chamber mounted at the selection valve was adopted without the need of sophisticated lab-on-valve components. Coupled to flame atomic absorption spectrometry (FAAS), the potential of this lab-at-valve scheme is demonstrated for trace lead determination in environmental and biological water samples. A hydrophobic complex of lead with ammonium pyrrolidine dithiocarbamate (APDC) was formed on-line and subsequently extracted into an 80 μL plug of chloroform. The extraction procedure was performed by forming micro-droplets of aqueous phase into the plug of the extractant. All critical parameters that affect the efficiency of the system were studied and optimized. The proposed method offered good performance characteristics and high preconcentration ratios. For 10 mL sample consumption an enhancement factor of 125 was obtained. The detection limit was 1.8 μg L{sup −1} and the precision expressed as relative standard deviation (RSD) at 50.0 μg L{sup −1} of lead was 2.9%. The proposed method was evaluated by analyzing certified reference materials and applied for lead determination in natural waters and urine samples.

Extraction and PTP1B inhibitory activity of bromophenols from the marine red alga Symphyocladia latiuscula

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Liu, Xu; Li, Xiaoming; Gao, Lixin; Cui, Chuanming; Li, Chunshun; Li, Jia; Wang, Bingui

2011-05-01

Previously, we had characterized several structurally interesting brominated phenols from the marine red alga Symphyocladia latiuscula collected from various sites. However, Phytochemical investigations on this species collected from the Weihai coastline of Shandong Province remains blank. Therefore, we characterized the chemical constituents of individuals of this species collected from the region. Eight bromophenols were isolated and identified. Using detailed spectroscopic techniques and comparisons with published data, these compounds were identified as 2,3-dibromo-4,5-dihydroxybenzyl methyl ether ( 1), 3,5-dibromo-4-hydroxybenzoic acid ( 2), 2,3,6-tribromo-4,5-dihydroxymethylbenzene ( 3), 2,3,6-tribromo-4,5-dihydroxybenzaldehyde ( 4), 2,3,6-tribromo-4,5-dihydroxybenzyl methyl ether ( 5), bis(2,3,6-tribromo-4,5-dihydroxyphenyl)methane ( 6), 1,2-bis(2,3,6-tribromo-4,5-dihydroxyphenyl)-ethane ( 7), and 1-(2,3,6-tribromo-4,5-dihydroxybenzyl)-pyrrolidin-2-one ( 8). Among these compounds, 1 and 2 were isolated for the first time from S. latiuscula. Each compound was evaluated on the ability to inhibit protein tyrosine phosphatase 1B (PTP1B), which is a potential therapeutic target in the treatment of type 2 diabetes. Bromophenols 5, 6, and 7 showed strong activities with IC50 values of 3.9, 4.3, and 3.5 μmol/L, respectively. This study provides further evidence that bromophenols are predominant among the chemical constituents of Symphyocladia, and that some of these compounds may be candidates for the development of anti-diabetes drugs.

The effect of nucleotides and adenosine on stimulus-evoked glutamate release from rat brain cortical slices.

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Bennett, G C; Boarder, M R

2000-10-01

Evidence has previously been presented that P1 receptors for adenosine, and P2 receptors for nucleotides such as ATP, regulate stimulus-evoked release of biogenic amines from nerve terminals in the brain. Here we investigated whether adenosine and nucleotides exert presynaptic control over depolarisation-elicited glutamate release. Slices of rat brain cortex were perfused and stimulated with pulses of 46 mM K(+) in the presence of the glutamate uptake inhibitor L-trans-pyrrolidine-2,4-dicarboxylic acid (0.2 mM). High K(+) substantially increased efflux of glutamate from the slices. Basal glutamate release was unchanged by the presence of nucleotides or adenosine at concentrations of 300 microM. Adenosine, ATP, ADP and adenosine 5'-O-(3-thiotriphoshate) at 300 microM attenuated depolarisation-evoked release of glutamate. However UTP, 2-methylthio ATP, 2-methylthio ADP, and alpha,beta-methylene ATP at 300 microM had no effect on stimulated glutamate efflux. Adenosine deaminase blocked the effect of adenosine, but left the response to ATP unchanged. The A(1) antagonist 8-cyclopentyl-1, 3-dipropylxanthine antagonised the inhibitory effect of both adenosine and ATP. Cibacron blue 3GA inhibited stimulus-evoked glutamate release when applied alone. When cibacron blue 3GA was present with ATP, stimulus-evoked glutamate release was almost eliminated. However, this P2 antagonist had no effect on the inhibition by adenosine. These results show that the release of glutamate from depolarised nerve terminals of the rat cerebral cortex is inhibited by adenosine and ATP. ATP appears to act directly and not through conversion to adenosine.

Development of new portable miniaturize solid phase microextraction of silver-APDC complex using micropipette tip in-syringe system couple with electrothermal atomic absorption spectrometry.

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Naeemullah; Kazi, Tasneem Gul; Afridi, Hassan Imran; Shah, Faheem; Arain, Sadaf Sadia; Arain, Salma Aslam; Panhwar, Abdul Haleem; Arain, Mariam Shahzadi; Samoon, Muhammad Kashif

2016-02-05

An innovative and simple miniaturized solid phase microextraction (M-SPME) method, was developed for preconcentration and determination of silver(I) in the fresh and waste water samples. For M-SPME, a micropipette tip packed with activated carbon cloth (ACC) as sorbent, in a syringe system. The size, morphology and elemental composition of ACC before and after adsorption of analyte have been characterized by scanning electron microscopy and energy dispersive spectroscopy. The sample solution treated with a complexing reagent, ammonium pyrrolidine dithiocarbamate (APDC), was drawn into the syringe filled with ACC and dispensed manually for 2 to 10 aspirating/dispensing cycle. Then the Ag- complex sorbed on the ACC in micropipette was quantitatively eluted by drawing and dispensing of different concentrations of acids for 2 to 5 aspirating/dispensing cycles. The extracted Ag ions with modifier were injected directly into the electrothermal atomic absorption spectrometry for analysis. The influence of different variables on the extraction efficiency, including the concentration of ligand, pH, sample volume, eluent type, concentration and volume was investigated. Validity and accuracy of the developed method was checked by the standard addition method. Reliability of the proposed methodology was checked by the relative standard deviation (%RSD), which was found to be <5%. Under the optimized experimental variables, the limits of detection (LOD) and enhancement factors (EF), were obtained to be 0.86 ng L(-1) and 120, respectively. The proposed method was successfully applied for the determination of trace levels of silver ions in fresh and waste water samples. Copyright © 2015 Elsevier B.V. All rights reserved.

Inhibition of NF-κB promotes autophagy via JNK signaling pathway in porcine granulosa cells

International Nuclear Information System (INIS)

Gao, Hui; Lin, Lu; Haq, Ihtesham Ul; Zeng, Shen-ming

2016-01-01

The transcription factor nuclear factor-κB (NF-κB) plays an important role in diverse processes, including cell proliferation and differentiation, apoptosis and inflammation. However, the role of NF-κB in porcine follicle development is not clearly elucidated. In this study, we demonstrated that follicle stimulating hormone (FSH) increased the level of inhibitor of NF-κB (IκB) protein and promoted the cytoplasmic localization of p65, indicating that FSH inhibits the activation of NF-κB in porcine granulosa cells. Moreover, inhibition of NF-κB by FSH or another specific inhibitor of NF-κB, pyrrolidine dithiocarbamate (PDTC), could activate JNK signaling and enhance autophagic activity in porcine granulosa cells. Knockdown of RelA (p65) Subunit of NF-κB by RNA interference abrogated the activation of JNK signaling pathway and the increase of autophagic protein expression by FSH. Meanwhile, the functional significance of FSH or PDTC-mediated autophagy were further investigated. Our results demonstrated that the increased autophagy promoted progesterone secretion in porcine granulosa cells. Blockage of autophagy by chloroquine obviated the FSH or PDTC-induced progesterone production. Taken together, these results indicate that inhibition of NF-κB increased autophagy via JNK signaling, and promote steroidogenesis in porcine granulosa cells. Our results provide new insights into the regulation and function of autophagy in mammalian follicle development. - Highlights: • FSH inhibits the activation of NF-κB in porcine primary granulosa cells. • Inhibition of NF-κB by FSH promotes autophagy via JNK signaling in granulosa cells. • Increased autophagy contributes to progesterone production in granulosa cells. • This is the first report against beclin1 regulation in porcine granulosa cells.

Comparative studies of the phytochemistry, proximate analysis, mineral and vitamin compositions of the methanol leaf extracts of Cucumis sativus L. and Daucus carota L.

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Essien Augustine Dick

2016-08-01

Full Text Available     Cucumis sativus  and Daucus carota are medicinal plants used in folkloric medicine to treat and prevent various diseases but the basis for this has not been highlighted. Quantitative phytochemicial analysis revealed the presence of anthocyanins, flavonoids, carotenoids and pyrrolidine in D. carota leaf methanol extract but in C. sativus only flavonoids and carotenoids was found present although in a lower amounts. Proximate analysis revealed  that both plants methanol leaf extracts contain moisture, protein, carbohydrate, fat, fiber and ash. The moisture content of C. sativus (95 ± 0.02% was more than that of D. Carota (82.20 ± 0.01% but the protein, carbohydrate, fat, ash and fiber contents of D. Carota was more than that of C. sativus. The mineral compositions also revealed the presence of Ca, P, Mg, Fe,Zn,Na, and K in both C.sativus and D. carota although in various proportions. The P, Ca, Mg, Fe and Na contents in D. carota were more than that of C. Sativus, but C. sativus has a higher Zn and K contents than D. carota. The vitamin analysis also revealed the presence of important vitamins including A, B1, B2,  B6 ,  C,E, niacin and folate. The vitamin A content of  D. carota were very high (2,901 ± 0.02µg compared to that of  C. Sativus (23 ± 0.01µg. These important macroelements, minerals and vitamins embedded in these important plants may be the reasons behind its use in forklore medicine for its various dietary and therapeutic applications.

Identification of quenchers of photoexcited States as novel agents for skin photoprotection.

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Wondrak, Georg T; Jacobson, Myron K; Jacobson, Elaine L

2005-02-01

Photooxidative stress is a key mechanism in UVA-induced skin photodamage. Photoexcited states of endogenous UVA chromophores such as porphyrins, melanin precursors, and cross-link-fluorophores of skin collagen exert skin photodamage by direct reaction with substrate molecules (type I photosensitization) or molecular oxygen (type II), leading to formation of reactive oxygen species. Based on our previous research on the role of photoexcited states of endogenous skin chromophores as sensitizers of photooxidative stress, we describe here the identification of a novel class of chemopreventive agents for topical skin photoprotection: quenchers of photoexcited states (QPES). QPES compounds antagonize the harmful excited state chemistry of endogenous sensitizers by physical quenching, facilitating the harmless return of the sensitizer excited state to the electronic ground state by energy dissipation. To identify QPES compounds suitable for development, we designed a primary screening assay based on QPES suppression of photosensitized plasmid cleavage using conditions that exclude antioxidants. This screen is followed with a screen to test for nonsacrificial quenching of dye-sensitized singlet oxygen ((1)O(2)) formation by electron paramagnetic resonance detection of 2,2,6,6-tetramethyl-piperidine-1-oxyl, a stable free radical indicative of (1)O(2) formation. These initial screens identified a pyrrolidine pharmacophore with pronounced QPES activity, and l-proline and other noncytotoxic proline derivatives containing this pharmacophore were then screened for efficacy in cellular models of sensitized photodamage. These compounds showed QPES protection against dye-sensitized and psoralen-UVA-induced apoptosis and suppression of proliferation in cultured human skin keratinocytes and fibroblasts. Furthermore, QPES photoprotection of reconstructed full thickness human skin exposed to solar simulated light has been demonstrated.

[Expression of PARP/NF-κB and intervention effect of 5-AIQ/PDTC in SAP rats with adrenal damage].

Science.gov (United States)

Yang, Bo; Guo, Wen-Yi; Yu, Jia; Zhao, Kai-liang; Shi, Qiao; Zuo, Teng; Wang, Wei-xing

2013-10-15

To explore the expression of poly (ADP-ribose) polymerase/nuclear factor-κB (PARP/NF-κB) and intervention effect of 5-aminoisoquinolinone/pyrrolidine dithiocarbamate (5-AIQ/PDTC) in severe acute pancreatitis (SAP) rats with adrenal damage. The primarily cultured adrenocortical cells were quantitatively divided into control group (SO), pancreatitis group (SAP), PDTC drug control group (SO+PDTC), PDTC intervention group (SAP+PDTC), 5-AIQ drug control group (SO+ 5-AIQ) and 5-AIQ intervention group (SAP+5-AIQ). The SAP and 2 intervention groups were stimulated with the sera of SAP rats. Then corresponding drugs were added and culture continued for 12 hours. The corticosterone levels and PARP/NF-κB expression were observed for each group. Adrenal cells in vitro cultured were round or oval, had secretory granules and could be stained by 3β-hydroxysteroid dehydrogenase antibody. The adherence rate was 60% after 48-hour culturing. The corticosterone level of SAP group was significantly lower than that of SO group [ (216.4 ± 15.7) vs (294.8 ± 16.3) µg/L, P SAP group (P SAP and PDTC intervention groups were higher than SO group while 5-AIQ intervention group was significantly lower than SAP and PDTC intervention groups, but higher than SO and drug control groups. The expression of NF-κB in SAP group was higher than that in SO group. Two intervention groups were lower than SAP group, but higher than SO and drug control groups. The pathway of PARP/NF-κB participates in adrenal damage of SAP rats. To a certain extent, the uses of 5-AIQ and PDTC may alleviate adrenal damage.

Alpha-amylase inhibitor, CS-1036 binds to serum amylase in a concentration-dependent and saturable manner.

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Honda, Tomohiro; Kaneno-Urasaki, Yoko; Ito, Takashi; Kimura, Takako; Matsushima, Nobuko; Okabe, Hiromi; Yamasaki, Atsushi; Izumi, Takashi

2014-03-01

(2R,3R,4R)-4-hydroxy-2-(hydroxymethyl)pyrrolidin-3-yl 4-O-(6-deoxy-β-D-glucopyranosyl)-α-D-glucopyranoside (CS-1036), which is an α-amylase inhibitor, exhibited biphasic and sustained elimination with a long t1/2 (18.4-30.0 hours) in rats and monkeys, but exhibited a short t1/2 (3.7-7.9 hours) in humans. To clarify the species differences in the t1/2, the plasma protein binding of CS-1036 was evaluated by ultrafiltration. A concentration-dependent and saturable plasma protein binding of CS-1036 was observed in rats and monkeys with the dissociation rate constant (KD) of 8.95 and 27.2 nM, and maximal binding capacity (Bmax) of 52.8 and 22.1 nM, respectively. By the assessments of the recombinant amylase and immunoprecipitation, the major binding protein of CS-1036 in rats was identified as salivary amylase (KD 5.64 nM). CS-1036 also showed concentration-dependent and saturable binding to human salivary and pancreatic amylase, with similar binding affinity in rats. However, the protein binding of CS-1036 was constant in human plasma (≤10.2%) due to the lower serum amylase level compared with rats and monkeys. From the calculation of the unbound fraction (fu) in plasma based on in vitro KD and Bmax, the dose-dependent increase in fu after oral administration is speculated to lead to a dose-dependent increase in total body clearance and a high area under the curve/dose at lower doses, such as 0.3 mg/kg in rats.

Preparation and in-vitro evaluation of indomethacin nanoparticles

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A Rezaei Mokarram

2010-09-01

Full Text Available "nBackground and the purpose of the study: During the last two decades one of the most important problems in drug formulations has been low aqueous solubility of new molecules. However, numerous techniques, such as milling, co-solvent solubilization and solid dispersion have been used conventionally for aqueous solubility enhancement and the rate of solubility. Recently, nanoparticle engineering processes have been developed and reported for pharmaceutical applications to increase the dissolution rate of low-soluble drugs which in turn may leads to substantial increases in bioavailability. In this study, a controlled precipitation method was used to produce indomethacin nano-solid suspension in a polymeric matrix (as a model, in order to increase the solubility and rate of the dissolution of poorly soluble model drug. "nMethods: Nano-solid suspension of indomethacin in polyvinyl pyrrolidine (PVP was prepared by controlled precipitation technique, characterized by differential scanning calorimetry (DSC, X-ray diffraction (XRD, Fourier Transform Infrared Spectroscopy (FTIR and evaluated for in vitro solubility and dissolution rate. Results and major conclusion:Absence of thermal and diffractional peaks in DSC and XRD studies indicated that indomethacin interacts with PVP in solid phase. The solubility of indomethacin in nano-solid suspension compared to crystalline form was increased to about four-fold. It was found that particle size distribution depend to the polymer MW and drug: polymer ratios. Spectroscopy methods and Transmission Electron Microscopy (TEM images showed that indomethacin dispersed as amorphous nanosize particles in freeze dried powder. Enhanced solubility and dissolution rate of indomethacin compared to physical mixtures and crystalline form of indomethacin (polymorph I, demonstrated that it interacts with PVP via hydrogen bond and probably forming eutectic mixture.

A acetamida de pirrolidona como medicação auxiliar no tratamento da paralisia cerebral Pyrrolidone acetamide as an auxiliary drug in the treatment of cerebral palsy

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Francisca Salete Pinheiro Chagas Ribeiro

1976-06-01

Full Text Available Vinte crianças, com diagnóstico de paralisia cerebral (PC e sob tratamento clássico, fisioterápico e pedagógico, receberam piracetam (acetamida de pirrolidona como medicação auxiliar. O objetivo foi melhorar os problemas de espasticidade, apredizagem, neurolabilidade, visando a um rendimento melhor do tratamento global da PC. O grupo medicado foi comparado com um grupo controle de 20 crianças que só eram objeto do tratamento habitual. A comparação mostrou resultados favoráveis no grupo medicado. A droga foi administrada na dose de 80 mg/kg/dia durante 10 semanas. Os critérios de avaliação dos resultados foram psicológicos, clínico, fisioterápico e pedagógico. A droga foi administrada em nova forma de apresentação: solução, para uso oral, a 6%.Twenty children, with the diagnosis of cerebral palsy (CP and under classical, physiotherapeutical and pedagogical, treatment, received piracetam (pyrrolidine acetamide as an auxiliary drug. The goal was to better spasticity, learning and nervous instability problems aiming at better results of over-all treatment of CP. The group that received the drug has been compared to a control group of 20 children treated by the customary treatment only. The comparison showed favourable results for the medicated group. The drug was administered in the dose of 80 mg/kg/day during 10 weeks. The criteria for evaluation have been psychological, clinical, physiotherapeutical and pedagogical. The drug has been given in a new form of presentation: 6% solution for oral use.

Diclofenac Salts, VIII. Effect of the Counterions on the Permeation through Porcine Membrane from Aqueous Saturated Solutions

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Fini, Adamo; Bassini, Glenda; Monastero, Annamaria; Cavallari, Cristina

2012-01-01

The following bases: monoethylamine (EtA), diethylamine (DEtA), triethylamine (TEtA), monoethanolamine (MEA), diethanolamine (DEA), triethanolamine (TEA), pyrrolidine (Py), piperidine (Pp), morpholine (M), piperazine (Pz) and their N-2-hydroxyethyl (HE) analogs were employed to prepare 14 diclofenac salts. The salts were re-crystallized from water in order to obtain forms that are stable in the presence of water. Vertical Franz-type cells with a diffusional surface area of 9.62 cm2 were used to study the permeation of these diclofenac salts from their saturated solutions through an internal pig ear membrane. The receptor compartments of the cells contained 100 mL of phosphate buffer (pH 7.4); a saturated solution (5 mL) of each salt was placed in the donor compartment, thermostated at 37 °C. Aliquots were withdrawn at predetermined time intervals over 8 h and then immediately analyzed by HPLC. Fluxes were determined by plotting the permeated amount, normalized for the membrane surface area versus time. Permeation coefficients were obtained dividing the flux values J by the concentration of the releasing phase—that is, water solubility of each salt. Experimental results show that fluxes could be measured when diclofenac salts with aliphatic amines are released from a saturated aqueous solution. Different chemical species (acid, anion, ion pairs) contribute to permeation of the anti-inflammatory agent even though ion-pairs could be hypothesized to operate to a greater extent. Permeation coefficients were found higher when the counterion contains a ring; while hydroxy groups alone do not appear to play an important role, the ring could sustain permeation, disrupting the organized domains of the membrane. PMID:24300300

Trace and ultratrace determination of heavy metal ions by energy-dispersive X-ray fluorescence spectrometry using graphene as solid sorbent in dispersive micro solid-phase extraction

Energy Technology Data Exchange (ETDEWEB)

Kocot, Karina; Sitko, Rafal, E-mail: rafal.sitko@us.edu.pl

2014-04-01

In this paper, the adsorptive properties of graphene nanosheets were used for simultaneous preconcentration of cobalt, nickel, copper and lead ions from water samples. The developed methodology is based on dispersive micro-solid phase extraction (DMSPE) which is miniaturized and a simplified version of classical solid phase extraction technique. In proposed procedure only 200 μL of suspension containing graphene (0.2 mg), ammonium pyrrolidine dithiocarbamate (APDC) (0.8 mg) and Triton-X-100 (0.1 mg) is rapidly injected to 50 mL of water sample. Then, graphene nanosheets with adsorbed metal-APDC chelates are collected on membrane filter and measured using energy-dispersive X-ray fluorescence (EDXRF) spectrometry. The various parameters including pH, amount of APDC, sample volume, amount of Triton-X-100 and sorption time were optimized in order to obtain the best recoveries. The experiment shows that Co, Ni, Cu and Pb can be simultaneously preconcentrated at pH of 5 with high recoveries (97%, 96%, 99% and 96% for Co, Ni, Cu and Pb, respectively) and very good precision (RSDs within 2.6–3.4%). Due to the excellent enrichment factors ranging from 400 to 2500 the proposed DMSPE–EDXRF procedure offers low detection limits. For optimized measurement conditions (voltage and current of X-ray tube, primary beam filter) the detection limits are even 0.08, 0.07, 0.08 and 0.20 ng mL{sup −1} for Co, Ni, Cu and Pb, respectively. - Highlights: • Excellent detection limits using EDXRF • A new preconcentration procedure combining DMSPE and EDXRF measurement • Graphene as a promising and efficient solid sorbent in DMSPE • Simple, fast, inexpensive and environmental friendly method.

Structures of the Class D Carbapenemase OXA-24 from Acinetobacter baumannii in Complex with Doripenem

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Schneider, Kyle D.; Ortega, Caleb J.; Renck, Nicholas A.; Bonomo, Robert A.; Powers, Rachel A.; Leonard, David A. (Case Western); (Grand Valley)

2012-02-08

The emergence of class D {beta}-lactamases with carbapenemase activity presents an enormous challenge to health practitioners, particularly with regard to the treatment of infections caused by Gram-negative pathogens such as Acinetobacter baumannii. Unfortunately, class D {beta}-lactamases with carbapenemase activity are resistant to {beta}-lactamase inhibitors. To better understand the details of the how these enzymes bind and hydrolyze carbapenems, we have determined the structures of two deacylation-deficient variants (K84D and V130D) of the class D carbapenemase OXA-24 with doripenem bound as a covalent acyl-enzyme intermediate. Doripenem adopts essentially the same configuration in both OXA-24 variant structures, but varies significantly when compared to the non-carbapenemase class D member OXA-1/doripenem complex. The alcohol of the 6a hydroxyethyl moiety is directed away from the general base carboxy-K84, with implications for activation of the deacylating water. The tunnel formed by the Y112/M223 bridge in the apo form of OXA-24 is largely unchanged by the binding of doripenem. The presence of this bridge, however, causes the distal pyrrolidine/sulfonamide group to bind in a drastically different conformation compared to doripenem bound to OXA-1. The resulting difference in the position of the side-chain bridge sulfur of doripenem is consistent with the hypothesis that the tautomeric state of the pyrroline ring contributes to the different carbapenem hydrolysis rates of OXA-1 and OXA-24. These findings represent a snapshot of a key step in the catalytic mechanism of an important class D enzyme, and might be useful for the design of novel inhibitors.

In vitro antiproliferative effect of fractions from the caribbean marine sponge Myrmekioderma gyroderma

Directory of Open Access Journals (Sweden)

Diana Márquez Fernández

Full Text Available Introduction: studies performed to Myrmekioderma genus sponges show phospholipid fatty acids, volatile compounds, sterols, bioactive cyclic diterpenes, sesquiterpenes, lineal diterpenes and glycolipid ethers. Objetive: to evaluate the antiproliferative effect of seven fractions (F1-F7 obtained by flash column chromatography from the most bioactive extract of the sponge Myrmekioderma gyroderma, and to analyze the chemical composition of the most active fraction. Methods: samples of dried sponge were extracted with two different solvents: CH2Cl2 (2 x 50 mL, and CH3OH (2 x 50 mL. Each fraction was evaluated on tumor cell derived cell lines; and the cell growth, and viability were determined by a colorimeter assay using sulforhodamine B. Fatty acids structure of the most active fraction was possible by GC-MS analysis of the methyl ester, and pyrrolidine derivatives. Results: the fraction with higher activity on the assessed tumor cell lines is F4 due to it totally inhibited MDA-MB-231, and HT29 cell line growth to 5, and 25 µg/mL concentration (IC50< 1 µg/mL. Fatty acids identified in bioactive F4 fraction of the M. gyroderma sponge can be classified on the following groups: lineal chain saturated, branched-saturated, unsaturated, and a 3-hydroxy acid. Conclusions: 43 fatty acids among saturated, branched-saturated, and unsaturated were identified out of the F4 fraction with activity on the cell lines derived of breast cancer MDA-MB-231, colon carcinoma HT29, and lung carcinoma cells A-549. These results show the growth inhibitory effect shown by the fractions, on the tumor cell lines, depends on the dose.

Isentropic compressibilities of (amide + water) mixtures: A comparative study

International Nuclear Information System (INIS)

Papamatthaiakis, Dimitris; Aroni, Fryni; Havredaki, Vasiliki

2008-01-01

The density and ultrasonic velocity of aqueous solutions of formamide (FA), N-methylformamide (NMF), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), pyrrolidin-2-one (PYR), N-methyl-2-pyrrolidinone (NMP), and their pure phases have been measured at 298.15 K and atmospheric pressure. Densities and ultrasonic velocities in pure amides have been also measured at the temperature range 288.15 K to 308.15 K for the computation of their thermal expansivities. Isentropic compressibility, intermolecular free length, relative association, apparent molar compressibility, as well as the excess quantities, ultrasonic velocity, isentropic compressibility, intermolecular free length, have been evaluated and fitted to the Redlich-Kister type equation. The deviation from ideal mixing law in ultrasonic velocity is positive while the deviations in isentropic compressibility and intermolecular free length are negative for all (amide + water) mixtures. This behavior reveals the nature and the magnitude of intermolecular interactions between the amide-water molecules. The sequence of superimposed curves of various ultrasonic parameters vs. the amide mole fraction is related to the strength of interactions between the unlike molecules and the role of -CH 3 substitution in amides. The comparison of ultrasonic to volumetric properties reveals differences on the position of the extrema and their relation with the degree of substitution while the interpretation of these differences is discussed. Two different approaches on the computation of excess functions, applied in this work, brought out a difference in the magnitude of deviations and a partial reversion to the sequence of amides curves suggesting a different estimation in terms of deviations from ideal mixing law and therefore of the relative molecular interactions

Water analysis in Londrina, PR, using a portable EDXRF system

International Nuclear Information System (INIS)

Melquiades, Fabio L.; Silva, Wislley D.; Parreira, Paulo S.; Lopes, Fabio; Appoloni, Carlos R.

2009-01-01

The use of Energy Dispersive X-Ray Fluorescence (EDXRF) for analysis of environmental samples has gained expressive attention in the last years. With the objective of identification and quantification of heavy metals in water, EDXRF methodology with portable equipment was employed. The work consisted on the use of a portable EDXRF system constituted by a X-ray tube to excite the samples, a Si-Pin detector, a holder for the excitation-detection system and samples positioning, with the standard data acquisition electronics to register the spectra. The samples were filtered in ester cellulose membranes for suspended particulate matter retention. After this, Ammonium Pyrrolidine Dithiocarbamate (APDC) precipitation methodology was applied for sample preconcentration with posterior filtering in membranes. So, the dissolved and non dissolved metal fractions were determined separately. The detection limits were, in mg L -1 : 0.006 (Fe), 0.015 (Co), 0.004 (Cu), 0.002 (Zn), 0.004 (Se) and 0.005 (Pb), with 5% deviations for 95% of confidence. Considering all the sampling locations, it was possible to quantify the following range of concentrations, in mg L -1 : Ca (0.043 - 0.021), Ti (0.137 - 0.014), Mn (0.052 - 0.008), Fe (1.66 - 0.035), Ni (0.012 - 0.010), Cu (0.010 - 0.007), Zn (0.070 - 0.007) and Pb (0.85 - 1.01). The results presented relative deviation from 5% to 22%, within 95% of confidence level, which is considered very satisfactory when using portable equipment. In 4 h of field work it was possible to filter 14 membranes and measure around 16 samples. (author)

Activation of AMPA receptor promotes TNF-α release via the ROS-cSrc-NFκB signaling cascade in RAW264.7 macrophages

Energy Technology Data Exchange (ETDEWEB)

Cheng, Xiu-Li [Department of Physiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing (China); Ding, Fan [Office of Scientific R& D, Tsinghua University, Beijing (China); Li, Hui; Tan, Xiao-Qiu [Department of Physiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing (China); Liu, Xiao [Department of Pathophysiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing (China); Cao, Ji-Min, E-mail: caojimin@126.com [Department of Physiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing (China); Gao, Xue, E-mail: longlongnose@163.com [Department of Pathophysiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing (China)

2015-05-29

The relationship between glutamate signaling and inflammation has not been well defined. This study aimed to investigate the role of AMPA receptor (AMPAR) in the expression and release of tumor necrosis factor-alpha (TNF-α) from macrophages and the underlying mechanisms. A series of approaches, including confocal microscopy, immunofluorescency, flow cytometry, ELISA and Western blotting, were used to estimate the expression of AMPAR and downstream signaling molecules, TNF-α release and reactive oxygen species (ROS) generation in the macrophage-like RAW264.7 cells. The results demonstrated that AMPAR was expressed in RAW264.7 cells. AMPA significantly enhanced TNF-α release from RAW264.7 cells, and this effect was abolished by CNQX (AMPAR antagonist). AMPA also induced elevation of ROS production, phosphorylation of c-Src and activation of nuclear factor (NF)-κB in RAW264.7 cells. Blocking c-Src by PP2, scavenging ROS by glutathione (GSH) or inhibiting NF-κB activation by pyrrolidine dithiocarbamate (PDTC) decreased TNF-α production from RAW264.7 cells. We concluded that AMPA promotes TNF-α release in RAW264.7 macrophages likely through the following signaling cascade: AMPAR activation → ROS generation → c-Src phosphorylation → NF-κB activation → TNF-α elevation. The study suggests that AMPAR may participate in macrophage activation and inflammation. - Highlights: • AMPAR is expressed in RAW264.7 macrophages and is upregulated by AMPA stimulation. • Activation of AMPAR stimulates TNF-α release in macrophages through the ROS-cSrc-NFκB signaling cascade. • Macrophage AMPAR signaling may play an important role in inflammation.

Studies on the metabolism of the α-pyrrolidinophenone designer drug methylenedioxy-pyrovalerone (MDPV) in rat and human urine and human liver microsomes using GC-MS and LC-high-resolution MS and its detectability in urine by GC-MS.

Science.gov (United States)

Meyer, Markus R; Du, Peng; Schuster, Frank; Maurer, Hans H

2010-12-01

Since the late 1990s, many derivatives of the α-pyrrolidinophenone (PPP) drug class appeared on the drugs of abuse market. The latest compound was described in 2009 to be a classic PPP carrying a methylenedioxy moiety remembering the classic entactogens (ecstasy). Besides Germany, 3,4-methylene-dioxypyrovalerone (MDPV) has appeared in many countries in Europe and Asia, indicating its worldwide importance for forensic and clinical toxicology. The aim of the presented work was to identify the phase I and II metabolites of MDPV and the human cytochrome-P450 (CYP) isoenzymes responsible for its main metabolic step(s). Finally, the detectability of MDPV in urine by the authors' systematic toxicological analysis (STA) should be studied. The urine samples were extracted after and without enzymatic cleavage of conjugates. The metabolites were separated and identified after work-up by GC-MS and liquid chromatography (LC)-high-resolution MS (LC-HR-MS). The studies revealed the following phase I main metabolic steps in rat and human: demethylenation followed by methylation, aromatic and side chain hydroxylation and oxidation of the pyrrolidine ring to the corresponding lactam as well as ring opening to the corresponding carboxylic acid. Using LC-HR-MS, most metabolite structures postulated according to GC-MS fragmentation could be confirmed and the phase II metabolites were identified. Finally, the formation of the initial metabolite demethylenyl-MDPV could be confirmed using incubation of human liver microsomes. Using recombinant human CYPs, CYP 2C19, CYP 2D6 and CYP 1A2 were found to catalyze this initial step. Finally, the STA allowed the detection of MDPV metabolites in the human urine samples. Copyright © 2010 John Wiley & Sons, Ltd.

Inhibition of NF-κB promotes autophagy via JNK signaling pathway in porcine granulosa cells

Energy Technology Data Exchange (ETDEWEB)

Gao, Hui; Lin, Lu; Haq, Ihtesham Ul; Zeng, Shen-ming, E-mail: zengshenming@gmail.com

2016-04-22

The transcription factor nuclear factor-κB (NF-κB) plays an important role in diverse processes, including cell proliferation and differentiation, apoptosis and inflammation. However, the role of NF-κB in porcine follicle development is not clearly elucidated. In this study, we demonstrated that follicle stimulating hormone (FSH) increased the level of inhibitor of NF-κB (IκB) protein and promoted the cytoplasmic localization of p65, indicating that FSH inhibits the activation of NF-κB in porcine granulosa cells. Moreover, inhibition of NF-κB by FSH or another specific inhibitor of NF-κB, pyrrolidine dithiocarbamate (PDTC), could activate JNK signaling and enhance autophagic activity in porcine granulosa cells. Knockdown of RelA (p65) Subunit of NF-κB by RNA interference abrogated the activation of JNK signaling pathway and the increase of autophagic protein expression by FSH. Meanwhile, the functional significance of FSH or PDTC-mediated autophagy were further investigated. Our results demonstrated that the increased autophagy promoted progesterone secretion in porcine granulosa cells. Blockage of autophagy by chloroquine obviated the FSH or PDTC-induced progesterone production. Taken together, these results indicate that inhibition of NF-κB increased autophagy via JNK signaling, and promote steroidogenesis in porcine granulosa cells. Our results provide new insights into the regulation and function of autophagy in mammalian follicle development. - Highlights: • FSH inhibits the activation of NF-κB in porcine primary granulosa cells. • Inhibition of NF-κB by FSH promotes autophagy via JNK signaling in granulosa cells. • Increased autophagy contributes to progesterone production in granulosa cells. • This is the first report against beclin1 regulation in porcine granulosa cells.

Synthesis, physical-chemical and biological properties of 1,8-disubstituted compounds of theobromine. III. 8-Amino-p-chlorobenzyltheobromines

Directory of Open Access Journals (Sweden)

D. G. Ivanchenko

2014-08-01

Full Text Available Introduction. This work is a follow-up to a series of research activities dedicated to the search of biologically active compounds among the xanthine derivatives. Aim of the Work.Development of simple laboratory-based methods for 8-amino-1-p-chlorobenzyltheobromines synthesis and the study of antioxidant, antimicrobial and antifungal effect of the synthesized compounds. Materials and Methods of Research.The melting point has been determined with the help of an open capillary method with TAP device (M. Elemental analysis has been performed with the helpof the instrument ElementarVario L cube, NMR-spectra have been taken on a spectrometer Bruker SF-400 (operating frequency of 400 MHz, solvent DMSO-d6 or DMSO-d6 + CDCl3, internal standard – TMS. These data correspond to thecalculated elemental analysis. The synthesis of 8-aminosubstituted 1-p-chlorobenzyltheobromine (2,3.Mixture 0.01 mole of8-bromo-1-p-chlorobenzyltheobromine (1, 0.03 mole of pyrrolidine (2 or piperidine (3, 40 ml of cellosolve is boiled during 4 hours, then it is allowed to steam out dry in a vacuum. Dry residue is processed with water, then residual matter which has been formed is filtered out, washed with water and recrystallized from the aqueous ethanol. The synthesis of 8-amino-1-p-chlorobenzyltheobromines (4-7. Mixture 0.01 mole of initial compound (1, 0.03 mole of the respective amine and 40 ml of cellosolve is boiled during 4 hours, thenit is allowed to cool down and is diluted with water. After this, residual matter which has been formed is filtered out, washed with water and aqueous propanol-2 and recrystallized from the water ethanol. Molecular descriptors have been calculated using the computer programs ALOGPS and DRAGON, whereas biological properties of the synthesized compounds have been calculated with the help of GUSAR and ACD / Percepta Platform. Antioxidant activity (AOA has been studied in vitro applying the method of nonenzymic initiation of free

Solid-phase extraction with slurry injection of the resin into ETAAS for trace determination of thallium in natural water

International Nuclear Information System (INIS)

Isoshi, Nukatsuka; Hiroyuki, Seitoh; Kunio, Ohzeki

2004-01-01

Thallium in natural water samples was determined by electrothermal atomic absorption spectrometry after 1000-fold enrichment by mini solid-phase extraction from a 100-mL sample solution. A TI-pyrrolidine-1-carbodithioate complex formed in a sample solution of pH 1.6 was extracted on fine particles of a cellulose nitrate resin dispersed in the sample solution. The cellulose nitrate resin was then collected on a membrane filter (25 mm ) by filtration under suction using a glass funnel with an effective filtration area of 0.64 cm 2 . As a result, a circular thin layer of the resin phase with a diameter of 9 mm was obtained. Then the resin phase was carved out by an acrylate resin puncher with a 10-mm hole to put it into a sample cup containing 100 μL of 10 mM HNO 3 containing 0.5 mM NaCl. The resin phase was suspended in the solution by ultrasonication. 1000-fold enrichment was thus attained within 15 min, and the suspension was delivered to electrothermal atomic absorption spectrometry. The linear calibration graph was obtained in the range of 0-4 ng of TI in 100 mL of a sample solution. The detection limit obtained by 3 σ method was 0.19 ng. The proposed method was applied to the determination of TI in natural water samples. The results showed the concentration of TI in seawater was 12.1 ± 1.8 pg mL -1 for the calibration graph method and 12.6 ± 1.4 pg mL -1 for the standard addition method. A snowmelt sample contained 20.7 ± 1.0 pg mL -1 of TI. (author)

Characterization of prejunctional serotonin receptors modulating [3H]acetylcholine release in the human detrusor.

Science.gov (United States)

D'Agostino, Gianluigi; Condino, Anna M; Gallinari, Paola; Franceschetti, Gian P; Tonini, Marcello

2006-01-01

Bladder overactivity (OAB) is a chronic and debilitating lower urinary tract (LUT) disorder that affects millions of individuals worldwide. LUT symptoms associated with OAB, such as urgency and urinary incontinence, cause a hygienic and social concern to patients, but their current pharmacological treatment is largely inadequate due to the lack of uroselectivity. Although OAB etiology remains multifactorial and poorly understood, increasing evidence indicates that serotonin [5-hydroxytryptamine (5-HT)] is an endogenous substance involved in the control of micturition at central and peripheral sites. In this study, we demonstrated the presence of three distinct 5-HT receptors localized at parasympathetic nerve terminals of the human bladder by measuring electrically evoked tritiated acetylcholine release in isolated detrusor strips. These prejunctional receptors, involved in both positive and negative feedback mechanisms regulating cholinergic transmission, have been characterized by means of three highly selective 5-HT antagonists for 5-HT(4), 5-HT(7), and 5-HT(1A) receptors, namely GR113808A ([1-[2-[(-methylsulphonyl) amino] ethyl]4-piperinidyl]methyl1-methyl-1H-indole-3-carboxylate succinate), SB269970 [(R)-3-(2-(2-(4-methylpiperidin-1-yl)ethyl)pyrrolidine-1-sulfonyl)phenol hydrochloride], and WAY100635 [N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridyl)-cyclohexane-carboxamide trichloride]. Under these conditions, we confirmed the facilitatory role of 5-HT(4) heteroreceptors on acetylcholine release and revealed for the first time the occurrence of 5-HT(7) and 5-HT(1A) heteroreceptors with a facilitatory and an inhibitory action, respectively. Our findings strengthen the novel concept for the use of recently patented selective 5-HT agonists and antagonists for the control of OAB dysfunctions associated with inflammatory conditions, although their therapeutic efficacy needs to be explored in the clinical setting.

Quantitative chemical analysis of lead in canned chillis by spectrophotometric and nuclear techniques

International Nuclear Information System (INIS)

Sanchez Paz, L.A.

1991-01-01

The objectives of this work are the quantification of lead contents in two types of canned chilli of three trademarks, determining its inside of maximum permissible level (2 ppm), comparing moreover two trademarks that have flask and canned presentation for to determine the filling effect in the final content of lead, moreover make a comparative study of the techniques using on base to exactitude, linearity and sensibility. The techniques used were atomic absorption spectrophotometry, plasma emission spectrometry and x-ray fluorescence. The preliminary treatment of the samples was by calcination, continued of the ashes dissolution in acid medium, for later gauge a determinate volume for analyze by atomic absorption and plasma emission. For the analysis by x-ray fluorescence, after solubilyzing ashes, its precipitate the lead with PCDA (Pyrrolidine carbodithioic ammonium acid) then its filtered, filter paper is dried and counted directly. The standards preparation is made following the same procedure as in samples using lead titrisol solution. For each technique the recovery percent is determined by the addition of enough know amount. For each technique calibration curves are plotted been determined that the three are lineal in the established range of work. The recovery percent in three cases is superior to ninety five percent. By means of a variance analysis it was determined that lead contain in samples do not exceed two ppm., and the lead content in canned chillis is superior to contained in glass containers (1.7, 0.4 ppm respectively). X-ray fluorescence analysis is different to the attained results by the other two techniques due to its sensibility is less. The most advisable techniques for this kind of analysis are atomic absorption spectrophotometry and plasma emission. (Author)

HPLC detection of loss rate and cell migration of HUVECs in a proanthocyanidin cross-linked recombinant human collagen-peptide (RHC)–chitosan scaffold

Energy Technology Data Exchange (ETDEWEB)

Zhang, Jing; Deng, Aipeng [School of Environmental and Biological Engineering, Nanjing University of Science and Technology, Nanjing 210094 (China); Yang, Yang [Faculty of Engineering, University of Nottingham, Nottingham NG7 2RD (United Kingdom); Gao, Lihu; Xu, Na; Liu, Xin; Hu, Lunxiang; Chen, Junhua [School of Environmental and Biological Engineering, Nanjing University of Science and Technology, Nanjing 210094 (China); Yang, Shulin, E-mail: yshulin@njust.edu.cn [School of Environmental and Biological Engineering, Nanjing University of Science and Technology, Nanjing 210094 (China)

2015-11-01

Porous scaffolds with appropriate pore structure, biocompatibility, mechanical property and processability play an important role in tissue engineering. In this paper, we fabricated a recombinant human collagen-peptide (RHC)–chitosan scaffold cross-linked by premixing 30% proanthocyanidin (PA) in one-step freeze-drying. To remove the residual acetic acid, optimized 0.2 M phosphate buffer of pH 6.24 with 30% ethanol (PBSE) was selected to neutralize the lyophilized scaffold followed by three times deionized water rinse. Ninhydrin assay was used to characterize the components loss during the fabrication process. To detect the exact RHC loss under optimized neutralization condition, high performance liquid chromatography (HPLC) equipped size exclusion chromatography column was used and the total RHC loss rate through PBSE rinse was 19.5 ± 5.08%. Fourier transform infrared spectroscopy (FT-IR) indicated hydrogen bonding among RHC, chitosan and PA, it also presented a probative but not strong hydrophobic interaction between phenyl rings of polyphenols and pyrrolidine rings of proline in RHC. Further, human umbilical vein endothelial cell (HUVEC) viability analyzed by a scanning electron microscope (SEM) and acridine orange/ethidium bromide (AO/EB) fluorescence staining exhibited that this scaffold could not only promote cell proliferation on scaffold surface but also permit cells migration into the scaffold. qRT-PCR exhibited that the optimized scaffold could stimulate angiogenesis associated genes VEGF and CD31 expression. These characterizations indicated that this scaffold can be considered as an ideal candidate for tissue engineering. - Highlights: • PA cross-linked recombinant human collagen–chitosan scaffold. • Fabrication in one-step lyophilization with neutralization. • HPLC detection of RHC loss rate • HUVEC proliferation and migration in scaffold • Angiogenesis associated gene expressions were increased in scaffold cell culturing.

Randomized phase I trial HIV-CORE 003: Depletion of serum amyloid P component and immunogenicity of DNA vaccination against HIV-1.

Science.gov (United States)

Borthwick, Nicola J; Lane, Thirusha; Moyo, Nathifa; Crook, Alison; Shim, Jung Min; Baines, Ian; Wee, Edmund G; Hawkins, Philip N; Gillmore, Julian D; Hanke, Tomáš; Pepys, Mark B

2018-01-01

The failure of DNA vaccination in humans, in contrast to its efficacy in some species, is unexplained. Observational and interventional experimental evidence suggests that DNA immunogenicity may be prevented by binding of human serum amyloid P component (SAP). SAP is the single normal DNA binding protein in human plasma. The drug (R)-1-[6-[(R)-2-carboxypyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid (CPHPC, miridesap), developed for treatment of systemic amyloidosis and Alzheimer's disease, depletes circulating SAP by 95-99%. The proof-of-concept HIV-CORE 003 clinical trial tested whether SAP depletion by CPHPC would enhance the immune response in human volunteers to DNA vaccination delivering the HIVconsv immunogen derived from conserved sub-protein regions of HIV-1. Human volunteers received 3 intramuscular immunizations with an experimental DNA vaccine (DDD) expressing HIV-1-derived immunogen HIVconsv, with or without prior depletion of SAP by CPHPC. All subjects were subsequently boosted by simian (chimpanzee) adenovirus (C)- and poxvirus MVA (M)-vectored vaccines delivering the same immunogen. After administration of each vaccine modality, the peak total magnitudes, kinetics, functionality and memory subsets of the T-cell responses to HIVconsv were thoroughly characterized. No differences were observed between the CPHPC treated and control groups in any of the multiple quantitative and qualitative parameters of the T-cell responses to HIVconsv, except that after SAP depletion, there was a statistically significantly greater breadth of T-cell specificities, that is the number of recognized epitopes, following the DDDC vaccination. The protocol used here for SAP depletion by CPHPC prior to DNA vaccination produced only a very modest suggestion of enhanced immunogenicity. Further studies will be required to determine whether SAP depletion might have a practical value in DNA vaccination for other plasmid backbones and/or immunogens. Clinicaltrials

Acidic pH stimulates the production of the angiogenic CXC chemokine, CXCL8 (interleukin-8), in human adult mesenchymal stem cells via the extracellular signal-regulated kinase, p38 mitogen-activated protein kinase, and NF-kappaB pathways.

Science.gov (United States)

Bischoff, David S; Zhu, Jian-Hua; Makhijani, Nalini S; Yamaguchi, Dean T

2008-07-01

Blood vessel injury results in limited oxygen tension and diffusion leading to hypoxia, increased anaerobic metabolism, and elevated production of acidic metabolites that cannot be easily removed due to the reduced blood flow. Therefore, an acidic extracellular pH occurs in the local microenvironment of disrupted bone. The potential role of acidic pH and glu-leu-arg (ELR(+)) CXC chemokines in early events in bone repair was studied in human mesenchymal stem cells (hMSCs) treated with medium of decreasing pH (7.4, 7.0, 6.7, and 6.4). The cells showed a reciprocal increase in CXCL8 (interleukin-8, IL-8) mRNA levels as extracellular pH decreased. At pH 6.4, CXCL8 mRNA was induced >60x in comparison to levels at pH 7.4. hMSCs treated with osteogenic medium (OGM) also showed an increase in CXCL8 mRNA with decreasing pH; although, at a lower level than that seen in cells grown in non-OGM. CXCL8 protein was secreted into the medium at all pHs with maximal induction at pH 6.7. Inhibition of the G-protein-coupled receptor alpha, G(alphai), suppressed CXCL8 levels in response to acidic pH; whereas phospholipase C inhibition had no effect on CXCL8. The use of specific mitogen-activated protein kinase (MAPK) signal transduction inhibitors indicated that the pH-dependent increase in CXCL8 mRNA is due to activation of ERK and p38 pathways. The JNK pathway was not involved. NF-kappaB inhibition resulted in a decrease in CXCL8 levels in hMSCs grown in non-OGM. However, OGM-differentiated hMSCs showed an increase in CXCL8 levels when treated with the NF-kappaB inhibitor PDTC, a pyrrolidine derivative of dithiocarbamate. 2008 Wiley-Liss, Inc.

Centrally Acting Oximes in Reactivation of Tabun-Phosphoramidated AChE

Science.gov (United States)

Kovarik, Zrinka; Maček, Nikolina; Sit, Rakesh K.; Radić, Zoran; Fokin, Valery V.; Sharpless, K. Barry; Taylor, Palmer

2012-01-01

Organophosphates (OP) inhibit acetylcholinesterase (AChE, E.C.3.1.1.7), both in peripheral tissues and central nervous system (CNS), causing adverse and sometimes fatal effects due to the accumulation of neurotransmitter acetylcholine (ACh). The currently used therapy, focusing on the reactivation of inhibited AChE, is limited to peripheral tissues because commonly used quaternary pyridinium oxime reactivators do not cross the blood brain barrier (BBB) at therapeutically relevant levels. A directed library of thirty uncharged oximes that contain tertiary amine or imidazole protonable functional groups that should cross the BBB as unionized species was tested as tabun-hAChE conjugate reactivators along with three reference oximes: DAM (diacetylmonoxime), MINA (monoisonitrosoacetone), and 2-PAM. The oxime RS150D [N-((1-(3-(2-((hydroxyimino)methyl)-1H-imidazol-1-yl)propyl)-1H-1,2,3-triazol-4-yl)methyl)benzamide] was highlighted as the most promising reactivator of the tabun-hAChE conjugate. We also observed that oximes RS194B [N-(2-(azepan-1-yl)ethyl)-2-(hydroxyimino)acetamide] and RS41A [2-(hydroxyimino)-N-(2-(pyrrolidin-1-yl)ethyl)acetamide], which emerged as lead uncharged reactivators of phosphylated hAChE with other OPs (sarin, cyclosarin and VX), exhibited only moderate reactivation potency for tabun inhibited hAChE. This implies that geometry of oxime access to the phosphorus atom conjugated to the active serine is an important criterion for efficient reactivation, along with the chemical nature of the conjugated moiety: phosphorate, phosphonate, or phosphoramidate. Moreover, modification of the active center through mutagenesis enhances the rates of reactivation. The phosphoramidated-hAChE choline-binding site mutant Y337A showed three-times enhanced reactivation capacity with non-triazole imidazole containing aldoximes (RS113B, RS113A and RS115A) and acetamide derivative (RS194B) than with 2PAM. PMID:22960624

Effect of nuclear factor kappa B on intercellular adhesion molecule-1 expression and neutrophil infiltration in lung injury induced by intestinal ischemia/reperfusion in rats

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Tian, Xiao-Feng; Yao, Ji-Hong; Li, Ying-Hua; Zhang, Xue-Song; Feng, Bing-An; Yang, Chun-Ming; Zheng, Shu-Sen

2006-01-01

AIM: To investigate the role of nuclear factor kappa B (NF-κB) in the pathogenesis of lung injury induced by intestinal ischemia/reperfusion (I/R), and its effect on intercellular adhesion molecule-1 (ICAM-1) expression and neutrophil infiltration. METHODS: Twenty-four Wistar rats were divided randomly into control, I/R and pyrrolidine dithiocarbamate (PDTC) treatment groups, n = 8 in each. I/R group and PDTC treatment group received superior mysenteric artery (SMA) occluding for 1 h and reperfusion for 2 h. PDTC group was administrated with intraperitoneal injection of 2% 100 mg/kg PDTC 1 h before surgery. Lung histology and bronchia alveolus lung fluid (BALF) protein were assayed. Serum IL-6, lung malondialdehyde (MDA) and myeloperoxidase (MPO) as well as the expression level of NF-κB and ICAM-1 were measured. RESULTS: Lung injury induced by intestinal I/R, was characterized by edema, hemorrhage and neutrophil infiltration as well as by the significant rising of BALF protein. Compared to control group, the levels of serum IL-6 and lung MDA and MPO increased significantly in I/R group (P = 0.001). Strong positive expression of NF-κB p65 and ICAM-1 was observed. After the administration of PDTC, the level of serum IL-6, lung MDA and MPO as well as NF-κB and ICAM-1 decreased significantly (P < 0.05) when compared to I/R group. CONCLUSION: The activation of NF-κB plays an important role in the pathogenesis of lung injury induced by intestinal I/R through upregulating the neutrophil infiltration and lung ICAM-1 expression. PDTC as an inhibitor of NF-κB can prevent lung injury induced by intestinal I/R through inhibiting the activity of NF-κB. PMID:16489637

Studies on the microbial biotransformation of the novel psychoactive substance methylenedioxypyrovalerone (MDPV) in wastewater by means of liquid chromatography-high resolution mass spectrometry/mass spectrometry.

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Mardal, Marie; Meyer, Markus R

2014-09-15

Sewage profiling as a mean to estimate consumption of drugs of abuse is gaining increasing attention. However, only scarce data are available so far on the impact of microbial biotransformation on the presence and hence detectability of drugs of abuse and their metabolites in wastewater (WW) samples. The aim of this work was therefore to study the biotransformation pathways of the novel psychoactive substance 3,4-methylenedioxypyrovalerone (MPDV) in WW by incubating it, based on the OECD guideline 314 A. MDPV was incubated (100 μg/L) for 10d at 22 °C in WW from a local WW treatment plant. Furthermore, urine and feces collected from rats administered 20mg MDPV/kg BW were incubated correspondingly. Samples were worked-up either by centrifugation/filtration and solid-phase (HCX) extraction or QuEChERS. High resolution (HR) mass spectra (MS) were recorded using an Orbitrap mass spectrometer. All products were identified via their HR-MS(2) spectra and chromatographic properties. The observed biotransformations in WW were: demethylenation and subsequent O-methylation, hydroxylation at the phenyl part, hydroxylation at the pyrrolidine part with subsequent methylation or oxidation, N-demethylation, and hydroxylation at the alkyl part as well as combination of them. In total, 12 biotransformation products were identified after 10 days of incubation. Three of these biotransformation products were previously reported to be also rat and human metabolites. No additional MDPV biotransformation products could be found after incubating the rat urine and feces samples. Instead, the urinary phase II glucuronides were nearly completely cleaved after one day of WW incubation. The presented study indicates that demethylenyl-methyl MDPV, the most abundant metabolite in human urine, should be the best indicator in WW to estimate its use. Copyright © 2014 Elsevier B.V. All rights reserved.

Synthesis, crystal structure, DFT studies, acid dissociation constant, and antimicrobial activity of methyl 2-(4-chlorophenyl)-7a-((4-chlorophenyl)carbamothioyl)-1-oxo-5,5-diphenyl-3-thioxo-hexahydro-1H-pyrrolo[1,2-e]imidazole-6-carboxylate

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Nural, Yahya; Gemili, Muge; Seferoglu, Nurgul; Sahin, Ertan; Ulger, Mahmut; Sari, Hayati

2018-05-01

A novel bicyclic thiohydantoin fused to pyrrolidine compound, methyl 2-(4-chlorophenyl)-7a-((4-chlorophenyl)carbamothioyl)-1-oxo-5,5-diphenyl-3-thioxo-hexahydro-1H-pyrrolo[1,2-e]imidazole-6-carboxylate, was synthesized by the cyclization reaction of dimethyl 5,5-diphenylpyrrolidine-2,4-dicarboxylate and 4-chlorophenyl isothiocyanate in the presence of 4-(dimethylamino)pyridine to form methyl 2-(4-chlorophenyl)-1-oxo-5,5-diphenyl-3-thioxo-hexahydro-1H-pyrrolo[1,2-e]imidazole-6-carboxylate with concomitant addition reaction of the 4-chlorophenyl isothiocyanate in 79% yield. The structural characterization was performed by NMR, FT-IR, MS and HRMS techniques, and the stereochemistry of the compound was determined by single crystal X-ray diffraction study. In addition, the molecular structure and 1H and 13C NMR chemical shifts of the compound were obtained with the density functional theory and Hartree-Fock calculations. Acid dissociation constants of the compound were determined using potentiometric titration method in 25% (v/v) dimethyl sulfoxide-water hydroorganic solvent at 25 ± 0.1 °C, at an ionic background of 0.1 mol/L of NaCl using the HYPERQUAD computer program. Four acid dissociation constants were obtained for the compound, and we suggest that these acid dissociation constants are related to the NH, for two groups of enthiols and enol groups. Antimicrobial activity study was performed against S. aureus, B. subtilis, A. hydrophila, E. coli and A. baumannii as bacterial standard strains, and against M. tuberculosis H37Rv as mycobacterial strain. The compound exhibited antibacterial activity in the range of 31.25-62.5 μg/mL, and antimycobacterial activity with a MIC value of 40 μg/mL against the indicated strains.

Correlation of NF-κB signal pathway with tumor metastasis of human head and neck squamous cell carcinoma

International Nuclear Information System (INIS)

Yan, Ming; Xu, Qin; Zhang, Ping; Zhou, Xiao-jian; Zhang, Zhi-yuan; Chen, Wan-tao

2010-01-01

Nuclear factor-kappa B (NF-κB) signaling constitutes a key event in the multistep process of carcinogenesis, progression and treatment in many cancer types. However, the significance of NF-κB pathway for complex and tissue-specific aspects of head and neck cancer progression, such as invasion and metastasis, is less understood. The expression of NF-κB p65 in squamous cell carcinoma of the head and neck (SCCHN) clinical specimens by immunohistochemistry. The role of NF-κB activity in head and neck squamous cell carcinoma was determined by western blot, reporter assay and EMSA analysis in vitro and metastasis assays in vivo in different metastatic potential tumor cells. Furthermore, the apoptosis rate and expression of metastasis-related protein such as MMP9 and VEGF were examined by Annexin V/PI staining and Western blot, respectively. A higher level of active nuclear-localized NF-κB was observed in the metastatic SCCHN specimens group (p < 0.01). The NF-κB activities of SCCHN cell lines with different metastatic potentials were then determined and in excellent agreement with results found in SCCHN specimens, highly metastatic SCCHN cell lines expressed high level of NF-κB activity. The treatment of highly metastatic SCCHN cells with NF-κB inhibitors reduced the in vitro cell invasion capacity of the cells without affecting the apoptotic rate. Additionally, the NF-κB inhibitors significantly inhibited the experimental lung metastasis of Tb cells and lymph node metastasis of TL cells in nude mice. Furthermore, the expression of metastasis-related proteins, such as matrix metalloproteinase 9 and vascular endothelial growth factor, was inhibited by pyrrolidine dithiocarbonate. This study suggests that NF-κB activity significantly contributes to tumor hematologic and lymphatic metastases and may aid in the development of early detection methods or therapies targeting non-conventional molecular targets

Histamine Induces Bovine Rumen Epithelial Cell Inflammatory Response via NF-κB Pathway

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Xudong Sun

2017-06-01

Full Text Available Background/Aims: Subacute ruminal acidosis (SARA is a common disease in high-producing lactating cows. Rumenitis is the initial insult of SARA and is associated with the high concentrations of histamine produced in the rumen of dairy cows during SARA. However, the exact mechanism remains unclear. The objective of the current study is to investigate whether histamine induces inflammation of rumen epithelial cells and the underlying mechanism of this process. Methods: Bovine rumen epithelial cells were cultured and treated with different concentrations of histamine and pyrrolidine dithiocarbamate (PDTC, an NF-κB inhibitor cultured in different pH medium (pH 7.2 or 5.5. qRT-PCR, Western-blotting, ELISA and immunocytofluorescence were used to evaluate whether histamine activated the NF-κB pathway and inflammatory cytokines. Results: The results showed that histamine significantly increased the activity of IKK β and the phosphorylation levels of IκB α, as well as upregulated the mRNA and protein expression levels of NF-κB p65 in the rumen epithelial cells cultured in neutral (pH=7.2 and acidic (pH=5.5 medium. Furthermore, histamine treatment also significantly increased the transcriptional activity of NF-κB p65. High expression and transcriptional activity of NF-κB p65 significantly increased the mRNA expressions and concentrations of inflammatory cytokines, tumor necrosis factor alpha (TNF-α, interleukin 6 (IL-6 and interleukin 1 beta (IL-1β, thereby inducing the inflammatory response in bovine rumen epithelial cells. However, inhibition of NF-κB p65 by PDTC significantly decreased the expressions and concentrations of the inflammatory cytokines induced by histamine in the rumen epithelial cells cultured in the neutral and acidic medium. Conclusion: The present data indicate that histamine induces the inflammatory response of bovine rumen epithelial cells through the NF-κB pathway.

The cognition-enhancing activity of E1R, a novel positive allosteric modulator of sigma-1 receptors

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Zvejniece, L; Vavers, E; Svalbe, B; Vilskersts, R; Domracheva, I; Vorona, M; Veinberg, G; Misane, I; Stonans, I; Kalvinsh, I; Dambrova, M

2014-01-01

Background and Purpose Here, we describe the in vitro and in vivo effects of (4R,5S)-2-(5-methyl-2-oxo-4-phenyl-pyrrolidin-1-yl)-acetamide (E1R), a novel positive allosteric modulator of sigma-1 receptors. Experimental Approach E1R was tested for sigma receptor binding activity in a [3H](+)-pentazocine assay, in bradykinin (BK)-induced intracellular Ca2+ concentration ([Ca2+]i) assays and in an electrically stimulated rat vas deferens model. E1R's effects on cognitive function were tested using passive avoidance (PA) and Y-maze tests in mice. A selective sigma-1 receptor antagonist (NE-100), was used to study the involvement of the sigma-1 receptor in the effects of E1R. The open-field test was used to detect the effects of E1R on locomotion. Key Results Pretreatment with E1R enhanced the selective sigma-1 receptor agonist PRE-084's stimulating effect during a model study employing electrically stimulated rat vasa deferentia and an assay measuring the BK-induced [Ca2+]i increase. Pretreatment with E1R facilitated PA retention in a dose-related manner. Furthermore, E1R alleviated the scopolamine-induced cognitive impairment during the PA and Y-maze tests in mice. The in vivo and in vitro effects of E1R were blocked by treatment with the selective sigma-1 receptor antagonist NE-100. E1R did not affect locomotor activity. Conclusion and Implications E1R is a novel 4,5-disubstituted derivative of piracetam that enhances cognition and demonstrates efficacy against scopolamine-induced cholinergic dysfunction in mice. These effects are attributed to its positive modulatory action on the sigma-1 receptor and this activity may be relevant when developing new drugs for treating cognitive symptoms related to neurodegenerative diseases. PMID:24490863

Differential regulation of iron chelator-induced IL-8 synthesis via MAP kinase and NF-κB in immortalized and malignant oral keratinocytes

International Nuclear Information System (INIS)

Lee, Hwa-Jeong; Lee, Jun; Lee, Sun-Kyung; Lee, Suk-Keun; Kim, Eun-Cheol

2007-01-01

Interleukin-8 (IL-8) is a cytokine that plays an important role in tumor progression in a variety of cancer types; however, its regulation is not well understood in oral cancer cells. In the present study, we examined the expression and mechanism of IL-8 in which it is involved by treating immortalized (IHOK) and malignant human oral keratinocytes (HN12) cells with deferoxamine (DFO). IL-8 production was measured by an enzyme-linked immunoabsorbent assay and reverse transcriptase-polymerase chain reaction (RT-PCR) analysis. Electrophoretic mobility shift assays was used to determine NF-κB binding activity. Phosphorylation and degradation of the I-κB were analyized by Western blot. IHOK cells incubated with DFO showed increased expression of IL-8 mRNA, as well as higher release of the IL-8 protein. The up-regulation of DFO-induced IL-8 expression was higher in IHOK cells than in HN12 cells and was concentration-dependent. DFO acted additively with IL-1β to strongly up-regulate IL-8 in IHOK cells but not in HN12 cells. Accordingly, selective p38 and ERK1/2 inhibitors for both kinases abolished DFO-induced IL-8 expression in both IHOK and HN12 cells. Furthermore, DFO induced the degradation and phosphorylation of IκB, and activation of NF-κB. The IL-8 inducing effects of DFO were mediated by a nitric oxide donor (S-nitrosoglutathione), and by pyrrolidine dithiocarbamate, an inhibitor of NF-κB, as well as by wortmannin, which inhibits the phosphatidylinositol 3-kinase-dependent activation of NAD(P)H oxidase. This results demonstrate that DFO-induced IL-8 acts via multiple signaling pathways in immortalized and malignant oral keratinocytes, and that the control of IL-8 may be an important target for immunotheraphy against human oral premalignant lesions

[18F]Fallypride: Metabolism studies and quantification of the radiotracer and its radiometabolites in plasma using a simple and rapid solid-phase extraction method

International Nuclear Information System (INIS)

Peyronneau, Marie-Anne; Saba, Wadad; Goutal, Sébastien; Kuhnast, Bertrand; Dollé, Frédéric; Bottlaender, Michel; Valette, Héric

2013-01-01

Introduction: [ 18 F]Fallypride, a fluorinated and substituted benzamide with high affinity for D 2 /D 3 receptors, is a useful PET radioligand for the study of striatal/extrastriatal areas. Since [ 18 F]fallypride is extensively metabolized in vivo and since PET examinations are long lasting in humans, the rapid measurement of the unchanged radiotracer in plasma is essential for the quantification of images. The present study aims: i) to evaluate if the radiometabolites of [ 18 F]fallypride cross the blood–brain barrier in rodents, ii) to identify these radiometabolites in baboon plasma and iii) to develop a rapid solid phase extraction method (SPE) suitable for human applications to quantify both [ 18 F]fallypride and its radiometabolites in plasma. Methods: The metabolites P450-dependant in rat and human liver microsomes were characterized by LC–MS–MS and compared to those detected in vivo. Sequential solvent elution on Oasis®-MCX-SPE cartridges was used to quantify [ 18 F]fallypride and its radiometabolites. Result: In rat microsomal incubations, five metabolites generated upon N/O-dealkylation or hydroxylation at the pyrrolidine and/or at the benzamide moiety were identified. No radiometabolite was detected in the rat brain. N-dealkylated and hydroxylated derivatives were detected in human microsomal incubations as well as in baboon plasma. The use of SPE (total recovery 100.2% ± 2.8%, extraction yield 95.5% ± 0.3%) allowed a complete separation of [ 18 F]fallypride from its radiometabolites in plasma and evaluate [ 18 F]fallypride at 150 min pi to be 22% ± 5% of plasma radioactivity. Conclusions: The major in vivo radiometabolites of [ 18 F]fallypride were produced by N-dealkylation and hydroxylation. Allowing the rapid analysis of multiple plasma samples, SPE is a method of choice for the determination of [ 18 F]fallypride until late images required for quantitative PET imaging in humans

Thermal Degradation of Synthetic Cathinones: Implications for Forensic Toxicology.

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Kerrigan, Sarah; Savage, Megan; Cavazos, Cassandra; Bella, Paige

2016-01-01

The synthetic cathinones represent an important class of designer drugs. The widespread attention and publicity associated with these psychostimulants have resulted in numerous legislative actions at state and federal levels throughout the USA. These amphetamine-like compounds are characterized by a β-keto functional group. Although the synthetic cathinones share many properties of their phenethylamine counterparts, the presence of the ketone moiety is responsible for a number of unique and distinct differences in terms of their chemical characteristics and properties. Thermal degradation of methcathinone was first reported several decades ago but has received limited attention. In this study, we identified in situ thermal degradation products for 18 cathinones during gas chromatography-mass spectrometry (GC-MS) analysis. Oxidative degradation arises from the loss of two hydrogens, yielding a characteristic 2 Da mass shift. Degradation products were characterized by prominent iminium base peaks with mass-to-charge ratios 2 Da lower than the parent drug, and in the case of the pyrrolidine-containing cathinones, prominent molecular ions arising from the 2,3-enamine. Chromatographic and mass spectroscopic data are described for 4-ethylmethcathinone, 4-methylethcathinone, buphedrone, butylone, ethcathinone, ethylone, flephedrone, 3,4-methylenedioxy-α-pyrrolidinobutiophenone, 3,4-methylenedioxypyrovalerone, mephedrone, methcathinone, methedrone, methylone, 4-methyl-α-pyrrolidinobutiophenone, naphyrone, pentedrone, pentylone and pyrovalerone. Degradation was minimized by lowering injection temperatures, residence time in the inlet and eliminating active sites during chromatographic analysis. Chromatographic and mass spectral data for the cathinone degradation products are presented and discussed within the context of forensic toxicological analysis, selection of appropriate instrumental methods and implications for the interpretation of results. © The Author 2015

Activation of the canonical nuclear factor-κB pathway is involved in isoflurane-induced hippocampal interleukin-1β elevation and the resultant cognitive deficits in aged rats

International Nuclear Information System (INIS)

Li, Zheng-Qian; Rong, Xiao-Ying; Liu, Ya-Jie; Ni, Cheng; Tian, Xiao-Sheng; Mo, Na; Chui, De-Hua; Guo, Xiang-Yang

2013-01-01

Highlights: •Isoflurane induces hippocampal IL-1β elevation and cognitive deficits in aged rats. •Isoflurane transiently activates the canonical NF-κB pathway in aged rat hippocampus. •NF-κB inhibitor mitigates isoflurane-induced IL-1β elevation and cognitive deficits. •We report a linkage between NF-κB signaling, IL-1β expression, and cognitive changes. -- Abstract: Although much recent evidence has demonstrated that neuroinflammation contributes to volatile anesthetic-induced cognitive deficits, there are few existing mechanistic explanations for this inflammatory process. This study was conducted to investigate the effects of the volatile anesthetic isoflurane on canonical nuclear factor (NF)-κB signaling, and to explore its association with hippocampal interleukin (IL)-1β levels and anesthetic-related cognitive changes in aged rats. After a 4-h exposure to 1.5% isoflurane in 20-month-old rats, increases in IκB kinase and IκB phosphorylation, as well as a reduction in the NF-κB inhibitory protein (IκBα), were observed in the hippocampi of isoflurane-exposed rats compared with control rats. These events were accompanied by an increase in NF-κB p65 nuclear translocation at 6 h after isoflurane exposure and hippocampal IL-1β elevation from 1 to 6 h after isoflurane exposure. Nevertheless, no significant neuroglia activation was observed. Pharmacological inhibition of NF-κB activation by pyrrolidine dithiocarbamate markedly suppressed the IL-1β increase and NF-κB signaling, and also mitigated the severity of cognitive deficits in the Morris water maze task. Overall, our results demonstrate that isoflurane-induced cognitive deficits may stem from upregulation of hippocampal IL-1β, partially via activation of the canonical NF-κB pathway, in aged rats

Silver Nanoparticles in the Lung: Toxic Effects and Focal Accumulation of Silver in Remote Organs

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Martin Wiemann

2017-12-01

Full Text Available The distribution of silver (Ag into remote organs secondary to the application of Ag nanoparticles (Ag-NP to the lung is still incompletely understood and was investigated in the rat with imaging methods. Dose-finding experiments were carried out with 50 nm- or 200 nm-sized polyvinyl pyrrolidine (PVP-coated Ag-NP using alveolar macrophages in vitro and female rats, which received Ag-NP via intratracheal instillation. In the main study, we administered 37.5–300 µg per rat lung of the more toxic Ag50-PVP and assessed the broncho-alveolar lavage fluid (BALF for inflammatory cells, total protein and fibronectin after three and 21 days. In parallel, lung tissue was analysed for DNA double-strand breaks and altered cell proliferation. While 75–150 µg Ag50-PVP per rat lung caused a reversible inflammation, 300 µg led to DNA damage, accelerated cell proliferation and progressively increasing numbers of neutrophilic granulocytes. Ag accumulation was significant in homogenates of liver and other peripheral organs upon lung dose of ≥75 µg. Quantitative laser-ablation inductively-coupled plasma mass spectrometry (LA-ICP-MS combined with enhanced dark field microscopy and autometallography revealed focal accumulations of Ag and/or Ag-NP in sections of peripheral organs: mediastinal lymph nodes contained Ag-NP especially in peripheral macrophages and Ag in argyrophilic fibres. In the kidney, Ag had accumulated within proximal tubuli, while renal filter structures contained no Ag. Discrete localizations were also observed in immune cells of liver and spleen. Overall, the study shows that concentrations of Ag-NP, which elicit a transient inflammation in the rat lung, lead to focal accumulations of Ag in peripheral organs, and this might pose a risk to particular cell populations in remote sites.

ß-Hydroxybutyrate Activates the NF-κB Signaling Pathway to Promote the Expression of Pro-Inflammatory Factors in Calf Hepatocytes

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Xiaoxia Shi

2014-01-01

Full Text Available Background/Aims: ß-hydroxybutyrate (BHBA is the major component of ketone bodies in ketosis. Dairy cows with ketosis often undergo oxidative stress. BHBA is related to the inflammation involved in other diseases of dairy cattle. However, whether BHBA can induce inflammatory injury in dairy cow hepatocytes and the potential mechanism of this induction are not clear. The NF-κB pathway plays a vital role in the inflammatory response. Methods: Therefore, this study evaluated the oxidative stress, pro-inflammatory factors and NF-κB pathway in cultured calf hepatocytes treated with different concentrations of BHBA, pyrrolidine dithiocarbamate (PDTC, an NF-κB pathway inhibitor and N-acetylcysteine (NAC, antioxidant. Results: The results showed that BHBA could significantly increase the levels of oxidation indicators (MDA, NO and iNOS, whereas the levels of antioxidation indicators (GSH-Px, CAT and SOD were markedly decreased in hepatocytes. The IKKß activity and phospho-IκBa (p-IκBa contents were increased in BHBA-treated hepatocytes. This increase was accompanied by the increased expression level and transcription activity of p65. The expression levels of NF-κB-regulated inflammatory cytokines, namely TNF-a, IL-6 and IL-1ß, were markedly increased after BHBA treatment, while significantly decreased after NAC treatment. However, the p-IκBa level and the expression and activity of p65 and its target genes were markedly decreased in the PDTC + BHBA group compared with the BHBA (1.8 mM group. Moreover, immunocytofluorescence of p65 showed a similar trend. Conclusion: The present data indicate that higher concentrations of BHBA can induce cattle hepatocyte inflammatory injury through the NF-κB signaling pathway, which may be activated by oxidative stress.

Supraspinal and spinal effects of L-trans-PDC, an inhibitor of glutamate transporter, on the micturition reflex in rats.

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Honda, Masashi; Yoshimura, Naoki; Hikita, Katsuya; Hinata, Nobuyuki; Muraoka, Kuniyasu; Saito, Motoaki; Chancellor, Michael B; Takenaka, Atsushi

2013-09-01

Glutamate is a major excitatory transmitter in the central nervous system, controlling lower urinary tract function. Five types of glutamate transporters such as GLAST (EAAT1), GLT-1 (EAAT2), EAAC-1 (EAAT3), EAAT4, and EAAT5 have been cloned so far. In the current study we tested whether L-trans-pyrrolidine-2,4-dicarboxylic acid (L-trans-PDC), a non-selective inhibitor of glutamate transporters that increases endogenous glutamate concentration, can affect the micturition reflex in urethane anesthetized rats. Continuous cystometrograms (CMG, 0.04 ml/min infusion rate) were performed in two groups of urethane-anesthetized rats. A group of 18 rats was used for intrathecal administration of 1-10 µg of L-trans-PDC via an intrathecal catheter. In the second group of 18 rats, 1-10 µg of L-trans-PDC were administered intracerebroventricularly via a catheter inserted into the lateral ventricle. Micturition parameters were recorded and compared before and after drug administration. Intrathecal administration of L-trans-PDC at 1, 3, and 10 µg (n = 6 per dose) increased intercontraction intervals in dose dependent fashion, but did not affect postvoid residual or basal pressure at any doses tested. Intracerebroventricular administration of L-trans-PDC at 1, 3, and 10 µg (n = 6 per dose) also increased intercontraction intervals in dose dependent fashion, but did not affect postvoid residual or basal pressure at any doses tested. The current results show that, in urethane-anesthetized rats, suppression of glutamate transporters by L-trans-PDC has an inhibitory effect on the micturition reflex at supraspinal and spinal sites, possibly via activation of glutamate-mediated inhibitory pathways. Copyright © 2012 Wiley Periodicals, Inc.

Exogenous hydrogen sulfide eliminates spatial memory retrieval impairment and hippocampal CA1 LTD enhancement caused by acute stress via promoting glutamate uptake.

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He, Jin; Guo, Ruixian; Qiu, Pengxin; Su, Xingwen; Yan, Guangmei; Feng, Jianqiang

2017-05-14

Acute stress impairs the hippocampus-dependent spatial memory retrieval, and its synaptic mechanisms are associated with hippocampal CA1 long-term depression (LTD) enhancement in the adult rats. Endogenous hydrogen sulfide (H 2 S) is recognized as a novel gasotransmitter and has the neural protective roles. However, very little attention has been paid to understanding the effects of H 2 S on spatial memory retrieval impairment. We observed the protective effects of NaHS (a donor of H 2 S) against spatial memory retrieval impairment caused by acute stress and its synaptic mechanisms. Our results showed that NaHS abolished spatial memory retrieval impairment and hippocampal CA1 LTD enhancement caused by acute stress, but not by glutamate transporter inhibitor l-trans-pyrrolidine-2,4-dicarboxylic (tPDC), indicating that the activation of glutamate transporters is necessary for exogenous H 2 S to exert its roles. Moreover, NaHS restored the decreased glutamate uptake in the hippocampal CA1 synaptosomal fraction caused by acute stress. Dithiothreitol (DTT, a disulfide reducing agent) abolished a decrease in the glutamate uptake caused by acute stress, and NaHS eradicated the decreased glutamate uptake caused by 5,5'-dithio-bis(2-nitrobenzoic)acid (DTNB, a thiol oxidizing agent), collectively, revealing that exogenous H 2 S increases glutamate uptake by reducing disulfide bonds of the glutamate transporters. Additionally, NaHS inhibited the increased expression level of phosphorylated c-Jun-N-terminal kinase (JNK) in the hippocampal CA1 region caused by acute stress. The JNK inhibitor SP600125 eliminated spatial memory retrieval impairment, hippocampal CA1 LTD enhancement and the decreased glutamate uptake caused by acute stress, indicating that exogenous H 2 S exerts these roles by inhibiting the activation of JNK signaling pathway. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

Dispersive liquid–liquid microextraction using diethyldithiocarbamate as a chelating agent and the dried-spot technique for the determination of Fe, Co, Ni, Cu, Zn, Se and Pb by energy-dispersive X-ray fluorescence spectrometry

International Nuclear Information System (INIS)

Kocot, Karina; Zawisza, Beata; Sitko, Rafal

2012-01-01

Dispersive liquid–liquid microextraction (DLLME) using sodium diethyldithiocarbamate (DDTC) as a chelating agent was investigated for the simultaneous determination of iron, cobalt, nickel, copper, zinc, selenium and lead ions in water samples. The procedure was performed using 5 mL of the sample, 100 μL of a 0.5% solution of DDTC, 30 μL of carbon tetrachloride (extraction phase) and 500 μL of methanol (disperser solvent). The experiments showed that Fe, Co, Ni, Cu, Zn and Pb can be simultaneously extracted at a pH of 5 and that Se can be extracted at a pH of 2–3. The results were compared with those obtained using ammonium pyrrolidine dithiocarbamate as a chelating agent. For all analytes, a linear range was observed up to 0.4 μg mL −1 . If Fe and Zn are present in concentrations 10 times higher than those of the other analytes, then the linearity is observed up to 0.2 μg mL −1 . In the present study, the organic phase that contained preconcentrated elements was deposited onto a Millipore filter and measured using energy-dispersive X-ray fluorescence spectrometry. The obtained detection limits were 2.9, 1.5, 2.0, 2.3, 2.5, 2.0 and 3.9 ng mL −1 for Fe, Co, Ni, Cu, Zn, Se and Pb, respectively. This combination of DLLME and the dried-spot technique is promising for multielement analyses using other spectroscopy techniques, such as laser ablation‐inductively coupled plasma‐mass spectrometry, laser-induced breakdown spectroscopy or total-reflection X-ray fluorescence spectrometry. - Highlights: ► Multielement trace analysis using dried-spot technique and dispersive liquid–liquid microextraction. ► Possibility of combination of LPME with EDXRF, LIBS or LA-ICP-MS. ► Comparison of APDC and DDTC as chelating agents.

(4S)-4-(3,4-Dichloro?phen?yl)-1?-methyl-4?-phenyl-3,4-dihydronaphthalene-2-spiro-3?-pyrrolidine-2?-spiro-1??-acenaphthyl?ene-1,2??(2H,1??H)-dione

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Murugan, R.; Gunasekaran, B.; Narayanan, S. Sriman; Manivannan, V.

2008-01-01

In the title compound, C37H27Cl2NO2, the 3,4-dichloro?phenyl ring makes a dihedral angle of 46.66?(6)? with the phenyl ring. The mol?ecular structure is stabilized by weak intra?molecular C?H?O inter?actions and the crystal structure is stabilized by weak inter?molecular C?H?O inter?actions. The C?C?C?C?C five-membered ring is planar, while the C?C?C?C?N five-membered ring adopts a half-chair conformation.

Fluorinated benzamide neuroleptics--III. Development of (S)-N-[(1-allyl-2-pyrrolidinyl)methyl]-5-(3-[{sup 18}F]fluoropropyl)-2,3- dimethoxybenzamide as an improved dopamine D-2 receptor tracer

Energy Technology Data Exchange (ETDEWEB)

Mukherjee, Jogeshwar; Zhiying, Yang; Das, Malay K; Brown, Terry

1995-04-01

We have prepared five new analogs (n-propyl, iso-propyl, allyl, n-butyl, and iso-butyl) of the dopamine D-2 receptor antagonist, FPMB which result from modifications of the ethyl group at the pyrrolidine nitrogen in FPMB. As expected, all new derivatives showed higher apparent lipophilicity (log k{sub w}), with iso-butyl being the most lipophilic (log k{sub w} = 2.52), followed by the allyl derivative (log k{sub w} = 2.43). The allyl group showed the largest increase in affinity (from 0.26 nM for the ethyl substituent to 0.03 nM for the allyl substituent, almost 10-fold), followed by the n-propyl substituent which showed approximately five-fold better affinity than did the ethyl substituent. Radiosynthesis of S-N-[(1-allyl-2-pyrrolidinyl)methyl]-5-(3-[{sup 18}F]fluoropropyl)-2,3-dimethoxybenzamide ([{sup 18}F]fallypride) was carried out by nucleophilic substitution reaction of (S)-N-[(1-allyl-2-pyrrolidinyl)methyl]-5-(3-tosyloxypropyl)-2,3- dimethoxybenzamide with no carrier added {sup 18}F{sup -}. [{sup 18}F]Fallypride was obtained in approximately 20-40% yields (EOS/EOB, decay corrected) in specific activities of 900-1700 Ci/mmol after reverse phase HPLC purification in 60 min from EOB. High striatal uptake (upto 2.5% injected dose/g) of [{sup 18}F]fallypride in rats was observed with striatal/cerebellar ratios of 17, 42, 63 and 122 at 30, 60, 90 and 120 min post-injection, respectively. PET experiments with [{sup 18}F]fallypride in a cebus monkey showed a brain uptake of 0.10% injected dose/cc. In rhesus monkeys [{sup 18}F]fallypride showed rapid specific uptake in the striata (0.04-0.06% injected dose/cc) with striata/cerebellum ratios of approx. 3.0 at 14 min, 5.0 at 35 min and 8 at 70 min post-injection. Specifically bound [{sup 18}F]fallypride was displaced with haloperidol (1 mg/kg) with a half-life of 18 min in the rhesus monkey.

Enhanced expression of two discrete isoforms of matrix metalloproteinase-2 in experimental and human diabetic nephropathy.

Directory of Open Access Journals (Sweden)

Sang Soo Kim

Full Text Available We recently reported on the enhanced expression of two isoforms of matrix metalloproteinase-2 (MMP-2 in human renal transplantation delayed graft function. These consist of the conventional secreted, full length MMP-2 isoform (FL-MMP-2 and a novel intracellular N-Terminal Truncated isoform (NTT-MMP-2 generated by oxidative stress-mediated activation of an alternate promoter in the MMP-2 first intron. Here we evaluated the effect of hyperglycemia and diabetes mellitus on the in vitro and in vivo expression of the two MMP-2 isoforms.We quantified the abundance of the FL-MMP-2 and NTT-MMP-2 transcripts by qPCR in HK2 cells cultured in high glucose or 4-hydroxy-2-hexenal (HHE and tested the effects of the NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC. The streptozotocin (STZ murine model of Type I diabetes mellitus and renal biopsies of human diabetic nephropathy were used in this study.Both isoforms of MMP-2 in HK2 cells were upregulated by culture in high glucose or with HHE. PDTC treatment did not suppress high glucose-mediated FL-MMP-2 expression but potently inhibited NTT-MMP-2 expression. With STZ-treated mice, renal cortical expression of both isoforms was increased (FL-MMP-2, 1.8-fold; NTT-MMP-2, greater than 7-fold. Isoform-specific immunohistochemical staining revealed low, but detectable levels of the FL-MMP-2 isoform in controls, while NTT-MMP-2 was not detected. While there was a modest increase in tubular epithelial cell staining for FL-MMP-2 in STZ-treated mice, NTT-MMP-2 was intensely expressed in a basolateral pattern. FL-MMP-2 and NTT-MMP-2 isoform expression as quantified by qPCR were both significantly elevated in renal biopsies of human diabetic nephropathy (12-fold and 3-fold, respectively.The expression of both isoforms of MMP-2 was enhanced in an experimental model of diabetic nephropathy and in human diabetic nephropathy. Selective MMP-2 isoform inhibition could offer a novel approach for the treatment of diabetic renal

Hypoxia-Induced Collagen Synthesis of Human Lung Fibroblasts by Activating the Angiotensin System

Directory of Open Access Journals (Sweden)

Shan-Shan Liu

2013-12-01

Full Text Available The exact molecular mechanism that mediates hypoxia-induced pulmonary fibrosis needs to be further clarified. The aim of this study was to explore the effect and underlying mechanism of angiotensin II (Ang II on collagen synthesis in hypoxic human lung fibroblast (HLF cells. The HLF-1 cell line was used for in vitro studies. Angiotensinogen (AGT, angiotensin converting enzyme (ACE, angiotensin II type 1 receptor (AT1R and angiotensin II type 2 receptor (AT2R expression levels in human lung fibroblasts were analysed using real-time polymerase chain reaction (RT-PCR after hypoxic treatment. Additionally, the collagen type I (Col-I, AT1R and nuclear factor κappaB (NF-κB protein expression levels were detected using Western blot analysis, and NF-κB nuclear translocation was measured using immunofluorescence localization analysis. Ang II levels in HLF-1 cells were measured with an enzyme-linked immunosorbent assay (ELISA. We found that hypoxia increased Col-I mRNA and protein expression in HLF-1 cells, and this effect could be inhibited by an AT1R or AT2R inhibitor. The levels of NF-κB, RAS components and Ang II production in HLF-1 cells were significantly increased after the hypoxia exposure. Hypoxia or Ang II increased NF-κB-p50 protein expression in HLF-1 cells, and the special effect could be inhibited by telmisartan (TST, an AT1R inhibitor, and partially inhibited by PD123319, an AT2R inhibitor. Importantly, hypoxia-induced NF-κB nuclear translocation could be nearly completely inhibited by an AT1R or AT2R inhibitor. Furthermore pyrrolidine dithiocarbamate (PDTC, a NF-κB blocker, abolished the expression of hypoxia-induced AT1R and Col-I in HLF-1 cells. Our results indicate that Ang II-mediated NF-κB signalling via ATR is involved in hypoxia-induced collagen synthesis in human lung fibroblasts.

Sequential cloud point extraction for the speciation of mercury in seafood by inductively coupled plasma optical emission spectrometry

Energy Technology Data Exchange (ETDEWEB)

Li Yingjie [Department of Chemistry, Wuhan University, Wuhan 430072 (China); Hu Bin [Department of Chemistry, Wuhan University, Wuhan 430072 (China)], E-mail: binhu@whu.edu.cn

2007-10-15

A novel nonchromatographic speciation technique for the speciation of mercury by sequential cloud point extraction (CPE) combined with inductively coupled plasma optical emission spectrometry (ICP-OES) was developed. The method based on Hg{sup 2+} was complexed with I{sup -} to form HgI{sub 4}{sup 2-}, and the HgI{sub 4}{sup 2-} reacted with the methyl green (MG) cation to form hydrophobic ion-associated complex, and the ion-associated complex was then extracted into the surfactant-rich phase of the non-ionic surfactant octylphenoxypolyethoxyethanol (Triton X-114), which are subsequently separated from methylmercury (MeHg{sup +}) in the initial solution by centrifugation. The surfactant-rich phase containing Hg(II) was diluted with 0.5 mol L{sup -1} HNO{sub 3} for ICP-OES determination. The supernatant is also subjected to the similar CPE procedure for the preconcentration of MeHg{sup +} by the addition of a chelating agent, ammonium pyrrolidine dithiocarbamate (APDC), in order to form water-insolvable complex with MeHg{sup +}. The MeHg{sup +} in the micelles was directly analyzed after disposal as describe above. Under the optimized conditions, the extraction efficiency was 93.5% for Hg(II) and 51.5% for MeHg{sup +} with the enrichment factor of 18.7 for Hg(II) and 10.3 for MeHg{sup +}, respectively. The limits of detection (LODs) were 56.3 ng L{sup -1} for Hg(II) and 94.6 ng L{sup -1} for MeHg{sup +} (as Hg) with the relative standard deviations (RSDs) of 3.6% for Hg(II) and 4.5% for MeHg{sup +} (C = 10 {mu}g L{sup -1}, n = 7), respectively. The developed technique was applied to the speciation of mercury in real seafood samples and the recoveries for spiked samples were found to be in the range of 93.2-108.7%. For validation, a certified reference material of DORM-2 (dogfish muscle) was analyzed and the determined values are in good agreement with the certified values.

Humic acid in drinking well water induces inflammation through reactive oxygen species generation and activation of nuclear factor-κB/activator protein-1 signaling pathways: A possible role in atherosclerosis

Energy Technology Data Exchange (ETDEWEB)

Hseu, You-Cheng [Department of Cosmeceutics, China Medical University, Taichung 40402, Taiwan (China); Department of Molecular and Cellular Oncology, University of Texas, MD Anderson Cancer Center, TX 77030 (United States); Senthil Kumar, K.J. [Department of Cosmeceutics, China Medical University, Taichung 40402, Taiwan (China); Chen, Chih-Sheng; Cho, Hsin-Ju; Lin, Shu-Wei; Shen, Pei-Chun [Institute of Nutrition, China Medical University, Taichung 40402, Taiwan (China); Lin, Cheng-Wen [Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung 40402, Taiwan (China); Lu, Fung-Jou [Institute of Medicine, Chun Shan Medical University, Taichung 40201, Taiwan (China); Yang, Hsin-Ling, E-mail: hlyang@mail.cmu.edu.tw [Institute of Nutrition, China Medical University, Taichung 40402, Taiwan (China); Department of Molecular and Cellular Oncology, University of Texas, MD Anderson Cancer Center, TX 77030 (United States)

2014-01-15

Humic acid (HA) has been implicated as one of the etiological factors in the peripheral vasculopathy of blackfoot disease (BFD) in Taiwan. However, the underlying pathophysiological mechanisms of BFD are not well defined. In this study, we used an in vitro and in vivo model, in which HA (25–200 μg/mL) activated macrophages to produce pro-inflammatory molecules by activating their transcriptional factors. HA exposure induced NO and PGE{sub 2} production followed by induction of iNOS and COX-2 through NF-κB/AP-1 transactivation in macrophages. In addition, the production of TNF-α and IL-1β was significantly increased by HA. Moreover, HA-induced iNOS and COX-2 expression were down-regulated by the NF-κB and AP-1 inhibitors pyrrolidine dithiocarbamate (PDTC) and Tanshinone, respectively. Furthermore, generations of ROS and nitrotyrosine, as well as activation of the AKT and MAPKs signaling cascades were observed after HA exposure. Specifically, HA-induced NF-κB activation was mediated by ROS and AKT, and that HA-induced AP-1 activation was mediated by JNK and ERK. Notably, HA-mediated AKT, JNK, and ERK activation was ROS-independent. The inflammatory potential of HA was correlated with increased expression of HO-1 and Nrf2. Furthermore, an in vivo study confirms that mice exposed to HA, the serum levels of TNF-α and IL-1β was significantly increased in a dose-dependent manner. This report marks the first confirmation that environmental exposure of HA induces inflammation in macrophages, which may be one of the main causes of early atherogenesis in blackfoot disease. - Highlights: • Humic acid (HA) induce pro-inflammatory cytokines and mediators in macrophages. • HA-induced inflammation is mediated by ROS and NF-κB/AP-1 signaling pathways. • The inflammatory potential of HA correlated with activation of Nrf2/HO-1 genes. • HA exposure to mice increased pro-inflammatory cytokines production in vivo. • HA may be one of the main causes of early

Inhibition of NF-κB activity in the hypothalamic paraventricular nucleus attenuates hypertension and cardiac hypertrophy by modulating cytokines and attenuating oxidative stress

Energy Technology Data Exchange (ETDEWEB)

Yu, Xiao-Jing [Department of Physiology and Pathophysiology, Xi' an Jiaotong University School of Basic Medical Sciences, Xi' an Jiaotong University Cardiovascular Research Center, Xi' an Jiaotong University Health Science Center, Xi' an 710061 (China); Zhang, Dong-Mei [Department of Physiology, Dalian Medical University, Dalian 116044 (China); Jia, Lin-Lin; Qi, Jie; Song, Xin-Ai; Tan, Hong [Department of Physiology and Pathophysiology, Xi' an Jiaotong University School of Basic Medical Sciences, Xi' an Jiaotong University Cardiovascular Research Center, Xi' an Jiaotong University Health Science Center, Xi' an 710061 (China); Cui, Wei [Department of Endocrinology and Metabolism, First Affiliated Hospital of Xi' an Jiaotong University, Xi' an Jiaotong University Health Science Center, Xi' an 710061 (China); Chen, Wensheng [Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi' an 710032 (China); Zhu, Guo-Qing [Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Physiology, Nanjing Medical University, Nanjing 210029 (China); Qin, Da-Nian, E-mail: dnqin@stu.edu.cn [Department of Physiology, Shantou University Medical College, Shantou 515041 (China); Kang, Yu-Ming, E-mail: ykang@mail.xjtu.edu.cn [Department of Physiology and Pathophysiology, Xi' an Jiaotong University School of Basic Medical Sciences, Xi' an Jiaotong University Cardiovascular Research Center, Xi' an Jiaotong University Health Science Center, Xi' an 710061 (China)

2015-05-01

We hypothesized that chronic inhibition of NF-κB activity in the hypothalamic paraventricular nucleus (PVN) delays the progression of hypertension and attenuates cardiac hypertrophy by up-regulating anti-inflammatory cytokines, reducing pro-inflammatory cytokines (PICs), attenuating nuclear factor-κB (NF-κB) p65 and NAD(P)H oxidase in the PVN of young spontaneously hypertensive rats (SHR). Young normotensive Wistar–Kyoto (WKY) and SHR rats received bilateral PVN infusions with NF–κB inhibitor pyrrolidine dithiocarbamate (PDTC) or vehicle for 4 weeks. SHR rats had higher mean arterial pressure and cardiac hypertrophy as indicated by increased whole heart weight/body weight ratio, whole heart weight/tibia length ratio, left ventricular weight/tibia length ratio, cardiomyocyte diameters of the left cardiac ventricle, and mRNA expressions of cardiac atrial natriuretic peptide (ANP) and beta-myosin heavy chain (β-MHC). These SHR rats had higher PVN levels of proinflammatory cytokines (PICs), reactive oxygen species (ROS), the chemokine monocyte chemoattractant protein-1 (MCP-1), NAD(P)H oxidase activity, mRNA expression of NOX-2 and NOX-4, and lower PVN IL-10, and higher plasma levels of PICs and NE, and lower plasma IL-10. PVN infusion of NF-κB inhibitor PDTC attenuated all these changes. These findings suggest that NF-κB activation in the PVN increases sympathoexcitation and hypertensive response, which are associated with the increases of PICs and oxidative stress in the PVN; PVN inhibition of NF-κB activity attenuates PICs and oxidative stress in the PVN, thereby attenuates hypertension and cardiac hypertrophy. - Highlights: • Spontaneously hypertensive rats exhibit neurohormonal excitation in the PVN. • PVN inhibition of NF-κB attenuates hypertension-induced cardiac hypertrophy. • PVN inhibition of NF-κB attenuates hypertension-induced neurohormonal excitation. • PVN inhibition of NF-κB attenuates hypertension-induced imbalance of cytokines

Determinação de cobre, ferro, manganês e zinco, num mesmo extrato de planta, por potometria de chama de absorção The determination of copper, iron, manganese and zinc in a bulk plant extract by atomic absorption spectrophotometry

Directory of Open Access Journals (Sweden)

J. Romano Gallo

1971-05-01

Full Text Available É apresentado um método de determinação, num mesmo extrato de planta, de ferro, manganês e zinco na fase aquosa, e de cobre, após sua extração em solvente orgânico. Para êsse estudo usou-se um analisador automático de absorção atômica Perkin-Elmer, modêlo 4A. Somente á silica, em certas concentrações, poderá constituir problema na determinação de manganês ou ferro, na ausência de cálcio. Na extração quantitativa do cobre é necessário conservar o pH abaixo de 2, para evitar interferência de ferro.A method was developed to determine quantitatively Cu, Fe, Mn and Zn in a bulk plant extract, using flame absorption photometry. The process measures Fe, Mn and Zn directly in the aqueous solution, but a concentration of the extract with organic solvents is required for copper determination. Essentially the process consists in obtaining the plant extract through digestion of 1.000 g of the ground dry samples, with HNO3 and later with HC10(4-H2S0(4 (7:1 v/v, then the solution is diluted to 50 ml with water. Thirty ml of this solution are transferred to a separatory funnel, where the copper is extracted by the ammonium pyrrolidine dithiocarbamate/ methyl isobutyl ketone system, and its amount determined. It is necessary to keep the pH below 2 to avoid interference of Fe on Cu determination. Mn, Fe and Zn are determined directly in the remaining 20 ml of plant extract. It has been noticed that silicon might cause some problems in the determination of Fe and Mn, in the absence of Ca. All the determinations were made in a Perkin-Elmer mod. 4A atomic absorption automatic analyser.

Histamine Induces Bovine Rumen Epithelial Cell Inflammatory Response via NF-κB Pathway.

Science.gov (United States)

Sun, Xudong; Yuan, Xue; Chen, Liang; Wang, Tingting; Wang, Zhe; Sun, Guoquan; Li, Xiaobing; Li, Xinwei; Liu, Guowen

2017-01-01

Subacute ruminal acidosis (SARA) is a common disease in high-producing lactating cows. Rumenitis is the initial insult of SARA and is associated with the high concentrations of histamine produced in the rumen of dairy cows during SARA. However, the exact mechanism remains unclear. The objective of the current study is to investigate whether histamine induces inflammation of rumen epithelial cells and the underlying mechanism of this process. Bovine rumen epithelial cells were cultured and treated with different concentrations of histamine and pyrrolidine dithiocarbamate (PDTC, an NF-κB inhibitor) cultured in different pH medium (pH 7.2 or 5.5). qRT-PCR, Western-blotting, ELISA and immunocytofluorescence were used to evaluate whether histamine activated the NF-κB pathway and inflammatory cytokines. The results showed that histamine significantly increased the activity of IKK β and the phosphorylation levels of IκB α, as well as upregulated the mRNA and protein expression levels of NF-κB p65 in the rumen epithelial cells cultured in neutral (pH=7.2) and acidic (pH=5.5) medium. Furthermore, histamine treatment also significantly increased the transcriptional activity of NF-κB p65. High expression and transcriptional activity of NF-κB p65 significantly increased the mRNA expressions and concentrations of inflammatory cytokines, tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6) and interleukin 1 beta (IL-1β), thereby inducing the inflammatory response in bovine rumen epithelial cells. However, inhibition of NF-κB p65 by PDTC significantly decreased the expressions and concentrations of the inflammatory cytokines induced by histamine in the rumen epithelial cells cultured in the neutral and acidic medium. The present data indicate that histamine induces the inflammatory response of bovine rumen epithelial cells through the NF-κB pathway. © 2017 The Author(s). Published by S. Karger AG, Basel.

Stability of Synthetic Cathinones in Urine.

Science.gov (United States)

Glicksberg, Lindsay; Kerrigan, Sarah

2018-03-01

In this report, we evaluate the concentration, pH, temperature and analyte-dependent effects on cathinone stability in preserved human urine. A total of 22 synthetic cathinones were evaluated at 100 ng/mL and 1,000 ng/mL in pH 4 and pH 8 urine over 6 months. Specimens were stored at -20°C, 4°C, 20°C and 32°C. The stability of synthetic cathinones was highly dependent on urine pH and storage temperature. Cathinones were considerably more stable in acidic urine (pH 4) at low temperature. In alkaline urine (pH 8) at 32°C, significant losses (>20%) were observed within hours for the majority of drugs. In contrast, all drugs were stable in frozen and refrigerated urine at pH 4 for the duration of the study. These results highlight the importance of sample storage and the potential for pre-analytical changes in concentration during routine shipping and handling of specimens. Significant structural influence was also observed. Cathinones bearing a tertiary amine (pyrrolidine group) were significantly more stable than their secondary amine counterparts. The methylenedioxy group also exerted a significant stabilizing effect on both the tertiary and secondary amines. In the absence of the methylenedioxy group, no significant differences in stability were observed between the unsubstituted and ring substituted secondary amines. Half-lives at ambient temperature in pH 8 urine ranged from 9 h (3-fluoromethcathinone) to 4.3 months (methylenedioxypyrovalerone and 3,4-methylenedioxy-α-pyrrolidinobutiophenone), demonstrating the importance of analyte dependence, and the dual stabilizing effect of both the pyrollidine and methylenedioxy groups. Biological evidence may be subjected to a variety of environmental conditions prior to, and during transport to the forensic laboratory. These findings demonstrate the inherent instability of certain cathinone species in biological evidence under some conditions. Moreover, this study highlights the need for quantitative drug findings in

Inhibitory Effects of Ethyl Acetate Extract of Andrographis paniculata on NF-κB Trans-Activation Activity and LPS-Induced Acute Inflammation in Mice

Directory of Open Access Journals (Sweden)

Wen-Wan Chao

2011-01-01

Full Text Available This study was to investigate anti-inflammatory effect of Andrographis paniculata (Burm. f. Nees (Acanthaceae (AP. The effects of ethyl acetate (EtOAc extract from AP on the level of inflammatory mediators were examined first using nuclear factor kappa B (NF-κB driven luciferase assay. The results showed that AP significantly inhibited NF-κB luciferase activity and tumor necrosis factor α (TNF-α, interleukin 6 (IL-6, macrophage inflammatory protein-2 (MIP-2 and nitric oxide (NO secretions from lipopolysaccharide (LPS/interferon-γ stimulated Raw264.7 cells. To further evaluate the anti-inflammatory effects of AP in vivo, BALB/c mice were tube-fed with 0.78 (AP1, 1.56 (AP2, 3.12 (AP3 and 6.25 (AP4 mg kg−1 body weight (BW/day in soybean oil, while the control and PDTC (pyrrolidine dithiocarbamate, an anti-inflammatory agent groups were tube-fed with soybean oil only. After 1 week of tube-feeding, the PDTC group was injected with 50 mg kg−1 BW PDTC and 1 h later, all of the mice were injected with 15 mg kg−1 BW LPS. The results showed that the AP1, AP2, AP3 and PDTC groups, but not AP4, had significantly higher survival rate than the control group. Thus, the control, AP1, AP2, AP3 and PDTC groups were repeated for in vivo parameters. The results showed that the AP and PDTC groups had significantly lower TNF-α, IL-12p40, MIP-2 or NO in serum or peritoneal macrophages and infiltration of inflammatory cells into the lung of mice. The AP1 group also had significantly lower MIP-2 mRNA expression in brain. This study suggests that AP can inhibit the production of inflammatory mediators and alleviate acute hazards at its optimal dosages.

Humic acid in drinking well water induces inflammation through reactive oxygen species generation and activation of nuclear factor-κB/activator protein-1 signaling pathways: A possible role in atherosclerosis

International Nuclear Information System (INIS)

Hseu, You-Cheng; Senthil Kumar, K.J.; Chen, Chih-Sheng; Cho, Hsin-Ju; Lin, Shu-Wei; Shen, Pei-Chun; Lin, Cheng-Wen; Lu, Fung-Jou; Yang, Hsin-Ling

2014-01-01

Humic acid (HA) has been implicated as one of the etiological factors in the peripheral vasculopathy of blackfoot disease (BFD) in Taiwan. However, the underlying pathophysiological mechanisms of BFD are not well defined. In this study, we used an in vitro and in vivo model, in which HA (25–200 μg/mL) activated macrophages to produce pro-inflammatory molecules by activating their transcriptional factors. HA exposure induced NO and PGE 2 production followed by induction of iNOS and COX-2 through NF-κB/AP-1 transactivation in macrophages. In addition, the production of TNF-α and IL-1β was significantly increased by HA. Moreover, HA-induced iNOS and COX-2 expression were down-regulated by the NF-κB and AP-1 inhibitors pyrrolidine dithiocarbamate (PDTC) and Tanshinone, respectively. Furthermore, generations of ROS and nitrotyrosine, as well as activation of the AKT and MAPKs signaling cascades were observed after HA exposure. Specifically, HA-induced NF-κB activation was mediated by ROS and AKT, and that HA-induced AP-1 activation was mediated by JNK and ERK. Notably, HA-mediated AKT, JNK, and ERK activation was ROS-independent. The inflammatory potential of HA was correlated with increased expression of HO-1 and Nrf2. Furthermore, an in vivo study confirms that mice exposed to HA, the serum levels of TNF-α and IL-1β was significantly increased in a dose-dependent manner. This report marks the first confirmation that environmental exposure of HA induces inflammation in macrophages, which may be one of the main causes of early atherogenesis in blackfoot disease. - Highlights: • Humic acid (HA) induce pro-inflammatory cytokines and mediators in macrophages. • HA-induced inflammation is mediated by ROS and NF-κB/AP-1 signaling pathways. • The inflammatory potential of HA correlated with activation of Nrf2/HO-1 genes. • HA exposure to mice increased pro-inflammatory cytokines production in vivo. • HA may be one of the main causes of early atherogenesis

In-vitro antimicrobial screening and molecular docking studies of synthesized 2-chloro-N-(4-phenylthiazol-2-ylacetamide derivatives

Directory of Open Access Journals (Sweden)

Rahmat Ali

2015-01-01

Full Text Available Introduction: Glucosamine-6-phosphate (GlcN6P synthase biosynthetic pathway has been identified as potential targets for the development of new antimicrobial agents. Aim: A series of 2-chloro-N-(42-phenylthiazol-25-ylacetamide derivatives (3a-r was synthesized and evaluated their antimicrobial activity. Materials and Methods: The 2-chloro-N-(Para substituted phenylthiazol-25-yl acetamide (2a-c were synthesized by stirring intermediates (1a-c with 2-chloroacetylchloride in dichloromethane in the presence of K2CO3. The intermediate (2a-c were further reacted with different secondary amine such as pyrrolidine, N-methyl piperazine, N-ethyl piperazine, thiomorpholine, morpholine, piperidine etc in ethanol in presence of TEA Triethylamine (TEA to get desired compounds (3a-r. Compounds were characterized by a spectroscopic technique such as Fourier transform infraredFTIR, 1 H-NMR, 13 C-NMR, and mass spectrometry. The synthesized thiazole derivatives (3a-r were screened for anti-bacterial and anti-fungal activity against Escherichia coli, Staphylococcus aureus NCTC 6571, Pseudomonas aeruginosa NCTC 10662, CandidaC. albicans (MTCC-183, AspergillusA. niger (MTCC 281 NCTC 10418 and AspergillusA. flavus (MTCC 277. Result and Conclusion: The results of anti-bacterial screening revealed that among all the screened compounds, eight compounds viz. 3b, 3c, 3d, 3e, 3i, 3j, 3k, and 3p showed moderate to good anti-bacterial and antifungal activity having minimum inhibitory concentration (MIC between 6.25- and 25 µg/ml. While compound 3d showed the most promising antibacterial activity against E. coli and S. aureus, while the compound 3j showed promising antifungal activity with MIC value 6.25 µg/ml against C. albicans, A. niger and A. flavus. In addition, all these eight potential molecules were also examined for possible binding on enzyme GlcN6Pglucosamine-6-phosphate synthase by molecular docking studies on (PDB ID 1JXA.

Sequential cloud point extraction for the speciation of mercury in seafood by inductively coupled plasma optical emission spectrometry

International Nuclear Information System (INIS)

Li Yingjie; Hu Bin

2007-01-01

A novel nonchromatographic speciation technique for the speciation of mercury by sequential cloud point extraction (CPE) combined with inductively coupled plasma optical emission spectrometry (ICP-OES) was developed. The method based on Hg 2+ was complexed with I - to form HgI 4 2- , and the HgI 4 2- reacted with the methyl green (MG) cation to form hydrophobic ion-associated complex, and the ion-associated complex was then extracted into the surfactant-rich phase of the non-ionic surfactant octylphenoxypolyethoxyethanol (Triton X-114), which are subsequently separated from methylmercury (MeHg + ) in the initial solution by centrifugation. The surfactant-rich phase containing Hg(II) was diluted with 0.5 mol L -1 HNO 3 for ICP-OES determination. The supernatant is also subjected to the similar CPE procedure for the preconcentration of MeHg + by the addition of a chelating agent, ammonium pyrrolidine dithiocarbamate (APDC), in order to form water-insolvable complex with MeHg + . The MeHg + in the micelles was directly analyzed after disposal as describe above. Under the optimized conditions, the extraction efficiency was 93.5% for Hg(II) and 51.5% for MeHg + with the enrichment factor of 18.7 for Hg(II) and 10.3 for MeHg + , respectively. The limits of detection (LODs) were 56.3 ng L -1 for Hg(II) and 94.6 ng L -1 for MeHg + (as Hg) with the relative standard deviations (RSDs) of 3.6% for Hg(II) and 4.5% for MeHg + (C = 10 μg L -1 , n = 7), respectively. The developed technique was applied to the speciation of mercury in real seafood samples and the recoveries for spiked samples were found to be in the range of 93.2-108.7%. For validation, a certified reference material of DORM-2 (dogfish muscle) was analyzed and the determined values are in good agreement with the certified values

The effect of ozone on nicotine desorption from model surfaces:evidence for heterogeneous chemistry

Energy Technology Data Exchange (ETDEWEB)

Destaillats, Hugo; Singer, Brett C.; Lee, Sharon K.; Gundel, LaraA.

2005-05-01

Assessment of secondhand tobacco smoke exposure using nicotine as a tracer or biomarker is affected by sorption of the alkaloid to indoor surfaces and by its long-term re-emission into the gas phase. However, surface chemical interactions of nicotine have not been sufficiently characterized. Here, the reaction of ozone with nicotine sorbed to Teflon and cotton surfaces was investigated in an environmental chamber by monitoring nicotine desorption over a week following equilibration in dry or humid air (65-70 % RH). The Teflon and cotton surfaces had N{sub 2}-BET surface areas of 0.19 and 1.17 m{sup 2} g{sup -1}, and water mass uptakes (at 70 % RH) of 0 and 7.1 % respectively. Compared with dry air baseline levels in the absence of O{sub 3}, gas phase nicotine concentrations decrease, by 2 orders of magnitude for Teflon after 50 h at 20-45 ppb O{sub 3}, and by a factor of 10 for cotton after 100 h with 13-15 ppb O{sub 3}. The ratios of pseudo first-order rate constants for surface reaction (r) to long-term desorption (k) were r/k = 3.5 and 2.0 for Teflon and cotton surfaces, respectively. These results show that surface oxidation was competitive with desorption. Hence, oxidative losses could significantly reduce long-term re-emissions of nicotine from indoor surfaces. Formaldehyde, N-methylformamide, nicotinaldehyde and cotinine were identified as oxidation products, indicating that the pyrrolidinic N was the site of electrophilic attack by O{sub 3}. The presence of water vapor had no effect on the nicotine-O{sub 3} reaction on Teflon surfaces. By contrast, nicotine desorption from cotton in humid air was unaffected by the presence of ozone. These observations are consistent with complete inhibition of ozone-nicotine surface reactions in an aqueous surface film present in cotton but not in Teflon surfaces.

Efficacy of antipsychotic agents at human 5-HT(1A) receptors determined by [3H]WAY100,635 binding affinity ratios: relationship to efficacy for G-protein activation.

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Newman-Tancredi, A; Verrièle, L; Touzard, M; Millan, M J

2001-10-05

5-HT(1A) receptors are implicated in the aetiology of schizophrenia. Herein, the influence of 15 antipsychotics on the binding of the selective 'neutral' antagonist, [3H]WAY100,635 ([3H]N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)-cyclo-hexanecarboxamide), was examined at human 5-HT(1A) receptors expressed in Chinese Hamster Ovary cells. In competition binding experiments, 5-HT displayed biphasic isotherms which were shifted to the right in the presence of the G-protein uncoupling agent, GTPgammaS (100 microM). In analogy, the isotherms of ziprasidone, quetiapine and S16924 (((R-2-[1-[2-(2,3-dihydro-benzo[1,4]dioxin-5-yloxy)-ethyl]-pyrrolidin-3yl]-1-(4-fluoro-phenyl)-ethanone), were displaced to the right by GTPgammaS, consistent with agonist actions. Binding of several other antipsychotics, such as ocaperidone, olanzapine and risperidone, was little influenced by GTPgammaS. Isotherms of the neuroleptics, haloperidol, chlorpromazine and thioridazine were shifted to the left in the presence of GTPgammaS, suggesting inverse agonist properties. For most ligands, the magnitude of affinity changes induced by GTPgammaS (alteration in pK(i) values) correlated well with their previously determined efficacies in [35S]GTPgammaS binding studies [Eur. J. Pharmacol. 355 (1998) 245]. In contrast, the affinity of the 'atypical' antipsychotic agent, clozapine, which is a known partial agonist at 5-HT(1A) receptors, was less influenced by GTPgammaS. When the ratio of high-/low-affinity values was plotted against efficacy, hyperbolic isotherms were obtained, consistent with a modified ternary complex model which assumes that receptors can adopt active conformations in the absence of agonist. In conclusion, modulation of [3H]-WAY100,635 binding by GTPgammaS differentiated agonist vs. inverse agonist properties of antipsychotics at 5-HT(1A) receptors. These may contribute to differing profiles of antipsychotic activity.

Pharmacokinetics of oxiracetam and its degraded substance (HOPAA after oral and intravenous administration in rats

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Xinhuan Wan

2014-12-01

Full Text Available The pharmacokinetics of oxiracetam and its degraded substance (4-hydroxy-2-oxo-1-pyrrolidine acetic acid, HOPAA after oral and intravenous administration in rats were studied using an established UPLC-MS/MS method. Three groups of rats after an overnight fasted received 10 g/kg (n = 6 oxiracetam suspensions orally, and 2 g/kg (n = 6 normal or degraded oxiracetam injections intravenously via a caudal tail vein, respectively. Before the pharmacokinetic experiment, a simple safety evaluation test was conducted on the degraded oxiracetam injections containing 16.16% HOPAA in mice. There was no mortality by a single intravenous dose of 2 g/kg of degraded oxiracetam injections within two weeks, demonstrating that HOPAA was non-toxic in mice. Following intravenous administration of the normal injections, the plasma concentration-time curves of oxiracetam and HOPAA both showed a rapid elimination phase. The values of t1/2 were 3.1 ± 1.5 h for oxiracetam and 0.8 ± 0.2 h for HOPAA, and the mean residence times (MRT were 1.2 ± 0.1 h and 0.8 ± 0.1 h, respectively. Oxiracetam and HOPAA after intravenous administration of the degraded oxiracetam injections presented elimination patterns similar to those observed in the normal injections. Oral pharmacokinetic results showed that the Tmax was less than 1.5 h for the two analytes, and both had a longer t1/2 and MRT than those of intravenous administration. Contents of HOPAA in three groups were calculated based on AUC0–t values of the two analytes. The quantitative change of HOPAA in vivo was also evaluated by comparing the plasma concentrations of HOPAA and oxiracetam at the same time for every group. Additionally, the values of absolute bioavailability of oxiracetam were about 8.0% and 7.4% calculated by the normal or degraded oxiracetam injections, which were far less than the value of 75% reported in literature, indicating the necessity of further study.

Structurally related antitumor effects of flavanones in vitro and in vivo: involvement of caspase 3 activation, p21 gene expression, and reactive oxygen species production

International Nuclear Information System (INIS)

Shen, S.-C.; Ko, C.H.; Tseng, S.-W.; Tsai, S.-H.; Chen, Y.-C.

2004-01-01

Flavonoids exist extensively in plants and Chinese herbs, and several biological effects of flavonoids have been demonstrated. The antitumor effects in colorectal carcinoma cells (HT29, COLO205, and COLO320HSR) of eight flavanones including flavanone, 2'-OH flavanone, 4'-OH flavanone, 6-OH flavanone, 7-OH flavanone, naringenin, nargin, and taxifolin were investigated. Results of the MTT assay indicate that 2'-OH flavanone showed the most potent cytotoxic effect on these three cells, and cell death induced by 2'-OH flavanone was via the occurrence of DNA ladders, apoptotic bodies, and hypodiploid cells, all characteristics of apoptosis. Induction of caspase 3 protein processing and enzyme activity associated with cleavage of poly(ADP-ribose) polymerase (PARP) was identified in 2'-OH flavanone-treated cells, and a peptidyl inhibitor (Ac-DEVD-FMK) of caspase 3 attenuated the cytotoxicity of 2'-OH flavanone in COLO205 and HT-29 cells. Elevation of p21 (but not p53) and a decrease in Mcl-1 protein were found in 2'-OH flavanone-treated COLO205 and HT-29 cells. Elevation of intracellular reactive oxygen species (ROS) was detected in 2'-OH flavanone-treated cells by the 2',7'-dichlorodihydrofluorescein diacetate (DCHF-DA) assay, and ROS scavengers including 4,5-dihydro-1,3-benzene disulfonic acid (tiron), catalase, superoxide dismutase (SOD), and pyrrolidine dithiocarbamate (PDTC) suppressed the 2'-OH flavanone-induced cytotoxic effect. Subcutaneous injection of COLO205 induced tumor formation in nude mice, and 2'-OH flavanone showed a significant inhibitory effect on tumor formation. The appearance of apoptotic cells with H and E staining, and an increase in p21, but not p53, protein by immunohistochemistry were observed in tumor tissues under 2'-OH flavanone treatment. Primary tumor cells (COLO205-X) derived from a tumor specimen elicited by COLO205 were established, and 2'-OH flavanone showed an significant apoptotic effect in COLO205-X cells in accordance with the

The structure and conformations of piracetam (2-oxo-1-pyrrolidineacetamide): Gas-phase electron diffraction and quantum chemical calculations

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Ksenafontov, Denis N.; Moiseeva, Natalia F.; Khristenko, Lyudmila V.; Karasev, Nikolai M.; Shishkov, Igor F.; Vilkov, Lev V.

2010-12-01

The geometric structure of piracetam was studied by quantum chemical calculations (DFT and ab initio), gas electron diffraction (GED), and FTIR spectroscopy. Two stable mirror symmetric isomers of piracetam were found. The conformation of pyrrolidine ring is an envelope in which the C4 atom deviates from the ring plane, the angle between the planes (C3 sbnd C4 sbnd C5) and (C2 sbnd C3 sbnd C5) is 154.1°. The direction of the deviation is the same as that of the side acetamide group. The piracetam molecule is stabilized in the gas phase by an intramolecular hydrogen bond between the N9H 2 group and the oxygen O6, bonded to C2. The principal structural parameters ( re, Å and ∠e, degrees; uncertainties are 3 σLS values) were found to be: r(С3 sbnd С4) = 1.533(1), r(C4 sbnd C5) = 1.540(1), r(N1 sbnd C5) = 1.456(1), r(C2 sbnd C3) = 1.520(1), r(N1 sbnd C7) = 1.452(1), r(C7 sbnd C8) = 1.537(1), r(N1 sbnd C2) = 1.365(2), r(C8 sbnd N9) = 1.360(2), r(C2 dbnd O6) = 1.229(1), r(C8 dbnd O10) = 1.221(1), ∠C2 sbnd N1 sbnd C5 = 113.4(6), ∠N1 sbnd C2 sbnd C3 = 106.9(6), ∠N1 sbnd C7 sbnd C8 = 111.9(6), ∠C7 sbnd C8 sbnd N9 = 112.5(6), ∠N1 sbnd C2 sbnd O6 = 123.0(4), ∠C3 sbnd N1 sbnd C7 = 120.4(4), ∠C7 sbnd C8 sbnd O10 = 120.2(4), ∠C5 sbnd N1 sbnd C2 sbnd O6 = 170(6), ∠C3 sbnd C2 sbnd N1 sbnd C7 = 178(6), ∠C2 sbnd N1 sbnd C7 sbnd C8 = 84.2, ∠N1 sbnd C7 sbnd C8 sbnd O10 = 111.9.

The use of dispersive X-ray fluorescence technique for pollution evaluation of heavy metals in water samples and lake sediments

International Nuclear Information System (INIS)

Vives, Ana Elisa Sirito de; Brienza, Sandra Maria Boscolo

2002-01-01

The energy dispersive X-ray fluorescence technique (EDXRF) was used to determine metals concentration in water and bottom sediments samples in lakes at Santa Gertrudes region, Sao Paulo state, Brazil. The studied area is about 12 ha, with several lakes formed by argil extraction and present high volume of waste which can be dangerous and cause risks to water flora and fauna and also to human health by direct or indirect contact with the residues. To evaluate contamination degree by heavy metals water samples were collected in three lakes, in 2000 July and November, corresponding to the dry and rainy season. In two lakes the sampling procedure were superficial, and in the third lake, sampling was done at central region and in different deepness. Sediment samples were collected at two lakes, in 2000, July (dry) and November (rainy). To determine biologically available metals concentration (no-residual fraction) in the sediment, an acid extraction procedure was used. To quantitative analysis of both samples, metals were pre concentrated by complexation with ammonium pyrrolidine dithiocarbamate. Samples were excited with a X-ray tube with Mo target and Zr filter, operated at 25 kV/10 mA, and X-ray characteristics measure were done with a Si(Li) semi conductor detector. In water samples, were determined the elements Fe, Cu, Zn and Pb. Among the analyzed elements, Fe presented the highest concentration, independent of the sampling local. Was verified that all the analyzed elements presented concentrations below the maximum limit allowed to waters class 2, which may be distributed to domestic provisioning, to primary contact recreation, to vegetables and fruitier plants irrigation and to the natural and/or intensive breeding (agriculture) of species destined to the alimentation. In the sediment samples were determined Fe, Co, Ni, Cu, Zn and Pb, and was observed high contents to the elements Fe, Zn and Pb and relatively low concentrations of Co, Ni and Cu. It was verified

Inhibition of nuclear factor kappa-B signaling reduces growth in medulloblastoma in vivo

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Deckard Lindsey A

2011-04-01

Full Text Available Abstract Background Medulloblastoma is a highly malignant pediatric brain tumor that requires surgery, whole brain and spine irradiation, and intense chemotherapy for treatment. A more sophisticated understanding of the pathophysiology of medulloblastoma is needed to successfully reduce the intensity of treatment and improve outcomes. Nuclear factor kappa-B (NFκB is a signaling pathway that controls transcriptional activation of genes important for tight regulation of many cellular processes and is aberrantly expressed in many types of cancer. Methods To test the importance of NFκB to medulloblastoma cell growth, the effects of multiple drugs that inhibit NFκB, pyrrolidine dithiocarbamate, diethyldithiocarbamate, sulfasalazine, curcumin and bortezomib, were studied in medulloblastoma cell lines compared to a malignant glioma cell line and normal neurons. Expression of endogenous NFκB was investigated in cultured cells, xenograft flank tumors, and primary human tumor samples. A dominant negative construct for the endogenous inhibitor of NFκB, IκB, was prepared from medulloblastoma cell lines and flank tumors were established to allow specific pathway inhibition. Results We report high constitutive activity of the canonical NFκB pathway, as seen by Western analysis of the NFκB subunit p65, in medulloblastoma tumors compared to normal brain. The p65 subunit of NFκB is extremely highly expressed in xenograft tumors from human medulloblastoma cell lines; though, conversely, the same cells in culture have minimal expression without specific stimulation. We demonstrate that pharmacological inhibition of NFκB in cell lines halts proliferation and leads to apoptosis. We show by immunohistochemical stain that phosphorylated p65 is found in the majority of primary tumor cells examined. Finally, expression of a dominant negative form of the endogenous inhibitor of NFκB, dnIκB, resulted in poor xenograft tumor growth, with average tumor volumes

Therapeutic Efficacy and Tolerability of the Topical Treatment of Inflammatory Conditions of the Oral Cavity with a Mouthwash Containing Diclofenac Epolamine : A Randomized, Investigator-Blind, Parallel-Group, Controlled, Phase III Study.

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Serafini, Giampiero; Trevisan, Silvia; Saponati, Giorgio; Bandettini, Bernardo

2012-01-01

Non-steroidal anti-inflammatory drugs (NSAIDs), including diclofenac, are the mainstay of analgesic and anti-inflammatory treatment in dentistry. Diclofenac epolamine [diclofenac N-(2-hydroxyethyl)pyrrolidine; DHEP] is a diclofenac salt with greater water solubility and better cutaneous absorption properties than other commonly used forms of the drug. IBSA has recently developed a mouthwash formulation of DHEP for the topical treatment of inflammatory conditions of the oral cavity. The aim of this study was to compare the efficacy and tolerability of DHEP mouthwash (Osmal®) with that of a reference product (commercially available diclofenac mouthwash). This was a randomized, investigator-blind, parallel-group, controlled, phase III study that enrolled 80 patients with conditions affecting the oral cavity, characterized by an inflammatory component, and eligible for analgesic and anti-inflammatory treatment. Patients were randomized 1 : 1 to DHEP mouthwash (0.103% DHEP in aqueous solution) or to diclofenac mouthwash (0.074% free diclofenac in aqueous solution). The treatment regimen was the same in both groups: 1-minute rinse with 15 mL of mouthwash, twice daily for 7 days. Visits were scheduled at study inclusion (D0), and 3 days (D3) and 7 days (D7) after treatment initiation. During each visit assessments were made of pain severity (using a 5-point semi-quantitative scale and a 100-mm visual analogue scale [VAS]) and inflammatory signs (using a 5-point scale). The primary study endpoint was the change in pain severity scores from D0 to D3 and D7. Secondary endpoints included effects of treatment on inflammation score, quality of sleep, compliance with treatment and the safety and tolerability of treatment. The two treatment arms were homogeneous in terms of patient characteristics. The most prevalent oral condition was gingivitis. Overall both topical treatments were effective in alleviating pain and inflammation, as evidenced by decreases in pain and

Design, synthesis, and validation of a β-turn mimetic library targeting protein-protein and peptide-receptor interactions.

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Whitby, Landon R; Ando, Yoshio; Setola, Vincent; Vogt, Peter K; Roth, Bryan L; Boger, Dale L

2011-07-06

The design and synthesis of a β-turn mimetic library as a key component of a small-molecule library targeting the major recognition motifs involved in protein-protein interactions is described. Analysis of a geometric characterization of 10,245 β-turns in the protein data bank (PDB) suggested that trans-pyrrolidine-3,4-dicarboxamide could serve as an effective and synthetically accessible library template. This was confirmed by initially screening select compounds against a series of peptide-activated GPCRs that recognize a β-turn structure in their endogenous ligands. This validation study was highlighted by identification of both nonbasic and basic small molecules with high affinities (K(i) = 390 and 23 nM, respectively) for the κ-opioid receptor (KOR). Consistent with the screening capabilities of collaborators and following the design validation, the complete library was assembled as 210 mixtures of 20 compounds, providing a total of 4200 compounds designed to mimic all possible permutations of 3 of the 4 residues in a naturally occurring β-turn. Unique to the design and because of the C(2) symmetry of the template, a typical 20 × 20 × 20-mix (8000 compounds prepared as 400 mixtures of 20 compounds) needed to represent 20 variations in the side chains of three amino acid residues reduces to a 210 × 20-mix, thereby simplifying the library synthesis and subsequent screening. The library was prepared using a solution-phase synthetic protocol with liquid-liquid or liquid-solid extractions for purification and conducted on a scale that insures its long-term availability for screening campaigns. Screening the library against the human opioid receptors (KOR, MOR, and DOR) identified not only the activity of library members expected to mimic the opioid receptor peptide ligands but also additional side-chain combinations that provided enhanced receptor binding selectivities (>100-fold) and affinities (as low as K(i) = 80 nM for KOR). A key insight to emerge from

Naftopidil inhibits 5-hydroxytryptamine-induced bladder contraction in rats.

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Sakai, Takumi; Kasahara, Ken-ichi; Tomita, Ken-ichi; Ikegaki, Ichiro; Kuriyama, Hiroshi

2013-01-30

Naftopidil is an α(1D) and α(1A) subtype-selective α(1)-adrenoceptor antagonist that has been used to treat lower urinary tract symptoms of benign prostatic hyperplasia. In this study, we investigated the effects of naftopidil on 5-hydroxytryptamine (5-HT)-induced rat bladder contraction (10(-8)-10(-4) M). Naftopidil (0.3, 1, and 3 μM) inhibited 5-HT-induced bladder contraction in a concentration-dependent manner. On the other hand, other α(1)-adrenoceptor antagonists, tamsulosin, silodosin or prazosin, did not inhibit 5-HT-induced bladder contraction. The 5-HT-induced bladder contraction was inhibited by both ketanserin and 4-(4-fluoronaphthalen-1-yl)-6-propan-2-ylpyrimidin-2-amine (RS127445), serotonin 5-HT(2A) and 5-HT(2B) receptor antagonists, respectively. In addition, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and α-methyl-5-HT, 5-HT(2A) and 5-HT(2) receptor agonists, respectively, induced bladder contraction. The 5-HT-induced bladder contraction was not inhibited by N-[2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]-N-pyridin-2-yl-cyclohexanecarboxamide (WAY-100635), [1-[2[(methylsulfonyl)amino]ethyl]-4-piperidinyl]methyl-1-methyl-1H-indole-3-carboxylate (GR113808) or (R)-3-[2-[2-(4-methylpiperidin-1-yl)ethyl]pyrrolidine-1-sulphonyl]phenol (SB269970), 5-HT(1A), 5-HT(4) and 5-HT(7) receptor antagonists, respectively. Naftopidil inhibited both the 5-HT(2A) and 5-HT(2) receptor agonists-induced bladder contractions. Naftopidil binds to the human 5-HT(2A) and 5-HT(2B) receptors with pKi values of 6.55 and 7.82, respectively. These results suggest that naftopidil inhibits 5-HT-induced bladder contraction via blockade of the 5-HT(2A) and 5-HT(2B) receptors in rats. Furthermore, 5-HT-induced bladder contraction was enhanced in bladder strips obtained from bladder outlet obstructed rats, with this contraction inhibited by naftopidil. The beneficial effects of naftopidil on storage symptoms such as urinary frequency and nocturia in patients with benign

Characterization and H2-O2 reactivity of noble nano-metal tailored single wall nano-carbons

International Nuclear Information System (INIS)

K Kaneko; T Itoh; E Bekyarova; H Kanoh; S Utsumi; H Tanaka; M Yudasaka; S Iijima; S Iijima

2005-01-01

Full text of publication follows: Single wall carbon nano-tube (SWNT) and single wall carbon nano-horn (SWNH) have nano-spaces in their particles and the nano-spaces become open by oxidation. In particular, SWNH forms a unique colloidal structure which has micropores and meso-pores between the SWNH particles. Although non-treated SWNH colloids have quasi-one dimensional nano-pores [1], oxidized SWNH colloids have both of interstitial and internal nano-pores [2-5]. SWNH colloids show excellent supercritical methane storage ability [6], molecular sieving effect [7], and unique hydrogen adsorption characteristic [8]. Selective adsorptivity of SWNH colloids for H 2 and D 2 due to uncertainty principle of those molecules was shown [9-10]. As SWNH has no metallic impurities, we can study the effect of tailoring of metallic nano-particles on the surface activities of SWNH [11]. We tailored Pd or Pt nano-particles on SWNH and SWNH oxidized at 823 K (ox-SWNH) using poly[(2-oxo-pyrrolidine-1-yl)ethylene]. The oxidation of SWNH donates nano-scale windows to the single wall. The tailored metal amount was determined by TG analysis. TEM showed uniform dispersion of nano-metal particles of 2-3 nm in the diameter on SWNH. The nitrogen adsorption amount of SWNH oxidized decreases by tailoring, indicating that nano-particles are attached to the nano-scale windows. The electronic states of tailored metals were characterized by X-ray photoelectron spectroscopy. The surface activities of Pd tailored SWNH and ox-SWNH were examined for the reaction of hydrogen and oxygen near room temperature. The catalytic reactivities of Pd tailored SWNH and ox-SWNH were 4 times greater than that of Pd-dispersed activated carbon. The temperature dependence of the surface activity will be discussed with the relevance to the tube porosity. References [1] T. Ohba et al, J. Phys. Chem. In press. [2] S. Utsumi et al, J. Phys. Chem. In press. [3] C.- Min Yang, et al. Adv. Mater. In press. [4]C.M. Yang, J

CD44+/CD24- breast cancer cells exhibit phenotypic reversion in three-dimensional self-assembling peptide RADA16 nanofiber scaffold

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Mi K

2015-04-01

formation assay further supported of the functional changes caused by the reversion in 3D RADA16 culture. Expression levels of intercellular surface adhesion molecule-1 were upregulated in cells cultured in RADA16 scaffolds, and the NF-kappa B inhibitor pyrrolidine dithiocarbamate could inhibit RADA16-induced upregulation of intercellular surface adhesion molecule-1 and the phenotype reversion of MDA-MB-453S cells.Conclusion: Culturing a CD44+/CD24--enriched breast cancer cell population in 3D RADA16 peptide nanofiber scaffold led to a significant phenotypic reversion compared with Matrigel and collagen I. Keywords: 3D culture, phenotype, reversion

Investigation of the effect of mutations of rat albumin on the binding affinity to the alpha(4)beta(1) integrin antagonist, 4-[1-[3-chloro-4-[N'-(2-methylphenyl)ureido]phenylacetyl]-(4S)-fluoro-(2S)-pyrrolidine-2-yl]methoxybenzoic acid (D01-4582), using recombinant rat albumins.

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Ito, Takashi; Takahashi, Masayuki; Okazaki, Osamu; Sugiyama, Yuichi

2010-08-02

The authors reported previously rat strain differences in plasma protein binding to alpha(4)beta(1) antagonist D01-4582, resulting in a great strain difference in its pharmacokinetics (19-fold differences in the AUC). The previous study suggested that amino acid changes of V238L and/or T293I in albumin reduced the binding affinity. In order to elucidate the relative significance of these mutations, an expression system was developed to obtain recombinant rat albumins (rRSA) using Pichia pastoris, followed by a binding analysis of four rRSAs by the ultracentrifugation method. The equilibrium dissociation constant (K(d)) of wild-type rRSA was 210 nM, while K(d) of rRSA that carried both V238L and T293I mutations was 974 nM. K(d) of artificial rRSA that carried only V238L was 426 nM, and K(d) of artificial rRSA that carried only T293I was 191 nM. These results suggested that V238L would be more important in the alteration of K(d). However, since none of the single mutations were sufficient to explain the reduction of affinity, the possibility was also suggested that T293I interacted cooperatively to reduce the binding affinity of rat albumin to D01-4582. Further investigation is required to elucidate the mechanism of the possible cooperative interaction.

Metal-Free Approaches to Sterically-Hindered Bonds

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Dunham, Veronica Vin-yi

variety of nitrimines and amines including piperidine, pyrrolidine, dibenzylamine, substituted indolines, and substituted N-methylanilines. Further investigations into the applicability of nitrimines for the synthesis of sterically-hindered bonds led to the discovery of formal carbon-carbon cross coupling reactions involving nitrimines and carbon nucleophiles such as indole, pyrrole, and hydroxycoumarin. Under optimized conditions, moderate to high yields of the desired dior tri-substituted alkene product were obtained with electron-rich and electron-poor nitrimines. Furthermore, by strategic modification of the reaction conditions, control over the E/Z selectivity of the tri-substituted alkene products gave up to 19:1 ratio of Z:E isomers. This nitrimine-based formal carbon-carbon cross coupling methodology was then applied to the synthesis of a small target molecule, phenprocoumon, which was obtained in an overall 67% yield. The undeniable utility of urea catalysis operating through hydrogen bond donor (HBD) interactions has prompted the examination into enhanced HBD catalysts. Through the incorporation of a strategically placed Lewis acid on a urea scaffold, a new family of highly tunable HBD catalysts benefitting from enhanced activity was established. After determining the pKa of various urea catalysts using Bordwell's method of overlapping indicators and comparing catalysts in two reaction systems, it was observed that the choice of Lewis acid and its associated ligands had an effect on urea reactivity, acidity, and polarization. In addition to Lewis acid assisted urea catalysts, silanediols have been discovered to participate as enhanced HBD catalysts. Taking advantage of the ability of our silanediol catalysts to participate in asymmetric anion-binding catalysis, a strategy toward an enantioselective synthesis of the sterically-encumbered molecule gonytolide A, an innate immune promoter, is underway.

Ethnomedical uses and pharmacological activities of most prevalent species of genus Piper in Panama: A review.

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Durant-Archibold, Armando A; Santana, Ana I; Gupta, Mahabir P

2018-05-10

uses are by native Amerindians of Panama. These include ailments such as liver pains, common colds, skin infections, insecticidal, as a bath to alleviate colds, snakebites, different types of pains, skin ailments, wound healing, rheumatism, women's health, antipyretic, and anti-inflammatory. Other Panamanian species are widely used in many countries of the world. Of all the Piper species, P. aduncum has the most ethnomedical uses. Panamanian uses are different from the ones in other countries. A total of 61 compounds present in Piper species reported in this review have shown a variety of biological activities in vitro. These compounds belong to different chemical types, such as chromenes, amides, alkaloids, benzopyrans, benzoates, essential oils, pyrrolidines, flavokaines, chalcones, methylenedioxy propiophenones, cinnamates, monoterpenes, sesquiterpenes, phenols, among others. From this review it is evident that extracts and pure compounds isolated from Piper species have shown a wide array of mainly in vitro activity and some ethnomedical uses may be correlated with their activities reported. Plants of this genus have provided bioactive species, both from crude extracts and pure compounds thus substantiating their efficacy in traditional medicine. In vivo and toxicological studies are still limited, but the results of different activities of Piper reported point out the great potential of these species for obtaining bioactive principles that may be useful in treating diseases. However, a thorough investigation of Piper species relating to chemistry, in vivo pharmacological activities, with emphasis on their mechanism of action, safety and efficacy and toxicity is warranted. Copyright © 2018 Elsevier B.V. All rights reserved.

Peripheral and spinal 5-HT receptors participate in the pronociceptive and antinociceptive effects of fluoxetine in rats.

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Cervantes-Durán, C; Rocha-González, H I; Granados-Soto, V

2013-11-12

The role of 5-HT receptors in fluoxetine-induced nociception and antinociception in rats was assessed. Formalin produced a typical pattern of flinching and licking/lifting behaviors. Local peripheral ipsilateral, but not contralateral, pre-treatment with fluoxetine (0.3-3 nmol/paw) increased in a dose-dependent fashion 0.5% formalin-induced nociception. In contrast, intrathecal pretreatment with fluoxetine (0.3-3 nmol/rat) prevented nociception induced by formalin. The peripheral pronociceptive effect of fluoxetine was prevented by the 5-HT2A (ketanserin, 3-10 pmol/paw), 5-HT2B (3-(2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl)-2,4(1H,3H)-quinazolinedione(+) tartrate, RS-127445, 3-10 pmol/paw), 5-HT2C (8-[5-(2,4-dimethoxy-5-(4-trifluoromethylphenylsulphonamido) phenyl-5-oxopentyl]1,3,8-triazaspiro[4.5] decane-2,4-dione hydrochloride, RS-102221, 3-10 pmol/paw), 5-HT3 (ondansetron, 3-10 nmol/paw), 5-HT4 ([1-[2-methylsulphonylamino ethyl]-4-piperidinyl]methyl 1-methyl-1H-indole-3-carboxylate, GR-113808, 3-100 fmol/paw), 5-HT6 (4-iodo-N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]benzene-sulfonamide hydrochloride, SB-258585, 3-10 pmol/paw) and 5-HT7 ((R)-3-(2-(2-(4-methylpiperidin-1-yl) ethyl) pyrrolidine-1-sulfonyl) phenol hydrochloride, SB-269970, 0.3-1 nmol/paw), but not by the 5-HT1A (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide maleate, WAY-100635, 0.3-1 nmol/paw), 5-HT1B/1D (N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-1,1'-biphenyl-4-carboxamide hydrochloride hydrate, GR-127935, 0.3-1 nmol/paw), 5-HT1B (1'-methyl-5-[[2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]carbonyl]-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine hydrochloride, SB-224289, 0.3-1 nmol/paw), 5-HT1D (4-(3-chlorophenyl)-α-(diphenylmethyl)-1-piperazineethanol hydrochloride, BRL-15572, 0.3-1nmol/paw) nor 5-HT5A ((N-[2-(dimethylamino)ethyl]-N-[[4'-[[(2-phenylethyl)amino]methyl][1,1'-biphenyl]-4

Carbon-11 labelling of S38419, a novel alpha-4-beta-2-selective ligand for PET imaging of nicotinic acetylcholine receptors

International Nuclear Information System (INIS)

Dolle, F.; Demphel, St.; Saba, W.; Schollhorn-Peyronneau, M.A.; Deverre, J.R.; Bottlaender, M.; Valette, H.; Charton, Y.; Goldstein, S.; Lestage, P.

2011-01-01

Complete text of publication follows: Objectives: There is considerable evidence that a variety of functions and disorders (e.g. Alzheimer's and Parkinson's disease) of the CNS is associated with the neuronal nicotinic acetylcholine receptors and particularly with the subtypes containing α4 and β2 subunits (nAChRs). The consistent and severe loss of these receptors in the diseases mentioned above has prompted extensive efforts, over more than two decades now, into the design of PET radioligands for non-invasive in vivo imaging of these receptors and the quantification of their density in the human brain. Not only analogues of the alkaloid epibatidine were labelled with positron-emitters but also series of 3-pyridyl ethers bearing either the traditional nicotinic-like pyrrolidine ring (e.g. [ 11 C]A-84543) or the azetidine motive (e.g. 2-[ 18 F]F-A-85380). Novel structures, still possessing high affinity and selectivity for nAChRs but not displaying any saturated, nitrogen-containing, 5- or 4-membered rings were also reported (e.g. [ 11 C]p-PVPMEMA). Recently, a novel series of highly potent α4β2-selective 3-pyridinamines (exhibiting a cyclopropane ring together with a non-cyclic amino function) has been developed by Servier Laboratories. Within this series, S38419 (1, N-methyl-N-[[1-(methylamino)cyclopropyl]methyl]pyridin-3-amine) was selected on the basis of its pharmacological and biological characteristics as a potent candidate for PET imaging and was isotopically labelled with carbon-11 using [ 11 C]methyl triflate. Methods: Carbon-11 labelling of S38419 (1) was performed using a TRACERLab FX-C Pro synthesizer (GEMS) and comprises (1) trapping at -10 C of [ 11 C]MeOTf in DMF (0.3 mL) containing the nor-derivative (N-demethylated, 1.8-2.0 mg); (2) heating at 120 C for 2 min; (3) taking up the residue in 1.0 mL of the HPLC mobile phase; (4) purification using semi-preparative reversed-phase HPLC (Waters Symmetry R C-18 - eluent: CH 3 CN / H 2 O / TEA: 20 / 80

Use and acute toxicity associated with the novel psychoactive substances diphenylprolinol (D2PM) and desoxypipradrol (2-DPMP).

Science.gov (United States)

Wood, David M; Dargan, Paul I

2012-09-01

Over the last decade there has been greater use of novel psychoactive substances ('legal highs') across Europe and the United States, including increasing reports of use of diphenylprolinol (D2PM) and desoxypipradrol (2-DPMP). This review will discuss the pharmacology and mechanisms of action of these two compounds, available data on their sources and prevalence of use and reports of acute toxicity and fatalities associated with their use. PubMed was searched using the search terms 'D2PM', '2-DPMP', 'diphenyl-2-pyrrolidinyl-methanol', 'diphenylprolinol', '2-diphenylmethylpiperidine' and 'desoxypipradrol'. These searches identified 70 articles, only five of which were relevant. PHARMACOLOGY AND MECHANISMS OF ACTION: D2PM is a pyrrolidine analogue and 2-DPMP is a desoxy analogue of pipradrol. Animal studies have shown that 2-DPMP increases the release of dopamine and decreases dopamine re-uptake comparable to the effects of cocaine. The binding and activity of D2PM at the dopamine re-uptake transporter, based on currently published data, is also similar to cocaine, although it appears that D2PM has less biological activity. SOURCES AND PREVALENCE OF USE: D2PM and 2-DPMP is available from internet-based suppliers and street level drug dealers; there is currently no systematic data to be able to determine the relative importance of these routes of supply. There is no population level, and limited subpopulation level, data on the prevalence of use of D2PM/2-DPMP. In one 2011 study, 1.6% of 315 individuals in 'gay friendly' nightclubs in South London reported that they had used a pipradrol: 1.0% had used within the last year and 0.6% had used or were planning to use a pipradrol on the night of the survey. ACUTE TOXICITY: Reports on internet discussion fora describe prolonged euphoria and stimulant effects including euphoria, sweating and bruxism with use of D2PM and 2-DPMP. The first report of analytically confirmed acute D2PM toxicity described chest pain and

Spectroscopic Evidence for Covalent Binding of Sulfadiazine to Natural Soils via 1,4-nucleophilic addition (Michael Type Addition) studied by Spin Labeling ESR

Science.gov (United States)

Aleksandrova, Olga

2015-04-01

Among different classes of veterinary pharmaceuticals, Sulfadiazine (SDZ) is widely used in animal husbandry. Its residues were detected in different environmental compartments. However, soil is a hot spot for SDZ as it receives a large portion of excreted compounds through the application of manure during soil fertilization. Ample studies on the fate of SDZ in soils showed that a large portion forms nonextractable residues (NER) along with transformation products and a low mineralization (Mueller et al., 2013). A common observation was an initially fast formation of NER up to 10% of the applied amount promptly after the application of SDZ to soil, and this portion increased up to 50% within a few days (Mueller et al., 2013; Nowak et al., 2011). A common finding for SDZ, as for other sulfonamides, was biphasic kinetics of the formation of NER, which was attributed to the occurrence of two reaction processes: a rapid, often reversible process and a slower, irreversible process (Weber et al., 1996). A single-phase reaction process was also established under anaerobic treatment (Gulkowska et al., 2014). A major focus of this work is to elucidate a reaction mechanism of covalent binding of SDZ to soil that is currently required to estimate a risk of NER formed by SDZ in soils for human health. Taking into account a key role of the amine functional groups of SDZ on its reactivity in soil, nitroxide radicals with the sewed aromatic or aliphatic amines labeled soil samples and then, were investigated by means of ESR spectroscopy. 2,5,5-Trimethyl-2-(3-aminophenyl)pyrrolidin-1-yloxy and 4-amino-2,2,6,6-Tetramethylpiperidin-1-oxyl modeled decomposition products of SDZ with the aromatic and aliphatic amines, respectively. The application of the defined combination of both spin labels (SL) to different soils well simulated a change of a paramagnetic signal of soil organic radicals interacted with SDZ. After their application to soil, SL were found in soil sites characterized

Microinjection moulding of polymeric composites with functionalized carbon nanotubes =

Science.gov (United States)

Ferreira, Tania Sofia Araujo Figueiras

Microinjection moulding of polymeric composites with functionalized carbon nanotubes The unique electronic, mechanical, and structural properties of carbon nanotubes (CNT) make them suitable for applications in the fields of electronics, sensors, medical devices, aerospace and automotive industries. The preparation of CNT/polymer nanocomposites presents particular interest among the various possible applications. However, the long entangled nanotubes form agglomerates that poses serious obstacles to further development of nanocomposites with the target properties. One of the approaches to overcome the CNT chemical inertness, enhance the compatibility with the matrix and improve homogeneous dispersion through the matrix is through its covalent functionalization. This is expected to improve the CNT interface with the polymer matrix, thus improving the mechanical properties of the nanocomposites at very low content. One of the purposes of this thesis was to implement the covalent modification of the CNT surface using a simple functionalization method, to increase the CNT surface reactivity and possibly help their dispersion into the polyamide matrix without inducing structural damage on the CNT. The functionalization of CNT was carried out through the 1,3-dipolar cycloaddition reaction of azomethine ylides using a solvent-free reaction route. CNT were successful functionalized with pyrrolidine groups through a simple and fast procedure that was scaled up, and may be compatible with current industrial processes. Another objective was to disperse the CNT in polyamide 6 (PA6) using melt mixing, and to produce PA6/CNT nanocomposites by microinjection molding (plM). Finally, the morphological and physical properties of the mouldings produced were evaluated. The plM process is becoming of greater importance for the manufacturing of polymeric micro- components considering its low cost and short cycle times, useful for mass production. The as-received and functionalized CNT

[Effects of hypoxia on the phenotype transformation of human dermal fibroblasts to myofibroblasts and the mechanism].

Science.gov (United States)

Zhao, B; Han, F; Zhang, W; Wang, X J; Zhang, J; Yang, F F; Shi, J H; Su, L L; Hu, D H

2017-06-20

Objective: To investigate the effects of hypoxia on the phenotype transformation of human dermal fibroblasts to myofibroblasts and the mechanism. Methods: The third passage of healthy adult human dermal fibroblasts in logarithmic phase were cultured in DMEM medium containing 10% fetal bovine serum for the following five experiments. (1) In experiments 1, 2, and 3, cells were divided into normoxia group and hypoxia group according to the random number table, with 10 dishes in each group. Cells of normoxia group were cultured in incubator containing 21% oxygen, while those of hypoxia group with 1% oxygen. At post culture hour (PCH) 0 and 48, 5 dishes of cells were collected from each group, respectively. mRNA expressions of markers of myofibroblasts including alpha smooth muscle actin (α-SMA), type Ⅰ collagen, and type Ⅲ collagen of cells were determined with real time fluorescent quantitative reverse transcription polymerase chain reaction in experiment 1. Protein expressions of α-SMA, type Ⅰ collagen, and type Ⅲ collagen of cells were determined with Western blotting in experiment 2. The protein expression of nuclear factor-kappa B (NF-κB) of cells was determined with Western blotting in experiment 3. (2) In experiment 4, cells were divided into normoxia group, hypoxia group, and hypoxia+ pyrrolidine dithiocarbamate (PDTC) group according to the random number table, with 5 dishes in each group. Cells in the former two groups were treated the same as those in experiment 1. Cells in hypoxia+ PDTC group were treated the same as those in hypoxia group plus adding 4 mL PDTC with a final molarity of 10 μmol/L in the culture medium. At PCH 48, the protein expression of NF-κB of cells was determined with Western blotting. (3) In experiment 5, cells were divided into normoxia group, hypoxia group, hypoxia+ PDTC group, and normoxia+ PDTC group according to the random number table, with 5 dishes in each group. Cells in the former three groups were treated the