C-H bond functionalization via hydride transfer: formation of α-arylated piperidines and 1,2,3,4-tetrahydroisoquinolines via stereoselective intramolecular amination of benzylic C-H bonds.

PubMed

Vadola, Paul A; Carrera, Ignacio; Sames, Dalibor

2012-08-17

We here report a study of the intramolecular amination of sp(3) C-H bonds via the hydride transfer cyclization of N-tosylimines (HT-amination). In this transformation, 5-aryl aldehydes are subjected to N-toluenesulfonamide in the presence of BF(3)·OEt(2) to effect imine formation and HT-cyclization, leading to 2-arylpiperidines and 3-aryl-1,2,3,4-tetrahydroisoquinolines in a one-pot procedure. We examined the reactivity of a range of aldehyde substrates as a function of their conformational flexibility. Substrates of higher conformational rigidity were more reactive, giving higher yields of the desired products. However, a single substituent on the alkyl chain linking the N-tosylimine and the benzylic sp(3) C-H bonds was sufficient for HT-cyclization to occur. In addition, an examination of various arenes revealed that the electronic character of the hydridic C-H bonds dramatically affects the efficiency of the reaction. We also found that this transformation is highly stereoselective; 2-substituted aldehydes yield cis-2,5-disubstituted piperidines, while 3-substituted aldehydes afford trans-2,4-disubstituted piperidines. The stereoselectivity is a consequence of thermodynamic control. The pseudoallylic strain between the arene and tosyl group on the piperidine ring is proposed to rationalize the greater stability of the isomer with the aryl ring in the axial position. This preferential placement of the arene is proposed to affect the observed stereoselectivity.

Crystal structure of 4-meth-oxy-N-(piperidine-1-carbono-thio-yl)benzamide.

PubMed

Suhud, Khairi; Hasbullah, Siti Aishah; Ahmad, Musa; Heng, Lee Yook; Kassim, Mohammad B

2017-10-01

In the title compound, C 14 H 18 N 2 O 2 S, the piperidine ring has a chair conformation. Its mean plane is twisted with respect to the 4-meth-oxy-benzoyl ring, with a dihedral angle of 63.0 (3)°. The central N-C(=S)-N(H)-C(=O) bridge is twisted with an N-C-N-C torsion angle of 74.8 (6)°. In the crystal, mol-ecules are linked by N-H⋯O and C-H⋯O hydrogen bonds, forming chains along the c -axis direction. Adjacent chains are linked by C-H⋯π inter-actions, forming layers parallel to the ac plane. The layers are linked by offset π-π inter-actions [inter-centroid distance = 3.927 (3) Å], forming a supra-molecular three-dimensional structure.

Crystal structure of 4-meth­oxy-N-(piperidine-1-carbono­thio­yl)benzamide

PubMed Central

Suhud, Khairi; Hasbullah, Siti Aishah; Ahmad, Musa; Heng, Lee Yook

2017-01-01

In the title compound, C14H18N2O2S, the piperidine ring has a chair conformation. Its mean plane is twisted with respect to the 4-meth­oxy­benzoyl ring, with a dihedral angle of 63.0 (3)°. The central N—C(=S)—N(H)—C(=O) bridge is twisted with an N—C—N—C torsion angle of 74.8 (6)°. In the crystal, mol­ecules are linked by N—H⋯O and C—H⋯O hydrogen bonds, forming chains along the c-axis direction. Adjacent chains are linked by C—H⋯π inter­actions, forming layers parallel to the ac plane. The layers are linked by offset π–π inter­actions [inter­centroid distance = 3.927 (3) Å], forming a supra­molecular three-dimensional structure. PMID:29250374

Synthesis of stereodefined piperidines from aziridines and their transformation into conformationally constrained amino acids, amino alcohols and 2,7-diazabicyclo[3.3.1]nonanes.

PubMed

Vervisch, Karel; D'hooghe, Matthias; Törnroos, Karl W; De Kimpe, Norbert

2010-11-19

2-(2-Cyano-2-phenylethyl)aziridines were converted into novel cis- and trans-2-chloromethyl-4-phenylpiperidine-4-carbonitriles via alkylation with 1-bromo-2-chloroethane followed by microwave-assisted 6-exo-tet cyclization and regiospecific ring opening. The latter piperidines were used as eligible substrates for the synthesis of stereodefined 2-chloromethyl-, 2-hydroxymethyl-, and 2-carboxymethyl-4-phenylpiperidine-4-carboxylic acids, 2-hydroxymethyl-4-phenylpiperidine-4-carbonitriles, 3-hydroxy-5-phenylazepane-5-carbonitriles, and 5-phenyl-2,7-diazabicyclo[3.3.1]nonanes.

Piperidine carboxylic acid derivatives of 10H-pyrazino[2,3-b][1,4]benzothiazine as orally-active adhesion molecule inhibitors.

PubMed

Kaneko, Toshihiko; Clark, Richard S J; Ohi, Norihito; Ozaki, Fumihiro; Kawahara, Tetsuya; Kamada, Atsushi; Okano, Kazuo; Yokohama, Hiromitsu; Ohkuro, Masayoshi; Muramoto, Kenzo; Takenaka, Osamu; Kobayashi, Seiichi

2004-06-01

Novel piperidine carboxylic acid derivatives of 10H-pyrazino[2,3-b][1,4]benzothiazine were prepared and evaluated for their inhibitory activity on the upregulation of adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1). Replacement of the methanesulfonyl group on the piperidine ring of previously prepared derivatives with a carboxylic acid-containing moiety resulted in a number of potent adhesion molecule inhibitors. Of these, (anti) [3-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)methyl-3-azabicyclo[3.3.1]non-9-yl]acetic acid 2q (ER-49890), showed the most potent oral inhibitory activities against neutrophil migration in an interleukin-1 (IL-1) induced paw inflammation model using mice, and leukocyte accumulation in a carrageenan pleurisy model in the rat, and therapeutic effect on collagen-induced arthritis in rats.

Visualizing the 16-membered ring macrolides tildipirosin and tilmicosin bound to their ribosomal site.

PubMed

Poehlsgaard, Jacob; Andersen, Niels M; Warrass, Ralf; Douthwaite, Stephen

2012-08-17

The veterinary antibiotic tildipirosin (20,23-dipiperidinyl-mycaminosyl-tylonolide, Zuprevo) was developed recently to treat bovine and swine respiratory tract infections caused by bacterial pathogens such as Pasteurella multocida. Tildipirosin is a derivative of the naturally occurring compound tylosin. Here, we define drug-target interactions by combining chemical footprinting with structure modeling and show that tildipirosin, tylosin, and an earlier tylosin derivative, tilmicosin (20-dimethylpiperidinyl-mycaminosyl-tylonolide, Micotil), bind to the same macrolide site within the large subunit of P. multocida and Escherichia coli ribosomes. The drugs nevertheless differ in how they occupy this site. Interactions of the two piperidine components, which are unique to tildipirosin, distinguish this drug from tylosin and tilmicosin. The 23-piperidine of tildipirosin contacts ribosomal residues on the tunnel wall while its 20-piperidine is oriented into the tunnel lumen and is positioned to interfere with the growing nascent peptide.

Influence of ring size on the cognition-enhancing activity of DM235 and MN19, two potent nootropic drugs.

PubMed

Guandalini, L; Martini, E; Di Cesare Mannelli, L; Dei, S; Manetti, D; Scapecchi, S; Teodori, E; Ghelardini, C; Romanelli, M N

2012-03-01

A series of analogs of DM235 and MN19, characterized by rings with different size, have been prepared and evaluated for their nootropic activity in the mouse passive-avoidance test. It was found that the optimal ring size for the analogs of DM235, showing endocyclic both amidic groups, is 6 or 7 atoms. For the compounds structurally related to MN19, carrying an exocyclic amide group, the piperidine ring is the moiety which gives the most interesting compounds. Copyright © 2012 Elsevier Ltd. All rights reserved.

Structure-activity relationships of substituted N-benzyl piperidines in the GBR series: Synthesis of 4-(2-(bis(4-fluorophenyl)methoxy)ethyl)-1-(2-trifluoromethylbenzyl)piperidine, an allosteric modulator of the serotonin transporter.

PubMed

Boos, Terrence L; Greiner, Elisabeth; Calhoun, W Jason; Prisinzano, Thomas E; Nightingale, Barbara; Dersch, Christina M; Rothman, Richard B; Jacobson, Arthur E; Rice, Kenner C

2006-06-01

A series of 4-(2-(bis(4-fluorophenyl)methoxy)ethyl)-(substituted benzyl) piperidines with substituents at the ortho and meta positions in the aromatic ring of the N-benzyl side chain were synthesized and their affinities and selectivities for the dopamine transporter (DAT), serotonin transporter (SERT), and norepinephrine transporter (NET) were determined. One analogue, 4-(2-(bis(4-fluorophenyl)methoxy)ethyl)-1-(2-trifluoromethylbenzyl)piperidine (the C(2)-trifluoromethyl substituted compound), has been found to act as an allosteric modulator of hSERT binding and function. It had little affinity for any of the transporters. Several compounds showed affinity for the DAT in the low nanomolar range and displayed a broad range of SERT/DAT selectivity ratios and very little affinity for the NET. The pharmacological tools provided by the availability of compounds with varying transporter affinity and selectivity could be used to obtain additional information about the properties a compound should have to act as a useful pharmacotherapeutic agent for cocaine addiction and help unravel the pharmacological mechanisms relevant to stimulant abuse.

Piperidine-1-carboximidamide

PubMed Central

Tiritiris, Ioannis

2012-01-01

In the title compound, C6H13N3, the C=N and C—N bond lengths in the CN3 unit are 1.3090 (17), and 1.3640 (17) (C–NH2) and 1.3773 (16) Å, indicating double- and single-bond character, respectively. The N—C—N angles are 116.82 (12), 119.08 (11) and 124.09 (11)°, showing a deviation of the CN3 plane from an ideal trigonal–planar geometry. The piperidine ring is in a chair conformation. In the crystal, mol­ecules are linked by N—H⋯N hydrogen bonds, forming a two-dimensional network along the ac plane. PMID:23284550

Lipophilicity-related inhibition of blood platelet aggregation by nipecotic acid anilides.

PubMed

De Marco, Agostino; De Candia, Modesto; Carotti, Andrea; Cellamare, Saverio; De Candia, Erica; Altomare, Cosimo

2004-06-01

Using N-[4-(hexyloxy)phenyl]piperidine-3-carboxamide (17c) as a structural lead, a number of isomers, derivatives, and ring-opened analogs were synthesized and tested for their ability to block the in vitro aggregation of human platelets induced by adenosine 5'-diphosphate (ADP). For the most active compounds, inhibition of the platelet aggregation triggered by arachidonic acid (AA) and ADP-induced intraplatelet calcium mobilization was also demonstrated. Based on quantitative structure-activity relationships (QSARs), we proved the impact of hydrophobicity on antiplatelet activity by a nonlinear (parabolic or bilinear) relationship between pIC(50) and lipophilicity, as assessed by RP-HPLC capacity factors and ClogP (i.e. calculated 1-octanol-water partition coefficients). This study highlighted the following additional SARs: quasi-isolipophilic isomers of 17c (isonipecotanilides and pipecolinanilides) and ring-opened analogs (e.g. anilide of beta-alanine) exhibited lower antiplatelet activity; methylation of the piperidine nitrogen of 17c has no effect, whereas alkylation with an n-propyl group decreases the activity by a factor of approximately 2, most likely due to a conformation-dependent decrease in lipophilicity.

Synthesis and DNA cleavage activity of Bis-3-chloropiperidines as alkylating agents.

PubMed

Zuravka, Ivonne; Roesmann, Rolf; Sosic, Alice; Wende, Wolfgang; Pingoud, Alfred; Gatto, Barbara; Göttlich, Richard

2014-09-01

Nitrogen mustards are an important class of bifunctional alkylating agents routinely used in chemotherapy. They react with DNA as electrophiles through the formation of highly reactive aziridinium ion intermediates. The antibiotic 593A, with potential antitumor activity, can be considered a naturally occurring piperidine mustard containing a unique 3-chloropiperidine ring. However, the total synthesis of this antibiotic proved to be rather challenging. With the aim of designing simplified analogues of this natural product, we developed an efficient bidirectional synthetic route to bis-3-chloropiperidines joined by flexible, conformationally restricted, or rigid diamine linkers. The key step involves an iodide-catalyzed double cyclization of unsaturated bis-N-chloroamines to simultaneously generate both piperidine rings. Herein we describe the synthesis and subsequent evaluation of a series of novel nitrogen-bridged bis-3-chloropiperidines, enabling the study of the impact of the linker structure on DNA alkylation properties. Our studies reveal that the synthesized compounds possess DNA alkylating abilities and induce strand cleavage, with a strong preference for guanine residues. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Synthesis, spectroscopic (UV-Vis, FT-IR and NMR), single crystal XRD of 3,5-diethyl -2,6-di(thiophen-2-yl)piperidin-4-on-1-ium picrate: A comprehensive experimental and computational study

NASA Astrophysics Data System (ADS)

Arockia doss, M.; Rajarajan, G.; Thanikachalam, V.; Selvanayagam, S.; Sridhar, B.

2017-01-01

A piperidin-4-one containing picrate 3,5-diethyl -2,6-di(thiophen-2-yl)piperidin-4-on-1-ium picrate [3,5-DPPP] was synthesized. The molecular structure of 3,5-DPPP was confirmed by FT-IR, NMR, Uv-Vis, single crystal XRD analysis and DFT and HF methods with 6-31G(d,p) basis set. The XRD data confirm the transfer of protons from picric acid (O2) to piperidin-4-one ring (N1). The 3,5-DPPP compound is stabilized by the presence of intermolecular and intramolecular hydrogen bonds (N-H⋯O, C-H⋯S and C-H⋯O). Density functional theory and HF calculations have been used widely for calculating a wide variety of molecular properties such as optimized structure, FT-IR and Uv-Vis spectra, and provided reliable results which are in agreement with experimental data. The charge density data have been used to understand the properties of molecular systems. Furthermore, several quantum chemical insights have been obtained in the form of the total and partial density of states, the HOMO-LUMO energy gap and electrostatic potential map etc. In addition, the polarizability and first hyperpolarizability were calculated to show the potential applications of 3,5-DPPP in nonlinear optics.

Synthesis and analgesic activity of some side-chain modified anpirtoline derivatives.

PubMed

Rádl, S; Hezky, P; Proska, J; Hejnová, L; Krejcí, I

2000-05-01

New derivatives of anpirtoline and deazaanpirtoline modified in the side chain have been synthesized. The series includes compounds 3 with side-chains containing piperidine or pyrrolidine rings, compounds 4 containing 8-azabicyclo[3.2.1]octane moiety, and compounds 5 having piperazine ring in their side-chains. Their receptor binding profiles (5-HT1A, 5-HT1B) and analgesic activity (hot plate, acetic acid induced writhing) have been studied. Optimized structures (PM3-MOPAC, Alchemy 2000, Tripos Inc.) of the synthesized compounds 3-5 were compared with that of anpirtoline.

The identification and analytical characterization of 2,2'-difluorofentanyl.

PubMed

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

2018-04-01

New psychoactive substances (NPS) have expanded their distribution and become widely available in the global market in recent years. The illicit use of fentanyl and its analogs has become an important worldwide concern linked to their high potency and risk of fatal overdose. This study describes the analytical characterization of a new fentanyl derivative N-(1-(2-fluorophenethyl)-4-piperidinyl)-N-(2-fluorophenyl)propionamide (2,2'-difluorofentanyl). Identification was based on ultra-high-performance liquid chromatography-quadrupole time-of-flight-mass spectrometry (UHPLC-QTOF-MS), gas chromatography-mass spectrometry (GC-MS), Fourier transform infrared (FTIR) spectroscopy, and nuclear magnetic resonance (NMR) spectroscopy. To our knowledge, this study is the first to report on analytical data for this compound. The most abundant fragment ion in the electrospray ionization (ESI) mass spectrum under collision-induced dissociation (CID) mode was formed by the cleavage between the piperidine ring and the N-phenyl-amide moiety of the protonated molecule. Two diagnostic ions in the electron ionization (EI) mass spectrum were formed by the loss of a tropylium ion (M-91), and by the degradation of the piperidine ring and dissociate of the COC 2 H 5 moiety altogether, respectively. Copyright © 2017 John Wiley & Sons, Ltd.

Crystal structures of resorcin[4]arene and pyrogallol[4]arene complexes with DL-pipecolinic acid. Model compounds for the recognition of the pipecolinyl ring, a key fragment of FK506, through C-H⋯π interaction

NASA Astrophysics Data System (ADS)

Fujisawa, Ikuhide; Kitamura, Yuji; Kato, Ryo; Murayama, Kazutaka; Aoki, Katsuyuki

2014-01-01

Resorcin[4]arene (resorcinol cyclic tetramer, abbreviated as RCT) or pyrogallol[4]arene (pyrogallol cyclic tetramer, PCT) form host-guest 1:1 complexes with DL-pipecolinic acid (DL-pipeH), RCT·DL-pipeH·EtOH·8H2O (1), PCT DL-pipeH·EtOH·4H2O (2), and PCT·DL-pipeH·3H2O (3), whose crystal structures have been determined. In each complex, the pipeH ligand is incorporated into the bowl-shaped cavity of the RCT or PCT host molecules through C-H⋯π interactions between alkyl protons of the piperidine ring of pipeH and π-rings of RCT or PCT, forming an [(RCT/PCT)·pipeH] structural fragment. In 1 and 3, two [(RCT/PCT) pipeH] fragments self-associate across an inversion center to form a guest-mediated, obliquely declined dimeric structure [(RCT/PCT)·L-pipeH·D-pipeH (RCT/PCT)]. In 2, each PCT-capped pipeH ligand bridges to two adjacent PCT molecules to form guest-mediated, optically-discrete helical polymers [PCT·L-pipeH]n or [PCT·D-pipeH]n. An 1H NMR experiment shows that the complexation through C-H⋯π interaction between the piperidine ring of pipeH and π-rings of RCT or PCT occurs also in solution, with the binding constants of 9.7 ± 0.6 M-1 for RCT and 26.5 ± 1.5 M-1 for PCT. These complexes provide a synthetic model for the recognition of the pipecolinyl-ring moiety, a key constituent of immunosuppressant drugs such as FK506, FK520 or rapamycin, by their binding proteins through C-H⋯π interaction.

Diastereoselective intramolecular Ritter reaction: generation of a cis-fused hexahydro-4aH-indeno[1,2-b]pyridine ring system with 4a,9b-diangular substituents.

PubMed

Van Emelen, K; De Wit, T; Hoornaert, G J; Compernolle, F

2000-10-05

Indanol intermediates 5, prepared via Michael addition of 1-indanone beta-ketoester and acrylonitrile followed by reduction or Grignard reaction of the ketone group, were submitted to intramolecular Ritter reaction using various acid reaction conditions to produce tricyclic lactams 4. This cis-fused hexahydro-4aH-indeno[1,2-b]pyridine ring system, substituted at both angular positions 4a and 9b, provides access to constrained analogues of non-peptide NK(1)-antagonists with monocyclic piperidine structure.

Probes for Narcotic Receptor Mediated Phenomena. 39. Enantiomeric N-Substituted Benzofuro[2,3-c]pyridin-6-ols: Synthesis and Topological Relationship to Oxide-Bridged Phenylmorphans

DTIC Science & Technology

2009-01-01

ray crystallographic analysis of the salt (-)-10 3R-(-)- mandelate (Figure 2). N-Alkylation of the secondary amine 4aR,9aS-9 or 4aS,9aR-10 (Scheme 3... rmsd ) between the heavy atoms of both the dihydrofuran and the piperidine rings. Conformer B1 is epimeric to A and was obtained by nitrogen inversion... rmsd value of the fitting is 0.13, 0.12, and 0.07 Å. The dihydrofuran ring of conformer C overlaps well with that of the para-d isomer that is known to

A kryptoracemic salt: 2-{[2,8-bis-(tri-fluoro-meth-yl)quinolin-4-yl](hy-droxy)meth-yl}piperidin-1-ium (+)-3,3,3-tri-fluoro-2-meth-oxy-2-phenyl-propanoate.

PubMed

Wardell, James L; Wardell, Solange M S V; Tiekink, Edward R T

2016-06-01

The asymmetric unit of the title salt, C17H17F6N2O(+)·C10H8F3O3 (-), comprises two piperidin-1-ium cations and two carboxyl-ate anions. The cations, each having an l-shaped conformation owing to the near orthogonal relationship between the quinolinyl and piperidin-1-ium residues, are pseudo-enanti-omeric. The anions have the same absolute configuration but differ in the relative orientations of the carboxyl-ate, meth-oxy and benzene groups. Arguably, the most prominent difference between the anions occurs about the Cq-Om bond as seen in the Cc-Cq-Om-Cm torsion angles of -176.1 (3) and -67.1 (4)°, respectively (q = quaternary, m = meth-oxy and c = carboxyl-ate). The presence of Oh-H⋯Oc and Np-H⋯Oc hydrogen bonds leads to the formation of a supra-molecular chain along the a axis (h = hy-droxy and p = piperidin-1-ium); weak intra-molecular Np-H⋯Oh hydrogen bonds are also noted. Chains are connected into a three-dimensional architecture by C-H⋯F inter-actions. Based on a literature survey, related mol-ecules/cations adopt a uniform conformation in the solid state based on the letter L.

Saturated amine oxides: Part 8. Hydroacridines: Part 27. Effects of N-oxidation and of N-quaternization on the 15N NMR chemical shifts of N-methylpiperidine-derived mono-, bi-, and tricycloaliphatic tertiary amines.

PubMed

Potmischil, Francisc; Duddeck, Helmut; Nicolescu, Alina; Deleanu, Calin

2007-03-01

The (15)N chemical shifts of 13 N-methylpiperidine-derived mono-, bi- and tricycloaliphatic tertiary amines, their methiodides and their N-epimeric pairs of N-oxides were measured, and the contributions of specific structural parameters to the chemical shifts were determined by multilinear regression analysis. Within the examined compounds, the effects of N-oxidation upon the (15)N chemical shifts of the amines vary from +56 ppm to +90 ppm (deshielding), of which approx. +67.7 ppm is due to the inductive effect of the incoming N(+)--O(-) oxygen atom, whereas the rest is due to the additive shift effects of the various C-alkyl substituents of the piperidine ring. The effects of quaternization vary from -3.1 ppm to +29.3 ppm, of which approx. +8.9 ppm is due to the inductive effect of the incoming N(+)--CH(3) methyl group, and the rest is due to the additive shift effects of the various C-alkyl substituents of the piperidine ring. The shift effects of the C-alkyl substituents in the amines, the N-oxides and the methiodides are discussed. Copyright (c) 2007 John Wiley & Sons, Ltd.

Synthesis and biological characterization of (3R,4R)-4-(2-(benzhydryloxy)ethyl)-1-((R)-2-hydroxy-2-phenylethyl)-piperidin-3-ol and its stereoisomers for monoamine transporters

PubMed Central

Kharkar, Prashant S.; Batman, Angela M.; Zhen, Juan; Beardsley, Patrick M.; Reith, Maarten E. A.

2012-01-01

In this report we describe synthesis and biological evaluation of a series of asymmetric 4-(2-(benzhydryloxy)ethyl)-1-((R)-2-hydroxy-2-phenylethyl)-piperidin-3-ol based dihydroxy compounds where the hydroxy groups are located both on the piperidine ring and also on the N-phenylethyl side chain exo-cyclically. In vitro uptake inhibition data indicates high affinity of these molecules for the dopamine transporter (DAT) in addition to their moderate to high affinity for the norepinephrine transporter (NET). Interestingly, compounds 9b and 9d exhibited affinities for all three monoamine transporters with highest potency at DAT and NET and moderate potency at the serotonin transporter (SERT) (Ki 2.29, 78.4 and 155 nM for 9b and 1.55, 14.1 and 259 nM for 9d, respectively). Selected compounds, 9a, 9d and 9d’ were tested for their locomotor activity effects in mice, and for their ability to occasion the cocaine discriminative stimulus in rats. These test compounds generally exhibited a much longer duration of action than cocaine for elevating locomotor activity, and dose-dependently completely generalized the cocaine discriminative stimulus. PMID:19449323

Role of choline and glycine betaine in the formation of N,N-dimethylpiperidinium (mepiquat) under Maillard reaction conditions.

PubMed

Bessaire, Thomas; Tarres, Adrienne; Stadler, Richard H; Delatour, Thierry

2014-01-01

This study is the first to examine the role of choline and glycine betaine, naturally present in some foods, in particular in cereal grains, to generate N,N-dimethylpiperidinium (mepiquat) under Maillard conditions via transmethylation reactions involving the nucleophile piperidine. The formation of mepiquat and its intermediates piperidine - formed by cyclisation of free lysine in the presence of reducing sugars - and N-methylpiperidine were monitored over time (240°C, up to 180 min) using high-resolution mass spectrometry in a model system comprised of a ternary mixture of lysine/fructose/alkylating agent (choline or betaine). The reaction yield was compared with data recently determined for trigonelline, a known methylation agent present naturally in coffee beans. The role of choline and glycine betaine in nucleophilic displacement reactions was further supported by experiments carried out with stable isotope-labelled precursors (¹³C- and deuterium-labelled). The results unequivocally demonstrated that the piperidine ring of mepiquat originates from the carbon chain of lysine, and that either choline or glycine betaine furnishes the N-methyl groups. The kinetics of formation of the corresponding demethylated products of both choline and glycine betaine, N,N-demethyl-2-aminoethanol and N,N-dimethylglycine, respectively, were also determined using high-resolution mass spectrometry.

Crystal structure of (3S*,4R*)-4-fluoro-3-(4-meth-oxy-phen-yl)-1-oxo-2-phenyl-1,2,3,4-tetra-hydro-iso-quinoline-4-carb-oxy-lic acid.

PubMed

Lehmann, Anna; Lechner, Lisa; Radacki, Krzysztof; Braunschweig, Holger; Holzgrabe, Ulrike

2017-06-01

The title compound, C 23 H 18 FNO 4 , crystallized as a racemate. It exhibits a cis conformation with respect to the F atom and the methine H atom. The piperidine ring has a screw-boat conformation. The meth-oxy-phenyl ring and the phenyl ring are inclined to the mean plane of the iso-quinoline ring system by 89.85 (4) and 46.62 (5)°, respectively, and by 78.15 (5)° to one another. In the crystal, mol-ecules are linked by an O-H⋯O hydrogen bond forming chains propagating along the a -axis direction. The chains are linked by C-H⋯F hydrogen bonds, forming layers lying parallel to the ab plane.

Synthesis and biological characterization of (3R,4R)-4-(2-(benzhydryloxy)ethyl)-1-((R)-2-hydroxy-2-phenylethyl)-piperidin-3-ol and its stereoisomers for activity toward monoamine transporters.

PubMed

Kharkar, Prashant S; Batman, Angela M; Zhen, Juan; Beardsley, Patrick M; Reith, Maarten E A; Dutta, Aloke K

2009-07-01

A novel series of optically active molecules based on a 4-(2-(benzhydryloxy)ethyl)-1-((R)-2-hydroxy-2-phenylethyl)-piperidin-3-ol template were developed. Depending on stereochemistry, the compounds exhibit various degrees of affinity for three dopamine, serotonin, and norepinephrine transporters. These molecules have the potential for treating several neurological disorders such as drug abuse, depression, and attention deficit hyperactivity disorder.Herein we describe the synthesis and biological evaluation of a series of asymmetric 4-(2-(benzhydryloxy)ethyl)-1-((R)-2-hydroxy-2-phenylethyl)-piperidin-3-ol-based dihydroxy compounds in which the hydroxy groups are located on both the piperidine ring and the N-phenylethyl side chain. In vitro uptake inhibition data of these molecules indicate high affinity for the dopamine transporter (DAT) in addition to moderate to high affinity for the norepinephrine transporter (NET). Interestingly, compounds 9 b and 9 d exhibit affinities for all three monoamine transporters, with highest potency at DAT and NET, and moderate potency at the serotonin transporter (SERT) (K(i): 2.29, 78.4, and 155 nM for 9 b and 1.55, 14.1, and 259 nM for 9 d, respectively). Selected compounds 9 a, 9 d, and 9 d' were tested for their locomotor activity effects in mice and for their ability to occasion the cocaine-discriminative stimulus in rats. These test compounds generally exhibit a much longer duration of action than cocaine for elevating locomotor activity, and completely generalize the cocaine-discriminative stimulus in a dose-dependent manner.

Structure–Activity Relationships for a Novel Series of Dopamine D2-like Receptor Ligands Based on N-Substituted 3-Aryl-8-azabicyclo[3.2.1]octan-3-ol

PubMed Central

Paul, Noel M.; Taylor, Michelle; Kumar, Rakesh; Deschamps, Jeffrey R.; Luedtke, Robert R.; Newman, Amy Hauck

2011-01-01

Discovering dopamine D2-like receptor subtype-selective ligands has been a focus of significant investigation. The D2R-selective antagonist 3-[4-(4-chlorophenyl)-4-hydroxypiperidinyl]methylindole (1, L741,626; Ki(D2R/D3R) = 11.2:163 nM) has previously provided a lead template for chemical modification. Herein, analogues have been synthesized where the piperidine was replaced by a tropane ring that reversed the selectivity seen in the parent compound, in human hD2LR- or hD3R-transfected HEK 293 cells (31, Ki(D2R/D3R) = 33.4: 15.5 nM). Further exploration of both N-substituted and aryl ring-substituted analogues resulted in the discovery of several high affinity D2R/D3R ligands with 3-benzofurylmethyl-substituents (e.g., 45, Ki(D2R/D3R) = 1.7:0.34 nM) that induced high affinity not achieved in similarly N-substituted piperidine analogues and significantly (470-fold) improved D3R binding affinity compared to the parent ligand 1. X-ray crystallographic data revealed a distinctive spatial arrangement of pharmacophoric elements in the piperidinol vs tropine analogues, providing clues for the diversity in SAR at the D2 and D3 receptor subtypes. PMID:18774793

Synthesis of a new series of dithiocarbamates with effective human carbonic anhydrase inhibitory activity and antiglaucoma action.

PubMed

Bozdag, Murat; Carta, Fabrizio; Vullo, Daniela; Akdemir, Atilla; Isik, Semra; Lanzi, Cecilia; Scozzafava, Andrea; Masini, Emanuela; Supuran, Claudiu T

2015-05-15

A new series of dithiocarbamates (DTCs) was prepared from primary/secondary amines incorporating amino/hydroxyl-alkyl, mono- and bicyclic aliphatic ring systems based on the quinuclidine, piperidine, hydroxy-/carboxy-/amino-substituted piperidine, morpholine and piperazine scaffolds, and carbon disulfide. The compounds were investigated for the inhibition of four mammalian α-carbonic anhydrases (CAs, EC 4.2.1.1) of pharmacologic relevance, that is, the human (h) hCA I, II, IX and XII, drug targets for antiglaucoma (hCA II and XII) or antitumor (hCA IX/XII) agents. The compounds were moderate or inefficient hCA I inhibitors (off-target isoform for both applications), efficiently inhibited hCA II, whereas some of them were low nanomolar/subnanomolar hCA IX/XII inhibitors. One DTC showed excellent intraocular pressure (IOP) lowering properties in an animal model of glaucoma, with a two times better efficiency compared to the clinically used sulfonamide dorzolamide. Copyright © 2015 Elsevier Ltd. All rights reserved.

Thermodynamics and binding mode of novel structurally related 1,2,4-thiadiazole derivatives with native and modified cyclodextrins

NASA Astrophysics Data System (ADS)

Terekhova, Irina V.; Chislov, Mikhail V.; Brusnikina, Maria A.; Chibunova, Ekaterina S.; Volkova, Tatyana V.; Zvereva, Irina A.; Proshin, Alexey N.

2017-03-01

Study of complex formation of cyclodextrins with 1,2,4-thiadiazole derivatives intended for Alzheimer's disease treatment was carried out using 1H NMR, ITC and phase solubility methods. Structure of cyclodextrins and thiadiazoles affects the binding mode and thermodynamics of complexation. The larger cavity of β- and γ-cyclodextrins is more appropriate for deeper insertion of 1,2,4-thiadiazole derivatives which is accompanied by intensive dehydration and solvent reorganization. Benzene ring of the thiadiazoles is located inside macrocyclic cavity while piperidine ring is placed outside the cavity and can form H-bonds with cyclodextrin exterior. Complexation with cyclodextrins induces the enhancement of aqueous solubility of 1,2,4-thiadiazole derivatives.

Synthesis of densely functionalized enantiopure indolizidines by ring-closing metathesis (RCM) of hydroxylamines from carbohydrate-derived nitrones

PubMed Central

Bonanni, Marco; Marradi, Marco; Cardona, Francesca; Cicchi, Stefano; Goti, Andrea

2007-01-01

Background Indolizidine alkaloids widely occur in nature and display interesting biological activity. This is the reason for which their total synthesis as well as the synthesis of non-natural analogues still attracts the attention of many research groups. To establish new straightforward accesses to these molecules is therefore highly desirable. Results The ring closing metathesis (RCM) of enantiopure hydroxylamines bearing suitable unsaturated groups cleanly afforded piperidine derivatives in good yields. Further cyclization and deprotection of the hydroxy groups gave novel highly functionalized indolizidines. The synthesis of a pyrroloazepine analogue is also described. Conclusion We have developed a new straightforward methodology for the synthesis of densely functionalized indolizidines and pyrroloazepine analogues in 6 steps and 30–60% overall yields from enantiopure hydroxylamines obtained straightforwardly from carbohydrate-derived nitrones. PMID:18076753

Piperidine alkaloids: human and food animal teratogens.

PubMed

Green, Benedict T; Lee, Stephen T; Panter, Kip E; Brown, David R

2012-06-01

Piperidine alkaloids are acutely toxic to adult livestock species and produce musculoskeletal deformities in neonatal animals. These teratogenic effects include multiple congenital contracture (MCC) deformities and cleft palate in cattle, pigs, sheep, and goats. Poisonous plants containing teratogenic piperidine alkaloids include poison hemlock (Conium maculatum), lupine (Lupinus spp.), and tobacco (Nicotiana tabacum) [including wild tree tobacco (Nicotiana glauca)]. There is abundant epidemiological evidence in humans that link maternal tobacco use with a high incidence of oral clefting in newborns; this association may be partly attributable to the presence of piperidine alkaloids in tobacco products. In this review, we summarize the evidence for piperidine alkaloids that act as teratogens in livestock, piperidine alkaloid structure-activity relationships and their potential implications for human health. Copyright © 2012 Elsevier Ltd. All rights reserved.

Identification of potent, selective, CNS-targeted inverse agonists of the ghrelin receptor.

PubMed

McClure, Kim F; Jackson, Margaret; Cameron, Kimberly O; Kung, Daniel W; Perry, David A; Orr, Suvi T M; Zhang, Yingxin; Kohrt, Jeffrey; Tu, Meihua; Gao, Hua; Fernando, Dilinie; Jones, Ryan; Erasga, Noe; Wang, Guoqiang; Polivkova, Jana; Jiao, Wenhua; Swartz, Roger; Ueno, Hirokazu; Bhattacharya, Samit K; Stock, Ingrid A; Varma, Sam; Bagdasarian, Victoria; Perez, Sylvie; Kelly-Sullivan, Dawn; Wang, Ruduan; Kong, Jimmy; Cornelius, Peter; Michael, Laura; Lee, Eunsun; Janssen, Ann; Steyn, Stefanus J; Lapham, Kimberly; Goosen, Theunis

2013-10-01

The optimization for selectivity and central receptor occupancy for a series of spirocyclic azetidine-piperidine inverse agonists of the ghrelin receptor is described. Decreased mAChR muscarinic M2 binding was achieved by use of a chiral indane in place of a substituted benzylic group. Compounds with desirable balance of human in vitro clearance and ex vivo central receptor occupancy were discovered by incorporation of heterocycles. Specifically, heteroaryl rings with nitrogen(s) vicinal to the indane linkage provided the most attractive overall properties. Copyright © 2013 Elsevier Ltd. All rights reserved.

Dithiocarbamates with potent inhibitory activity against the Saccharomyces cerevisiae β-carbonic anhydrase.

PubMed

Bozdag, Murat; Carta, Fabrizio; Vullo, Daniela; Isik, Semra; AlOthman, Zeid; Osman, Sameh M; Scozzafava, Andrea; Supuran, Claudiu T

2016-01-01

Dithiocarbamates (DTCs) prepared from primary or secondary amines, which incorporated amino/hydroxyl-alkyl, mono-/bicyclic aliphatic/heterocyclic rings based on the quinuclidine, piperidine, hydroxy-/carboxy-/amino-substituted piperidine, morpholine and piperazine scaffolds, were investigated for the inhibition of α- and β-carbonic anhydrases (CAs, EC 4.2.1.1) of pharmacologic relevance, such as the human (h) isoform hCA I and II, as well as the Saccharomyces cerevisiae β-CA, scCA. The yeast and its β-CA were shown earlier to be useful models of pathogenic fungal infections. The DTCs investigated here were medium potency hCA I inhibitors (K(I)s of 66.5-910 nM), were more effective as hCA II inhibitors (K(I)s of 8.9-107 nM) and some of them showed excellent, low nanomolar activity against the yeast enzyme, with inhibition constants ranging between 6.4 and 259 nM. The detailed structure activity relationship for inhibition of the yeast and human enzymes is discussed. Several of the investigated DTCs showed excellent selectivity ratios for inhibiting the yeast over the human cytosolic CA isoforms.

Effect of halo-substituted aromatic salts on counterion binding constants obtained from cationic nanoparticle catalyzed reactions of piperidine and phenyl salicylate

NASA Astrophysics Data System (ADS)

Fagge, Ibrahim I.; Yusof, Nor Saadah M.; Zain, Sharifuddin Md; Khan, M. Niyaz

2017-12-01

Halo-substitutions at 3-position of benzene ring of the salts of aromatic carboxylate, MX, revealed the effect of two different halide ions (Br- and Cl-) on the counterion binding constants obtained from cationic nanoparticle catalyzed piperidinolysis of ionized phenyl salicylate (PhS-). The values of observed rate constant, kobs, determined at a constant total concentration of cetyltrimethylammonium bromide, [CTABr]T, piperidine, ([P]T), [PhS-]T, NaOH, and various concentration of MX (MX = 3-BrC6H4CO2Na and 3-ClC6H4CO2Na), were determined using UV-visible X spectrophotometric technique at 35 °C and 370 nm. The average value of nanoparticle binding constant, KXBr, for X- = 3-BrC6H4CO2- (RXBr = 57) was found to be about 2-fold larger than that for X- = 3-ClC6H4CO2- (RXBr = 30). These XX values were dependent of substituents 3-Br and 3-Cl, and independent of [CTABr]T. Both are related to the presence of different extent of viscoelastic worm-like nanoparticles formation in the [CTABr]T of 6 and 10 mM.

Teratogenic effects in cattle of Conium maculatum and conium alkaloids and analogs.

PubMed

Keeler, R F; Balls, L D

1978-01-01

The plant Conium maculatum produced congenital defects in calves born to cows gavaged the fresh green plant during days 50-75 of gestation. Both arthrogryposis and spinal curvature were produced and were similar to the defects produced by the piperidine alkaloid coniine. The arthrogrypotic manifestations of the condition markedly increased in severity as the animals aged. Animals gavaged dry plant had either normal or equivocally deformed offspring. A number of chain length and ring saturation analogs of coniine were not teratogenic. No congenital defects arose in offspring from maternal inhalation of either the teratogenic alkaloid coniine, or from the teratogenic green plant.

Pyrrolidine and Piperidine Formation Via Copper(II) Carboxylate Promoted Intramolecular Carboamination of Unactivated Olefins: Diastereoselectivity and Mechanism

PubMed Central

Sherman, Eric S.; Fuller, Peter H.; Kasi, Dhanalakshmi; Chemler, Sherry R.

2008-01-01

An expanded substrate scope and in depth analysis of the reaction mechanism of the copper(II) carboxylate promoted intramolecular carboamination of unactivated alkenes is described. This method provides access to N-functionalized pyrrolidines and piperidines. Both aromatic and aliphatic γ- and δ-alkenyl N-arylsulfonamides undergo the oxidative cyclization reaction efficiently. N-Benzoyl-2-allylaniline also underwent the oxidative cyclization. The terminal olefin substrates examined were more reactive than those with internal olefins, and the latter terminated in elimination rather than carbon-carbon bond formation. The efficiency of the reaction was enhanced by the use of more organic soluble copper(II) carboxylate salts, copper(II) neodecanoate in particular. The reaction times were reduced by the use of microwave heating. High levels of diastereoselectivity were observed in the synthesis of 2,5-disubstituted pyrrolidines, wherein the cis substitution pattern predominates. The mechanism of the reaction is discussed in the context of the observed reactivity and in comparison to analogous reactions promoted by other reagents and conditions. Our evidence supports a mechanism wherein the N-C bond is formed via intramolecular syn aminocupration and the C-C bond is formed via intramolecular addition of a primary carbon radical to an aromatic ring. PMID:17428100

Comprehensive analysis of ß-lactam antibiotics including penicillins, cephalosporins, and carbapenems in poultry muscle using liquid chromatography coupled to tandem mass spectrometry.

PubMed

Berendsen, Bjorn J A; Gerritsen, Henk W; Wegh, Robin S; Lameris, Steven; van Sebille, Ralph; Stolker, Alida A M; Nielen, Michel W F

2013-09-01

A comprehensive method for the quantitative residue analysis of trace levels of 22 ß-lactam antibiotics, including penicillins, cephalosporins, and carbapenems, in poultry muscle by liquid chromatography in combination with tandem mass spectrometric detection is reported. The samples analyzed for ß-lactam residues are hydrolyzed using piperidine in order to improve compound stability and to include the total residue content of the cephalosporin ceftifour. The reaction procedure was optimized using a full experimental design. Following detailed isotope labeling, tandem mass spectrometry studies and exact mass measurements using high-resolution mass spectrometry reaction schemes could be proposed for all ß-lactams studied. The main reaction occurring is the hydrolysis of the ß-lactam ring under formation of the piperidine substituted amide. For some ß-lactams, multiple isobaric hydrolysis reaction products are obtained, in accordance with expectations, but this did not hamper quantitative analysis. The final method was fully validated as a quantitative confirmatory residue analysis method according to Commission Decision 2002/657/EC and showed satisfactory quantitative performance for all compounds with trueness between 80 and 110% and within-laboratory reproducibility below 22% at target level, except for biapenem. For biapenem, the method proved to be suitable for qualitative analysis only.

Biotransformation and bioactivation reactions of alicyclic amines in drug molecules.

PubMed

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.

Discovery of 5-substituted tetrahydronaphthalen-2yl-methyl with N-phenyl-N-(piperidin-4-yl)propionamide derivatives as potent opioid receptor ligands.

PubMed

Deekonda, Srinivas; Wugalter, Lauren; Kulkarni, Vinod; Rankin, David; Largent-Milnes, Tally M; Davis, Peg; Bassirirad, Neemah M; Lai, Josephine; Vanderah, Todd W; Porreca, Frank; Hruby, Victor J

2015-09-15

A new series of novel opioid ligands have been designed and synthesized based on the 4-anilidopiperidine scaffold containing a 5-substituted tetrahydronaphthalen-2yl)methyl group with different N-phenyl-N-(piperidin-4-yl)propionamide derivatives to study the biological effects of these substituents on μ and δ opioid receptor interactions. Recently our group reported novel 4-anilidopiperidine analogues, in which several aromatic ring-contained amino acids were conjugated with N-phenyl-N-(piperidin-4-yl)propionamide and examined their biological activities at the μ and δ opioid receptors. In continuation of our efforts in these novel 4-anilidopiperidine analogues, we took a peptidomimetic approach in the present design, in which we substituted aromatic amino acids with tetrahydronaphthalen-2yl methyl moiety with amino, amide and hydroxyl substitutions at the 5th position. In in vitro assays these ligands, showed very good binding affinity and highly selective toward the μ opioid receptor. Among these, the lead ligand 20 showed excellent binding affinity (2 nM) and 5000 fold selectivity toward the μ opioid receptor, as well as functional selectivity in GPI assays (55.20 ± 4.30 nM) and weak or no agonist activities in MVD assays. Based on the in vitro bioassay results the lead compound 20 was chosen for in vivo assessment for efficacy in naïve rats after intrathecal administration. Compound 20 was not significantly effective in alleviating acute pain. This discrepancy between high in vitro binding affinity, moderate in vitro activity, and low in vivo activity may reflect differences in pharmacodynamics (i.e., engaging signaling pathways) or pharmacokinetics (i.e., metabolic stability). In sum, our data suggest that further optimization of this compound 20 is required to enhance in vivo activity. Copyright © 2015 Elsevier Ltd. All rights reserved.

σ-1 Receptor at the Mitochondrial-Associated Endoplasmic Reticulum Membrane Is Responsible for Mitochondrial Metabolic Regulation

PubMed Central

Marriott, Karla-Sue C.; Prasad, Manoj; Thapliyal, Veena

2012-01-01

The mitochondria-associated endoplasmic reticulum (ER) membrane (MAM) is a small section of the outer mitochondrial membrane tethered to the ER by lipid and protein filaments. One such MAM protein is the σ-1 receptor, which contributes to multiple signaling pathways. We found that short interfering RNA-mediated knockdown of σ-1 reduced pregnenolone synthesis by 95% without affecting expression of the inner mitochondrial membrane resident enzyme, 3-β-hydroxysteroid dehydrogenase 2. To explore the underlying mechanism of this effect, we generated a series of σ-receptor ligands: 5,6-dimethoxy-3-methyl-N-phenyl-N-(3-(piperidin-1-yl)propyl)benzofuran-2-carboxamide (KSCM-1), 3-methyl-N-phenyl-N-(3-(piperidin-1-yl)propyl)benzofuran-2-carboxamide (KSCM-5), and 6-methoxy-3-methyl-N-phenyl-N-(3-(piperidin-1-yl) propyl)benzofuran-2-carboxamide (KSCM-11) specifically bound to σ-1 in the nanomolar range, whereas KSCM-5 and KSCM-11 also bound to σ-2. Treatment of cells with the KSCM ligands led to decreased cell viability, with KSCM-5 having the most potent effect followed by KSCM-11. KSCM-1 increased σ-1 expression by 4-fold and progesterone synthesis, whereas the other compounds decreased progesterone synthesis. These differences probably are caused by ligand molecular structure. For example, KSCM-1 has two methoxy substituents at C-5 and C-6 of the benzofuran ring, whereas KSCM-11 has one at C-6. KSCM ligands or σ-1 knockdown did not alter the expression of ER resident enzymes that synthesize steroids. However, coimmunoprecipitation of the σ-1 receptor pulled down voltage-dependent anion channel 2 (VDAC2), whose expression was enhanced by KSCM-1. VDAC2 plays a key role in cholesterol transport into the mitochondria, suggesting that the σ-1 receptor at the MAM coordinates with steroidogenic acute regulatory protein for cholesterol trafficking into the mitochondria for metabolic regulation. PMID:22923735

40 CFR 721.9527 - Bis(1,2,2,6,6-pentamethyl-4-piperidin-4-ol) ester of cy-clo-ali-phatic spiroketal.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Bis(1,2,2,6,6-pentamethyl-4-piperidin-4-ol) ester of cy-clo-ali-phatic spiroketal. 721.9527 Section 721.9527 Protection of Environment...-piperidin-4-ol) ester of cy-clo-ali-phatic spiroketal. (a) Chemical substance and significant new uses...

Degradation of Morpholine by an Environmental Mycobacterium Strain Involves a Cytochrome P-450

PubMed Central

Poupin, P.; Truffaut, N.; Combourieu, B.; Besse, P.; Sancelme, M.; Veschambre, H.; Delort, A. M.

1998-01-01

A Mycobacterium strain (RP1) was isolated from a contaminated activated sludge collected in a wastewater treatment unit of a chemical plant. It was capable of utilizing morpholine and other heterocyclic compounds, such as pyrrolidine and piperidine, as the sole source of carbon, nitrogen, and energy. The use of in situ 1H nuclear magnetic resonance (1H NMR) spectroscopy allowed the determination of two intermediates in the biodegradative pathway, 2-(2-aminoethoxy)acetate and glycolate. The inhibitory effects of metyrapone on the degradative abilities of strain RP1 indicated the involvement of a cytochrome P-450 in the biodegradation of morpholine. This observation was confirmed by spectrophotometric analysis and 1H NMR. Reduced cell extracts from morpholine-grown cultures, but not succinate-grown cultures, gave rise to a carbon monoxide difference spectrum with a peak near 450 nm, which indicated the presence of a soluble cytochrome P-450. 1H NMR allowed the direct analysis of the incubation medium containing metyrapone, a specific inhibitor of cytochrome P-450. The inhibition of morpholine degradation was dependent on the morpholine/metyrapone ratio. The heme-containing monooxygenase was also detected in pyrrolidine- and piperidine-grown cultures. The abilities of different compounds to support strain growth or the induction of a soluble cytochrome P-450 were assayed. The results suggest that this enzyme catalyzes the cleavage of the C—N bond of the morpholine ring. PMID:9435074

Isolation, Identification, and Xanthine Oxidase Inhibition Activity of Alkaloid Compound from Peperomia pellucida

NASA Astrophysics Data System (ADS)

Fachriyah, E.; Ghifari, M. A.; Anam, K.

2018-04-01

The research of the isolation and xanthine oxidation inhibition activity of alkaloid compound from Peperomia pellucida has been carried out. Alkaloid extract is isolated by column chromatography and preparative TLC. Alkaloid isolate is identified spectroscopically by UV-Vis spectrophotometer, FT-IR, and LC-MS/MS. Xanthine oxidase inhibition activity is carried out by in vitro assay. The result showed that the alkaloid isolated probably has piperidine basic structure. The alkaloid isolate has N-H, C-H, C = C, C = O, C-N, C-O-C groups and the aromatic ring. The IC50 values of ethanol and alkaloid extract are 71.6658 ppm and 76.3318 ppm, respectively. Alkaloid extract of Peperomia pellucida showed higher activity than ethanol extract.

Pharmacophore mapping of arylbenzothiophene derivatives for MCF cell inhibition using classical and 3D space modeling approaches.

PubMed

Mukherjee, Subhendu; Nagar, Shuchi; Mullick, Sanchita; Mukherjee, Arup; Saha, Achintya

2008-01-01

Considering the worth of developing non-steroidal estrogen analogs, the present study explores the pharmacophore features of arylbenzothiophene derivatives for inhibitory activity to MCF-7 cells using classical QSAR and 3D space modeling approaches. The analysis shows that presence of phenolic hydroxyl group and ketonic linkage in the basic side chain of 2-arylbenzothiophene core of raloxifene derivatives are crucial. Additionally piperidine ring connected through ether linkage is favorable for inhibition of breast cancer cell line. These features for inhibitory activity are also highlighted through 3D space modeling approach that explored importance of critical inter features distance among HB-acceptor lipid, hydrophobic and HB-donor features in the arylbenzothiophene scaffold for activity.

Lead optimization of 2-(piperidin-3-yl)-1H-benzimidazoles: identification of 2-morpholin- and 2-thiomorpholin-2-yl-1H-benzimidazoles as selective and CNS penetrating H₁-antihistamines for insomnia.

PubMed

Ravula, Satheesh Babu; Yu, Jinghua; Tran, Joe A; Arellano, Melissa; Tucci, Fabio C; Moree, Wilna J; Li, Bin-Feng; Petroski, Robert E; Wen, Jianyun; Malany, Siobhan; Hoare, Samuel R J; Madan, Ajay; Crowe, Paul D; Beaton, Graham

2012-01-01

The structure-activity relationships of 2-(piperidin-3-yl)-1H-benzimidazoles, 2-morpholine and 2-thiomorpholin-2-yl-1H-benzimidazoles are described. In the lead optimization process, the pK(a) and/or logP of benzimidazole analogs were reduced either by attachment of polar substituents to the piperidine nitrogen or incorporation of heteroatoms into the piperidine heterocycle. Compounds 9a and 9b in the morpholine series and 10g in the thiomorpholine series demonstrated improved selectivity and CNS profiles compared to lead compound 2 and these are potential candidates for evaluation as sedative hypnotics. Copyright © 2011 Elsevier Ltd. All rights reserved.

Synthesis and structure-activity relationships for extended side chain analogues of the antitubercular drug (6S)-2-nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (PA-824).

PubMed

Palmer, Brian D; Sutherland, Hamish S; Blaser, Adrian; Kmentova, Iveta; Franzblau, Scott G; Wan, Baojie; Wang, Yuehong; Ma, Zhenkun; Denny, William A; Thompson, Andrew M

2015-04-09

Novel extended side chain nitroimidazooxazine analogues featuring diverse linker groups between two aryl rings were studied as a potential strategy to improve solubility and oral activity against chronic infection by Mycobacterium tuberculosis. Both lipophilic and highly polar functionalities (e.g., carboxamide, alkylamine, piperazine, piperidine, but not sulfonamide) were well tolerated in vitro, and the hydrophilic linkers provided some solubility improvements, particularly in combination with pyridine rings. Most of the 18 compounds further assessed showed high microsomal stabilities, although in the acute infection mouse model, just one stilbene (6-fold) and two pyridine-containing acetylene derivatives (5-fold and >933-fold) gave in vivo efficacies notably superior to the clinical stage compound pretomanid (PA-824). The most efficacious analogue also displayed outstanding in vivo activity in the stringent chronic model (up to 24-fold better than the drug delamanid and 4-fold greater than our previous best phenylpyridine candidate), with favorable pharmacokinetics, including good oral bioavailability in the rat.

Synthesis, structural and conformational study of some esters derived from 3-methyl-3-azabicyclo[3.2.1]octan-8(α and β)-ols

NASA Astrophysics Data System (ADS)

Iriepa, I.; Bellanato, J.

2014-09-01

A series of α and β-esters bearing a 3-methyl-3-azabicyclo[3.2.1]octane moiety as well as methyl and aryl substituents were synthesized and studied by 1H and 13C NMR spectroscopies. In CDCl3 solution, at room temperature, a chair-envelope conformation for the bicycle moiety with the N-CH3 group in equatorial position with respect to the chair ring is proposed for both, α and β-esters. The chair conformation of the piperidine ring is puckered at C8 in the α-epimers and it is flattened at N3, in the β-epimers. Free rotation of the acyloxy group around the C8sbnd O bond has also been deduced. Analgesic activity of four of these substances was studied. 8β-Benzoyloxy-3-methyl-3-azabicyclo[3.2.1]octane demonstrated significant analgesic activity in the hot plate test compared to morphine. By measuring the rectal temperature in mice, results also showed a significant antipyretic activity of this compound.

Iron- and cobalt-catalyzed arylation of azetidines, pyrrolidines, and piperidines with Grignard reagents.

PubMed

Barré, Baptiste; Gonnard, Laurine; Campagne, Rémy; Reymond, Sébastien; Marin, Julien; Ciapetti, Paola; Brellier, Marie; Guérinot, Amandine; Cossy, Janine

2014-12-05

Iron- and cobalt-catalyzed cross-couplings between iodo-azetidines, -pyrrolidines, -piperidines, and Grignard reagents are disclosed. The reaction is efficient, cheap, chemoselective and tolerates a large variety of (hetero)aryl Grignard reagents.

Piperidine alkaloids: Human and food animal teratogens

USDA-ARS?s Scientific Manuscript database

Piperidine alkaloids are acutely toxic to adult livestock species and produce musculoskeletal deformities in neonatal animals. These teratogenic effects include multiple congenital contracture (MCC) deformities and cleft palate in cattle, pigs, sheep, and goats. Poisonous plants containing teratogen...

Optimization of three- and four-component reactions for polysubstituted piperidines: application to the synthesis and preliminary biological screening of a prototype library.

PubMed

Ulaczyk-Lesanko, Agnieszka; Pelletier, Eric; Lee, Maria; Prinz, Heino; Waldmann, Herbert; Hall, Dennis G

2007-01-01

Several solid- and solution-phase strategies were evaluated for the preparation of libraries of polysubstituted piperidines of type 7 using the tandem aza[4+2]cycloaddition/allylboration multicomponent reaction between 1-aza-4-boronobutadienes, maleimides, and aldehydes. A novel four-component variant of this chemistry was developed in solution phase, and it circumvents the need for pre-forming the azabutadiene component. A parallel synthesis coupled with compound purification by HPLC with mass-based fraction collection allowed the preparation of a library of 944 polysubstituted piperidines in a high degree of purity suitable for biological screening. A representative subset of 244 compounds was screened against a panel of phosphatase enzymes, and despite the modest levels of activity obtained, this study demonstrated that piperidines of type 7 display the right physical properties (e.g., solubility) to be assayed effectively in high-throughput enzymatic tests.

Excretion, metabolism, and pharmacokinetics of 1-(8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl)-4-(ethylamino)piperidine-4-carboxamide, a selective cannabinoid receptor antagonist, in healthy male volunteers.

PubMed

Miao, Zhuang; Sun, Hao; Liras, Jennifer; Prakash, Chandra

2012-03-01

The disposition of 1-(8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H- purin-6-yl)-4-(ethylamino)-piperidine-4-carboxamide (CP-945,598), an orally active antagonist of the cannabinoid CB1 receptor, was studied after a single 25-mg oral dose of [(14)C]CP-945,598 to healthy human subjects. Serial blood samples and complete urine and feces were collected up to 672 h after dose. The mean total recovery of radioactivity was 60.1 ± 12.8 from the urine and feces, with the majority of the dose excreted in the feces. The absorption of CP-945,598 in humans was slow with T(max) at 6 h. Less than 2% of the dose was recovered as unchanged drug in the combined excreta, suggesting that CP-945,598 is extensively metabolized. The primary metabolic pathway of CP-945,598 involved N-de-ethylation to form an N-desethyl metabolite (M1), which was then subsequently metabolized by amide hydrolysis (M2), N-hydroxylation (M3), piperidine ring hydroxylation (M6), and ribose conjugation (M9). M3 was further metabolized to oxime (M4) and keto (M5) metabolites. M1, M4, and M5 were the major circulating metabolites, with AUC((0-48)) values 4.7-, 1.5-, and 1.1-fold greater than that of CP-945,598. M1, M2, and M9 accounted for 5.6, 33.6, and 6.30% of the dose, respectively, in excreta. The results from in vitro experiments with recombinant isoforms suggested that the oxidative metabolism of CP-945,598 to M1 is catalyzed primarily by CYP3A4/3A5. The molecular docking study showed that the N-ethyl moiety of CP-945,598 can access to the heme iron-oxo of CYP3A4 in an energetically favored orientation. Together, these data suggest that CP-945,598 is well absorbed and eliminated largely by CYP3A4/3A5-catalyzed metabolism.

Impact of passive permeability and gut efflux transport on the oral bioavailability of novel series of piperidine-based renin inhibitors in rodents.

PubMed

Lévesque, Jean-François; Bleasby, Kelly; Chefson, Amandine; Chen, Austin; Dubé, Daniel; Ducharme, Yves; Fournier, Pierre-André; Gagné, Sébastien; Gallant, Michel; Grimm, Erich; Hafey, Michael; Han, Yongxin; Houle, Robert; Lacombe, Patrick; Laliberté, Sébastien; MacDonald, Dwight; Mackay, Bruce; Papp, Robert; Tschirret-Guth, Richard

2011-09-15

An oral bioavailability issue encountered during the course of lead optimization in the renin program is described herein. The low F(po) of pyridone analogs was shown to be caused by a combination of poor passive permeability and gut efflux transport. Substitution of pyridone ring for a more lipophilic moiety (logD>1.7) had minimal effect on rMdr1a transport but led to increased passive permeability (P(app)>10 × 10(-6) cm/s), which contributed to overwhelm gut transporters and increase rat F(po). LogD and in vitro passive permeability determination were found to be key in guiding SAR and improve oral exposure of renin inhibitors. Copyright © 2011 Elsevier Ltd. All rights reserved.

The Pauson-Khand Reaction as a New Entry to the Synthesis of Bridged Bicyclic Heterocycles: Application to the Enantioselective Total Synthesis of (−)-Alstonerine

PubMed Central

Miller, Kenneth A.; Shanahan, Charles S.; Martin, Stephen F.

2008-01-01

The first application of the Pauson-Khand reaction (PKR) to the synthesis of azabridged bicyclic structures is described. Compounds containing azabicyclo[3.3.1]nonane and azabicyclo[3.2.1]octane rings fused to cyclopentenones were efficiently constructed via the PKR of cis-2,6-disubstituted N-acyl piperidine enyne substrates, many of which can be readily prepared from 4-methoxypyridine in a few steps. Moreover, the PKR of cis-2,6-disubstituted piperazine enynes allowed the preparation of diazabicyclo[3.3.1]nonanes fused to cyclopentenones. This new strategy for the synthesis of azabridged bicyclic frameworks was exploited as a key step in a concise, enantioselective total synthesis of the macroline alklaoid (−)-alstonerine. PMID:19122869

The Pauson-Khand Reaction as a New Entry to the Synthesis of Bridged Bicyclic Heterocycles: Application to the Enantioselective Total Synthesis of (-)-Alstonerine.

PubMed

Miller, Kenneth A; Shanahan, Charles S; Martin, Stephen F

2008-01-01

The first application of the Pauson-Khand reaction (PKR) to the synthesis of azabridged bicyclic structures is described. Compounds containing azabicyclo[3.3.1]nonane and azabicyclo[3.2.1]octane rings fused to cyclopentenones were efficiently constructed via the PKR of cis-2,6-disubstituted N-acyl piperidine enyne substrates, many of which can be readily prepared from 4-methoxypyridine in a few steps. Moreover, the PKR of cis-2,6-disubstituted piperazine enynes allowed the preparation of diazabicyclo[3.3.1]nonanes fused to cyclopentenones. This new strategy for the synthesis of azabridged bicyclic frameworks was exploited as a key step in a concise, enantioselective total synthesis of the macroline alklaoid (-)-alstonerine.

Synthesis of (+)-dumetorine and congeners by using flow chemistry technologies.

PubMed

Riva, Elena; Rencurosi, Anna; Gagliardi, Stefania; Passarella, Daniele; Martinelli, Marisa

2011-05-23

An efficient total synthesis of the natural alkaloid (+)-dumetorine by using flow technology is described. The process entailed five separate steps starting from the enantiopure (S)-2-(piperidin-2-yl)ethanol 4 with 29% overall yield. Most of the reactions were carried out by exploiting solvent superheating and by using packed columns of immobilized reagents or scavengers to minimize handling. New protocols for performing classical reactions under continuous flow are disclosed: the ring-closing metathesis reaction with a novel polyethylene glycol-supported Hoveyda catalyst and the unprecedented flow deprotection/Eschweiler-Clarke methylation sequence. The new protocols developed for the synthesis of (+)-dumetorine were applied to the synthesis of its simplified natural congeners (-)-sedamine and (+)-sedridine. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Quantitative structure-activity relationship studies of threo-methylphenidate analogs.

PubMed

Misra, Milind; Shi, Qing; Ye, Xiaocong; Gruszecka-Kowalik, Ewa; Bu, Wei; Liu, Zhanzhu; Schweri, Margaret M; Deutsch, Howard M; Venanzi, Carol A

2010-10-15

Complementary two-dimensional (2D) and three-dimensional (3D) Quantitative Structure-Activity Relationship (QSAR) techniques were used to derive a preliminary model for the dopamine transporter (DAT) binding affinity of 80 racemic threo-methylphenidate (MP) analogs. A novel approach based on using the atom-level E-state indices of the 14 common scaffold atoms in a sphere exclusion protocol was used to identify a test set for 2D- and 3D-QSAR model validation. Comparative Molecular Field Analysis (CoMFA) contour maps based on the structure-activity data of the training set indicate that the 2' position of the phenyl ring cannot tolerate much steric bulk and that addition of electron-withdrawing groups to the 3' or 4' positions of the phenyl ring leads to improved DAT binding affinity. In particular, the optimal substituents were found to be those whose bulk is mainly in the plane of the phenyl ring. Substituents with significant bulk above or below the plane of the ring led to decreased binding affinity. Suggested alterations to be explored in the design of new compounds are the placement at the 3' and 4' position of the phenyl ring of electron-withdrawing groups that lie chiefly in the plane of the ring, for example, halogen substituents on the 3',4'-benzo analog, 79. A complementary 2D-QSAR approach-partial least squares analysis using a reduced set of Molconn-Z descriptors-supports the CoMFA structure-activity interpretation that phenyl ring substitution is a major determinant of DAT binding affinity. The potential usefulness of the CoMFA models was demonstrated by the prediction of the binding affinity of methyl 2-(naphthalen-1-yl)-2-(piperidin-2-yl)acetate, an analog not in the original data set, to be in good agreement with the experimental value. Copyright © 2010 Elsevier Ltd. All rights reserved.

Adolescent Experiences with the Vaginal Ring

PubMed Central

Epstein, Laura B.; Sokal-Gutierrez, Karen; Ivey, Susan L.; Raine, Tina; Auerswald, Colette

2011-01-01

Purpose To understand racial/ethnic minority adolescent females’ experiences with the vaginal ring. Methods We conducted in-depth interviews with a clinic-based sample of 32 young women aged 15–24 years who had used the vaginal ring. Results Qualitative analysis using grounded theory revealed that adolescents undergo a multi-stage process when trying the ring and adopting ring use. These stages include hearing about the ring, initial reactions, first experiences with insertion and removal, and first sexual experiences. Adolescents subsequently enter an assessment and adjustment stage in which they decide whether to adopt or discontinue ring use. Ultimately they share their experiences with friends. Conclusions The model developed provides a context within which providers may advise adolescents as they begin use of the ring. Some specific recommendations are offered. PMID:18565439

Synthesis and receptor binding studies of novel 4,4-disubstituted arylalkyl/arylalkylsulfonyl piperazine and piperidine-based derivatives as a new class of σ1 ligands.

PubMed

Sadeghzadeh, Masoud; Sheibani, Shahab; Ghandi, Mehdi; Daha, Fariba Johari; Amanlou, Massoud; Arjmand, Mohammad; Hasani Bozcheloie, Abolfazl

2013-06-01

This study presents the synthesis and biological evaluation of a new series of arylalkyl/arylalkylsulfonyl piperazine and piperidine-based derivatives as sigma receptor ligands. It was found that a number of halogen substituted sulfonamides display relatively high and low affinities to σ1 and σ2 receptors, respectively. The σ1 affinities and subtype selectivities of four piperidine derivatives were also found to be generally comparable to those of piperazine analogues. Compared to σ1-Rs compounds with n = 0 and 2, those with n = 1 proved to have optimal length of carbon chain by exhibiting higher affinities. Within this series, the 4-benzyl-1-(3-iodobenzylsulfonyl)piperidine sigma ligand was identified with 96-fold σ1/σ2 selectivity ratio (Kiσ1 = 0.96 ± 0.05 nM and Kiσ2 = 91.8 ± 8.1 nM). Copyright © 2013 Elsevier Masson SAS. All rights reserved.

Neopetrosiamine A, biologically active bis-piperidine alkaloid from the Caribbean sea sponge Neopetrosia proxima.

PubMed

Wei, Xiaomei; Nieves, Karinel; Rodríguez, Abimael D

2010-10-01

A new tetracyclic bis-piperidine alkaloid, neopetrosiamine A (1), has been extracted from the marine sponge Neopetrosiaproxima collected off the west coast of Puerto Rico. The structure of compound 1 was elucidated by analysis of spectroscopic data coupled with careful comparisons of its (1)H and (13)C NMR data with those of a well-known 3-alkylbis-piperidine alkaloid model. The new alkaloid displayed strong in vitro cytotoxic activity against a panel of cancer cell lines as well as in vitro inhibitory activity against the pathogenic microbes Mycobacterium tuberculosis and Plasmodium falciparum. Copyright © 2010 Elsevier Ltd. All rights reserved.

Discovery of Novel 3,3-Disubstituted Piperidines as Orally Bioavailable, Potent, and Efficacious HDM2-p53 Inhibitors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bogen, Stéphane L.; Pan, Weidong; Gibeau, Craig R.

2016-03-10

A new subseries of substituted piperidines as p53-HDM2 inhibitors exemplified by 21 has been developed from the initial lead 1. Research focused on optimization of a crucial HDM2 Trp23–ligand interaction led to the identification of 2-(trifluoromethyl)thiophene as the preferred moiety. Further investigation of the Leu26 pocket resulted in potent, novel substituted piperidine inhibitors of the HDM2-p53 interaction that demonstrated tumor regression in several human cancer xenograft models in mice. The structure of HDM2 in complex with inhibitors 3, 10, and 21 is described.

The Actions of Piperidine Alkaloids at Fetal Muscle-Type and Autonomic-Type Nicotinic Acetylcholine Receptors

USDA-ARS?s Scientific Manuscript database

Piperidine alkaloids are found in many species of plants including Conium maculatum, Nicotiana spp., and Lupinus spp. A pharmacodynamic comparison was made of the alkaloids ammodendrine, anabasine, anabaseine, and coniine in; SH-SY5Y cells which express autonomic-type nicotinic acetylcholine recept...

Novel selective kappa-opioid ligands.

PubMed

Peeters, O M; Jamroz, D; Blaton, N M; De Ranter, C J

1999-03-15

The single-crystal X-ray structures of (-)-dimethyl[(2S)-1-(5,6,7,8- tetrahydro-5-oxonaphthalene-2-acetyl)piperidin-2-ylmethyl ]ammonium chloride, C20H29N2O2+.Cl-(BRL-53001A), and (-)-ethylmethyl[(2S)-1-(5,6,7,8-tetrahydro-5-oxonaphthalene- 2- acetyl)piperidin-2-ylmethyl]-ammonium chloride dihydrate, C21H31N2O2+.Cl-.2H2O (BRL-53188A), have been determined. The two molecules have different conformations in the 1-tetralon-6-ylacetyl residue but the same conformation in the 1-acetyl-2-(dialkylaminomethyl)piperidine moiety. The conformations found are in agreement with the required chemical features for kappa affinity and antinociceptive potency.

A pharmacodynamic comparison of piperidine and pyridine alkaloid actions at fetal muscle-type nicotinic acetylcholine receptors (nAChR)

USDA-ARS?s Scientific Manuscript database

Piperidine and pyridine alkaloids are found in many species of plants including Lobelia spp., Conium spp., Nicotiana spp., and Lupinus spp. Some of these alkaloids cause multiple congenital contracture deformities (MCC) and cleft palates in cattle, pigs, sheep, and goats. The mechanism behind MCC ...

Carbon-carbon bond activation of 2,2,6,6-tetramethyl-piperidine-1-oxyl by a Rh(II) metalloradical: a combined experimental and theoretical study.

PubMed

Chan, Kin Shing; Li, Xin Zhu; Dzik, Wojciech I; de Bruin, Bas

2008-02-13

Competitive major carbon-carbon bond activation (CCA) and minor carbon-hydrogen bond activation (CHA) channels are identified in the reaction between rhodium(II) meso-tetramesitylporphyrin [Rh(II)(tmp)] (1) and 2,2,6,6-tetramethyl-piperidine-1-oxyl (TEMPO) (2). The CCA and CHA pathways lead to formation of [Rh(III)(tmp)Me] (3) and [Rh(III)(tmp)H] (5), respectively. In the presence of excess TEMPO, [Rh(II)(tmp)] is regenerated from [Rh(III)(tmp)H] with formation of 2,2,6,6-tetramethyl-piperidine-1-ol (TEMPOH) (4) via a subsequent hydrogen atom abstraction pathway. The yield of the CCA product [Rh(III)(tmp)Me] increased with higher temperature at the cost of the CHA product TEMPOH in the temperature range 50-80 degrees C. Both the CCA and CHA pathways follow second-order kinetics. The mechanism of the TEMPO carbon-carbon bond activation was studied by means of kinetic investigations and DFT calculations. Broken symmetry, unrestricted b3-lyp calculations along the open-shell singlet surface reveal a low-energy transition state (TS1) for direct TEMPO methyl radical abstraction by the Rh(II) radical (SH2 type mechanism). An alternative ionic pathway, with a somewhat higher barrier, was identified along the closed-shell singlet surface. This ionic pathway proceeds in two sequential steps: Electron transfer from TEMPO to [Rh(II)(por)] producing the [TEMPO]+ [RhI(por)]- cation-anion pair, followed by net CH3+ transfer from TEMPO+ to Rh(I) with formation of [Rh(III)(por)Me] and (DMPO-like) 2,2,6-trimethyl-2,3,4,5-tetrahydro-1-pyridiniumolate. The transition state for this process (TS2) is best described as an SN2-like nucleophilic substitution involving attack of the d(z)2 orbital of [Rh(I)(por)]- at one of the C(Me)-C(ring) sigma* orbitals of [TEMPO]+. Although the calculated barrier of the open-shell radical pathway is somewhat lower than the barrier for the ionic pathway, R-DFT and U-DFT are not likely comparatively accurate enough to reliably distinguish between these possible pathways. Both the radical (SH2) and the ionic (SN2) pathway have barriers which are low enough to explain the experimental kinetic data.

Caste specific alkaloid chemistry of Solenopsis maboya and S

Treesearch

J.A. Torres; V.E. Zottig; J.E. Co; T.H. Jones; R.R. Snelling

2001-01-01

Examination of the alkaloids of Solenopsis maboya Snelling and comparison with those previously found in S. Torresi Snelling, reveals a clear example of caste-specific alkaloid production in the queens and workers of each species. The queens of Solenopsis maboya contain a single piperidine while the workers produce a different piperidine along with two indolizidine...

Approaches to the synthesis of (+/-)-strychnine via the cobalt-mediated [2 + 2 + 2] cycloaddition: rapid assembly of a classic framework.

PubMed

Eichberg, M J; Dorta, R L; Grotjahn, D B; Lamottke, K; Schmidt, M; Vollhardt, K P

2001-09-26

Five synthetic approaches to racemic strychnine (1), with the cobalt-mediated [2 + 2 + 2] cycloaddition of alkynes to indoles as the key step, are described. These include the generation and attempted cyclization of macrocycle 8 and the synthesis of dihydrocarbazoles 15, 22, and 26 and their elaboration to pentacyclic structures via a conjugate addition, dipolar cycloaddition, and propellane-to-spirofused skeletal rearrangement, respectively. Finally, the successful total synthesis of 1 is discussed. The development of a short, highly convergent route (14 steps in the longest linear sequence) is highlighted by the cyclization of enynoylindole 40 with acetylene and the formal intramolecular 1,8-conjugate addition of amine 49 to form pentacycle 50. Numerous attempts toward the formation of the piperidine ring of 1 from vinyl iodide 56 were made and its successful formation via palladium-, nickel-, and radical-mediated processes is described.

Crystal structure of [propane-1,3-diylbis(piperidine-4,1-di-yl)]bis-[(pyridin-4-yl)methanone]-4,4'-oxydi-benzoic acid (1/1).

PubMed

Low, Emily M; LaDuca, Robert L

2014-09-01

In the title co-crystal, C25H32N4O2·C14H10O5, mol-ecules are connected into supra-molecular chains aligned along [102] by O-H⋯N hydrogen bonding. These aggregate into supra-molecular layers oriented parallel to (20-1) by C-H⋯O inter-actions. These layers then stack in an ABAB pattern along the c crystal direction to give the full three-dimensional crystal structure. The central chain in the dipyridylamide has an anti-anti conformation. The dihedral angle between the aromatic ring planes is 29.96 (3)°. Disorder is noted in some of the residues in the structure and this is manifested in two coplanar dispositions of one statistically disordered carb-oxy-lic acid group.

9-(3,4-Dimeth-oxy-phen-yl)-3,3,6,6-tetra-methyl-4,5,6,9-tetra-hydro-3H-xanthene-1,8(2H,7H)-dione.

PubMed

Mehdi, Sayed Hasan; Sulaiman, Othman; Ghalib, Raza Murad; Yeap, Chin Sing; Fun, Hoong-Kun

2011-07-01

The asymmetric unit of the title xanthene compound, C(25)H(30)O(5), contains two mol-ecules in which the pyran ring and the dimeth-oxy-phenyl ring are nearly perpendicular to one another [dihedral angles = 86.81 (8) and 84.45 (9)°]. One of the meth-oxy groups in one mol-ecule is twisted away from the phenyl ring [C-O-C-C torsion angle = -103.40 (16)°]. The pyran ring adopts a boat conformation whereas the two fused cyclo-hexane rings adopt envelope conformations in both mol-ecules. In the crystal, mol-ecules are linked into a three-dimensional network by C-H⋯O hydrogen bonds.

Halogenated naphthyl methoxy piperidines for mapping serotonin transporter sites

DOEpatents

Goodman, Mark M.; Faraj, Bahjat

1999-01-01

Halogenated naphthyl methoxy piperidines having a strong affinity for the serotonin transporter are disclosed. Those compounds can be labeled with positron-emitting and/or gamma emitting halogen isotopes by a late step synthesis that maximizes the useable lifeterm of the label. The labeled compounds are useful for localizing serotonin transporter sites by positron emission tomography and/or single photon emission computed tomography.

Halogenated naphthyl methoxy piperidines for mapping serotonin transporter sites

DOEpatents

Goodman, M.M.; Faraj, B.

1999-07-06

Halogenated naphthyl methoxy piperidines having a strong affinity for the serotonin transporter are disclosed. Those compounds can be labeled with positron-emitting and/or gamma emitting halogen isotopes by a late step synthesis that maximizes the useable lifeterm of the label. The labeled compounds are useful for localizing serotonin transporter sites by positron emission tomography and/or single photon emission computed tomography.

Modulators of the human CCR5 receptor. Part 1: Discovery and initial SAR of 1-(3,3-diphenylpropyl)-piperidinyl amides and ureas.

PubMed

Burrows, Jeremy N; Cumming, John G; Fillery, Shaun M; Hamlin, Gordon A; Hudson, Julian A; Jackson, Ruth J; McLaughlin, Sharon; Shaw, John S

2005-01-03

Investigation of weak screening hits led to the identification of N-alkyl-N-[1-(3,3-diphenylpropyl)piperidin-4-yl]-2-phenylacetamides and N-alkyl-N-[1-(3,3-diphenylpropyl)piperidin-4-yl]-N'-benzylureas as potent, selective ligands for the human CCR5 chemokine receptor.

Synthetic versatility of 2-substituted-6-methyl 2,3-dihydropyridinones in the synthesis of polyfunctional piperidine-based compounds and related β amino acid derivatives.

PubMed

Yang, Yang; Hardman, Clayton

2017-10-18

Chiral 2-substituted-6-methyl 2,3-dihydropyidinones 9, which can be facilely obtained from an asymmetric vinylogous Mannich reaction (VMR) with 1,3-bis-trimethysily enol ether, were used as versatile intermediates in constructing chiral polyfunctional piperidine-based compounds. The 6-methyl group of such compounds can be conveniently functionalized via alkylation and acylation reactions to provide efficient entries to the synthesis of a variety of chiral multi-substituted piperidine-based compounds. Further elaboration of the corresponding intermediates also provided access to polyfunctional indolizidine-based compounds. These methods were showcased in an asymmetric synthesis of 2,6-di-substituted piperidine compound 13, reported as the key intermediate in the synthesis of (+)-calvine and a natural alkaloid (-)-indolizidine 209D. Furthermore, selective C5 iodination of compound 9 enabled the installation of additional functional groups at this position. Finally, we demonstrated that the oxidative cleavage of 2-substituted-6-methyl-2,3-dihydropyidinones is a practical and efficient method for the enantioselective synthesis of β-amino acids, which can undergo further intra-molecular cyclization to give the corresponding chiral four-membered β-lactam derivatives.

9-(3,4-Dimeth-oxy-phen-yl)-3,4,5,6,7,9-hexa-hydroxanthene-1,8(2H)-dione.

PubMed

Mehdi, Sayed Hasan; Hashim, Rokiah; Ghalib, Raza Murad; Yeap, Chin Sing; Fun, Hoong-Kun

2011-06-01

In the title compound, C(21)H(22)O(5), the mean planes of the pyran and dimeth-oxy-phenyl rings are nearly perpendicular to one another, with the dihedral angle between them being 88.21 (8)°. The pyran ring adopts a boat conformation whereas the two fused cyclo-hexane rings adopt envelope conformations. In the crystal, mol-ecules are linked into a three-dimensional network by inter-molecular C-H⋯O hydrogen bonds.

Discovery of piperidin-4-yl-aminopyrimidine derivatives as potent non-nucleoside HIV-1 reverse transcriptase inhibitors.

PubMed

Wan, Zheng-Yong; Yao, Jin; Tao, Yuan; Mao, Tian-Qi; Wang, Xin-Long; Lu, Yi-Pei; Wang, Hai-Feng; Yin, Hong; Wu, Yan; Chen, Fen-Er; De Clercq, Erik; Daelemans, Dirk; Pannecouque, Christophe

2015-06-05

A novel series of piperidin-4-yl-aminopyrimidine derivatives were designed fusing the pharmacophore templates of etravirine-VRX-480773 hybrids our group previously described and piperidine-linked aminopyrimidines. Most compounds displayed significantly improved activity against wild-type HIV-1 with EC50 values in single-digit nanomolar concentrations compared to etravirine-VRX-480773 hybrids. Selected compounds were also evaluated for activity against reverse transcriptase, and had lower IC50 values than that of nevirapine. The improved potency observed in this in vitro model of HIV RNA replication partly validates the mechanism by which this class of allosteric pyrimidine derivatives inhibits reverse transcriptase, and represents a remarkable step forward in the development of AIDS therapeutics. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

A critical review of both the synthesis approach and the receptor profile of the 8-chloro-1-(2',4'-dichlorophenyl)-N-piperidin-1-yl-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-c]pyrazole-3-carboxamide and analogue derivatives.

PubMed

Lazzari, Paolo; Distinto, Rita; Manca, Ilaria; Baillie, Gemma; Murineddu, Gabriele; Pira, Marilena; Falzoi, Matteo; Sani, Monica; Morales, Paula; Ross, Ruth; Zanda, Matteo; Jagerovic, Nadine; Pinna, Gérard Aimè

2016-10-04

8-Chloro-1-(2',4'-dichlorophenyl)-N-piperidin-1-yl-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-c]pyrazole-3-carboxamide 9a was discovered as potent and selective CB1 antagonist by part of our group few years ago. In particular it was reported to have an affinity towards the CB1 cannabinoid receptor (CB1R), expressed as Ki, of 0.00035 nM. Nevertheless significantly divergent data were reported for the same compound from other laboratories. To unequivocally define the receptor profile of 9a, we have critically reviewed both its synthesis approach and binding data. Here we report that, in contrast to our previously reported data, 9a showed a Ki value for CB1R in the order of nanomolar rather than of fentomolar range. The new determined receptor profile of 9a was also ascertained for analogue derivatives 9b-i, as well as for 12. Moreover, the structural features of the synthesized compounds necessary for CB1R were investigated. Amongst the novel series, effects on CB1R intrinsic activity was highlighted due to the substituents at the position 3 of the pyrazole ring of the 1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-c]pyrazole scaffold. Although the cannabinoid receptor profile of 9a was reviewed in this work, the relevance of this compound in CB1R antagonist based drug discovery is confirmed. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Rational Design, Pharmacomodulation, and Synthesis of Dual 5-Hydroxytryptamine 7 (5-HT7)/5-Hydroxytryptamine 2A (5-HT2A) Receptor Antagonists and Evaluation by [(18)F]-PET Imaging in a Primate Brain.

PubMed

Deau, Emmanuel; Robin, Elodie; Voinea, Raluca; Percina, Nathalie; Satała, Grzegorz; Finaru, Adriana-Luminita; Chartier, Agnès; Tamagnan, Gilles; Alagille, David; Bojarski, Andrzej J; Morisset-Lopez, Séverine; Suzenet, Franck; Guillaumet, Gérald

2015-10-22

We report the synthesis of 46 tertiary amine-bearing N-alkylated benzo[d]imidazol-2(3H)-ones, imidazo[4,5-b]pyridin-2(3H)-ones, imidazo[4,5-c]pyridin-2(3H)-ones, benzo[d]oxazol-2(3H)-ones, oxazolo[4,5-b]pyridin-2(3H)-ones and N,N'-dialkylated benzo[d]imidazol-2(3H)-ones. These compounds were evaluated against 5-HT7R, 5-HT2AR, 5-HT1AR, and 5-HT6R as potent dual 5-HT7/5-HT2A serotonin receptors ligands. A thorough study of the structure-activity relationship of the aromatic rings and their substituents, the alkyl chain length and the tertiary amine was conducted. 1-(4-(4-(4-Fluorobenzoyl)piperidin-1-yl)butyl)-1H-benzo[d]imidazol-2(3H)-one (79) and 1-(6-(4-(4-fluorobenzoyl)piperidin-1-yl)hexyl)-1H-benzo[d]imidazol-2(3H)-one (81) were identified as full antagonist ligands on cyclic adenosine monophosphate (cAMP, KB = 4.9 and 5.9 nM, respectively) and inositol monophosphate (IP1, KB = 0.6 and 16 nM, respectively) signaling pathways of 5-HT7R and 5-HT2AR. Both antagonists crossed the blood-brain barrier as evaluated with [(18)F] radiolabeled compounds [(18)F]79 and [(18)F]81 in a primate's central nervous system using positron emission tomography. Both radioligands showed standard uptake values ranging from 0.8 to 1.1, a good plasmatic stability, and a distribution consistent with 5-HT7R and 5-HT2AR in the CNS.

Design, Synthesis of Novel Lipids as Chemical Permeation Enhancers and Development of Nanoparticle System for Transdermal Drug Delivery

PubMed Central

Shah, Punit P.; Etukala, Jagan Reddy; Vemuri, Adithi; Singh, Mandip

2013-01-01

In the present study, we designed and developed novel lipids that include (Z)-1-(Octadec-9-en-1-yl)-pyrrolidine (Cy5T), 1, 1-Di-((Z)-octadec-9-en-1-yl)pyrrolidin-1-ium iodide (Cy5), (Z)-1-(Octadec-9-en-1-yl)-piperidine (Cy6T), and 1, 1-Di-((Z)-octadec-9-en-1-yl) piperidin-1-ium iodide (Cy6) to enhance the transdermal permeation of some selected drugs. Firstly, we evaluated the transdermal permeation efficacies of these lipids as chemical permeation enhancers in vehicle formulations for melatonin, ß-estradiol, caffeine, α-MSH, and spantide using franz diffusion cells. Among them Cy5 lipid was determined to be the most efficient by increasing the transdermal permeation of melatonin, ß-estradiol, caffeine, α-MSH, and spantide by 1.5 to 3.26-fold more at the epidermal layer and 1.3 to 2.5-fold more at the dermal layer, in comparison to either NMP or OA. Hence we developed a nanoparticle system (cy5 lipid ethanol drug nanoparticles) to evaluate any further improvement in the drug penetration. Cy5 lipid formed uniformly sized nanoparticles ranging from 150–200 nm depending on the type of drug. Further, Cy5 based nanoparticle system significantly (p<0.05) increased the permeation of all the drugs in comparison to the lipid solution and standard permeation enhancers. There were about 1.54 to 22-fold more of drug retained in the dermis for the Cy5 based nanoparticles compared to OA/NMP standard enhancers and 3.87 to 66.67-fold more than lipid solution. In addition, epifluorescent microscopic analysis in rhodamine-PE permeation studies confirmed the superior permeation enhancement of LEDs (detection of fluorescence up to skin depth of 340 μm) more than lipid solution, which revealed fluorescence up to skin depth of only 260 μm. In summary the present findings demonstrate that i) cationic lipid with 5 membered amine heterocyclic ring has higher permeating efficacy than the 6 membered amine hertocyclic ring. ii) The nanoparticle system prepared with Cy5 showed significant (p<0.05) increase in the permeation of the drugs than the control penetration enhancers, oleic acid and NMP. PMID:24349315

Enantioselective synthesis of substituted piperidines by addition of aryl Grignard reagents to pyridine N-oxides.

PubMed

Hussain, Munawar; Banchelin, Thomas Sainte-Luce; Andersson, Hans; Olsson, Roger; Almqvist, Fredrik

2013-01-04

The synthesis of optically active piperidines by enantioselective addition of aryl Grignard reagents to pyridine N-oxides and lithium binolate followed by reduction is reported for the first time. The reaction results in high yields (51-94%) in combination with good ee (54-80%). Some of these products were subsequently recrystallized, affording enhanced optical purities (>99% ee).

Piperidine Synthesis.

DTIC Science & Technology

1992-09-01

ORGANIZATION NAME(S) AND ADORESS(ES) B . PERFORMING ORGANIZATION CDR, CRDEC, ATTN: SMCCR-RSC-O, APG, MD REPORT NUMBER 21010-5423 CRDEC-TR-409 9. SPONSORING...hydroxypyridine with iodomethane or benzyl chloride followed by sodium borohydride reduction and HBr cleavage of the enol ether is yet another effective...Piperidine, Elsevier, New York, 1991. ( b ) Armardgo, W.L.F., "Stereochemistry of Heterocyclic Compounds, Part 1," John Wiley & Sons, New York, 1977. (c

Effect of the composition of a solution on the enthalpies of solvation of piperidine in methanol-acetonitrile and dimethylsulfoxide-acetonitrile mixed solvents

NASA Astrophysics Data System (ADS)

Kuz'mina, I. A.; Volkova, M. A.; Sitnikova, K. A.; Sharnin, V. A.

2014-01-01

Heat effects of dissolution of piperidine (ppd) are measured by calorimetry at 298.15 K over the range of composition of acetonitrile-methanol (AN-MeOH) mixed solvents. Based on the Δsol H ○(ppd)AN-MeOH values obtained using the literature data on Δsol H ○ (ppd) in acetonitrile-dimethylsulfoxide (AN-DMSO) mixed solvents and the vaporization enthalpy of ppd, the enthalpies of solvation of amine in AN-MeOH and AN-DMSO binary mixtures are calculated. A rise in the exothermicity of solvation of piperidine is observed upon the transition from AN to DMSO and MeOH, due mainly to the enhanced solvation of the amino group of ppd as a result of changes in the acid-base properties of the mixed solvent.

9-(3,4-Dimeth­oxy­phen­yl)-3,4,5,6,7,9-hexa­hydroxanthene-1,8(2H)-dione

PubMed Central

Mehdi, Sayed Hasan; Hashim, Rokiah; Ghalib, Raza Murad; Yeap, Chin Sing; Fun, Hoong-Kun

2011-01-01

In the title compound, C21H22O5, the mean planes of the pyran and dimeth­oxy­phenyl rings are nearly perpendicular to one another, with the dihedral angle between them being 88.21 (8)°. The pyran ring adopts a boat conformation whereas the two fused cyclo­hexane rings adopt envelope conformations. In the crystal, mol­ecules are linked into a three-dimensional network by inter­molecular C—H⋯O hydrogen bonds. PMID:21754824

1-(4,5-Dinitro-10-aza­tricyclo­[6.3.1.02,7]dodeca-2,4,6-trien-10-yl)-2,2,2-trifluoro­ethanone

PubMed Central

Xu, Hao; Quan, Ji-Cai; Xu, Jian; Chen, Jing; Wang, Jin-Tang

2008-01-01

In the title compound, C13H10F3N3O5, a derivative of andrographolide, the five-membered ring adopts an envelope conformation, while the non-planar six-membered ring has a chair conformation. An intra­molecular C—H⋯F hydrogen bond results in the formation of a non-planar six-membered ring adopting a twisted conformation. In the crystal structure, inter­molecular C—H⋯O hydrogen bonds link the mol­ecules into centrosymmetric dimers. PMID:21581393

Fetal-muscle type nicotinic acetylcholine receptor activation in TE-671 cells, and inhibition of fetal movement in a day 40 pregnant goat model by optical isomers of the piperidine alkaloid coniine

USDA-ARS?s Scientific Manuscript database

Coniine is an optically active toxic piperidine alkaloid and nicotinic acetylcholine receptor (nAChR) agonist found in poison hemlock (Conium maculatum L.). Coniine teratogenicity is hypothesized to be due to the binding, activation, and prolonged desensitization of fetal muscle-type nAChR which re...

N-Substituted cis-4a-(3-Hydroxyphenyl)-8a-methyloctahydroisoquinolines Are Opioid Receptor Pure Antagonists

PubMed Central

Carroll, F. Ivy; Chaudhari, Sachin; Thomas, James B.; Mascarella, S. Wayne; Gigstad, Kenneth M.; Deschamps, Jeffrey; Navarro, Hernán A.

2008-01-01

N-Substituted cis-4a-(3-hydroxyphenyl)-8a-methyloctahydroisoquinolines (6a–g) were designed and synthesized as conformationally constrained analogues of the trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine (4) class of opioid receptor pure antagonists. The methyloctahydroisoquinolines 6a–g can exist in conformations where the 3-hydroxyphenyl substituent is either axial or equatorial similar to the (3-hydroxyphenyl)piperidines 4. The 3-hydroxyphenyl equatorial conformation is responsible for the antagonist activity observed in the (3-hydroxyphenyl)piperidine antagonists. Single crystal X-ray analysis of 6a shows that the 3-hydroxyphenyl equatorial conformation is favored in the solid state. Molecular modeling studies also suggest that the equatorial conformation has the lower potential energy relative to the axial conformation. Evaluation of compounds 6a–g in the [35S]GTP-γ-S in vitro functional assay showed that they were opioid receptor pure antagonists. N-[4a-(3-Hydroxyphenyl)-8a-methyl-2-(3-phenylpropyl)octahydroisoquinoline-6-yl]-3-(piperidin-1-yl)propionamide (6d) with a Ke of 0.27 nM at the κ opioid receptor with 154- and 46-fold selectively relative to the μ and δ receptors, respectively, possessed the best combination of κ potency and selectivity. PMID:16366600

Effect of Partially Fluorinated N-Alkyl-Substituted Piperidine-2-carboxamides on Pharmacologically Relevant Properties.

PubMed

Vorberg, Raffael; Trapp, Nils; Zimmerli, Daniel; Wagner, Björn; Fischer, Holger; Kratochwil, Nicole A; Kansy, Manfred; Carreira, Erick M; Müller, Klaus

2016-10-06

The modulation of pharmacologically relevant properties of N-alkyl-piperidine-2-carboxamides was studied by selective introduction of 1-3 fluorine atoms into the n-propyl and n-butyl side chains of the local anesthetics ropivacaine and levobupivacaine. The basicity modulation by nearby fluorine substituents is essentially additive and exhibits an exponential attenuation as a function of topological distance between fluorine and the basic center. The intrinsic lipophilicity of the neutral piperidine derivatives displays the characteristic response noted for partially fluorinated alkyl groups attached to neutral heteroaryl systems. However, basicity decrease by nearby fluorine substituents affects lipophilicities at neutral pH, so that all partially fluorinated derivatives are of similar or higher lipophilicity than their non-fluorinated parents. Aqueous solubilities were found to correlate inversely with lipophilicity with a significant contribution from crystal packing energies, as indicated by variations in melting point temperatures. All fluorinated derivatives were found to be somewhat more readily oxidized in human liver microsomes, the rates of degradation correlating with increasing lipophilicity. Because the piperidine-2-carboxamide core is chiral, pairs with enantiomeric N-alkyl groups are diastereomeric. While little response to such stereoisomerism was observed for basicity or lipophilicity, more pronounced variations were observed for melting point temperatures and oxidative degradation. © 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

9-(3,4-Dimeth­oxy­phen­yl)-3,3,6,6-tetra­methyl-4,5,6,9-tetra­hydro-3H-xanthene-1,8(2H,7H)-dione

PubMed Central

Mehdi, Sayed Hasan; Sulaiman, Othman; Ghalib, Raza Murad; Yeap, Chin Sing; Fun, Hoong-Kun

2011-01-01

The asymmetric unit of the title xanthene compound, C25H30O5, contains two mol­ecules in which the pyran ring and the dimeth­oxy­phenyl ring are nearly perpendicular to one another [dihedral angles = 86.81 (8) and 84.45 (9)°]. One of the meth­oxy groups in one mol­ecule is twisted away from the phenyl ring [C—O—C—C torsion angle = −103.40 (16)°]. The pyran ring adopts a boat conformation whereas the two fused cyclo­hexane rings adopt envelope conformations in both mol­ecules. In the crystal, mol­ecules are linked into a three-dimensional network by C—H⋯O hydrogen bonds. PMID:21837111

Rubber-Modified Epoxies: Transitions and Morphology.

DTIC Science & Technology

1980-09-01

Hill. New Jersey 07974 i .i -2- INTRODUCTION Low levels of carboxyl-terminated reactive liquid rubber copolymers of butadiene and acrylonitrile ( CTBN ...parts per hundred parts resin (phr) of CTBN , and 5 phr piperidine is homo- geneous at the start of cure if the cure temperature is above some critical...solubility temperature (which is designated Tso). In the presence of piperidine there is a rapid reaction of the carboxyl end groups of the CTBN with

4-Bicyclic heteroaryl-piperidine derivatives as potent, orally bioavailable Stearoyl-CoA desaturase-1 (SCD1) inhibitors. Part 1: urea-based analogs.

PubMed

Yang, Shyh-Ming; Tang, Yuting; Zhang, Rui; Lu, Huajun; Kuo, Gee-Hong; Gaul, Michael D; Li, Yaxin; Ho, George; Conway, James G; Liang, Yin; Lenhard, James M; Demarest, Keith T; Murray, William V

2013-12-15

A new series of urea-based, 4-bicyclic heteroaryl-piperidine derivatives as potent SCD1 inhibitors is described. The structure-activity relationships focused on bicyclic heteroarenes and aminothiazole-urea portions are discussed. A trend of dose-dependent decrease in body weight gain in diet-induced obese (DIO) mice is also demonstrated. Copyright © 2013 Elsevier Ltd. All rights reserved.

3,3,6,6-Tetra-methyl-9-(2-nitro-phen-yl)-3,4,6,7-tetra-hydro-2H-xanthene-1,8(5H,9H)-dione.

PubMed

Mo, Yingming; Zang, Hong-Jun; Cheng, Bo-Wen

2010-07-31

In the title compound, C(23)H(25)NO(5), the pyran ring adopts a flattened boat conformation, while the two cyclo-hexenone rings are in envelope conformations. The 3-nitro-phenyl ring is almost perpendicular to the pyran ring, making a dihedral angle of 87.1 (3)°.

Azaglycomimetics: Natural Occurrence, Biological Activity, and Application

NASA Astrophysics Data System (ADS)

Asano, Naoki

A large number of alkaloids mimicking the structures of monosaccharides or oligosaccharides have been isolated from plants and microorganisms. The sugar mimicking alkaloids with a nitrogen in the ring are called azasugars or iminosugars. Naturally occurring azasugars are classified into five structural classes: polyhydroxylated piperidines, pyrrolidines, indolizidines, pyrrolizidines, and nortropanes. They are easily soluble in water because of their polyhydroxylated structures and inhibit glycosidases because of a structural resemblance to the sugar moiety of the natural substrate. Glycosidases are involved in a wide range of anabolic and catabolic processes, such as digestion, lysosomal catabolism of glycoconjugates, biosynthesis of glycoproteins, and the endoplasmic reticulum (ER) quality control and ER-associated degradation of glycoproteins. Hence, modifying or blocking these processes in vivo by inhibitors is of great interest from a therapeutic point of view. Azasugars are an important class of glycosidase inhibitors and are arousing great interest for instance as antidiabetics, antiobesity drugs, antivirals, and therapeutic agents for some genetic disorders. This review describes the recent studies on isolation, characterization, glycosidase inhibitory activity, and therapeutic application of azaglycomimetics.

Evaluation and Synthesis of Polar Aryl- and Heteroaryl Spiroazetidine-Piperidine Acetamides as Ghrelin Inverse Agonists

PubMed Central

2014-01-01

Several polar heteroaromatic acetic acids and their piperidine amides were synthesized and evaluated as ghrelin or type 1a growth hormone secretagogue receptor (GHS-R1a) inverse agonists. Efforts to improve pharmacokinetic and safety profile was achieved by modulating physicochemical properties and, more specifically, emphasizing increased polarity of our chemical series. ortho-Carboxamide containing compounds provided optimal physicochemical, pharmacologic, and safety profile. pH-dependent chemical stability was also assessed with our series. PMID:25699143

Identification of fentanyl metabolites in rat urine by gas chromatography-mass spectrometry with stable-isotope tracers

DOE Office of Scientific and Technical Information (OSTI.GOV)

Goromaru, T.; Matsuura, H.; Furuta, T.

The metabolites of fentanyl (l), which has been widely used as a neuroleptic analgesic agent, were identified in urine of rats by gas chromatography-mass spectrometry combined with a stable-isotope tracer technique. After the oral administration of an equimolar mixture of l and deuterium-labeled l (l/l-d5), the urinary metabolites were extracted with chloroform at pH 9.0. Extracts were derivatized and analyzed by GC/MS. Metabolites were identified by the presence of doublet ion peaks separated by 5 amu, and chemical structures were established from analyses of fragmentation pathways. The metabolites were identified as 4-N-(N-propionylanilino)-piperidine, 4-N-(N-hydroxypropionylanilino)piperidine, 4-N-(N-propionylanilino) hydroxypiperidine, 1-(2-phenethyl)-4-N-(N-hydroxypropionylanilino)piperidine and 1-(2-phenethyl)-4-N-(N-propionylanilino)hydroxypiperidine. These metabolites,more » together with unchanged l, were also detected in urine of rats receiving l/l-d5 intravenously, by selected-ion monitoring of the specific cluster ions.« less

Synthesis and biological evaluation of some novel 1-substituted fentanyl analogs in Swiss albino mice

PubMed Central

Yadav, Shiv Kumar; Maurya, Chandra Kant; Gupta, Pradeep Kumar; Jain, Ajai Kumar; Ganesan, Kumaran

2014-01-01

Fentanyl [N-(1-phenethyl-4-piperidinyl)propionanilide] is a potent opioid analgesic agent, but a has narrow therapeutic index. We reported earlier on the synthesis and bioefficacy of fentanyl and its 1-substituted analogs (1–4) in mice. Here we report the synthesis and biological evaluation of four additional analogs, viz. N-isopropyl-3-(4-(N-phenylpropionamido)piperidin-1-yl)propanamide (5), N-t-butyl-3-(4-(N-phenylpropionamido)piperidin-1-yl)propanamide (6), isopropyl 2-[4-(N-phenylpropionamido)piperidin-1-yl]propionate (7) and t-butyl 2-[4-(N-phenylpropionamido)piperidin-1-yl]propionate (8). The median lethal dose (LD50) determined by intravenous, intraperitoneal and oral routes suggests these analogs to be comparatively less toxic than fentanyl. On the basis of observational assessment on spontaneous activities of the central, peripheral, and autonomic nervous systems, all the analogs were found to be similar to fentanyl. Naloxone hydrochloride abolished the neurotoxic effects of these analogs, thereby ascertaining their opioid receptor-mediated effects. All the analogs displayed significant analgesic effects, measured by formalin-induced hind paw licking and tail immersion tests at their respective median effective dose (ED50). They also exhibited 8–12 fold increase in therapeutic index over fentanyl. However, 5 and 6 alone produced lower ED50 (20.5 and 21.0 µg/kg, respectively) and higher potency ratio (1.37 and 1.33, respectively) compared to fentanyl. They could thus be considered for further studies on pain management. PMID:26109885

3,3,6,6-Tetra­methyl-9-(2-nitro­phen­yl)-3,4,6,7-tetra­hydro-2H-xanthene-1,8(5H,9H)-dione

PubMed Central

Mo, Yingming; Zang, Hong-Jun; Cheng, Bo-Wen

2010-01-01

In the title compound, C23H25NO5, the pyran ring adopts a flattened boat conformation, while the two cyclo­hexenone rings are in envelope conformations. The 3-nitro­phenyl ring is almost perpendicular to the pyran ring, making a dihedral angle of 87.1 (3)°. PMID:21588418

Discovery, synthesis, and pharmacological evaluation of spiropiperidine hydroxamic acid based derivatives as structurally novel histone deacetylase (HDAC) inhibitors.

PubMed

Varasi, Mario; Thaler, Florian; Abate, Agnese; Bigogno, Chiara; Boggio, Roberto; Carenzi, Giacomo; Cataudella, Tiziana; Dal Zuffo, Roberto; Fulco, Maria Carmela; Rozio, Marco Giulio; Mai, Antonello; Dondio, Giulio; Minucci, Saverio; Mercurio, Ciro

2011-04-28

New spiro[chromane-2,4'-piperidine] and spiro[benzofuran-2,4'-piperidine] hydroxamic acid derivatives as HDAC inhibitors have been identified by combining privileged structures with a hydroxamic acid moiety as zinc binding group. The compounds were evaluated for their ability to inhibit nuclear extract HDACs and for their in vitro antiproliferative activity on different tumor cell lines. This work resulted in the discovery of spirocycle 30d that shows good oral bioavailability and tumor growth inhibition in an HCT-116 murine xenograft model.

Synthesis and pharmacological profile of a new selective G protein-coupled receptor 119 agonist; 6-((2-fluoro-3-(1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)propyl)amino)-2,3-dihydro-1H-inden-1-one.

PubMed

Sakairi, Masao; Kogami, Masakazu; Torii, Masafumi; Makino, Mitsuhiro; Kataoka, Daisuke; Okamoto, Ryuji; Miyazawa, Toshiyuki; Inoue, Megumi; Takahashi, Naoki; Harada, Satoko; Watanabe, Nobuhide

2012-01-01

6-((2-Fluoro-3-(1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)propyl)amino)-2,3-dihydro-1H-inden-1-one is a potent drug-like G protein-coupled receptor 119 (GPR119) agonist. It is hoped that this compound would be instrumental in probing the pharmacological potential of GPR119 agonists.

Lupines, poison-hemlock and Nicotiana spp: toxicity and teratogenicity in livestock.

PubMed

Panter, K E; James, L F; Gardner, D R

1999-02-01

Many species of lupines contain quinolizidine or piperidine alkaloids known to be toxic or teratogenic to livestock. Poison-hemlock (Conium maculatum) and Nicotiana spp. including N. tabacum and N. glauca contain toxic and teratogenic piperidine alkaloids. The toxic and teratogenic effects from these plant species have distinct similarities including maternal muscular weakness and ataxia and fetal contracture-type skeletal defects and cleft palate. It is believed that the mechanism of action of the piperidine and quinolizidine alkaloid-induced teratogenesis is the same; however, there are some differences in incidence, susceptible gestational periods, and severity between livestock species. Wildlife species have also been poisoned after eating poison-hemlock but no terata have been reported. The most widespread problem for livestock producers in recent times has been lupine-induced "crooked calf disease." Crooked calf disease is characterized as skeletal contracture-type malformations and occasional cleft palate in calves after maternal ingestion of lupines containing the quinolizidine alkaloid anagyrine during gestation days 40-100. Similar malformations have been induced in cattle and goats with lupines containing the piperidine alkaloids ammodendrine, N-methyl ammodendrine, and N-acetyl hystrine and in cattle, sheep, goats, and pigs with poison-hemlock containing predominantly coniine or gamma-coniceine and N. glauca containing anabasine. Toxic and teratogenic effects have been linked to structural aspects of these alkaloids, and the mechanism of action is believed to be associated with an alkaloid-induced inhibition of fetal movement during specific gestational periods. This review presents a historical perspective, description and distribution of lupines, poison-hemlock and Nicotiana spp., toxic and teratogenic effects and management information to reduce losses.

Substitution determination of Fmoc‐substituted resins at different wavelengths

PubMed Central

Kley, Markus; Bächle, Dirk; Loidl, Günther; Meier, Thomas; Samson, Daniel

2017-01-01

In solid‐phase peptide synthesis, the nominal batch size is calculated using the starting resin substitution and the mass of the starting resin. The starting resin substitution constitutes the basis for the calculation of a whole set of important process parameters, such as the number of amino acid derivative equivalents. For Fmoc‐substituted resins, substitution determination is often performed by suspending the Fmoc‐protected starting resin in 20% (v/v) piperidine in DMF to generate the dibenzofulvene–piperidine adduct that is quantified by ultraviolet–visible spectroscopy. The spectrometric measurement is performed at the maximum absorption wavelength of the dibenzofulvene–piperidine adduct, that is, at 301.0 nm. The recorded absorption value, the resin weight and the volume are entered into an equation derived from Lambert–Beer's law, together with the substance‐specific molar absorption coefficient at 301.0 nm, in order to calculate the nominal substitution. To our knowledge, molar absorption coefficients between 7100 l mol−1 cm−1 and 8100 l mol−1 cm−1 have been reported for the dibenzofulvene–piperidine adduct at 301.0 nm. Depending on the applied value, the nominal batch size may differ up to 14%. In this publication, a determination of the molar absorption coefficients at 301.0 and 289.8 nm is reported. Furthermore, proof is given that by measuring the absorption at 289.8 nm the impact of wavelength accuracy is reduced. © 2017 The Authors Journal of Peptide Science published by European Peptide Society and John Wiley & Sons Ltd. PMID:28635051

Alkaloid Profiling as an Approach to Differentiate Lupinus garfieldensis, Lupinus sabinianus and Lupinus sericeus.

PubMed

Cook, Daniel; Lee, Stephen T; Pfister, James A; Stonecipher, Clint A; Welch, Kevin D; Green, Benedict T; Panter, Kip E

2012-01-01

Many species in the Lupinus genus are poorly defined morphologically, potentially resulting in improper taxonomic identification. Lupine species may contain quinolizidine and/or piperidine alkaloids that can be acutely toxic and/or teratogenic, the latter resulting in crooked calf disease. To identify characteristic alkaloid profiles of Lupinus sabinianus, L. garfieldensis and L. sericeus which would aid in discriminating these species from each other and from L. sulphureus. Quinolizidine and piperidine alkaloids were extracted from herbarium specimens and recent field collections of L. sabinianus, L. garfieldensis and L. sericeus. The alkaloid composition of each species was defined using GC-FID and GC-MS and compared using multivariate statistics. Each of the three species investigated contained a diagnostic chemical fingerprint composed of quinolizidine and/or piperidine alkaloids. The alkaloid profiles of Lupinus sabinianus, L. garfieldensis and L. sericeus can be used as a tool to discriminate these species from each other and L. sulphureus as long as one considers locality of the collection in the case of L. sabinianus. Published 2011. This article is a US Government work and is in the public domain in the USA.

Network Formation in Piperidine-Cured Epoxy and Epoxy-Rubber Systems: Effects of Cure Time.

NASA Astrophysics Data System (ADS)

D'Oyen, Raquel M.; Carr, Stephen H.

1996-03-01

The system, piperidine-cured diglycidyl ether of bisphenol-A (DGEBA) to which various amounts of carboxyl terminated acrylonitrile-butadiene (CTBN) have been added, is used as a model rubber modified thermoset. The glass transition temperatures (T_g) of a low molecular weight (374 g/eq) epoxy, cured with piperidine at 120 degC, have been measured by differential scanning calorimetry in order to follow the curing process. The maximum Tg is found after curing for 16 hours. Systems that have been modified with varied concentrations of an adducted CTBN, also show Tg maxima at this time. Addition of 5-20in long-time T_gs, indicating complete segregation of the rubber. The T_gs of the CTBN modified systems at short times are higher than in the unmodified epoxy. This acceleration of the initial stage of cure indicates that the CTBN acts as a diluent, increasing the initial rate of reaction by changing the mobility of the reactive sites. The mechanical properties--toughness, yield and modulus--are related to the CTBN content and to the degree of cure of the system.

1-(4-(6-Fluorobenzo [d] isoxazol-3-yl) piperidin-1-yl)-2-(4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl) ethanone: Synthesis, spectroscopic characterization, Hirshfeld surface analysis, cytotoxic studies and docking studies

NASA Astrophysics Data System (ADS)

Govindhan, M.; Viswanathan, V.; Karthikeyan, S.; Subramanian, K.; Velmurugan, D.

2017-08-01

Compound 1-(4-(6-fluorobenzo[d] isoxazol-3-yl) piperidin-1-yl)-2-(4-(hydroxymethyl)-1H-1, 2,3-triazol-1-yl) ethanone was synthesized in good yield by using click chemistry approach with 2-azido-1-(4-(6-flurobenzo[d]isooxazol-3-yl)piperidin-1-yl)ethanone as a starting material. The synthesized compound was characterized using IR, NMR and MS studies. Thermal stability of the compound was analyzed by using TGA and DSC technique. The single crystal XRD analysis was taken part, to confirm the structure of the compound. The intercontacts in the crystal structure are analyzed using Hirshfeld surfaces computational method. Cytotoxicity of the synthesized compound was evaluated and the results were reported. The binding analysis carried out between the newly synthesized molecule with human serum albumin using fluorescence spectroscopy technique to understand the pharmacokinetics nature of the compound for further biological application. The molecular docking studies were evaluated for the compound to elucidate insights of new molecules in carrier protein.

The radii of Uranian rings alpha, beta, gamma, delta, epsilon, eta, 4, 5, and 6 from their occultations of SAO 158687

NASA Technical Reports Server (NTRS)

Elliot, J. L.; Dunham, E.; Wasserman, L. H.; Millis, R. L.; Churms, J.

1978-01-01

All available timing data for the occultations of SAO 158687 on March 10, 1977, by the cited rings of Uranus are analyzed. Least-squares fits to the data are performed using a model which postulates that rings alpha, beta, gamma, and delta are circular and coplanar. A solution obtained under the assumption that the ring plane coincides with the plane of the satellite orbits is adopted which yields radii of 44,844 km for ring alpha, 45,799 km for ring beta, 47,746 km for ring gamma, and 48,423 km for ring delta. The uncertainties in these values are discussed along with the apparent shapes and inclinations of these main rings. The mean radii estimated for the other rings are: 47,323 km for ring eta, 42,663 km for ring 4, 42,360 km for ring 5, and 41,980 km for ring 6.

High concentrations of landiolol, a beta(1)-adrenoceptor antagonist, stimulate smooth muscle contraction of the rat trachea through the Rho-kinase pathway.

PubMed

Shibata, Osamu; Nishioka, Kenji; Yamaguchi, Masakazu; Makita, Tetsuji; Sumikawa, Koji

2008-01-01

Gradually progressing contraction of airway smooth muscle is suggested to be due to the Rho-kinase signaling pathway. In our preliminary study in rat tracheas, landiolol, a beta(1)-adrenoceptor antagonist, at high doses caused gradually progressing contraction, and this contraction reached a plateau after 20 min. Therefore, this study was carried out to clarify whether landiolol could stimulate the Rho-kinase pathway or the phosphatidylinositol (PI) response in the rat trachea. Seventy-eight male Wistar rats weighing 250-350 g were used for the experiments. Their tracheas were cut into 3-mm-wide ring segments or 1-mm-wide slices. Measurements of isometric tension and [(3)H] inositol monophosphate (IP(1)) production were conducted, using these tracheal rings or slices. Data values are expressed as means +/- SD, and statistical significance (P < 0.05) was determined using analysis of variance (ANOVA). Landiolol (700 microM)-induced contraction was completely inhibited by fasudil at 30 microM, while the landiolol-induced contraction was not inhibited by 4-diphenylacetoxy-N-methyl-piperidine methobromide (4-DAMP), ketanserin, or nicardipine. Landiolol did not stimulate IP(1) production. These results suggest that high concentrations of landiolol could cause airway smooth muscle contraction through the Rho-kinase pathway, but not through the PI response coupled with muscarinic M(3) receptors, 5-HT receptors or the activation of L-type Ca(2+) channels.

Neopetrosiamine A, biologically active bis-piperidine alkaloid from the Caribbean Sea sponge Neopetrosia proxima

PubMed Central

Wei, Xiaomei; Nieves, Karinel; Rodríguez, Abimael D.

2010-01-01

A new tetracyclic bis-piperidine alkaloid, neopetrosiamine A (1), has been extracted from the marine sponge Neopetrosia proxima collected off the west coast of Puerto Rico. The structure of compound 1 was elucidated by analysis of spectroscopic data coupled with careful comparisons of its 1H and 13C NMR data with those of a well-known 3-alkylbispiperidine alkaloid model. The new alkaloid displayed strong in vitro cytotoxic activity against a panel of cancer cell lines as well as in vitro inhibitory activity against the pathogenic microbes Mycobacterium tuberculosis and Plasmodium falciparum. PMID:20727745

Discovery and structure-activity relationships of piperidinone- and piperidine-constrained phenethylamines as novel, potent, and selective dipeptidyl peptidase IV inhibitors.

PubMed

Pei, Zhonghua; Li, Xiaofeng; von Geldern, Thomas W; Longenecker, Kenton; Pireh, Daisy; Stewart, Kent D; Backes, Bradley J; Lai, Chunqiu; Lubben, Thomas H; Ballaron, Stephen J; Beno, David W A; Kempf-Grote, Anita J; Sham, Hing L; Trevillyan, James M

2007-04-19

Dipeptidyl peptidase IV (DPP4) inhibitors are emerging as a new class of therapeutic agents for the treatment of type 2 diabetes. They exert their beneficial effects by increasing the levels of active glucagon-like peptide-1 and glucose-dependent insulinotropic peptide, which are two important incretins for glucose homeostasis. Starting from a high-throughput screening hit, we were able to identify a series of piperidinone- and piperidine-constrained phenethylamines as novel DPP4 inhibitors. Optimized compounds are potent, selective, and have good pharmacokinetic profiles.

Pellitorine, a potential anti-cancer lead compound against HL6 and MCT-7 cell lines and microbial transformation of piperine from Piper Nigrum.

PubMed

Ee, Gwendoline Cheng Lian; Lim, Chyi Meei; Rahmani, Mawardi; Shaari, Khozirah; Bong, Choon Fah Joseph

2010-04-05

Pellitorine (1), which was isolated from the roots of Piper nigrum, showed strong cytotoxic activities against HL60 and MCT-7 cell lines. Microbial transformation of piperine (2) gave a new compound 5-[3,4-(methylenedioxy)phenyl]-pent-2-ene piperidine (3). Two other alkaloids were also found from Piper nigrum. They are (E)-1-[3',4'-(methylenedioxy)cinnamoyl]piperidine (4) and 2,4-tetradecadienoic acid isobutyl amide (5). These compounds were isolated using chromatographic methods and their structures were elucidated using MS, IR and NMR techniques.

The discovery of tropane-derived CCR5 receptor antagonists.

PubMed

Armour, Duncan R; de Groot, Marcel J; Price, David A; Stammen, Blanda L C; Wood, Anthony; Perros, Manos; Burt, Catherine

2006-04-01

The development of compound 1, a piperidine-based CCR5 receptor antagonist with Type I CYP2D6 inhibition, into the tropane-derived analogue 5, is described. This compound, which is devoid of CYP2D6 liabilities, is a highly potent ligand for the CCR5 receptor and has broad-spectrum activity against a range of clinically relevant HIV isolates. The identification of human ether a-go-go-related gene channel inhibition within this series is described and the potential for QTc interval prolongation discussed. Furthermore, structure activity relationship (SAR) around the piperidine moiety is also described.

Crystal structure of methyl 3'-benzamido-4'-(4-meth-oxy-phen-yl)-1'-methyl-spiro-[indeno-[1,2-b]quinoxaline-11,2'-pyrrolidine]-3'-carboxyl-ate.

PubMed

Chandralekha, Kuppan; Sureshbabu, Adukamparai Rajukrishnan; Gavaskar, Deivasigamani; Lakshmi, Srinivasakannan

2016-09-01

In the title compound, C 35 H 30 N 4 O 3 , the spiro C atom connects the five-membered pyrrolidine ring and the indeno-quinoxaline ring system. The pyrrolidine ring adopts a twist conformation. An intra-molecular N-H⋯N inter-action between the amino group and the pyrazine ring is observed. In the crystal, mol-ecules are linked by a pairs of C-H⋯O hydrogen bonds, forming inversion dimers.

Nucleophilic ring opening reactions of aziridines.

PubMed

Akhtar, Rabia; Naqvi, Syed Ali Raza; Zahoor, Ameer Fawad; Saleem, Sameera

2018-05-04

Aziridine ring opening reactions have gained tremendous importance in the synthesis of nitrogen containing biologically active molecules. During recent years, a great effort has been put forward by scientists toward unique bond construction methodologies via ring opening of aziridines. In this regard, a wide range of chiral metal- and organo-catalyzed desymmetrization reactions of aziridines have been reported with carbon, sulfur, oxygen, nitrogen, halogen, and other nucleophiles. In this review, an outline of methodologies adopted by a number of scientists during 2013-2017 for aziridine ring opening reactions as well as their synthetic applications is described.

Synthesis and discovery of novel piperidone-grafted mono- and bis-spirooxindole-hexahydropyrrolizines as potent cholinesterase inhibitors.

PubMed

Kia, Yalda; Osman, Hasnah; Kumar, Raju Suresh; Murugaiyah, Vikneswaran; Basiri, Alireza; Perumal, Subbu; Wahab, Habibah A; Bing, Choi Sy

2013-04-01

Three-component reaction of a series of 1-acryloyl-3,5-bisbenzylidenepiperidin-4-ones with isatin and L-proline in 1:1:1 and 1:2:2 molar ratios in methanol afforded, respectively the piperidone-grafted novel mono- and bisspiro heterocyclic hybrids comprising functionalized piperidine, pyrrolizine and oxindole ring systems in good yields. The in vitro evaluation of cholinesterase enzymes inhibitory activity of these cycloadducts disclosed that monospiripyrrolizines (8a-k), are more active with IC50 ranging from 3.36 to 20.07 μM than either the dipolarophiles (5a-k) or bisspiropyrrolizines (9a-k). The compounds, 8i and 8e with IC50 values of 3.36 and 3.50 μM, respectively showed the maximum inhibition of acethylcholinesterase (AChE) and butrylylcholinestrase (BuChE). Molecular modeling simulation, disclosed the binding interactions of the most active compounds to the active site residues of their respective enzymes. The docking results were in accordance with the IC50 values obtained from in vitro cholinesterase assay. Copyright © 2013 Elsevier Ltd. All rights reserved.

Synthesis and structural and conformational study of some esters derived from 8-β-hydroxy-3-phenethyl-3- azabicyclico [3.2.11] octan-8-α-carboxylic acid

NASA Astrophysics Data System (ADS)

Diez, M.; Izquierdo, M. L.; Arias, M. S.; Galvez, E.; Matesanz, E.; Martinez-Ripoll, M.

1991-09-01

A series of 8-β-hydroxy-8-α-alkoxycarbonyl- N-phenethyl-3-azabicyclo [3.2.1.]octane derivatives have been synthesized and studied by IR, 1H and 13C NMR spectroscopy, and the crystal structure of ethyl-8-β-hydroxy-3-phenethyl-3-azabicyclo [3.2.1] octan-8-α-carboxylate ( Va) has been determined by X-ray diffraction. In deuterochloroform and deuterobenzene the cyclopentane and piperidine rings of the title compounds show an envelope conformation flattened at C8 and a distorted chair conformation puckered at C8 and flattened at N3, respectively, with the N-substituent in an equatorial position. These results are in close agreement with that found for compound Va in the crystalline state. By comparing the NMR and X-ray parameters of the title compounds with those of the corresponding 8-α-hydroxy-8β-alkoxycarbonyl- N-phenethyl-3- azabicyclo [3.2.1] octane epimers and 3-phenethyl-3-azabicyclo [3.2.1] octan-8-α-(andβ)ol, several stereoelectronic effects have been deduced.

Substitution determination of Fmoc-substituted resins at different wavelengths.

PubMed

Eissler, Stefan; Kley, Markus; Bächle, Dirk; Loidl, Günther; Meier, Thomas; Samson, Daniel

2017-10-01

In solid-phase peptide synthesis, the nominal batch size is calculated using the starting resin substitution and the mass of the starting resin. The starting resin substitution constitutes the basis for the calculation of a whole set of important process parameters, such as the number of amino acid derivative equivalents. For Fmoc-substituted resins, substitution determination is often performed by suspending the Fmoc-protected starting resin in 20% (v/v) piperidine in DMF to generate the dibenzofulvene-piperidine adduct that is quantified by ultraviolet-visible spectroscopy. The spectrometric measurement is performed at the maximum absorption wavelength of the dibenzofulvene-piperidine adduct, that is, at 301.0 nm. The recorded absorption value, the resin weight and the volume are entered into an equation derived from Lambert-Beer's law, together with the substance-specific molar absorption coefficient at 301.0 nm, in order to calculate the nominal substitution. To our knowledge, molar absorption coefficients between 7100 l mol -1  cm -1 and 8100 l mol -1  cm -1 have been reported for the dibenzofulvene-piperidine adduct at 301.0 nm. Depending on the applied value, the nominal batch size may differ up to 14%. In this publication, a determination of the molar absorption coefficients at 301.0 and 289.8 nm is reported. Furthermore, proof is given that by measuring the absorption at 289.8 nm the impact of wavelength accuracy is reduced. © 2017 The Authors Journal of Peptide Science published by European Peptide Society and John Wiley & Sons Ltd. © 2017 The Authors Journal of Peptide Science published by European Peptide Society and John Wiley & Sons Ltd.

Analysis of Heat-Labile Sites Generated by Reactions of Depleted Uranium and Ascorbate in Plasmid DNA

PubMed Central

Wilson, Janice; Young, Ashley; Civitello, Edgar R.

2013-01-01

The goal of this study was to characterize how depleted uranium (DU) causes DNA damage. Procedures were developed to assess the ability of organic and inorganic DNA adducts to convert to single strand breaks (SSB) in pBR322 plasmid DNA in the presence of heat or piperidine. DNA adducts formed by methyl methanesulfonate (MMS), cis-platin (cis-Pt), and chromic chloride were compared to those formed by reaction of uranyl acetate (UA) and ascorbate (Asc). Uranyl ion in the presence of Asc produced U-DNA adducts that converted to SSB upon heating. Piperidine, which acted on DNA methylated by MMS to convert methyl-DNA adducts to SSB, served in the opposite fashion with U-DNA adducts by decreasing SSB. The observation that piperidine also decreased the gel shift for metal-DNA adducts formed by monofunctional cis-Pt and chromic chloride was interpreted to suggest that piperidine served to remove U-DNA adducts. Radical scavengers did not affect formation of U-induced SSB, suggesting that SSB arose from the presence of U-DNA adducts and not from free radicals. A model is proposed to predict how U-DNA adducts may serve as initial lesions that convert to SSB or AP sites. Results suggest that DU can act as a chemical genotoxin that does not require radiation for its mode of action. Characterizing the DNA lesions formed by DU is necessary to assess the relative importance of different DNA lesions in the formation of DU-induced mutations. Understanding mechanisms of formation of DU-induced mutations may contribute to identification of biomarkers of DU exposures in humans. PMID:24218036

Synthesis and biological evaluation of novel quinazoline-4-piperidinesulfamide derivatives as inhibitors of NPP1.

PubMed

Forcellini, Elsa; Boutin, Sophie; Lefebvre, Carole-Anne; Shayhidin, Elnur Elyar; Boulanger, Marie-Chloé; Rhéaume, Gabrielle; Barbeau, Xavier; Lagüe, Patrick; Mathieu, Patrick; Paquin, Jean-François

2018-03-10

The ecto-nucleotide pyrophosphatase/phosphodiesterase-1 (NPP1) was recently shown to promote mineralization of the aortic valve, hence, its inhibition represents a significant target. A quinazoline-4-piperidine sulfamide compound (QPS1) has been described as a specific and non-competitive inhibitor of NPP1. We report herein the synthesis and in vitro inhibition studies of novel quinazoline-4-piperidine sulfamide analogues using QPS1 as the lead compound. Of the 26 derivatives prepared, four compounds were found to have K i  < 105 nM against human NPP1. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

AZD-4818, a chemokine CCR1 antagonist: WO2008103126 and WO2009011653.

PubMed

Norman, Peter

2009-11-01

The applications WO2008103126 and WO2009011653, respectively, claim: i) Combinations of a spirocyclic piperidine chemokine CCR1 antagonist with a corticosteroid, and their use for the treatment of asthma and chronic obstructive pulmonary disease. ii) Processes for the preparation of a spirocyclic piperidine derivative, a chemokine CCR1 antagonist. These applications point to the preferred compound being a development compound. The evidence for this compound being AZD-4818, a chemokine CCR1 antagonist that was in Phase II development for the treatment of chronic obstructive pulmonary disease, is reviewed in the light of these and earlier patents relating to it.

Identification of radiolytic products from N-nitrosodimethylamine and N-nitrosopyrrolidine by gas chromatography and mass spectrometry

NASA Astrophysics Data System (ADS)

Ahn, Hyun-Joo; Lee, Cherl-Ho; Kim, Jae-Hyun; Han, Sang-Bae; Jo, Cheorun; Kim, Sung; Byun, Myung-Woo

2004-01-01

The radiolytic products of N-nitrosodimethylamine (NDMA) and N-nitrosopyrrolidine (NPYR) dissolved in dichloromethane (DCM) were identified after gamma irradiation. The UV spectra of NDMA and NPYR indicated that irradiation reduced the typical peak of NDMA at 258 nm and NPYR at 260 nm.The major radiolytic components identified in irradiated NDMA were ethyl acetate and 2-dimethyl propanol. The irradiated NPYR dissolved in DCM and produced 2-butanone and 2-methyl-6-propyl piperidine as the major radiolytic components. 2-Methyl-6-propyl piperidine was the component detected in the greatest concentration in irradiated NPYR.

Hemlock alkaloids from Socrates to poison aloes.

PubMed

Reynolds, Tom

2005-06-01

Hemlock (Conium maculatum L. Umbelliferae) has long been known as a poisonous plant. Toxicity is due to a group of piperidine alkaloids of which the representative members are coniine and gamma-coniceine. The latter is the more toxic and is the first formed biosynthetically. Its levels in relation to coniine vary widely according to environmental conditions and to provenance of the plants. Surprisingly, these piperidine alkaloids have turned up in quite unrelated species in the monocotyledons as well as the dicotyledons. Aloes, for instance, important medicinal plants, are not regarded as poisonous although some species are very bitter. Nevertheless a small number of mostly local species contain the alkaloids, especially gamma-coniceine and there have been records of human poisoning. The compounds are recognized by their characteristic mousy smell. Both acute and chronic symptoms have been described. The compounds are neurotoxins and death results from respiratory failure, recalling the effects of curare. Chronic non-lethal ingestion by pregnant livestock leads to foetal malformation. Both acute and chronic toxicity are seen with stock in damp meadows and have been recorded as problems especially in North America. The alkaloids derive biosynthetically from acetate units via the polyketide pathway in contrast to other piperidine alkaloids which derive from lysine.

Piperine, a piperidine alkaloid from Piper nigrum re-sensitizes P-gp, MRP1 and BCRP dependent multidrug resistant cancer cells.

PubMed

Li, Sen; Lei, Yu; Jia, Yingjie; Li, Na; Wink, Michael; Ma, Yonggang

2011-12-15

Over-expression of P-gp, MRP1 and BCRP in tumor cells is one of the important mechanisms leading to multidrug resistance (MDR), which impairs the efficacy of chemotherapy. P-gp, MRP1 and BCRP are ABC (ATP-Binding Cassette) transporters, which can expel a variety of lipophilic anti-cancer drugs and protect tumor cells. During a screening of MDR reversal agents among alkaloids of various structural types, a piperidine alkaloid, piperine (a main piperidine alkaloid in Piper nigurm) was identified as an inhibitor. Piperine can potentiate the cytotoxicity of anti-cancer drugs in resistant sublines, such as MCF-7/DOX and A-549/DDP, which were derived from MCF-7 and A-549 cell lines. At a concentration of 50 μM piperine could reverse the resistance to doxorubicin 32.16 and 14.14 folds, respectively. It also re-sensitized cells to mitoxantrone 6.98 folds. In addition, long-term treatment of cells by piperine inhibits transcription of the corresponding ABC transporter genes. These results suggest that piperine can reverse MDR by multiple mechanisms and it may be a promising lead compound for future studies. Copyright © 2011 Elsevier GmbH. All rights reserved.

SYNERGISTIC EFFECT OF HALIDE IONS ON THE CORROSION INHIBITION OF MILD STEEL IN SULPHURIC ACID USING METHYL, N-METHYL ETHYL AND ETHYL SUBSTITUTED γ-2,c-6-DIPHENYL PIPERIDIN-4-ONE SEMICARBAZONES

NASA Astrophysics Data System (ADS)

Priya, V. Shanmuga; Rani, C. Uma; Velrani, S.

The synergistic effect of halide ions such as KCl, KBr and KI on the corrosion inhibition of mild steel in 1 N sulphuric acid by γ-2,c-6-diphenyl-t-3-methyl piperdin-4-ones with semicarbazone (01SC), γ-2,c-6-diphenyl-N-methyl-t-3-ethyl piperdin-4-ones with semicarbazone (02SC) and 2,6-diphenyl-t-3-ethyl piperdin-4-one with semicarbazone (03SC) has been examined by weight loss method, potentiodynamic polarization measurements and electrochemical AC impedance spectroscopy. Results show that substituted γ-2,c-6-diphenyl piperidin-4-ones with semicarbazone act as the perfect corrosion inhibitors and their inhibition efficiency increases with the addition of halide ions. The inhibitor (01SC) shows the inhibition efficiency of 78.28% (0.2mM) by using a weight loss method. The influence of I-, Br- and Cl- anions raises the inhibition efficiency of the substituted 2,6-diphenyl piperidin-4-ones with semicarbazone due to the synergistic effect. The synergistic effect of halide ions was formed in the following order: KI > KBr > KCl.

3-(4-Chloro­phen­yl)-7-methyl-4-(4-methyl­phen­yl)-1-oxa-2,7-diaza­spiro­[4.5]dec-2-en-10-one

PubMed Central

Gayathri, D.; Velmurugan, D.; Ranjith Kumar, R.; Perumal, S.; Ravikumar, K.

2008-01-01

In the title compound, C21H21ClN2O2, the dihydro­isoxazole ring adopts an envelope conformation and the piperidinone ring is in a chair conformation. The dihedral angle between the two benzene rings is 84.2 (1)°. The crystal used was an inversion twin. PMID:21201426

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sun, S.-W., E-mail: sunsw0819@163.com; Zhang, X., E-mail: zhangx@hit.edu.cn; Wang, G.-F.

A series of 2-arylidenebenzocycloalkanones containing heterocyclic rings 1–8 were prepared and characterized by IR, {sup 1}H NMR and elemental analyses. X-ray diffraction study of 6 reveals that the cyclohexyl ring of the 3,4-dihydronaphthalen-1(2H)-one adopts a chair conformation with a maximum deviation of 0.547(3) Å and makes dihedral angles of 52.24(17)° and 11.23(16)°, respectively, with the benzene plane and the mean plane of the benzimidazole ring.

Tests of oil scraper piston ring and piston fitted with oil drain holes

NASA Technical Reports Server (NTRS)

Mcdewell, H S

1922-01-01

Tests were conducted to determine whether or not a properly located and properly designed oil scraper piston ring, installed on a piston provided with oil drain holes of sufficient area, would prevent the excessive oiling of the Liberty engine, particularly with the engine running at idling speed with full oil pressure. Results showed that excessive oiling was in fact prevented. It is strongly recommended that scraper rings and pistons be adopted for aircraft engines.

Crystal structure of 5''-(4-chloro-benzyl-idene)-4'-(4-chloro-phen-yl)-1'-methyltri-spiro[acenapthylene-1,2'-pyrrolidine-3',1''-cyclo-hexane-3'',2'''-[1,3]dioxane]-2(1H),6''-dione.

PubMed

Chandralekha, Kuppan; Gavaskar, Deivasigamani; Sureshbabu, Adukamparai Rajukrishnan; Lakshmi, Srinivasakannan

2015-11-01

In the title compound, C36H29Cl2NO4, two spiro links connect the methyl-substituted pyrrolidine ring to the ace-naphthyl-ene and cyclo-hexa-none rings. The cyclo-hexa-none ring is further connected to the dioxalane ring by a third spiro junction. The five-membered ring of the ace-naphthylen-1-one ring system adopts a flattened envelope conformation, with the ketonic C atom as the flap, whereas the dioxalane and pyrrolidine rings each have a twist conformation. The cyclo-hexenone ring assumes a boat conformation. An intra-molecular C-H⋯O hydrogen-bond inter-action is present. In the crystal, mol-ecules are linked by non-classical C-H⋯O hydrogen bonds, forming chains extending parallel to the a axis.

3-(Adamantan-1-yl)-4-ethyl-1-{[4-(2-meth-oxy-phen-yl)piperazin-1-yl]meth-yl}-1H-1,2,4-triazole-5(4H)-thione.

PubMed

El-Emam, Ali A; Al-Tuwaijri, Hanaa M; Al-Abdullah, Ebtehal S; Chidan Kumar, C S; Fun, Hoong-Kun

2014-01-01

In the title compound, C26H37N5OS, the piperazine ring adopts a chair conformation. The triazole ring forms dihedral angles of 67.85 (9) and 59.41 (9)° with the piperazine and benzene rings, respectively, resulting in an approximate V-shaped conformation for the mol-ecule. An intra-molecular C-H⋯O hydrogen bond generates an S(6) ring motif. The crystal structure features C-H⋯π inter-actions, producing a two-dimensional supramolecular architecture.

4-(4-Methoxy­phen­yl)-1-phenyl­pyridine-2,6(1H,3H)-dione

PubMed Central

Das, Ushati; Chheda, Shardul B.; Pednekar, Suhas R.; Karambelkar, Narendra P.; Guru Row, T. N.

2009-01-01

In the title compound, C18H15NO3, the pyridine-2,6-dione ring adopts an envelope conformation. The phenyl ring lies approximately perpendicular to the mean plane of the pyridine-2,6-dione ring [dihedral angle = 81.5 (1)°], while the methoxy­phenyl ring is tilted to the same plane by a dihedral angle of 34.8 (1)°. Inter­molecular C—H⋯O inter­actions link the mol­ecules into chains along [100]. PMID:21583176

N-(Adamantan-1-yl)-1,2,3,4-tetra-hydro-iso-quinoline-2-carbo-thio-amide.

PubMed

El-Emam, Ali A; Al-Abdullah, Ebtehal S; Al-Tuwaijri, Hanaa M; Chidan Kumar, C S; Fun, Hoong-Kun

2013-11-23

In the title compound, C20H26N2S, the N-containing six-membered ring adopts a boat conformation and the dihedral angle between the thio-carbamide group and the benzene ring is 49.67 (9)°. An intra-molecular C-H⋯S hydrogen bond generates an S(6) ring motif. The N-H group is sterically hindered and there are no significant inter-molecular inter-actions beyond van der Waals contacts.

Crystal structure of 5''-benzyl-idene-1'-methyl-4'-phenyl-tri-spiro-[ace-naphthyl-ene-1,2'-pyrrolidine-3',1''-cyclo-hexane-3'',2'''-[1,3]dioxane]-2,6''-dione.

PubMed

Chandralekha, Kuppan; Gavaskar, Deivasigamani; Sureshbabu, Adukamparai Rajukrishnan; Lakshmi, Srinivasakannan

2016-03-01

In the title compound, C36H31NO4, two spiro links connect the methyl-substituted pyrrolidine ring to the ace-naphthyl-ene and cyclo-hexa-none rings. The cyclo-hexa-none ring is further connected to the dioxalane ring by a third spiro junction. The five-membered ring of the ace-naphthylen-1-one ring system adopts a flattened envelope conformation with the ketonic C atom as flap, whereas the dioxalane and pyrrolidine rings each have a twist conformation. The cyclo-hexa-none ring assumes a boat conformation. Three intra-molecular C-H⋯O hydrogen bonds involving both ketonic O atoms as acceptors are present. In the crystal, C-H⋯O hydrogen bonds connect centrosymmetrically related mol-ecule into chains parallel to the b axis, forming rings of R 2 (2)(10)and R 2 (2)(8) graph-set motifs.

2-[(4-Benzhydrylpipérazin-1-yl)méthyl]acrylonitrile

PubMed Central

Ben Amor, Fatma; Ould M’hamed, Mohamed; Mrabet, Hédi; Driss, Ahmed; Efrit, Mohamed Lotfi

2008-01-01

In the title compound, 2-[(4-benz­hydryl­piperazin-1-yl)­methyl]­acrylo­nitrile, C21H23N3, the substituted piperazine ring adopts a chair conformation and the dihedral angle between the mean planes of the aromatic rings is 71.61 (8)°. PMID:21201087

Chemical surface modification of polycrystalline platinum thin-films to promote preferential chemisorption of n-hexane, piperidine, and cyclohexane

DOE Office of Scientific and Technical Information (OSTI.GOV)

Thomas, V.; Schwank, J.; Gland, J.

In this study, hard/soft Lewis acid-base (HSAB) principles are used to modify a thin-polycrystalline platinum film to promote preferential chemisorption of molecules such as piperidine, n-hexane, and cyclohexane. Specifically, the particle size and electron density distribution of the platinum surface is modified using thermal treatment and co-adsorption of electro-positive and negative species. These studies are conducted in an ultra-high vacuum chamber. The platinum surface is characterized, before and after modification protocols, using a variety of in-situ and ex-situ techniques. These include temperature programmed desorption (TPD), both resistance change and work function measurements, and both X-ray photoelectron spectroscopy and diffraction.

Studies of tricyclic piperazine/piperidine furnished molecules as novel integrin αvβ3/αIIbβ3 dual antagonists using 3D-QSAR and molecular docking.

PubMed

Yan, Yulian; Li, Yan; Zhang, Shuwei; Ai, Chunzhi

2011-02-01

The development of injectable integrin α(v)β(3)/α(IIb)β(3) dual antagonists attracts much attention of research for treating of acute ischemic diseases in recent years. In this work, based on a dataset composed of 102 tricyclic piperazine/piperidine furnished dual α(v)β(3) and α(IIb)β(3) antagonists, a variety of in silico modeling approaches including the comparative molecular field analysis (CoMFA), comparative similarity indices analysis (CoMSIA), and molecular docking were applied to reveal the requisite 3D structural features impacting the biological activities. Our statistical results show that the ligand-based 3D-QSAR models for both the α(v)β(3) and α(IIb)β(3) studies exhibited satisfactory internal and external predictability, i.e., for the CoMFA models, results of Q(2)=0.48, R(ncv)(2)=0.87, R(pred)(2)=0.71 for α(v)β(3) and Q(2)=0.50, R(ncv)(2)=0.85, R(pred)(2)=0.72 for α(IIb)β(3) analysis were obtained, and for the CoMSIA ones, the outcomes of Q(2)=0.55, R(ncv)(2)=0.90, R(pred)(2)=0.72 for α(v)β(3) and Q(2)=0.52, R(ncv)(2)=0.88, R(pred)(2)=0.74 for α(IIb)β(3) were achieved respectively. In addition, through a comparison between 3D-QSAR contour maps and docking results, it is revealed that that the most crucial interactions occurring between the tricyclic piperazine/piperidine derivatives and α(v)β(3)/α(IIb)β(3) receptor ligand binding pocket are H-bonding, and the key amino acids impacting the interactions are Arg214, Asn215, Ser123, and Lys253 for α(v)β(3), but Arg214, Asn215, Ser123 and Tyr190 for α(IIb)β(3) receptors, respectively. Halogen-containing groups at position 15 and 16, benzene sulfonamide substituent at position 23, and the replacement of piperazine with 4-aminopiperidine of ring B may increase the α(v)β(3)/α(IIb)β(3) antagonistic activity. The potencies for antagonists to inhibit isolated α(v)β(3) and α(IIb)β(3) are linear correlated, indicating that similar interaction mechanisms may exist for the series of molecules. To our best knowledge this is the first report on 3D-QSAR modeling of these dual α(v)β(3)/α(IIb)β(3) antagonists. The results obtained should provide information for better understanding of the mechanism of antagonism and thus be helpful in design of novel potent dual α(v)β(3)/α(IIb)β(3) antagonists. Copyright © 2011 Elsevier Inc. All rights reserved.

Selective kappa-opioid agonists: synthesis and structure-activity relationships of piperidines incorporating on oxo-containing acyl group.

PubMed

Giardina, G; Clarke, G D; Dondio, G; Petrone, G; Sbacchi, M; Vecchietti, V

1994-10-14

This study describes the synthesis and the structure-activity relationships (SARs) of the (S)-(-)-enantiomers of a novel class of 2-(aminomethyl)piperidine derivatives, using kappa-opioid binding affinity and antinociceptive potency as the indices of biological activity. Compounds incorporating the 1-tetralon-6-ylacetyl residue (30 and 34-45) demonstrated an in vivo antinociceptive activity greater than predicted on the basis of their kappa-binding affinities. In particular, (2S)-2-[(dimethylamino)methyl]-1-[(5,6,7,8-tetrahydro-5-oxo-2- naphthyl)acetyl]piperidine (34) was found to have a potency similar to spiradoline in animal models of antinociception after subcutaneous administration, with ED50s of 0.47 and 0.73 mumol/kg in the mouse and in the rat abdominal constriction tests, respectively. Further in vivo studies in mice and/or rats revealed that compound 34, compared to other selective kappa-agonists, has a reduced propensity to cause a number of kappa-related side effects, including locomotor impairment/sedation and diuresis, at antinociceptive doses. For example, it has an ED50 of 26.5 mumol/kg sc in the rat rotarod model, exhibiting a ratio of locomotor impairment/sedation vs analgesia of 36. Possible reasons for this differential activity and its clinical consequence are discussed.

1-[(6-Chloro-3-pyrid­yl)meth­yl]-5-eth­oxy-8-nitro-1,2,3,5,6,7-hexa­hydro­imidazo[1,2-a]pyridine

PubMed Central

Tian, Zhongzhen; Li, Dongmei; Li, Zhong

2009-01-01

In the title compound, C15H19ClN4O3, an active agrochemical possessing insecticidal activity, the dihedral angle between the mean planes passing through the pyridine ring and the five-membered ring is 87.3 (2)°. The fused pyridine ring adopts a twisted sofa conformation. The mol­ecular structure features close intra­molecular C—H⋯N and C—H⋯O hydrogen bonding. PMID:21577964

Crystal structure of 3-({[(morpholin-4-yl)carbono-thio-yl]sulfan-yl}acet-yl)phenyl benzoate.

PubMed

Ambekar, Sachin P; Mahesh Kumar, K; Shirahatti, Arun Kumar M; Kotresh, O; Anil Kumar, G N

2014-11-01

In the title compound, C20H19NO4S2, the morpholine ring adopts the expected chair conformation. The central phenyl ring makes dihedral angles of 67.97 (4) and 7.74 (3)°, respectively, with the benzoate phenyl ring and the morpholine mean plane. In the crystal, mol-ecules are linked by C-H⋯O hydrogen bonds, forming zigzag chains along the b-axis direction. C-H⋯π inter-actions link centrosymmetrically related mol-ecules, reinforcing the three-dimensional structure.

Hydroxyproline Ring Pucker Causes Frustration of Helix Parameters in the Collagen Triple Helix

NASA Astrophysics Data System (ADS)

Ying Chow, W.; Bihan, Dominique; Forman, Chris J.; Slatter, David A.; Reid, David G.; Wales, David J.; Farndale, Richard W.; Duer, Melinda J.

2015-07-01

Collagens, the most abundant proteins in mammals, are defined by their triple-helical structures and distinctive Gly-Xaa-Yaa repeating sequence, where Xaa is often proline and Yaa, hydroxyproline (Hyp/O). It is known that hydroxyproline in the Yaa position stabilises the triple helix, and that lack of proline hydroxylation in vivo leads to dysfunctional collagen extracellular matrix assembly, due to a range of factors such as a change in hydration properties. In addition, we note that in model peptides, when Yaa is unmodified proline, the Xaa proline has a strong propensity to adopt an endo ring conformation, whilst when Yaa is hydroxyproline, the Xaa proline adopts a range of endo and exo conformations. Here we use a combination of solid-state NMR spectroscopy and potential energy landscape modelling of synthetic triple-helical collagen peptides to understand this effect. We show that hydroxylation of the Yaa proline causes the Xaa proline ring conformation to become metastable, which in turn confers flexibility on the triple helix.

Hydroxyproline Ring Pucker Causes Frustration of Helix Parameters in the Collagen Triple Helix

PubMed Central

Ying Chow, W.; Bihan, Dominique; Forman, Chris J.; Slatter, David A.; Reid, David G.; Wales, David J.; Farndale, Richard W.; Duer, Melinda J.

2015-01-01

Collagens, the most abundant proteins in mammals, are defined by their triple-helical structures and distinctive Gly-Xaa-Yaa repeating sequence, where Xaa is often proline and Yaa, hydroxyproline (Hyp/O). It is known that hydroxyproline in the Yaa position stabilises the triple helix, and that lack of proline hydroxylation in vivo leads to dysfunctional collagen extracellular matrix assembly, due to a range of factors such as a change in hydration properties. In addition, we note that in model peptides, when Yaa is unmodified proline, the Xaa proline has a strong propensity to adopt an endo ring conformation, whilst when Yaa is hydroxyproline, the Xaa proline adopts a range of endo and exo conformations. Here we use a combination of solid-state NMR spectroscopy and potential energy landscape modelling of synthetic triple-helical collagen peptides to understand this effect. We show that hydroxylation of the Yaa proline causes the Xaa proline ring conformation to become metastable, which in turn confers flexibility on the triple helix. PMID:26220399

Methyl 2-methyl-4-(oxiran-2-ylmeth-oxy)-2H-1,2-benzothia-zine-3-carboxyl-ate 1,1-dioxide.

PubMed

Ahmad, Matloob; Siddiqui, Hamid Latif; Zia-Ur-Rehman, Muhammad; Elsegood, Mark R J; Weaver, George W

2010-01-09

In the title compound, C(14)H(15)NO(6)S, the thia-zine ring adopts a distorted half-chair conformation. The structure displays several cooperative weak inter-molecular C-H⋯O hydrogen-bonding inter-actions, giving rise to a two-dimensional sheet packing motif. The CH(2) group in the meth-oxy linker to the oxirane ring, and the CH group in that ring, exhibit twofold positional disorder. The three-membered oxirane ring is twisted approximately perpendicular with respect to thia-zine ring (dihedral angle = 60/86° for the major/minor disorder components). 1,2-Benzothia-zines of this kind have a wide range of biological activities and are mainly used as medicines in the treatment of inflammation and rheumatoid arthritis.

Ethyl 2-{4-[(1,5-dibenzyl-2,4-dioxo-2,3,4,5-tetra-hydro-1H-1,5-benzo-diazepin-3-yl)meth-yl]-1H-1,2,3-triazol-1-yl}acetate.

PubMed

Jabli, Hind; Kandri Rodi, Y; Ladeira, Sonia; Essassi, El Mokhtar; Ng, Seik Weng

2009-12-12

The reaction of 1,5-dibenzyl-3-propargyl-1,5-benzodiazepine-2,4-dione with ethyl azido-acetate in the presence of copper sulfate pentahydrate and sodium ascorbate leads to the formation of the title regioisomer, C(30)H(29)N(5)O(4), which features a phenyl-ene ring fused with a seven-membered diazepinyl ring. The latter ring adopts a boat conformation (with the methyl-triazolylacetate-bearing C atom as the prow and the fused-ring C atoms as the stern). The benzyl groups connected to the diazepinyl ring jprotrude from the sides; the methyl-triazolylacetate substituent occupies an axial position.

Proton donor acidity controls selectivity in nonaromatic nitrogen heterocycle synthesis.

PubMed

Duttwyler, Simon; Chen, Shuming; Takase, Michael K; Wiberg, Kenneth B; Bergman, Robert G; Ellman, Jonathan A

2013-02-08

Piperidines are prevalent in natural products and pharmaceutical agents and are important synthetic targets for drug discovery and development. We report on a methodology that provides highly substituted piperidine derivatives with regiochemistry selectively tunable by varying the strength of acid used in the reaction. Readily available starting materials are first converted to dihydropyridines via a cascade reaction initiated by rhodium-catalyzed carbon-hydrogen bond activation. Subsequent divergent regio- and diastereoselective protonation of the dihydropyridines under either kinetic or thermodynamic control provides two distinct iminium ion intermediates that then undergo highly diastereoselective nucleophilic additions. X-ray structural characterization of both the kinetically and thermodynamically favored iminium ions along with density functional theory calculations provide a theoretical underpinning for the high selectivities achieved for the reaction sequences.

Discovery of a novel, CNS penetrant M4 PAM chemotype based on a 6-fluoro-4-(piperidin-1-yl)quinoline-3-carbonitrile core.

PubMed

Bewley, Blake R; Spearing, Paul K; Weiner, Rebecca L; Luscombe, Vincent B; Zhan, Xiaoyan; Chang, Sichen; Cho, Hyekyung P; Rodriguez, Alice L; Niswender, Colleen M; Conn, P Jeffrey; Bridges, Thomas M; Engers, Darren W; Lindsley, Craig W

2017-09-15

This Letter details the discovery and subsequent optimization of a novel M 4 PAM scaffold based on an 6-fluoro-4-(piperidin-1-yl)quinoline-3-carbonitrile core, which represents a distinct departure from the classical M 4 PAM chemotypes. Optimized compounds in this series demonstrated improved M 4 PAM potency on both human and rat M 4 (4 to 5-fold relative to HTS hit), and displayed attractive physicochemical and DMPK profiles, including good CNS penetration (rat brain:plasma K p =5.3, K p,uu =2.4; MDCK-MDR1 (P-gp) ER=1.1). Copyright © 2017 Elsevier Ltd. All rights reserved.

An improved ring removal procedure for in-line x-ray phase contrast tomography

NASA Astrophysics Data System (ADS)

Massimi, Lorenzo; Brun, Francesco; Fratini, Michela; Bukreeva, Inna; Cedola, Alessia

2018-02-01

The suppression of ring artifacts in x-ray computed tomography (CT) is a required step in practical applications; it can be addressed by introducing refined digital low pass filters within the reconstruction process. However, these filters may introduce additional ringing artifacts when simultaneously imaging pure phase objects and elements having a non-negligible absorption coefficient. Ringing originates at sharp interfaces, due to the truncation of spatial high frequencies, and severely affects qualitative and quantitative analysis of the reconstructed slices. In this work, we discuss the causes of ringing artifacts, and present a general compensation procedure to account for it. The proposed procedure has been tested with CT datasets of the mouse central nervous system acquired at different synchrotron radiation facilities. The results demonstrate that the proposed method compensates for ringing artifacts induced by low pass ring removal filters. The effectiveness of the ring suppression filters is not altered; the proposed method can thus be considered as a framework to improve the ring removal step, regardless of the specific filter adopted or the imaged sample.

An improved ring removal procedure for in-line x-ray phase contrast tomography.

PubMed

Massimi, Lorenzo; Brun, Francesco; Fratini, Michela; Bukreeva, Inna; Cedola, Alessia

2018-02-12

The suppression of ring artifacts in x-ray computed tomography (CT) is a required step in practical applications; it can be addressed by introducing refined digital low pass filters within the reconstruction process. However, these filters may introduce additional ringing artifacts when simultaneously imaging pure phase objects and elements having a non-negligible absorption coefficient. Ringing originates at sharp interfaces, due to the truncation of spatial high frequencies, and severely affects qualitative and quantitative analysis of the reconstructed slices. In this work, we discuss the causes of ringing artifacts, and present a general compensation procedure to account for it. The proposed procedure has been tested with CT datasets of the mouse central nervous system acquired at different synchrotron radiation facilities. The results demonstrate that the proposed method compensates for ringing artifacts induced by low pass ring removal filters. The effectiveness of the ring suppression filters is not altered; the proposed method can thus be considered as a framework to improve the ring removal step, regardless of the specific filter adopted or the imaged sample.

Bromine isotopic signature facilitates de novo sequencing of peptides in free-radical-initiated peptide sequencing (FRIPS) mass spectrometry.

PubMed

Nam, Jungjoo; Kwon, Hyuksu; Jang, Inae; Jeon, Aeran; Moon, Jingyu; Lee, Sun Young; Kang, Dukjin; Han, Sang Yun; Moon, Bongjin; Oh, Han Bin

2015-02-01

We recently showed that free-radical-initiated peptide sequencing mass spectrometry (FRIPS MS) assisted by the remarkable thermochemical stability of (2,2,6,6-tetramethyl-piperidin-1-yl)oxyl (TEMPO) is another attractive radical-driven peptide fragmentation MS tool. Facile homolytic cleavage of the bond between the benzylic carbon and the oxygen of the TEMPO moiety in o-TEMPO-Bz-C(O)-peptide and the high reactivity of the benzylic radical species generated in •Bz-C(O)-peptide are key elements leading to extensive radical-driven peptide backbone fragmentation. In the present study, we demonstrate that the incorporation of bromine into the benzene ring, i.e. o-TEMPO-Bz(Br)-C(O)-peptide, allows unambiguous distinction of the N-terminal peptide fragments from the C-terminal fragments through the unique bromine doublet isotopic signature. Furthermore, bromine substitution does not alter the overall radical-driven peptide backbone dissociation pathways of o-TEMPO-Bz-C(O)-peptide. From a practical perspective, the presence of the bromine isotopic signature in the N-terminal peptide fragments in TEMPO-assisted FRIPS MS represents a useful and cost-effective opportunity for de novo peptide sequencing. Copyright © 2015 John Wiley & Sons, Ltd.

Substituent effect of N-benzylated gramine derivatives that prevent the PP2A inhibition and dissipate the neuronal Ca2+ overload, as a multitarget strategy for the treatment of Alzheimer's disease.

PubMed

Gonzalez, Dorleta; Arribas, Raquel L; Viejo, Lucia; Lajarin-Cuesta, Rocio; de Los Rios, Cristobal

2018-05-15

Following the premises of the multitarget-directed ligands approach for the drug R&D against neurodegenerative diseases, where Alzheimer's disease (AD) outstands, we have synthesized and evaluated analogues of the gramine derivative ITH12657 (1-benzyl-5-methyl-3-(piperidin-1-ylmethyl-1H-indole, 2), which had shown important neuroprotective properties, such as blocking effect of voltage-gated Ca 2+ channels (VGCC), and prevention of phosphoprotein phosphatase 2A (PP2A) inhibition. The new analogues present different substitutions at the pending phenyl ring, what slightly modified their pharmacological characteristics. The VGCC blockade was enhanced in derivatives possessing nitro groups, while the pro-PP2A feature was ameliorated by the presence of fluorine. Chlorine atoms supplied good activities over the two biological targets aimed; nevertheless that substitution provoked loss of viability at 100-fold higher concentrations (10 μM), what discards them for a deeper pharmacological study. Overall, the para-fluorine derivative of ITH12657 was the most promising candidate for further preclinical assays. Copyright © 2018 Elsevier Ltd. All rights reserved.

OPC-28326, a selective femoral arterial vasodilator, augments ischemia induced angiogenesis.

PubMed

Sumi, Makoto; Sata, Masataka; Hashimoto, Ayako; Imaizumi, Takashi; Yanaga, Katsuhiko; Ohki, Takao; Mori, Toyoki; Nagai, Ryozo

2007-05-01

OPC-28326, 4-(N-methyl-2-phenylethylamino)-1-(3,5-dimethyl-4-propionyl-aminobenzoyl) piperidine hydrochloride monohydrate, is a newly developed selective peripheral vasodilator and increases blood flow to lower extremities with alpha2-adrenergic antagonist property. Here, we investigated the effect of OPC-28326 on ischemia-induced angiogenesis. OPC-28326 enhanced tube formation by human aortic endothelial cells (HAECs). Moreover, OPC-28326 enhanced the number of microvessels sprouting from aortic rings embedded in collagen gel. OPC-28326 markedly induced phosphorylation of endothelial nitric oxide synthase (eNOS) in HAECs via phosphatidylinositol-3 kinase PI3K/Akt (PI3K/Akt) pathway. Next, the angiogenic effect of OPC-28326 was evaluated in a mouse hindlimb ischemia model. Blood flow recovery to the ischemic leg was significantly enhanced by OPC-28326. Furthermore, anti-CD31 immunostaining revealed that OPC-28326 increased capillary density in the ischemic muscle. However, OPC-28326 failed to promote blood flow recovery in ischemic hindlimb in eNOS-deficient mice. These results suggest that OPC-28326 promotes angiogenesis, which was associated with activation of eNOS via PI3K/Akt pathway. OPC-28326 might be promising to treat patients with ischemic vascular diseases.

Ethyl 2-{N-[N-(4-chloro-6-methoxy­pyrimidin-2-yl)carbamo­yl]sulfamo­yl}benzoate

PubMed Central

Lu, Chui; Li, Fang-Shi; Yu, Da-Sheng; Yao, Wei; Liu, Yin-Hong

2008-01-01

The asymmetric unit of the title compound, C15H15ClN4O6S, contains two independent mol­ecules, in which the pyrimidine and benzene rings are oriented at dihedral angles of 75.21 (3) and 86.00 (3)°. Intra­molecular N—H⋯N and C—H⋯O hydrogen bonds result in the formation of two five- and two six-membered rings. The six-membered rings have flattened-boat conformations, while the five-membered rings adopt envelope conformations. In the crystal structure, inter­molecular N—H⋯O hydrogen bonds link the mol­ecules. PMID:21202882

Methyl 4-(4-fluoro­phen­yl)-6-isopropyl-2-[N-methyl-N-(methylsulfonyl)amino]­pyrimidine-5-carboxyl­ate

PubMed Central

He, Wei; Yang, Dong-Ling; Cui, Yong-Tao; Xu, Ye-Ming; Guo, Cheng

2008-01-01

In the mol­ecule of the title compound, C17H20FN3O4S, the pyrimidine and benzene rings are oriented at a dihedral angle of 35.59 (3)°. Intra­molecular C—H⋯N and C—H⋯O hydrogen bonds result in the formation of one five- and two six-membered non-planar rings. One of the six-membered rings adopts a chair conformation, while the other six-membered ring and the five-membered ring exhibit envelope conformations with O and N atoms displaced by 0.837 (3) and 0.152 (3) Å, respectively from the planes of the other ring atoms. In the crystal structure, inter­molecular C—H⋯F hydrogen bonds link the mol­ecules into infinite chains. PMID:21202637

4,5,7,8,17-Penta-hydr-oxy-14,18-dimethyl-6-methyl-ene-3,10-dioxapenta-cyclo-[9.8.0.0.0.0]nona-dec-14-ene-9,16-dione methanol solvate dihydrate.

PubMed

Teh, Chin Hoe; Teoh, Siew Chin; Yeap, Chin Sing; Chan, Kit Lam; Fun, Hoong-Kun

2009-03-28

The title quassinoid compound, C(20)H(24)O(9)·CH(3)OH·2H(2)O, is a natural eurycomanone isolated from the roots of Eurycoma longifolia. The mol-ecules contain a fused five-ring system, with one tetra-hydro-furan ring adopting an envelope conformation, one tetra-hydro-pyran-2-one ring in a screw boat conformation, one cyclo-hexenone ring in a half-chair conformation and two cyclo-hexane rings in chair conformations. Intra-molecular C-H⋯O inter-actions generate S(5) ring motifs and an O-H⋯O inter-action generates an S(7) ring motif. In the crystal, mol-ecules are linked via inter-molecular O-H⋯O inter-actions along the b axis and further stacked along a axis. The absolute configuration of the title compound was inferred from previously solved structures of its analogues.

Ethyl 2-(1,2,3,4-tetrahydro­spiro­[carba­zole-3,2′-[1,3]dioxolan]-9-yl)acetate

PubMed Central

Löffler, Philipp M. G.; Ulven, Trond; Bond, Andrew D.

2009-01-01

In the title compound, C18H21NO4, the hydrogenated six-membered ring of the carbazole unit adopts a half-chair conformation. The dioxolane ring and ethyl­acetate substituent point to opposite sides of the carbazole plane. The ethyl­acetate substituent adopts an essentially fully extended conformation, and its mean plane forms a dihedral angle of 83.8 (1)° with respect to the carbazole mean plane. The mol­ecules are arranged into stacks in which the carbazole planes form a dihedral angle of 4.4 (1)° and have an approximate inter­planar separation of 3.6 Å. PMID:21582427

Identification, isolation, and synthesis of seven novel impurities of anti-diabetic drug Repaglinide.

PubMed

Kancherla, Prasad; Keesari, Srinivas; Alegete, Pallavi; Khagga, Mukkanti; Das, Parthasarathi

2018-01-01

Seven unknown impurities in Repaglinide bulk drug batches at below 0.1% (ranging from 0.05 to 0.10%) were detected by an ultra-performance liquid chromatographic (UPLC) method. These impurities were isolated from the crude sample of Repaglinide using preparative high performance liquid chromatography (prep-HPLC). Based on liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI/MS) study, the chemical structures of seven new impurities (8, 9, 10, 11, 13, 14, and 16) were presumed and characterized as 4-(cyanomethyl)-2-ethoxybenzoic acid (8), 4-(cyanomethyl)-2-ethoxy-N-(3-methyl-1-(2-(piperidin-1-yl)phenyl)butyl)benzamide (9), 4-(2-amino-2-oxoethyl)-2-ethoxy-N-(3-methyl-1-(2-(piperidin-1-yl)phenyl)butyl) benzamide (10) and 2-(3-ethoxy-4-((3-methyl-1-(2-(piperidin-1-yl)phenyl)butyl) carbamoyl) phenyl) acetic acid (11) and 4-(cyanomethyl)-N-cyclohexyl-2-ethoxybenzamide (13), 2-(4-(cyclohexylcarbamoyl)-3-ethoxyphenyl) acetic acid (14) and N-cyclohexyl-4-(2-(cyclohexylamino)-2-oxoethyl)-2-ethoxybenzamide (16). The complete spectral analysis, proton nuclear magnetic resonance ( 1 H NMR), 13 C NMR, MS, and infrared (IR) confirmed the proposed chemical structures of impurities. Identification, structural characterization, formation, and their synthesis was first reported in this study. The impurity 11 was crystallized and structure was solved by single crystal X-ray diffraction. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

Design synthesis and structure-activity relationship of 5-substituted (tetrahydronaphthalen-2yl)methyl with N-phenyl-N-(piperidin-2-yl)propionamide derivatives as opioid ligands.

PubMed

Deekonda, Srinivas; Rankin, David; Davis, Peg; Lai, Josephine; Vanderah, Todd W; Porecca, Frank; Hruby, Victor J

2016-01-15

Here, we report the design, synthesis and structure activity relationship of novel small molecule opioid ligands based on 5-amino substituted (tetrahydronaphthalen-2-yl)methyl moiety with N-phenyl-N-(piperidin-2-yl)propionamide derivatives. We synthesized various molecules including amino, amide and hydroxy substitution on the 5th position of the (tetrahydronaphthalen-2-yl)methyl moiety. In our further designs we replaced the (tetrahydronaphthalen-2-yl)methyl moiety with benzyl and phenethyl moiety. These N-phenyl-N-(piperidin-2-yl)propionamide analogues showed moderate to good binding affinities (850-4 nM) and were selective towards the μ opioid receptor over the δ opioid receptors. From the structure activity relationship studies, we found that a hydroxyl substitution at the 5th position of (tetrahydronapthalen-2yl)methyl group, ligands 19 and 20, showed excellent binding affinities 4 and 5 nM, respectively, and 1000 fold selectivity towards the μ opioid relative to the delta opioid receptor. The ligand 19 showed potent agonist activities 75±21 nM, and 190±42 nM in the GPI and MVD assays. Surprisingly the fluoro analogue 20 showed good agonist activities in MVD assays 170±42 nM, in contrast to its binding affinity results. Copyright © 2015 Elsevier Ltd. All rights reserved.

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

PubMed

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

2012-09-12

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.

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

PubMed Central

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

Crystal structure of 3-({[(morpholin-4-yl)carbono­thio­yl]sulfan­yl}acet­yl)phenyl benzoate

PubMed Central

Ambekar, Sachin P.; Mahesh Kumar, K.; Shirahatti, Arun Kumar M.; Kotresh, O.; Anil Kumar, G. N.

2014-01-01

In the title compound, C20H19NO4S2, the morpholine ring adopts the expected chair conformation. The central phenyl ring makes dihedral angles of 67.97 (4) and 7.74 (3)°, respectively, with the benzoate phenyl ring and the morpholine mean plane. In the crystal, mol­ecules are linked by C—H⋯O hydrogen bonds, forming zigzag chains along the b-axis direction. C—H⋯π inter­actions link centrosymmetrically related mol­ecules, reinforcing the three-dimensional structure. PMID:25484757

Fire ants

MedlinePlus

... a fire ant delivers a harmful substance, called venom, into your skin. This article is for information ... in the United States. Poisonous Ingredient Fire ant venom contains a chemical called piperidine. Where Found Fire ...

Synthesis and evaluation of 4-substituted piperidines and piperazines as balanced affinity μ opioid receptor (MOR) agonist/δ opioid receptor (DOR) antagonist ligands.

PubMed

Bender, Aaron M; Clark, Mary J; Agius, Michael P; Traynor, John R; Mosberg, Henry I

2014-01-15

In this letter, we describe a series of 4-substituted piperidine and piperazine compounds based on tetrahydroquinoline 1, a compound that shows balanced, low nanomolar binding affinity for the mu opioid receptor (MOR) and the delta opioid receptor (DOR). We have shown that by changing the length and flexibility profile of the side chain in this position, binding affinity is improved at both receptors by a significant degree. Furthermore, several of the compounds described herein display good efficacy at MOR, while simultaneously displaying DOR antagonism. The MOR agonist/DOR antagonist has shown promise in the reduction of negative side effects displayed by selective MOR agonists, namely the development of dependence and tolerance. Copyright © 2013 Elsevier Ltd. All rights reserved.

4-N-Hydroxy-4-[1-(sulfonyl)piperidin-4-yl]-butyramides as HDAC inhibitors.

PubMed

Rossi, Cristina; Fincham, Christopher I; D'Andrea, Piero; Porcelloni, Marina; Ettorre, Alessandro; Mauro, Sandro; Bigioni, Mario; Binaschi, Monica; Maggi, Carlo A; Nardelli, Federica; Parlani, Massimo; Fattori, Daniela

2011-11-15

A series of N-substituted 4-alkylpiperidine hydroxamic acids, corresponding to the basic structure of histone deacetylase (HDAC) inhibitors (zinc binding moiety-linker-capping group) has been previously reported by our group. Linker length and aromatic capping group connection were systematically varied to find the optimal geometric parameters. A new series of submicromolar inhibitors was thus identified, which showed antiproliferative activity on HCT-116 colon carcinoma cells. We report here the second part of the strategy used in our research group to find a new class of HDAC inhibitors, namely the SAR study for the compounds bearing a sulfonyl group on the piperidine nitrogen. In the present work, we have considered both sulfonamides and sulfonyl ureas. Copyright © 2011 Elsevier Ltd. All rights reserved.

Electric dipole moment of magnetoexciton in concentric quantum rings

NASA Astrophysics Data System (ADS)

García, L. F.; Mikhailov, I. D.; Revinova, S. Yu

2017-12-01

We study properties of exciton in a weakly coupled concentric quantum rings, penetrated by an axially directed magnetic flux and subjected to an electric field in the ring’s plane. To this end, we adopt a simple model of quasi-one-dimensional rotator, for which the wave functions and the corresponding energies we found by using the double Fourier series expansion method. Revealed multiple intersections of the energy levels provide conditions for abrupt changes of the radial and the angular quantum numbers, making possible the tunnelling of carriers between rings and allowing the formation of a permanent large dipole moment. We show that the electric and magnetic polarizability of concentric quantum rings with a trapped exciton are very sensible to external electric and magnetic fields.

Mechanical improvement of metal reinforcement rings for a finite ring-shaped superconducting bulk

NASA Astrophysics Data System (ADS)

Huang, Chen-Guang; Zhou, You-He

2018-03-01

As a key technique, reinforcement of type-II superconducting bulks with metal rings can efficiently improve their mechanical properties to enhance the maximum trapped field. In this paper, we study the magnetostrictive and fracture behaviors of a finite superconducting ring bulk reinforced by three typical reinforcing structures composed of metal rings during the magnetizing process by means of the minimization of magnetic energy and the finite element method. After a field-dependent critical current density is adopted, the magnetostriction, pinning-induced stress, and crack tip stress intensity factor are calculated considering the demagnetization effects. The results show that the mechanical properties of the ring bulk are strongly dependent on the reinforcing structure and the material and geometrical parameters of the metal rings. Introducing the metal ring can significantly reduce the hoop stress, and the reduction effect by internal reinforcement is much improved relative to external reinforcement. By comparison, bilateral reinforcement seems to be the best candidate structure. Only when the metal rings have particular Young's modulus and radial thickness will they contribute to improve the mechanical properties the most. In addition, if an edge crack is pre-existing in the ring bulk, the presence of metal rings can effectively avoid crack propagation since it reduces the crack tip stress intensity factor by nearly one order of magnitude.

N-alkyl functionalised expanded ring N-heterocyclic carbene complexes of rhodium(I) and iridium(I): structural investigations and preliminary catalytic evaluation.

PubMed

Dunsford, Jay J; Tromp, Dorette S; Cavell, Kingsley J; Elsevier, Cornelis J; Kariuki, Benson M

2013-05-28

A series of new N-alkyl functionalised 6- and 7-membered expanded ring N-heterocyclic carbene (NHC) pro-ligands 3-6 and their corresponding complexes of rhodium(I) and iridium(I), [M(NHC)(COD)Cl] 7-14 and [M(NHC)(CO)2Cl] 15-22 are described. The complexes have been characterised by (1)H and (13)C{(1)H} NMR, mass spectrometry, IR and X-ray diffraction. It is noted from X-ray diffraction studies that the N-alkyl substituents are found to orientate themselves away from the metal centre due to unfavourable steric interactions resulting in low percent buried volume (%V(bur)) values in the solid state. The heterocycle ring size is also found to dictate the spatial orientation of the N-alkyl substituents in the neopentyl functionalised derivatives 10 and 14. The 7-membered derivative 14 allows for a conformational 'twist' of the heterocycle ring with the N-alkyl substituents adopting a mutually trans configuration with respect to each other, while the more rigid 6-membered system 10 does not allow for this conformational 'twist' and consequently the N-alkyl substituents adopt a mutually cis configuration. The σ-donor function of this new class of expanded ring NHC ligand has also been probed by measured IR stretching frequencies of the [M(NHC)(CO)2Cl] complexes 15-22. A preliminary catalytic survey of the hydrogenation of functionalised alkenes with molecular hydrogen under mild conditions has also been undertaken with complex , affording an insight into the application of large ring NHC ancillary ligands bearing N-alkyl substituents in hydrogenation transformations.

Theoretical study of structure, bonding, and electronic behavior of novel sandwich complexes Os3(C6H6) n ( n = 1, 2)

NASA Astrophysics Data System (ADS)

Zhou, K.; Zhao, C. B.; Huang, W. D.

2017-11-01

The correlations between structural and electronic properties of the monolayer cluster Os3 and sandwich complexes of Os3(C6H6) n ( n = 1, 2) were studied with density functional theory. Every Os adopts η2 fashion to coordinate with C6H6 in Os3(C6H6), while every Os adopts η2 and η1 fashion to coordinate with below and above C6H6 rings in Os3(C6H6)2. η2 fashion is σ donation and π back bond, and η1 fashion belong to σ bond. The first binding energy between Os3 and below C6H6 ring is-114.23 kJ/mol, which is weaker than the second binding energy with-174.16 kJ/mol between Os3(C6H6) and above C6H6 ring. The reason is that the change of spin multiplicity is different, which leads the symmetry of Os3(C6H6)2 to be broken.

Penetration of magnetosonic waves into the plasmasphere observed by the Van Allen Probes

DOE PAGES

Xiao, Fuliang; Zhou, Qinghua; He, Yihua; ...

2015-09-11

During the small storm on 14–15 April 2014, Van Allen Probe A measured a continuously distinct proton ring distribution and enhanced magnetosonic (MS) waves along its orbit outside the plasmapause. Inside the plasmasphere, strong MS waves were still present but the distinct proton ring distribution was falling steeply with distance. We adopt a sum of subtracted bi-Maxwellian components to model the observed proton ring distribution and simulate the wave trajectory and growth. MS waves at first propagate toward lower L shells outside the plasmasphere, with rapidly increasing path gains related to the continuous proton ring distribution. The waves then graduallymore » cross the plasmapause into the deep plasmasphere, with almost unchanged path gains due to the falling proton ring distribution and higher ambient density. These results present the first report on how MS waves penetrate into the plasmasphere with the aid of the continuous proton ring distributions during weak geomagnetic activities.« less

Photometric studies of Saturn's ring and eclipses of the Galilean satellites

NASA Technical Reports Server (NTRS)

Brunk, W. E.

1972-01-01

Reliable data defining the photometric function of the Saturn ring system at visual wavelengths are interpreted in terms of a simple scattering model. To facilitate the analysis, new photographic photometry of the ring has been carried out and homogeneous measurements of the mean surface brightness are presented. The ring model adopted is a plane parallel slab of isotropically scattering particles; the single scattering albedo and the perpendicular optical thickness are both arbitrary. Results indicate that primary scattering is inadequate to describe the photometric properties of the ring: multiple scattering predominates for all angles of tilt with respect to the Sun and earth. In addition, the scattering phase function of the individual particles is significantly anisotropic: they scatter preferentially towards the sun. Photoelectric photometry of Ganymede during its eclipse by Jupiter indicate that neither a simple reflecting-layer model nor a semi-infinite homogeneous scattering model provides an adequate physical description of the Jupiter atmosphere.

Methyl 2-methyl-4-(oxiran-2-ylmeth­oxy)-2H-1,2-benzothia­zine-3-carboxyl­ate 1,1-dioxide

PubMed Central

Ahmad, Matloob; Siddiqui, Hamid Latif; Zia-ur-Rehman, Muhammad; Elsegood, Mark R. J.; Weaver, George W.

2010-01-01

In the title compound, C14H15NO6S, the thia­zine ring adopts a distorted half-chair conformation. The structure displays several cooperative weak inter­molecular C—H⋯O hydrogen-bonding inter­actions, giving rise to a two-dimensional sheet packing motif. The CH2 group in the meth­oxy linker to the oxirane ring, and the CH group in that ring, exhibit twofold positional disorder. The three-membered oxirane ring is twisted approximately perpendicular with respect to thia­zine ring (dihedral angle = 60/86° for the major/minor disorder components). 1,2-Benzothia­zines of this kind have a wide range of biological activities and are mainly used as medicines in the treatment of inflammation and rheumatoid arthritis. PMID:21579762

Nobiletin: a citrus flavonoid displaying potent physiological activity.

PubMed

Noguchi, Shuji; Atsumi, Haruka; Iwao, Yasunori; Kan, Toshiyuki; Itai, Shigeru

2016-02-01

Nobiletin [systematic name: 2-(3,4-dimethoxyphenyl)-5,6,7,8-tetramethoxy-4H-chromen-4-one; C21H22O8] is a flavonoid found in citrus peels, and has been reported to show a wide range of physiological properties, including anti-inflammatory, anticancer and antidementia activities. We have solved the crystal structure of nobiletin, which revealed that the chromene and arene rings of its flavone moiety, as well as the two methoxy groups bound to its arene ring, were coplanar. In contrast, the C atoms of the four methoxy groups bound to the chromene ring are out of the plane, making the molecule conformationally chiral. A comparison of the crystal structures of nobiletin revealed that it could adopt a variety of different conformations through rotation of the covalent bond between the chromene and arene rings, and the orientations of methoxy groups bound to the chromene ring.

Ethyl 2-(4-chloro-2-oxo-2,3-dihydro-1,3-benzothia­zol-3-yl)acetate

PubMed Central

Shen, Wen-Tong; Yao, Cheng

2009-01-01

In the mol­ecule of the title compound, C11H10ClNO3S, the benzene and thia­zole rings are oriented at a dihedral angle of 1.25 (3)°. Intra­molecular C—H⋯O and C—H⋯Cl inter­actions result in the formation of two five-membered rings which both adopt envelope conformations. PMID:21582452

1-(4-Methyl-1-naphth­yl)ethanone

PubMed Central

Hu, Yong-Hong; Zhao, Xiao-Lei; Yang, Wen-Ge; Yao, Jin-Feng; Lu, Xiu-Tao

2008-01-01

In the mol­ecule of the title compound, C13H12O, the two aromatic rings are oriented at a dihedral angle of 2.90 (3)°. An intra­molecular C—H⋯O hydrogen bond results in the formation of a non-planar six-membered ring, which adopts an envelope conformation. In the crystal structure, inter­molecular C—H⋯O hydrogen bonds link the mol­ecules. PMID:21581284

Infrared spectrum, NBO, HOMO-LUMO, MEP and molecular docking studies (2E)-3-(3-nitrophenyl)-1-[4-piperidin-1-yl]prop-2-en-1-one.

PubMed

Panicker, C Yohannan; Varghese, Hema Tresa; Nayak, Prakash S; Narayana, B; Sarojini, B K; Fun, H K; War, Javeed Ahamad; Srivastava, S K; Van Alsenoy, C

2015-09-05

FT-IR spectrum of (2E)-3-(3-nitrophenyl)-1-[4-piperidin-1-yl]prop-2-en-1-one was recorded and analyzed. The vibrational wavenumbers were computed using HF and DFT quantum chemical calculations. The data obtained from wavenumber calculations are used to assign IR bands. Potential energy distribution was done using GAR2PED software. The geometrical parameters of the title compound are in agreement with the XRD results. NBO analysis, HOMO-LUMO, first and second hyperpolarizability and molecular electrostatic potential results are also reported. The possible electrophile attacking sites of the title molecule is identified using MEP surface plot study. Molecular docking results predicted the anti-leishmanic activity for the compound. Copyright © 2015. Published by Elsevier B.V.

Identification and characterization of potential impurities of donepezil.

PubMed

Krishna Reddy, K V S R; Moses Babu, J; Kumar, P Anil; Chandrashekar, E R R; Mathad, Vijayavitthal T; Eswaraiah, S; Reddy, M Satyanarayana; Vyas, K

2004-09-03

Five unknown impurities ranging from 0.05 to 0.2% in donepezil were detected by a simple isocratic reversed-phase high performance liquid chromatography (HPLC). These impurities were isolated from crude sample of donepezil using isocratic reversed-phase preparative high performance liquid chromatography. Based on the spectral data (IR, NMR and MS), the structures of these impurities were characterised as 5,6-dimethoxy-2-(4-pyridylmethyl)-1-indanone (impurity I), 4-(5,6-dimethoxy-2,3-dihydro-1H-2-indenylmethyl) piperidine (impurity II), 2-(1-benzyl-4-piperdylmethyl)-5,6-dimethoxy-1-indanol (impurity III) 1-benzyl-4(5,6-dimethoxy-2,3-dihydro-1H-2-indenylmethyl) piperidine (impurity IV) and 1,1-dibenzyl-4(5,6-dimethoxy-1-oxo-2,3-dihydro-2H-2-indenylmethyl)hexahydropyridinium bromide (impurity V). The synthesis of these impurities and their formation was discussed.

Mechanism of hydrodenitrogenation on phosphides and sulfides.

PubMed

Oyama, S Ted; Lee, Yong-Kul

2005-02-17

The mechanism of hydrodenitrogenation (HDN) of 2-methylpiperidine was studied over a silica-supported nickel phosphide catalyst (Ni2P/SiO2, Ni/P = 1/2) and a commercial Ni-Mo-S/Al2O3 catalyst in a three-phase trickle-bed reactor operated at 3.1 MPa and 450-600 K. Analysis of the product distribution as a function of contact time indicated that the reaction proceeded in both cases predominantly by a substitution mechanism, with a smaller contribution of an elimination mechanism. Fourier transform infrared spectroscopy (FTIR) of the 2-methylpiperidine indicated that at reaction conditions a piperidinium ion intermediate was formed on both the sulfide and the phosphide. It is concluded that the mechanism of HDN on nickel phosphide is very similar to that on sulfides. The mechanism on the nickel phosphide was also probed by comparing the reactivity of piperidine and several of its derivatives in the presence of 3000 ppm S. The relative elimination rates depended on the structure of the molecules, and followed the sequence: 4-methylpiperidine approximately piperidine > 3-methylpiperidine > 2,6-dimethylpiperidine > 2-methylpiperidine. [Chemical structure: see text] This order of reactivity was not dependent on the number of alpha-H or beta-H atoms in the molecules, ruling out their reaction through a single, simple mechanism. It is likely that the unhindered piperidine molecules reacted by an S(N)2 substitution process and the more hindered 2,6-dimethylpiperidine reacted by an E2 elimination process.

Fetal muscle-type nicotinic acetylcholine receptor activation in TE-671 cells and inhibition of fetal movement in a day 40 pregnant goat model by optical isomers of the piperidine alkaloid coniine.

PubMed

Green, Benedict T; Lee, Stephen T; Welch, Kevin D; Pfister, James A; Panter, Kip E

2013-01-01

Coniine is an optically active toxic piperidine alkaloid and nicotinic acetylcholine receptor (nAChR) agonist found in poison hemlock (Conium maculatum L.). Coniine teratogenicity is hypothesized to be attributable to the binding, activation, and prolonged desensitization of fetal muscle-type nAChR, which results in the complete inhibition of fetal movement. However, pharmacological evidence of coniine actions at fetal muscle-type nAChR is lacking. The present study compared (-)-coniine, (+)-coniine, and nicotine for the ability to inhibit fetal movement in a day 40 pregnant goat model and in TE-671 cells that express fetal muscle-type nAChR. Furthermore, α-conotoxins (CTx) EI and GI were used to antagonize the actions of (+)- and (-)-coniine in TE-671 cells. (-)-Coniine was more effective at eliciting electrical changes in TE-671 cells and inhibiting fetal movement than was (+)-coniine, suggesting stereoselectivity by the receptor. The pyridine alkaloid nicotine did not inhibit fetal movement in a day 40 pregnant goat model, suggesting agonist specificity for the inhibition of fetal movement. Low concentrations of both CTxs potentiated the TE-671 cell response and higher concentrations of CTx EI, and GI antagonized the actions of both coniine enantiomers demonstrating concentration-dependent coagonism and selective antagonism. These results provide pharmacological evidence that the piperidine alkaloid coniine is acting at fetal muscle-type nAChR in a concentration-dependent manner.

77 FR 60144 - Importer of Controlled Substances; Notice of Registration; United States Pharmacopeial Convention

Federal Register 2010, 2011, 2012, 2013, 2014

2012-10-02

...-piperidine (8333).. II Phenylacetone (8501) II Alphaprodine (9010) II Anileridine (9020) II Cocaine (9041) II... with United States obligations under international treaties, conventions, or protocols in effect on May...

76 FR 62447 - Importer of Controlled Substances; Notice of Registration

Federal Register 2010, 2011, 2012, 2013, 2014

2011-10-07

... narcotic raw material are not appropriate. With regard to all non-Narcotic Raw Material drugs on this...-phenethyl-4-piperidine (8333)... II Phenylacetone (8501) II Opium, raw (9600) II Poppy Straw Concentrate...

Studies of lysine cyclodeaminase from Streptomyces pristinaespiralis: Insights into the complex transition NAD+ state.

PubMed

Ying, Hanxiao; Wang, Jing; Shi, Ting; Zhao, Yilei; Wang, Xin; Ouyang, Pingkai; Chen, Kequan

2018-01-01

Lysine cyclodeaminase (LCD) catalyzes the piperidine ring formation in macrolide-pipecolate natural products metabolic pathways from a lysine substrate through a combination of cyclization and deamination. This enzyme belongs to a unique enzyme class, which uses NAD + as the catalytic prosthetic group instead of as the co-substrate. To understand the molecular details of NAD + functions in lysine cyclodeaminase, we have determined four ternary crystal structure complexes of LCD-NAD + with pipecolic acid (LCD-PA), lysine (LCD-LYS), and an intermediate (LCD-INT) as ligands at 2.26-, 2.00-, 2.17- and 1.80 Å resolutions, respectively. By combining computational studies, a NAD + -mediated "gate keeper" function involving NAD + /NADH and Arg49 that control the binding and entry of the ligand lysine was revealed, confirming the critical roles of NAD + in the substrate access process. Further, in the gate opening form, a substrate delivery tunnel between ε-carboxyl moiety of Glu264 and the α-carboxyl moiety of Asp236 was observed through a comparison of four structure complexes. The LCD structure details including NAD + -mediated "gate keeper" and substrate tunnel may assist in the exploration the NAD + function in this unique enzyme class, and in regulation of macrolide-pipecolate natural product synthesis. Copyright © 2017 Elsevier Inc. All rights reserved.

Novel oxotremorine-related heterocyclic derivatives: Synthesis and in vitro pharmacology at the muscarinic receptor subtypes.

PubMed

Dallanoce, Clelia; De Amici, Marco; Barocelli, Elisabetta; Bertoni, Simona; Roth, Bryan L; Ernsberger, Paul; De Micheli, Carlo

2007-12-15

A set of novel heterocyclic ligands (6-27) structurally related to Oxotremorine 2 was designed, synthesized and tested at muscarinic receptor subtypes (mAChRs). In the binding experiments at cloned human receptors (hm1-5), compounds 7 and 15 evidenced a remarkable affinity and selectivity for the hm2 subtype. The in vitro functional assays, performed on a selected group of derivatives at M(1), M(2), and M(3) tissue preparations, singled out the 3-butynyloxy-5-methylisoxazole trimethylammonium salt 7 as a potent unselective muscarinic agonist [pEC(50): 7.40 (M(1)), 8.18 (M(2)), and 8.14 (M(3))], whereas its 5-phenyl analogue 12 behaved as a muscarinic antagonist, slightly selective for the M(1) subtype [pK(B): 6.88 (M(1)), 5.95 (M(2)), 5.53 (M(3))]. Moreover, the functional data put in evidence that the presence of the piperidine ring may generate a functional selectivity, e.g., an M(1) antagonist/M(2) partial agonist/M(3) full agonist profile (compound 21), at variance with the corresponding quaternary ammonium salt (compound 22) which behaved as a muscarinic agonist at all M(1-3) receptors, with an appreciable selectivity for the cardiac M(2) receptors.

Improvement of the performances of a tandem simulated moving bed chromatography by controlling the yield level of a key product of the first simulated moving bed unit.

PubMed

Mun, Sungyong; Wang, Nien-Hwa Linda

2017-03-10

One of the trustworthy processes for ternary separation is a tandem simulated moving bed (SMB) process, which consists of two subordinate four-zone SMB units (Ring I and Ring II). To take full advantage of a tandem SMB as a means of recovering all three products with high purities and high economical efficiency, it is important to understand how the separation condition in Ring II is affected by that in Ring I, and further to reflect such point in the stage of designing a tandem SMB. In regard to such issue, it was clarified in this study that the Ring I factors affecting the Ring II condition could be represented by the yield level of a key product of Ring I (Y key RingI ). As the Y key RingI level became higher, the amount of the Ring I key-product that was reloaded into Ring II was reduced, which affected favorably the Ring II separation condition. On the other hand, the higher Y key RingI level caused a larger dilution for the stream from Ring I to Ring II, which affected adversely the Ring II separation condition. As a result, a minimum in the desorbent usage of a tandem SMB occurred at the Y key RingI level where the two aforementioned factors could be balanced with each other. If such an optimal Y key RingI level was adopted, the desorbent usage could be reduced by up to 25%. It was also found that as the throughput of a tandem SMB became higher, the factor related to the migration of the Ring I key-product into Ring II was more influential in the performances of a tandem SMB than the factor related to the dilution of the stream from Ring I to Ring II. Copyright © 2016 Elsevier B.V. All rights reserved.

2-Hy-droxy-16-[(E)-4-methyl-benzyl-idene]-13-(4-methyl-phen-yl)-12-phenyl-1,11-diaza-penta-cyclo-[12.3.1.0.0.0]octa-deca-3(8),4,6-triene-9,15-dione.

PubMed

Kumar, Raju Suresh; Osman, Hasnah; Abdul Rahim, Aisyah Saad; Goh, Jia Hao; Fun, Hoong-Kun

2010-07-24

In the title compound, C(37)H(32)N(2)O(3), an intra-molecular 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 mol-ecules are inter-connected into chains propagating along the [010] direction via inter-molecular C-H⋯O hydrogen bonds. Further stabilization is provided by weak C-H⋯π inter-actions.

40 CFR Appendix A to Part 68 - Table of Toxic Endpoints

Code of Federal Regulations, 2011 CFR

2011-07-01

...-51-2 Phosphine 0.0035 10025-87-3 Phosphorus oxychloride [Phosphoryl chloride] 0.0030 7719-12-2 Phosphorus trichloride [Phosphorous trichloride] 0.028 110-89-4 Piperidine 0.022 107-12-0 Propionitrile...

40 CFR Appendix A to Part 68 - Table of Toxic Endpoints

Code of Federal Regulations, 2010 CFR

2010-07-01

...-51-2 Phosphine 0.0035 10025-87-3 Phosphorus oxychloride [Phosphoryl chloride] 0.0030 7719-12-2 Phosphorus trichloride [Phosphorous trichloride] 0.028 110-89-4 Piperidine 0.022 107-12-0 Propionitrile...

Determination of pKa values of new phenacyl-piperidine derivatives by potentiometric titration method in aqueous medium at room temperature (25±0.5oC).

PubMed

Zafar, Shaista; Akhtar, Shamim; Tariq, Talat; Mushtaq, Noushin; Akram, Arfa; Ahmed, Ahsaan; Arif, Muhammad; Naeem, Sabahat; Anwar, Sana

2014-07-01

Dissociation constant (pKa) of ten novel phenacyl derivatives of piperidine were determined by potentiometric titration method in aqueous medium at room temperature (25 ±0.5°C). The sample solutions were prepared in deionized water with ionic strength 0.01M and titrated with 0.1M NaOH solution. In addition, ΔG values were also calculated. Different prediction software programs were used to calculate pKa values too and compared to the experimentally observed pKa values. The experimental and theoretical values were found in close agreement. The results obtained in this research would help to predict the good absorption of the studied compounds and can be selected as lead molecules for the synthesis of CNS active agents because of their lipophilic nature especially compound VII.

3-(2-Bromo-4,5-dimethoxy­phen­yl)propiononitrile

PubMed Central

Liu, Yan-Ping; Wang, De-Cai; Chen, Hui; Kang, Si-Shun; Huang, Xin-Ming

2008-01-01

In the mol­ecule of the title compound, C11H12BrNO2, a weak intra­molecular C—H⋯Br hydrogen bond results in the formation of a five-membered ring, which adopts an envelope conformation with the H atom displaced by 0.486 Å from the plane of the other ring atoms. In the crystal structure, inter­molecular C—H⋯O hydrogen bonds link the mol­ecules. PMID:21202583

4,5,7,8,17-Penta­hydr­oxy-14,18-dimethyl-6-methyl­ene-3,10-dioxapenta­cyclo­[9.8.0.01,7.04,19.013,18]nona­dec-14-ene-9,16-dione methanol solvate dihydrate

PubMed Central

Teh, Chin Hoe; Teoh, Siew Chin; Yeap, Chin Sing; Chan, Kit Lam; Fun, Hoong-Kun

2009-01-01

The title quassinoid compound, C20H24O9·CH3OH·2H2O, is a natural eurycomanone isolated from the roots of Eurycoma longifolia. The mol­ecules contain a fused five-ring system, with one tetra­hydro­furan ring adopting an envelope conformation, one tetra­hydro­pyran-2-one ring in a screw boat conformation, one cyclo­hexenone ring in a half-chair conformation and two cyclo­hexane rings in chair conformations. Intra­molecular C—H⋯O inter­actions generate S(5) ring motifs and an O—H⋯O inter­action generates an S(7) ring motif. In the crystal, mol­ecules are linked via inter­molecular O—H⋯O inter­actions along the b axis and further stacked along a axis. The absolute configuration of the title compound was inferred from previously solved structures of its analogues. PMID:21582604

5.0 kV breakdown-voltage vertical GaN p-n junction diodes

NASA Astrophysics Data System (ADS)

Ohta, Hiroshi; Hayashi, Kentaro; Horikiri, Fumimasa; Yoshino, Michitaka; Nakamura, Tohru; Mishima, Tomoyoshi

2018-04-01

A high breakdown voltage of 5.0 kV has been achieved for the first time in vertical GaN p-n junction diodes by using our newly developed guard-ring structures. A resistance device was inserted between the main diode portion and the guard-ring portion in a ring-shaped p-n diode to generate a voltage drop over the resistance device by leakage current flowing through the guard-ring portion under negatively biased conditions before breakdown. The voltage at the outer mesa edge of the guard-ring portion, where the electric field intensity is highest and the destructive breakdown usually occurs, is decreased by the voltage drop, so the electric field concentration in the portion is reduced. By adopting this structure, the breakdown voltage (V B) is raised by about 200 V. Combined with a low measured on-resistance (R on) of 1.25 mΩ cm2, Baliga’s figure of merit (V\\text{B}2/R\\text{on}) was as high as 20 GW/cm2.

CYP2C8 and CYP3A4 are the principal enzymes involved in the human in vitro biotransformation of the insulin secretagogue repaglinide

PubMed Central

Bidstrup, Tanja Busk; Bjørnsdottir, Inga; Sidelmann, Ulla Grove; Thomsen, Mikael Søndergård; Hansen, Kristian Tage

2003-01-01

Aims To identify the principal human cytochrome P450 (CYP) enzyme(s) responsible for the human in vitro biotransformation of repaglinide. Previous experiments have identified CYP3A4 as being mainly responsible for the in vitro metabolism of repaglinide, but the results of clinical investigations have suggested that more than one enzyme may be involved in repaglinide biotransformation. Methods [14C]-Repaglinide was incubated with recombinant CYP and with human liver microsomes (HLM) from individual donors in the presence of inhibitory antibodies specific for individual CYP enzymes. Metabolites, measured by high-performance liquid chromatography (HPLC) with on-line radiochemical detection, were identified by liquid chromatography-mass spectrophotometry (LC-MS) and LC-MS coupled on-line to a nuclear magnetic resonance spectrometer (LC-MS-NMR). Results CYP3A4 and CYP2C8 were found to be responsible for the conversion of repaglinide into its two primary metabolites, M4 (resulting from hydroxylation on the piperidine ring system) and M1 (an aromatic amine). Specific inhibitory monoclonal antibodies against CYP3A4 and CYP2C8 significantly inhibited (> 71%) formation of M4 and M1 in HLM. In a panel of HLM from 12 individual donors formation of M4 and M1 varied from approximately 160–880 pmol min−1 mg−1 protein and from 100–1110 pmol min−1 mg−1 protein, respectively. The major metabolite generated by CYP2C8 was found to be M4. The rate of formation of this metabolite in HLM correlated significantly with paclitaxel 6α-hydroxylation (rs = 0.80; P = 0.0029). Two other minor metabolites were also detected. One of them was M1 and the other was repaglinide hydroxylated on the isopropyl moiety (M0-OH). The rate of formation of M4 in CYP2C8 Supersomes™ was 2.5 pmol min−1 pmol−1 CYP enzyme and only about 0.1 pmol min−1 pmol−1 CYP enzyme in CYP3A4 Supersomes™. The major metabolite generated by CYP3A4 was M1. The rate of formation of this metabolite in HLM correlated significantly with testosterone 6β-hydroxylation (rs = 0.90; P = 0.0002). Three other metabolites were identified, namely, M0-OH, M2 (a dicarboxylic acid formed by oxidative opening of the piperidine ring) and M5. The rate of M1 formation in CYP3A4 Supersomes™ was 1.6 pmol min−1 pmol−1 CYP enzyme but in CYP2C8 Super-somes™ it was only approximately 0.4 pmol min−1 pmol−1 CYP enzyme. Conclusions The results confirm an important role for both CYP3A4 and CYP2C8 in the human in vitro biotransformation of repaglinide. This dual CYP biotransformation may have consequences for the clinical pharmacokinetics and drug-drug interactions involving repaglinide if one CYP pathway has sufficient capacity to compensate if the other is inhibited. PMID:12919179

Crystal structure of (1S,2S,2′R,3a′S,5R)-2′-[(5-bromo-1H-indol-3-yl)meth­yl]-2-isopropyl-5,5′-dimethyl­dihydro-2′H-spiro­[cyclo­hexane-1,6′-imidazo[1,5-b]isoxazol]-4′(5′H)-one

PubMed Central

Ghannay, Siwar; Brahmi, Jihed; Nasri, Soumaya; Aouadi, Kaïss; Jeanneau, Erwann; Msaddek, Moncef

2016-01-01

In the title compound, C24H32BrN3O2, the six-membered cyclo­hexane ring adopts a chair conformation and the isoxasolidine ring adopts a twisted conformation. The mol­ecule has five chiral centres and the absolute configuration has been determined in this analysis. The mol­ecular structure is stabilized by weak intra­molecular C—H⋯O and C—H⋯N contacts. In the crystal, mol­ecules are linked by N—H⋯N and C—H⋯O hydrogen bonds, forming undulating sheets parallel to the bc plane. PMID:27536387

77 FR 55503 - Importer of Controlled Substances; Notice of Registration; Cambrex Charles City, Inc.

Federal Register 2010, 2011, 2012, 2013, 2014

2012-09-10

... hearings on applications to import narcotic raw material are not appropriate. 72 FR 3417 (2007). DEA has...-piperidine (8333).. II Phenylacetone (8501) II Opium, raw (9600) II Poppy Straw Concentrate (9670) II The...

In vivo structure of the E. coli FtsZ-ring revealed by photoactivated localization microscopy (PALM).

PubMed

Fu, Guo; Huang, Tao; Buss, Jackson; Coltharp, Carla; Hensel, Zach; Xiao, Jie

2010-09-13

The FtsZ protein, a tubulin-like GTPase, plays a pivotal role in prokaryotic cell division. In vivo it localizes to the midcell and assembles into a ring-like structure-the Z-ring. The Z-ring serves as an essential scaffold to recruit all other division proteins and generates contractile force for cytokinesis, but its supramolecular structure remains unknown. Electron microscopy (EM) has been unsuccessful in detecting the Z-ring due to the dense cytoplasm of bacterial cells, and conventional fluorescence light microscopy (FLM) has only provided images with limited spatial resolution (200-300 nm) due to the diffraction of light. Hence, given the small sizes of bacteria cells, identifying the in vivo structure of the Z-ring presents a substantial challenge. Here, we used photoactivated localization microscopy (PALM), a single molecule-based super-resolution imaging technique, to characterize the in vivo structure of the Z-ring in E. coli. We achieved a spatial resolution of ∼35 nm and discovered that in addition to the expected ring-like conformation, the Z-ring of E. coli adopts a novel compressed helical conformation with variable helical length and pitch. We measured the thickness of the Z-ring to be ∼110 nm and the packing density of FtsZ molecules inside the Z-ring to be greater than what is expected for a single-layered flat ribbon configuration. Our results strongly suggest that the Z-ring is composed of a loose bundle of FtsZ protofilaments that randomly overlap with each other in both longitudinal and radial directions of the cell. Our results provide significant insight into the spatial organization of the Z-ring and open the door for further investigations of structure-function relationships and cell cycle-dependent regulation of the Z-ring.

3β,5α,6β-Trihy­droxy­androstan-17-one

PubMed Central

Andrade, L.C.R.; de Almeida, M.J.B.M.; Paixão, J.A.; Carvalho, J.F.S.; Sá e Melo, M.L.

2011-01-01

The title compound, C19H30O4, is an androstan-17-one derivative synthesized from the dehydro­epiandrosterone through a sequential addition of an oxidant, followed by a trans-diaxial opening of the epoxide generated, with Bi(OTf)3 (OTf is trifluoro­methane­sulfonate). The six-membered rings have a slightly flattened chair conformation, while the five-membered ring adopts a 14-α envelope conformation. All rings are trans fused. In the crystal, the mol­ecules are connected by O—H⋯O hydrogen bonds involving the hydroxyl and carbonyl groups, forming a three-dimensional network. A quantum mechanical ab initio Roothan Hartree–Fock calculation of the free mol­ecule gives bond lengths, valency angles and ring torsion angles of the free molecule at equilibrium geometry (energy minimum) close to the experimental values. PMID:21754383

On focusing of a ring ripple on a Gaussian electromagnetic beam in a plasma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Misra, Shikha; Mishra, S. K.

In this communication the authors have investigated the focusing of a ring ripple on a Gaussian electromagnetic beam propagating in a plasma, considering each of the three kinds of basic nonlinearities, namely, ponderomotive, collisional, and relativistic. In this analysis, the electric field profile of the propagating beam is assumed to be composed of the radial electric field distribution of the Gaussian beam as well as that of the ring ripple; a paraxial like approach has been adopted to analyze the characteristics of the propagation. Thus, one considers a unique dielectric function for the beam propagation and a radial field sensitivemore » diffraction term, appropriate to the vicinity of the maximum of the irradiance distribution of the ring ripple. Further, the variation of the phase associated with the beam on account of the r independent terms in the eikonal has also been accounted for.« less

Actions of Piperidine Alkaloid Teratogens at Fetal Nicotinic Acetylcholine Receptors.

USDA-ARS?s Scientific Manuscript database

Teratogenic alkaloids are found in many species of plants including Conium maculatum L., Nicotiana glauca, Nicotiana tabaccum, and multiple Lupinus spp. Fetal musculoskeletal defects produced by alkaloids from these plants include arthrogyropisis, scoliosis, torticollis, kyposis, lordosis, and clef...

1,5-Bis(penta­fluoro­phen­yl)-3-phenyl­pent-2-ene-1,5-dione

PubMed Central

Schwarzer, Anke; Weber, Edwin

2009-01-01

In the title compound, C23H8F10O2, the three arene rings are twisted one with respect to the other: the two perfluorinated arene rings are tilted to each other by an angle of 60.39 (7)°. They are inclined to the non-fluorinated phenyl unit by 38.85 (7) and 78.74 (7)°. The olefinic double bond adopts an E configuration. The carbonyl groups are not in a coplanar alignment with reference to the neighbouring arene rings. The crystal packing features a number of weak C—H⋯F inter­actions, which leads to the formation of a three-dimensional network. PMID:21578393

Crystal structure of 1-ferrocenyl-2-(4-methyl-benzo-yl)spiro-[11H-pyrrolidizine-3,11'-indeno[1,2-b]quinoxaline].

PubMed

Chandralekha, Kuppan; Gavaskar, Deivasigamani; Sureshbabu, Adukamparai Rajukrishnan; Lakshmi, Srinivasakannan

2014-09-01

In the title compound, [Fe(C5H5)(C34H28N3O)], the four-fused-rings system of the 11H-indeno-[1,2-b]quinoxaline unit is approximately planar [maximum deviation = 0.167 (4) Å] and forms a dihedral angle of 37.25 (6)° with the plane of the benzene ring of the methyl-benzoyl group. Both pyrrolidine rings adopt a twist conformation. An intra-molecular C-H⋯O hydrogen bond is observed. In the crystal, mol-ecules are linked by C-H⋯O hydrogen bonds and weak C-H⋯π inter-actions, forming double chains extending parallel to the c axis.

Ethyl methyl 1,4-dihydro-4-(3-nitrophenyl)-2, 6-bis(1-piperidylmethyl)pyridine-3,5-dicarboxylate.

PubMed

Duque, J; Novoa De Armas, H; Pomés Hernández, R; Suárez Navarro, M; Ochoa Rodríguez, E; Salfrán, E; Verdecia Reyes, Y; Blaton, N M; Peeters, O M; De Ranter, C J

2000-11-01

In the title compound, C(28)H(38)N(4)O(6), the 4-aryl substituent occupies a pseudo-axial position approximately orthogonal to the plane of the dihydropyridine ring [88.1 (3) degrees ]. The dihydropyridine ring adopts a flattened boat conformation. The H atom on the pyridine N atom is involved in a bifurcated intramolecular hydrogen bond, the acceptors being the N atoms of the two piperidylmethyl groups [N.N 2.629 (4) and 2.695 (4) A].

2,6-Bis[1-(2-isopropyl­phenyl­imino)­ethyl]­pyridine

PubMed Central

Agrifoglio, Giuseppe; Reyes, Julian; Atencio, Reinaldo; Briceño, Alexander

2008-01-01

The title compound, C27H31N3, has E substitution at each imine double bond where the two N atoms adopt a trans–trans relationship. The benzene rings are twisted out of the mean plane of the pyridine ring; the mean planes of the aromatic groups are rotated by 63.0 (1) and 72.58 (8)°. The crystal structure is sustained mainly by C—H⋯π and hydro­phobic methyl–methyl inter­actions. PMID:21200845

Crystal structure of N-de­acetyl­lappa­coni­tine

PubMed Central

Shi, Xin-Wei; Lu, Qiang-Qiang; Zhou, Jun-Hui; Cui, Xin-Ai

2015-01-01

The title compound, C30H42N2O7 [systematic name: (1S,4S,5S,7S,8S,9S,10S,11S,13R,14S,16S,17R)-20-ethyl-4,8,9-trihy­droxy-1,14,16-tri­meth­oxy­aconitan-4-yl 2-amino­benzoate], isolated from roots of Aconitum sinomontanum Nakai, is a typical aconitane-type C19-diterpenoid alkaloid, which crystallizes with two independent mol­ecules in the asymmetric unit. The conformations of the two independent mol­ecules are closely similar. Each mol­ecule comprises four six-membered rings (A, B, D and E) including one six-membered N-containing heterocyclic ring (E), and two five-membered rings (C and F). Rings A, B and E adopt chair conformations, while ring D displays a boat conformation. Five-membered rings C and F exhibit envelope conformations. IntramolecularN—H⋯O hydrogen bonds between the amino group and carbonyl O atom help to stabilize molecular structure. In the crystal, O—H⋯O hydrogen bonds link the mol­ecules into zigzag chains propagating in [010]. PMID:26396805

The RING domain of the scaffold protein Ste5 adopts a molten globular character with high thermal and chemical stability.

PubMed

Walczak, Michal J; Samatanga, Brighton; van Drogen, Frank; Peter, Matthias; Jelesarov, Ilian; Wider, Gerhard

2014-01-27

Ste5 is a scaffold protein that controls the pheromone response of the MAP-kinase cascade in yeast cells. Upon pheromone stimulation, Ste5 (through its RING-H2 domain) interacts with the β and γ subunits of an activated heterodimeric G protein and promotes activation of the MAP-kinase cascade. With structural and biophysical studies, we show that the Ste5 RING-H2 domain exists as a molten globule under native buffer conditions, in yeast extracts, and even in denaturing conditions containing urea (7 M). Furthermore, it exhibits high thermal stability in native conditions. Binding of the Ste5 RING-H2 domain to the physiological Gβ/γ (Ste4/Ste18) ligand is accompanied by a conformational transition into a better folded, more globular structure. This study reveals novel insights into the folding mechanism and recruitment of binding partners by the Ste5 RING-H2 domain. We speculate that many RING domains may share a similar mechanism of substrate recognition and molten-globule-like character. Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Modelling and simulation of a thermally induced optical transparency in a dual micro-ring resonator

PubMed Central

2017-01-01

This paper introduces the simulation and modelling of a novel dual micro-ring resonator. The geometric configuration of the resonators, and the implementation of a simulated broadband excitation source, results in the realization of optical transparencies in the combined through port output spectrum. The 130 nm silicon on insulator rib fabrication process is adopted for the simulation of the dual-ring configuration. Two titanium nitride heaters are positioned over the coupling regions of the resonators, which can be operated independently, to control the spectral position of the optical transparency. A third heater, centrally located above the dual resonator rings, can be used to red shift the entire spectrum to a required reference resonant wavelength. The free spectral range with no heater currents applied is 4.29 nm. For a simulated heater current of 7 mA (55.7 mW heater power) applied to one of the through coupling heaters, the optical transparency exhibits a red shift of 1.79 nm from the reference resonant wavelength. The ring-to-ring separation of approximately 900 nm means that it can be assumed that there is a zero ring-to-ring coupling field in this model. This novel arrangement has potential applications as a gas mass airflow sensor or a gas species identification sensor. PMID:28791167

Modelling and simulation of a thermally induced optical transparency in a dual micro-ring resonator.

PubMed

Lydiate, Joseph

2017-07-01

This paper introduces the simulation and modelling of a novel dual micro-ring resonator. The geometric configuration of the resonators, and the implementation of a simulated broadband excitation source, results in the realization of optical transparencies in the combined through port output spectrum. The 130 nm silicon on insulator rib fabrication process is adopted for the simulation of the dual-ring configuration. Two titanium nitride heaters are positioned over the coupling regions of the resonators, which can be operated independently, to control the spectral position of the optical transparency. A third heater, centrally located above the dual resonator rings, can be used to red shift the entire spectrum to a required reference resonant wavelength. The free spectral range with no heater currents applied is 4.29 nm. For a simulated heater current of 7 mA (55.7 mW heater power) applied to one of the through coupling heaters, the optical transparency exhibits a red shift of 1.79 nm from the reference resonant wavelength. The ring-to-ring separation of approximately 900 nm means that it can be assumed that there is a zero ring-to-ring coupling field in this model. This novel arrangement has potential applications as a gas mass airflow sensor or a gas species identification sensor.

Structure and assembly of the essential RNA ring component of a viral DNA packaging motor

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ding, Fang; Lu, Changrui; Zhao, Wei

2011-07-25

Prohead RNA (pRNA) is an essential component in the assembly and operation of the powerful bacteriophage {psi}29 DNA packaging motor. The pRNA forms a multimeric ring via intermolecular base-pairing interactions between protomers that serves to guide the assembly of the ring ATPase that drives DNA packaging. Here we report the quaternary structure of this rare multimeric RNA at 3.5 {angstrom} resolution, crystallized as tetrameric rings. Strong quaternary interactions and the inherent flexibility helped rationalize how free pRNA is able to adopt multiple oligomerization states in solution. These characteristics also allowed excellent fitting of the crystallographic pRNA protomers into previous prohead/pRNAmore » cryo-EM reconstructions, supporting the presence of a pentameric, but not hexameric, pRNA ring in the context of the DNA packaging motor. The pentameric pRNA ring anchors itself directly to the phage prohead by interacting specifically with the fivefold symmetric capsid structures that surround the head-tail connector portal. From these contacts, five RNA superhelices project from the pRNA ring, where they serve as scaffolds for binding and assembly of the ring ATPase, and possibly mediate communication between motor components. Construction of structure-based designer pRNAs with little sequence similarity to the wild-type pRNA were shown to fully support the packaging of {psi}29 DNA.« less

Discovery of Spiro-Piperidine Inhibitors and Their Modulation of the Dynamics of the M2 Proton Channel from Influenza A Virus

PubMed Central

Wang, Jun; Cady, Sarah D.; Balannik, Victoria; Pinto, Lawrence H.; DeGrado, William F.; Hong, Mei

2013-01-01

Amantadine has been used for decades as an inhibitor of the influenza A virus M2 protein (AM2) in the prophylaxis and treatment of influenza A infections, but its clinical use has been limited by its central nervous system (CNS) side effects as well as emerging drug-resistant strains of the virus. With the goal of searching for new classes of M2 inhibitors, a structure–activity relation study based on 2-[3-azaspiro(5,5)undecanol]-2-imidazoline (BL-1743) was initiated. The first generation BL-1743 series of compounds has been synthesized and tested by two-electrode voltage-clamp (TEV) assays. The most active compound from this library, 3-azaspiro[5,5]undecane hydrochloride (9), showed an IC50 as low as 0.92 ± 0.11 μM against AM2, more than an order of magnitude more potent than amantadine (IC50 = 16 μM). 15N and 13C solid-state NMR was employed to determine the effect of compound 9 on the structure and dynamics of the transmembrane domain of AM2 (AM2-TM) in phospholipid bilayers. Compared to amantadine, spiro-piperidine 9 (1) induces a more homogeneous conformation of the peptide, (2) reduces the dynamic disorder of the G34-I35 backbone near the water-filled central cavity of the helical bundle, and (3) influences the dynamics and magnetic environment of more residues within the transmembrane helices. These data suggest that spiro-piperidine 9 binds more extensively with the AM2 channel, thus leading to stronger inhibitory potency. PMID:19469531

Negative allosteric modulators that target human alpha4beta2 neuronal nicotinic receptors.

PubMed

Henderson, Brandon J; Pavlovicz, Ryan E; Allen, Jerad D; González-Cestari, Tatiana F; Orac, Crina M; Bonnell, Andrew B; Zhu, Michael X; Boyd, R Thomas; Li, Chenglong; Bergmeier, Stephen C; McKay, Dennis B

2010-09-01

Allosteric modulation of neuronal nicotinic acetylcholine receptors (nAChRs) is considered to be one of the most promising approaches for therapeutics. We have previously reported on the pharmacological activity of several compounds that act as negative allosteric modulators (NAMs) of nAChRs. In the following studies, the effects of 30 NAMs from our small chemical library on both human alpha4beta2 (Halpha4beta2) and human alpha3beta4 (Halpha3beta4) nAChRs expressed in human embryonic kidney ts201 cells were investigated. During calcium accumulation assays, these NAMs inhibited nAChR activation with IC(50) values ranging from 2.4 microM to more than 100 microM. Several NAMs showed relative selectivity for Halpha4beta2 nAChRs with IC(50) values in the low micromolar range. A lead molecule, KAB-18, was identified that shows relative selectivity for Halpha4beta2 nAChRs. This molecule contains three phenyl rings, one piperidine ring, and one ester bond linkage. Structure-activity relationship (SAR) analyses of our data revealed three regions of KAB-18 that contribute to its relative selectivity. Predictive three-dimensional quantitative SAR (comparative molecular field analysis and comparative molecular similarity indices analysis) models were generated from these data, and a pharmacophore model was constructed to determine the chemical features that are important for biological activity. Using docking approaches and molecular dynamics on a Halpha4beta2 nAChR homology model, a binding mode for KAB-18 at the alpha/beta subunit interface that corresponds to the predicted pharmacophore is described. This binding mode was supported by mutagenesis studies. In summary, these studies highlight the importance of SAR, computational, and molecular biology approaches for the design and synthesis of potent and selective antagonists targeting specific nAChR subtypes.

Negative Allosteric Modulators That Target Human α4β2 Neuronal Nicotinic Receptors

PubMed Central

Henderson, Brandon J.; Pavlovicz, Ryan E.; Allen, Jerad D.; González-Cestari, Tatiana F.; Orac, Crina M.; Bonnell, Andrew B.; Zhu, Michael X.; Boyd, R. Thomas; Li, Chenglong; Bergmeier, Stephen C.

2010-01-01

Allosteric modulation of neuronal nicotinic acetylcholine receptors (nAChRs) is considered to be one of the most promising approaches for therapeutics. We have previously reported on the pharmacological activity of several compounds that act as negative allosteric modulators (NAMs) of nAChRs. In the following studies, the effects of 30 NAMs from our small chemical library on both human α4β2 (Hα4β2) and human α3β4 (Hα3β4) nAChRs expressed in human embryonic kidney ts201 cells were investigated. During calcium accumulation assays, these NAMs inhibited nAChR activation with IC50 values ranging from 2.4 μM to more than 100 μM. Several NAMs showed relative selectivity for Hα4β2 nAChRs with IC50 values in the low micromolar range. A lead molecule, KAB-18, was identified that shows relative selectivity for Hα4β2 nAChRs. This molecule contains three phenyl rings, one piperidine ring, and one ester bond linkage. Structure–activity relationship (SAR) analyses of our data revealed three regions of KAB-18 that contribute to its relative selectivity. Predictive three-dimensional quantitative SAR (comparative molecular field analysis and comparative molecular similarity indices analysis) models were generated from these data, and a pharmacophore model was constructed to determine the chemical features that are important for biological activity. Using docking approaches and molecular dynamics on a Hα4β2 nAChR homology model, a binding mode for KAB-18 at the α/β subunit interface that corresponds to the predicted pharmacophore is described. This binding mode was supported by mutagenesis studies. In summary, these studies highlight the importance of SAR, computational, and molecular biology approaches for the design and synthesis of potent and selective antagonists targeting specific nAChR subtypes. PMID:20551292

(7-Chloro-2-oxo-2H-chromen-4-yl)methyl pyrrolidine-1-carbodi­thio­ate

PubMed Central

Kotresh, O.; Devarajegowda, H. C.; Shirahatti, Arunkumar; Kumar, K. Mahesh; Mahabhaleshwaraiah, N. M.

2013-01-01

In the title compound, C15H14ClNO2S2, the 2H-chromene ring system is essentially planar, with a maximum deviation of 0.0133 (10) Å. Three C atoms and their attached H atoms of the pyrrolidine ring are disordered [occupany ratio 0.874 (7):0.126 (7)] with both disorder components adopting a twisted conformation. The dihedral angle between the 2H-chromene ring system and the major occupancy component of the pyrrolidine ring is 89.45 (7)°. In the crystal, inversion dimers linked by pairs of C—H⋯S and C—H⋯O inter­actions generate R 2 2(24) and R 2 2(10) loops, respectively. Further C—H⋯O hydrogen bonds link the dimers into [100] chains. C—H⋯π inter­actions also occur and there is very weak π–π stacking [inter­planar spacing = 3.650 (5) Å; centroid–centroid distance = 4.095 (7) Å] between inversion-related chloro­benzene rings. PMID:24454115

78 FR 9451 - Academy Express, L.L.C.-Acquisition of Property-Golden Ring Travel & Transportation, Inc.

Federal Register 2010, 2011, 2012, 2013, 2014

2013-02-08

... decision can be made on the record as developed, a procedural schedule will be adopted to reconsider the... Justice, Antitrust Division, 10th Street & Pennsylvania Avenue NW., Washington, DC 20530; and (3) the U.S...

Phylogenetic examination of two chemotypes of Lupinus leucophyllus

USDA-ARS?s Scientific Manuscript database

Lupines (Lupinus spp.) are a common legume found on western U.S. rangelands. Lupinus spp. may contain quinolizidine and or piperidine alkaloids that could be toxic and or teratogenic to grazing livestock. Lupinus leucohyllus and Lupinus polyphyllus represent important species in the rangelands of ...

78 FR 12104 - Manufacturer of Controlled Substances; Notice of Registration; Cedarburg Pharmaceuticals, Inc.

Federal Register 2010, 2011, 2012, 2013, 2014

2013-02-21

... DEPARTMENT OF JUSTICE Drug Enforcement Administration Manufacturer of Controlled Substances... Badger Circle, Grafton, Wisconsin 53024, made application by renewal to the Drug Enforcement... substances: Drug Schedule 4-Anilino-N-phenethyl-4-piperidine ANPP) II (8333). Fentanyl (9801) II The company...

Designer Drug (DD) abuse in Poland; a review of the psychoactive and toxic properties of substances found from seizures of illegal drug products and the legal consequences thereof. Part II--piperazines/piperidines, phenylethylamines, tryptamines and miscellaneous 'others'.

PubMed

Biliński, Przemysław; Hołownia, Piotr; Kapka-Skrzypczak, Lucyna; Wojtyła, Andrzej

2012-01-01

As the second and concluding part, this paper continues the summary review of the scientific evidence obtained from the literature and focuses on the remaining 4/6 groupings of DDs identified in illegal products found in the huge drug seizures made recently in Poland. They consist of piperazines/piperidines, phenylethylamines, tryptamines, (briefly mentioned), and a miscellaneous 'others' category; cannabinoids and cathinones derivatives having being reviewed in the first part. Also included in the introduction and discussion sections, in both reviews, are some legal aspects variously interwoven with the science. It is thus intended that these two articles may help suitable legislation to be rapidly devised to make the prohibition of DDs permanent whenever deemed necessary, as well as providing an up-to-date reference source for those engaged in the DD issue; whether scientists or regulatory bodies.

Protective effects of some creatine derivatives in brain tissue anoxia.

PubMed

Perasso, Luisa; Lunardi, Gian Luigi; Risso, Federica; Pohvozcheva, Anna V; Leko, Maria V; Gandolfo, Carlo; Florio, Tullio; Cupello, Aroldo; Burov, Sergey V; Balestrino, Maurizio

2008-05-01

Some derivatives more lipophylic than creatine, thus theoretically being capable to better cross the blood-brain barrier, were studied for their protective effect in mouse hippocampal slices. We found that N-amidino-piperidine is harmful to brain tissue, and that phosphocreatine is ineffective. Creatine, creatine-Mg-complex (acetate) and phosphocreatine-Mg-complex (acetate) increased the latency to population spike disappearance during anoxia. Creatine and creatine-Mg-complex (acetate) also increased the latency of anoxic depolarization, while the delay induced by phosphocreatine-Mg-complex (acetate) was of borderline significance (P = 0.056). Phosphocreatine-Mg-complex (acetate) significantly reduced neuronal hyperexcitability during anoxia, an effect that no other compound (including creatine itself) showed. For all parameters except reduced hyperexcitability the effects statistically correlated with tissue levels of creatine or phosphocreatine. Summing up, exogenous phosphocreatine and N-amidino piperidine are not useful for brain protection, while chelates of both creatine and phosphocreatine do replicate some of the known protective effects of creatine. In addition, phosphocreatine-Mg-complex (acetate) also reduced neuronal hyperexcitability during anoxia.

Synthesis, spectral characterization and density functional theory exploration of 1-(quinolin-3-yl)piperidin-2-ol

NASA Astrophysics Data System (ADS)

Suresh, M.; Syed Ali Padusha, M.; Bharanidharan, S.; Saleem, H.; Dhandapani, A.; Manivarman, S.

2015-06-01

The experimental and theoretical vibrational frequencies of a newly synthesized compound, namely 1-(quinolin-3-yl)piperidin-2-ol (QPPO) are analyzed. The experimental FT-IR (4000-400 cm-1) and FT-Raman (4000-100 cm-1) of the molecule in solid phase have been recorded. The optimized molecular structure, vibrational assignments of QPPO have been investigated experimentally and theoretically using Gaussian03W software package. The stability of the molecule arising from hyper-conjugative interaction and charge delocalization has been analyzed using NBO analysis. The first order hyperpolarizability (β0) is calculated to find its character in non-linear optics. Gauge including atomic orbital (GIAO) method is used to calculate 1H NMR chemical shift calculations were carried out and compared with experimental data. The electronic properties like UV-Visible spectral analysis and HOMO-LUMO energies were reported. The energy gap shows that the charge transfer occurs within the molecule. Thermodynamic parameters of the title compound were calculated at various temperatures.

Cytotoxicity mechanisms in melanoma cells and UPLC-QTOF/MS2 chemical characterization of two Brazilian stingless bee propolis: Uncommon presence of piperidinic alkaloids.

PubMed

Cisilotto, Júlia; Sandjo, Louis P; Faqueti, Larissa G; Fernandes, Heloísa; Joppi, Débora; Biavatti, Maique W; Creczynski-Pasa, Tânia Beatriz

2018-02-05

The present study characterized propolis extracts produced by Scaptotrigona bipunctata (Tubuna) and Melipona quadrifasciata (Mandaçaia) by LC-MS/MS; their cytotoxicity as well as the mechanism of action in a melanoma cellular model were also assessed. The chemical characterization performed by UPLC-ESI-QTOF/MS 2 analysis revealed uncommon presence of piperidinic alkaloids in Tubuna's propolis extract together with C-glycopyranoside flavonoids. Mandaçaia's propolis collected in the same area rather presented terpenoids and flavonoids. Regarding the mechanism of cytotoxicity, propolis extracts increased the accumulation of reactive oxygen species (ROS), reduced the potential of mitochondrial membrane, induced a decrease in the proteins Bcl-2 and AKT-3 levels, and decreased melanoma cells' migration and invasion. Both propolis extracts induced apoptosis while only Mandaçaia's propolis extract induced cell cycle arrest in G2/M. Copyright © 2017 Elsevier B.V. All rights reserved.

Identification and quantification of phencyclidine pyrolysis products formed during smoking.

PubMed

Lue, L P; Scimeca, J A; Thomas, B F; Martin, B R

1986-01-01

As a result of frequent phencyclidine (PCP) abuse, pyrolysis studies were conducted to further investigate its fate during smoking. Marijuana placebo cigarettes were impregnated with 3H-PCP X HCI and burned under conditions simulating smoking. Mainstream smoke was passed through glass wool filters as well as acidic and basic traps. Approximately 90% of the starting material could be accounted for in the first glass wool trap and cigarette holder. HPLC and GC/MS analysis of methanol extracts of these glass wool traps revealed the presence of 1-phenyl-1-cyclohexene (47% of the starting material) greater than PCP (40%) greater than piperidine (15%) greater than N-acetylpiperidine (9%). It was not possible to fully account for the remainder of the piperidine moiety. It has been reported that at high temperatures PCP is converted to numerous polynuclear aromatic compounds which include styrene, alpha-methylstyrene, naphthalene, 2-methylnaphthalene, 1-methylnaphthalene, biphenyl, cyclohexylbenzene, acenaphthene, phenanthrene, and anthracene. These compounds were not formed from PCP under smoking conditions.

4-aminoquinolone piperidine amides: noncovalent inhibitors of DprE1 with long residence time and potent antimycobacterial activity.

PubMed

Naik, Maruti; Humnabadkar, Vaishali; Tantry, Subramanyam J; Panda, Manoranjan; Narayan, Ashwini; Guptha, Supreeth; Panduga, Vijender; Manjrekar, Praveena; Jena, Lalit Kumar; Koushik, Krishna; Shanbhag, Gajanan; Jatheendranath, Sandesh; Manjunatha, M R; Gorai, Gopinath; Bathula, Chandramohan; Rudrapatna, Suresh; Achar, Vijayashree; Sharma, Sreevalli; Ambady, Anisha; Hegde, Naina; Mahadevaswamy, Jyothi; Kaur, Parvinder; Sambandamurthy, Vasan K; Awasthy, Disha; Narayan, Chandan; Ravishankar, Sudha; Madhavapeddi, Prashanti; Reddy, Jitendar; Prabhakar, Kr; Saralaya, Ramanatha; Chatterji, Monalisa; Whiteaker, James; McLaughlin, Bob; Chiarelli, Laurent R; Riccardi, Giovanna; Pasca, Maria Rosalia; Binda, Claudia; Neres, João; Dhar, Neeraj; Signorino-Gelo, François; McKinney, John D; Ramachandran, Vasanthi; Shandil, Radha; Tommasi, Ruben; Iyer, Pravin S; Narayanan, Shridhar; Hosagrahara, Vinayak; Kavanagh, Stefan; Dinesh, Neela; Ghorpade, Sandeep R

2014-06-26

4-Aminoquinolone piperidine amides (AQs) were identified as a novel scaffold starting from a whole cell screen, with potent cidality on Mycobacterium tuberculosis (Mtb). Evaluation of the minimum inhibitory concentrations, followed by whole genome sequencing of mutants raised against AQs, identified decaprenylphosphoryl-β-d-ribose 2'-epimerase (DprE1) as the primary target responsible for the antitubercular activity. Mass spectrometry and enzyme kinetic studies indicated that AQs are noncovalent, reversible inhibitors of DprE1 with slow on rates and long residence times of ∼100 min on the enzyme. In general, AQs have excellent leadlike properties and good in vitro secondary pharmacology profile. Although the scaffold started off as a single active compound with moderate potency from the whole cell screen, structure-activity relationship optimization of the scaffold led to compounds with potent DprE1 inhibition (IC50 < 10 nM) along with potent cellular activity (MIC = 60 nM) against Mtb.

Potent and Selective Amidopyrazole Inhibitors of IRAK4 That Are Efficacious in a Rodent Model of Inflammation

DOE Office of Scientific and Technical Information (OSTI.GOV)

McElroy, William T.; Tan, Zheng; Ho, Ginny

IRAK4 is a critical upstream kinase in the IL-1R/TLR signaling pathway. Inhibition of IRAK4 is hypothesized to be beneficial in the treatment of autoimmune related disorders. A screening campaign identified a pyrazole class of IRAK4 inhibitors that were determined by X-ray crystallography to exhibit an unusual binding mode. SAR efforts focused on the identification of a potent and selective inhibitor with good aqueous solubility and rodent pharmacokinetics. Pyrazole C-3 piperidines were well tolerated, with N-sulfonyl analogues generally having good rodent oral exposure but poor solubility. N-Alkyl piperidines exhibited excellent solubility and reduced exposure. Pyrazoles possessing N-1 pyridine and fluorophenyl substituentsmore » were among the most active. Piperazine 32 was a potent enzyme inhibitor with good cellular activity. Compound 32 reduced the in vivo production of proinflammatory cytokines and was orally efficacious in a mouse antibody induced arthritis disease model of inflammation.« less

Thermodynamic parameters of phase transitions of perfluoro-N-(4-methylcyclohexyl)piperidine

NASA Astrophysics Data System (ADS)

Druzhinina, A. I.; Efimova, A. A.; Varushchenko, R. M.; Chelovskaya, N. V.

2007-12-01

The heat capacity of perfluoro-N-(4-methylcyclohexyl)piperidine (PMCP) was measured by low-temperature adiabatic calorimetry. The purity of the substance ( N 1 = 99.66 mol %), triple point temperature ( T tp = 293.26 K), and enthalpy of fusion (Δfus H {m/°} = 8.32 kJ/mol) were determined. The enthalpy of vaporization was measured by calorimetry at 298.15 K (Δvap H {m/°}(298.15 K) = 56.56 kJ/mol). The temperature dependence of the saturated vapor pressure of PMCP over the pressure range 6.2-101.6 kPa was determined by comparative ebulliometry. The normal boiling point ( T n.b. = 460.74 K), ehthalpies of vaporization (at various temperatures), and critical parameters of PMCP were calculated. The calculated and experimental values of Δvap H {m/°}(298.15 K) agree to within measurement errors, which proves the reliability of these values and pT parameters used in calculations.

Stereoselectivity of the demethylation of nicotine piperidine homologues by Nicotiana plumbaginifolia cell suspension cultures.

PubMed

Bartholomeusz, Trixie Ann; Molinié, Roland; Roscher, Albrecht; Felpin, François-Xavier; Gillet, Françoise; Lebreton, Jacques; Mesnard, François; Robins, Richard J

2005-08-01

The metabolism of (R,S)-N-methylanabasine and (R,S)-N-methylanatabine has been studied in a cell suspension culture of Nicotiana plumbaginifolia. Both substrates are effectively demethylated, anabasine or anatabine, respectively, accumulating in the medium. Similarly, there is strong stereoselectivity for the (R)-isomers of both substrates. The kinetics of metabolism of (R,S)-N-methylanabasine differ significantly from those of nicotine in that no further degradation of the initial demethylation product occurs. (R,S)-N-Methylanatabine, however, shows kinetics closer to those of nicotine, with loss of alkaloid from the system. Further more, (R,S)-N-methylanabasine does not diminish (S)-nicotine demethylation, indicating a lack of competition. However, the metabolism of (S)-nicotine is affected by the presence of (R,S)-N-methylanabasine. Hence, the demethylation of the piperidine homologues of nicotine is seen to be similar but not identical to that of the pyridine analogues. The implications of these different metabolic profiles in relation to the demethylation activity are discussed.

Identification and quantification of phencyclidine pyrolysis products formed during smoking

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lue, L.P.; Scimeca, J.A.; Thomas, B.F.

As a result of frequent phencyclidine (PCP) abuse, pyrolysis studies were conducted to further investigate its fate during smoking. Marijuana placebo cigarettes were impregnated with /sup 3/H-PCP HCl and burned under conditions simulating smoking. Mainstream smoke was passed through glass wool filters as well as acidic and basic traps. Approximately 90% of the starting material could be accounted for in the first glass wool trap and cigarette holder. HPLC and GC/MS analysis of methanol extracts of these glass wool traps revealed the presence of 1-phenyl-1-cyclohexene (47% of the starting material) > PCP (40%) > piperidine (15%) > N-acetylpiperidine (9%). Itmore » was not possible to fully account for the remainder of the piperidine moiety. It has been reported that at high temperatures PCP is converted to numerous polynuclear aromatic compounds which include styrene, ..cap alpha..-methylstyrene, naphthalene, 2-methyl-naphthalene, 1-methylnaphthalene, biphenyl, cyclohexylbenzene, acenaphthene, phenanthrene, and anthracene. These compounds were not formed from PCP under smoking conditions.« less

Dimethyl 4-[3-(4-meth­oxy­phen­yl)-1-phenyl-1H-pyrazol-4-yl]-2,6-dimethyl-1,4-dihydro­pyridine-3,5-dicarboxyl­ate dihydrate

PubMed Central

Fun, Hoong-Kun; Ooi, Chin Wei; Garudachari, B.; Shivananda, Kammasandra Nanjunda; Isloor, Arun M.

2012-01-01

In the title compound, C27H27N3O5·2H2O, the dihydro­pyridine ring adopts a flattened boat conformation. The central pyrazole ring is essentially planar [maximum deviation of 0.003 (1) Å] and makes dihedral angles of 50.42 (6) and 26.44 (6)° with the benzene rings. In the crystal, mol­ecules are linked via N—H⋯O, O—H⋯O, O—H⋯N and C—H⋯O hydrogen bonds into two-dimensional networks parallel to the bc plane. The crystal structure is further consolidated by weak C—H⋯π inter­actions. PMID:22798871

Crystal structure of 2-(1,3-dioxoindan-2-yl)iso-quinoline-1,3,4-trione.

PubMed

Ghalib, Raza Murad; Chidan Kumar, C S; Hashim, Rokiah; Sulaiman, Othman; Fun, Hoong-Kun

2015-01-01

In the title iso-quinoline-1,3,4-trione derivative, C18H9NO5, the five-membered ring of the indane fragment adopts an envelope conformation with the nitro-gen-substituted C atom being the flap. The planes of the indane benzene ring and the iso-quinoline-1,3,4-trione ring make a dihedral angle of 82.06 (6)°. In the crystal, mol-ecules are linked into chains extending along the bc plane via C-H⋯O hydrogen-bonding inter-actions, enclosing R 2 (2)(8) and R 2 (2)(10) loops. The chains are further connected by π-π stacking inter-ations, with centroid-to-centroid distances of 3.9050 (7) Å, forming layers parallel to the b axis.

Classification of ring artifacts for their effective removal using type adaptive correction schemes.

PubMed

Anas, Emran Mohammad Abu; Lee, Soo Yeol; Hasan, Kamrul

2011-06-01

High resolution tomographic images acquired with a digital X-ray detector are often degraded by the so called ring artifacts. In this paper, a detail analysis including the classification, detection and correction of these ring artifacts is presented. At first, a novel idea for classifying rings into two categories, namely type I and type II rings, is proposed based on their statistical characteristics. The defective detector elements and the dusty scintillator screens result in type I ring and the mis-calibrated detector elements lead to type II ring. Unlike conventional approaches, we emphasize here on the separate detection and correction schemes for each type of rings for their effective removal. For the detection of type I ring, the histogram of the responses of the detector elements is used and a modified fast image inpainting algorithm is adopted to correct the responses of the defective pixels. On the other hand, to detect the type II ring, first a simple filtering scheme is presented based on the fast Fourier transform (FFT) to smooth the sum curve derived form the type I ring corrected projection data. The difference between the sum curve and its smoothed version is then used to detect their positions. Then, to remove the constant bias suffered by the responses of the mis-calibrated detector elements with view angle, an estimated dc shift is subtracted from them. The performance of the proposed algorithm is evaluated using real micro-CT images and is compared with three recently reported algorithms. Simulation results demonstrate superior performance of the proposed technique as compared to the techniques reported in the literature. Copyright © 2011 Elsevier Ltd. All rights reserved.

Self-gravity and dissipation in polar rings

NASA Technical Reports Server (NTRS)

Dubinski, John; Christodoulou, Dimitris M.

1994-01-01

Studies of inclined rings inside galaxy potentials have mostly considered the influence of self-gravity and viscous dissipation separately. In this study, we construct models of highly inclined ('polar') rings in an external potential including both self-gravity and dissipation due to a drag force. We do not include pressure forces and thus ignore shock heating that dominates the evolution of gaseous rings inside strongly nonspherical potentials. We adopt an oblate spheroidal scale-free logarithmic potential with axis ratio q = 0.85 and an initial inclination of 80 deg for the self-gravitating rings. We find that stellar (dissipationless) rings suffer from mass loss during their evolution. Mass loss also drives a secular change of the mean inclination toward the poles of the potential. As much as half of the ring mass escapes in the process and forms an inner and an outer shell of precessing orbits. If the remaining mass is more than approximately 0.02 of the enclosed galaxy mass, rings remain bound and do not fall apart from differential precession. The rings precess at a constant rate for more than a precession period tau(sub p) finding the configuration predicted by Sparke in 1986 which warps at larger radii toward the poles of the potential. We model shear viscosity with a velocity-dependent drag force and find that nuclear inflow dominates over self-gravity if the characteristic viscous inflow time scale tau(sub vi) is shorter than approximately 25(tau(sub p)). Rings with (tau(sub vi))/(tau(sub p)) less than or approximately equal to 25 collapse toward the nucleus of the potential within one precession period independent of the amount of self-gravity. Our results imply that stars and gas in real polar rings exhibit markedly different dynamical evolutions.

Design, synthesis and antibacterial evaluation of honokiol derivatives.

PubMed

Wu, Bo; Fu, Su-Hong; Tang, Huan; Chen, Kai; Zhang, Qiang; Peng, Ai-Hua; Ye, Hao-Yu; Cheng, Xing-Jun; Lian, Mao; Wang, Zhen-Ling; Chen, Li-Juan

2018-02-15

Staphylococcus aureus is a major and dangerous human pathogen that causes a range of clinical manifestations of varying severity, and is the most commonly isolated pathogen in the setting of skin and soft tissue infections, pneumonia, suppurative arthritis, endovascular infections, foreign-body associated infections, septicemia, osteomyelitis, and toxic shocksyndrome. Honokiol, a pharmacologically active natural compound derived from the bark of Magnolia officinalis, has antibacterial activity against Staphylococcus aureus which provides a great inspiration for the discovery of potential antibacterial agents. Herein, honokiol derivatives were designed, synthesized and evaluated for their antibacterial activity by determining the minimum inhibitory concentration (MIC) against S. aureus ATCC25923 and Escherichia coli ATCC25922 in vitro. 7c exhibited better antibacterial activity than other derivatives and honokiol. The structure-activity relationships indicated piperidine ring with amino group is helpful to improve antibacterial activity. Further more, 7c showed broad spectrum antibacterial efficiency against various bacterial strains including eleven gram-positive and seven gram-negative species. Time-kill kinetics against S. aureus ATCC25923 in vitro revealed that 7c displayed a concentration-dependent effect and more rapid bactericidal kinetics better than linezolid and vancomycin with the same concentration. Gram staining assays of S. aureus ATCC25923 suggested that 7c could destroy the cell walls of bacteria at 1×MIC and 4×MIC. Copyright © 2017. Published by Elsevier Ltd.

Predicting relative binding affinities of non-peptide HIV protease inhibitors with free energy perturbation calculations

NASA Astrophysics Data System (ADS)

McCarrick, Margaret A.; Kollman, Peter A.

1999-03-01

The relative binding free energies in HIV protease of haloperidol thioketal (THK) and three of its derivatives were examined with free energy calculations. THK is a weak inhibitor (IC50 = 15 μM) for which two cocrystal structures with HIV type 1 proteases have been solved [Rutenber, E. et al., J. Biol. Chem., 268 (1993) 15343]. A THK derivative with a phenyl group on C2 of the piperidine ring was expected to be a poor inhibitor based on experiments with haloperidol ketal and its 2- phenyl derivative (Caldera, P., personal communication). Our calculations predict that a 5-phenyl THK derivative, suggested based on examination of the crystal structure, will bind significantly better than THK. Although there are large error bars as estimated from hysteresis, the calculations predict that the 5-phenyl substituent is clearly favored over the 2-phenyl derivative as well as the parent compound. The unfavorable free energies of solvation of both phenyl THK derivatives relative to the parent compound contributed to their predicted binding free energies. In a third simulation, the change in binding free energy for 5-benzyl THK relative to THK was calculated. Although this derivative has a lower free energy in the protein, its decreased free energy of solvation increases the predicted ΔΔG(bind) to the same range as that of the 2-phenyl derivative.

Aminopiperidine-Fused Imidazoles as Dipeptidyl Peptidase-IV Inhibitors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Edmondson, S.; Mastracchio, A; Cox, J

2009-01-01

A new series of DPP-4 inhibitors derived from piperidine-fused benzimidazoles and imidazopyridines is described. Optimization of this class of DPP-4 inhibitors led to the discovery of imidazopyridine 34. The potency, selectivity, cross-species DMPK profiles, and in vivo efficacy of 34 is reported.

N-(2-{[5-Bromo-2-(morpholin-4-yl)pyrimidin-4-yl]sulfan­yl}-4-meth­oxy­phen­yl)-4-chloro­benzene­sulfonamide

PubMed Central

Kumar, Mohan; Mallesha, L.; Sridhar, M. A.; Kapoor, Kamini; Gupta, Vivek K.; Kant, Rajni

2012-01-01

In the title compound, C21H20BrClN4O4S2, the benzene rings bridged by the sulfonamide group are tilted relative to each other by a dihedral angle of 70.2 (1)° and the dihedral angle between the sulfur-bridged pyrimidine and benzene rings is 69.5 (1)°. The mol­ecular conformation is stabilized by a weak intra­molecular π–π stacking inter­action between the pyrimidine and the 4-chloro­benzene rings [centroid–centroid distance = 3.978 (2) Å]. The morpholine ring adopts a chair conformation. In the crystal, mol­ecules are linked into inversion dimers by pairs of C—H⋯N hydrogen bonds and these dimers are further connected by N—H⋯O hydrogen bonds, forming a tape along the a axis. PMID:22969673

Redetermined structure, inter-molecular inter-actions and absolute configuration of royleanone.

PubMed

Fun, Hoong-Kun; Chantrapromma, Suchada; Salae, Abdul Wahab; Razak, Ibrahim Abdul; Karalai, Chatchanok

2011-05-01

The structure of the title diterpenoid, C(20)H(28)O(3), {systematic name: (4bS,8aS)-3-hy-droxy-2-isopropyl-4b,8,8-trimethyl-4b,5,6,7,8,8a,9,10-octa-hydro-phenanthrene-1,4-dione} is confirmed [Eugster et al. (1993 ▶). Private communication (refcode HACGUN). CCDC, Union Road, Cambridge] and its packing is now described. Its absolute structure was established by refinement against data collected with Cu radiation: the two stereogenic centres both have S configurations. One cyclo-hexane ring adopts a chair conformation whereas the other cyclo-hexane ring is in a half-chair conformation and the benzoquinone ring is slightly twisted. An intra-molecular O-H⋯O hydrogen bond generates an S(5) ring motif. In the crystal, mol-ecules are linked into chains along [010] by O-H⋯O hydrogen bonds and weak C-H⋯O inter-actions. The packing also features C⋯O [3.131 (3) Å] short contacts.

CN rings in full protoplanetary disks around young stars as probes of disk structure

NASA Astrophysics Data System (ADS)

Cazzoletti, P.; van Dishoeck, E. F.; Visser, R.; Facchini, S.; Bruderer, S.

2018-01-01

Aims: Bright ring-like structure emission of the CN molecule has been observed in protoplanetary disks. We investigate whether such structures are due to the morphology of the disk itself or if they are instead an intrinsic feature of CN emission. With the intention of using CN as a diagnostic, we also address to which physical and chemical parameters CN is most sensitive. Methods: A set of disk models were run for different stellar spectra, masses, and physical structures via the 2D thermochemical code DALI. An updated chemical network that accounts for the most relevant CN reactions was adopted. Results: Ring-shaped emission is found to be a common feature of all adopted models; the highest abundance is found in the upper outer regions of the disk, and the column density peaks at 30-100 AU for T Tauri stars with standard accretion rates. Higher mass disks generally show brighter CN. Higher UV fields, such as those appropriate for T Tauri stars with high accretion rates or for Herbig Ae stars or for higher disk flaring, generally result in brighter and larger rings. These trends are due to the main formation paths of CN, which all start with vibrationally excited H_2^* molecules, that are produced through far ultraviolet (FUV) pumping of H2. The model results compare well with observed disk-integrated CN fluxes and the observed location of the CN ring for the TW Hya disk. Conclusions: CN rings are produced naturally in protoplanetary disks and do not require a specific underlying disk structure such as a dust cavity or gap. The strong link between FUV flux and CN emission can provide critical information regarding the vertical structure of the disk and the distribution of dust grains which affects the UV penetration, and could help to break some degeneracies in the SED fitting. In contrast with C2H or c-C3H2, the CN flux is not very sensitive to carbon and oxygen depletion.

Pure moment testing for spinal biomechanics applications: Fixed versus sliding ring cable-driven test designs.

PubMed

Eguizabal, Johnny; Tufaga, Michael; Scheer, Justin K; Ames, Christopher; Lotz, Jeffrey C; Buckley, Jenni M

2010-05-07

In vitro multi-axial bending testing using pure moment loading conditions has become the standard in evaluating the effects of different types of surgical intervention on spinal kinematics. Simple, cable-driven experimental set-ups have been widely adopted because they require little infrastructure. Traditionally, "fixed ring" cable-driven experimental designs have been used; however, there have been concerns with the validity of this set-up in applying pure moment loading. This study involved directly comparing the loading state induced by a traditional "fixed ring" apparatus versus a novel "sliding ring" approach. Flexion-extension bending was performed on an artificial spine model and a single cadaveric test specimen, and the applied loading conditions to the specimen were measured with an in-line multiaxial load cell. The results showed that the fixed ring system applies flexion-extension moments that are 50-60% less than the intended values. This design also imposes non-trivial anterior-posterior shear forces, and non-uniform loading conditions were induced along the length of the specimen. The results of this study indicate that fixed ring systems have the potential to deviate from a pure moment loading state and that our novel sliding ring modification corrects this error in the original test design. This suggests that the proposed sliding ring design should be used for future in vitro spine biomechanics studies involving a cable-driven pure moment apparatus. Copyright 2010 Elsevier Ltd. All rights reserved.

Heating and scattering of ring-beam distributions by turbulence

NASA Technical Reports Server (NTRS)

Gray, P. C.; Pontius, D. H., Jr.; Matthaeus, W. H.

1995-01-01

Pickup ions in the solar wind are initially are born in ring-beam distributions, i.e. f(v) varies as delta(v(sub perpendicular) - V(sub sw)sin(Theta)) delta(v(sub parallel) - V(sub sw)cos(Theta)), where Theta is the angle between the solar wind velocity and the IMF(Interplanetary Magnetic Field), and V(sub sw) is the solar wind speed. Often the distribution has been presumed to relax to a distribution that is isotropic in Theta and essentially mono-energetic, a shell or a 'bi-spherical distribution.' However solar wind turbulence is capable of heating the ring distribution on the timescale of a few tens of gyroperiods, a timescale not greatly distinct from that required for pitch angle scattering to a shell. To describe this effect, we have performed test-particle studies of the heating/scattering of the ring beam distribution by MHD turbulence, adopting various models for the MHD fluctuations, including slab and fully dynamic 2D and 3D incompressible turbulence. Furthermore, a system composed of a cold ion ring and a background plasma is unstable to several kinetic plasma instabilities. We carried out kinetic simulations of the ring beam distribution, showing that plasma instabilities also rapidly energize and scatter particles. Results will be presented comparing relaxation and heating rates of the ring-beam distribution by the various mechanisms.

First principles calculations for interaction of tyrosine with (ZnO)3 cluster

NASA Astrophysics Data System (ADS)

Singh, Satvinder; Singh, Gurinder; Kaura, Aman; Tripathi, S. K.

2018-04-01

First Principles Calculations have been performed to study interactions of Phenol ring of Tyrosine (C6H5OH) with (ZnO)3 atomic cluster. All the calculations have been performed under the Density Functional Theory (DFT) framework. Structural and electronic properties of (ZnO)3/C6H5OH have been studied. Gaussian basis set approach has been adopted for the calculations. A ring type most stable (ZnO)3 atomic cluster has been modeled, analyzed and used for the calculations. The compatibility of the results with previous studies has been presented here.

Arctigenin: a lignan from Arctium lappa.

PubMed

Gao, Haiyan; Li, Guanglei; Zhang, Junhe; Zeng, Jie

2008-07-19

The title compound {systematic name: (3R-trans)-4-[(3,4-dimethoxy-phen-yl)meth-yl]-3-[(4-hydr-oxy-3-methoxy-phen-yl)meth-yl]-4,5-dihydrofuran-2(3H)-one}, C(21)H(24)O(6), has a dibenz-yl-butyrolactone skeleton. The two aromatic rings are inclined at a dihedral angle of 68.75 (7)° with respect to each other. The lactone ring adopts an envelope conformation. A series of O-H⋯O and C-H⋯O hydrogen bonds contribute to the stabilization of the crystal packing. The absolute configuration was assigned on the basis of the published literature.

Acceptability and use of a dapivirine vaginal ring in a phase III trial

PubMed Central

Montgomery, Elizabeth T.; van der Straten, Ariane; Chitukuta, Miria; Reddy, Krishnaveni; Woeber, Kubashni; Atujuna, Millicent; Bekker, Linda-Gail; Etima, Juliane; Nakyanzi, Teopista; Mayo, Ashley J.; Katz, Ariana; Laborde, Nicole; Grossman, Cynthia I.; Soto-Torres, Lydia; Palanee-Phillips, Thesla; Baeten, Jared M.

2017-01-01

Background The MTN-020/ASPIRE trial evaluated the safety and effectiveness of the dapivirine vaginal ring for prevention of HIV-1 infection among African women. A nested qualitative component was conducted at six of 15 study sites in Uganda, Malawi, Zimbabwe and South Africa to evaluate acceptability of and adherence to the ring. Method Qualitative study participants (n = 214) were interviewed with one of three modalities: single in-depth interview, up to three serial interviews or an exit Focus Group Discussion. Using semistructured guides administered in local languages, 280 interviews were audio-recorded, transcribed, translated, coded and analyzed. Results We identified three key findings: first, despite initial fears about the ring's appearance and potential side effects, participants grew to like it and developed a sense of ownership of the ring once they had used it. Second, uptake and sustained adherence challenges were generally overcome with staff and peer support. Participants developed gradual familiarity with ring use through trial progression, and most reported that it was easy to use and integrate into their lives. Using the ring in ASPIRE was akin to joining a team and contributing to a broader, communal good. Third, the actual or perceived dynamics of participants' male partner relationship(s) were the most consistently described influence (which ranged from positive to negative) on participants' acceptability and use of the ring. Conclusion It is critical that demonstration projects address challenges during the early adoption stages of ring diffusion to help achieve its potential public health impact as an effective, long-acting, female-initiated HIV prevention option addressing women's disproportionate HIV burden. PMID:28441175

Acceptability and use of a dapivirine vaginal ring in a phase III trial.

PubMed

Montgomery, Elizabeth T; van der Straten, Ariane; Chitukuta, Miria; Reddy, Krishnaveni; Woeber, Kubashni; Atujuna, Millicent; Bekker, Linda-Gail; Etima, Juliane; Nakyanzi, Teopista; Mayo, Ashley J; Katz, Ariana; Laborde, Nicole; Grossman, Cynthia I; Soto-Torres, Lydia; Palanee-Phillips, Thesla; Baeten, Jared M

2017-05-15

The MTN-020/ASPIRE trial evaluated the safety and effectiveness of the dapivirine vaginal ring for prevention of HIV-1 infection among African women. A nested qualitative component was conducted at six of 15 study sites in Uganda, Malawi, Zimbabwe and South Africa to evaluate acceptability of and adherence to the ring. Qualitative study participants (n = 214) were interviewed with one of three modalities: single in-depth interview, up to three serial interviews or an exit Focus Group Discussion. Using semistructured guides administered in local languages, 280 interviews were audio-recorded, transcribed, translated, coded and analyzed. We identified three key findings: first, despite initial fears about the ring's appearance and potential side effects, participants grew to like it and developed a sense of ownership of the ring once they had used it. Second, uptake and sustained adherence challenges were generally overcome with staff and peer support. Participants developed gradual familiarity with ring use through trial progression, and most reported that it was easy to use and integrate into their lives. Using the ring in ASPIRE was akin to joining a team and contributing to a broader, communal good. Third, the actual or perceived dynamics of participants' male partner relationship(s) were the most consistently described influence (which ranged from positive to negative) on participants' acceptability and use of the ring. It is critical that demonstration projects address challenges during the early adoption stages of ring diffusion to help achieve its potential public health impact as an effective, long-acting, female-initiated HIV prevention option addressing women's disproportionate HIV burden.

Complete inhibition of fetal movement in the day 40 pregnant goat model by the piperidine alkaloid anabasine but not related alkaloids

USDA-ARS?s Scientific Manuscript database

Four chemically similar alkaloids, anabasine, anabaseine, epibatidine and dimethylphenylpiperazinium (DMPP), are potent nicotinic acetylcholine receptor agonists of fetal muscle nicotinic acetylcholine receptors in human TE-671 cells. Based on results with these cells, we hypothesized that these alk...

Plant alkaloids that cause developmental defects through the disruption of cholinergic neurotransmission

USDA-ARS?s Scientific Manuscript database

The exposure of a developing embryo or fetus to alkaloids from plants, plant products, or plant extracts has the potential to cause developmental defects in humans and animals. These defects may have multiple causes but those induced by piperidine and quinolizidine alkaloids arise from the inhibiti...

Alkaloid profiling as an approach to differentiate Lupinus garfieldensis, Lupinus sabinianus, and Lupinus sericeus

USDA-ARS?s Scientific Manuscript database

Introduction – Many species in the Lupinus genus are poorly defined resulting in improper taxonomic identification. Lupine species may contain quinolizidine and/or piperidine alkaloids that can be acutely toxic and/or teratogenic resulting in crooked calf disease. Objective – To identify any char...

Piperidine, pyridine alkaloid inhibition of fetal movement in a day 40 pregnant goat model

USDA-ARS?s Scientific Manuscript database

The inhibition of fetal movement is one mechanism behind the development of multiple congenital contracture-type defects and cleft palate in developing fetuses of humans and animals. In this study, we tested the alkaloids anabasine, lobeline, and myosmine for agonist actions, and sensitivity to alp...

21 CFR 1310.04 - Maintenance of records.

Code of Federal Regulations, 2013 CFR

2013-04-01

... kilogram. 8675 Ergonovine and its salts 10 grams. 8676 Ergotamine and its salts 20 grams. 8678 Ethylamine.... 8791 Phenylacetic acid, its esters, and its salts 1 kilogram. 2704 Piperidine and its salts 500 grams. 8750 Piperonal (also called heliotropine) 4 kilograms. 8328 Propionic anhydride 1 gram. 8323 Safrole 4...

21 CFR 1310.04 - Maintenance of records.

Code of Federal Regulations, 2012 CFR

2012-04-01

... kilogram. 8675 Ergonovine and its salts 10 grams. 8676 Ergotamine and its salts 20 grams. 8678 Ethylamine.... 8791 Phenylacetic acid, its esters, and its salts 1 kilogram. 2704 Piperidine and its salts 500 grams. 8750 Piperonal (also called heliotropine) 4 kilograms. 8328 Propionic anhydride 1 gram. 8323 Safrole 4...

21 CFR 1310.04 - Maintenance of records.

Code of Federal Regulations, 2011 CFR

2011-04-01

... kilogram. 8675 Ergonovine and its salts 10 grams. 8676 Ergotamine and its salts 20 grams. 8678 Ethylamine.... 8791 Phenylacetic acid, its esters, and its salts 1 kilogram. 2704 Piperidine and its salts 500 grams. 8750 Piperonal (also called heliotropine) 4 kilograms. 8328 Propionic anhydride 1 gram. 8323 Safrole 4...

21 CFR 1310.04 - Maintenance of records.

Code of Federal Regulations, 2014 CFR

2014-04-01

... kilogram. 8675 Ergonovine and its salts 10 grams. 8676 Ergotamine and its salts 20 grams. 8678 Ethylamine.... 8791 Phenylacetic acid, its esters, and its salts 1 kilogram. 2704 Piperidine and its salts 500 grams. 8750 Piperonal (also called heliotropine) 4 kilograms. 8328 Propionic anhydride 1 gram. 8323 Safrole 4...

Synthesis of densely substituted trans-configured 4-acylated piperidine-2,4-diones as 3:1 adducts of imines and ketenes.

PubMed

Cabrera, José; Hellmuth, Tina; Peters, René

2010-06-18

An operationally simple method is described to form densely substituted diastereomerically pure trans-configured and potentially biologically interesting 5,6-dihydropyridone derivatives as 3:1 adducts of ketenes formed in situ from acyl bromides and aromatic imines.

(S)-N-{1-[5-(4-Chloro-benzyl-sulfanyl)-1,3,4-oxadiazol-2-yl]eth-yl}-4-methyl-benzene-sulfonamide.

PubMed

Syed, Tayyaba; Hameed, Shahid; Jones, Peter G

2011-10-01

The title compound, C(18)H(18)ClN(3)O(3)S(2), adopts by folding the form of a distorted disc. Inter-planar angles are 29.51 (7) and 63.43 (7)° from the five-membered ring to the aromatic systems and 34.80 (6)° between these two latter rings. The absolute configuration was confirmed by determination of the Flack parameter. In the crystal, the mol-ecules are linked by four hydrogen bonds, one classical (N-H⋯N) and three 'weak' (C-H⋯O), forming layers parallel to the ac plane; these are in turn linked in the third dimension by Cl⋯N [3.1689 (16) Å] and Cl⋯O [3.3148 (13) Å] contacts to the heterocyclic ring.

Radio and optical observations of 0218+357 - The smallest Einstein ring?

NASA Technical Reports Server (NTRS)

O'Dea, Christopher P.; Baum, Stefi A.; Stanghellini, Carlo; Dey, Arjun; Van Breugel, Wil; Deustua, Susana; Smith, Eric P.

1992-01-01

VLA radio observations and optical imaging and spectroscopy of the Einstein radio ring 0218+357 are presented. The ring is detected at 22.4 GHz and shows a basically similar structure at 5, 15, and 22.4 GHz. The B component has varied and was about 15 percent brighter in the 8.4 GHz data than in the data of Patnaik et al. (1992). The ring is highly polarized. A weak jetlike feature extending out roughly 2 arcsec to the southeast of component A is detected at 6 cm. The source has amorphous radio structure extending out to about 11 arcsec from the core. For an adopted redshift of 0.68, the extended radio emission is very powerful. The optical spectrum is rather red and shows no strong features. A redshift of about 0.68 is obtained. The identification is a faint compact m(r) about 20 galaxy which extends to about 4.5 arcsec (about 27 kpc). As much as 50 percent of the total light may be due to a central AGN. The observed double core and ring may be produced by an off-center radio core with extended radio structure.

Structure of a Glomulin-RBX1-CUL1 complex: inhibition of a RING E3 ligase through masking of its E2-binding surface

PubMed Central

Duda, David M.; Olszewski, Jennifer L.; Tron, Adriana E.; Hammel, Michal; Lambert, Lester J.; Waddell, M. Brett; Mittag, Tanja; DeCaprio, James A.; Schulman, Brenda A.

2012-01-01

Summary The ~300 human Cullin-RING ligases (CRLs) are multisubunit E3s in which a RING protein, either RBX1 or RBX2, recruits an E2 to catalyze ubiquitination. RBX1-containing CRLs also can bind Glomulin (GLMN), which binds RBX1’s RING domain, regulates the RBX1-CUL1-containing SCFFBW7 complex, and is disrupted in the disease Glomuvenous Malformation. Here we report the crystal structure of a complex between GLMN, RBX1, and a fragment of CUL1. Structural and biochemical analyses reveal that GLMN adopts a HEAT-like repeat fold that tightly binds the E2-interacting surface of RBX1, inhibiting CRL-mediated chain formation by the E2 CDC34. The structure explains the basis for GLMN’s selectivity toward RBX1 over RBX2, and how disease-associated mutations disrupt GLMN-RBX1 interactions. Our study reveals a mechanism for RING E3 ligase regulation whereby an inhibitor blocks E2 access, and raises the possibility that other E3s are likewise controlled by cellular proteins that mask E2-binding surfaces to mediate inhibition. PMID:22748924

Structure of the 26S proteasome with ATP-γS bound provides insights into the mechanism of nucleotide-dependent substrate translocation

PubMed Central

Śledź, Paweł; Unverdorben, Pia; Beck, Florian; Pfeifer, Günter; Schweitzer, Andreas; Förster, Friedrich; Baumeister, Wolfgang

2013-01-01

The 26S proteasome is a 2.5-MDa, ATP-dependent multisubunit proteolytic complex that processively destroys proteins carrying a degradation signal. The proteasomal ATPase heterohexamer is a key module of the 19S regulatory particle; it unfolds substrates and translocates them into the 20S core particle where degradation takes place. We used cryoelectron microscopy single-particle analysis to obtain insights into the structural changes of 26S proteasome upon the binding and hydrolysis of ATP. The ATPase ring adopts at least two distinct helical staircase conformations dependent on the nucleotide state. The transition from the conformation observed in the presence of ATP to the predominant conformation in the presence of ATP-γS induces a sliding motion of the ATPase ring over the 20S core particle ring leading to an alignment of the translocation channels of the ATPase and the core particle gate, a conformational state likely to facilitate substrate translocation. Two types of intersubunit modules formed by the large ATPase domain of one ATPase subunit and the small ATPase domain of its neighbor exist. They resemble the contacts observed in the crystal structures of ClpX and proteasome-activating nucleotidase, respectively. The ClpX-like contacts are positioned consecutively and give rise to helical shape in the hexamer, whereas the proteasome-activating nucleotidase-like contact is required to close the ring. Conformational switching between these forms allows adopting different helical conformations in different nucleotide states. We postulate that ATP hydrolysis by the regulatory particle ATPase (Rpt) 5 subunit initiates a cascade of conformational changes, leading to pulling of the substrate, which is primarily executed by Rpt1, Rpt2, and Rpt6. PMID:23589842

Excitonic energy transfer in light-harvesting complexes in purple bacteria

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ye Jun; Sun Kewei; Zhao Yang

Two distinct approaches, the Frenkel-Dirac time-dependent variation and the Haken-Strobl model, are adopted to study energy transfer dynamics in single-ring and double-ring light-harvesting (LH) systems in purple bacteria. It is found that the inclusion of long-range dipolar interactions in the two methods results in significant increase in intra- or inter-ring exciton transfer efficiency. The dependence of exciton transfer efficiency on trapping positions on single rings of LH2 (B850) and LH1 is similar to that in toy models with nearest-neighbor coupling only. However, owing to the symmetry breaking caused by the dimerization of BChls and dipolar couplings, such dependence has beenmore » largely suppressed. In the studies of coupled-ring systems, both methods reveal an interesting role of dipolar interactions in increasing energy transfer efficiency by introducing multiple intra/inter-ring transfer paths. Importantly, the time scale (4 ps) of inter-ring exciton transfer obtained from polaron dynamics is in good agreement with previous studies. In a double-ring LH2 system, non-nearest neighbor interactions can induce symmetry breaking, which leads to global and local minima of the average trapping time in the presence of a non-zero dephasing rate, suggesting that environment dephasing helps preserve quantum coherent energy transfer when the perfect circular symmetry in the hypothetic system is broken. This study reveals that dipolar coupling between chromophores may play an important role in the high energy transfer efficiency in the LH systems of purple bacteria and many other natural photosynthetic systems.« less

Attitudes Towards the Vaginal Ring and Transdermal Patch Among Adolescents and Young Women

PubMed Central

Raine, Tina R.; Epstein, Laura B.; Harper, Cynthia C.; Brown, Beth A.; Boyer, Cherrie B.

2009-01-01

Purpose The vaginal ring and the transdermal patch offer important contraceptive options for women at high risk of unintended pregnancy. Little is known about what adolescents and young women think about these methods and why use of the ring has been relatively low compared to the patch. We sought to examine young women’s attitudes and perceptions about the ring and the patch to better understand the relationship between perceptions of these methods and decisions to use them. Methods Sixteen focus groups of young women aged 15–26 years (n=113) from family planning clinics in the San Francisco Bay Area were convened. Data from the focus groups were analyzed using standard content analysis. Results While young women expressed apprehension and doubt about both methods, for the most part women expressed more positive attitudes about the patch. Two related themes for the ring and the patch were identified: “lack of trust in effectiveness,” and “method use concerns. Two themes unique to the ring: “concerns regarding vaginal insertion” and “sexual partner perceptions” and three themes unique to the patch: “ease of remembering”, “visibility issues”, and “perceived health risk” were identified. Conclusions Increased provider education about apprehensions related to the ring and the patch may lead to increased use of the ring and counter recent declines in use of the patch. It would be unfortunate if these safe and effective options for young women are underutilized because negative attitudes and perceptions about these methods act as barriers to adoption. PMID:19699422

76 FR 35241 - Importer of Controlled Substances; Notice of Application

Federal Register 2010, 2011, 2012, 2013, 2014

2011-06-16

...-Piperidine (8333).. II Phenylacetone (8501) II Raw Opium (9600) II Concentrate of Poppy Straw (9670) II The... Technologies, 72 FR 3417 (2007), comments and requests for hearings on applications to import narcotic raw material are not appropriate. Any bulk manufacturer who is presently, or is applying to be, registered with...

Anagyrine desensitization of peripheral nicotinic acetylcholine receptors. A potential biomarker of quinolizidine alkaloid teratogenesis in cattle.

USDA-ARS?s Scientific Manuscript database

Anagyrine, a teratogenic quinolizidine alkaloid found in certain Lupinus spp., has been proposed to undergo metabolism by pregnant cattle to a piperidine alkaloid which acts inhibit fetal movement, the putative mechanism behind crooked calf syndrome. The objective of this study was to test the hypot...

The non-competitive blockade of GABAA receptors by an aqueous extract of water hemlock (Cicuta douglassi) tubers

USDA-ARS?s Scientific Manuscript database

Teratogenic alkaloids can cause developmental defects due to the inhibition of fetal movement from the desensitization of fetal muscle-type nicotinic acetylcholine receptors (nAChR). In this study, we tested the hypothesis that the piperidine alkaloid anabaseine a 1,2-dehydropiperidine and anabasin...

A novel three-component reaction for the synthesis of 1,3-benzoxazines in water.

PubMed

Rostami-Charati, Faramarz

2013-12-01

A simple and proficient method for the synthesis of 1,3-benzoxazine derivatives via three-component reaction of isocyanide and isoquinoline with 1-(6-hydroxy-2-isopropenyl-1-benzofuran-yl)-1-ethanone or 4-hydroxycumarine in water in the presence of piperidine at 70°C is reported.

Synthesis, characterization, stereochemistry and biological investigation of certain N-dichloroacetyl-bis(2-chlorophenyl)piperidin-4-ones

NASA Astrophysics Data System (ADS)

Kayalvizhi, R.; Ponnuswamy, S.; Gomathi, K.; Ezhilarasi, K. S.; Usha, G.

2018-02-01

A new series of N-dichloroacetyl-bis(2-chlorophenyl)piperidin-4-ones 4-6 has been synthesized and characterized using IR, 1H, 13C, DEPT and 2D (COSY and HSQC) NMR spectral techniques. The NMR spectral data indicate that the N-acylpiperidin-4-ones 4-6 prefer to exist in an equilibrium between the twist boat conformations with coplanar orientation of Nsbnd Cdbnd O moiety. Furthermore, the antibacterial and antifungal studies have been carried out for compounds 1-6 and the results show that they possess significant activity towards the bacterial organisms Staphylococcus aureus and Salmoneela paratyphi and better activity against the remaining bacterial organisms. All the compounds 1-6 possess moderate antifungal activity. The compounds 4-6 have been docked with the structure of MRSA and the results demonstrate that the compounds 4-6 have similar docking score and glide energy when compared to each other and thus having equal binding affinity. The antioxidant studies show greater activity for compound 4 and poor activity for compounds 5 &6 when compared to the standard drug.

N-(3,4-Dimethyl-phen-yl)-4-hydr-oxy-2-methyl-2H-1,2-benzothia-zine-3-carboxamide 1,1-dioxide.

PubMed

Siddiqui, Waseeq Ahmad; Ali, Muhammad; Zia-Ur-Rehman, Muhammad; Sharif, Saima; Tizzard, Graham John

2009-03-28

1,2-Benzothia-zines similar to the title compound, C(18)H(18)N(2)O(4)S, are well known in the literature for their biological activities and are used as medicines in the treatment of inflammation and rheumatoid arthritis. The thia-zine ring adopts a distorted half-chair conformation. The enolic H atom is involved in an intra-molecular O-H⋯O hydrogen bond, forming a six-membered ring. In the crystal, mol-ecules arrange themselves into centrosymmetric dimers by means of pairs of weak inter-molecular N-H⋯O hydrogen bonds.

Crystal structure of (E)-2-hy-droxy-4'-meth-oxy-aza-stilbene.

PubMed

Chantrapromma, Suchada; Kaewmanee, Narissara; Boonnak, Nawong; Chantrapromma, Kan; Ghabbour, Hazem A; Fun, Hoong-Kun

2015-06-01

The title aza-stilbene derivative, C14H13NO2 {systematic name: (E)-2-[(4-meth-oxy-benzyl-idene)amino]-phenol}, is a product of the condensation reaction between 4-meth-oxy-benzaldehyde and 2-amino-phenol. The mol-ecule adopts an E conformation with respect to the azomethine C=N bond and is almost planar, the dihedral angle between the two substituted benzene rings being 3.29 (4)°. The meth-oxy group is coplanar with the benzene ring to which it is attached, the Cmeth-yl-O-C-C torsion angle being -1.14 (12)°. There is an intra-molecular O-H⋯N hydrogen bond generating an S(5) ring motif. In the crystal, mol-ecules are linked via C-H⋯O hydrogen bonds, forming zigzag chains along [10-1]. The chains are linked via C-H⋯π inter-actions, forming a three-dimensional structure.

Two conformers of 10,11-dihydro-5H-dibenzo[a,d]cycloheptene spiro-linked with homobenzoquinone epoxide.

PubMed

Asahara, Haruyasu; Koizumi, Takuya; Mochizuki, Eiko; Oshima, Takumi

2006-03-01

The crystal structures of the two thermally equilibrated conformational isomers of the epoxide 1',5'-dimethylspiro[10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5,8'-4'-oxatricyclo[5.1.0.0(3,5)]octane]-2',6'-dione, C23H20O3, have been determined by X-ray diffraction. In the tricyclic dione skeleton, the oxirane and cyclopropane rings adopt an anti structure with respect to the conjunct quinone frame. The spiro-linked 10,11-dihydro-5H-dibenzo[a,d]cycloheptene ring of the major isomer has a fairly twisted boat form, folding opposite to the adjoining cyclopropane methyl substituent, whereas the seven-membered ring of the minor isomer has an almost ideal twist-boat form, inversely folding to the side of the relevant methyl group. The conformational structures of these isomers have been compared with those of the corresponding isomers of the unepoxidized homobenzoquinone.

Modified screening interaction potential on dust lattice waves in dusty plasma ring

NASA Astrophysics Data System (ADS)

He, Kerong; Chen, Hui; Liu, Sanqiu

2017-05-01

In the present paper, the modified screening interaction potential was adopted to investigate the dust lattice waves in dusty ring. Firstly, the influence of parameter ε on the modified screening interaction potential was analyzed; and it was found that the parameter ε has a long-range effect on the pairwise interaction between the particles. Secondly, the dispersion relations of longitudinal and transverse waves are obtained, and the effect of long-range action parameter ε, dimensionless lattice parameter α and dimensionless shielding parameter \\tilde{κ } on the dust lattice waves propagation in dusty ring are studied. Some interesting phenomena, such as the coupling of longitudinal and transverse waves, and instabilities of transverse waves are found, which are in good agreement with some previous works. Finally, the transverse wave instabilities and the relevant critical lattice parameter αc are presented and discussed.

N,N′-Dicyclo­hexyl­naphthalene-1,8;4:5-dicarboximide

PubMed Central

Shukla, Deepak; Rajeswaran, Manju

2008-01-01

The title compound, C26H26N2O4, synthesized by the reaction of naphthalene-1,4,5,8-tetra­carboxylic acid anhydride and cyclo­hexyl­amine, exhibits good n-type semiconducting properties. Accordingly, thin-film transistor devices comprising this compound show n-type behavior with high field-effect electron moblity ca 6 cm2/Vs [Shukla, Nelson, Freeman, Rajeswaran, Ahearn, Meyer & Carey(2008 ▶). Chem. Mater. Submitted]. The asymmetric unit comprises one-quarter of the centrosymmetric mol­ecule in which all but two methyl­ene C atoms of the cyclo­hexane ring lie on a mirror plane; the point-group symmetry is 2/m. The naphthalene­diimide unit is strictly planar, and the cyclo­hexane rings adopt chair conformations with the diimide unit in an equatorial position on each ring. PMID:21201718

Modelling dust rings in early-type galaxies through a sequence of radiative transfer simulations and 2D image fitting

NASA Astrophysics Data System (ADS)

Bonfini, P.; González-Martín, O.; Fritz, J.; Bitsakis, T.; Bruzual, G.; Cervantes Sodi, B.

2018-07-01

A large fraction of early-type galaxies (ETGs) hosts prominent dust features, and central dust rings are arguably the most interesting among them. We present here `Lord of the Rings', a new methodology which allows to integrate the extinction by dust rings in a 2D-fittingmodelling of the surface brightness distribution. Our pipeline acts in two steps, first using the surface-fitting software GALFIT to determine the unabsorbed stellar emission, and then adopting the radiative transfer code SKIRT to apply dust extinction. We apply our technique to NGC 4552 and NGC 4494, two nearby ETGs. We show that the extinction by a dust ring can mimic, in a surface brightness profile, a central point source (e.g. an unresolved nuclear stellar cluster or an active galactic nucleus; AGN) superimposed to a `core' (i.e. a central flattening of the stellar light commonly observed in massive ETGs). We discuss how properly accounting for dust features is of paramount importance to derive correct fluxes, especially for low-luminosity AGNs (LLAGNs). We suggest that the geometries of dust features are strictly connected with how relaxed is the gravitational potential, i.e. with the evolutionary stage of the host galaxy. Additionally, we find hints that the dust mass contained in the ring relates to the AGN activity.

Investigation of sliding DNA clamp dynamics by single-molecule fluorescence, mass spectrometry and structure-based modeling

PubMed Central

Gadkari, Varun V; Harvey, Sophie R; Raper, Austin T; Chu, Wen-Ting; Wang, Jin; Wysocki, Vicki H; Suo, Zucai

2018-01-01

Abstract Proliferating cell nuclear antigen (PCNA) is a trimeric ring-shaped clamp protein that encircles DNA and interacts with many proteins involved in DNA replication and repair. Despite extensive structural work to characterize the monomeric, dimeric, and trimeric forms of PCNA alone and in complex with interacting proteins, no structure of PCNA in a ring-open conformation has been published. Here, we use a multidisciplinary approach, including single-molecule Förster resonance energy transfer (smFRET), native ion mobility-mass spectrometry (IM-MS), and structure-based computational modeling, to explore the conformational dynamics of a model PCNA from Sulfolobus solfataricus (Sso), an archaeon. We found that Sso PCNA samples ring-open and ring-closed conformations even in the absence of its clamp loader complex, replication factor C, and transition to the ring-open conformation is modulated by the ionic strength of the solution. The IM-MS results corroborate the smFRET findings suggesting that PCNA dynamics are maintained in the gas phase and further establishing IM-MS as a reliable strategy to investigate macromolecular motions. Our molecular dynamic simulations agree with the experimental data and reveal that ring-open PCNA often adopts an out-of-plane left-hand geometry. Collectively, these results implore future studies to define the roles of PCNA dynamics in DNA loading and other PCNA-mediated interactions. PMID:29529283

Modelling dust rings in early-type galaxies through a sequence of radiative transfer simulations and 2D image fitting

NASA Astrophysics Data System (ADS)

Bonfini, P.; González-Martín, O.; Fritz, J.; Bitsakis, T.; Bruzual, G.; Sodi, B. Cervantes

2018-05-01

A large fraction of early-type galaxies (ETGs) host prominent dust features, and central dust rings are arguably the most interesting among them. We present here `Lord Of The Rings' (LOTR), a new methodology which allows to integrate the extinction by dust rings in a 2D fitting modelling of the surface brightness distribution. Our pipeline acts in two steps, first using the surface fitting software GALFIT to determine the unabsorbed stellar emission, and then adopting the radiative transfer code SKIRT to apply dust extinction. We apply our technique to NGC 4552 and NGC 4494, two nearby ETGs. We show that the extinction by a dust ring can mimic, in a surface brightness profile, a central point source (e.g. an unresolved nuclear stellar cluster or an active galactic nucleus; AGN) superimposed to a `core' (i.e. a central flattening of the stellar light commonly observed in massive ETGs). We discuss how properly accounting for dust features is of paramount importance to derive correct fluxes especially for low luminosity AGNs (LLAGNs). We suggest that the geometries of dust features are strictly connected with how relaxed is the gravitational potential, i.e. with the evolutionary stage of the host galaxy. Additionally, we find hints that the dust mass contained in the ring relates to the AGN activity.

Axial coordination and conformational heterogeneity of nickel(II) tetraphenylprophyrin complexes with nitrogenous bases

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jia, S.L.; Song, X.Z.; Ma, J.G.

1998-08-24

Axial ligation of nickel(II) 5,10,15,20-tetraphenylporphyrin (NiTPP) with pyrrolidine or piperidine has been investigated using X-ray crystallography, UV-visible spectroscopy, resonance Raman spectroscopy, and molecular mechanics (MM) calculations. Distinct v{sub 4} Raman lines are found for the 4-, 5-, and 6-coordinate species of NiTPP. The equilibrium constants for addition of the first and second pyrrolidine axial ligands are 1.1 and 3.8 M{sup {minus}1}, respectively. The differences in the calculated energies of the conformers having different ligand rotational angles are small so they may coexist in solution. Because of the similarity in macrocyclic structural parameters of these conformers and the free rotation ofmore » the axial ligands, narrow and symmetric v{sub 2} and v{sub 8} Raman lines are observed. Nonetheless, the normal-coordinate structural-decomposition analysis of the nonplanar distortions of the calculated structures and the crystal structure of the bis(piperidine) complex reveals a relationship between the orientations of axial ligand(s) and the macrocyclic distortions. For the 5-coordinate complex with the plane of the axial ligand bisecting the Ni-N{sub pyrrole} bonds, a primarily ruffled deformation results. With the ligand plane eclipsing the Ni-N{sub pyrrole} bonds, a mainly saddled deformation occurs. With the addition of the second axial ligand, the small doming of the 5-coordinate complexes disappears, and ruffling or saddling deformations change depending on the relative orientation of the two axial ligands. The crystal structure of the NiTPP bis(piperidine) complex shows a macrocycle distortion composed of wav(x) and wav(y) symmetric deformations, but no ruffling, saddling, or doming. The difference in the calculated and observed distortions results partly from the phenyl group orientation imposed by crystal packing forces. MM calculations predict three stable conformers (ruf, sad, and planar) for 4-coordinate NiTPP, and resonance Raman evidence for these conformers was given previously.« less

Designing a Ring-VCO for RFID Transponders in 0.18 μm CMOS Process

PubMed Central

Jalil, Jubayer; Reaz, Mamun Bin Ibne; Bhuiyan, Mohammad Arif Sobhan; Rahman, Labonnah Farzana; Chang, Tae Gyu

2014-01-01

In radio frequency identification (RFID) systems, performance degradation of phase locked loops (PLLs) mainly occurs due to high phase noise of voltage-controlled oscillators (VCOs). This paper proposes a low power, low phase noise ring-VCO developed for 2.42 GHz operated active RFID transponders compatible with IEEE 802.11 b/g, Bluetooth, and Zigbee protocols. For ease of integration and implementation of the module in tiny die area, a novel pseudodifferential delay cell based 3-stage ring oscillator has been introduced to fabricate the ring-VCO. In CMOS technology, 0.18 μm process is adopted for designing the circuit with 1.5 V power supply. The postlayout simulated results show that the proposed oscillator works in the tuning range of 0.5–2.54 GHz and dissipates 2.47 mW of power. It exhibits a phase noise of −126.62 dBc/Hz at 25 MHz offset from 2.42 GHz carrier frequency. PMID:24587731

N-[2-(5-Bromo-2-morpholin-4-ylpyrim­idin-4-ylsulfan­yl)-4-meth­oxy­phen­yl]-2,4,6-trimethyl­benzene­sulfonamide

PubMed Central

Kumar, Mohan; Mallesha, L.; Sridhar, M. A.; Kapoor, Kamini; Gupta, Vivek K.; Kant, Rajni

2012-01-01

In the title compound, C24H27BrN4O4S2, the mol­ecule is twisted at the sulfonyl S atom with a C—S(O2)—N(H)—C torsion angle of 62.6 (3)°. The benzene rings bridged by the sulfonamide group are tilted to each other by a dihedral angle of 60.6 (1)°. The dihedral angle between the sulfur-bridged pyrimidine and benzene rings is 62.7 (1)°. The morpholine ring adopts a chair conformation. The mol­ecular conformation is stabilized by a weak intra­molecular π–π stacking inter­action between the pyrimidine and the 2,4,6-trimethyl­benzene rings [centroid–centroid distance = 3.793 (2) Å]. In the crystal, mol­ecules are linked by N—H⋯O hydrogen bonds into a chain along the b axis. PMID:23284396

N-(2-{[5-Bromo-2-(morpholin-4-yl)pyrimidin-4-yl]sulfan­yl}-4-meth­oxy­phen­yl)-4-methyl­benzene­sulfonamide

PubMed Central

Kant, Rajni; Gupta, Vivek K.; Kapoor, Kamini; Kumar, Mohan; Mallesha, L.; Sridhar, M. A.

2012-01-01

In the title compound, C22H23BrN4O4S2, the benzene rings bridged by the sulfonamide group are tilted relative to each other by 68.9 (1)° and the dihedral angle between the sulfur-bridged pyrimidine and benzene rings is 69.7 (1)°. The mol­ecular conformation is stabilized by a weak intra­molecular π–π stacking inter­action between the pyrimidine and the 4-methylbenzene rings [centroid–centroid distance = 3.934 (2) Å]. The morpholine ring adopts a chair conformation and is disordered over two positions with an occupancy ratio of 0.853 (6):0.147 (6). In the crystal, mol­ecules are linked by N—H⋯O hydrogen bonds into chains extending along the a axis and further, through C—H⋯N and C—H⋯O inter­actions, into a three-dimensional supramolecular structure. PMID:22905015

4-{2-[2-(4-Chloro­benzyl­idene)hydrazinyl­idene]-3,6-dihydro-2H-1,3,4-thia­diazin-5-yl}-3-phenyl­sydnone

PubMed Central

Fun, Hoong-Kun; Loh, Wan-Sin; Nithinchandra; Kalluraya, Balakrishna

2011-01-01

The title compound, C18H13ClN6O2S, exists in trans and cis configurations with respect to the acyclic C=N bonds [C=N = 1.2837 (15) and 1.3000 (14) Å, respectively]. The 3,6-dihydro-2H-1,3,4-thia­diazine ring adopts a half-boat conformation. The sydnone ring is approximately planar [maximum deviation = 0.002 (1) Å] and forms dihedral angles of 50.45 (7) and 61.21 (6)° with the aromatic rings. In the crystal, inter­molecular N—H⋯N, C—H⋯Cl and C—H⋯S hydrogen bonds link the mol­ecules into layers parallel to ab plane. The crystal packing is stabilized by C—H⋯π inter­actions and further consolidated by π–π inter­actions involving the phenyl rings [centroid–centroid distance = 3.6306 (7) Å]. PMID:21754481

Researches on the Piston Ring

NASA Technical Reports Server (NTRS)

Ehihara, Keikiti

1944-01-01

In internal combustion engines, steam engines, air compressors, and so forth, the piston ring plays an important role. Especially, the recent development of Diesel engines which require a high compression pressure for their working, makes, nowadays, the packing action of the piston ring far more important than ever. Though a number of papers have been published in regard to researches on the problem of the piston ring, none has yet dealt with an exact measurement of pressure exerted on the cylinder wall at any given point of the ring. The only paper that can be traced on this subject so far is Mr. Nakagawa's report on the determination of the relative distribution of pressure on the cylinder wall, but the measuring method adopted therein appears to need further consideration. No exact idea has yet been obtained as to how the obturation of gas between the piston and cylinder, the frictional resistance of the piston, and the wear of the cylinder wall are affected by the intensity and the distribution of the radial pressure of the piston ring. Consequently, the author has endeavored, by employing an apparatus of his own invention, to get an exact determination of the pressure distribution of the piston ring. By means of a newly devised ring tester, to which piezoelectricity of quartz was applied, the distribution of the radial pressure of many sample rings on the market was accurately determined. Since many famous piston rings show very irregular pressure distribution, the author investigated and achieved a manufacturing process of the piston ring which will exert uniform pressure on the cylinder wall. Temperature effects on the configuration and on the mean spring power have also been studied. Further, the tests were performed to ascertain how the gas tightness of the piston ring may be affected by the number or spring power. The researches as to the frictional resistance between the piston ring and the cylinder wall were carried out, too. The procedure of study, and experiments conducted by the author, on this subject will be fully described in the following paragraphs.

Functional Chemical Groups that May Likely Become a Source for the Synthesis of Novel Central Nervous System (CNS) Acting Drugs.

PubMed

Saganuwan, Saganuwan A

2017-01-01

Central Nervous System (CNS) disorders are on increase perhaps due to genetic, enviromental, social and dietetic factors. Unfortunately, a large number of CNS drugs have adverse effects such as addiction, tolerance, psychological and physical dependence. In view of this, literature search was carried out with a view to identify functional chemical groups that may serve as lead molecules for synthesis of compounds that may have CNS activity. The search revealed that heterocycles that have heteroatoms such as nitrogen (N), sulphur (S) and oxygen (O) form the largest class of organic compounds. They replace carbon in a benzene ring to form pyridine. Compounds with furan, thiophene, pyrrole, pyridine, azole, imidazole, indole, purine, pyrimidine, esters, carboxylic acid, aldehyde, pyrylium, pyrone, pyrodine, barbituric acid, barbiturate, quinoline, quinolone, isoquinolone, coumarin, alkylpyridine, picoline, piperidine, diazine, carboxamide, flavonoid glycoside, oxindole, aminophenol, benzimidazole, benzoxazole, benzothiazole, and chromone chemical groups among others may have CNS effects ranging from depression passing through euphoria to convulsion. Examples of the compounds with the functional groups include but not limited to coal tar, pyridostigmine, pralidoxime, quinine, mefloquine, pyrilamine, pyronaridine, ciprofloxacin and piroxicam. A number of them can undergo keto-enol tautomerism. Chiral amines may be used for derivation of chiral carboxylic acids which are components of tautomers. Some tautomers may cause parkinsonism and Stevens Johnson syndrome. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Pharmacology of irinotecan.

PubMed

Kuhn, J G

1998-08-01

Irinotecan (CPT-11 [Camptosar]), a semisynthetic derivative of the plant alkaloid camptothecin, is bioactivated by carboxylesterases (EC3.1.1-) to the topoisomerase I inhibitor SN-38, a minor metabolite. Bioactivation of intravenously administered irinotecan by carboxylesterases occurs predominantly in the liver. Two human carboxylesterase isoforms responsible for SN-38 formation have been characterized. At relevant hepatic irinotecan concentrations up to 12 micrograms/mL, a low-Km isoform is responsible for irinotecan bioactivation. High concentrations of drugs commonly coadministered with irinotecan do not inhibit carboxylesterase activity. Intestinal carboxylesterases can also generate SN-38, followed by subsequent oral absorption. A second major polar metabolite of irinotecan, aminopentanecarboxylic acid (APC), is the product of CYP3A4-mediated oxidation of the terminal piperidine ring. APC is 100-fold less active than SN-38 as a topoisomerase I inhibitor and is a relatively weak inhibitor of acetylcholinesterase. SN-38 is eliminated mainly through conjugation by hepatic uridine glucuronosyltransferase (UGT*1.1), the same isoezyme responsible for glucuronidation of bilirubin. Grade 4 irinotecan-related toxicity (ie, neutropenia, diarrhea) has recently been reported in two patients with deficient UGT*1.1 activity. SN-38 glucuronide (SN-38G), which has only 1/100th the antitumor activity of SN-38, is actively secreted into the bile by a canalicular multispecific organic anion transporter. Deconjugation of SN-38G to SN-38 by beta-glucuronidase produced by the intestinal flora may contribute to enterohepatic recirculation of SN-38 and delayed intestinal toxicity.

Structure of a Glomulin-RBX1-CUL1 Complex: Inhibition of a RING E3 Ligase through Masking of Its E2-Binding Surface

DOE Office of Scientific and Technical Information (OSTI.GOV)

Duda, David M.; Olszewski, Jennifer L.; Tron, Adriana E.

2012-11-01

The approximately 300 human cullin-RING ligases (CRLs) are multisubunit E3s in which a RING protein, either RBX1 or RBX2, recruits an E2 to catalyze ubiquitination. RBX1-containing CRLs also can bind Glomulin (GLMN), which binds RBX1's RING domain, regulates the RBX1-CUL1-containing SCF{sup FBW7} complex, and is disrupted in the disease Glomuvenous Malformation. Here we report the crystal structure of a complex between GLMN, RBX1, and a fragment of CUL1. Structural and biochemical analyses reveal that GLMN adopts a HEAT-like repeat fold that tightly binds the E2-interacting surface of RBX1, inhibiting CRL-mediated chain formation by the E2 CDC34. The structure explains themore » basis for GLMN's selectivity toward RBX1 over RBX2, and how disease-associated mutations disrupt GLMN-RBX1 interactions. Our study reveals a mechanism for RING E3 ligase regulation, whereby an inhibitor blocks E2 access, and raises the possibility that other E3s are likewise controlled by cellular proteins that mask E2-binding surfaces to mediate inhibition.« less

JLEIC SRF cavity RF Design

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Shaoheng; Guo, Jiquan; Wang, Haipeng

2016-05-01

The initial design of a low higher order modes (HOM) impedance superconducting RF (SRF) cavity is presented in this paper. The design of this SRF cavity is for the proposed Jefferson Lab Electron Ion Collider (JLEIC). The electron ring of JLEIC will operate with electrons of 3 to 10 GeV energy. The ion ring of JLEIC will operate with protons of up to 100 GeV energy. The bunch lengths in both rings are ~12 mm (RMS). In order to maintain the short bunch length in the ion ring, SRF cavities are adopted to provide large enough gradient. In the firstmore » phase of JLEIC, the PEP II RF cavities will be reused in the electron ring to lower the initial cost. The frequency of the SRF cavities is chosen to be the second harmonic of PEP II cavities, 952.6 MHz. In the second phase of JLEIC, the same frequency SRF cavities may replace the normal conducting PEP II cavities to achieve higher luminosity at high energy. At low energies, the synchro-tron radiation damping effect is quite weak, to avoid the coupled bunch instability caused by the intense closely-spaced electron bunches, low HOM impedance of the SRF cavities combined with longitudinal feedback sys-tem will be necessary.« less

Application of 1-aminocyclohexane carboxylic acid to protein nanostructure computer design

PubMed Central

Rodríguez-Ropero, Francisco; Zanuy, David; Casanovas, Jordi; Nussinov, Ruth; Alemán, Carlos

2009-01-01

Conformationally restricted amino acids are promising candidates to serve as basic pieces in redesigned protein motifs which constitute the basic modules in synthetic nanoconstructs. Here we study the ability of constrained cyclic amino acid 1-aminocyclohexane-1-carboxylic acid (Ac6c) to stabilize highly regular β-helical motifs excised from naturally occurring proteins. Calculations indicate that the conformational flexibility observed in both the ring and the main chain is significantly higher than that detected for other 1-aminocycloalkane-1-carboxylic acid (Acnc, where n refers to the size of the ring) with smaller cycles. Incorporation of Ac6c into the flexible loops of β-helical motifs indicates that the stability of such excised building blocks as well as the nano-assemblies derived from them is significantly enhanced. Thus, the intrinsic Ac6c tendency to adopt folded conformations combined with the low structural strain of the cyclohexane ring confers the ability to both self-adapt to the β-helix motif and to stabilize the overall structure by absorbing part of its conformational fluctuations. Comparison with other Acnc residues indicates that the ability to adapt to the targeted position improves considerably with the ring size, i.e. when the rigidity introduced by the strain of the ring decreases. PMID:18201062

Genetic variation of piperidine alkaloids in Pinus ponderosa from a common garden

Treesearch

Elizabeth A. Gerson; Rick G. Kelsey; Bradley J. St. Clair

2012-01-01

Most species of pine and spruce synthesize and accumulate variable quantities of alkaloids in their tissues. These compounds express numerous types of biological activities in bioassay and could potentially offer resistance against enemies, although this function has never been confirmed for any known enemies of pine or spruce under natural conditions. The...

Concentration-dependent actions of piperidine alkaloids on the inhibition of fetal movement in day 40 pregnant goats and comparison to cell-based models

USDA-ARS?s Scientific Manuscript database

Anabasine and anabaseine are potent and effective agonists at nicotinic acetylcholine receptors (nAChR). Anabasine in livestock species is teratogenic and has been shown to cause developmental defects that include arthrogyrposis, kyposis, lordosis, scoliosis, and torticollis. We have postulated that...

The Evolution of Saturn's Rings Under the Influence of the Edgeworth-Kuiper Belt Micrometeoroid Flux: Tightening the Constraints on Ring Age

NASA Astrophysics Data System (ADS)

Estrada, Paul R.; Durisen, Richard H.; Cuzzi, Jeffrey N.

2016-10-01

Results of the Cassini Dust Analyzer (CDA) experiment indicate that the determined range of the micrometeoroid flux at infinity for Saturn (Altobelli et al., 2015) may be comparable to the nominal value of the incident, flat-plate and one-sided meteoroid flux value currently adopted for use in ballistic transport applications and models (e.g., Estrada et al., 2015). Moreover, the source of the micrometeoroid flux has been localized to the Edgeworth-Kuiper Belt (EKB) and is not cometary in origin as previously assumed. Apart from suggesting an altogether different composition for the ring pollutant, a major consequence of these new measurements is that the EKB flux is much more gravitationally focused than the cometary case because it is isotropic in the planet rather than the heliocentric frame. Thus, the lower velocities at infinity that characterize the EKB flux can increase the impact flux on the rings by a factor of ˜25. This means that even for the lower bound of the range of the newly measured flux, the amount of material hitting the rings may be considerably higher and thus the process of micrometeoroid bombardment and ballistic transport is likely even more influential in the rings' structural and compositional evolution over time. Here, we calculate the new EKB ejecta distribution using the model of Cuzzi and Durisen (1990) and compare this with the nominal cometary one, and then demonstrate using new simulations the consequences of the EKB flux on the evolution of ring composition and structure. The constraining of the micrometeoroid flux represents a very important step in being able to associate an absolute age for the rings. We argue that the new EKB flux poses a serious problem for "primordial" or "old" ring origin scenarios and favors more a scenario in which the rings, at least the way we see them today, cannot be much older than a few 100 Myrs.

Crystal structure of 3-[(4-benzyl-piperazin-1-yl)meth-yl]-5-(thio-phen-2-yl)-2,3-di-hydro-1,3,4-oxa-diazole-2-thione.

PubMed

Al-Omary, Fatmah A M; El-Emam, Ali A; Ghabbour, Hazem A; Chidan Kumar, C S; Quah, Ching Kheng; Fun, Hoong-Kun

2015-03-01

The title 1,3,4-oxa-diazole-2-thione derivative, C18H20N4OS2, crystallized with two independent mol-ecules (A and B) in the asymmetric unit. The 2-thienyl rings in both mol-ecules are rotationally disordered over two orientations by approximately 180° about the single C-C bond that connects it to the oxa-diazole thione ring; the ratios of site occupancies for the major and minor components were fixed in the structure refinement at 0.8:0.2 and 0.9:0.1 in mol-ecules A and B, respectively. The 1,3,4-oxa-diazole-2-thione ring forms dihedral angles of 7.71 (16), 10.0 (11) and 77.50 (12)° (mol-ecule A), and 6.5 (3), 6.0 (9) and 55.30 (12)° (mol-ecule B) with the major and minor parts of the disordered thio-phene ring and the mean plane of the adjacent piperazine ring, respectively, resulting in approximately V-shaped conformations for the mol-ecules. The piperazine ring in both mol-ecules adopts a chair conformation. The terminal benzene ring is inclined towards the mean plane of the piperazine ring with N-C-C-C torsion angles of -58.2 (3) and -66.2 (3)° in mol-ecules A and B, respectively. In the crystal, no inter-molecular hydrogen bonds are observed. The crystal packing features short S⋯S contacts [3.4792 (9) Å] and π-π inter-actions [3.661 (3), 3.664 (11) and 3.5727 (10) Å], producing a three-dimensional network.

Crystal structure of 1,2,3,4-di-O-methyl­ene-α-d-galacto­pyran­ose

PubMed Central

Tiritiris, Ioannis; Tussetschläger, Stefan; Kantlehner, Willi

2015-01-01

The title compound, C8H12O6, was synthesized by de­acetyl­ation of 6-acetyl-1,2,3,4-di-O-methyl­ene-α-d-galactose with sodium methoxide. The central part of the mol­ecule consists of a six-membered C5O pyran­ose ring with a twist-boat conformation. Both fused dioxolane rings adopt an envelope conformation with C and O atoms as the flap. In the crystal, O—H⋯O and C—H⋯O hydrogen bonds are present between adjacent mol­ecules, generating a three-dimensional network. PMID:26870551

14-Meth­oxy-4,6-dimethyl-9-phenyl-8,12-dioxa-4,6-di­aza­tetra­cyclo­[8.8.0.02,7.013,18]octa­deca-2(7),13,15,17-tetra­ene-3,5,11-trione

PubMed Central

Jagadeesan, G; Jayashree, S.; Kannan, D.; Bakthadoss, M.; Aravindhan, S.

2013-01-01

The title compound, C23H20N2O6, crystallizes with two mol­ecules in the asymmetric unit in which the dihedral angles between the mean planes of the pyran and phenyl rings are 66.6 (1) and 61.9 (1) °. The fused pyrone and pyran rings each adopts a sofa conformation. In the crystal, C—H⋯O hydrogen bonds link the mol­ecules, forming a two-dimensional network parallel to [001]. PMID:24109298

14-Eth­oxy-4,6-dimethyl-9-phenyl-8,12-dioxa-4,6-diaza­tetra­cyclo­[8.8.0.02,7.013,18]octa­deca-2(7),13,15,17-tetra­ene-3,5,11-trione

PubMed Central

Jagadeesan, G.; Kannan, D.; Bakthadoss, M.; Aravindhan, S.

2013-01-01

In the title compound, C23H20N2O6, the fused pyrone and pyran rings each adopt a sofa conformation. The dihedral angle between the mean planes of the pyran and phenyl rings is 61.9 (1)°. In the crystal, mol­ecules are linked by two pairs of C—H⋯O hydrogen bonds, forming dimers. These dimers are linked via a third C—H⋯O hydrogen bond, forming a two-dimensional network parallel to (10-2). PMID:23476462

7-Chloro-5-cyclo­propyl-9-methyl-5H-4,5,6,10-tetra­aza­dibenzo[a,d]cyclo­hepten-11(10H)-one

PubMed Central

Naveen, S.; Thimmegowda, N. R.; Manjunath, H. R.; Sridhar, M. A.; Prasad, J. Shashidhara; Rangappa, K. S.

2011-01-01

In the title compound, C15H13ClN4O, which is a chloro derivative of the drug Nevirapine, the diazepine ring is in a twisted boat conformation. The pyridine rings fused to the diazepine fragment form a dihedral angle of 58.44 (10)° and the mol­ecule adopts a butterfly shape. The mol­ecules are joined via N—H⋯N hydrogen bonding into polymeric chains down the b axis. All weaker C—H⋯O inter­actions involve the carbonyl O atom as acceptor. PMID:21754822

Intermixing of InP-based quantum dots and application to micro-ring resonator wavelength-selective filter for photonic integrated devices

NASA Astrophysics Data System (ADS)

Matsumoto, Atsushi; Matsushita, Asuka; Takei, Yuki; Akahane, Kouichi; Matsushima, Yuichi; Ishikawa, Hiroshi; Utaka, Katsuyuki

2014-09-01

In this study, we investigated quantum dot intermixing (QDI) for InAs/InGaAlAs highly stacked QDs on an InP(311)B substrate with low-temperature annealing at 650 °C in order to realize integrated photonic devices with QDs and passive waveguides. In particular, we adopted the method of introducing point defects by ICP-RIE to realize a blue shift of the PL peak wavelength by about 150 nm. Moreover, we successfully fabricated double micro-ring resonators by QDI. The output power contrasts of the devices were found to be 9.0 and 8.6 dB for TE and TM modes, respectively.

N-(2,3-Dimethyl-phen-yl)-4-hydr-oxy-2-methyl-2H-1,2-benzothia-zine-3-carboxamide 1,1-dioxide.

PubMed

Siddiqui, Waseeq Ahmad; Bukahari, Iftikhar Hussain; Zia-Ur-Rehman, Muhammad; Khan, Islam Ullah; Tizzard, Graham John

2009-02-28

In the crystal structure of the title compound, C(18)H(18)N(2)O(4)S, the thia-zine ring adopts a distorted half-chair conformation. 1,2-Benzothia-zines of this kind have a wide range of biological activities and are mainly used as medicines in the treatment of inflammation and rheumatoid arthritis. The enolic H atom is involved in an intra-molecular O-H⋯O hydrogen bond, forming a six-membered ring. The mol-ecules arrange themselves into centrosymmetric dimers by means of inter-molecular N-H⋯O hydrogen bonds. A weak inter-molcular C-H⋯O inter-action is also present.

N-(3,4-Dimethyl­phen­yl)-4-hydr­oxy-2-methyl-2H-1,2-benzothia­zine-3-carboxamide 1,1-dioxide

PubMed Central

Siddiqui, Waseeq Ahmad; Ali, Muhammad; Zia-ur-Rehman, Muhammad; Sharif, Saima; Tizzard, Graham John

2009-01-01

1,2-Benzothia­zines similar to the title compound, C18H18N2O4S, are well known in the literature for their biological activities and are used as medicines in the treatment of inflammation and rheumatoid arthritis. The thia­zine ring adopts a distorted half-chair conformation. The enolic H atom is involved in an intra­molecular O—H⋯O hydrogen bond, forming a six-membered ring. In the crystal, mol­ecules arrange themselves into centrosymmetric dimers by means of pairs of weak inter­molecular N—H⋯O hydrogen bonds. PMID:21582605

Ring discharge on the backsurface of a composite skin with ohmic anisotropy in response to frontal high current injection

NASA Astrophysics Data System (ADS)

Lee, T. S.; Robb, J. D.

The ring discharge hazard to a carbon-reinforced-composites fuel tank skin under lightning strike conditions is investigated. A model of anisotropy in electric conductivity is adopted whereby longitudinal conductivity and transverse conductivity are considered separately. It is concluded that the current flow pattern contains a stagnation-dominated near-field region and a geometry-dominated far-field decaying region. While this pattern is unaltered by anisotropy in conductivity, the accompanying nonliner electrical field pattern is greatly distorted. It is noted that conclusions applicable to the ignition hazard which were derived from the model of a uniform scalar conductivity for the skin still remain intact.

2-[4-(2-Chloro-acet-yl)phen-yl]-2-methyl-1-(pyrrolidin-1-yl)propan-1-one.

PubMed

Ren, Dong-Mei

2013-01-01

The asymmetric unit of the title compound, C16H20ClNO2, contains two mol-ecules 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 mol-ecules, the five-membered ring adopts an envelope conformation with one of the β-C atoms as the flap. In the crystal, mol-ecules are connected via C-H⋯O hydrogen bonds, forming chains along the b-axis direction. These chains are further linked by C-H⋯π inter-actions, forming a three-dimensional network.

2-[Anilino(phen-yl)meth-yl]cyclo-heptan-one.

PubMed

Eftekhari-Sis, Bagher; Mohajer, Sahar; Zirak, Maryam; Mozaffarnia, Sakineh; Büyükgüngör, Orhan

2013-01-01

In the title compound, C20H23NO, the cyclo-hepta-none ring adopts a twist-chair conformation, with the amino-methyl substituent in an equatorial position. The relative configuration of the two stereocenters is R,R. In the crystal, mol-ecules are linked by N-H⋯O hydrogen bonds into chains along [100].

Boron Clusters Come of Age

ERIC Educational Resources Information Center

Grimes, Russell N.

2004-01-01

Boron is the only element other than carbon that can build molecules of unlimited size by covalently boding to itself, a property known as catenation. In contrast to the chains and rings favored by carbon, boron arguably adopts a cluster motif that is reflected in the various forms of the pure element and in the huge area of polyhedral borane…

4-Benzyl-4-methyl­morpholinium hexa­fluoro­phosphate

PubMed Central

Su, Qiu-hong; Zang, Hong-Jun; Xu, Tian-lin; Ren, Yuan-Lin

2010-01-01

In the title compound, C12H18NO+·PF6 −, the asymmetric unit consists of two cation–anion pairs. The six F atoms of one anion are disordered over two sets of sites in a 0.592 (6):0.408 (6) ratio. The morpholinium rings adopt chair conformations. PMID:21587663

Structure of complex of N-methylpiperidine betaine with p-hydroxybenzoic acid studied by X-ray, FT-IR and DFT methods

NASA Astrophysics Data System (ADS)

Dega-Szafran, Z.; Dutkiewicz, G.; Kosturkiewicz, Z.; Szafran, M.

2008-03-01

Crystal structure of the complex of N-methylpiperidine betaine ( N-carboxymethyl- N-methylpiperidinium inner salt, MPB) with p-hydroxybenzoic acid (HBA) has been determined by X-ray diffraction. The crystals are triclinic, space group Pī, with a = 6.1156(5), b = 10.6869(10), c = 12.0320(10) Å, α = 109.55(1)°, β = 95.25(1)°, γ = 99.22(1)°, Z = 2, R = 0.034. Two molecules of p-hydroxybenzoic acid and two molecules of N-methylpiperidine betaine are linked together forming a centrosymmetric dimer, (MPB·HBA) 2, by four O-H···O hydrogen bonds of lengths 2.622(1) and 2.617(1) Å, between the carboxylic and hydroxy groups of HBA and both oxygen atoms of the carboxylate group of MPB, respectively. The piperidine ring has a chair conformation with the CH 2COO - substituent in the axial position and the CH 3 group in the equatorial one. Two parallel aromatic rings in (MPB·HBA) 2 are distanced by 3.457 Å. In the crystals the complexes form "islands" related to the neighboring complexes by the inversion centers, weak C-H···O bonds and van der Waals forces. A broad band in the 3100-2400 cm -1 region and two bands attributed to the νC dbnd O (1689 cm -1) and νasCOO (1607 cm -1) vibrations in the FT-IR spectrum confirm the structure of the title complex. The two structures of MPB·HBA, denoted as A and B, have been optimized by the B3LYP/6-31G(d,p) method. In A, MPB forms a O-H···O hydrogen bond (2.562 Å) with the carboxylic group of HBA shorter than in the crystals, while in B it interacts with the phenolic group of HBA by a longer O-H···O hydrogen bond (2.661 Å) than in the crystals. Complex A is slightly more stable than B (0.15 kcal/mol).

Novel type of ornithine-glutathione double conjugate excreted as a major metabolite into the bile of rats administered clebopride.

PubMed

Ishizuka, T; Komiya, I; Hiratsuka, A; Watabe, T

1990-06-01

Rats orally given radioactive Clebopride [[14C]CP; N-(1'-benzyl-4'-piperidyl)-2-[14C]methoxy-4-amino-5-chlorobenzamide++ +], an antiulcer agent, excreted a novel type of ornithine (Orn)-GSH double conjugate in the bile as a major metabolite [( 14C]BMCP), corresponding to 18% of the dose. The present study provides the first evidence for Orn conjugation of a xenobiotic in mammals and demonstrates that the structure of the radioactive conjugate differs fundamentally from those known in birds and reptiles. The structure of the biliary metabolite, [14C]BMCP, purified to homogeneity by silica gel thin layer and reverse phase high pressure liquid chromatography, was elucidated as S-[2-ornithylamino-4-[14C]methoxy-5-(1'-methyl-4'-piperidylamin o) carboxyphenyl]glutathione, based mainly on the following facts: 1) BMCP showed a protonated molecular ion (M + H)+ peak at m/z 683 in the secondary ion mass spectrum and 2) [14C]BMCP afforded Orn, glutamic acid, glycine, S-(2-amino-4-[14C]methoxy-5-carboxyphenyl)cysteine [( 14C]AMCC), and 1-methyl-4-aminopiperidine (MAP) quantitatively, in an equal molar ratio, by complete hydrolysis with peptidase. Thus, BMCP was a metabolite with three enzymatically hydrolyzable amide bonds in addition to the one existing originally in the parent structure of the drug, which produces MAP by peptic digestion. Of the three additional amide bonds of BMCP, one was a novel type of bond formed by condensation of the alpha-carboxylic acid group of Orn with the primary aromatic amino group of the drug and the other two were in the S-glutathionyl residue, substituted for the chlorine atom vicinal to the Orn-conjugating primary amino group in the aromatic ring and affording glutamic acid, glycine, and the S-cysteine conjugate AMCC by hydrolysis of BMCP with the peptidase. Substitution of a methyl group for the benzyl group at the piperidine ring nitrogen atom, leading to the formation of MAP by peptic digestion, also occurred during metabolism of CP to BMCP.

Depolymerization dynamics of individual filaments of bacterial cytoskeletal protein FtsZ

PubMed Central

Mateos-Gil, Pablo; Paez, Alfonso; Hörger, Ines; Rivas, Germán; Vicente, Miguel; Tarazona, Pedro; Vélez, Marisela

2012-01-01

We report observation and analysis of the depolymerization filaments of the bacterial cytoskeletal protein FtsZ (filament temperature-sensitive Z) formed on a mica surface. At low concentration, proteins adsorbed on the surface polymerize forming curved filaments that close into rings that remain stable for some time before opening irreversibly and fully depolymerizing. The distribution of ring lifetimes (T) as a function of length (N), shows that the rate of ring aperture correlates with filament length. If this ring lifetime is expressed as a bond survival time, (Tb ≡ NT), this correlation is abolished, indicating that these rupture events occur randomly and independently at each monomer interface. After rings open irreversibly, depolymerization of the remaining filaments is fast, but can be slowed down and followed using a nonhydrolyzing GTP analogue. The histogram of depolymerization velocities of individual filaments has an asymmetric distribution that can be fit with a computer model that assumes two rupture rates, a slow one similar to the one observed for ring aperture, affecting monomers in the central part of the filaments, and a faster one affecting monomers closer to the open ends. From the quantitative analysis, we conclude that the depolymerization rate is affected both by nucleotide hydrolysis rate and by its exchange along the filament, that all monomer interfaces are equally competent for hydrolysis, although depolymerization is faster at the open ends than in central filament regions, and that all monomer–monomer interactions, regardless of the nucleotide present, can adopt a curved configuration. PMID:22566654

Clinical toxicology of newer recreational drugs.

PubMed

Hill, Simon L; Thomas, Simon H L

2011-10-01

Novel synthetic 'designer' drugs with stimulant, ecstasy-like (entactogenic) and/or hallucinogenic properties have become increasingly popular among recreational drug users in recent years. The substances used change frequently in response to market trends and legislative controls and it is an important challenge for poisons centres and clinical toxicologists to remain updated on the pharmacological and toxicological effects of these emerging agents. To review the available information on newer synthetic stimulant, entactogenic and hallucinogenic drugs, provide a framework for classification of these drugs based on chemical structure and describe their pharmacology and clinical toxicology. A comprehensive review of the published literature was performed using PUBMED and Medline databases, together with additional non-peer reviewed information sources, including books, media reports, government publications and internet resources, including drug user web forums. Novel synthetic stimulant, entactogenic or hallucinogenic designer drugs are increasingly available to users as demonstrated by user surveys, poisons centre calls, activity on internet drug forums, hospital attendance data and mortality data. Some population sub groups such as younger adults who attend dance music clubs are more likely to use these substances. The internet plays an important role in determining the awareness of and availability of these newer drugs of abuse. Most novel synthetic stimulant, entactogenic or hallucinogenic drugs of abuse can be classified according to chemical structure as piperazines (e.g. benzylpiperazine (BZP), trifluoromethylphenylpiperazine), phenethylamines (e.g. 2C or D-series of ring-substituted amfetamines, benzodifurans, cathinones, aminoindans), tryptamines (e.g. dimethyltryptamine, alpha-methyltryptamine, ethyltryptamine, 5-methoxy-alphamethyltryptamine) or piperidines and related substances (e.g. desoxypipradrol, diphenylprolinol). Alternatively classification may be based on clinical effects as either primarily stimulant, entactogenic or hallucinogenic, although most drugs have a combination of such effects. CLINICAL TOXICOLOGY: Piperazines, phenethylamines, tryptamines and piperidines have actions at multiple central nervous system (CNS) receptor sites, with patterns of effects varying between agents. Predominantly stimulant drugs (e.g. benzylpiperazine, mephedrone, naphyrone, diphenylprolinol) inhibit monoamine (especially dopamine) reuptake and are characteristically associated with a sympathomimetic toxidrome. Entactogenic drugs (e.g. phenylpiperazines, methylone) provoke central serotonin release, while newer hallucinogens (e.g. 5-methoxy-N,N-diisopropyltryptamine (5-MeO-DiPT), 2,5-dimethoxy-4-bromoamfetamine (DOB)) are serotonin receptor agonists. As a result, serotoninergic effects predominate in toxicity. There are limited reliable data to guide clinicians managing patients with toxicity due to these substances. The harms associated with emerging recreational drugs are not fully documented, although it is clear that they are not without risk. Management of users with acute toxic effects is pragmatic and primarily extrapolated from experience with longer established stimulant or hallucinogenic drugs such as amfetamines, 3,4-methylenedioxymethamfetamine (MDMA) and lysergic acid diethylamide (LSD).

Concise, Stereocontrolled Synthesis of the Citrinadin B Core Architecture

PubMed Central

Guerrero, Carlos A.; Sorensen, Erik J.

2011-01-01

A concise, stereocontrolled synthesis of the citrinadin B core architecture from scalemic, readily available starting materials is disclosed. Highlights include ready access to both cyclic tryptophan tautomer and TRANS-2,6-disubstituted piperidine fragments, an efficient, stereoretentive mixed Claisen acylation for the coupling of these halves, and further diastereoselective carbonyl addition and oxidative rearrangement for assembly of the core. PMID:21894952

Inhibitory activities of venom alkaloids of Red Imported Fire Ant against Clavibacter michiganensis subsp. michiganensis in vitro and the application of piperidine alkaloids to manage symptom development..

USDA-ARS?s Scientific Manuscript database

Bacterial canker of tomato caused by Clavibacter michiganensis subsp. michiganensis (CMM) is a highly destructive disease and has caused major economic losses in tomato production worldwide. There are limited methods available to manage this disease. In searching for disease management alternatives,...

DNA damage induced by ascorbate in the presence of Cu2+.

PubMed

Kobayashi, S; Ueda, K; Morita, J; Sakai, H; Komano, T

1988-01-25

DNA damage induced by ascorbate in the presence of Cu2+ was investigated by use of bacteriophage phi X174 double-stranded supercoiled DNA and linear restriction fragments as substrates. Single-strand cleavage was induced when supercoiled DNA was incubated with 5 microM-10 mM ascorbate and 50 microM Cu2+ at 37 degrees C for 10 min. The induced DNA damage was analyzed by sequencing of fragments singly labeled at their 5'- or 3'-end. DNA was cleaved directly and almost uniformly at every nucleotide by ascorbate and Cu2+. Piperidine treatment after the reaction showed that ascorbate and Cu2+ induced another kind of DNA damage different from the direct cleavage. The damage proceeded to DNA cleavage by piperidine treatment and was sequence-specific rather than random. These results indicate that ascorbate induces two classes of DNA damage in the presence of Cu2+, one being direct strand cleavage, probably via damage to the DNA backbone, and the other being a base modification labile to alkali treatment. These two classes of DNA damage were inhibited by potassium iodide, catalase and metal chelaters, suggesting the involvement of radicals generated from ascorbate hydroperoxide.

Hit Optimization of 5-Substituted-N-(piperidin-4-ylmethyl)-1H-indazole-3-carboxamides: Potent Glycogen Synthase Kinase-3 (GSK-3) Inhibitors with in Vivo Activity in Model of Mood Disorders.

PubMed

Furlotti, Guido; Alisi, Maria Alessandra; Cazzolla, Nicola; Dragone, Patrizia; Durando, Lucia; Magarò, Gabriele; Mancini, Francesca; Mangano, Giorgina; Ombrato, Rosella; Vitiello, Marco; Armirotti, Andrea; Capurro, Valeria; Lanfranco, Massimiliano; Ottonello, Giuliana; Summa, Maria; Reggiani, Angelo

2015-11-25

Novel treatments for bipolar disorder with improved efficacy and broader spectrum of activity are urgently needed. Glycogen synthase kinase 3β (GSK-3β) has been suggested to be a key player in the pathophysiology of bipolar disorder. A series of novel GSK-3β inhibitors having the common N-[(1-alkylpiperidin-4-yl)methyl]-1H-indazole-3-carboxamide scaffold were prepared taking advantage of an X-ray cocrystal structure of compound 5 with GSK-3β. We probed different substitutions at the indazole 5-position and at the piperidine-nitrogen to obtain potent ATP-competitive GSK-3β inhibitors with good cell activity. Among the compounds assessed in the in vivo PK experiments, 14i showed, after i.p. dosing, encouraging plasma PK profile and brain exposure, as well as efficacy in a mouse model of mania. Compound 14i was selected for further in vitro/in vivo pharmacological evaluation, in order to elucidate the use of ATP-competitive GSK-3β inhibitors as new tools in the development of new treatments for mood disorders.

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

PubMed

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.

Biomarkers and biometric measures of adherence to use of ARV-based vaginal rings.

PubMed

Stalter, Randy M; Moench, Thomas R; MacQueen, Kathleen M; Tolley, Elizabeth E; Owen, Derek H

2016-01-01

Poor adherence to product use has been observed in recent trials of antiretroviral (ARV)-based oral and vaginal gel HIV prevention products, resulting in an inability to determine product efficacy. The delivery of microbicides through vaginal rings is widely perceived as a way to achieve better adherence but vaginal rings do not eliminate the adherence challenges exhibited in clinical trials. Improved objective measures of adherence are needed as new ARV-based vaginal ring products enter the clinical trial stage. To identify technologies that have potential future application for vaginal ring adherence measurement, a comprehensive literature search was conducted that covered a number of biomedical and public health databases, including PubMed, Embase, POPLINE and the Web of Science. Published patents and patent applications were also searched. Technical experts were also consulted to gather more information and help evaluate identified technologies. Approaches were evaluated as to feasibility of development and clinical trial implementation, cost and technical strength. Numerous approaches were identified through our landscape analysis and classified as either point measures or cumulative measures of vaginal ring adherence. Point measurements are those that give a measure of adherence at a particular point in time. Cumulative measures attempt to measure ring adherence over a period of time. Approaches that require modifications to an existing ring product are at a significant disadvantage, as this will likely introduce additional regulatory barriers to the development process and increase manufacturing costs. From the point of view of clinical trial implementation, desirable attributes would be high acceptance by trial participants, and little or no additional time or training requirements on the part of participants or clinic staff. We have identified four promising approaches as being high priority for further development based on the following measurements: intracellular drug levels, drug levels in hair, the accumulation of a vaginal analyte that diffuses into the ring, and the depletion of an intrinsic ring constituent. While some approaches show significant promise over others, it is recommended that a strategy of using complementary biometric and behavioural approaches be adopted to best understand participants' adherence to ARV-based ring products in clinical trials.

Structural characterization of two novel potential anticholinesterasic agents

NASA Astrophysics Data System (ADS)

Oliveira, Paulo R.; Wiectzycosky, Franciele; Basso, Ernani A.; Gonçalves, Regina A. C.; Pontes, Rodrigo M.

2003-09-01

Two novel compounds with possible anticholinesterase activity have been synthesized containing a carbamate and a dimethylamine group in 1,2-positions of a cyclohexane ring ( cis and trans isomers). Conformer populations were established by a combination of NMR 1H coupling constant analysis and DFT (B3LYP/6-311+G(d,p)) calculations. 13C chemical shifts were calculated in order to confirm signal attributions. The cis isomer adopts a conformation in which the carbamate group lies at the axial position (>99%), whereas the trans isomer adopts a diequatorial arrangement (98%). These preferences have been explained in terms of syn-1,3-diaxial interactions of the individual groups.

Dual RING E3 Architectures Regulate Multiubiquitination and Ubiquitin Chain Elongation by APC/C.

PubMed

Brown, Nicholas G; VanderLinden, Ryan; Watson, Edmond R; Weissmann, Florian; Ordureau, Alban; Wu, Kuen-Phon; Zhang, Wei; Yu, Shanshan; Mercredi, Peter Y; Harrison, Joseph S; Davidson, Iain F; Qiao, Renping; Lu, Ying; Dube, Prakash; Brunner, Michael R; Grace, Christy R R; Miller, Darcie J; Haselbach, David; Jarvis, Marc A; Yamaguchi, Masaya; Yanishevski, David; Petzold, Georg; Sidhu, Sachdev S; Kuhlman, Brian; Kirschner, Marc W; Harper, J Wade; Peters, Jan-Michael; Stark, Holger; Schulman, Brenda A

2016-06-02

Protein ubiquitination involves E1, E2, and E3 trienzyme cascades. E2 and RING E3 enzymes often collaborate to first prime a substrate with a single ubiquitin (UB) and then achieve different forms of polyubiquitination: multiubiquitination of several sites and elongation of linkage-specific UB chains. Here, cryo-EM and biochemistry show that the human E3 anaphase-promoting complex/cyclosome (APC/C) and its two partner E2s, UBE2C (aka UBCH10) and UBE2S, adopt specialized catalytic architectures for these two distinct forms of polyubiquitination. The APC/C RING constrains UBE2C proximal to a substrate and simultaneously binds a substrate-linked UB to drive processive multiubiquitination. Alternatively, during UB chain elongation, the RING does not bind UBE2S but rather lures an evolving substrate-linked UB to UBE2S positioned through a cullin interaction to generate a Lys11-linked chain. Our findings define mechanisms of APC/C regulation, and establish principles by which specialized E3-E2-substrate-UB architectures control different forms of polyubiquitination. Copyright © 2016 Elsevier Inc. All rights reserved.

Structure of the torque ring of the flagellar motor and the molecular basis for rotational switching.

PubMed

Lee, Lawrence K; Ginsburg, Michael A; Crovace, Claudia; Donohoe, Mhairi; Stock, Daniela

2010-08-19

The flagellar motor drives the rotation of flagellar filaments at hundreds of revolutions per second, efficiently propelling bacteria through viscous media. The motor uses the potential energy from an electrochemical gradient of cations across the cytoplasmic membrane to generate torque. A rapid switch from anticlockwise to clockwise rotation determines whether a bacterium runs smoothly forward or tumbles to change its trajectory. A protein called FliG forms a ring in the rotor of the flagellar motor that is involved in the generation of torque through an interaction with the cation-channel-forming stator subunit MotA. FliG has been suggested to adopt distinct conformations that induce switching but these structural changes and the molecular mechanism of switching are unknown. Here we report the molecular structure of the full-length FliG protein, identify conformational changes that are involved in rotational switching and uncover the structural basis for the formation of the FliG torque ring. This allows us to propose a model of the complete ring and switching mechanism in which conformational changes in FliG reverse the electrostatic charges involved in torque generation.

Design Considerations and Experimental Verification of a Rail Brake Armature Based on Linear Induction Motor Technology

NASA Astrophysics Data System (ADS)

Sakamoto, Yasuaki; Kashiwagi, Takayuki; Hasegawa, Hitoshi; Sasakawa, Takashi; Fujii, Nobuo

This paper describes the design considerations and experimental verification of an LIM rail brake armature. In order to generate power and maximize the braking force density despite the limited area between the armature and the rail and the limited space available for installation, we studied a design method that is suitable for designing an LIM rail brake armature; we considered adoption of a ring winding structure. To examine the validity of the proposed design method, we developed a prototype ring winding armature for the rail brakes and examined its electromagnetic characteristics in a dynamic test system with roller rigs. By repeating various tests, we confirmed that unnecessary magnetic field components, which were expected to be present under high speed running condition or when a ring winding armature was used, were not present. Further, the necessary magnetic field component and braking force attained the desired values. These studies have helped us to develop a basic design method that is suitable for designing the LIM rail brake armatures.

RiPPAS: A Ring-Based Privacy-Preserving Aggregation Scheme in Wireless Sensor Networks

PubMed Central

Zhang, Kejia; Han, Qilong; Cai, Zhipeng; Yin, Guisheng

2017-01-01

Recently, data privacy in wireless sensor networks (WSNs) has been paid increased attention. The characteristics of WSNs determine that users’ queries are mainly aggregation queries. In this paper, the problem of processing aggregation queries in WSNs with data privacy preservation is investigated. A Ring-based Privacy-Preserving Aggregation Scheme (RiPPAS) is proposed. RiPPAS adopts ring structure to perform aggregation. It uses pseudonym mechanism for anonymous communication and uses homomorphic encryption technique to add noise to the data easily to be disclosed. RiPPAS can handle both sum() queries and min()/max() queries, while the existing privacy-preserving aggregation methods can only deal with sum() queries. For processing sum() queries, compared with the existing methods, RiPPAS has advantages in the aspects of privacy preservation and communication efficiency, which can be proved by theoretical analysis and simulation results. For processing min()/max() queries, RiPPAS provides effective privacy preservation and has low communication overhead. PMID:28178197

Simulation of double stage hall thruster with double-peaked magnetic field

NASA Astrophysics Data System (ADS)

Ding, Yongjie; Li, Peng; Sun, Hezhi; Wei, Liqiu; Xu, Yu; Peng, Wuji; Su, Hongbo; Li, Hong; Yu, Daren

2017-07-01

This study adopts double permanent magnetic rings and four permanent magnetic rings to form two symmetrical magnetic peaks and two asymmetrical magnetic peaks in the channel of a Hall thruster, and uses a 2D-3V PIC-MCC model to analyze the influence of magnetic strength on the discharge characteristic and performance of Hall thrusters with an intermediate electrode and double-peaked magnetic field. As opposed to the two symmetrical magnetic peaks formed by double permanent magnetic rings, increasing the magnetic peak value deep within the channel can cause propellant ionization to occur; with the increase in the magnetic peak deep in the channel, the propellant utilization, thrust, and anode efficiency of the thruster are significantly improved. Double-peaked magnetic field can realize separate control of ionization and acceleration in a Hall thruster, and provide technical means for further improving thruster performance. Contribution to the Topical Issue "Physics of Ion Beam Sources", edited by Holger Kersten and Horst Neumann.

(4S,5S)-2-(2-Fluoro­phen­yl)-1,3-dioxolane-4,5-dicarboxamide

PubMed Central

Li, Xin-Hua; Wang, De-Cai; Liu, Bo-Nian; Xu, Wei

2008-01-01

In the mol­ecule of the title compound, C11H11FN2O4, the five-membered ring adopts an envelope conformation. An intra­molecular N—H⋯F hydrogen bond occurs. In the crystal structure, inter­molecular N—H⋯O hydrogen bonds link the mol­ecules. PMID:22262969

(E)-1,3-Bis(2,3,4,5,6-penta­fluoro­phen­yl)prop-2-en-1-one

PubMed Central

Schwarzer, Anke; Weber, Edwin

2010-01-01

In the title compound, C15H2F10O, the two perfluorinated arene rings are tilted at an angle of 66.08 (5)° with respect to each other. The olefinic double bond adopts an E configuration and the single bond between the olefinic and carbonyl double bonds has an s-trans conformation. The carbonyl group is not in a coplanar alignment with respect to the neighbouring arene ring (0.963 Å from aryl plane) while being coplanar with regard to the olefinic double bond (0.0805 Å from olefinic bond). The crystal packing does not feature significant hydrogen-bond-type or stacking inter­actions. PMID:21588260

The NGC 7742 star cluster luminosity function: a population analysis revisited

NASA Astrophysics Data System (ADS)

de Grijs, Richard; Ma, Chao

2018-02-01

We re-examine the properties of the star cluster population in the circumnuclear starburst ring in the face-on spiral galaxy NGC 7742, whose young cluster mass function has been reported to exhibit significant deviations from the canonical power law. We base our reassessment on the clusters’ luminosities (an observational quantity) rather than their masses (a derived quantity), and confirm conclusively that the galaxy’s starburst-ring clusters—and particularly the youngest subsample, {log}(t {{{yr}}}-1)≤ 7.2—show evidence of a turnover in the cluster luminosity function well above the 90% completeness limit adopted to ensure the reliability of our results. This confirmation emphasizes the unique conundrum posed by this unusual cluster population.

1′-Methyl-4′-(1-naphth­yl)-3′′-(1-naphthyl­methyl­ene)acenaphthene-1-spiro-2′-pyrrolidine-3′-spiro-1′′-cyclo­hexane-2,2′′-dione

PubMed Central

Athimoolam, S.; Radha, V. Anu; Bahadur, S. Asath; Kumar, R. Ranjith; Perumal, S.

2008-01-01

In the title compound, C42H33NO2, the six-membered cyclo­hexa­none ring adopts a slightly distorted chair conformation and the five-membered pyrrolidine ring is in an envelope conformation. The mol­ecular structure features four intra­molecular C—H⋯O inter­actions and an intra­molecular C—H⋯π inter­action. Furthermore, the crystal packing is stabilized by an inter­molecular C—H⋯O and three inter­molecular C—H⋯π inter­actions. PMID:21200972

beta-1,2,3-Triazolyl-nucleosides as nicotinamide riboside mimics.

PubMed

Amigues, E J; Armstrong, E; Dvorakova, M; Migaud, M E; Huang, M

2009-03-01

The synthesis of a series of pyridine- and piperidine-substituted 1,2,3-triazolides linked to a riboside moiety is described. The presence of a triazolide substituent on the pyridine moiety permitted the facile reduction of the latter under mild hydrogenation conditions. These analogues were modelled as to define their similarity to nicotinamide riboside and quantify their ability to bind NAD-dependent protein deacetylases.

Chemoselective room temperature E1cB N-N cleavage of oxazolidinone hydrazides from enantioselective aldehyde α-hydrazination: synthesis of (+)-1,4-dideoxyallonojirimycin.

PubMed

Ferreira, Jasmin; Rees-Jones, Sophie C M; Ramaotsoa, Valerie; Msutu, Ath'enkosi; Hunter, Roger

2016-02-07

Room temperature E1cB N-N cleavage of oxazolidinone hydrazides via N-alkylation with diethyl bromomalonate and potassium or caesium carbonate as base in acetonitrile is presented. The new method has a much improved chemoselectivity, which is illustrated by a concise total synthesis of the piperidine iminosugar (+)-1,4-dideoxyallonojirimycin.

Piperidine alkaloids from Piperretrofractum Vahl. protect against high-fat diet-induced obesity by regulating lipid metabolism and activating AMP-activated protein kinase

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kim, Kyung Jin; Lee, Myoung-Su; Jo, Keunae

Highlights: {yields} Piperidine alkaloids from Piperretrofractum Vahl. (PRPAs), including piperine, pipernonaline, and dehydropipernonaline, are isolated as the anti-obesity constituents. {yields} PRPA administration significantly reduces body weight gain without altering food intake and fat pad mass. {yields} PRPA reduces high-fat diet-induced triglyceride accumulation in liver. {yields} PRPAs attenuate HFD-induced obesity by activating AMPK and PPAR{delta}, and regulate lipid metabolism, suggesting their potential anti-obesity effects. -- Abstract: The fruits of Piperretrofractum Vahl. have been used for their anti-flatulent, expectorant, antitussive, antifungal, and appetizing properties in traditional medicine, and they are reported to possess gastroprotective and cholesterol-lowering properties. However, their anti-obesity activity remainsmore » unexplored. The present study was conducted to isolate the anti-obesity constituents from P. retrofractum Vahl. and evaluate their effects in high-fat diet (HFD)-induced obese mice. Piperidine alkaloids from P. retrofractum Vahl. (PRPAs), including piperine, pipernonaline, and dehydropipernonaline, were isolated as the anti-obesity constituents through a peroxisome proliferator-activated receptor {delta} (PPAR{delta}) transactivation assay. The molecular mechanism was investigated in 3T3-L1 adipocytes and L6 myocytes. PRPA treatment activated AMP-activated protein kinase (AMPK) signaling and PPAR{delta} protein and also regulated the expression of lipid metabolism-related proteins. In the animal model, oral PRPA administration (50, 100, or 300 mg/kg/day for 8 weeks) significantly reduced HFD-induced body weight gain without altering the amount of food intake. Fat pad mass was reduced in the PRPA treatment groups, as evidenced by reduced adipocyte size. In addition, elevated serum levels of total cholesterol, low-density lipoprotein cholesterol, total lipid, leptin, and lipase were suppressed by PRPA treatment. PRPA also protected against the development of nonalcoholic fatty liver by decreasing hepatic triglyceride accumulation. Consistent with the in vitro results, PRPA activated AMPK signaling and altered the expression of lipid metabolism-related proteins in liver and skeletal muscle. Taken together, these findings demonstrate that PRPAs attenuate HFD-induced obesity by activating AMPK and PPAR{delta}, and regulate lipid metabolism, suggesting their potential anti-obesity effects.« less

Novel types of tetra-, hexa-, octa-, and dodecanuclear silver clusters containing (2,7-Di-tert-butylfluoren-9-ylidene)methanedithiolate.

PubMed

Vicente, José; González-Herrero, Pablo; García-Sánchez, Yolanda; Jones, Peter G

2009-03-02

The reaction of AgClO(4) with piperidinium 2,7-di-tert-butyl-9H-fluorene-9-carbodithioate (pipH)[S(2)C(t-Bu-Hfy)] (1) (t-Bu-Hfy = 2,7-di-tert-butylfluoren-9-yl) afforded [Ag(n){S(2)C(t-Bu-Hfy)}(n)] (2), which reacted with phosphines to give [Ag{S(2)C(t-Bu-Hfy)}L(2)] [L = PPh(3) (3a); L(2) = bis(diphenylphosphino)ethane (dppe, 3b), 1,1'-bis(diphenylphosphino)ferrocene (dppf, 3c). By reacting complex 2 with AgClO(4) and piperidine in a 1:1:1 molar ratio, the dodecanuclear cluster [Ag(12){S(2)C(t-Bu-fy)}(6)] (4) (t-Bu-fy = 2,7-di-tert-butylfluoren-9-ylidene) was obtained. Compound 4 can also be directly prepared from the reaction of 1 with AgClO(4) and piperidine in a 1:2:1 molar ratio. The reactions of 1 with AgClO(4), phosphines, and piperidine afforded the compounds [Ag(6){S(2)C(t-Bu-fy)}(3)L(5)] [1:2:2:1 molar ratio; L = PPh(3) (5a), P(p-To)(3) (5b)], [Ag(4){S(2)C(t-Bu-fy)}(2)(dppf)(2)] (6) (1:2:1:1 molar ratio), [Ag(n){S(2)C(t-Bu-fy)}(n/2){P(i-Pr)(3)}(n)] (7) (1:2:2:1 molar ratio), or [Ag(8){S(2)C(t-Bu-fy)}(4){P(i-Pr)(3)}(4)] (8) (1:2:1:1 molar ratio). Complexes 5a,b, 6, 7, and 8 can be also obtained by reacting 4 with the corresponding phosphine in the appropriate molar ratio. The crystal structures of 4, 5b, and 8 have been determined by X-ray diffraction studies. The nuclearity of complex 6 was established from its (31)P{(1)H} NMR data, which reveal a very fast dynamic process leading to an average coupling of each of the P atoms of the dppf ligands with four Ag atoms.

Morphology and variability of the Titan ringlet and Huygens ringlet edges

NASA Astrophysics Data System (ADS)

Jerousek, Richard G.; Colwell, Joshua E.; Esposito, Larry W.

2011-11-01

We present a forward modeling approach for determining, in part, the ring particle spatial distribution in the vicinity of sharp ring or ringlet edges. Synthetic edge occultation profiles are computed based on a two-parameter particle spatial distribution model. One parameter, h, characterizes the vertical extent of the ring and the other, δ, characterizes the radial scale over which the ring optical depth transitions from the background ring value to zero. We compare our synthetic occultation profiles to high resolution stellar occultation light curves observed by the Cassini Ultraviolet Imaging Spectrograph (UVIS) High Speed Photometer (HSP) for occultations by the Titan ringlet and Huygens ringlet edges. More than 100 stellar occultations of the Huygens ringlet and Titan ringlet edges were studied, comprising 343 independent occultation cuts of the edges of these two ringlets. In 237 of these profiles the measured light-curve was fit well with our two-parameter edge model. Of the remaining edge occultations, 69 contained structure that could only be fit with extremely large values of the ring-plane vertical thickness ( h > 1 km) or by adopting a different model for the radial profile of the ring optical depth. An additional 37 could not be fit by our two-parameter model. Certain occultations at low ring-plane incidence angles as well as occultations nearly tangent to the ring edge allow the direct measurement of the radial scale over which the particle packing varies at the edge of the ringlet. In 24 occultations with these particular viewing geometries, we find a wide variation in the radial scale of the edge. We are able to constrain the vertical extent of the rings at the edge to less than ˜300 m in the 70% of the occultations with appropriate viewing geometry, however tighter constraints could not be placed on h due to the weaker sensitivity of the occultation profile to vertical thickness compared to its sensitivity to δ. Many occultations of a single edge could not be fit to a single value of δ, indicating large temporal or azimuthal variability, although the azimuthal variation in δ with respect to the longitudes of various moons in the system did not show any discernible pattern.

Ringing in an HNBody Upgrade

NASA Astrophysics Data System (ADS)

Rimlinger, Thomas; Hamilton, Douglas; Hahn, Joseph M.

2017-06-01

We are in the process of developing a useful extension to the N-body integrator HNBody (Rauch & Hamilton 2002), enabling it to simulate a viscous, self-gravitating ring orbiting an oblate body. Our algorithm follows that used in the symplectic integrator epi_int (Hahn & Spitale 2013), in which the ring is simulated as many (~100) interacting, elliptic, confocal streamlines. This idea was first introduced in an analytic context by Goldreich & Tremaine (1979) and enabled rapid progress in the theory of ring evolution; since then, such discretization has been standard in the literature. While we adopt epi_int’s streamline formalism, we nevertheless improve upon its design in several ways. Epi_int uses epicyclic elements in its drift step; approximating these elements introduces small, systematic errors that build up with time. We sidestep this problem by instead using the more traditional Keplerian osculating elements. In addition, epi_int uses several particles per wire to effectively calculate the inter-gravitational forces everywhere along each streamline. We replicate this ability but can often gain a speed boost by using a single tracer particle per streamline; while this restricts us to simulating rings dominated by the m = 1 mode, this is typical of most observed narrow eccentric ringlets. We have also extended epi_int’s two dimensional algorithm into 3D. Finally, whereas epi_int is written in IDL, HNBody is written in C, which yields considerably faster integrations.Braga-Ribas et al. (2014) reported a set of narrow rings orbiting the Centaur Chariklo, but neither their investigation nor that of Pan & Wu (2016) yielded a satisfactory origin and evolution scenario. Eschewing the assumption that such rings must be short-lived, we instead argue (as in Rimlinger et al. 2016) that sufficiently eccentric rings can self-confine for hundreds of millions of years while circularizing. In this case, Chariklo may have formed rings as a KBO. We are working towards demonstrating both the feasibility of this theory and the utility of the HNBody extension by using it to simulate such a ring around Chariklo.

A combined variable temperature 600 MHz NMR/MD study of the calcium release agent cyclic adenosine diphosphate ribose (cADPR): Structure, conformational analysis, and thermodynamics of the conformational equilibria.

PubMed

Javornik, Uroš; Plavec, Janez; Wang, Baifan; Graham, Steven M

2018-01-02

A combined variable temperature 600 MHz NMR/molecular dynamics study of the Ca 2+ -release agent cyclic adenosine 5'-diphosphate ribose (cADPR) was conducted. In addition to elucidating the major and minor orientations of the conformationally flexible furanose rings, γ- (C4'-C5'), and β- (C5'-O5') bonds, the thermodynamics (ΔH o , ΔS o ) associated with each of these conformational equilibria were determined. Both furanose rings were biased towards a south conformation (64-74%) and both β-bonds heavily favored trans conformations. The R-ring γ-bond was found to exist almost exclusively as the γ + conformer, whereas the A-ring γ-bond was a mixture of the γ + and γ t conformers, with the trans conformer being slightly favored. Enthalpic factors accounted for most of the observed conformational preferences, although the R-ring furanose exists as its major conformation based solely on entropic factors. There was excellent agreement between the NMR and MD results, particularly with regard to the conformer identities, but the MD showed a bias towards γ + conformers. The MD results showed that both N-glycosidic χ-bonds are exclusively syn. Collectively the data allowed for the construction of a model for cADPR in which many of the conformationally flexible units in fact effectively adopt single orientations and where most of the conformational diversity resides in its A-ring furanose and γ-bond. Copyright © 2017 Elsevier Ltd. All rights reserved.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kozikowski, Alan P.; Gunosewoyo, Hendra; Guo, Songpo

Bipolar disorder is characterized by a cycle of mania and depression, which affects approximately 5 million people in the United States. Current treatment regimes include the so-called 'mood-stabilizing drugs', such as lithium and valproate that are relatively dated drugs with various known side effects. Glycogen synthase kinase-3{beta} (GSK-3{beta}) plays a central role in regulating circadian rhythms, and lithium is known to be a direct inhibitor of GSK-3{beta}. We designed a series of second generation benzofuran-3-yl-(indol-3-yl)maleimides containing a piperidine ring that possess IC{sub 50} values in the range of 4 to 680 nM against human GSK-3{beta}. One of these compounds exhibitsmore » reasonable kinase selectivity and promising preliminary absorption, distribution, metabolism, and excretion (ADME) data. The administration of this compound at doses of 10 to 25 mg kg{sup -1} resulted in the attenuation of hyperactivity in amphetamine/chlordiazepoxide-induced manic-like mice together with enhancement of prepulse inhibition, similar to the effects found for valproate (400 mg kg{sup -1}) and the antipsychotic haloperidol (1 mg kg{sup -1}). We also tested this compound in mice carrying a mutation in the central transcriptional activator of molecular rhythms, the CLOCK gene, and found that the same compound attenuates locomotor hyperactivity in response to novelty. This study further demonstrates the use of inhibitors of GSK-3{beta} in the treatment of manic episodes of bipolar/mood disorders, thus further validating GSK-3{beta} as a relevant therapeutic target in the identification of new therapies for bipolar patients.« less

"These Things Do Not Ring True to Me": Preservice Teacher Dispositions to Social Justice Literature in a Remote State Teacher Education Program

ERIC Educational Resources Information Center

Han, Keonghee Tao

2013-01-01

This study describes preservice teachers' (PTs) dispositions toward diversity education in a remote small town university. The purpose of the study is to find out whether PTs in an undergraduate elementary literacy methods class in this locale are willing to accept and adopt multicultural children's and youth literature as pedagogical tools and…

2-[Anilino(phen­yl)meth­yl]cyclo­heptan­one

PubMed Central

Eftekhari-Sis, Bagher; Mohajer, Sahar; Zirak, Maryam; Mozaffarnia, Sakineh; Büyükgüngör, Orhan

2013-01-01

In the title compound, C20H23NO, the cyclo­hepta­none ring adopts a twist-chair conformation, with the amino­methyl substituent in an equatorial position. The relative configuration of the two stereocenters is R,R. In the crystal, mol­ecules are linked by N—H⋯O hydrogen bonds into chains along [100]. PMID:23476371

A Thumbwheel Mechanism for APOA1 Activation of LCAT Activity in HDL.

PubMed

Cooke, Allison L; Morris, Jamie; Melchior, John T; Street, Scott E; Jerome, W Gray; Huang, Rong; Herr, Andrew B; Smith, Loren E; Segrest, Jere P; Remaley, Alan T; Shah, Amy S; Thompson, Thomas B; Davidson, W Sean

2018-05-17

APOA1 is the most abundant protein in HDL. It modulates interactions that affect HDLs cardioprotective functions, in part via its activation of the enzyme LCAT. On nascent, discoidal HDL, APOA1 comprises 10 alpha-helical repeats arranged in an anti-parallel, stacked-ring structure that encapsulates a lipid bilayer. Previous chemical cross-linking studies suggested that these APOA1 rings can adopt at least two different orientations, or registries, with respect to each other; however, the functional impact of these structural changes is unknown. Here, we placed Cys-residues at locations predicted to form disulfide bonds in each orientation and then measured APOA1s ability to adopt the two registries during HDL particle formation. We found that most APOA1 oriented with the fifth helix of one molecule across from fifth helix of the other (5/5 helical registry), but a fraction adopted a 5/2 registry. Engineered HDL that were locked in 5/5 or 5/2 registries by disulfide bonds equally promoted cholesterol efflux from macrophages - indicating functional particles. However, unlike the 5/5 registry or the wild-type, the 5/2 registry impaired LCAT cholesteryl esterification activity (p<0.001), despite LCAT binding equally to all particles. Chemical cross-linking studies suggest that full LCAT activity requires a hybrid epitope composed of helices 5-7 on one APOA1 molecule and 3-4 on the other. Thus, APOA1 may use a reciprocating, thumbwheel-like mechanism to activate HDL-remodeling proteins. Published under license by The American Society for Biochemistry and Molecular Biology, Inc.

Ballistic Transport: After the Cassini Grand Finale, is there a Final Consensus on Ring Origin and Age?

NASA Astrophysics Data System (ADS)

Estrada, P. R.; Durisen, R. H.; Cuzzi, J. N.

2017-12-01

As the Cassini mission comes to its much anticipated end, somewhat befittingly to be immortalized and enshrined for all time within the gaseous confines of a planet named for the Greek god of time (Kronos), we find the time appropriate to return to the subject of ring age and origin. During Cassini's remarkable tenure, important measurements have been obtained that can help to elucidate and perhaps settle the debate once and for all on whether the rings are young or old. At the forefront lie the results of the Cassini Dust Analyzer (CDA) experiment which indicate that the range of the micrometeoroid flux at infinity for Saturn are comparable to the nominal value of the meteoroid flux value currently adopted for use in ballistic transport (BT) applications and models (Estrada et al., 2015, 2017). Moreover, the source of the micrometeoroid flux has been localized to the Edgeworth-Kuiper Belt (EKB) and is not cometary in origin as previously assumed (Altobelli et al., 2015). A major consequence of these measurements is that the EKB flux is much more gravitationally focused increasing the impact flux on the rings by a factor of ˜25 relative to cometary. This implies that the process of micrometeoroid bombardment and BT is likely even more influential in the rings' structural and compositional evolution over time. This measurement taken together with recent analysis of the bulk mass fraction of non-icy constituents (Zhang et al., 2017a,b) using Cassini radiometry data argue strongly for young rings. Another observation that will help to provide a constraint (though not absolute) is the pending measurement of the (B) ring mass. A high mass estimate as argued by some does not necessarily mean old rings, whereas a low mass ring would certainly imply as much. There are several factors that can offer insight on to the age of the rings from BT modeling, such as saturation of the ramp(s), color differences across the B-C (A-CD) boundaries, color differences across plateaus, in addition to the (hopefully) soon to be known mass of the B ring vis-à-vis the observed non-icy constituent mass fractions, which we will be discussed.

High-resolution VLBA Observations of Three 7 mm SiO Masers toward VX Sgr at Five Epochs

NASA Astrophysics Data System (ADS)

Su, J. B.; Shen, Z.-Q.; Chen, X.; Yi, Jiyune; Jiang, D. R.; Yun, Y. J.

2012-07-01

VX Sgr is a red supergiant at an adopted distance of 1.6 kpc with intense 43 GHz SiO maser emission. In this paper, we present the high-resolution very long baseline interferometry (VLBI) observations of SiO masers toward VX Sgr at five epochs. We used the Very Long Baseline Array to map the J = 1→0 (v = 1, 2) 28SiO masers and confirmed a ring-like structure. In the first two epochs, the v = 1 masers form a ring, but v = 2 maser spots residing only in the southern and northern regions do not form a complete ring. In the third epoch, the two masers are distributed in a ring structure and the v = 2 masers are a bit closer to the central star. In the last two epochs, many new maser spots appear and overlap each other. These overlapping maser spots can be related to the shock waves and reflect the collisional pumping. We compare the observations with the pumping models and speculate that the real pumping mechanism may be complex in VX Sgr and vary with time. The J = 1→0 (v = 0) 29SiO line emission is also detected, but is too weak to produce any VLBI map.

A 1kW EUV source for lithography based on FEL emission in a compact storage ring

NASA Astrophysics Data System (ADS)

Feser, Michael; Ruth, Ron; Loewen, Rod

2017-10-01

EUV has long been hailed as the next generation lithography technology. Its adoption into high volume manufacturing (HVM), however, has been delayed several technology nodes due to technical issues, many of which can be attributed to the EUV source performance. Today's EUV lithography scanners are powered by laser produce plasma (LPP) sources. They have issues with power scaling beyond 300 W, reliability and contamination. Free Electron Lasers (FELs) have been considered as an alternative EUV source. Advantages of accelerator based sources are the maturity of the accelerator technology, lack of debris/contamination, and ability to provide high power. Industry turned away from this technology because of the requirement to feed up to 10 scanners from one linear FEL to make it economically feasible, the large footprint, and generation of radioactive byproducts. All of these issues are overcome in the presented concept using a compact storage ring with steady-state FEL lasing action. At 1 kW output power, comparable cost and footprint to an LPP source, this source is ideally suited for use on a single scanner and promises reliable, contamination free operation. FEL action in the storage ring is sustained by operating the FEL well below the saturation regime and preserving the equilibrium low emittance and energy distribution of the ring.

4-[(1-Benzyl-1H-1,2,3-triazol-4-yl)meth-oxy]benzene-1,2-dicarbo-nitrile: crystal structure, Hirshfeld surface analysis and energy-minimization calculations.

PubMed

Shamsudin, Norzianah; Tan, Ai Ling; Young, David J; Jotani, Mukesh M; Otero-de-la-Roza, A; Tiekink, Edward R T

2016-04-01

In the solid state, the title compound, C18H13N5O, adopts a conformation whereby the phenyl ring and meth-oxy-benzene-1,2-dicarbo-nitrile residue (r.m.s. deviation of the 12 non-H atoms = 0.041 Å) lie to opposite sides of the central triazolyl ring, forming dihedral angles of 79.30 (13) and 64.59 (10)°, respectively; the dihedral angle between the outer rings is 14.88 (9)°. This conformation is nearly 7 kcal mol(-1) higher in energy than the energy-minimized structure which has a syn disposition of the outer rings, enabling intra-molecular π-π inter-actions. In the crystal, methyl-ene-C-H⋯N(triazol-yl) and carbo-nitrile-N⋯π(benzene) inter-actions lead to supra-molecular chains along the a axis. Supra-molecular layers in the ab plane arise as the chains are connected by benzene-C-H⋯N(carbo-nitrile) inter-actions; layers stack with no directional inter-actions between them. The specified inter-molecular contacts along with other, weaker contributions to the supra-molecular stabilization are analysed in a Hirshfeld surface analysis.

Improving the Ionospheric Auroral Conductance in a Global Ring Current Model and the Effects on the Ionospheric Electrodynamics

NASA Astrophysics Data System (ADS)

Yu, Y.; Jordanova, V. K.; McGranaghan, R. M.; Solomon, S. C.

2017-12-01

The ionospheric conductance, height-integrated electric conductivity, can regulate both the ionospheric electrodynamics and the magnetospheric dynamics because of its key role in determining the electric field within the coupled magnetosphere-ionosphere system. State-of-the-art global magnetosphere models commonly adopt empirical conductance calculators to obtain the auroral conductance. Such specification can bypass the complexity of the ionosphere-thermosphere chemistry but on the other hand breaks the self-consistent link within the coupled system. In this study, we couple a kinetic ring current model RAM-SCB-E that solves for anisotropic particle distributions with a two-stream electron transport code (GLOW) to more self-consistently compute the height-dependent electric conductivity, provided the auroral electron precipitation from the ring current model. Comparisons with the traditional empirical formula are carried out. It is found that the newly coupled modeling framework reveals smaller Hall and Pedersen conductance, resulting in a larger electric field. As a consequence, the subauroral polarization streams demonstrate a better agreement with observations from DMSP satellites. It is further found that the commonly assumed Maxwellian spectrum of the particle precipitation is not globally appropriate. Instead, a full precipitation spectrum resulted from wave particle interactions in the ring current accounts for a more comprehensive precipitation spectrum.

77 FR 75082 - Notice of Receipt of Several Pesticide Petitions Filed for Residues of Pesticide Chemicals in or...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-12-19

...-dimethylethyl) phenyl]-2-methyl-propyl] piperidine in or on banana, unbagged fruit at 9 parts per million (ppm) and banana, pulp from unbagged fruit at 0.4 ppm using the Organization for Economic Cooperation and...- isomers, as a seed treatment in or on potato at 0.02 ppm and potato, wet peel at 0.06 ppm. Various crops...

A Catalytic Asymmetric Synthesis of Polysubstituted Piperidines Using a Rhodium (I) Catalyzed [2+2+2] Cycloaddition Employing a Cleavable Tether

PubMed Central

Martin, Timothy J.; Rovis, Tomislav

2013-01-01

An enantioselective rhodium (I) catalyzed [2+2+2] cycloaddition with a cleavable tether has been developed. The reaction proceeds with a variety of alkyne substrates in good yield and high enantioselectivity. Upon reduction of the vinylogous amide in high diastereoselectivity (>19:1) and cleavage of the tether, N-methylpiperidine products with functional group handles can be accessed. PMID:23606664

Drug Abuse and Criminal Violence in Urban Communities.

DTIC Science & Technology

1987-01-01

for smoking or freebasing. 6. Heroin: "Semisynthetic derivative of morphine. Chemical name is deacethylmorphine hydrochloride . Synthesized in 1898 in...is Sernyl. Chemical name is I-(l-phencyclohexyl) piperidine hydrochloride . Sold in the form of a white crystal or powder that can be injected, smoked...neurotransmitters... * - [. Usually sold in the form of capsules and tablets but also in powder or liquid form." 1 0 10. Methadone : "Synthetic narcotic less

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

PubMed

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.

Alkaloid venom weaponry of three Megalomyrmex thief ants and the behavioral response of Cyphomyrmex costatus host ants.

PubMed

Adams, Rachelle M M; Jones, Tappey H; Longino, John T; Weatherford, Robert G; Mueller, Ulrich G

2015-04-01

Social parasites exploit other societies by invading and stealing resources. Some enter protected nests using offensive chemical weaponry made from alkaloid-based venom. We characterized the venoms of three Megalomyrmex thief ant species (M. mondabora, M. mondaboroides, and M. silvestrii) that parasitize the fungus-growing ants, and developed an ethogram to describe host ant reactions to raiding M. mondaboroides and M. silvestrii parasites. We compared piperidine, pyrrolidine, and pyrolizidine venom alkaloid structures with synthetic samples from previous studies, and describe the novel stereochemistry of trans 2-hexyl-5-[8-oxononyl]-pyrrolidine (3) from M. mondabora. We showed that workers of Cyphomyrmex costatus, the host of M. mondaboroides and M. silvestrii, react to a sting by Megalomyrmex parasites mainly with submissive behavior, playing dead or retreating. Host submission also followed brief antennal contact. The behavior of C. costatus ants observed in this study was similar to that of Cyphomyrmex cornutus, host of M. mondabora, suggesting that the alkaloidal venoms with pyrrolidines from M. mondabora, piperidines from M. mondaboroides, and pyrolizidines from M. silvestrii may function similarly as appeasement and repellent allomones against host ants, despite their different chemical structure. With the use of these chemical weapons, the Megalomyrmex thief ants are met with little host resistance and easily exploit host colony resources.

Synthesis and evaluation of 4',5'-dihydrospiro[piperidine-4,7'-thieno[2,3-c]pyran] analogues against both active and dormant Mycobacterium tuberculosis.

PubMed

Alluri, Kiran Kumar; Reshma, Rudraraju Srilakshmi; Suraparaju, Raghuram; Gottapu, Suryanarayana; Sriram, Dharmarajan

2018-05-01

Need for new drugs to fight against tuberculosis (TB) is increasing day by day. In the present work we have taken a spiro compound (GSK 2200150A) reported by GSK as a lead and we modified the structure of the lead to study the antitubercular activity. For structure activity profiling twenty-one molecules have been synthesized, characterized and evaluated for their antimycobacterial potency against both active and dormant TB. Compound 06, 1-((4-methoxyphenyl)sulfonyl)-4',5'-dihydrospiro[piperidine-4,7'-thieno[2,3-c]pyran] was found to be the most potent compound (MIC: 8.23 µM) in active TB and was less effective than the lead but more potent than standard first line drug ethambutol. It was also found to be more efficacious than Isoniazid and Rifampicin and equipotent as Moxifloxacin against dormant Mycobacterium tuberculosis (MTB). Compound 06 also showed good inhibitory potential against over expressed latent MTB enzyme lysine ε-amino transferase with an IC 50 of 1.04 ± 0.32 µM. This compound is a good candidate for drug development owing to potential against both active and dormant stages of MTB. Copyright © 2017 Elsevier Ltd. All rights reserved.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mattia, A.; Marquis, K.L.; Leccese, A.P.

1988-08-01

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 inmore » 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 (/sup 3/H)PCP displacement experiments using crude rat brain homogenates.« less

Psychotomimetic opiate receptors labeled and visualized with (+)-(/sup 3/H)3-(3-hydroxyphenyl)-N-(1-propyl)piperidine

DOE Office of Scientific and Technical Information (OSTI.GOV)

Largent, B.L.; Gundlach, A.L.; Snyder, S.H.

1984-08-01

3-(3-Hydroxyphenyl)-N-(1-propyl)piperidine (3-PPP) has been proposed as a selective dopamine autoreceptor agonist in the central nervous system. This report describes the pharmacology and localization of specific high-affinity binding sites for (+)-(/sup 3/H)3-PPP in brain. The drug specificity of (+)-(/sup 3/H)3-PPP binding is identical to that of sigma receptors, which may mediate psychotomimetic effects of some opiates. Haloperidol and the opioid derivatives, pentazocine, cyclazocine, and SKF 10,047 are potent inhibitors of (+)-(/sup 3/H)3-PPP binding. Stereoselectivity is exhibited for the (+) isomers of cyclazocine and SKF 10.047 at the sigma site, opposite to the stereoselectivity seen at ..mu.., sigma, and k opiate receptors.more » (+)-(/sup 3/H)3-PPP does not label dopamine receptors, as potent dopamine agonists and antagonists are weak inhibitors of binding and the localization of specific (+)-(/sup 3/H)3-PPP binding sites does not parallel that of dopamine neurons. Discrete localizations of (+)-(/sup 3/H)3-PPP binding sites in many brain areas including limbic, midbrain, brainstem, and cerebellar regions may explain psychotomimetic actions of opiates and behavior effects of 3-PPP. 41 references, 2 figures, 1 table.« less

Synthesis and SARs of novel lincomycin derivatives Part 5: optimization of lincomycin analogs exhibiting potent antibacterial activities by chemical modification at the 6- and 7-positions.

PubMed

Wakiyama, Yoshinari; Kumura, Ko; Umemura, Eijiro; Masaki, Satomi; Ueda, Kazutaka; Sato, Yasuo; Hirai, Yoko; Hayashi, Yoshio; Ajito, Keiichi

2018-02-01

In order to modify lincomycin at the C-6 and C-7 positions, we prepared target molecules, which have substituted pipecolinic acid at the 6-amino group and a para-substituted phenylthio group at the C-7 position, in application of palladium-catalyzed cross-coupling as a key reaction. As the result of structure-activity relationship (SAR) studies at the 6-position, analogs possessing 4'-cis-(cyclopropylmethyl)piperidine showed significantly strong antibacterial activities against Streptococcus pneumoniae and Streptococcus pyogenes with an erm gene. On the basis of SAR, we further synthesized novel analogs possessing 4'-cis-(cyclopropylmethyl)piperidine by transformation of a C-7 substituent. Consequently, novel derivatives possessing a para-heteroaromatic-phenylthio group at the C-7 position exhibited significantly strong activities against S. pneumoniae and S. pyogenes with an erm gene even when compared with those of telithromycin. Finally, in vivo efficacy of selected two derivatives was evaluated in a rat pulmonary infection model with resistant S. pneumoniae with erm + mef genes. One of them exhibited strong and constant in vivo efficacy in this model, and both compounds showed strong in vivo efficacy against resistant S. pneumoniae with a mef gene.

Pyrolytic fate of piperidinocyclohexanecarbonitrile, a contaminant of phencyclidine, during smoking

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lue, L.P.; Scimeca, J.A.; Thomas, B.F.

The pyrolysis products of 1-(1-piperidino)cyclo-hexanecarbonitrile (PCC), the major contaminant of illicit phencyclidine (PCP), have not been previously reported. In order to quantify PCC in mainstream smoke as well as to identify the pyrolysis products, (/sup 3/H)piperidino-(/sup 14/C)cyano-PCC was synthesized. Marijuana placebo cigarettes were impregnated with this double-labeled PCC and burned with an apparatus that simulated smoking. The mainstream smoke was passed through a series of traps containing glass wool, H/sub 2/SO/sub 4/, or NaOH. Approximately 75% of the /sup 3/H was collected in these traps, and 46, 11, and 5% of the /sup 14/C was found in the glass wool,more » H/sub 2/SO/sub 4/, and NaOH traps, respectively. Contents of the traps were analyzed by GC/MS. The glass wool trap contained 1-(1-piperidino)-1-cyclo-hexene, PCC, piperidine, and N-acetylpiperidine, and cyanide ion was detected in all three traps. Approximately 47% of the PCC was found intact in mainstream smoke. Approximately 58% was cleaved to form cyanide and 1-(1-piperidino)-1-cyclohexene. The latter was further broken down to cyclohexanone (which represented 21% of the starting material), piperidine (29%), and N-acetylpiperidine (7%), and about 2% remained intact.« less

6-[3-(p-Tolyl­sulfonyl­amino)­prop­yl]diquino­thia­zine1

PubMed Central

Jeleń, Małgorzata; Shkurenko, Aleksander; Suwińska, Kinga; Pluta, Krystian; Morak-Młodawska, Beata

2013-01-01

In the title mol­ecule {systematic name: N-[3-(diquino[3,2-b;2′,3′-e][1,4]thia­zin-6-yl)prop­yl]-4-methyl­benzene­sulfon­amide}, C28H24N4O2S2, the penta­cyclic system is relatively planar [maximum deviation from the mean plane = 0.242 (1) Å]. The dihedral angle between two quinoline ring systems is 8.23 (2)° and that between the two halves of the 1,4-thia­zine ring is 5.68 (3)°. The conformation adopted by the 3-(p-tolyl­sulfonyl­amino)­propyl substituent allows for the formation of an intra­molecular N—H⋯N hydrogen bond and places the benzene ring of this substituent above one of the quinoline fragments of the penta­cyclic system. In the crystal, mol­ecules are arranged via π–π stacking inter­actions into (0-11) layers [centroid–centroid distances = 3.981 (1)–4.320 (1) Å for the rings in the penta­cyclic system and 3.645 (1) Å for the tolyl benzene rings]. In addition, mol­ecules are involved in weak C—H⋯O, which connect the layers, and C—H⋯S hydrogen bonds. The title compound shows promising anti­cancer activity against renal cancer cell line UO-31. PMID:23795128

A temperature monitor circuit with small voltage sensitivity using a topology-reconfigurable ring oscillator

NASA Astrophysics Data System (ADS)

Kishimoto, Tadashi; Ishihara, Tohru; Onodera, Hidetoshi

2018-04-01

In this paper, we propose a temperature monitor circuit that exhibits a small supply voltage sensitivity adopting a circuit topology of a reconfigurable ring oscillator. The circuit topology of the monitor is crafted such that the oscillation frequency is determined by the amount of subthreshold leakage current, which has an exponential dependence on temperature. Another important characteristic of the monitor is its small supply voltage sensitivity. The measured oscillation frequency of a test chip fabricated in a 65 nm CMOS process varies only 2.6% under a wide range of supply voltages from 0.4 to 1.0 V at room temperature. The temperature estimation error ranges from -0.3 to 0.4 °C over a temperature range of 10 to 100 °C.

N-(2,3-Dimethyl­phen­yl)-4-hydr­oxy-2-methyl-2H-1,2-benzothia­zine-3-carboxamide 1,1-dioxide

PubMed Central

Siddiqui, Waseeq Ahmad; Bukahari, Iftikhar Hussain; Zia-ur-Rehman, Muhammad; Khan, Islam Ullah; Tizzard, Graham John

2009-01-01

In the crystal structure of the title compound, C18H18N2O4S, the thia­zine ring adopts a distorted half-chair conformation. 1,2-Benzothia­zines of this kind have a wide range of biological activities and are mainly used as medicines in the treatment of inflammation and rheumatoid arthritis. The enolic H atom is involved in an intra­molecular O—H⋯O hydrogen bond, forming a six-membered ring. The mol­ecules arrange themselves into centrosymmetric dimers by means of inter­molecular N—H⋯O hydrogen bonds. A weak inter­molcular C—H⋯O inter­action is also present. PMID:21582293

Design and Dynamic Modeling of Flexible Rehabilitation Mechanical Glove

NASA Astrophysics Data System (ADS)

Lin, M. X.; Ma, G. Y.; Liu, F. Q.; Sun, Q. S.; Song, A. Q.

2018-03-01

Rehabilitation gloves are equipment that helps rehabilitation doctors perform finger rehabilitation training, which can greatly reduce the labour intensity of rehabilitation doctors and make more people receive finger rehabilitation training. In the light of the defects of the existing rehabilitation gloves such as complicated structure and stiff movement, a rehabilitation mechanical glove is designed, which provides driving force by using the air cylinder and adopts a rope-spring mechanism to ensure the flexibility of the movement. In order to fit the size of different hands, the bandage ring which can adjust size is used to make the mechanism fixed. In the interest of solve the complex problem of dynamic equation, dynamic simulation is carried out by using Adams to obtain the motion curve, which is easy to optimize the structure of ring position.

4′,5-Dihy­droxy-7-meth­oxy­flavanone dihydrate

PubMed Central

Brito, Iván; Bórquez, Jorge; Simirgiotis, Mario; Cárdenas, Alejandro; López-Rodríguez, Matías

2012-01-01

The title compound, C16H14O5·2H2O [systematic name: 5-hy­droxy-2-(4-hy­droxy­phen­yl)-7-meth­oxy­chroman-4-one dihydrate], is a natural phytoalexin flavone isolated from the native chilean species Heliotropium taltalense and crystallizes with an organic mol­ecule and two water mol­ecules in the asymmetric unit. The 5-hy­droxy group forms a strong intra­molecular hydrogen bond with the carbonyl group, resulting in a six-membered ring. In the crystal, the components are linked by O—H⋯O hydrogen bonds, forming a three-dimensional network. The 4-hy­droxy­phenyl benzene ring is bonded equatorially to the pyrone ring, which adopts a slightly distorted sofa conformation. The title compound is the hydrated form of a previously reported structure [Shoja (1990 ▶). Acta Cryst. C46, 1969–1971]. There are only slight variations in the mol­ecular geometry between the two compounds. PMID:22259537

A model for particle confinement in a toroidal plasma subject to strong radial electric fields

NASA Technical Reports Server (NTRS)

Roth, J. R.

1977-01-01

The approach adopted in the NASA Lewis Bumpy Torus experiment is to confine and heat a toroidal plasma by the simultaneous application of strong dc magnetic fields and electric fields. Strong radial electric fields (about 1 kV/cm) are imposed by biasing the plasma with up to 12 negative electrode rings which surround its minor circumference. The plasma containment is consistent with a balance of two processes: a radial infusion of ions in those sectors not containing electrode rings, resulting from the radially inward electric fields; and ion losses to the electrode rings, each of which acts as a sink and draws ions out the plasma in the manner of a Langmuir probe in the ion saturation regime. The highest density on axis which has been observed so far in this steady-state plasma is 6.2 trillion particles per cu cm, for which the particle containment time is 2.5 msec. The deuterium ion kinetic temperature for these conditions was in the range of 360 to 520 eV.

Individualistic and Time-Varying Tree-Ring Growth to Climate Sensitivity

PubMed Central

Carrer, Marco

2011-01-01

The development of dendrochronological time series in order to analyze climate-growth relationships usually involves first a rigorous selection of trees and then the computation of the mean tree-growth measurement series. This study suggests a change in the perspective, passing from an analysis of climate-growth relationships that typically focuses on the mean response of a species to investigating the whole range of individual responses among sample trees. Results highlight that this new approach, tested on a larch and stone pine tree-ring dataset, outperforms, in terms of information obtained, the classical one, with significant improvements regarding the strength, distribution and time-variability of the individual tree-ring growth response to climate. Moreover, a significant change over time of the tree sensitivity to climatic variability has been detected. Accordingly, the best-responder trees at any one time may not always have been the best-responders and may not continue to be so. With minor adjustments to current dendroecological protocol and adopting an individualistic approach, we can improve the quality and reliability of the ecological inferences derived from the climate-growth relationships. PMID:21829523

Structures of NADH and CH[subscript 3]-H[subscript 4] Folate Complexes of Escherichia coli Methylenetetrahydrofolate Reductase Reveal a Spartan Strategy for a Ping-Pong Reaction

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pejchal, Robert; Sargeant, Ryan; Ludwig, Martha L.

Methylenetetrahydrofolate reductases (MTHFRs; EC 1.7.99.5) catalyze the NAD(P)H-dependent reduction of 5,10-methylenetetrahydrofolate (CH{sub 2}-H{sub 4}folate) to 5-methyltetrahydrofolate (CH{sub 3}-H{sub 4}folate) using flavin adenine dinucleotide (FAD) as a cofactor. The initial X-ray structure of Escherichia coli MTHFR revealed that this 33-kDa polypeptide is a ({beta}{alpha}){sub 8} barrel that aggregates to form an unusual tetramer with only 2-fold symmetry. Structures of reduced enzyme complexed with NADH and of oxidized Glu28Gln enzyme complexed with CH{sub 3}-H{sub 4}folate have now been determined at resolutions of 1.95 and 1.85 {angstrom}, respectively. The NADH complex reveals a rare mode of dinucleotide binding; NADH adopts a hairpin conformationmore » and is sandwiched between a conserved phenylalanine, Phe223, and the isoalloxazine ring of FAD. The nicotinamide of the bound pyridine nucleotide is stacked against the si face of the flavin ring with C4 adjoining the N5 of FAD, implying that this structure models a complex that is competent for hydride transfer. In the complex with CH{sub 3}-H{sub 4}folate, the pterin ring is also stacked against FAD in an orientation that is favorable for hydride transfer. Thus, the binding sites for the two substrates overlap, as expected for many enzymes that catalyze ping-pong reactions, and several invariant residues interact with both folate and pyridine nucleotide substrates. Comparisons of liganded and substrate-free structures reveal multiple conformations for the loops {beta}2-{alpha}2 (L2), {beta}3-{alpha}3 (L3), and {beta}4-{alpha}4 (L4) and suggest that motions of these loops facilitate the ping-pong reaction. In particular, the L4 loop adopts a 'closed' conformation that allows Asp120 to hydrogen bond to the pterin ring in the folate complex but must move to an 'open' conformation to allow NADH to bind.« less

QSAR analyses of 3-(4-benzylpiperidin-1-yl)-N-phenylpropylamine derivatives as potent CCR5 antagonists.

PubMed

Roy, Kunal; Leonard, J Thomas

2005-01-01

CCR5 receptor binding affinity of a series of 3-(4-benzylpiperidin-1-yl)propylamine congeners was subjected to QSAR study using the linear free energy related (LFER) model of Hansch. Appropriate indicator variables encoding different group contributions and different physicochemical variables such as hydrophobicity (pi), electronic (Hammett sigma), and steric (molar refractivity, STERIMOL values) parameters of phenyl ring substituents of the compounds were used as predictor variables. The Hansch analysis explores the importance of the lipophilicity and electron-donating substituents for the binding affinity. However, this method could not give more insight into the structure-activity relationships because of the diverse molecular features in the data set. 3D-QSAR analyses of the same data set using Molecular Shape Analysis (MSA), Receptor Surface Analysis (RSA), and Molecular Field Analysis (MFA) techniques were also performed. The best model with acceptable statistical quality was derived from the MSA, which showed the importance of the relative negative charge (RNCG): substituents with a high RNCG value have more binding affinity than the unsubstituted piperidine and phenyl (R1 position) congeners. The relative negative charge surface area (RNCS) is detrimental (e.g. R2 = 3,4-Cl2) for the activity. An increase in the length of the molecule in the Z dimension (Lz) is conducive (e.g. R3 = sulfonylmorpholino), while an increase in the area of the molecular shadow in the XZ plane (Sxz) is detrimental (e.g. R1 = N-c-hexylmethyl-5-oxopyrrolidin-3-yl) for the binding affinity. The presence of a chiral center makes the molecule less active (e.g. R1 = N-methyl-5-oxopyrrolidin-3-yl). An increase in the van der Waals area, the molecular volume, and the difference between the volume of the individual molecule and the shape reference compound are conducive (e.g. R3 = (CH3)2NSO2-) for the binding affinity. Substituents with higher JursFPSA_2 values (fractional charged partial surface area) like the N-methylsulfonylpiperidin-4-yl (R1 position) group have better binding affinity than the substituents such as 4-chlorophenylamino (R1 position). Unsubstituted piperidines (R1 position) with less JursFNSA_1 values have lower binding affinity than the 4-chlorophenyl substituted compounds. The MFA derived equation shows interaction energies at different grid points, while the RSA model shows the importance of hydrophobicity and charge at different regions of the molecules. The models were validated through the leave-one-out, leave-15%-out, and leave-25%-out cross-validation techniques. The developed models were also subjected to a randomization test (99% confidence level). Although the MSA derived models had excellent statistical qualities both for the training as well as test sets, RSA and MFA results for the test sets are not comparable statistically with the MSA derived models.

Structure of the Z Ring-associated Protein, ZapD, Bound to the C-terminal Domain of the Tubulin-like Protein, FtsZ, Suggests Mechanism of Z Ring Stabilization through FtsZ Cross-linking.

PubMed

Schumacher, Maria A; Huang, Kuo-Hsiang; Zeng, Wenjie; Janakiraman, Anuradha

2017-03-03

Cell division in most bacteria is mediated by the tubulin-like FtsZ protein, which polymerizes in a GTP-dependent manner to form the cytokinetic Z ring. A diverse repertoire of FtsZ-binding proteins affects FtsZ localization and polymerization to ensure correct Z ring formation. Many of these proteins bind the C-terminal domain (CTD) of FtsZ, which serves as a hub for FtsZ regulation. FtsZ ring-associated proteins, ZapA-D (Zaps), are important FtsZ regulatory proteins that stabilize FtsZ assembly and enhance Z ring formation by increasing lateral assembly of FtsZ protofilaments, which then form the Z ring. There are no structures of a Zap protein bound to FtsZ; therefore, how these proteins affect FtsZ polymerization has been unclear. Recent data showed ZapD binds specifically to the FtsZ CTD. Thus, to obtain insight into the ZapD-CTD interaction and how it may mediate FtsZ protofilament assembly, we determined the Escherichia coli ZapD-FtsZ CTD structure to 2.67 Å resolution. The structure shows that the CTD docks within a hydrophobic cleft in the ZapD helical domain and adopts an unusual structure composed of two turns of helix separated by a proline kink. FtsZ CTD residue Phe-377 inserts into the ZapD pocket, anchoring the CTD in place and permitting hydrophobic contacts between FtsZ residues Ile-374, Pro-375, and Leu-378 with ZapD residues Leu-74, Trp-77, Leu-91, and Leu-174. The structural findings were supported by mutagenesis coupled with biochemical and in vivo studies. The combined data suggest that ZapD acts as a molecular cross-linking reagent between FtsZ protofilaments to enhance FtsZ assembly. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

The sensitive and selective adsorption of aromatic compounds with highly crosslinked polymer nanoparticles

NASA Astrophysics Data System (ADS)

Liu, Shuqin; Chen, Darui; Zheng, Juan; Zeng, Lewei; Jiang, Jijun; Jiang, Ruifeng; Zhu, Fang; Shen, Yong; Wu, Dingcai; Ouyang, Gangfeng

2015-10-01

This study presents the preparation and characterization of a nanoscale Davankov-type hyper-crosslinked-polymer (HCP) as an adsorbent of benzene-ring-containing dyes and organic pollutants. HCP nanoparticles post-crosslinked from a poly(DVB-co-VBC) precursor were synthesized in this study, possessing ultrahigh surface area, hydrophobicity and stability. The as-synthesized Davankov-type HCP exhibited a rapid and selective adsorption ability towards the benzene-ring-containing dyes due to its highly conjugated structure. Besides, for the first time, the prepared HCP nanoparticles were adopted for the adsorption of nonpolar organic pollutants by means of solid-phase microextraction (SPME). Owing to its high hydrophobicity, diverse pore size distribution and highly conjugated structure, a 10 μm HCP coating exhibited excellent adsorption abilities towards benzene-ring-containing polycyclic aromatic hydrocarbons (PAHs) and benzene series compounds (benzene, toluene, ethylbenzene and o-xylene; abbreviated to BTEX) and to highly hydrophobic long-chain n-alkanes. Finally, the HCP-nanoparticles-coated SPME fiber was applied to the simultaneous analysis of five PAHs in environmental water samples and satisfactory recoveries were achieved. The findings could provide a new benchmark for the exploitation of superb HCPs as effective adsorbents for SPME or other adsorption applications.This study presents the preparation and characterization of a nanoscale Davankov-type hyper-crosslinked-polymer (HCP) as an adsorbent of benzene-ring-containing dyes and organic pollutants. HCP nanoparticles post-crosslinked from a poly(DVB-co-VBC) precursor were synthesized in this study, possessing ultrahigh surface area, hydrophobicity and stability. The as-synthesized Davankov-type HCP exhibited a rapid and selective adsorption ability towards the benzene-ring-containing dyes due to its highly conjugated structure. Besides, for the first time, the prepared HCP nanoparticles were adopted for the adsorption of nonpolar organic pollutants by means of solid-phase microextraction (SPME). Owing to its high hydrophobicity, diverse pore size distribution and highly conjugated structure, a 10 μm HCP coating exhibited excellent adsorption abilities towards benzene-ring-containing polycyclic aromatic hydrocarbons (PAHs) and benzene series compounds (benzene, toluene, ethylbenzene and o-xylene; abbreviated to BTEX) and to highly hydrophobic long-chain n-alkanes. Finally, the HCP-nanoparticles-coated SPME fiber was applied to the simultaneous analysis of five PAHs in environmental water samples and satisfactory recoveries were achieved. The findings could provide a new benchmark for the exploitation of superb HCPs as effective adsorbents for SPME or other adsorption applications. Electronic supplementary information (ESI) available: Fig. S1-S8, details of optimization of the SPME condition, Tables S1-S5. See DOI: 10.1039/c5nr04624f

3-Phenyl­pyridinium tetra­chlorido­aurate(III)

PubMed Central

Amani, Vahid; Safari, Nasser; Khavasi, Hamid Reza

2010-01-01

In the title mol­ecular salt, (C11H10N)[AuCl4], the AuIII atom adopts an almost regular square-planar coordination geometry and the dihedral angle between the aromatic rings of the 3-phenyl­pyridinium cation is 23.1 (3)°. In the crystal, the ions inter­act by way of N—H⋯Cl and C—H⋯Cl hydrogen bonds. PMID:21580276

Machinery of protein folding and unfolding.

PubMed

Zhang, Xiaodong; Beuron, Fabienne; Freemont, Paul S

2002-04-01

During the past two years, a large amount of biochemical, biophysical and low- to high-resolution structural data have provided mechanistic insights into the machinery of protein folding and unfolding. It has emerged that dual functionality in terms of folding and unfolding might exist for some systems. The majority of folding/unfolding machines adopt oligomeric ring structures in a cooperative fashion and utilise the conformational changes induced by ATP binding/hydrolysis for their specific functions.

3-(6-Methyl-2-pyrid­yl)-2-phenyl-3,4-dihydro-1,3,2-benzoxaza­phosphinine 2-oxide

PubMed Central

Surendra Babu, V. H. H.; Krishnaiah, M.; Anil Kumar, M.; Suresh Reddy, C.; Kant, Rajni

2009-01-01

In the title compound, C19H17N2O2P, the six-membered 1,3,2-oxaza­phosphinine ring adopts a boat conformation with the phosphoryl O atom in an equatorial position. The dihedral angle between the 6-methyl-2-pyridyl and phenyl groups is 75.5 (1)°. These substituents are trans to each other, and are oriented at angles of 57.2 (1) and 74.8 (1)°, respectively, to the benzene ring. The crystal structure is stabilized by intra- and inter­molecular hydrogen bonds. The phosphoryl O atom participates in inter­molecular C—H⋯O inter­actions with the neighbouring mol­ecules, forming centrosymmetric R 2 2(14) dimers. PMID:21578300

Experimental realization of a CMOS-compatible optical directed priority encoder using cascaded micro-ring resonators

NASA Astrophysics Data System (ADS)

Xiao, Huifu; Li, Dezhao; Liu, Zilong; Han, Xu; Chen, Wenping; Zhao, Ting; Tian, Yonghui; Yang, Jianhong

2018-03-01

In this paper, we propose and experimentally demonstrate an integrated optical device that can implement the logical function of priority encoding from a 4-bit electrical signal to a 2-bit optical signal. For the proof of concept, the thermo-optic modulation scheme is adopted to tune each micro-ring resonator (MRR). A monochromatic light with the working wavelength is coupled into the input port of the device through a lensed fiber, and the four input electrical logic signals regarded as pending encode signals are applied to the micro-heaters above four MRRs to control the working states of the optical switches. The encoding results are directed to the output ports in the form of light. At last, the logical function of priority encoding with an operation speed of 10 Kbps is demonstrated successfully.

Corymbolone.

PubMed

Burrett, Stacey; Taylor, Dennis K; Tiekink, Edward R T

2014-07-01

The title compound, C15H24O2 [systematic name: (4S,4aR,6R,8aR)-4a-hy-droxy-4,8a-dimethyl-6-(prop-1-en-2-yl)octahydro-naphthalen-1(2H)-one], features two edge-shared six-membered rings with the hydroxyl and methyl substituents at this bridge being trans. One adopts a flattened chair conformation with the C atoms bearing the carbonyl and methyl substituents lying 0.5227 (16) and 0.6621 (15) Å, respectively, above and below the mean plane through the remaining four C atoms (r.m.s. deviation = 0.0145 Å). The second ring, bearing the prop-1-en-2-yl group, has a chair conformation. Supra-molecular helical chains along the b axis are found in the crystal packing, which are sustained by hy-droxy-carbonyl O-H⋯O hydrogen bonding.

Piperidinium bis­(2-oxidobenzoato-κ2 O 1,O 2)borate

PubMed Central

Tang, Zhi-Hua; Huang, Chaojun

2009-01-01

The asymmetric unit of the title compound, C5H12N+·C14H8BO6 − or [C5H12N][BO4(C7H4O)2], contains two piperidinium cations and two bis­(salicylato)borate anions. The coordination geometries around the B atoms are distorted tetra­hedral. In the two mol­ecules, the aromatic rings are oriented at dihedral angles of 76.27 (3) and 83.86 (3)°. The rings containing B atoms have twist-boat conformations, while the two cations adopt chair conformations. In the crystal, the component species are linked by N—H⋯O hydrogen bonds. In the crystal structure, intra- and inter­molecular N—H⋯O hydrogen bonds link the mol­ecules. PMID:21581628

Conformational behavior of phenylglycines and hydroxyphenylglycines and non-planarity of phenyl rings.

PubMed

Nandel, Fateh S; Shafique, Mohd

2014-10-01

The non-proteinogenic amino acids--phenylglycine (PG) and hydroxyphenylglycine (HPG) are crucial components of certain peptidic natural products and are important for the preparation of various medicines. In this, study, the conformation of model dipeptides Ac-X-NHMe of PG, p-HPG and 3, 5-di-hydroxyphenylglycine (3, 5-DHPG) was studied both in R and S form by quantum mechanical (QM) and molecular dynamics approaches. On the energy scale, the conformational states of these molecules in both the R and S were found to be degenerate by QM studies, stabilized by non-covalent interactions like carbonyl--carbonyl interactions, carbonyl-lp .. π (aromatic ring) interactions etc. These interactions disappeared/weakened due to interaction of water molecules with carbonyl groups of backbone in simulation and water was found to interact with the aromatic ring through O(w)-H .. π or O(w)lp .. π interactions. The degeneracy of conformational states was lifted in favor of R-form of PG and DHPG and water molecules interactions with aromatic ring led to non-planarity of the aromatic ring. In simulation studies, irrespective of the starting geometry, the Φ, ψ values for the R form correspond to inverse β/inverse collagen region and for the S-form, the Φ, ψ values correspond to β/collagen region i.e., adopt single conformation. The obtained results were in conformity with the CD spectroscopic data on D-PG and D-p-HPG. The conformational behavior of the unusual amino acids might be of great help in designing of bioactive peptides/peptide based drugs to be realized in single conformation--an essential requirement.

Anticonvulsant effects of isomeric nonimidazole histamine H3 receptor antagonists

PubMed Central

Sadek, Bassem; Saad, Ali; Schwed, Johannes Stephan; Weizel, Lilia; Walter, Miriam; Stark, Holger

2016-01-01

Phenytoin (PHT), valproic acid, and modern antiepileptic drugs (AEDs), eg, remacemide, loreclezole, and safinamide, are only effective within a maximum of 70%–80% of epileptic patients, and in many cases the clinical use of AEDs is restricted by their side effects. Therefore, a continuous need remains to discover innovative chemical entities for the development of active and safer AEDs. Ligands targeting central histamine H3 receptors (H3Rs) for epilepsy might be a promising therapeutic approach. To determine the potential of H3Rs ligands as new AEDs, we recently reported that no anticonvulsant effects were observed for the (S)-2-(4-(3-(piperidin-1-yl)propoxy)benzylamino)propanamide (1). In continuation of our research, we asked whether anticonvulsant differences in activities will be observed for its R-enantiomer, namely, (R)-2-(4-(3-(piperidin-1-yl)propoxy)benzylamino)propaneamide (2) and analogs thereof, in maximum electroshock (MES)-, pentylenetetrazole (PTZ)-, and strychnine (STR)-induced convulsion models in rats having PHT and valproic acid (VPA) as reference AEDs. Unlike the S-enantiomer (1), the results show that animals pretreated intraperitoneally (ip) with the R-enantiomer 2 (10 mg/kg) were moderately protected in MES and STR induced models, whereas proconvulsant effect was observed for the same ligand in PTZ-induced convulsion models. However, animals pretreated with intraperitoneal doses of 5, 10, or 15 mg/kg of structurally bulkier (R)-enantiomer (3), in which 3-piperidinopropan-1-ol in ligand 2 was replaced by (4-(3-(piperidin-1-yl)propoxy)phenyl)methanol, and its (S)-enantiomer (4) significantly and in a dose-dependent manner reduced convulsions or exhibited full protection in MES and PTZ convulsions model, respectively. Interestingly, the protective effects observed for the (R)-enantiomer (3) in MES model were significantly greater than those of the standard H3R inverse agonist/antagonist pitolisant, comparable with those observed for PHT, and reversed when rats were pretreated with the selective H3R agonist R-(α)-methyl-histamine. Comparisons of the observed antagonistic in vitro affinities among the ligands 1–6 revealed profound stereoselectivity at human H3Rs with varying preferences for this receptor subtype. Moreover, the in vivo anticonvulsant effects observed in this study for ligands 1–6 showed stereoselectivity in different convulsion models in male adult rats. PMID:27853355

Anticonvulsant effects of isomeric nonimidazole histamine H3 receptor antagonists.

PubMed

Sadek, Bassem; Saad, Ali; Schwed, Johannes Stephan; Weizel, Lilia; Walter, Miriam; Stark, Holger

2016-01-01

Phenytoin (PHT), valproic acid, and modern antiepileptic drugs (AEDs), eg, remacemide, loreclezole, and safinamide, are only effective within a maximum of 70%-80% of epileptic patients, and in many cases the clinical use of AEDs is restricted by their side effects. Therefore, a continuous need remains to discover innovative chemical entities for the development of active and safer AEDs. Ligands targeting central histamine H 3 receptors (H 3 Rs) for epilepsy might be a promising therapeutic approach. To determine the potential of H 3 Rs ligands as new AEDs, we recently reported that no anticonvulsant effects were observed for the ( S )-2-(4-(3-(piperidin-1-yl)propoxy)benzylamino)propanamide ( 1 ). In continuation of our research, we asked whether anticonvulsant differences in activities will be observed for its R -enantiomer, namely, ( R )-2-(4-(3-(piperidin-1-yl)propoxy)benzylamino)propaneamide ( 2 ) and analogs thereof, in maximum electroshock (MES)-, pentylenetetrazole (PTZ)-, and strychnine (STR)-induced convulsion models in rats having PHT and valproic acid (VPA) as reference AEDs. Unlike the S -enantiomer ( 1 ), the results show that animals pretreated intraperitoneally (ip) with the R -enantiomer 2 (10 mg/kg) were moderately protected in MES and STR induced models, whereas proconvulsant effect was observed for the same ligand in PTZ-induced convulsion models. However, animals pretreated with intraperitoneal doses of 5, 10, or 15 mg/kg of structurally bulkier ( R )-enantiomer ( 3 ), in which 3-piperidinopropan-1-ol in ligand 2 was replaced by (4-(3-(piperidin-1-yl)propoxy)phenyl)methanol, and its ( S )-enantiomer ( 4 ) significantly and in a dose-dependent manner reduced convulsions or exhibited full protection in MES and PTZ convulsions model, respectively. Interestingly, the protective effects observed for the ( R )-enantiomer ( 3 ) in MES model were significantly greater than those of the standard H 3 R inverse agonist/antagonist pitolisant, comparable with those observed for PHT, and reversed when rats were pretreated with the selective H 3 R agonist R -(α)-methyl-histamine. Comparisons of the observed antagonistic in vitro affinities among the ligands 1 - 6 revealed profound stereoselectivity at human H 3 Rs with varying preferences for this receptor subtype. Moreover, the in vivo anticonvulsant effects observed in this study for ligands 1 - 6 showed stereoselectivity in different convulsion models in male adult rats.

7-Chloro-6-piperidin-1-yl-quinoline-5,8-dione (PT-262), a novel synthetic compound induces lung carcinoma cell death associated with inhibiting ERK and CDC2 phosphorylation via a p53-independent pathway.

PubMed

Hsu, Tzu-Sheng; Chen, Chinpiao; Lee, Pei-Ting; Chiu, Shu-Jun; Liu, Huei-Fang; Tsai, Chih-Chien; Chao, Jui-I

2008-10-01

The derivatives of 5,8-quinolinedione have been shown to exert anticancer activities. A new synthetic compound 7-chloro-6-piperidin-1-yl-quinoline-5,8-dione (designed as PT-262) derived from 6,7-dichloroquinoline-5,8-dione on its anticancer activity was investigated in this study. PT-262 was synthesized as the following: triethylamine (0.56 ml, 5.1 mmol) was added dropwise to a solution of 6,7-dichloroquinoline-5,8-dione (1.00 g, 4.4 mmol) and piperidine (0.50 ml, 5.1 mmol) in 150 ml of benzene with stirring at room temperature for 5 min, and the solvent was removed using rotary evaporator to give a dark brown solid. PT-262 was purified by flash chromatography using 50% ethyl acetate/hexanes to elute that displayed as brown solids. To examine the induction of apoptosis following PT-262 treatment, the lung cancer cells were subjected to apoptotic cell observation, caspase activation, and mitochondrial functional assays. The protein levels of phosphorylated ERK and CDC2 after treatment with PT-262 were analyzed by Western blot. Treatment with 1-20 microM PT-262 for 24 h induced cytotoxicity via a concentration-dependent manner in human lung cancer cells. PT-262 induced the loss of mitochondrial membrane potential and elevated the caspase-3 activation and apoptosis. Interestingly, the phosphorylation of ERK was inhibited by PT-262. The IC50 value of ERK phosphorylation inhibition was approximate around 5 microM. Treatment with a specific MEK1/2 (the upstream of ERK) inhibitor, PD98059, increased the PT-262-induced cytotoxicity in lung cancer cells. Moreover, PT-262 did not alter the protein expression of tumor suppressor p53. PT-262 elicited the cytotoxicity and accumulated the G2/M fractions in both the p53-wild type and p53-null lung cancer cells. The mitosis-regulated protein levels of cyclin B1 and phospho-CDC2 at Thr14, Tyr15, and Thr161 were repressed by PT-262 in these cells. PT-262 suppresses the phosphorylation of ERK and CDC2 associated with proliferation inhibition via a p53-independent pathway in human lung cancer cells.

HIGH-RESOLUTION VLBA OBSERVATIONS OF THREE 7 mm SiO MASERS TOWARD VX Sgr AT FIVE EPOCHS

DOE Office of Scientific and Technical Information (OSTI.GOV)

Su, J. B.; Shen, Z.-Q.; Chen, X.

2012-07-20

VX Sgr is a red supergiant at an adopted distance of 1.6 kpc with intense 43 GHz SiO maser emission. In this paper, we present the high-resolution very long baseline interferometry (VLBI) observations of SiO masers toward VX Sgr at five epochs. We used the Very Long Baseline Array to map the J = 1{yields}0 (v = 1, 2) {sup 28}SiO masers and confirmed a ring-like structure. In the first two epochs, the v = 1 masers form a ring, but v = 2 maser spots residing only in the southern and northern regions do not form a complete ring.more » In the third epoch, the two masers are distributed in a ring structure and the v = 2 masers are a bit closer to the central star. In the last two epochs, many new maser spots appear and overlap each other. These overlapping maser spots can be related to the shock waves and reflect the collisional pumping. We compare the observations with the pumping models and speculate that the real pumping mechanism may be complex in VX Sgr and vary with time. The J = 1{yields}0 (v = 0) {sup 29}SiO line emission is also detected, but is too weak to produce any VLBI map.« less

The Status of the Taiwan Photon Source

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kuo, C. C.; Wang, J. P.; Chen, J. R.

2010-06-23

NSRRC has been operating a 1.5 GeV synchrotron light source, the Taiwan Light Source (TLS), for over 15 years and has established a large user community. For the future development of synchrotron radiation research in Taiwan, a feasibility study report to construct a 3.0 GeV low-emittance storage ring, the Taiwan Photon Source (TPS), was issued in July 2005. The government approval of the TPS project was obtained in December 2007 and the machine will be built at current site of NSRRC. The project has progressed steadily since and reached several major milestones now: the architect firm has finished the sitemore » plan and civil design, the accelerator design has been fixed, and purchase of long-lead items begins its course. The TPS storage ring has a circumference of 518.4 meters with a concentric booster of 496.8 meters. The storage ring adopted a 24-cell double-bend structure with a 1.6 nm-rad natural emittance. There are six 12-m and eighteen 7-m ID straights. For user research, five new beamlines have been selected for the Phase I operations: the micro protein crystallography, the materials sub-micron diffraction, the inelastic soft x-ray scattering, the coherent x-ray scattering, and the nano probe beamlines. The civil construction is getting ready to start. The commissioning of the TPS storage ring is targeted for 2013.« less

meso-4,4′-Dimeth­oxy-2,2′-{[(3aR,7aS)-2,3,3a,4,5,6,7,7a-octa­hydro-1H-benz­imidazole-1,3-di­yl]bis­(methyl­ene)}diphenol

PubMed Central

Rivera, Augusto; Quiroga, Diego; Ríos-Motta, Jaime; Kučeraková, Monika; Dušek, Michal

2013-01-01

The title compound, C23H30N2O4, a di-Mannich base derived from 4-meth­oxy­phenol and cis-1,2-di­amine­cyclo­hexane, has a perhydro­benzimidazolidine nucleus, in which the cyclo­hexane ring adopts a chair conformation and the heterocyclic ring has a half-chair conformation with a C—N—C—C torsion angles of −48.14 (15) and −14.57 (16)°. The mean plane of the heterocycle makes dihedral angles of 86.29 (6) and 78.92 (6)° with the pendant benzene rings. The mol­ecular structure of the title compound shows the presence of two inter­actions between the N atoms of the imidazolidine ring and the hydroxyl groups through intra­molecular O—H⋯N hydrogen bonds with graph-set motif S(6). The unobserved lone pairs of the N atoms are presumed to be disposed in a syn conformation, being only the second example of an exception to the typical ‘rabbit-ears’ effect in 1,2-di­amines. PMID:24046631

4-[(1-Benzyl-1H-1,2,3-triazol-4-yl)meth­oxy]benzene-1,2-dicarbo­nitrile: crystal structure, Hirshfeld surface analysis and energy-minimization calculations

PubMed Central

Shamsudin, Norzianah; Tan, Ai Ling; Young, David J.; Jotani, Mukesh M.; Otero-de-la-Roza, A.; Tiekink, Edward R. T.

2016-01-01

In the solid state, the title compound, C18H13N5O, adopts a conformation whereby the phenyl ring and meth­oxy–benzene-1,2-dicarbo­nitrile residue (r.m.s. deviation of the 12 non-H atoms = 0.041 Å) lie to opposite sides of the central triazolyl ring, forming dihedral angles of 79.30 (13) and 64.59 (10)°, respectively; the dihedral angle between the outer rings is 14.88 (9)°. This conformation is nearly 7 kcal mol−1 higher in energy than the energy-minimized structure which has a syn disposition of the outer rings, enabling intra­molecular π–π inter­actions. In the crystal, methyl­ene-C—H⋯N(triazol­yl) and carbo­nitrile-N⋯π(benzene) inter­actions lead to supra­molecular chains along the a axis. Supra­molecular layers in the ab plane arise as the chains are connected by benzene-C—H⋯N(carbo­nitrile) inter­actions; layers stack with no directional inter­actions between them. The specified inter­molecular contacts along with other, weaker contributions to the supra­molecular stabilization are analysed in a Hirshfeld surface analysis. PMID:27375890

Structure-Activity Relationships of 33 Piperidines as Toxicants Against Female Adults of Aedes aegypti (Diptera: Culicidae)

DTIC Science & Technology

2007-03-01

alkaloid piperine and 12 syn- thetic derivatives have been evaluated against epimas- tigote and amastigote forms of the protozoan parasite Trypanosoma...O. Kris- tiansen, P. Maienfisch, A. Pascual, and A. Rindlisbacher. 2001. Synthesis and structure-activity relationships of benzophenone hydrazone...Am. J. Trop. Med. Hyg. 22: 124Ð 129. Creemer, L. C., H. A. Kirst, J.W. Paschal, and T. V.Worden. 2000. Synthesis and insecticidal activity of spinosyn

Noncircular features in Saturn's rings IV: Absolute radius scale and Saturn's pole direction

NASA Astrophysics Data System (ADS)

French, Richard G.; McGhee-French, Colleen A.; Lonergan, Katherine; Sepersky, Talia; Jacobson, Robert A.; Nicholson, Philip D.; Hedman, Mathew M.; Marouf, Essam A.; Colwell, Joshua E.

2017-07-01

We present a comprehensive solution for the geometry of Saturn's ring system, based on orbital fits to an extensive set of occultation observations of 122 individual ring edges and gaps. We begin with a restricted set of very high quality Cassini VIMS, UVIS, and RSS measurements for quasi-circular features in the C and B rings and the Cassini Division, and then successively add suitably weighted additional Cassini and historical occultation measurements (from Voyager, HST and the widely-observed 28 Sgr occultation of 3 Jul 1989) for additional non-circular features, to derive an absolute radius scale applicable across the entire classical ring system. As part of our adopted solution, we determine first-order corrections to the spacecraft trajectories used to determine the geometry of individual occultation chords. We adopt a simple linear model for Saturn's precession, and our favored solution yields a precession rate on the sky n^˙P = 0.207 ± 0 .006‧‧yr-1 , equivalent to an angular rate of polar motion ΩP = 0.451 ± 0 .014‧‧yr-1 . The 3% formal uncertainty in the fitted precession rate is approaching the point where it can provide a useful constraint on models of Saturn's interior, although realistic errors are likely to be larger, given the linear approximation of the precession model and possible unmodeled systematic errors in the spacecraft ephemerides. Our results are largely consistent with independent estimates of the precession rate based on historical RPX times (Nicholson et al., 1999 AAS/Division for Planetary Sciences Meeting Abstracts #31 31, 44.01) and from theoretical expectations that account for Titan's 700-yr precession period (Vienne and Duriez 1992, Astronomy and Astrophysics 257, 331-352). The fitted precession rate based on Cassini data only is somewhat lower, which may be an indication of unmodeled shorter term contributions to Saturn's polar motion from other satellites, or perhaps the result of inconsistencies in the assumed direction of Saturn's pole in the reconstructed Cassini spacecraft ephemerides. Overall, the agreement of our results with the widely-used French et al. (1993, Icarus 103, 163-214) radius scale is excellent, with very small (≲ 0.1 km) systematic differences, although differences in a few individual feature radii are as large as 6 km. Our new solution incorporates many more features across the ring system, and the fitted orbital elements correct for the several-km biases in the radii of many ring features in the French et al. (1993) catalog that were unresolved because of the large projected diameter of the occulted star in the 28 Sgr event. The formal errors in the fitted radii are generally quite small - on the order of tens of meters. Systematic errors stemming from uncertainty in the precession rate of Saturn's pole and its effect on the accuracy of the reconstructed Cassini trajectories are somewhat larger, but the absolute radius scale is relatively insensitive to 5-σ changes in the pole direction or precession rate, and we estimate the combined magnitude of these systematic errors and pole uncertainties to be of order 250 m. This estimate is likely to be improved once a new set of reconstructed Cassini trajectories has been developed, based on a self-consistent model for Saturn's pole. We demonstrate the utility of the new radius scale and the associated trajectory corrections in the analysis of short-wavelength density waves in the C ring. In online supplementary material, we provide in machine-readable form the more than 15,000 individual ring measurements used in this study, as well as details of the ring orbit fits underlying this work.

FT-IR, FT-Raman, UV, NMR spectra and molecular structure investigation of (E)-2-(3-chloropyrazin-2-yl)-1-(3-ethyl-2, 6-diphenyl piperidin-4-ylidene) hydrazine: A combined experimental and theoretical study

NASA Astrophysics Data System (ADS)

Therasa Alphonsa, A.; Loganathan, C.; Athavan Alias Anand, S.; Kabilan, S.

2015-11-01

This work presents the characterization of (E)-2-(3-chloropyrazin-2-yl)-1-(3-ethyl-2, 6-diphenyl piperidin-4-ylidene) hydrazine (HDE) by quantum chemical calculations and spectral techniques. The structure was investigated by FT-IR, FT-Raman, UV-vis and NMR techniques. The geometrical parameters and energies have been obtained from Density functional theory (DFT) B3LYP (6-31G (d, p)) basis set calculations. The geometry of the molecule was fully optimized, vibrational spectra were calculated and fundamental vibrations were assigned on the basis of total energy distribution (TED) of the vibrational modes, calculated with scaled quantum mechanics (SQM) method. 1H and 13C NMR chemical shifts of the molecule were calculated using Gauge-independent atomic orbital method (GIAO). The electronic properties such as excitation energies, wavelength, HOMO, LUMO energies performed by Time dependent density functional theory (TD-DFT) results complements with the experimental findings. NBO analysis has been performed for analyzing charge delocalization throughout the molecule. The calculation results were applied to simulate spectra of the title compound, which show excellent agreement with observed spectra. To provide information about the interactions between human cytochrome protein and the novel compound theoretically, docking studies were carried out using Schrödinger software.

Antimalarial agents against both sexual and asexual parasites stages: structure-activity relationships and biological studies of the Malaria Box compound 1-[5-(4-bromo-2-chlorophenyl)furan-2-yl]-N-[(piperidin-4-yl)methyl]methanamine (MMV019918) and analogues.

PubMed

Vallone, Alessandra; D'Alessandro, Sarah; Brogi, Simone; Brindisi, Margherita; Chemi, Giulia; Alfano, Gloria; Lamponi, Stefania; Lee, Soon Goo; Jez, Joseph M; Koolen, Karin J M; Dechering, Koen J; Saponara, Simona; Fusi, Fabio; Gorelli, Beatrice; Taramelli, Donatella; Parapini, Silvia; Caldelari, Reto; Campiani, Giuseppe; Gemma, Sandra; Butini, Stefania

2018-04-25

Therapies addressing multiple stages of Plasmodium falciparum life cycle are highly desirable for implementing malaria elimination strategies. MMV019918 (1, 1-[5-(4-bromo-2-chlorophenyl)furan-2-yl]-N-[(piperidin-4-yl)methyl]methanamine) was selected from the MMV Malaria Box for its dual activity against both asexual stages and gametocytes. In-depth structure-activity relationship studies and cytotoxicity evaluation led to the selection of 25 for further biological investigation. The potential transmission blocking activity of 25 versus P. falciparum was confirmed through the standard membrane-feeding assay. Both 1 and 25 significantly prolonged atrioventricular conduction time in Langendorff-isolated rat hearts, and showed inhibitory activity of Ba 2+ current through Ca v 1.2 channels. An in silico target-fishing study suggested the enzyme phosphoethanolamine methyltransferase (PfPMT) as a potential target. However, compound activity against PfPMT did not track with the antiplasmodial activity, suggesting the latter activity relies on a different molecular target. Nevertheless, 25 showed interesting activity against PfPMT, which could be an important starting point for the identification of more potent inhibitors active against both sexual and asexual stages of the parasite. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Tetraphenylporphyrin derivatives possessing piperidine group as potential agents for photodynamic therapy.

PubMed

Liao, Ping-Yong; Gao, Ying-Hua; Wang, Xin-Rong; Bao, Lei-Lei; Bian, Jun; Hu, Tai-Shan; Zheng, Mei-Zhen; Yan, Yi-Jia; Chen, Zhi-Long

2016-12-01

Photodynamic therapy (PDT) is a noninvasive therapeutic and promising procedure in cancer treatment and has attracted considerable attention in recent years. In the present paper, 2-piperidinetetraphenylporphyrin derivatives (P1-P3) conjugated with different substituents (Cl, Me, MeO group) at phenyl position were synthesized via nucleophilic substitution of 2-nitroporphyrin copper derivatives with piperidine by refluxing under a nitrogen atmosphere and then demetalization. The combination of 1 H NMR, 13 C NMR and HR-MS was used to elucidate the identities of them. Their photophysical and photochemical properties, intracellular localization, cytotoxicity in vitro and in vivo against QBC-939 cells were investigated. They have absorption at wavelength about 650nm. All synthesized photosensitizers showed low dark cytotoxicity and comparable with that of hematoporphyrin monomethyl ether (HMME). And they were more phototoxic than HMME to QBC-939 cells in vitro. In bearing QBC-939 tumor BALB/c nude mice, when it treated with 5mg/kg dose of PS and laser light (650nm, 100J/cm 2 , 180mW/cm 2 ), the growth of tumor was inhibited compared to the control group. Among them, P3 exhibited better photodynamic antitumor efficacy on BALB/c nude mice at lower concentration. These results indicate that P3 is a new potential antitumor photosensitizer in photodynamic therapy and deserves further investigation. Copyright © 2016 Elsevier B.V. All rights reserved.

Design, synthesis, acetylcholinesterase inhibition and larvicidal activity of girgensohnine analogs on Aedes aegypti, vector of dengue fever.

PubMed

Carreño Otero, Aurora L; Vargas Méndez, Leonor Y; Duque L, Jonny E; Kouznetsov, Vladimir V

2014-05-06

Girgensohnine alkaloid was used as a natural model in the design and generation of new alkaloid-like α-aminonitrile series that was completed by the use of SSA-catalyzed Strecker reaction between commercial and inexpensive substituted benzaldehydes, piperidine (pyrrolidine, morpholine and N-methylpiperazine) and acetone cyanohydrin. Calculated ADMETox parameters of the designed analogs revealed their good pharmacokinetic profiles indicating lipophilic characteristics. In vitro AChE enzyme test showed that obtained α-aminonitriles could be considered as AChEIs with micromolar IC50 values ranging from 42.0 to 478.0 μM (10.3-124.0 μg/mL). Among this series, the best AChE inhibitor was the pyrrolidine α-aminonitrile 3 (IC50 = 42 μM), followed by the piperidine α-aminonitriles 2 and 6 (IC50 = 45 μM and IC50 = 51 μM, respectively), and the compound 7 (IC50 = 51 μM). In vivo insecticidal activity of more active AChEIs against Aedes aegypti larvae was also performed showing a good larvicidal activity at concentrations less than 140 ppm, highlighting products 2 and 7 that could serve as lead compounds to develop new potent and selective insecticides. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Efficient modulation of γ-aminobutyric acid type A receptors by piperine derivatives.

PubMed

Schöffmann, Angela; Wimmer, Laurin; Goldmann, Daria; Khom, Sophia; Hintersteiner, Juliane; Baburin, Igor; Schwarz, Thomas; Hintersteininger, Michael; Pakfeifer, Peter; Oufir, Mouhssin; Hamburger, Matthias; Erker, Thomas; Ecker, Gerhard F; Mihovilovic, Marko D; Hering, Steffen

2014-07-10

Piperine activates TRPV1 (transient receptor potential vanilloid type 1 receptor) receptors and modulates γ-aminobutyric acid type A receptors (GABAAR). We have synthesized a library of 76 piperine analogues and analyzed their effects on GABAAR by means of a two-microelectrode voltage-clamp technique. GABAAR were expressed in Xenopus laevis oocytes. Structure-activity relationships (SARs) were established to identify structural elements essential for efficiency and potency. Efficiency of piperine derivatives was significantly increased by exchanging the piperidine moiety with either N,N-dipropyl, N,N-diisopropyl, N,N-dibutyl, p-methylpiperidine, or N,N-bis(trifluoroethyl) groups. Potency was enhanced by replacing the piperidine moiety by N,N-dibutyl, N,N-diisobutyl, or N,N-bistrifluoroethyl groups. Linker modifications did not substantially enhance the effect on GABAAR. Compound 23 [(2E,4E)-5-(1,3-benzodioxol-5-yl)-N,N-dipropyl-2,4-pentadienamide] induced the strongest modulation of GABAA (maximal GABA-induced chloride current modulation (IGABA-max = 1673% ± 146%, EC50 = 51.7 ± 9.5 μM), while 25 [(2E,4E)-5-(1,3-benzodioxol-5-yl)-N,N-dibutyl-2,4-pentadienamide] displayed the highest potency (EC50 = 13.8 ± 1.8 μM, IGABA-max = 760% ± 47%). Compound 23 induced significantly stronger anxiolysis in mice than piperine and thus may serve as a starting point for developing novel GABAAR modulators.

Efficient Modulation of γ-Aminobutyric Acid Type A Receptors by Piperine Derivatives

PubMed Central

2014-01-01

Piperine activates TRPV1 (transient receptor potential vanilloid type 1 receptor) receptors and modulates γ-aminobutyric acid type A receptors (GABAAR). We have synthesized a library of 76 piperine analogues and analyzed their effects on GABAAR by means of a two-microelectrode voltage-clamp technique. GABAAR were expressed in Xenopus laevis oocytes. Structure–activity relationships (SARs) were established to identify structural elements essential for efficiency and potency. Efficiency of piperine derivatives was significantly increased by exchanging the piperidine moiety with either N,N-dipropyl, N,N-diisopropyl, N,N-dibutyl, p-methylpiperidine, or N,N-bis(trifluoroethyl) groups. Potency was enhanced by replacing the piperidine moiety by N,N-dibutyl, N,N-diisobutyl, or N,N-bistrifluoroethyl groups. Linker modifications did not substantially enhance the effect on GABAAR. Compound 23 [(2E,4E)-5-(1,3-benzodioxol-5-yl)-N,N-dipropyl-2,4-pentadienamide] induced the strongest modulation of GABAA (maximal GABA-induced chloride current modulation (IGABA-max = 1673% ± 146%, EC50 = 51.7 ± 9.5 μM), while 25 [(2E,4E)-5-(1,3-benzodioxol-5-yl)-N,N-dibutyl-2,4-pentadienamide] displayed the highest potency (EC50 = 13.8 ± 1.8 μM, IGABA-max = 760% ± 47%). Compound 23 induced significantly stronger anxiolysis in mice than piperine and thus may serve as a starting point for developing novel GABAAR modulators. PMID:24905252

Demonstration of a potent RET transcriptional inhibitor for the treatment of medullary thyroid carcinoma based on an ellipticine derivative

PubMed Central

Kumarasamy, Vishnu Muthuraj; Sun, Daekyu

2017-01-01

Dominant-activating mutations in the RET (rearranged during transfection) proto-oncogene, which encodes a receptor tyrosine kinase, is often associated with the development of medullary thyroid carcinoma (MTC). The proximal promoter region of the RET gene consists of a guanine-rich sequence containing five runs of three consecutive guanine residues that serve as the binding site for transcriptional factors. As we have recently shown, this stretch of nucleotides in the promoter region is highly dynamic in nature and tend to form non-B DNA secondary structures called G-quadruplexes, which suppress the transcription of the RET gene. In the present study, ellipticine and its derivatives were identified as excellent RET G-quadruplex stabilizing agents. Circular dichroism (CD) spectroscopic studies revealed that the incorporation of a piperidine ring in an ellipticine derivative, NSC311153 improves its binding with the G-quadruplex structure and the stability induced by this compound is more potent than ellipticine. Furthermore, this compound also interfered with the transcriptional mechanism of the RET gene in an MTC derived cell line, TT cells and significantly decreased the endogenous RET protein expression. We demonstrated the specificity of NSC311153 by using papillary thyroid carcinoma (PTC) cells, the TPC1 cell line which lacks the G-quadruplex forming sequence in the promoter region due to chromosomal rearrangement. The RET downregulation selectively suppresses cell proliferation by inhibiting the intracellular Raf/MEK/ERK and PI3K/Akt/mTOR signaling pathways in the TT cells. In the present study, we also showed that the systemic administration of a water soluble NSC311153 analog in a mouse MTC xenograft model inhibited the tumor growth through RET downregulation. PMID:28498409

Study of the structures of photodegradation impurities and pathways of photodegradation of cilnidipine by liquid chromatography/Q-Orbitrap mass spectrometry.

PubMed

Zeng, Hongxia; Wang, Fan; Zhu, Bingqi; Zhong, Weihui; Shan, Weiguang; Wang, Jian

2016-08-15

The structures of photodegradation impurities in cilnidipine were studied by liquid chromatography/Q-Orbitrap mass spectrometry (LC/Q-Orbitrap MS) for the further improvement of the official monographs in Pharmacopoeias. The complete fragmentation patterns of impurities were investigated to obtain their structural information. Two pathways of photodegradation of cilnidipine were also explored to clarify the source of impurities in cilnidipine. Chromatographic separation was performed on a Boston Group C18 column (250 mm × 4.6 mm, 5 μm). The mobile phase consisted of acetonitrile/H2 O at a ratio of 75:25 (v/v). In order to determine the m/z values of the molecular ions and formulas of all detected impurities, full scan LC/MS in both positive and negative ion modes was firstly performed using a Thermo LC system coupled with a Q-Orbitrap high-resolution mass spectrometer. LC/MS/MS analysis was also carried out on target compounds to obtain as much structural information as possible. Five novel photodegradation impurities of cilnidipine were separated and identified based on the high-resolution MS/MS data. Impurity III was synthesized and its structure was confirmed by (1) H-NMR and (13) C-NMR data. Two photodegradation pathways to produce different photodegradation impurities were also revealed in this study. Among those impurities, impurities II and III were the main impurities which existed in the cilnidipine available on the market. Impurity II (the Z-isomer) was mainly produced when cilnidipine powder was directly exposed to daylight while impurity III (containing a piperidine ring) was mainly produced when cilnidipine was exposed to daylight in an ethanolic solution. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

An integrated molecular modeling approach for in silico design of new tetracyclic derivatives as ALK inhibitors.

PubMed

Peddi, Saikiran Reddy; Sivan, Sree Kanth; Manga, Vijjulatha

2016-10-01

Anaplastic lymphoma kinase (ALK), a promising therapeutic target for treatment of human cancers, is a receptor tyrosine kinase that instigates the activation of several signal transduction pathways. In the present study, in silico methods have been employed in order to explore the structural features and functionalities of a series of tetracyclic derivatives displaying potent inhibitory activity toward ALK. Initially docking was performed using GLIDE 5.6 to probe the bioactive conformation of all the compounds and to understand the binding modes of inhibitors. The docking results revealed that ligand interaction with Met 1199 plays a crucial role in binding of inhibitors to ALK. Further to establish a robust 3D-QSAR model using CoMFA and CoMSIA methods, the whole dataset was divided into three splits. Model obtained from Split 3 showed high accuracy ([Formula: see text] of 0.700 and 0.682, [Formula: see text] of 0.971 and 0.974, [Formula: see text] of 0.673 and 0.811, respectively for CoMFA and CoMSIA). The key structural requirements for enhancing the inhibitory activity were derived from CoMFA and CoMSIA contours in combination with site map analysis. Substituting small electronegative groups at Position 8 by replacing either morpholine or piperidine rings and maintaining hydrophobic character at Position 9 in tetracyclic derivatives can enhance the inhibitory potential. Finally, we performed molecular dynamics simulations in order to investigate the stability of protein ligand interactions and MM/GBSA calculations to compare binding free energies of co-crystal ligand and newly designed molecule N1. Based on the coherence of outcome of various molecular modeling studies, a set of 11 new molecules having potential predicted inhibitory activity were designed.

Role of protein sulfation in vasodilation induced by minoxidil sulfate, a K+ channel opener

DOE Office of Scientific and Technical Information (OSTI.GOV)

Meisheri, K.D.; Oleynek, J.J.; Puddington, L.

Evidence from contractile, radioisotope ion flux and electrophysiological studies suggest that minoxidil sulfate (MNXS) acts as a K+ channel opener in vascular smooth muscle. This study was designed to examine possible biochemical mechanisms by which MNXS exerts such an effect. Experiments performed in the isolated rabbit mesenteric artery (RMA) showed that MNXS, 5 microM, but not the parent compound minoxidil, was a potent vasodilator. Whereas the relaxant effects of an another K+ channel opener vasodilator, BRL-34915 (cromakalim), were removed by washing with physiological saline solution, the effects of MNXS persisted after repeated washout attempts. Furthermore, after an initial exposure ofmore » segments of intact RMA to (35S) MNXS, greater than 30% of the radiolabel was retained 2 hr after removal of the drug. In contrast, retention of radiolabel was not detected with either (3H)MNXS (label on the piperidine ring of MNXS) or (3H)minoxidil (each less than 3% after a 2-hr washout). These data suggested that the sulfate moiety from MNXS was closely associated with the vascular tissue. To determine if proteins were the acceptors of sulfate from MNXS, intact RMAs were incubated with (35S)MNXS, and then 35S-labeled proteins were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and analyzed by fluorography. Preferential labeling of a 116 kD protein was detected by 2 and 5 min of treatment. A 43 kD protein (resembling actin) also showed significant labeling. A similar profile of 35S-labeled proteins was observed in (35S) MNXS-treated A7r5 rat aortic smooth muscle cells, suggesting that the majority of proteins labeled by (35S)MNXS in intact RMA were components of smooth muscle cells.« less

2-[3-Furyl(hydroxy)methyl]-2,3-dimethylcyclohexanone.

PubMed

García, Esther; Mendoza, Virgilio; Guzmán, José Agustín; Maldonado Graniel, Luis Angel; Hernández-Ortega, Simón

2002-06-01

Contribution No. 1750 of the Instituto de Quimica, UNAM, Mexico. In the molecule of the title compound, C(13)H(18)O(3), there is a syn relationship between the two vicinal methyl groups. The six-membered ring adopts a chair conformation, with one equatorial and two axial groups, and the furyl group is almost parallel to the ketone group. Intermolecular hydrogen bonds [O[bond]H...O[double bond]C 2.814 (3) A] form chains along [100].

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kisaki, M., E-mail: kisaki.masashi@LHD.nifs.ac.jp; Ikeda, K.; Osakabe, M.

To improve the performance of negative-ion based neutral beam injection on the Large Helical Device, the accelerator was modified on the basis of numerical investigations. A field limiting ring was installed on the upper side of a grounded grid (GG) support and a multi-slot GG was adopted instead of a multi-aperture GG. As a result, the voltage holding capability is improved and the heat load on the GG decreases by 40%. In addition, the arc efficiency is improved significantly only by replacing the GG.

Two three-dimensional coordination polymers of lead(II) with iminodiacetate and naphthalene-dicarboxylate anions: Synthesis, characterization and luminescence behavior

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hazari, Debdoot; Jana, Swapan Kumar; Fleck, Michel

2014-11-15

Two lead(II) compounds [Pb{sub 3}(idiac){sub 3}(phen){sub 2}(H{sub 2}O)]·2(H{sub 2}O) (1) and [Pb(ndc)]{sub n} (2), where H{sub 2}idiac=iminodiacetic acid, phen=1,10-phenanthroline and H{sub 2}ndc=naphthalene-2,6-dicarboxylic acid, have been synthesized and structurally characterized. Single crystal X-ray diffraction analysis showed that compound 1 is a discrete trinuclear complex (of two-fold symmetry) which evolves to a supramolecular 3D network via π–π interactions, while in compound 2 the naphthalene dicarboxylate anion act as a linker to form a three dimensional architecture, where the anion adopts a bis-(bidentate bridging) coordination mode connecting four Pb(II) centers. The photoluminescence property of the two complexes has been studied. - graphical abstract:more » Two new topologically different 1D coordination polymers formed by Pb{sub 4} clusters have been synthesized and characterized by x-ray analysis. The luminescence and thermal properties have been studied. - Highlights: • 1 is a trinuclear complex of Pb(II) growing to 3D network via weak interactions. • In 1, layers of (4,4) rhomboidal topology are identified. • In 2, the ndc anion adopts interesting bis-(bidentate bridging) coordination. • In 2, network is reinforced by C–H…π-ring interactions between the ndc rings.« less

Transparent lattice characterization with gated turn-by-turn data of diagnostic bunch train

NASA Astrophysics Data System (ADS)

Li, Yongjun; Cheng, Weixing; Ha, Kiman; Rainer, Robert

2017-11-01

Methods of characterization of a storage ring's lattice have traditionally been intrusive to routine operations. More importantly, the lattice seen by particles can drift with the beam current due to collective effects. To circumvent this, we have developed a novel approach for dynamically characterizing a storage ring's lattice that is transparent to operations. Our approach adopts a dedicated filling pattern which has a short, separate diagnostic bunch train (DBT). Through the use of a bunch-by-bunch feedback system, the DBT can be selectively excited on demand. Gated functionality of a beam position monitor system is capable of collecting turn-by-turn data of the DBT, from which the lattice can then be characterized after excitation. As the DBT comprises only about one percent of the total operational bunches, the effects of its excitation are negligible to users. This approach allows us to localize the distributed quadrupolar wakefields generated in the storage ring vacuum chamber during beam accumulation. While effectively transparent to operations, our approach enables us to dynamically control the beta beat and phase beat, and unobtrusively optimize performance of the National Synchrotron Light Source-II accelerator during routine operations.

Transparent lattice characterization with gated turn-by-turn data of diagnostic bunch train

DOE PAGES

Li, Yongjun; Cheng, Weixing; Ha, Kiman; ...

2017-11-21

Methods of characterization of a storage ring's lattice have traditionally been intrusive to routine operations. More importantly, the lattice seen by particles can drift with the beam current due to collective effects. To circumvent this, we have developed a novel approach for dynamically characterizing a storage ring's lattice that is transparent to operations. Our approach adopts a dedicated filling pattern which has a short, separate Diagnostic Bunch-Train (DBT). Through the use of a bunch-by-bunch feedback system, the DBT can be selectively excited on-demand. Gated functionality of a beam position monitor system is capable of collecting turn-by-turn data of the DBT,more » from which the lattice can then be characterized after excitation. As the DBT comprises only about one percent of the total operational bunches, the effects of its excitation are negligible to users. Therefore, this approach allows us to localize the distributed quadrupolar wake fields generated in the storage ring vacuum chamber during beam accumulation. While effectively transparent to operations, our approach enables us to dynamically control the beta-beat and phase-beat, and unobtrusively optimize performance of National Synchrotron Light Source-II accelerator during routine operations.« less

(E)-N′-(4-Meth­oxy­benzyl­idene)pyridine-3-carbohydrazide dihydrate

PubMed Central

Novina, J. Josephine; Vasuki, G.; Suresh, M.; Padusha, M. Syed Ali

2013-01-01

In the title compound, C14H13N3O2·2H2O, the hydrazone mol­ecule adopts an E conformation with respect to the C=N bond. The dihedral angle between the benzene and pyridine rings is 8.55 (10)°. The methyl­idene–hydrazide [–C(=O)–N–N=C–] fragment is essentially planar, with a maximum deviation of 0.0375 (13) Å. The mean planes of the benzene and pyridine rings make dihedral angles of 2.71 (14) and 11.25 (13)°, respectively, with mean plane of the methyl­idene-hydrazide fragment. In the crystal, the benzohydrazide and water mol­ecules are linked by N—H⋯O, O—H⋯O and O—H⋯N hydrogen bonds into a three-dimensional network. PMID:24046719

Creation of diffraction-limited non-Airy multifocal arrays using a spatially shifted vortex beam

NASA Astrophysics Data System (ADS)

Lin, Han; Gu, Min

2013-02-01

Diffraction-limited non-Airy multifocal arrays are created by focusing a phase-modulated vortex beam through a high numerical-aperture objective. The modulated phase at the back aperture of the objective resulting from the superposition of two concentric phase-modulated vortex beams allows for the generation of a multifocal array of cylindrically polarized non-Airy patterns. Furthermore, we shift the spatial positions of the phase vortices to manipulate the intensity distribution at each focal spot, leading to the creation of a multifocal array of split-ring patterns. Our method is experimentally validated by generating the predicted phase modulation through a spatial light modulator. Consequently, the spatially shifted circularly polarized vortex beam adopted in a dynamic laser direct writing system facilitates the fabrication of a split-ring microstructure array in a polymer material by a single exposure of a femtosecond laser beam.

Size Effect on the Mechanical Properties of CF Winding Composite

NASA Astrophysics Data System (ADS)

Cui, Yuqing; Yin, Zhongwei

2017-12-01

Mechanical properties of filament winding composites are usually tested by NOL ring samples. Few people have studied the size effect of winding composite samples on the testing result of mechanical property. In this research, winding composite thickness, diameter, and geometry of NOL ring samples were prepared to investigate the size effect on the mechanical strength of carbon fiber (CF) winding composite. The CF T700, T1000, M40, and M50 were adopted for the winding composite, while the matrix was epoxy resin. Test results show that the tensile strength and ILSS of composites decreases monotonically with an increase of thickness from 1 mm to 4 mm. The mechanical strength of composite samples increases monotonically with the increase in diameter from 100 mm to 189 mm. The mechanical strength of composite samples with two flat sides are higher than those of cyclic annular samples.

4,4′-[Ethylenebis(nitrilomethylidyne)]dibenzonitrile

PubMed Central

Kia, Reza; Fun, Hoong-Kun; Kargar, Hadi

2009-01-01

The mol­ecule of the title Schiff base compound, C18H14N4, lies across a crystallographic inversion centre and adopts an E configuration with respect to the azomethine (C=N) bonds. The imino groups are coplanar with the aromatic rings with a maximum deviation of 0.1574 (12) Å for the N atom. Within the mol­ecule, the planar units are parallel, but extend in opposite directions from the dimethyl­ene bridge. In the crystal structure, pairs of inter­molecular C—H⋯N hydrogen bonds link neighbouring mol­ecules into centrosymmetric dimers with R 2 2(10) ring motifs. An inter­esting feature of the crystal structure is the short inter­molecular C⋯C inter­action with a distance of 3.3821 (13) Å, which is shorter than the sum of the van der Waals radius of a carbon atom. PMID:21582425

Structure of eukaryotic prefoldin and of its complexes with unfolded actin and the cytosolic chaperonin CCT

PubMed Central

Martín-Benito, Jaime; Boskovic, Jasminka; Gómez-Puertas, Paulino; Carrascosa, José L.; Simons, C.Torrey; Lewis, Sally A.; Bartolini, Francesca; Cowan, Nicholas J.; Valpuesta, José M.

2002-01-01

The biogenesis of the cytoskeletal proteins actin and tubulin involves interaction of nascent chains of each of the two proteins with the oligomeric protein prefoldin (PFD) and their subsequent transfer to the cytosolic chaperonin CCT (chaperonin containing TCP-1). Here we show by electron microscopy that eukaryotic PFD, which has a similar structure to its archaeal counterpart, interacts with unfolded actin along the tips of its projecting arms. In its PFD-bound state, actin seems to acquire a conformation similar to that adopted when it is bound to CCT. Three-dimensional reconstruction of the CCT:PFD complex based on cryoelectron microscopy reveals that PFD binds to each of the CCT rings in a unique conformation through two specific CCT subunits that are placed in a 1,4 arrangement. This defines the phasing of the CCT rings and suggests a handoff mechanism for PFD. PMID:12456645

Conformational Effects through Hydrogen Bonding in a Constrained γ-Peptide Template: From Intraresidue Seven-Membered Rings to a Gel-Forming Sheet Structure.

PubMed

Awada, Hawraà; Grison, Claire M; Charnay-Pouget, Florence; Baltaze, Jean-Pierre; Brisset, François; Guillot, Régis; Robin, Sylvie; Hachem, Ali; Jaber, Nada; Naoufal, Daoud; Yazbeck, Ogaritte; Aitken, David J

2017-05-05

A series of three short oligomers (di-, tri-, and tetramers) of cis-2-(aminomethyl)cyclobutane carboxylic acid, a γ-amino acid featuring a cyclobutane ring constraint, were prepared, and their conformational behavior was examined spectroscopically and by molecular modeling. In dilute solutions, these peptides showed a number of low-energy conformers, including ribbonlike structures pleated around a rarely observed series of intramolecular seven-membered hydrogen bonds. In more concentrated solutions, these interactions defer to an organized supramolecular assembly, leading to thermoreversible organogel formation notably for the tripeptide, which produced fibrillar xerogels. In the solid state, the dipeptide adopted a fully extended conformation featuring a one-dimensional network of intermolecularly H-bonded molecules stacked in an antiparallel sheet alignment. This work provides unique insight into the interplay between inter- and intramolecular H-bonded conformer topologies for the same peptide template.

Circularly split-ring-resonator-based frequency-reconfigurable antenna

NASA Astrophysics Data System (ADS)

Rahman, M. A.; Faruque, M. R. I.; Islam, M. T.

2017-01-01

In this paper, an antenna with frequency configurability in light of a circularly split-ring resonator (CSRR) is introduced. The proposed reconfigurable monopole antenna consists of a microstrip-fed hook-shaped structure and a CSRR having single reconfigurable split only. A new band of radiation unlike the band radiated from monopole only is observed due to magnetic coupling between the CSRR and the monopole antenna. The resonance frequency of the CSRR can be arbitrarily chosen by varying the dimension and relative position of its gap with the monopole, which leads the antenna to become reconfigurable one. By using a single switch with perfect electric conductor at the gap of CSRR cell, the effect of CSRR can be deactivated and, hence, it is possible to suppress the corresponding resonance, resulting in a frequency-reconfigurable antenna. Commercially available Computer Simulation Technology microwave studio based on finite integration technique was adopted throughout the study.

Crystal structure and absolute configuration of (3aS,4S,5R,7aR)-2,2,7-trimethyl-3a,4,5,7a-tetra-hydro-1,3-benzodioxole-4,5-diol.

PubMed

Macías, Mario A; Suescun, Leopoldo; Pandolfi, Enrique; Schapiro, Valeria; Tibhe, Gaurao D; Mombrú, Álvaro W

2015-09-01

The absolute configuration of the title compound, C10H16O4, determined as 3aS,4S,5R,7aR on the basis of the synthetic pathway, was confirmed by X-ray diffraction. The mol-ecule contains a five- and a six-membered ring that adopt twisted and envelope conformations, respectively. The dihedral angle between the mean planes of the rings is 76.80 (11)° as a result of their cis-fusion. In the crystal, mol-ecules are linked by two pairs of O-H⋯O hydrogen bonds, forming chains along [010]. These chains are further connected by weaker C-H⋯O inter-actions along [100], creating (001) sheets that inter-act only by weak van der Waals forces.

Evaluation of shrinkage and cracking in concrete of ring test by acoustic emission method

NASA Astrophysics Data System (ADS)

Watanabe, Takeshi; Hashimoto, Chikanori

2015-03-01

Drying shrinkage of concrete is one of the typical problems related to reduce durability and defilation of concrete structures. Lime stone, expansive additive and low-heat Portland cement are used to reduce drying shrinkage in Japan. Drying shrinkage is commonly evaluated by methods of measurement for length change of mortar and concrete. In these methods, there is detected strain due to drying shrinkage of free body, although visible cracking does not occur. In this study, the ring test was employed to detect strain and age cracking of concrete. The acoustic emission (AE) method was adopted to detect micro cracking due to shrinkage. It was recognized that in concrete using lime stone, expansive additive and low-heat Portland cement are effective to decrease drying shrinkage and visible cracking. Micro cracking due to shrinkage of this concrete was detected and evaluated by the AE method.

On the origin of fluorescence in bacteriophytochrome infrared fluorescent proteins

PubMed Central

Samma, Alex A.; Johnson, Chelsea K.; Song, Shuang; Alvarez, Samuel

2010-01-01

Tsien (Science, 2009, 324, 804-807) has recently reported the creation of the first infrared fluorescent protein (IFP). It was engineered from bacterial phytochrome by removing the PHY and histidine kinase-related domains, by optimizing the protein to prevent dimerization and by limiting the biliverdins conformational freedom, especially around its D ring. We have used database analyses and molecular dynamics simulations with freely rotating chromophoric dihedrals in order to model the dihedral freedom available to the biliverdin D ring in the excited state; to show that the tetrapyrrole ligands in phytochromes are flexible and can adopt many conformations, however their conformational space is limited/defined by the chemospatial characteristics of the protein cavity. Our simulations confirm that the reduced accessibility to conformations geared to an excited state proton transfer may be responsible for the fluorescence in IFP, just as has been suggested by Kennis (PNAS, 2010, 107, 9170-9175) for fluorescent bacteriophytochrome from Rhodopseudomonas palustris. PMID:21047084

A Fundamental Approach to Adhesion: Synthesis, Surface Analysis, Thermodynamics and Mechanics.

DTIC Science & Technology

1978-02-01

Polyphenylquinoxaline LSS - Lap Shear Strength Pasa-Jell - Commercial acid etch (See p. 15 ) Turco - Commercial base etch (See p. 17 ) CTBN - Carboxyl-Terminated...solvent- cast films or powders. SEM/EDAX results were obtained from the fracture surfaces of lap-shear tested specimens. Epoxy and two epoxy/ CTBN bulk...A - - 24 CTBN 1300X8 (Goodrich carboxyl- 5 5 terminated butadiene-acrylonitrile) Piperidine 5 5 5 L9 III. RESULTS AND DISCUSS10N A. Titanium 6-4 (SEM

Allylic aminations with hindered secondary amine nucleophiles catalyzed by heterobimetallic Pd-Ti complexes.

PubMed

Walker, Whitney K; Anderson, Diana L; Stokes, Ryjul W; Smith, Stacey J; Michaelis, David J

2015-02-06

Phosphinoamide-scaffolded heterobimetallic palladium-titanium complexes are highly effective catalysts for allylic aminations of allylic chlorides with hindered secondary amine nucleophiles. Three titanium-containing ligands are shown to assemble active catalysts in situ and enable catalysis at room temperature. A variety of sterically bulky secondary amines are efficiently allylated in high yields with as little as 1 mol % palladium catalyst. Piperidine and pyrrolidine products are also efficiently generated via intramolecular aminations with hindered amine nucleophiles.

Public health and potential complications of novel fashion accessories: an unusual foreign body in the upper gastrointestinal tract of an adolescent.

PubMed

Tsesmeli, Niki E; Savopoulos, Christos G; Hatzitolios, Apostolos I; Karamitsos, Dimitrios T

2007-12-01

Various foreign bodies (FB) may be ingested. Most of them harmlessly pass through the anus but sharp or pointed ones are likely to cause complications. Although FB's ingestion is commonly seen by the emergency room personnel, a case of an ingested tongue-ring in the stomach of a female adolescent has not been reported. A 16-year-old female was referred to us for swallowing a tongue-ring while eating, a day after she had swallowed its clip. After finishing her meal, she had replaced the ingested tongue-ring with a similar one! She had a history of accidental swollowing the clip during breakfast a day before as well. She had no history of mental illness, alcohol or drug abuse. An abdominal X-ray confirmed their presence in the gastrointestinal tract. On endoscopy, an intact esophagus' mucosa, a stomach filled with food, her tongue-ring in its greater curvature and a patulous pyloric channel were observed. She was turned in the right lateral position and small amounts of water were carefully used in order to shift the food residues to the antrum. The slippery object was grasped by a biopsy forceps and it was pulled out gently. The procedure was uneventful and she was discharged home on the same day. Our case of a tongue-ring ingested by an adolescent demonstrates a troublesome and possibly dangerous consequence of certain fashion accessories' easy adoption especially by younger subjects. It does not only send a social message, but it also might represent the first example of a potentially emerging medical condition.

Decreased recurrence rate in the laparoscopic herniorraphy in children: comparison between two techniques.

PubMed

Marte, Antonio; Sabatino, Maria D; Borrelli, Micaela; Parmeggiani, Pio

2009-04-01

The laparoscopic herniorraphy in children is still associated to a high recurrence rate. The aim of this study was to assess whether the addition of the lateral incision of the sac to the sole suture of the inner inguinal ring could reduce the recurrence rate. A retrospective review was performed of the collected data of 248 laparoscopic inguinal hernia repairs in 224 children (175 males, 49 females) between 8 months and 11 years of age (mean age, 5 years; median, 4) in our institution from January 2004 to December 2007. The hernia was unilateral in 204 patients (133 on the right side, 71 on the left) and bilateral in 20 patients. A 5-mm umbilical camera port for a 0-degree laparoscopic optics and two operative 2- or 3-mm reusable trocars inserted in the lower right and left quadrants of the abdominal wall were utilized. In a group of 123 patients, the inner inguinal ring was closed, adopting a W-shaped suture (inguinal ring suture; IRS). In the other group of 101 patients, a lateral incision of the sac of 1-2 cm was carried out before the W-shaped suture of the inner inguinal ring (inguinal ring incision suture; IRIS). At a mean follow-up of 24 months (range, 6-36), 5 of 133 (3.76%) hernias recurred between 6 and 12 months after surgery in the IRS group. In the IRIS group, none of the patients presented with recurrence. The rate of recurrences in the two groups was compared and analyzed with the x2 test. The resulting difference was statistically significant (P < 0.05). In our experience, the incision of the peritoneum lateral to the internal inguinal ring and the W-shaped suture, compared to the sole W-shaped suture, is safe and effective in preventing hernia recurrence.

Combined Structural and Compositional Evolution of Planetary Rings Due to Micrometeoroid Impacts and Ballistic Transport

NASA Technical Reports Server (NTRS)

Estrada, Paul R.; Durisen, Richard H.; Cuzzi, Jeffrey N.; Morgan, Demitri A.

2015-01-01

We introduce improved numerical techniques for simulating the structural and compositional evolution of planetary rings due to micrometeoroid bombardment and subsequent ballistic transport of impact ejecta. Our current, robust code is capable of modeling structural changes and pollution transport simultaneously over long times on both local and global scales. In this paper, we describe the methodology based on the original structural code of Durisen et al. (1989, Icarus 80, 136-166) and on the pollution transport code of Cuzzi and Estrada (1998, Icarus 132, 1-35). We provide demonstrative simulations to compare with, and extend upon previous work, as well as examples of how ballistic transport can maintain the observed structure in Saturn's rings using available Cassini occultation optical depth data. In particular, we explicitly verify the claim that the inner B (and presumably A) ring edge can be maintained over long periods of time due to an ejecta distribution that is heavily biased in the prograde direction through a balance between the sharpening effects of ballistic transport and the broadening effects of viscosity. We also see that a "ramp"-like feature forms over time just inside that edge. However, it does not remain linear for the duration of the runs presented here unless a less steep ejecta velocity distribution is adopted. We also model the C ring plateaus and find that their outer edges can be maintained at their observed sharpness for long periods due to ballistic transport. We hypothesize that the addition of a significant component of a retrograde-biased ejecta distribution may help explain the linearity of the ramp and is probably essential for maintaining the sharpness of C ring plateau inner edges. This component would arise for the subset of micrometeoroid impacts which are destructive rather than merely cratering. Such a distribution will be introduced in future work.

Combined structural and compositional evolution of planetary rings due to micrometeoroid impacts and ballistic transport

NASA Astrophysics Data System (ADS)

Estrada, Paul R.; Durisen, Richard H.; Cuzzi, Jeffrey N.; Morgan, Demitri A.

2015-05-01

We introduce improved numerical techniques for simulating the structural and compositional evolution of planetary rings due to micrometeoroid bombardment and subsequent ballistic transport of impact ejecta. Our current, robust code is capable of modeling structural changes and pollution transport simultaneously over long times on both local and global scales. In this paper, we describe the methodology based on the original structural code of Durisen et al. (Durisen, R.H. et al. [1989]. Icarus 80, 136-166) and on the pollution transport code of Cuzzi and Estrada (Cuzzi, J.N., Estrada, P.R. [1998]. Icarus 132, 1-35). We provide demonstrative simulations to compare with, and extend upon previous work, as well as examples of how ballistic transport can maintain the observed structure in Saturn's rings using available Cassini occultation optical depth data. In particular, we explicitly verify the claim that the inner B (and presumably A) ring edge can be maintained over long periods of time due to an ejecta distribution that is heavily biased in the prograde direction through a balance between the sharpening effects of ballistic transport and the broadening effects of viscosity. We also see that a "ramp"-like feature forms over time just inside that edge. However, it does not remain linear for the duration of the runs presented here unless a less steep ejecta velocity distribution is adopted. We also model the C ring plateaus and find that their outer edges can be maintained at their observed sharpness for long periods due to ballistic transport. We hypothesize that the addition of a significant component of a retrograde-biased ejecta distribution may help explain the linearity of the ramp and could provide a mechanism for maintaining the sharpness of C ring plateau inner edges. This component would arise for the subset of micrometeoroid impacts which are destructive rather than merely cratering. Such a distribution will be introduced in future work.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Takahashi, Sanemichi Z.; Inutsuka, Shu-ichiro, E-mail: sanemichi@astr.tohoku.ac.jp, E-mail: inutsuka@nagoya-u.jp

Recent ALMA observation has revealed multiple ring structures formed in a protoplanetary disk around HL Tau. Prior to the ALMA observation of HL Tau, theoretical analysis of secular gravitational instability (GI) described a possible formation of multiple ring structures with separations of 13 au around a radius of 100 au in protoplanetary disks under certain conditions. In this article, we reanalyze the viability of secular GI by adopting the physical values inferred from the observations. We derive the radial distributions of the most unstable wavelength and the growth timescale of secular GI and verify that secular GI can form themore » ring structures observed in HL Tau. When a turbulent viscosity coefficient α remains small in the inner region of the disk, secular GI grows in the whole disk. Thus, the formation of planetary mass objects should occur first in the inner region as a result of gravitational fragmentation after the nonlinear growth of secular GI. In this case, the resulting objects are expected to create gaps at r  ∼ 10 au and ∼30 au. As a result, all ring structures in HL Tau can be created by secular GI. If this scenario is realized in HL Tau, the outer region corresponds to the earlier growth phase of the most unstable mode of secular GI, and the inner region corresponds to the outcome of the nonlinear growth of secular GI. Therefore, this interpretation suggests that we are possibly witnessing both the beginning and the end of planet formation in HL Tau.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Buta, R.; de Vaucouleurs, G.

The diameters d/sub r/ of inner ring structures in disk galaxies are used as geometric distance indicators to derive the distances of 453 spiral and lenticular galaxies, mainly in the distance interval 4<..delta..<63 Mpc. The diameters are weighted means from the catalogs to Kormendy, Pedreros and Madore, and the authors. The distances are calculated by means of the two- and three-parameter formulae of Paper II; the adopted mean distance moduli ..mu../sub 0/(r) have mean errors from all sources of 0.6--0.7 mag for the well-observed galaxies.

Fermilab 4.3-MeV Electron Cooler

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nagaitsev, Sergei; Prost, Lionel; Shemyakin, Alexander

The Recycler Electron Cooler (REC) was the first cooler working at a relativistic energy (gamma = 9.5). It was successfully developed in 1995-2004 and was in operation at Fermilab in 2005-2011, providing cooling of antiprotons in the Recycler ring. After introducing the physics of electron cooling and the REC system, this paper describes measurements carried out to tune the electron beam and optimize its cooling properties. In particular, we discuss the cooling strategy adopted for maximizing the collider integrated luminosity.

Frequency analysis of a two-stage planetary gearbox using two different methodologies

NASA Astrophysics Data System (ADS)

Feki, Nabih; Karray, Maha; Khabou, Mohamed Tawfik; Chaari, Fakher; Haddar, Mohamed

2017-12-01

This paper is focused on the characterization of the frequency content of vibration signals issued from a two-stage planetary gearbox. To achieve this goal, two different methodologies are adopted: the lumped-parameter modeling approach and the phenomenological modeling approach. The two methodologies aim to describe the complex vibrations generated by a two-stage planetary gearbox. The phenomenological model describes directly the vibrations as measured by a sensor fixed outside the fixed ring gear with respect to an inertial reference frame, while results from a lumped-parameter model are referenced with respect to a rotating frame and then transferred into an inertial reference frame. Two different case studies of the two-stage planetary gear are adopted to describe the vibration and the corresponding spectra using both models. Each case presents a specific geometry and a specific spectral structure.

Synthesis and evaluation of a series of 2-substituted-5-thiopropylpiperazine (piperidine)-1,3,4-oxadiazoles derivatives as atypical antipsychotics.

PubMed

Chen, Yin; Xu, Xiangqing; Liu, Xin; Yu, Minquan; Liu, Bi-Feng; Zhang, Guisen

2012-01-01

It is important to develop novel antipsychotics that can effectively treat schizophrenia with minor side-effects. The aim of our work is to develop novel antipsychotics that act on dopamine D(2) and D(3), serotonin 5-HT(1A) and 5-HT(2A) receptors with low affinity for the serotonin 5-HT(2C) and H(1) receptors, which can effectively cure positive symptoms, negative symptoms and cognitive impairment without the weight gain side-effect. A series of 2-substituted-5-thiopropylpiperazine (piperidine) -1,3,4-oxadiazoles derivatives have been synthesized and the target compounds were evaluated for binding affinities to D(2), 5-HT(1A) and 5-HT(2A) receptors. Preliminary results indicated that compounds 14, 16 and 22 exhibited high affinities to D(2), 5-HT(1A) and 5-HT(2A) receptors among these compounds. Further binding tests showed that compound 22 had high affinity for D(3) receptor, and low affinity for serotonin 5-HT(2C) and H(1) receptors. In addition, compound 22 inhibited apomorphine-induced climbing behavior and MK-801-induced hyperactivity with no extrapyramidal symptoms liability in mice. Moreover, compound 22 exhibited acceptable pharmacokinetic properties. Compound 22 showed an atypical antipsychotic activity without liability for extrapyramidal symptoms. We anticipate compound 22 to be useful for developing a novel class of drug for the treatment of schizophrenia.

Synthesis, electronic structure investigation of 3-pentyl-2,6-di(furan-2-yl)piperidin-4-one by FT-IR, FT-Raman and UV-Visible spectral studies and ab initio/DFT calculations.

PubMed

Arockia Doss, M; Savithiri, S; Rajarajan, G; Thanikachalam, V; Anbuselvan, C

2015-12-05

FT-IR and FT-Raman spectra of 3-pentyl-2,6-di(furan-2-yl) piperidin-4-one (3-PFPO) were recorded in the solid phase. The structural and spectroscopic analyses of 3-PFPO were made by using B3LYP/HF level with 6-311++G(d, p) basis set. The fundamental vibrations are assigned on the basis of the total energy distribution (TED) of the vibrational modes, calculated with scaled quantum mechanics (SQM) method and PQS program. Comparison of the observed fundamental vibrational frequencies of 3-PFPO with calculated results by HF and DFT methods indicates that B3LYP is superior to HF method for molecular vibrational problems. The electronic properties such as excitation energies, oscillator strength, wavelengths and HOMO-LUMO energies were obtained by time-dependent DFT (TD-DFT) approach. The polarizability and first order hyperpolarizability of the title molecule were calculated and interpreted. The hyperconjugative interaction energy (E((2))) and electron densities of donor (i) and acceptor (j) bonds were calculated using NBO analysis. In addition, MEP and atomic charges of carbon, nitrogen, oxygen and hydrogen were calculated using B3LYP/6-311++G(d, p) level theory. Moreover, thermodynamic properties (heat capacities, entropy and enthalpy) of the title compound at different temperatures were calculated in gas phase. Copyright © 2015 Elsevier B.V. All rights reserved.

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

PubMed

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.

Rates of Chemical Cleavage of DNA and RNA Oligomers Containing Guanine Oxidation Products

PubMed Central

2016-01-01

The nucleobase guanine in DNA (dG) and RNA (rG) has the lowest standard reduction potential of the bases, rendering it a major site of oxidative damage in these polymers. Mapping the sites at which oxidation occurs in an oligomer via chemical reagents utilizes hot piperidine for cleaving oxidized DNA and aniline (pH 4.5) for cleaving oxidized RNA. In the present studies, a series of time-dependent cleavages of DNA and RNA strands containing various guanine lesions were examined to determine the strand scission rate constants. The guanine base lesions 8-oxo-7,8-dihydroguanine (OG), spiroiminodihydantoin (Sp), 5-guanidinohydantoin (Gh), 2,2,4-triamino-2H-oxazol-5-one (Z), and 5-carboxamido-5-formamido-2-iminohydantoin (2Ih) were evaluated in piperidine-treated DNA and aniline-treated RNA. These data identified wide variability in the chemical lability of the lesions studied in both DNA and RNA. Further, the rate constants for cleaving lesions in RNA were generally found to be significantly smaller than for lesions in DNA. The OG nucleotides were poorly cleaved in DNA and RNA; Sp nucleotides were slowly cleaved in DNA and did not cleave significantly in RNA; Gh and Z nucleotides cleaved in both DNA and RNA at intermediate rates; and 2Ih oligonucleotides cleaved relatively quickly in both DNA and RNA. The data are compared and contrasted with respect to future experimental design. PMID:25853314

Anti-trypanosomal activities and structural chemical properties of selected compound classes.

PubMed

Ponte-Sucre, Alicia; Bruhn, Heike; Schirmeister, Tanja; Cecil, Alexander; Albert, Christian R; Buechold, Christian; Tischer, Maximilian; Schlesinger, Susanne; Goebel, Tim; Fuß, Antje; Mathein, Daniela; Merget, Benjamin; Sotriffer, Christoph A; Stich, August; Krohne, Georg; Engstler, Markus; Bringmann, Gerhard; Holzgrabe, Ulrike

2015-02-01

Potent compounds do not necessarily make the best drugs in the market. Consequently, with the aim to describe tools that may be fundamental for refining the screening of candidates for animal and preclinical studies and further development, molecules of different structural classes synthesized within the frame of a broad screening platform were evaluated for their trypanocidal activities, cytotoxicities against murine macrophages J774.1 and selectivity indices, as well as for their ligand efficiencies and structural chemical properties. To advance into their modes of action, we also describe the morphological and ultrastructural changes exerted by selected members of each compound class on the parasite Trypanosoma brucei. Our data suggest that the potential organelles targeted are either the flagellar pocket (compound 77, N-Arylpyridinium salt; 15, amino acid derivative with piperazine moieties), the endoplasmic reticulum membrane systems (37, bisquaternary bisnaphthalimide; 77, N-Arylpyridinium salt; 68, piperidine derivative), or mitochondria and kinetoplasts (88, N-Arylpyridinium salt; 68, piperidine derivative). Amino acid derivatives with fumaric acid and piperazine moieties (4, 15) weakly inhibiting cysteine proteases seem to preferentially target acidic compartments. Our results suggest that ligand efficiency indices may be helpful to learn about the relationship between potency and chemical characteristics of the compounds. Interestingly, the correlations found between the physico-chemical parameters of the selected compounds and those of commercial molecules that target specific organelles indicate that our rationale might be helpful to drive compound design toward high activities and acceptable pharmacokinetic properties for all compound families.

Potential Antileukemia Effect and Structural Analyses of SRPK Inhibition by N-(2-(Piperidin-1-yl)-5-(Trifluoromethyl)Phenyl)Isonicotinamide (SRPIN340)

PubMed Central

Siqueira, Raoni Pais; Righetto, Germanna Lima; Seraphim, Thiago Vargas; Salgado, Rafael Locatelli; Ferreira, Joana Gasperazzo; Barros, Marcus Vinícius de Andrade; de Oliveira, Leandro Licursi; Laranjeira, Angelo Brunelli Albertoni; Almeida, Márcia Rogéria; Júnior, Abelardo Silva; Fietto, Juliana Lopes Rangel; Kobarg, Jörg; de Oliveira, Eduardo Basílio; Teixeira, Robson Ricardo; Borges, Júlio César; Yunes, Jose Andrés; Bressan, Gustavo Costa

2015-01-01

Dysregulation of pre-mRNA splicing machinery activity has been related to the biogenesis of several diseases. The serine/arginine-rich protein kinase family (SRPKs) plays a critical role in regulating pre-mRNA splicing events through the extensive phosphorylation of splicing factors from the family of serine/arginine-rich proteins (SR proteins). Previous investigations have described the overexpression of SRPK1 and SRPK2 in leukemia and other cancer types, suggesting that they would be useful targets for developing novel antitumor strategies. Herein, we evaluated the effect of selective pharmacological SRPK inhibition by N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)isonicotinamide (SRPIN340) on the viability of lymphoid and myeloid leukemia cell lines. Along with significant cytotoxic activity, the effect of treatments in regulating the phosphorylation of the SR protein family and in altering the expression of MAP2K1, MAP2K2, VEGF and FAS genes were also assessed. Furthermore, we found that pharmacological inhibition of SRPKs can trigger early and late events of apoptosis. Finally, intrinsic tryptophan fluorescence emission, molecular docking and molecular dynamics were analyzed to gain structural information on the SRPK/SRPIN340 complex. These data suggest that SRPK pharmacological inhibition should be considered as an alternative therapeutic strategy for fighting leukemias. Moreover, the obtained SRPK-ligand interaction data provide useful structural information to guide further medicinal chemistry efforts towards the development of novel drug candidates. PMID:26244849

Potential Antileukemia Effect and Structural Analyses of SRPK Inhibition by N-(2-(Piperidin-1-yl)-5-(Trifluoromethyl)Phenyl)Isonicotinamide (SRPIN340).

PubMed

Siqueira, Raoni Pais; Barbosa, Éverton de Almeida Alves; Polêto, Marcelo Depólo; Righetto, Germanna Lima; Seraphim, Thiago Vargas; Salgado, Rafael Locatelli; Ferreira, Joana Gasperazzo; Barros, Marcus Vinícius de Andrade; de Oliveira, Leandro Licursi; Laranjeira, Angelo Brunelli Albertoni; Almeida, Márcia Rogéria; Júnior, Abelardo Silva; Fietto, Juliana Lopes Rangel; Kobarg, Jörg; de Oliveira, Eduardo Basílio; Teixeira, Robson Ricardo; Borges, Júlio César; Yunes, Jose Andrés; Bressan, Gustavo Costa

2015-01-01

Dysregulation of pre-mRNA splicing machinery activity has been related to the biogenesis of several diseases. The serine/arginine-rich protein kinase family (SRPKs) plays a critical role in regulating pre-mRNA splicing events through the extensive phosphorylation of splicing factors from the family of serine/arginine-rich proteins (SR proteins). Previous investigations have described the overexpression of SRPK1 and SRPK2 in leukemia and other cancer types, suggesting that they would be useful targets for developing novel antitumor strategies. Herein, we evaluated the effect of selective pharmacological SRPK inhibition by N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)isonicotinamide (SRPIN340) on the viability of lymphoid and myeloid leukemia cell lines. Along with significant cytotoxic activity, the effect of treatments in regulating the phosphorylation of the SR protein family and in altering the expression of MAP2K1, MAP2K2, VEGF and FAS genes were also assessed. Furthermore, we found that pharmacological inhibition of SRPKs can trigger early and late events of apoptosis. Finally, intrinsic tryptophan fluorescence emission, molecular docking and molecular dynamics were analyzed to gain structural information on the SRPK/SRPIN340 complex. These data suggest that SRPK pharmacological inhibition should be considered as an alternative therapeutic strategy for fighting leukemias. Moreover, the obtained SRPK-ligand interaction data provide useful structural information to guide further medicinal chemistry efforts towards the development of novel drug candidates.

Structural and conformational analysis of pentostatin (2'-deoxycoformycin), a potent inhibitor of adenosine deaminase.

PubMed

Cox, M B; Arjunan, P; Arora, S K

1990-08-01

X-ray, NMR and molecular mechanics studies on pentostatin (C11H16N4O4), a potent inhibitor of the enzyme adenosine deaminase, have been carried out to study the structure and conformation. The crystals belong to the monoclinic space group P21 with the cell dimensions of a = 4.960(1), b = 10.746(3), c = 11.279(4)A, beta = 101.18(2) degrees and Z = 2. The structure was solved by direct methods and difference Fourier methods and refined to an R value of 0.047 for 997 reflections. The trihydrodiazepine ring is nonplanar and adopts a distorted sofa conformation with C(7) deviated from the mean plane by 0.66A. The deoxyribose ring adopts a C3'-endo conformation, different from coformycin where the sugar has a C2'-endo conformation. The observed glycosidic torsion angle (chi = -119.5 degrees) is in the anti range. The conformation about the C(4')-C(5') bond is gauche+. The conformation of the molecule is compared with that of coformycin and 2-azacoformycin. 1 and 2D NMR studies have been carried out and the dihedral angles obtained from coupling constants have been compared with those obtained from the crystal structure. The conformation of deoxyribose in solution is approximately 70% S and 30% N. Molecular mechanics studies were performed to obtain the energy minimized conformation, which is compared with X-ray and NMR results.

Self-oscillation of standing spin wave in ring resonator with proportional-integral-derivative control

DOE Office of Scientific and Technical Information (OSTI.GOV)

Peng, B.; Urazuka, Y.; Chen, H.

2014-05-07

We report on numerical analysis on self-oscillation of standing spin wave excited in a nanostructured active ring resonator, consists of a ferromagnetic nanowire with perpendicular anisotropy. The confined resonant modes are along the nanowire length. A positive feedback with proportional-integral-derivative gain control was adopted in the active ring. Stable excitation of the 1st order standing spin wave has been demonstrated with micromagnetic simulations, taking into account the thermal effect with a random field model. The stationary standing spin wave with a pre-determined set variable of precession amplitude was attained within 20 ns by optimizing the proportional-integral-derivative gain control parameters. The resultmore » indicates that a monochromatic oscillation frequency f{sub osc} is extracted from the initial thermal fluctuation state and selectively amplified with the positive feedback loop. The obtained f{sub osc} value of 5.22 GHz practically agrees with the theoretical prediction from dispersion relation of the magneto static forward volume wave. It was also confirmed that the f{sub osc} change due to the temperature rise can be compensated with an external perpendicular bias field H{sub b}. The observed quick compensation time with an order of nano second suggests the fast operation speed in the practical device application.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Huamg, C. W., E-mail: huang.zw@nsrrc.org.tw; Hwang, C. S., E-mail: cshwang@nsrrc.org.tw; Department of Electrophysics, National Chiao Tung University, Hsinchu 300, Taiwan

The Taiwan Photon Source (TPS) has been successfully commissioned. However, the minimum emittance in the TPS lattice is 1.6 nm rad. In the existing TPS storage ring lattice, it is imperative to reduce the emittance to below 1 nm rad. Therefore, a feasibility study for reducing the effective emittance of the TPS storage ring by using a Robinson wiggler was launched; the reduction is necessary to enhance the photon brilliance. In this study, a permanent-magnet multiperiod Robinson wiggler (MRW) was developed for use instead of the single-period Robinson wiggler. In general, the quadruple field of a combined function magnet inmore » the storage ring is approximately few tesla per meter. According to beam dynamic analysis, we found that it is necessary to adopt a high gradient (40 T/m) combined-function MRW magnet to reduce the emittance effectively. Therefore, a high gradient field strength is required in the combined function MRW magnet. In this study, the quadrupole field strength of the MRW magnet was allowed to be approximately 40 T/m at a magnet gap of 20 mm. The period length of the MRW magnet was 300 mm and the period number was 16. The of MRWs is discussed in regard to the possibility of increasing the photon brilliance from IU22.« less

An overview of SAFENET and its implications for aerospace applications

NASA Technical Reports Server (NTRS)

Collins, George C.; Bown, Rodney L.

1991-01-01

The survivable, adaptable fiber optic embeddable network (SAFENET) is a draft standard for local area networking (LAN) developed by the Navy which, when adopted, will become a military standard. The standard is being developed for procurement specifications of computer resources to be used on ships and aircraft and has some of the real-time concerns that network standards for space vehicles have. Architecture and survivability are considered. It is noted that the token-ring LAN must implement the IEEE 802.5 recommended practice for dual ring reconfiguration, which is currently being reviewed for inclusion into the IEEE standard. A trunk coupling unit is used at each station to isolate a station from the ring in case of failure. Up to five stations can be bypassed in this fashion. Communication architecture has an OSI profile but differs from the standard concept of the seven layers by allowing alternate suits and breaking the layers into three groupings of services to allow for physical interfacing. It also provides several paths, even if only one profile is used. Management and synchronization protocols are discussed and security issues are addressed. Implications for aerospace applications are considered and it is projected that interoperability with the Navy and other U.S. Government systems may require SAFENET specifications for NASA systems.

Discovery of a new Wolf-Rayet star and its ring nebula in Cygnus

NASA Astrophysics Data System (ADS)

Gvaramadze, V. V.; Fabrika, S.; Hamann, W.-R.; Sholukhova, O.; Valeev, A. F.; Goranskij, V. P.; Cherepashchuk, A. M.; Bomans, D. J.; Oskinova, L. M.

2009-11-01

We report the serendipitous discovery of a ring nebula around a candidate Wolf-Rayet (WR) star, HBHA4202-22, in Cygnus using the Spitzer Space Telescope archival data. Our spectroscopic follow-up observations confirmed the WR nature of this star (we named it WR138a) and showed that it belongs to the WN8-9h subtype. We thereby add a new example to the known sample of late WN stars with circumstellar nebulae. We analysed the spectrum of WR138a by using the Potsdam Wolf-Rayet (PoWR) model atmospheres, obtaining a stellar temperature of 40kK. The stellar wind composition is dominated by helium with 20 per cent of hydrogen. The stellar spectrum is highly reddened and absorbed (EB- V = 2.4mag, AV = 7.4mag). Adopting a stellar luminosity of logL/Lsolar = 5.3, the star has a mass-loss rate of 10-4.7Msolaryr-1, and resides in a distance of 4.2 kpc. We measured the proper motion for WR138a and found that it is a runaway star with a peculiar velocity of ~=50kms-1. Implications of the runaway nature of WR138a for constraining the mass of its progenitor star and understanding the origin of its ring nebula are discussed.

Mechanisms associated with the high adsorption of dibenzo-p-dioxin from water by smectite clays.

PubMed

Liu, Cun; Li, Hui; Teppen, Brian J; Johnston, Cliff T; Boyd, Stephen A

2009-04-15

Clay minerals may be an important unrecognized sorptive phase for dioxins in soils and clay deposits. Smectites, especially Cs-saponite, effectively adsorbed dibenzo-p-dioxin (DD) from water, reaching 0.8% (wt/wt). Adsorption was promoted by exchangeable cations with low hydration energies, and negative charge in the smectite arising from the tetrahedral siloxane sheets. X-ray diffraction measurements revealed that as DD loading increased to > or =8000 mg/kg the clay basal spacing increased abruptly from 12.3 to 15.2 A demonstrating DD intercalation. The 12.3 A spacing provides an interlayer distance that closely matches the molecular thickness of DD. In this configuration DD is essentially dehydrated as it interacts with the opposing hydrophobic siloxane sheets and with coplanar Cs+ via one of the dioxin ring oxygens. Ab initio calculations suggest that geometrical structures form at higher loadings in which intercalated DD molecules adopt a butterfly geometry sandwiched between dehydrated interlayer Cs+ and the siloxane surface, consistent with the 15.2 A spacing, wherein Cs+ interacts with dioxin ring oxygens and benzene ring pi-electrons. Fourier transformation infrared measurements confirm that adsorbed DD is present in orientations that are not parallel with the interlayer planar siloxane surfaces of smectite.

The unique N-terminal zinc finger of synaptotagmin-like protein 4 reveals FYVE structure.

PubMed

Miyamoto, Kazuhide; Nakatani, Arisa; Saito, Kazuki

2017-12-01

Synaptotagmin-like protein 4 (Slp4), expressed in human platelets, is associated with dense granule release. Slp4 is comprised of the N-terminal zinc finger, Slp homology domain, and C2 domains. We synthesized a compact construct (the Slp4N peptide) corresponding to the Slp4 N-terminal zinc finger. Herein, we have determined the solution structure of the Slp4N peptide by nuclear magnetic resonance (NMR). Furthermore, experimental, chemical modification of Cys residues revealed that the Slp4N peptide binds two zinc atoms to mediate proper folding. NMR data showed that eight Cys residues coordinate zinc atoms in a cross-brace fashion. The Simple Modular Architecture Research Tool database predicted the structure of Slp4N as a RING finger. However, the actual structure of the Slp4N peptide adopts a unique C 4 C 4 -type FYVE fold and is distinct from a RING fold. To create an artificial RING finger (ARF) with specific ubiquitin-conjugating enzyme (E2)-binding capability, cross-brace structures with eight zinc-ligating residues are needed as the scaffold. The cross-brace structure of the Slp4N peptide could be utilized as the scaffold for the design of ARFs. © 2017 The Protein Society.

An energy harvesting type ultrasonic motor.

PubMed

Wang, Guangqing; Xu, Wentan; Gao, Shuaishuai; Yang, Binqiang; Lu, Guoli

2017-03-01

An energy harvesting type ultrasonic motor is presented in this work. The novel motor not only can drive and/or position the motion mechanism, but also can harvest and convert the vibration-induced energy of the stator into electric energy to power small electronic devices. In the new motor, the stator is a sandwich structure of two PZT rings and an elastic metal body. The PZT ring bonded on the bottom surface is used to excite the stator metal body to generate a traveling wave with converse piezoelectric effect, and the other PZT ring bonded on top surface is used to harvest and convert the vibration-induced energy of the stator into electric energy with direct piezoelectric effect. Finite element method is adopted to analyze the vibration characteristics and the energetic characteristic. After the fabrication of a prototype, the mechanical output and electric energy output abilities are measured. The maximum no-load speed and maximum output torque of the prototype are 117rpm and 0.65Nm at an exciting voltage with amplitude of 134 V p-p and frequency of 40kHz, and the maximum harvesting output power of per sector area of the harvesting PZT is 327mW under an optimal equivalent load resistance of 6.9kΩ. Copyright © 2016 Elsevier B.V. All rights reserved.

Discovery, synthesis, selectivity modulation and DMPK characterization of 5-azaspiro[2.4]heptanes as potent orexin receptor antagonists.

PubMed

Stasi, Luigi Piero; Artusi, Roberto; Bovino, Clara; Buzzi, Benedetta; Canciani, Luca; Caselli, Gianfranco; Colace, Fabrizio; Garofalo, Paolo; Giambuzzi, Silvia; Larger, Patrice; Letari, Ornella; Mandelli, Stefano; Perugini, Lorenzo; Pucci, Sabrina; Salvi, Matteo; Toro, PierLuigi

2013-05-01

Starting from a orexin 1 receptor selective antagonist 4,4-disubstituted piperidine series a novel potent 5-azaspiro[2.4]heptane dual orexin 1 and orexin 2 receptor antagonist class has been discovered. SAR and Pharmacokinetic optimization of this series is herein disclosed. Lead compound 15 exhibits potent activity against orexin 1 and orexin 2 receptors along with low cytochrome P450 inhibition potential, good brain penetration and oral bioavailability in rats. Copyright © 2013 Elsevier Ltd. All rights reserved.

A selective estrogen receptor modulator for the treatment of hot flushes.

PubMed

Wallace, Owen B; Lauwers, Kenneth S; Dodge, Jeffrey A; May, Scott A; Calvin, Joel R; Hinklin, Ronald; Bryant, Henry U; Shetler, Pamela K; Adrian, Mary D; Geiser, Andrew G; Sato, Masahiko; Burris, Thomas P

2006-02-09

A selective estrogen receptor modulator (SERM) for the potential treatment of hot flushes is described. (R)-(+)-7,9-difluoro-5-[4-(2-piperidin-1-ylethoxy)phenyl]-5H-6-oxachrysen-2-ol, LSN2120310, potently binds ERalpha and ERbeta and is an antagonist in MCF-7 breast adenocarcinoma and Ishikawa uterine cancer cell lines. The compound is a potent estrogen antagonist in the rat uterus. In ovariectomized rats, the compound lowers cholesterol, maintains bone mineral density, and is efficacious in a morphine dependent rat model of hot flush efficacy.

Enzymatic Kinetic Resolution of 2-Piperidineethanol for the Enantioselective Targeted and Diversity Oriented Synthesis †

PubMed Central

Perdicchia, Dario; Christodoulou, Michael S.; Fumagalli, Gaia; Calogero, Francesco; Marucci, Cristina; Passarella, Daniele

2015-01-01

2-Piperidineethanol (1) and its corresponding N-protected aldehyde (2) were used for the synthesis of several natural and synthetic compounds. The existence of a stereocenter at position 2 of the piperidine skeleton and the presence of an easily-functionalized group, such as the alcohol, set 1 as a valuable starting material for enantioselective synthesis. Herein, are presented both synthetic and enzymatic methods for the resolution of the racemic 1, as well as an overview of synthesized natural products starting from the enantiopure 1. PMID:26712740

Synthesis and structure-activity relationship of piperidine-derived non-urea soluble epoxide hydrolase inhibitors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pecic, Stevan; Pakhomova, Svetlana; Newcomer, Marcia E.

2013-09-27

A series of potent amide non-urea inhibitors of soluble epoxide hydrolase (sEH) is disclosed. The inhibition of soluble epoxide hydrolase leads to elevated levels of epoxyeicosatrienoic acids (EETs), and thus inhibitors of sEH represent one of a novel approach to the development of vasodilatory and anti-inflammatory drugs. Structure–activities studies guided optimization of a lead compound, identified through high-throughput screening, gave rise to sub-nanomolar inhibitors of human sEH with stability in human liver microsomal assay suitable for preclinical development.

Alkaloids from Piper sarmentosum and Piper nigrum.

PubMed

Ee, G C L; Lim, C M; Lim, C K; Rahmani, M; Shaari, K; Bong, C F J

2009-01-01

Detailed chemical studies on the roots of Piper sarmentosum and Piper nigrum have resulted in several alkaloids. The roots of P. sarmentosum gave a new aromatic compound, 1-nitrosoimino-2,4,5-trimethoxybenzene (1). Piper nigrum roots gave pellitorine (2), (E)-1-[3',4'-(methylenedioxy)cinnamoyl]piperidine (3), 2,4-tetradecadienoic acid isobutyl amide (4), piperine (5), sylvamide (6), cepharadione A (7), piperolactam D (8) and paprazine (9). Structural elucidation of these compounds was achieved through NMR and MS techniques. Cytotoxic activity screening of the plant extracts indicated some activity.

Adenine specific DNA chemical sequencing reaction.

PubMed Central

Iverson, B L; Dervan, P B

1987-01-01

Reaction of DNA with K2PdCl4 at pH 2.0 followed by a piperidine workup produces specific cleavage at adenine (A) residues. Product analysis revealed the K2PdCl4 reaction involves selective depurination at adenine, affording an excision reaction analogous to the other chemical DNA sequencing reactions. Adenine residues methylated at the exocyclic amine (N6) react with lower efficiency than unmethylated adenine in an identical sequence. This simple protocol specific for A may be a useful addition to current chemical sequencing reactions. Images PMID:3671067

Microwave-assisted rapid synthesis of methyl 2,4,5-trimethoxyphenylpropionate, a metabolite of Cordia alliodora.

PubMed

Sinha, A K; Joshi, B P; Sharma, A; Kumar, J K; Kaul, V K

2003-12-01

Microwave assisted condensation of asaronaldehyde (2) with malonic acid in piperidine-AcOH provides 2,4,5-trimethoxycinnamic acid (3) in 87% yield within 4 min, which upon further reduction with PdCl2- HCOOH-aq. NaOH gives 3-(2,4,5-trimethoxy)phenyl propionic acid (4) in 88% yield within 3 min. Esterification of 4 with MeOH-H+ gives methyl 2,4,5-trimethoxyphenylpropionate (1), a metabolite of Cordia alliodora, in 94% yield within 3 min (overall 69% yield).

Bis(N'-{(E)-[(2E)-1,3-di-phenyl-prop-2-en-1-yl-idene]amino}-N-ethyl-carbamimido-thio-ato-κ2N',S)zinc(II): crystal structure and Hirshfeld surface analysis.

PubMed

Tan, Ming Yueh; Crouse, Karen A; Ravoof, Thahira B S A; Jotani, Mukesh M; Tiekink, Edward R T

2017-07-01

The title Zn II complex, [Zn(C 18 H 18 N 3 S) 2 ], (I), features two independent but chemically equivalent mol-ecules in the asymmetric unit. In each, the thio-semicarbazonate monoanion coordinates the Zn II atom via the thiol-ate-S and imine-N atoms, with the resulting N 2 S 2 donor set defining a distorted tetra-hedral geometry. The five-membered ZnSCN 2 chelate rings adopt distinct conformations in each independent mol-ecule, i.e. one ring is almost planar while the other is twisted about the Zn-S bond. In the crystal, the two mol-ecules comprising the asymmetric unit are linked by amine-N-H⋯N(imine) and amine-N-H⋯S(thiol-ate) hydrogen bonds via an eight-membered heterosynthon, {⋯HNCN⋯HNCS}. The dimeric aggregates are further consolidated by benzene-C-H⋯S(thiol-ate) inter-actions and are linked into a zigzag supra-molecular chain along the c axis via amine-N-H⋯S(thiol-ate) hydrogen bonds. The chains are connected into a three-dimensional architecture via phenyl-C-H⋯π(phen-yl) and π-π inter-actions, the latter occurring between chelate and phenyl rings [inter-centroid separation = 3.6873 (11) Å]. The analysis of the Hirshfeld surfaces calculated for (I) emphasizes the different inter-actions formed by the independent mol-ecules in the crystal and the impact of the π-π inter-actions between chelate and phenyl rings.

Controlling the Conformational Energy of a Phenyl Group by Tuning the Strength of a Nonclassical CH···O Hydrogen Bond: The Case of 5-Phenyl-1,3-dioxane.

PubMed

Bailey, William F; Lambert, Kyle M; Stempel, Zachary D; Wiberg, Kenneth B; Mercado, Brandon Q

2016-12-16

Anancomeric 5-phenyl-1,3-dioxanes provide a unique opportunity to study factors that control conformation. Whereas one might expect an axial phenyl group at C(5) of 1,3-dioxane to adopt a conformation similar to that in axial phenylcyclohexane, a series of studies including X-ray crystallography, NOE measurements, and DFT calculations demonstrate that the phenyl prefers to lie over the dioxane ring in order to position an ortho-hydrogen to participate in a stabilizing, nonclassical CH···O hydrogen bond with a ring oxygen of the dioxane. Acid-catalyzed equilibration of a series of anancomeric 2-tert-butyl-5-aryl-1,3-dioxane isomers demonstrates that remote substituents on the phenyl ring affect the conformational energy of a 5-aryl-1,3-dioxane: electron-withdrawing substituents decrease the conformational energy of the aryl group, while electron-donating substituents increase the conformational energy of the group. This effect is correlated in a very linear way to Hammett substituent parameters. In short, the strength of the CH···O hydrogen bond may be tuned in a predictable way in response to the electron-withdrawing or electron-donating ability of substituents positioned remotely on the aryl ring. This effect may be profound: a 3,5-bis-CF 3 phenyl group at C(5) in 1,3-dioxane displays a pronounced preference for the axial orientation. The results are relevant to broader conformational issues involving heterocyclic systems bearing aryl substituents.

2,5-difluorenyl-substituted siloles for the fabrication of high-performance yellow organic light-emitting diodes.

PubMed

Chen, Bin; Jiang, Yibin; Chen, Long; Nie, Han; He, Bairong; Lu, Ping; Sung, Herman H Y; Williams, Ian D; Kwok, Hoi Sing; Qin, Anjun; Zhao, Zujin; Tang, Ben Zhong

2014-02-10

2,3,4,5-Tetraarylsiloles are a class of important luminogenic materials with efficient solid-state emission and excellent electron-transport capacity. However, those exhibiting outstanding electroluminescence properties are still rare. In this work, bulky 9,9-dimethylfluorenyl, 9,9-diphenylfluorenyl, and 9,9'-spirobifluorenyl substituents were introduced into the 2,5-positions of silole rings. The resulting 2,5-difluorenyl-substituted siloles are thermally stable and have low-lying LUMO energy levels. Crystallographic analysis revealed that intramolecular π-π interactions are prone to form between 9,9'-spirobifluorene units and phenyl rings at the 3,4-positions of the silole ring. In the solution state, these new siloles show weak blue and green emission bands, arising from the fluorenyl groups and silole rings with a certain extension of π conjugation, respectively. With increasing substituent volume, intramolecular rotation is decreased, and thus the emissions of the present siloles gradually improved and they showed higher fluorescence quantum yields (Φ(F) =2.5-5.4%) than 2,3,4,5-tetraphenylsiloles. They are highly emissive in solid films, with dominant green to yellow emissions and good solid-state Φ(F) values (75-88%). Efficient organic light-emitting diodes were fabricated by adopting them as host emitters and gave high luminance, current efficiency, and power efficiency of up to 44,100 cd m(-2), 18.3 cd A(-1), and 15.7 lm W(-1), respectively. Notably, a maximum external quantum efficiency of 5.5% was achieved in an optimized device. Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

LEGEND, a LEO-to-GEO Environment Debris Model

NASA Technical Reports Server (NTRS)

Liou, Jer Chyi; Hall, Doyle T.

2013-01-01

LEGEND (LEO-to-GEO Environment Debris model) is a three-dimensional orbital debris evolutionary model that is capable of simulating the historical and future debris populations in the near-Earth environment. The historical component in LEGEND adopts a deterministic approach to mimic the known historical populations. Launched rocket bodies, spacecraft, and mission-related debris (rings, bolts, etc.) are added to the simulated environment. Known historical breakup events are reproduced, and fragments down to 1 mm in size are created. The LEGEND future projection component adopts a Monte Carlo approach and uses an innovative pair-wise collision probability evaluation algorithm to simulate the future breakups and the growth of the debris populations. This algorithm is based on a new "random sampling in time" approach that preserves characteristics of the traditional approach and captures the rapidly changing nature of the orbital debris environment. LEGEND is a Fortran 90-based numerical simulation program. It operates in a UNIX/Linux environment.

Anhydrous 1:1 proton-transfer compounds of isonipecotamide with picric acid and 3,5-dinitrosalicylic acid: 4-carbamoylpiperidinium 2,4,6-trinitrophenolate and two polymorphs of 4-carbamoylpiperidinium 2-carboxy-4,6-dinitrophenolate.

PubMed

Smith, Graham; Wermuth, Urs D

2010-12-01

The structures of the anhydrous 1:1 proton-transfer compounds of isonipecotamide (piperidine-4-carboxamide) with picric acid and 3,5-dinitrosalicylic acid, namely 4-carbamoylpiperidinium 2,4,6-trinitrophenolate, C(6)H(13)N(2)O(+)·C(6)H(2)N(3)O(7)(-), (I), and 4-carbamoylpiperidinium 2-carboxy-4,6-dinitrophenolate [two forms of which were found, the monoclinic α-polymorph, (II), and the triclinic β-polymorph, (III)], C(6)H(13)N(2)O(+)·C(7)H(3)N(2)O(7)(-), have been determined at 200 K. All three compounds form hydrogen-bonded structures, viz. one-dimensional in (II), two-dimensional in (I) and three-dimensional in (III). In (I), the cations form centrosymmetric cyclic head-to-tail hydrogen-bonded homodimers [graph set R(2)(2)(14)] through lateral duplex piperidinium-amide N-H...O interactions. These dimers are extended into a two-dimensional network structure through further interactions with phenolate and nitro O-atom acceptors, including a direct symmetric piperidinium-phenol/nitro N-H...O,O cation-anion association [graph set R(1)(2)(6)]. The monoclinic polymorph, (II), has a similar R(1)(2)(6) cation-anion hydrogen-bonding interaction to (I) but with an additional conjoint symmetrical R(1)(2)(4) interaction as well as head-to-tail piperidinium-amide N-H...O,O hydrogen bonds and amide-carboxyl N-H...O hydrogen bonds, giving a network structure which includes large R(4)(3)(20) rings. The hydrogen bonding in the triclinic polymorph, (III), is markedly different from that of monoclinic (II). The asymmetric unit contains two independent cation-anion pairs which associate through cyclic piperidinium-carboxyl N-H...O,O' interactions [graph set R(1)(2)(4)]. The cations also show the zigzag head-to-tail piperidinium-amide N-H...O hydrogen-bonded chain substructures found in (II), but in addition feature amide-nitro and amide-phenolate N-H...O associations. As well, there is a centrosymmetric double-amide N-H...O(carboxyl) bridged bis(cation-anion) ring system [graph set R(4)(2)(8)] in the three-dimensional framework. The structures reported here demonstrate the utility of the isonipecotamide cation as a synthon with previously unrecognized potential for structure assembly applications. Furthermore, the structures of the two polymorphic 3,5-dinitrosalicylic acid salts show an unusual dissimilarity in hydrogen-bonding characteristics, considering that both were obtained from identical solvent systems.

Apparatus for time-resolved and energy-resolved measurement of internal conversion electron emission induced by nuclear resonant excitation with synchrotron radiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kawauchi, Taizo; Matsumoto, Masuaki; Fukutani, Katsuyuki

2007-01-15

A high-energy and large-object-spot type cylindrical mirror analyzer (CMA) was constructed with the aid of electron trajectory simulations. By adopting a particular shape for the outer cylinder, an energy resolution of 7% was achieved without guide rings as used in conventional CMAs. Combined with an avalanche photodiode as an electron detector, the K-shell internal conversion electrons were successfully measured under irradiation of synchrotron radiation at 14.4 keV in an energy-resolved and time-resolved manner.

Crystal structure of 2-[chloro-(4-meth-oxy-phen-yl)meth-yl]-2-(4-meth-oxy-phen-yl)-5,5-di-methyl-cyclo-hexane-1,3-dione.

PubMed

Chelli, Saloua; Troshin, Konstantin; Lakhdar, Sami; Mayr, Herbert; Mayer, Peter

2016-03-01

In the title compound, C23H25ClO4, the cyclo-hexane ring adopts a chair conformation with the 4-meth-oxy-phenyl substituent in an axial position and the chloro-(4-meth-oxy-phen-yl)methyl substituent in an equatorial position. The packing features inversion dimers formed by pairs of C-H⋯O contacts and strands along [100] and [010] established by further C-H⋯O and C-H⋯Cl contacts, respectively.

Architectures of Lipid Transport Systems for the Bacterial Outer Membrane.

PubMed

Ekiert, Damian C; Bhabha, Gira; Isom, Georgia L; Greenan, Garrett; Ovchinnikov, Sergey; Henderson, Ian R; Cox, Jeffery S; Vale, Ronald D

2017-04-06

How phospholipids are trafficked between the bacterial inner and outer membranes through the hydrophilic space of the periplasm is not known. We report that members of the mammalian cell entry (MCE) protein family form hexameric assemblies with a central channel capable of mediating lipid transport. The E. coli MCE protein, MlaD, forms a ring associated with an ABC transporter complex in the inner membrane. A soluble lipid-binding protein, MlaC, ferries lipids between MlaD and an outer membrane protein complex. In contrast, EM structures of two other E. coli MCE proteins show that YebT forms an elongated tube consisting of seven stacked MCE rings, and PqiB adopts a syringe-like architecture. Both YebT and PqiB create channels of sufficient length to span the periplasmic space. This work reveals diverse architectures of highly conserved protein-based channels implicated in the transport of lipids between the membranes of bacteria and some eukaryotic organelles. Copyright © 2017 Elsevier Inc. All rights reserved.

2-tert-Butylamino-4-chloro-6-ethylamino-1,3,5-triazine: a structure with Z' = 4 containing two different molecular conformations and two independent chains of hydrogen-bonded R(2)2(8) rings.

PubMed

Quesada, Antonio; Fontecha, Maria A; López, Maria V; Low, John N; Glidewell, Christopher

2008-08-01

The title compound (trivial name terbutylazine), C(9)H(16)ClN(5), (I), crystallizes with Z' = 4 in the space group Pca2(1), and equal numbers of molecules adopt two different conformations for the ethylamine groups. The four independent molecules form two approximately enantiomorphic pairs. Eight independent N-H...N hydrogen bonds link the molecules into two independent chains of R(2)(2)(8) rings, in which the arrangement of the alkylamine substituents in the independent molecules precludes any further crystallographic symmetry. The significance of this study lies in its finding of two distinct molecular conformations within the structure and two distinct ways in which the molecules are organized into hydrogen-bonded chains, and in its comparison of the hydrogen-bonded structure of (I) with those of analogous 1,3,5-triazines and pyrimidines.

A family of zeolites with controlled pore size prepared using a top-down method

NASA Astrophysics Data System (ADS)

Roth, Wieslaw J.; Nachtigall, Petr; Morris, Russell E.; Wheatley, Paul S.; Seymour, Valerie R.; Ashbrook, Sharon E.; Chlubná, Pavla; Grajciar, Lukáš; Položij, Miroslav; Zukal, Arnošt; Shvets, Oleksiy; Čejka, Jiří

2013-07-01

The properties of zeolites, and thus their suitability for different applications, are intimately connected with their structures. Synthesizing specific architectures is therefore important, but has remained challenging. Here we report a top-down strategy that involves the disassembly of a parent zeolite, UTL, and its reassembly into two zeolites with targeted topologies, IPC-2 and IPC-4. The three zeolites are closely related as they adopt the same layered structure, and they differ only in how the layers are connected. Choosing different linkers gives rise to different pore sizes, enabling the synthesis of materials with predetermined pore architectures. The structures of the resulting zeolites were characterized by interpreting the X-ray powder-diffraction patterns through models using computational methods; IPC-2 exhibits orthogonal 12- and ten-ring channels, and IPC-4 is a more complex zeolite that comprises orthogonal ten- and eight-ring channels. We describe how this method enables the preparation of functional materials and discuss its potential for targeting other new zeolites.

The Muon g - 2 experiment at Fermilab

NASA Astrophysics Data System (ADS)

Mott, James; Muon g - 2 experiment

2017-06-01

The Muon g - 2 experiment at Fermilab will measure the anomalous magnetic moment of the muon to a precision of 140 ppb, reducing the experimental uncertainty by a factor of 4 compared to the previous measurement at BNL (E821). The measurement technique adopts the storage ring concept used for E821, with magic-momentum muons stored in a highly uniform 1.45 T magnetic dipole field. The spin precession frequency is extracted from an analysis of the modulation of the rate of higher-energy positrons from muon decays, detected by 24 calorimeters and 3 straw tracking detectors. Compared to the E821 experiment, muon beam preparation, storage ring internal hardware, field measuring equipment, and detector and electronics systems are all new or significantly upgraded. Herein, I report on the status of the experiment as of Sept. 2016, presenting the magnetic field uniformity results after the completion of the first round of shimming and outlining the construction progress of the main detector systems.

The Muon g $-$ 2 experiment at Fermilab

DOE PAGES

Mott, James

2017-06-21

Here, the Muon g-2 experiment at Fermilab will measure the anomalous magnetic moment of the muon to a precision of 140 ppb, reducing the experimental uncertainty by a factor of 4 compared to the previous measurement at BNL (E821). The measurement technique adopts the storage ring concept used for E821, with magic-momentum muons stored in a highly uniform 1.45 T magnetic dipole field. The spin precession frequency is extracted from an analysis of the modulation of the rate of higher-energy positrons from muon decays, detected by 24 calorimeters and 3 straw tracking detectors. Compared to the E821 experiment, muon beammore » preparation, storage ring internal hardware, field measuring equipment, and detector and electronics systems are all new or significantly upgraded. Herein, I report on the status of the experiment as of Sept. 2016, presenting the magnetic field uniformity results after the completion of the first round of shimming and outlining the construction progress of the main detector systems.« less

catena-Poly[[[triaqua­sulfatozinc(II)]-μ-3,3′-bis­(3-pyrid­yl)-1,1′-(m-phenyl­ene)diurea] methanol solvate monohydrate

PubMed Central

Adarsh, N. N.; Dastidar, Parthasarathi

2010-01-01

In the title coordination polymer, {[Zn(SO4)(C18H16N6O2)(H2O)3]·CH3OH·H2O}n, the Zn2+ ion adopts a slightly distorted cis-ZnN2O4 octa­hedral geometry arising from three coordinated water mol­ecules, one sulfate ion and two bridging 3,3′-bis­(3-pyrid­yl)-1,1′-(m-phenyl­ene)diurea (bpmpbu) ligands. The dihedral angles between the central benzene ring and two terminal pyridine rings of the bpmbpu mol­ecule are 10.58 (17) and 34.63 (16)°. In the crystal, the ligands bridge the ZnII ions, thus generating a one-dimensional zigzag coordination polymer propagating in [010]. The crystal structure features extensive N—H⋯O and O—H⋯O hydrogen-bonding inter­actions. PMID:21580512

Injection method of barrier bucket supported by off-aligned electron cooling for CRing of HIAF

NASA Astrophysics Data System (ADS)

Shen, Guo-Dong; Yang, Jian-Cheng; Xia, Jia-Wen; Mao, Li-Jun; Yin, Da-Yu; Chai, Wei-Ping; Shi, Jian; Sheng, Li-Na; Smirnov, A.; Wu, Bo; Zhao, He

2016-08-01

A new accelerator complex, HIAF (the High Intensity Heavy Ion Accelerator Facility), has been approved in China. It is designed to provide intense primary and radioactive ion beams for research in high energy density physics, nuclear physics, atomic physics as well as other applications. In order to achieve a high intensity of up to 5×1011 ppp 238U34+, the Compression Ring (CRing) needs to stack more than 5 bunches transferred from the Booster Ring (BRing). However, the normal bucket to bucket injection scheme can only achieve an intensity gain of 2, so an injection method, fixed barrier bucket (BB) supported by electron cooling, is proposed. To suppress the severe space charge effect during the stacking process, off-alignment is adopted in the cooler to control the transverse emittance. In this paper, simulation and optimization with the BETACOOL program are presented. Supported by New Interdisciplinary and Advanced Pilot Fund of Chinese Academy of Sciences

Tandem catalysis of ring-closing metathesis/atom transfer radical reactions with homobimetallic ruthenium–arene complexes

PubMed Central

Borguet, Yannick; Sauvage, Xavier; Zaragoza, Guillermo; Demonceau, Albert

2010-01-01

Summary The tandem catalysis of ring-closing metathesis/atom transfer radical reactions was investigated with the homobimetallic ruthenium–indenylidene complex [(p-cymene)Ru(μ-Cl)3RuCl(3-phenyl-1-indenylidene)(PCy3)] (1) to generate active species in situ. The two catalytic processes were first carried out independently in a case study before the whole sequence was optimized and applied to the synthesis of several polyhalogenated bicyclic γ-lactams and lactones from α,ω-diene substrates bearing trihaloacetamide or trichloroacetate functionalities. The individual steps were carefully monitored by 1H and 31P NMR spectroscopies in order to understand the intimate details of the catalytic cycles. Polyhalogenated substrates and the ethylene released upon metathesis induced the clean transformation of catalyst precursor 1 into the Ru(II)–Ru(III) mixed-valence compound [(p-cymene)Ru(μ-Cl)3RuCl2(PCy3)], which was found to be an efficient promoter for atom transfer radical reactions under the adopted experimental conditions. PMID:21160564

The Muon g $-$ 2 experiment at Fermilab

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mott, James

Here, the Muon g-2 experiment at Fermilab will measure the anomalous magnetic moment of the muon to a precision of 140 ppb, reducing the experimental uncertainty by a factor of 4 compared to the previous measurement at BNL (E821). The measurement technique adopts the storage ring concept used for E821, with magic-momentum muons stored in a highly uniform 1.45 T magnetic dipole field. The spin precession frequency is extracted from an analysis of the modulation of the rate of higher-energy positrons from muon decays, detected by 24 calorimeters and 3 straw tracking detectors. Compared to the E821 experiment, muon beammore » preparation, storage ring internal hardware, field measuring equipment, and detector and electronics systems are all new or significantly upgraded. Herein, I report on the status of the experiment as of Sept. 2016, presenting the magnetic field uniformity results after the completion of the first round of shimming and outlining the construction progress of the main detector systems.« less

Leishmanicidal activity of the crude extract, fractions and major piperidine alkaloids from the flowers of Senna spectabilis.

PubMed

de Albuquerque Melo, Gabriela Muniz; Silva, Marcela Campelo Rodrigues; Guimarães, Thaís Pereira; Pinheiro, Kátia Mantovani; da Matta, Carolina Barbosa Brito; de Queiroz, Aline Cavalcanti; Pivatto, Marcos; Bolzani, Vanderlan da Silva; Alexandre-Moreira, Magna Suzana; Viegas, Claudio

2014-02-15

Senna spectabilis (sin. Cassia excelsa, C. spectabilis) is an endemic tree of South America and Africa, very common in Brazil, where it is known as "canafistula-de-besouro" and "cassia-do-nordeste". In folk medicine, this plant is indicated for the treatment of constipation, insomnia, anxiety, epilepsy, malaria, dysentery and headache. Phytopharmacological studies have also confirmed anticonvulsive, sedative, anti-malarial, antimicrobial and cytotoxic properties of many parts of S. spectabilis. In this communication, we present a comparative study of the leishmanicidal activity of the crude ethanolic extract, its fractions and also the two major alkaloidal metabolites (-)-cassine/(-)-spectaline, trying to establish a relationship between the presence of piperidine alkaloidal constituents and leishmanicidal activity. The growth inhibitory effect of promastigote forms of Leishmania major was determined for the crude extract, fractions of the flowers of S. spectabilis and a mixture of (-)-cassine/(-)-spectaline in comparison to pentamidine used as standard drug. The cytotoxic effects were assessed on macrophage strain J774 by lactate dehydrogenase assay. Fractions dichloromethane (FL-DCM) and n-butanol (FL-Bu) and a mixture of (-)-cassine/(-)-spectaline (∼7:3) exhibited significant activity against the parasite Leishmania major (IC50 values of 0.6±0.1 μg/ml, 1.6±0.9 μg/ml and 24.9±1.4 μg/ml, respectively), without toxic effects on murine macrophages. Due to the promising results elicited, further studies in vivo need to be performed to confirm the therapeutic potential of Senna spectabilis. Copyright © 2013 Elsevier GmbH. All rights reserved.

Prediction of the binding site of 1-benzyl-4-[(5,6-dimethoxy-1-indanon-2-yl)methyl]piperidine in acetylcholinesterase by docking studies with the SYSDOC program

NASA Astrophysics Data System (ADS)

Pang, Yuan-Ping; Kozikowski, Alan P.

1994-12-01

In the preceding paper we reported on a docking study with the SYSDOC program for predicting the binding sites of huperzine A in acetylcholinesterase (AChE) [Pang, Y.-P. and Kozikowski, A.P., J. Comput.-Aided Mol. Design, 8 (1994) 669]. Here we present a prediction of the binding sites of 1-benzyl-4-[(5,6-dimethoxy-1-indanon-2-yl)methyl]piperidine (E2020) in AChE by the same method. E2020 is one of the most potent and selective reversible inhibitors of AChE, and this molecule has puzzled researchers, partly due to its flexible structure, in understanding how it binds to AChE. Based on the results of docking 1320 different conformers of E2020 into 69 different conformers of AChE and on the pharmacological data reported for E2020 and its analogs, we predict that both the R- and the S-isomer of E2020 span the whole binding cavity of AChE, with the ammonium group interacting mainly with Trp84, Phe330 and Asp72, the phenyl group interacting mainly with Trp84 and Phe330, and the indanone moiety interacting mainly with Tyr70 and Trp279. The topography of the calculated E2020 binding sites provides insights into understanding the high potency of E2020 in the inhibition of AChE and provides hints as to possible structural modifications for identifying improved AChE inhibitors as potential therapeutics for the palliative treatment of Alzheimer's disease.

Reactivity ratios and sequence structures of the copolymers prepared using photo-induced copolymerization of MMA with MTMP.

PubMed

Liu, Xiaoxuan; Zhang, Yongtao; Cui, Yanyan; Dong, Zhixian

2012-05-01

4-Methacryloyl-2,2,6,6-tetramethyl-piperidine (MTMP) was applied as reactive hindered amine piperidine. Photo-induced copolymerization of methyl methacrylate (MMA, M(1)) with MTMP (M(2)) was carried out in benzene solution at ambient temperature. The reactivity ratios for these monomers were measured by running a series of reactions at various feed ratios of initial monomers, and the monomer incorporation into copolymer was determined using (1)H NMR. Reactivity ratios of the MMA/MTMP system were measured to be r(1)= 0.37 and r(2)= 1.14 from extended Kelen-Tüdos method. The results show that monomer MTMP prefers homopolymerization to copolymerization in the system, whereas monomer MMA prefers copolymerization to homopolymerization. Sequence structures of the MMA/MTMP copolymers were characterized using (1)H NMR. The results show that the sequence structure for the main chain of the MMA/MTMP copolymers is mainly composed of a syndiotactic configuration, only with a little heterotactic configuration. Three kinds of the sequences of rr, rr', and lr' in the syndiotactic configuration are found. The sequence-length distribution in the MMA/MTMP copolymers is also obtained. For f(1)= 0.2, the monomer unit of MMA is mostly separated by MTMP units, and for f(1)= 0.6, the alternating tendency prevails and a large number of mono-sequences are formed; further up to f(1)= 0.8, the monomer unit of MTMP with the sequence of one unit is interspersed among the chain of MMA. Copyright © 2012 John Wiley & Sons, Ltd.

Design of new anti-Alzheimer drugs: ring-expansion synthesis and synchrotron X-ray diffraction study of dimethyl 4-ethyl-11-fluoro-1,4,5,6,7,8-hexa­hydro­azonino[5,6-b]indole-2,3-di­carboxyl­ate

PubMed Central

Toze, Flavien A. A.; Listratova, Anna V.; Voskressensky, Leonid G.; Chernikova, Natalia Yu.; Lobanov, Nikolai N.; Bilyachenko, Alexey N.

2018-01-01

The title compound, C20H23FN2O4, is the product of a ring-expansion reaction from a seven-membered fluorinated hexa­hydro­azepine to a nine-membered azonine. The nine-membered azonine ring of the mol­ecule adopts a chair–boat conformation. The C=C and C—N bond lengths [1.366 (3) and 1.407 (3) Å, respectively] indicate the presence of conjugation within the enamine CH2—C=C—N—CH2 fragment. The substituent planes at the C=C double bond of this fragment are twisted by 16.0 (3)° as a result of steric effects. The amine N(Et) N atom has a trigonal–pyramidal configuration (sum of the bond angles = 346.3°). The inter­planar angle between the two carboxyl­ate substituents is 60.39 (8)°. In the crystal, mol­ecules form zigzag chains along [010] by inter­molecular N—H⋯O hydrogen-bonding inter­actions, which are further packed in stacks toward [100]. The title azonino­indole might be considered as a candidate for the design of new Alzheimer drugs. PMID:29765710

Crystal structures of (±)-(1SR,5SR,6SR,7SR,10SR,11SR,13RS,14SR)-13-hy-droxy-7-meth-oxy-meth-oxy-11,15,18,18-tetra-methyl-3-oxo-2,4-dioxa-tetra-cyclo-[12.3.1.0(1,5).0(6,11)]octa-dec-15-en-10-yl benzoate, its 13-epimer and 13-one derivative.

PubMed

Oishi, Takeshi; Fukaya, Keisuke; Yamaguchi, Yu; Sugai, Tomoya; Watanabe, Ami; Sato, Takaaki; Chida, Noritaka

2015-05-01

The title compounds, C29H38O8·0.25C5H12, (A), C29H38O8, (B), and C29H36O8, (C), are tetra-cyclic benzoates possessing a taxane skeleton with a fused dioxolane ring as the core structure. In the asymmetric unit of (A), there are two independent benzoate mol-ecules (A and A') and a half mol-ecule of solvent pentane disordered about an inversion center. The mol-ecular conformations of (A), (B) and (C) are similar except for the flexible meth-oxy-meth-oxy group. The cyclo-hexane, cyclo-hexene and central cyclo-octane rings adopt chair, half-chair and chair-chair (extended crown) forms, respectively. The dioxolane rings are essentially planar, while the dioxolane ring of A' is slightly twisted from the mean plane. In the crystal of (A), inter-molecular O-H⋯O, C-H⋯O and C-H⋯π inter-actions link the independent benzoates alternately, forming a chain structure. In the crystals of (B) and (C), mol-ecules are linked through O-H⋯O and C-H⋯π inter-actions, and C-H⋯O hydrogen bonds, respectively, into similar chains. Further, weak inter-molecular C-H⋯O inter-actions connect the chains into a three-dimensional network in (A) and a sheet in (B), whereas no other interactions are observed for (C).

Ultraviolet spectroscopy of the blue supergiant SBW1: the remarkably weak wind of a SN 1987A analogue

NASA Astrophysics Data System (ADS)

Smith, Nathan; Groh, Jose H.; France, Kevin; McCray, Richard

2017-06-01

The Galactic blue supergiant SBW1 with its circumstellar ring nebula represents the best known analogue of the progenitor of SN 1987A. High-resolution imaging has shown Hα and infrared structures arising in an ionized flow that partly fills the ring's interior. To constrain the influence of the stellar wind on this structure, we obtained an ultraviolet (UV) spectrum of the central star of SBW1 with the Hubble Space Telescope Cosmic Origins Spectrograph. The UV spectrum shows none of the typical wind signatures, indicating a very low mass-loss rate. Radiative transfer models suggest an extremely low rate below 10-10 M⊙ yr-1, although we find that cooling time-scales probably become comparable to (or longer than) the flow time below 10-8 M⊙ yr-1. We therefore adopt this latter value as a conservative upper limit. For the central star, the model yields Teff = 21 000 ± 1000 K, log(geff) = 3.0, L ≃ 5 × 104 L⊙, and roughly Solar composition except for enhanced N abundance. SBW1's very low mass-loss rate may hinder the wind's ability to shape its nebula and to shed angular momentum. The spin-down time-scale for magnetic breaking is more than 500 times longer than the age of the ring. This, combined with the star's slow rotation rate, constrains merger scenarios to form ring nebulae. The mass-loss rate is at least 10 times lower than expected from mass-loss recipes, without any account of clumping. The physical explanation for why SBW1's wind is so weak presents an interesting mystery.

Styrene Polymerization under Ambient Conditions by using a Transient 1,3,2-Diazaphospholane-2-oxyl Complex.

PubMed

Heurich, Tobias; Qu, Zheng-Wang; Kunzmann, Robert; Schnakenburg, Gregor; Engeser, Marianne; Nožinović, Senada; Streubel, Rainer

2018-04-25

A combined theoretical and experimental study on the formation and reactivity of a P-OTEMP (P-bound TEMPO (TEMPO=2,2,6,6-tetramethyl-piperidin-1-oxyl)) substituted 1,3,2-diazaphospholane W(CO) 5 complex is presented, including DFT-based mechanistic details. The complex possesses a thermally labile O-N bond that cleaves homolytically yielding the transient 1,3,2-diazaphospholane-2-oxyl complex [(CO) 5 W(R 2 PO . )], which acts as a radical initiator for styrene polymerization under ambient conditions. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

A simple synthesis of N-perfluoroacylated and N-acylated glycals of neuraminic acid with a cyclic aminic substituent at the 4α position as possible inhibitors of sialidases.

PubMed

Rota, Paola; Allevi, Pietro; Agnolin, Irene S; Mattina, Roberto; Papini, Nadia; Anastasia, Mario

2012-04-14

A simple protocol for the synthesis of N-perfluoroacylated and N-acylated glycals of neuraminic acid, with a secondary cyclic amine (morpholine or piperidine) at the 4α position, has been set-up, starting from peracetylated N-acetylneuraminic acid methyl ester that undergoes, sequentially to its direct N-transacylation followed by a C-4 amination, a β-elimination, and a selective hydrolysis of the ester functions, without affecting the sensitive perfluorinated amide. This journal is © The Royal Society of Chemistry 2012

Homoserine as an Aspartic Acid Precursor for Synthesis of Proteoglycan Glycopeptide Containing Aspartic Acid and a Sulfated Glycan Chain.

PubMed

Yang, Weizhun; Ramadan, Sherif; Yang, Bo; Yoshida, Keisuke; Huang, Xuefei

2016-12-02

Among many hurdles in synthesizing proteoglycan glycopeptides, one challenge is the incorporation of aspartic acid in the peptide backbone and acid sensitive O-sulfated glycan chains. To overcome this, a new strategy was developed utilizing homoserine as an aspartic acid precursor. The conversion of homoserine to aspartic acid in the glycopeptide was successfully accomplished by late stage oxidation using (2,2,6,6-tetramethyl-piperidin-1-yl)oxyl (TEMPO) and bis(acetoxy)iodobenzene (BAIB). This is the first time that a glycopeptide containing aspartic acid and an O-sulfated glycan was synthesized.

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

PubMed

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.

Discovery of MK-7655, a β-lactamase inhibitor for combination with Primaxin®

DOE Office of Scientific and Technical Information (OSTI.GOV)

Blizzard, Timothy A.; Chen, Helen; Kim, Seongkon

2014-02-01

β-Lactamase inhibitors with a bicyclic urea core and a variety of heterocyclic side chains were prepared and evaluated as potential partners for combination with imipenem to overcome class A and C β-lactamase mediated antibiotic resistance. The piperidine analog 3 (MK-7655) inhibited both class A and C β-lactamases in vitro. It effectively restored imipenem’s activity against imipenem-resistant Pseudomonas and Klebsiella strains at clinically achievable concentrations. A combination of MK-7655 and Primaxin® is currently in phase II clinical trials for the treatment of Gram-negative bacterial infections.

Alkyl piperidine and piperazine hydroxamic acids as HDAC inhibitors.

PubMed

Rossi, Cristina; Porcelloni, Marina; D'Andrea, Piero; Fincham, Christopher I; Ettorre, Alessandro; Mauro, Sandro; Squarcia, Antonella; Bigioni, Mario; Parlani, Massimo; Nardelli, Federica; Binaschi, Monica; Maggi, Carlo A; Fattori, Daniela

2011-04-15

We report here the strategy used in our research group to find a new class of histone deacetylase (HDAC) inhibitors. A series of N-substituted 4-alkylpiperazine and 4-alkylpiperidine hydroxamic acids, corresponding to the basic structure of HDAC inhibitors (zinc binding moiety-linker-capping group) has been designed, prepared, and tested for HDAC inhibition. Linker length and aromatic capping group connection were systematically varied to find the optimal geometric parameters. A new series of submicromolar inhibitors was thus identified, which showed antiproliferative activity on HCT-116 colon carcinoma cells. Copyright © 2011 Elsevier Ltd. All rights reserved.

Classic histamine H1 receptor antagonists: a critical review of their metabolic and pharmacokinetic fate from a bird's eye view.

PubMed

Sharma, A; Hamelin, B A

2003-04-01

The so-called "classic" histamine H(1) receptor antagonists are highly lipophilic compounds associated with significant biotransformation and tissue distribution. They are categorized according to their chemical structure into ethanolamines, alkylamines, ethylenediamines, piperazines, phenothiazines and piperidines, all of which have characteristic metabolic fates. The former four categories undergo primarily cytochrome P450-mediated oxidative N-desalkylations and deamination whereas the aromatic rings of the latter two undergo P450-mediated oxidative hydroxylation and/or epoxide formation. The common tertiary amino group is susceptible to oxidative metabolism by flavin containing monooxygenases forming N-oxides, and the alicyclic tertiary amines produce small amounts (up to 7%) of N-glucuronides in humans. Species, sex and racial differences in the metabolism and pharmacokinetics of antihistamines are known. Specific P450-isozymes implicated in the metabolism were identified in a few cases, such as CYP2D6 that contributes to the metabolism of promethazine, diphenhydramine and chlorpheniramine. Low circulating plasma concentrations of antihistamines are in part explained by significant first-pass effect and tissue distribution. Antihistaminic effects last up to 6 hours though some compounds exhibit a longer duration of action due to circulating active metabolites. Importantly, diphenhydramine inhibited CYP2D6 leading to a clinically significant drug-drug interaction with metoprolol. Other classic antihistamines were shown to be potent in vitro inhibitors of CYP2D6 and CYP3A4. The prescription-free access to most classic antihistamines can easily lead to their co-administration with other drugs metabolized by the same enzyme system thereby leading to drug accumulation and adverse effects. In depth knowledge of the metabolic pathways of classic antihistamines and the enzymes involved is crucial to prevent the high incidence of drug interactions in humans, which are predictable based on pre-clinical data but unexpected when such data is unavailable.

Ava[L-Pro9,N-MeLeu10] substance P(7-11) (GR 73632) and Sar9, Met(O2)11 increase distention-induced peristalsis through activation of neurokinin-1 receptors on smooth muscle and interstitial cells of cajal.

PubMed

Nieuwmeyer, Florentine; Ye, Jing; Huizinga, Jan D

2006-04-01

Substance P is generally considered an excitatory neurotransmitter related to gut motor activity, although an inhibitory influence of neurokinin-1 (NK1) receptor activation on peristalsis has also been reported. With an optimized in vitro method to assess distention-induced peristalsis, our aim was to clarify the effect of NK1 receptor activation on peristaltic activity and to reveal the mechanisms by which NK1 activation alters peristalsis. Distention of the small intestine of the mouse and guinea pig induced periodic occurrence of rhythmic waves of propagating rings of circular muscle contraction, associated with slow waves and superimposed action potentials, that propelled intestinal contents aborally. Activation of NK1 receptors by Ava[l-Pro(9),N-MeLeu10] substance P(7-11) (GR 73632) and Sar(9), Met(O(2))(11) on smooth muscle cells resulted in prolongation of the activity periods and increased action potential generation occurring superimposed on the intestinal slow wave activity. Activation of NK1 receptors on interstitial cells of Cajal resulted in an increase in slow wave frequency. Slow wave amplitude increased, likely by increased cell-to-cell coupling. The NK1 antagonist (S)-1-(2-[3-(3,4-dichlorophenyl)-1-(3-isopropoxyphenylacetyl)piperidin-3-yl]ethyl)-4-phenyl-1-azoniabicyclo[2.2.2]octane chloride (SR 140333) induced a decrease in the slow wave frequency and duration of the activity periods evoked by distention, which makes it likely that NK1 receptor activation plays a role in the normal physiological distention-induced generation of peristaltic motor patterns. In summary, NK1 receptors play a role in normal development of peristalsis and NK1 receptor activation markedly increases propulsive peristaltic contractile activity.

Crystal structure of 2-oxopyrrolidin-3-yl 4-(2-phenyl-diazen-1-yl)benzoate.

PubMed

Elkin, Igor; Maris, Thierry; Melkoumov, Alexandre; Hildgen, Patrice; Banquy, Xavier; Leclair, Grégoire; Barrett, Christopher

2018-04-01

In the title compound, C 17 H 15 N 3 O 3 , the plane of the pyrrolidone ring is inclined at an angle of 59.791 (2)° to that of the azo-benzene segment, which adopts a configuration close to planar. In the crystal, mol-ecules are oriented pairwise by (2-oxopyrrolidin-3-yl)-oxy moieties at an angle of 76.257 (3)°, linked by hydrogen bonds and π-stacking inter-actions, forming zigzag supra-molecular chains parallel to [010] further linked via additional C-H⋯π inter-actions.

N,N′-Bis(3,5-dichloro­benzyl­idene)­ethane-1,2-diamine

PubMed Central

Fun, Hoong-Kun; Kia, Reza

2008-01-01

The mol­ecule of the title Schiff base compound, C16H12Cl4N2, lies across an inversion centre and adopts an E configuration with respect to the azomethine C=N bond. The imine groups are coplanar with the aromatic rings. Within the mol­ecule, the planar units are parallel but extend in opposite directions from the dimethyl­ene bridge. In the crystal structure, mol­ecules are linked together by inter­molecular C—H⋯Cl hydrogen bonds along the a axis. PMID:21580993

Selective determination of ertapenem in the presence of its degradation product

NASA Astrophysics Data System (ADS)

Hassan, Nagiba Y.; Abdel-Moety, Ezzat M.; Elragehy, Nariman A.; Rezk, Mamdouh R.

2009-06-01

Stability-indicative determination of ertapenem (ERTM) in the presence of its β-lactam open-ring degradation product, which is also the metabolite, is investigated. The degradation product has been isolated, via acid-degradation, characterized and elucidated. Selective quantification of ERTM, singly in bulk form, pharmaceutical formulations and/or in the presence of its major degradant is demonstrated. The indication of stability has been undertaken under conditions likely to be expected at normal storage conditions. Among the spectrophotometric methods adopted for quantification are first derivative ( 1D), first derivative of ratio spectra ( 1DD) and bivariate analysis.

(O-Methyl di-thio-carbonato-κS)tri-phenyl-tin(IV).

PubMed

Javed, Fatima; Ali, Saqib; Shah, Wajid; Tahir, M Nawaz; Ullah, Hameed

2013-06-01

In the title compound, [Sn(C6H5)3(C2H3OS2)], the Sn(IV) atom adopts a distorted SnC3S tetra-hedral coordination geometry. A short Sn⋯O contact [2.988 (4) Å] is also present. The phenyl rings are each disordered over two sets of sites with an occupancy ratio of 0.550 (8):0.450 (8). The crystal studied was found to be a racemic twin with a twin component ratio of 0.57 (18):0.43 (18).

(O-Methyl di­thio­carbonato-κS)tri­phenyl­tin(IV)

PubMed Central

Javed, Fatima; Ali, Saqib; Shah, Wajid; Tahir, M. Nawaz; Ullah, Hameed

2013-01-01

In the title compound, [Sn(C6H5)3(C2H3OS2)], the SnIV atom adopts a distorted SnC3S tetra­hedral coordination geometry. A short Sn⋯O contact [2.988 (4) Å] is also present. The phenyl rings are each disordered over two sets of sites with an occupancy ratio of 0.550 (8):0.450 (8). The crystal studied was found to be a racemic twin with a twin component ratio of 0.57 (18):0.43 (18). PMID:23794982

Synthesis and Preclinical Evaluation of Sulfonamido-based [11C-Carbonyl]-Carbamates and Ureas for Imaging Monoacylglycerol Lipase

PubMed Central

Wang, Lu; Mori, Wakana; Cheng, Ran; Yui, Joji; Hatori, Akiko; Ma, Longle; Zhang, Yiding; Rotstein, Benjamin H.; Fujinaga, Masayuki; Shimoda, Yoko; Yamasaki, Tomoteru; Xie, Lin; Nagai, Yuji; Minamimoto, Takafumi; Higuchi, Makoto; Vasdev, Neil; Zhang, Ming-Rong; Liang, Steven H.

2016-01-01

Monoacylglycerol lipase (MAGL) is a 33 kDa member of the serine hydrolase superfamily that preferentially degrades 2-arachidonoylglycerol (2-AG) to arachidonic acid in the endocannabinoid system. Inhibition of MAGL is not only of interest for probing the cannabinoid pathway but also as a therapeutic and diagnostic target for neuroinflammation. Limited attempts have been made to image MAGL in vivo and a suitable PET ligand for this target has yet to be identified and is urgently sought to guide small molecule drug development in this pathway. Herein we synthesized and evaluated the physiochemical properties of an array of eleven sulfonamido-based carbamates and ureas with a series of terminal aryl moieties, linkers and leaving groups. The most potent compounds were a novel MAGL inhibitor, N-((1-(1H-1,2,4-triazole-1-carbonyl)piperidin-4-yl) methyl)-4-chlorobenzenesulfonamide (TZPU; IC50 = 35.9 nM), and the known inhibitor 1,1,1,3,3,3-hexafluoropropan-2-yl 4-(((4-chlorophenyl)sulfonamido) methyl)piperidine-1-carboxylate (SAR127303; IC50 = 39.3 nM), which were also shown to be selective for MAGL over fatty acid amide hydrolase (FAAH), and cannabinoid receptors (CB1 & CB2). Both of these compounds were radiolabeled with carbon-11 via [11C]COCl2, followed by comprehensive ex vivo biodistribution and in vivo PET imaging studies in normal rats to determine their brain permeability, specificity, clearance and metabolism. Whereas TZPU did not show adequate specificity to warrant further evaluation, [11C]SAR127303 was advanced for preliminary PET neuroimaging studies in nonhuman primate. The tracer showed good brain permeability (ca. 1 SUV) and heterogeneous regional brain distribution which is consistent with the distribution of MAGL. PMID:27279908

Genetic variation of piperidine alkaloids in Pinus ponderosa: a common garden study.

PubMed

Gerson, Elizabeth A; Kelsey, Rick G; St Clair, J Bradley

2009-02-01

Previous measurements of conifer alkaloids have revealed significant variation attributable to many sources, environmental and genetic. The present study takes a complementary and intensive, common garden approach to examine genetic variation in Pinus ponderosa var. ponderosa alkaloid production. Additionally, this study investigates the potential trade-off between seedling growth and alkaloid production, and associations between topographic/climatic variables and alkaloid production. Piperidine alkaloids were quantified in foliage of 501 nursery seedlings grown from seed sources in west-central Washington, Oregon and California, roughly covering the western half of the native range of ponderosa pine. A nested mixed model was used to test differences among broad-scale regions and among families within regions. Alkaloid concentrations were regressed on seedling growth measurements to test metabolite allocation theory. Likewise, climate characteristics at the seed sources were also considered as explanatory variables. Quantitative variation from seedling to seedling was high, and regional variation exceeded variation among families. Regions along the western margin of the species range exhibited the highest alkaloid concentrations, while those further east had relatively low alkaloid levels. Qualitative variation in alkaloid profiles was low. All measures of seedling growth related negatively to alkaloid concentrations on a natural log scale; however, coefficients of determination were low. At best, annual height increment explained 19.4 % of the variation in ln(total alkaloids). Among the climate variables, temperature range showed a negative, linear association that explained 41.8 % of the variation. Given the wide geographic scope of the seed sources and the uniformity of resources in the seedlings' environment, observed differences in alkaloid concentrations are evidence for genetic regulation of alkaloid secondary metabolism in ponderosa pine. The theoretical trade-off with seedling growth appeared to be real, however slight. The climate variables provided little evidence for adaptive alkaloid variation, especially within regions.

A novel urotensin II receptor antagonist, KR-36996, improved cardiac function and attenuated cardiac hypertrophy in experimental heart failure.

PubMed

Oh, Kwang-Seok; Lee, Jeong Hyun; Yi, Kyu Yang; Lim, Chae Jo; Park, Byung Kil; Seo, Ho Won; Lee, Byung Ho

2017-03-15

Urotensin II and its receptor are thought to be involved in various cardiovascular diseases such as heart failure, pulmonary hypertension and atherosclerosis. Since the regulation of the urotensin II/urotensin II receptor offers a great potential for therapeutic strategies related to the treatment of cardiovascular diseases, the study of selective and potent antagonists for urotensin II receptor is more fascinating. This study was designed to determine the potential therapeutic effects of a newly developed novel urotensin II receptor antagonist, N-(1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)benzo[b]thiophene-3-carboxamide (KR-36996), in experimental models of heart failure. KR-36996 displayed a high binding affinity (Ki=4.44±0.67nM) and selectivity for urotensin II receptor. In cell-based study, KR-36996 significantly inhibited urotensin II-induced stress fiber formation and cellular hypertrophy in H9c2 UT cells. In transverse aortic constriction-induced cardiac hypertrophy model in mice, the daily oral administration of KR-36996 (30mg/kg) for 14 days significantly decreased left ventricular weight by 40% (P<0.05). In myocardial infarction-induced chronic heart failure model in rats, repeated echocardiography and hemodynamic measurements demonstrated remarkable improvement of the cardiac performance by KR-36996 treatment (25 and 50mg/kg/day, p.o.) for 12 weeks. Moreover, KR-36996 decreased interstitial fibrosis and cardiomyocyte hypertrophy in the infarct border zone. These results suggest that potent and selective urotensin II receptor antagonist could efficiently attenuate both cardiac hypertrophy and dysfunction in experimental heart failure. KR-36996 may be useful as an effective urotensin II receptor antagonist for pharmaceutical or clinical applications. Copyright © 2017 Elsevier B.V. All rights reserved.

Photooxidation of d(TpG) by phthalocyanines and riboflavin. Isolation and characterization of dinucleoside monophosphates containing the 4R* and 4S* diastereoisomers of 4,8-dihydro-4-hydroxy-8-oxo-2'-deoxy-guanosine.

PubMed Central

Buchko, G W; Cadet, J; Berger, M; Ravanat, J L

1992-01-01

Phthalocyanine mediated photosensitization of 2'-deoxyguanosine (dG) in oxygen saturated aqueous solution has previously been shown to result in the addition of molecular oxygen to the guanine base generating the 4R* and 4S* diastereoisomers of 4,8-dihydro-4-hydroxy-8-oxo-2'-deoxyguanosine (dO) (the asterisk denotes unambiguous assignment of the 4R and 4S diastereoisomers). The data presented here show that the same guanine modified bases are generated in a 1:1 ratio when thymidylyl-(3',5')-2'-deoxyguanosine (d(TpG)) is similarly photo-oxidized. These modified dinucleoside monophosphates, labelled d(TpO)-A and -B, have been isolated by high performance liquid chromatography and characterized by proton NMR spectrometry, fast atom bombardment mass spectrometry, and enzymatic digestions. Photosensitization in D2O instead of H2O leads to an increase in the rate of d(TpO) formation that is consistent with a type II (singlet oxygen) reaction mechanism. Three interesting properties of these modified dinucleoside monophosphates are: i) the rate of their digestion with spleen phosphodiesterase is greatly reduced relative to d(TpG), ii) they are not digested by snake venom phosphodiesterase, and iii) they are stable to 1.0 M piperidine at 90 degrees C for 30 min. The latter observation indicates that 4,8-dihydro-4-hydroxy-8-oxoguanine is not a base lesion responsible for the strand breaks observed following hot piperidine treatment of DNA exposed to type II photosensitizers or chemically generated singlet oxygen. PMID:1329029

Linear trichromium complexes with the anion of 2,6-di(phenylimino)piperidine.

PubMed

Clérac, R; Cotton, F A; Daniels, L M; Dunbar, K R; Murillo, C A; Zhou, H C

2000-07-24

The anion of 2,6-di(phenylimino)piperidine (DPhIP) has been found to support linear chains of three metal atoms. Three new compounds, [Cr3(DPhIP)4Cl]Cl.(1).5CH2Cl2.0.5H2O (1.1.5CH2Cl2.0.5H2O), [Cr3(DPhIP)4(CH3CN)]- (PF6)2.H2O.4CH3CN (2.H2O.4CH3CN), and [Cr3(DPhIP)4(F)(CH3CN)](BF4)2.5CH3CN (3.5CH3CN), have been synthesized and characterized by X-ray crystallography. Compound 1 has a linear chain of three chromium atoms arranged in an unsymmetrical fashion, with two of them forming a quadruply bonded unit (Cr-Cr distance 1.932(2) A) and the third being a non-metal-metal-bound 5-coordinate unit (Cr...Cr distance 2.659(2) A). The fifth coordination site is occupied by a chloride ion, and another chloride ion is located in the interstices of the crystal. The trimetal unit in compound 2 is structurally similar to that in compound 1 except that the axial ligand in 2 is a CH3CN molecule. Compound 3 is an oxidation product prepared by reaction of 1 with AgBF4. Here, a square pyramidal CrIII unit, FCrN4, and a Cr-Cr quadruply bonded (Cr-Cr distance 1.968(2) A) unit, with an axially coordinated acetonitrile molecule, form the trichromium chain. The CrIII...CrII separation of 2.594(2) A in 3 is too long to be considered a bonding interaction.

Catabolism of Tritiated Thymidine by Aquatic Microbial Communities and Incorporation of Tritium into RNA and Protein †

PubMed Central

Brittain, Andrew M.; Karl, David M.

1990-01-01

The incorporation of tritiated thymidine by five microbial ecosystems and the distribution of tritium into DNA, RNA, and protein were determined. All microbial assemblages tested exhibited significant labeling of RNA and protein (i.e., nonspecific labeling), as determined by differential acid-base hydrolysis. Nonspecific labeling was greatest in sediment samples, for which ≥95% of the tritium was recovered with the RNA and protein fractions. The percentage of tritium recovered in the DNA fraction ranged from 15 to 38% of the total labeled macromolecules recovered. Nonspecific labeling was independent of both incubation time and thymidine concentration over very wide ranges. Four different RNA hydrolysis reagents (KOH, NaOH, piperidine, and enzymes) solubilized tritium from cold trichloroacetic acid precipitates. High-pressure liquid chromatography separation of piperidine hydrolysates followed by measurement of isolated monophosphates confirmed the labeling of RNA and indicated that tritium was recovered primarily in CMP and AMP residues. We also evaluated the specificity of [2-3H]adenine incorporation into adenylate residues in both RNA and DNA in parallel with the [3H]thymidine experiments and compared the degree of nonspecific labeling by [3H]adenine with that derived from [3H]thymidine. Rapid catabolism of tritiated thymidine was evaluated by determining the disappearance of tritiated thymidine from the incubation medium and the appearance of degradation products by high-pressure liquid chromatography separation of the cell-free medium. Degradation product formation, including that of both volatile and nonvolatile compounds, was much greater than the rate of incorporation of tritium into stable macromolecules. The standard degradation pathway for thymidine coupled with utilization of Krebs cycle intermediates for the biosynthesis of amino acids, purines, and pyrimidines readily accounts for the observed nonspecific labeling in environmental samples. PMID:16348180

Studies on molecular properties prediction and histamine H3 receptor affinities of novel ligands with uracil-based motifs.

PubMed

Lipani, Luca; Odadzic, Dalibor; Weizel, Lilia; Schwed, Johannes-Stephan; Sadek, Bassem; Stark, Holger

2014-10-30

The histamine H3 receptor (H3R) plays a role in cognitive and memory processes and is involved in different neurological disorders, including Alzheimer's disease, schizophrenia, and narcolepsy. Therefore, several hH3R antagonists/inverse agonists entered clinical phases for a broad spectrum of mainly centrally occurring diseases. However, many other promising candidates failed due to their pharmacokinetic profile, mostly because of their strong lipophilicity accompanied with low solubility. Analysis of previous potential H3R selective antagonists/inverse agonists, e.g. pitolisant, revealed promising results concerning physicochemical properties and drug-likeness. Herein, a series of new hH3R ligands 8-20 consisting of piperidin-1-yl or piperidin-1-yl-propoxyphenyl coupled to different uracil, thymine, and 5,6-dimethyluracil related moieties, were synthesized, evaluated on their binding properties at the hH3R and the estimation of different physicochemical and drug-likeness properties. Due to the coupling to various positions at pyrimidine-2,4-(1H,3H)-dione, affinity at hH3Rs and drug-likeness parameters have been improved. For instance, compound 9 showed in addition to high affinity at the hH3R (pKi (hH3R) = 8.14) clog S, clog P, LE, LipE, and drug-likeness score values of -4.36, 3.47, 0.34, 4.63, and 1.54, respectively. Also, the methyl substituted analog 17 (pKi (hH3R) = 8.15) revealed LE, LipE and drug-likeness score values of -3.29, 2.47, 0.49, 5.52, and 1.76, respectively. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Characterising in situ activation and degradation of hindered amine light stabilisers using liquid extraction surface analysis-mass spectrometry.

PubMed

Paine, Martin R L; Barker, Philip J; Blanksby, Stephen J

2014-01-15

Changes in the molecular structure of polymer antioxidants such as hindered amine light stabilisers (HALS) is central to their efficacy in retarding polymer degradation and therefore requires careful monitoring during their in-service lifetime. The HALS, bis-(1-octyloxy-2,2,6,6-tetramethyl-4-piperidinyl) sebacate (TIN123) and bis-(1,2,2,6,6-pentamethyl-4-piperidinyl) sebacate (TIN292), were formulated in different polymer systems and then exposed to various curing and ageing treatments to simulate in-service use. Samples of these coatings were then analysed directly using liquid extraction surface analysis (LESA) coupled with a triple quadrupole mass spectrometer. Analysis of TIN123 formulated in a cross-linked polyester revealed that the polymer matrix protected TIN123 from undergoing extensive thermal degradation that would normally occur at 292°C, specifically, changes at the 1- and 4-positions of the piperidine groups. The effect of thermal versus photo-oxidative degradation was also compared for TIN292 formulated in polyacrylate films by monitoring the in situ conversion of N-CH3 substituted piperidines to N-H. The analysis confirmed that UV light was required for the conversion of N-CH3 moieties to N-H - a major pathway in the antioxidant protection of polymers - whereas this conversion was not observed with thermal degradation. The use of tandem mass spectrometric techniques, including precursor-ion scanning, is shown to be highly sensitive and specific for detecting molecular-level changes in HALS compounds and, when coupled with LESA, able to monitor these changes in situ with speed and reproducibility. Copyright © 2013 Elsevier B.V. All rights reserved.

In vivo labeling of phencyclidine (PCP) receptors with sup 3 H-TCP in the mouse brain

DOE Office of Scientific and Technical Information (OSTI.GOV)

Maurice, T.; Vignon, J.

1990-07-01

The phencyclidine (PCP) derivative N-(1-(2-thienyl)cyclohexyl)-piperidine (3H-TCP) was used to label in vivo the N-methyl-D-aspartate (NMDA) receptor-associated ionic channel in the mouse brain. After the injection of a tracer dose of 3H-TCP, a spread labeling throughout the brain was observed, but was the highest in the cerebellum. Preadministration of unlabeled TCP (30 mg/kg) resulted in a 90% reduction of 3H-TCP binding. PCP, TCP, MK-801, dexoxadrol, ketamine, and SKF 10,047 isomers dose-dependently prevented the in vivo 3H-TCP binding. ID50 determined in the cerebrum and the cerebellum were respectively correlated with K0.5 for 3H TCP high (rat cortex) and low affinity (rat cerebellum)more » sites in vitro. The pharmacological specificity of the 3H-TCP binding site in the cerebellum was significantly different from that in the cerebrum. ID50 values were generally higher than in the cerebrum and, particularly, MK-801, the most potent drug in the cerebrum, was without significant effect in the cerebellum, at any time and at doses as high as 30 mg/kg. N-(1-(2-benzo(b) thiophenyl)cyclohexyl)piperidine (BTCP), desipramine, and atropine showed a more efficient prevention of 3H-TCP binding in the cerebellum than in the cerebrum. The prevention of the binding by TCP or PCP, at doses close to their ID50 values, was rapid and then decreased slowly. The effect of MK-801 was long-lasting. This study confirm previous in vitro studies: 3H-TCP is an efficient tool for the labeling of the NMDA receptor-associated ionic channel.« less

Inhibition of IκB Kinase-Nuclear Factor-κB Signaling Pathway by 3,5-Bis(2-flurobenzylidene)piperidin-4-one (EF24), a Novel Monoketone Analog of Curcumin*

PubMed Central

Kasinski, Andrea L.; Du, Yuhong; Thomas, Shala L.; Zhao, Jing; Sun, Shi-Yong; Khuri, Fadlo R.; Wang, Cun-Yu; Shoji, Mamoru; Sun, Aiming; Snyder, James P.; Liotta, Dennis; Fu, Haian

2009-01-01

The nuclear factor-κB (NF-κB) signaling pathway has been targeted for therapeutic applications in a variety of human diseases, includuing cancer. Many naturally occurring substances, including curcumin, have been investigated for their actions on the NF-κB pathway because of their significant therapeutic potential and safety profile. A synthetic monoketone compound termed 3,5-bis(2-flurobenzylidene)piperidin-4-one (EF24) was developed from curcumin and exhibited potent anticancer activity. Here, we report a mechanism by which EF24 potently suppresses the NF-κB signaling pathway through direct action on IκB kinase (IKK). We demonstrate that 1) EF24 induces death of lung, breast, ovarian, and cervical cancer cells, with a potency about 10 times higher than that of curcumin; 2) EF24 rapidly blocks the nuclear translocation of NF-κB, with an IC50 value of 1.3 μM compared with curcumin, with an IC50 value of 13 μM; 3) EF24 effectively inhibits tumor necrosis factor (TNF)-α-induced IκB phosphorylation and degradation, suggesting a role of this compound in targeting IKK; and 4) EF24 indeed directly inhibits the catalytic activity of IKK in an in vitro-reconstituted system. Our study identifies IKK as an effective target for EF24 and provides a molecular explanation for a superior activity of EF24 over curcumin. The effective inhibition of TNF-α-induced NF-κB signaling by EF24 extends the therapeutic application of EF24 to other NF-κB-dependent diseases, including inflammatory diseases such as rheumatoid arthritis. PMID:18577686

Inhibition of IkappaB kinase-nuclear factor-kappaB signaling pathway by 3,5-bis(2-flurobenzylidene)piperidin-4-one (EF24), a novel monoketone analog of curcumin.

PubMed

Kasinski, Andrea L; Du, Yuhong; Thomas, Shala L; Zhao, Jing; Sun, Shi-Yong; Khuri, Fadlo R; Wang, Cun-Yu; Shoji, Mamoru; Sun, Aiming; Snyder, James P; Liotta, Dennis; Fu, Haian

2008-09-01

The nuclear factor-kappaB (NF-kappaB) signaling pathway has been targeted for therapeutic applications in a variety of human diseases, includuing cancer. Many naturally occurring substances, including curcumin, have been investigated for their actions on the NF-kappaB pathway because of their significant therapeutic potential and safety profile. A synthetic monoketone compound termed 3,5-bis(2-flurobenzylidene)piperidin-4-one (EF24) was developed from curcumin and exhibited potent anticancer activity. Here, we report a mechanism by which EF24 potently suppresses the NF-kappaB signaling pathway through direct action on IkappaB kinase (IKK). We demonstrate that 1) EF24 induces death of lung, breast, ovarian, and cervical cancer cells, with a potency about 10 times higher than that of curcumin; 2) EF24 rapidly blocks the nuclear translocation of NF-kappaB, with an IC(50) value of 1.3 microM compared with curcumin, with an IC(50) value of 13 microM; 3) EF24 effectively inhibits tumor necrosis factor (TNF)-alpha-induced IkappaB phosphorylation and degradation, suggesting a role of this compound in targeting IKK; and 4) EF24 indeed directly inhibits the catalytic activity of IKK in an in vitro-reconstituted system. Our study identifies IKK as an effective target for EF24 and provides a molecular explanation for a superior activity of EF24 over curcumin. The effective inhibition of TNF-alpha-induced NF-kappaB signaling by EF24 extends the therapeutic application of EF24 to other NF-kappaB-dependent diseases, including inflammatory diseases such as rheumatoid arthritis.

Keto-enol tautomerism in asymmetric Schiff bases derived from p-phenylenediamine

NASA Astrophysics Data System (ADS)

Užarević, Krunoslav; Rubčić, Mirta; Stilinović, Vladimir; Kaitner, Branko; Cindrić, Marina

2010-12-01

Reaction of dehydroacetic acid and p-phenylenediamine afforded a monosubstituted Schiff base, I, with the other amino group free. In further reactions with various salicylaldehyde derivatives, I served as a precursor for synthesis of asymmetric bis-Schiff bases. The synthesized compounds are thus comprised of two subunits, dehydroacetic ( dha) and salicylidene ( sal), which are bridged by the phenylene linker. All products were investigated by means of elemental analysis, FT-IR and NMR spectroscopy, thermal methods, powder X-ray diffraction and, when possible, by single crystal X-ray crystallography. Structural and spectroscopic studies revealed that in the bis-products, the dha subunit adopts the keto-amino tautomeric form, while the sal subunit adopts the enol-imino form. Tautomeric forms were not affected if a methoxo group was introduced on the salicylidene ring. Both tautomeric subunits are stabilized by strong resonance-assisted hydrogen bonds, RAHB. The two subunits of the prepared bis-Schiff bases predominantly retain in solution the same tautomeric forms as found in the solid state.

Sc-Decorated Porous Graphene for High-Capacity Hydrogen Storage: First-Principles Calculations.

PubMed

Chen, Yuhong; Wang, Jing; Yuan, Lihua; Zhang, Meiling; Zhang, Cairong

2017-08-02

The generalized gradient approximation (GGA) function based on density functional theory is adopted to investigate the optimized geometrical structure, electron structure and hydrogen storage performance of Sc modified porous graphene (PG). It is found that the carbon ring center is the most stable adsorbed position for a single Sc atom on PG, and the maximum number of adsorbed H₂ molecules is four with the average adsorption energy of -0.429 eV/H₂. By adding a second Sc atom on the other side of the system, the hydrogen storage capacity of the system can be improved effectively. Two Sc atoms located on opposite sides of the PG carbon ring center hole is the most suitable hydrogen storage structure, and the hydrogen storage capacity reach a maximum 9.09 wt % at the average adsorption energy of -0.296 eV/H₂. The adsorption of H₂ molecules in the PG system is mainly attributed to orbital hybridization among H, Sc, and C atoms, and Coulomb attraction between negatively charged H₂ molecules and positively charged Sc atoms.

Sc-Decorated Porous Graphene for High-Capacity Hydrogen Storage: First-Principles Calculations

PubMed Central

Chen, Yuhong; Wang, Jing; Yuan, Lihua; Zhang, Meiling

2017-01-01

The generalized gradient approximation (GGA) function based on density functional theory is adopted to investigate the optimized geometrical structure, electron structure and hydrogen storage performance of Sc modified porous graphene (PG). It is found that the carbon ring center is the most stable adsorbed position for a single Sc atom on PG, and the maximum number of adsorbed H2 molecules is four with the average adsorption energy of −0.429 eV/H2. By adding a second Sc atom on the other side of the system, the hydrogen storage capacity of the system can be improved effectively. Two Sc atoms located on opposite sides of the PG carbon ring center hole is the most suitable hydrogen storage structure, and the hydrogen storage capacity reach a maximum 9.09 wt % at the average adsorption energy of −0.296 eV/H2. The adsorption of H2 molecules in the PG system is mainly attributed to orbital hybridization among H, Sc, and C atoms, and Coulomb attraction between negatively charged H2 molecules and positively charged Sc atoms. PMID:28767084

Spoof Surface Plasmon Polaritons Power Divider with large Isolation.

PubMed

Zhou, Shiyan; Lin, Jing-Yu; Wong, Sai-Wai; Deng, Fei; Zhu, Lei; Yang, Yang; He, Yejun; Tu, Zhi-Hong

2018-04-13

Periodic corrugated metal structure is designed to support and propagate spoof surface plasmon polaritons (SSPPs) wave in the microwave frequencies. In this paper, firstly a plasmonic waveguide consisting of oval-ring shaped cells is proposed with the performance of high transmission efficiency in a wide frequency range. The coplanar waveguides (CPWs) with 50 Ω impedance are adopted to feed the energies or extract signals at both ends of the plasmonic waveguide. Then a well-isolated power divider is constructed based on the SSPPs waveguides aiming to equally split the energy of the SSPPs wave into two equal parts. The stepped-impedances are co-designed with the three input/output ports of the power divider to achieve the impedance-matching between the SSPPs waveguides and the coplanar waveguides. Besides, a single resistor is placed in the middle of two symmetrical half oval-rings to realize the isolation between the two output ports over the spectrum of 4.5-7.5 GHz. Finally, both plasmonic waveguide and the power divider are fabricated and tested to verify the predicted characteristics.

A ceramic radial insulation structure for a relativistic electron beam vacuum diode.

PubMed

Xun, Tao; Yang, Hanwu; Zhang, Jiande; Liu, Zhenxiang; Wang, Yong; Zhao, Yansong

2008-06-01

For one kind of a high current diode composed of a small disk-type alumina ceramic insulator water/vacuum interface, the insulation structure was designed and experimentally investigated. According to the theories of vacuum flashover and the rules for radial insulators, a "cone-column" anode outline and the cathode shielding rings were adopted. The electrostatic field along the insulator surface was obtained by finite element analysis simulating. By adjusting the outline of the anode and reshaping the shielding rings, the electric fields were well distributed and the field around the cathode triple junction was effectively controlled. Area weighted statistical method was applied to estimate the surface breakdown field. In addition, the operating process of an accelerator based on a spiral pulse forming line (PFL) was simulated through the PSPICE software to get the waveform of charging and diode voltage. The high voltage test was carried out on a water dielectric spiral PFL accelerator with long pulse duration, and results show that the diode can work stably in 420 kV, 200 ns conditions. The experimental results agree with the theoretical and simulated results.

Chip-integrated optical power limiter based on an all-passive micro-ring resonator

NASA Astrophysics Data System (ADS)

Yan, Siqi; Dong, Jianji; Zheng, Aoling; Zhang, Xinliang

2014-10-01

Recent progress in silicon nanophotonics has dramatically advanced the possible realization of large-scale on-chip optical interconnects integration. Adopting photons as information carriers can break the performance bottleneck of electronic integrated circuit such as serious thermal losses and poor process rates. However, in integrated photonics circuits, few reported work can impose an upper limit of optical power therefore prevent the optical device from harm caused by high power. In this study, we experimentally demonstrate a feasible integrated scheme based on a single all-passive micro-ring resonator to realize the optical power limitation which has a similar function of current limiting circuit in electronics. Besides, we analyze the performance of optical power limiter at various signal bit rates. The results show that the proposed device can limit the signal power effectively at a bit rate up to 20 Gbit/s without deteriorating the signal. Meanwhile, this ultra-compact silicon device can be completely compatible with the electronic technology (typically complementary metal-oxide semiconductor technology), which may pave the way of very large scale integrated photonic circuits for all-optical information processors and artificial intelligence systems.

(E)-2-[(2,4,6-Tri-meth-oxy-benzyl-idene)amino]-phenol.

PubMed

Kaewmanee, Narissara; Chantrapromma, Suchada; Boonnak, Nawong; Quah, Ching Kheng; Fun, Hoong-Kun

2014-01-01

There are two independent mol-ecules in the asymmetric unit of the title compound, C16H17NO4, with similar conformations but some differences in their bond angles. Each mol-ecule adopts a trans configuration with respect to the methyl-idene C=N bond and is twisted with a dihedral angle between the two substituted benzene rings of 80.52 (7)° in one mol-ecule and 83.53 (7)° in the other. All meth-oxy groups are approximately coplanar with the attached benzene rings, with Cmeth-yl-O-C-C torsion angles ranging from -6.7 (2) to 5.07 (19)°. In the crystal, independent mol-ecules are linked together by O-H⋯N and O-H⋯O hydrogen bonds and a π-π inter-action [centroid-centroid distance of 3.6030 (9) Å], forming a dimer. The dimers are further linked by weak C-H⋯O inter-actions and another π-π inter-action [centroid-centroid distance of 3.9452 (9) Å] into layers lying parallel to the ab plane.

A wireless fatigue monitoring system utilizing a bio-inspired tree ring data tracking technique.

PubMed

Bai, Shi; Li, Xuan; Xie, Zhaohui; Zhou, Zhi; Ou, Jinping

2014-03-05

Fatigue, a hot scientific research topic for centuries, can trigger sudden failure of critical structures such as aircraft and railway systems, resulting in enormous casualties as well as economic losses. The fatigue life of certain structures is intrinsically random and few monitoring techniques are capable of tracking the full life-cycle fatigue damage. In this paper, a novel in-situ wireless real-time fatigue monitoring system using a bio-inspired tree ring data tracking technique is proposed. The general framework, methodology, and verification of this intelligent system are discussed in details. The rain-flow counting (RFC) method is adopted as the core algorithm which quantifies fatigue damages, and Digital Signal Processing (DSP) is introduced as the core module for data collection and analysis. Laboratory test results based on strain gauges and polyvinylidene fluoride (PVDF) sensors have shown that the developed intelligent system can provide a reliable quick feedback and early warning of fatigue failure. With the merits of low cost, high accuracy and great reliability, the developed wireless fatigue sensing system can be further applied to mechanical engineering, civil infrastructures, transportation systems, aerospace engineering, etc.

Artificial light-regulation of an allosteric bi-enzyme complex by a photosensitive ligand.

PubMed

Kneuttinger, Andrea C; Winter, Martin; Simeth, Nadja A; Heyn, Kristina; Merkl, Rainer; König, Burkhard; Sterner, Reinhard

2018-05-29

The artificial regulation of proteins by light is an emerging sub-discipline of synthetic biology. Here, we used this concept in order to photo-control both catalysis and allostery within the heterodimeric enzyme complex imidazole glycerol phosphate synthase (ImGP-S). The ImGP-S consists of the cyclase subunit HisF and the glutaminase subunit HisH, which is allosterically stimulated by substrate binding to HisF. We show that a light-sensitive diarylethene (DTE)-based competitive inhibitor in its ring-open state binds with low micromolar affinity to the cyclase subunit and displaces its substrate from the active site. As a consequence, catalysis by HisF and allosteric stimulation of HisH are impaired. Following UV-light irradiation, the DTE-ligand adopts its ring-closed state and loses affinity for HisF, restoring activity and allostery. Our approach allows for the switching of ImGP-S activity and allostery during catalysis and appears to be generally applicable for the light-regulation of other multi-enzyme complexes. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Recent Approaches Toward Solid Phase Synthesis of β-Lactams

NASA Astrophysics Data System (ADS)

Mandal, Bablee; Ghosh, Pranab; Basu, Basudeb

Since the discovery of penicillin in 1929, β-lactam antibiotics have been recognized as potentially chemotherapeutic drugs of incomparable effectiveness, conjugating a broad spectrum of activity with very low toxicity. The primary motif azetidin-2-one ring (β-lactam) has been considered as specific pharmacophores and scaffolds. With the advent of combinatorial chemistry and automated parallel synthesis coupled with ample interests from the pharmaceutical industries, recent trends have been driven mostly by adopting solid phase techniques and polymer-supported synthesis of β-lactams. The present survey will present an overview of the developments on the polymer-supported and solid phase techniques for the preparation of β-lactam ring or β-lactam containing antibiotics published over the last decade. Both unsubstituted and substitutions with different functional groups at various positions of β-lactams have been synthesized using solid phase technology. However, Wang resin and application of Staudinger [2+2] cycloaddition reaction have remained hitherto the major choice. It may be expected that other solid phase approaches involving different resins would be developed in the coming years.

Modeling and Density Estimation of an Urban Freeway Network Based on Dynamic Graph Hybrid Automata

PubMed Central

Chen, Yangzhou; Guo, Yuqi; Wang, Ying

2017-01-01

In this paper, in order to describe complex network systems, we firstly propose a general modeling framework by combining a dynamic graph with hybrid automata and thus name it Dynamic Graph Hybrid Automata (DGHA). Then we apply this framework to model traffic flow over an urban freeway network by embedding the Cell Transmission Model (CTM) into the DGHA. With a modeling procedure, we adopt a dual digraph of road network structure to describe the road topology, use linear hybrid automata to describe multi-modes of dynamic densities in road segments and transform the nonlinear expressions of the transmitted traffic flow between two road segments into piecewise linear functions in terms of multi-mode switchings. This modeling procedure is modularized and rule-based, and thus is easily-extensible with the help of a combination algorithm for the dynamics of traffic flow. It can describe the dynamics of traffic flow over an urban freeway network with arbitrary topology structures and sizes. Next we analyze mode types and number in the model of the whole freeway network, and deduce a Piecewise Affine Linear System (PWALS) model. Furthermore, based on the PWALS model, a multi-mode switched state observer is designed to estimate the traffic densities of the freeway network, where a set of observer gain matrices are computed by using the Lyapunov function approach. As an example, we utilize the PWALS model and the corresponding switched state observer to traffic flow over Beijing third ring road. In order to clearly interpret the principle of the proposed method and avoid computational complexity, we adopt a simplified version of Beijing third ring road. Practical application for a large-scale road network will be implemented by decentralized modeling approach and distributed observer designing in the future research. PMID:28353664

Modeling and Density Estimation of an Urban Freeway Network Based on Dynamic Graph Hybrid Automata.

PubMed

Chen, Yangzhou; Guo, Yuqi; Wang, Ying

2017-03-29

In this paper, in order to describe complex network systems, we firstly propose a general modeling framework by combining a dynamic graph with hybrid automata and thus name it Dynamic Graph Hybrid Automata (DGHA). Then we apply this framework to model traffic flow over an urban freeway network by embedding the Cell Transmission Model (CTM) into the DGHA. With a modeling procedure, we adopt a dual digraph of road network structure to describe the road topology, use linear hybrid automata to describe multi-modes of dynamic densities in road segments and transform the nonlinear expressions of the transmitted traffic flow between two road segments into piecewise linear functions in terms of multi-mode switchings. This modeling procedure is modularized and rule-based, and thus is easily-extensible with the help of a combination algorithm for the dynamics of traffic flow. It can describe the dynamics of traffic flow over an urban freeway network with arbitrary topology structures and sizes. Next we analyze mode types and number in the model of the whole freeway network, and deduce a Piecewise Affine Linear System (PWALS) model. Furthermore, based on the PWALS model, a multi-mode switched state observer is designed to estimate the traffic densities of the freeway network, where a set of observer gain matrices are computed by using the Lyapunov function approach. As an example, we utilize the PWALS model and the corresponding switched state observer to traffic flow over Beijing third ring road. In order to clearly interpret the principle of the proposed method and avoid computational complexity, we adopt a simplified version of Beijing third ring road. Practical application for a large-scale road network will be implemented by decentralized modeling approach and distributed observer designing in the future research.

Investigation of the characteristics of a stacked direct borohydride fuel cell for portable applications

NASA Astrophysics Data System (ADS)

Kim, Cheolhwan; Kim, Kyu-Jung; Ha, Man Yeong

To investigate the possibility of the portable application of a direct borohydride fuel cell (DBFC), weight reduction of the stack and high stacking of the cells are investigated for practical running conditions. For weight reduction, carbon graphite is adopted as the bipolar plate material even though it has disadvantages in tight stacking, which results in stacking loss from insufficient material strength. For high stacking, it is essential to have a uniform fuel distribution among cells and channels to maintain equal electric load on each cell. In particular, the design of the anode channel is important because active hydrogen generation causes non-uniformity in the fuel flow-field of the cells and channels. To reduce the disadvantages of stacking force margin and fuel maldistribution, an O-ring type-sealing system with an internal manifold and a parallel anode channel design is adopted, and the characteristics of a single and a five-cell fuel cell stack are analyzed. By adopting carbon graphite, the stack weight can be reduced by 4.2 times with 12% of performance degradation from the insufficient stacking force. When cells are stacked, the performance exceeds the single-cell performance because of the stack temperature increase from the reduction of the radiation area from the narrow stacking of cells.

Comprehensive understanding of acetohydroxyacid synthase inhibition by different herbicide families.

PubMed

Garcia, Mario D; Nouwens, Amanda; Lonhienne, Thierry G; Guddat, Luke W

2017-02-14

Five commercial herbicide families inhibit acetohydroxyacid synthase (AHAS, E.C. 2.2.1.6), which is the first enzyme in the branched-chain amino acid biosynthesis pathway. The popularity of these herbicides is due to their low application rates, high crop vs. weed selectivity, and low toxicity in animals. Here, we have determined the crystal structures of Arabidopsis thaliana AHAS in complex with two members of the pyrimidinyl-benzoate (PYB) and two members of the sulfonylamino-carbonyl-triazolinone (SCT) herbicide families, revealing the structural basis for their inhibitory activity. Bispyribac, a member of the PYBs, possesses three aromatic rings and these adopt a twisted "S"-shaped conformation when bound to A. thaliana AHAS ( At AHAS) with the pyrimidinyl group inserted deepest into the herbicide binding site. The SCTs bind such that the triazolinone ring is inserted deepest into the herbicide binding site. Both compound classes fill the channel that leads to the active site, thus preventing substrate binding. The crystal structures and mass spectrometry also show that when these herbicides bind, thiamine diphosphate (ThDP) is modified. When the PYBs bind, the thiazolium ring is cleaved, but when the SCTs bind, ThDP is modified to thiamine 2-thiazolone diphosphate. Kinetic studies show that these compounds not only trigger reversible accumulative inhibition of AHAS, but also can induce inhibition linked with ThDP degradation. Here, we describe the features that contribute to the extraordinarily powerful herbicidal activity exhibited by four classes of AHAS inhibitors.

Comprehensive understanding of acetohydroxyacid synthase inhibition by different herbicide families

PubMed Central

Nouwens, Amanda; Lonhienne, Thierry G.; Guddat, Luke W.

2017-01-01

Five commercial herbicide families inhibit acetohydroxyacid synthase (AHAS, E.C. 2.2.1.6), which is the first enzyme in the branched-chain amino acid biosynthesis pathway. The popularity of these herbicides is due to their low application rates, high crop vs. weed selectivity, and low toxicity in animals. Here, we have determined the crystal structures of Arabidopsis thaliana AHAS in complex with two members of the pyrimidinyl-benzoate (PYB) and two members of the sulfonylamino-carbonyl-triazolinone (SCT) herbicide families, revealing the structural basis for their inhibitory activity. Bispyribac, a member of the PYBs, possesses three aromatic rings and these adopt a twisted “S”-shaped conformation when bound to A. thaliana AHAS (AtAHAS) with the pyrimidinyl group inserted deepest into the herbicide binding site. The SCTs bind such that the triazolinone ring is inserted deepest into the herbicide binding site. Both compound classes fill the channel that leads to the active site, thus preventing substrate binding. The crystal structures and mass spectrometry also show that when these herbicides bind, thiamine diphosphate (ThDP) is modified. When the PYBs bind, the thiazolium ring is cleaved, but when the SCTs bind, ThDP is modified to thiamine 2-thiazolone diphosphate. Kinetic studies show that these compounds not only trigger reversible accumulative inhibition of AHAS, but also can induce inhibition linked with ThDP degradation. Here, we describe the features that contribute to the extraordinarily powerful herbicidal activity exhibited by four classes of AHAS inhibitors. PMID:28137884

Discovery of novel BTK inhibitors with carboxylic acids.

PubMed

Gao, Xiaolei; Wang, James; Liu, Jian; Guiadeen, Deodial; Krikorian, Arto; Boga, Sobhana Babu; Alhassan, Abdul-Basit; Selyutin, Oleg; Yu, Wensheng; Yu, Younong; Anand, Rajan; Liu, Shilan; Yang, Chundao; Wu, Hao; Cai, Jiaqiang; Cooper, Alan; Zhu, Hugh; Maloney, Kevin; Gao, Ying-Duo; Fischmann, Thierry O; Presland, Jeremy; Mansueto, My; Xu, Zangwei; Leccese, Erica; Zhang-Hoover, Jie; Knemeyer, Ian; Garlisi, Charles G; Bays, Nathan; Stivers, Peter; Brandish, Philip E; Hicks, Alexandra; Kim, Ronald; Kozlowski, Joeseph A

2017-03-15

We report the design and synthesis of a series of novel Bruton's Tyrosine Kinase (BTK) inhibitors with a carboxylic acid moiety in the ribose pocket. This series of compounds has demonstrated much improved off-target selectivities including adenosine uptake (AdU) inhibition compared to the piperidine amide series. Optimization of the initial lead compound 4 based on BTK enzyme inhibition, and human peripheral blood mononuclear cell (hPBMC) and human whole blood (hWB) activity led to the discovery of compound 40, with potent BTK inhibition, reduced off target activities, as well as favorable pharmacokinetic profile in both rat and dog. Copyright © 2016 Elsevier Ltd. All rights reserved.

Practical Alkoxythiocarbonyl Auxiliaries for Iridium(I)-Catalyzed C-H Alkylation of Azacycles.

PubMed

Tran, Anh T; Yu, Jin-Quan

2017-08-21

The development of new and practical 3-pentoxythiocarbonyl auxiliaries for Ir I -catalyzed C-H alkylation of azacycles is described. This method allows for the α-C-H alkylation of a variety of substituted pyrrolidines, piperidines, and tetrahydroisoquinolines through alkylation with alkenes. While the practicality of these simple carbamate-type auxiliaries is underscored by the ease of installation and removal, the method's utility is demonstrated in its ability to functionalize biologically relevant l-proline and l-trans-hydroxyproline, delivering unique 2,5-dialkylated amino acid analogues that are not accessible by other C-H functionalization methods. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Synthesis and synergistic, additive inhibitory effects of novel spiro derivatives against ringworm infections.

PubMed

Sharma, Gajanand; Sharma, Richa; Dandia, Anshu; Bansal, Preeti

2013-01-01

An environmentally benign solvent free synthesis of various spiro-1,4-dihydropyridines (1,4-DHPs) incorporating 2-oxindole/piperidines is performed in 5-8 min with reasonable purity in 80-90% yield under microwave irradiation using montmorillonite KSF as an inorganic solid support. The reaction is found to be general with respect to various cyclic carbonyl compounds, e.g. cyclohexanone, substituted indole-2,3-dione, and piperidinone derivatives. In our study, these compounds were also found effective against dermatophytes and other fungal organisms. Our results suggest that novel spiro derivatives can be used for the treatment of dermatophytosis or ringworm infections.

2,6-Diiminopiperidin-1-ol: an overlooked motif relevant to uranyl and transition metal binding on poly(amidoxime) adsorbents

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kennedy, Zachary C.; Cardenas, Allan Jay P.; Corbey, Jordan F.

2016-01-01

Glutardiamidoxime, a structural motif on sorbents used in uranium extraction from seawater, was discovered to cyclize in situ at room temperature to 2,6-diimino-piperidin-1-ol in the presence of uranyl nitrate. The new diimino motif was also generated when exposed to competing transition metals Cu(II) and Ni(II). Multinuclear μ-O bridged U(VI), Cu(II), and Ni(II) complexes featuring bound diimino ligands were isolated. A Cu(II) complex with the historically relevant cyclic imide dioxime motif is also reported for structural comparison to the reported diimino complexes.

Electrochemistry of norcocaine nitroxide and related compounds: implications for cocaine hepatotoxicity.

PubMed

Charkoudian, J C; Shuster, L

1985-08-15

Norcocaine nitroxide, a free radical metabolite of cocaine, displays a reversible one-electron cyclic voltammogram which is abolished by the addition of reduced glutathione. The corresponding nitrosonium ion was synthesized. It showed the same electrochemical characteristics as the nitroxide. The spin label 4-hydroxy-2,2,6,6-tetramethyl piperidine-1-oxyl (TEMPOL) and its nitrosonium ion behaved like morcocaine nitroxide and its nitrosonium ion. The nitrosonium ion of TEMPOL caused hemolysis of red blood cells, but TEMPOL did not. These observations suggest that the highly reactive nitrosonium ion may be involved in the production of cocaine-induced hepatic necrosis in mice.

DNA lability induced by nimustine and ramustine in rat glioma cells.

PubMed Central

Mineura, K; Fushimi, S; Itoh, Y; Kowada, M

1988-01-01

The DNA labile sites induced by two nitrosoureas, nimustine (ACNU) and ramustine (MCNU) synthesised in Japan, have been examined in highly reiterated DNA sequences of rat glioma cells. Reiterated fragments of 167 and 203 base pairs (bp), obtained after Hind III and Hae III restriction endonuclease digestion of rat glioma cells DNA, were used as target DNA sequences to determine the labile sites. In vitro reaction with ACNU and MCNU resulted in scission products corresponding to the locations of guanine. Subsequent piperidine hydrolysis produced more frequent breaks of the phosphodiester bonds at guanine positions, thus forming alkali-labile sites. Images PMID:3236017