The effect of temperature and pressure on the crystal structure of piperidine.

Science.gov (United States)

Budd, Laura E; Ibberson, Richard M; Marshall, William G; Parsons, Simon

2015-01-01

The response of molecular crystal structures to changes in externally applied conditions such as temperature and pressure are the result of a complex balance between strong intramolecular bonding, medium strength intermolecular interactions such as hydrogen bonds, and weaker intermolecular van der Waals contacts. At high pressure the additional thermodynamic requirement to fill space efficiently becomes increasingly important. The crystal structure of piperidine-d11 has been determined at 2 K and at room temperature at pressures between 0.22 and 1.09 GPa. Unit cell dimensions have been determined between 2 and 255 K, and at pressures up to 2.77 GPa at room temperature. All measurements were made using neutron powder diffraction. The crystal structure features chains of molecules formed by NH…N H-bonds with van der Waals interactions between the chains. Although the H-bonds are the strongest intermolecular contacts, the majority of the sublimation enthalpy may be ascribed to weaker but more numerous van der Waals interactions. Analysis of the thermal expansion data in the light of phonon frequencies determined in periodic DFT calculations indicates that the expansion at very low temperature is governed by external lattice modes, but above 100 K the influence of intramolecular ring-flexing modes also becomes significant. The principal directions of thermal expansion are determined by the sensitivity of different van der Waals interactions to changes in distance. The principal values of the strain developed on application of pressure are similarly oriented to those determined in the variable-temperature study, but more isotropic because of the need to minimise volume by filling interstitial voids at elevated pressure. Graphical AbstractThough H-bonds are important interactions in the crystal structure of piperidine, the response to externally-applied conditions are determined by van der Waals interactions.

Synthesis of N-Substituted Piperidine Salts as Potential Muscarinic Ligands for Alzheimer's Applications

Czech Academy of Sciences Publication Activity Database

Boulos, J.; Jakubík, Jan; Randáková, Alena; Avila, C.

2013-01-01

Roč. 50, č. 6 (2013), s. 1363-1367 ISSN 0022-152X R&D Projects: GA ČR(CZ) GA305/09/0681 Institutional support: RVO:67985823 Keywords : N-piperidine substituted salts * muscarinic receptor antagonists * selectivity Subject RIV: ED - Physiology Impact factor: 0.873, year: 2013

Effects of a piperidine ligand on DNA modification by antitumor cisplatin analogues

Czech Academy of Sciences Publication Activity Database

Kašpárková, Jana; Nováková, Olga; Najajreh, Y.; Gibson, D.; Perez, J.M.; Brabec, Viktor

2003-01-01

Roč. 16, č. 11 (2003), s. 1424-1432 ISSN 0893-228X R&D Projects: GA ČR GA305/02/1552; GA AV ČR KJB5004301; GA AV ČR IBS5004009 Institutional research plan: CEZ:AV0Z5004920 Keywords : DNA * piperidine ligand * antitumor cisplatin analogues Subject RIV: BO - Biophysics Impact factor: 3.332, year: 2003

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

Science.gov (United States)

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...

One-pot multi-component green synthesis of highly substituted piperidines

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Ravi Bansal

2017-05-01

Full Text Available An effective and expeditious method of the synthesis of a highly functionalized piperidines, catalyzed by nontoxic, recyclable and environment friendly sodium lauryl sulfate (SLS, via one-pot multi-component condensation of aldehydes, amines and β-ketoesters in water at room temperature, has been developed. This new protocol has advantages such as moderate to high yields of products obtained after simple post reaction workup. Structure of the synthesized compounds 4a–4j have been elucidated based on the 1H NMR, 13C NMR, FT-IR spectroscopy and elemental analysis.

Crystal structure of 4,4′-bis[3-(piperidin-1-ylprop-1-yn-1-yl]-1,1′-biphenyl

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Anqi Walbaum

2017-06-01

Full Text Available The title compound, C28H32N2, (I, is one of a second generation of compounds designed and synthesized based on a very potent and selective α9α10 nicotinic acetylcholine receptor antagonist ZZ161C {1,1′-[[1,1′-biphenyl]-4,4′-diylbis(prop-2-yne-3,1-diyl]bis(3,4-dimethylpyridin-1-ium bromide}, which has shown analgesic effects in a chemotherapy-induced neuropathy animal model. Compound (I was synthesized by the reaction of 4,4′-bis(3-bromoprop-1-yn-1-yl-1,1′-biphenyl with piperidine at room temperature in acetonitrile. The single-crystal used for X-ray analysis was obtained by dissolving (I in a mixture of dichloromethane and methanol, followed by slow evaporation of the solvent. In the crystal of (I, the biphenyl moiety has a twisted conformation, with a dihedral angle of 25.93 (4° between the benzene rings. Both piperidine head groups in (I are in the chair conformation and are oriented so that the N-atom lone pairs of each piperidine group point away from the central biphenyl moiety.

Spectrophotometric determination of palladium (II) with rubeanic acid (RA) in presence of pyridine, piperidine and 3-picoline

International Nuclear Information System (INIS)

Hassiruzzaman, M.; Hossain, M.A.; Rahman, G.M.M.; Kamal, A.S.M.; Kabir, M.H.; Mustafa, A.I.

1999-01-01

Unpretentious and exclusive methods for the spectrophotometric determination of trace amount of divalent palladium (II) have been developed with rubeanic acid (dithio-oxamide) in presence of secondary ligands like pyridine, piperidine and 3-picoline. Both direct and extraction spectrophotometry showed that coloured rubeanates are only stable in acidic medium. The violent yellow coloured products are formed below ph 5.0 with an absorption maxima at 416.0 and 422.0 (pyridine), 405.0 and 416.5 (piperidine) and 418.0 and 422.0 (3-picoline) both in direct and isoamyl alcohol (IAA) extracted system, respectively. Results indicate that the highest sensitivity and molar absorptivity of Pd-RA pyridine system in direct spectrophotometry were 0.01497 mu g Pd(II) cm/sup -2/ and 7107.89 L mol sup -1/ cm/sup -1/ respectively. IAA extracted Pd-RA-piperidine system was found to give a sensitivity of 0.01087 mu g(Pd(II) cm /sup -2/ and molar absorptivity of 9788.80 L mol /sup -1/ cm/sup -1/ which were the highest of all the system. The effects due to variation of pH, reagent concentrations, order of addition of reagents, time, temperature and solvent media on the absorption spectra have been investigated and the optimum conditions determined. The effects of diverse ions and their tolerance limit have also been studies. (author)

Identification of a new psychoactive substance in seized material: the synthetic opioid N-phenyl-N-[1-(2-phenethyl)piperidin-4-yl]prop-2-enamide (Acrylfentanyl)

DEFF Research Database (Denmark)

Breindahl, Torben; Kimergård, Andreas; Andreasen, Mette Findal

2017-01-01

Among the new psychoactive substances (NPS) that have recently emerged on the market, many of the new synthetic opioids have shown to be particularly harmful. A new synthetic analogue of fentanyl, N-phenyl-N-[1-(2-phenethyl)piperidin-4-yl]prop-2-enamide (acrylfentanyl), was identified in powder...... from a seized capsule found at a forensic psychiatric ward in Denmark. Gas chromatography with mass spectrometry (GC-MS) identified a precursor to synthetic fentanyls, N-phenyl-1-(2-phenylethyl)piperidin-4-amine; however, the precursor 1-(2-phenethyl)piperidin-4-one, was not detected. Analysis...... of the electron impact mass spectrum of the main, unknown chromatographic peak (GC) tentatively identified an acryloyl analogue of fentanyl. Further analyses by quadrupole time-of-flight high resolution mass spectrometry (QTOF-MS), matrix-assisted laser ionization Orbitrap mass spectrometry (MALDI...

Volumetric properties of (piperidine + water) binary system: Measurements and modeling

International Nuclear Information System (INIS)

Afzal, Waheed; Valtz, Alain; Coquelet, Christophe; Richon, Dominique

2008-01-01

Densities of pure piperidine (CAS No.: 110-89-4) and of its mixtures with water have been measured over the whole range of compositions at temperatures from 283.15 K to 347.15 K using Anton Paar TM digital vibrating tube densimeter. The density of this system has been found increasing with mass fraction of water. Excess molar volumes have been calculated using the measured experimental densities and correlated using the Redlich-Kister equation. Redlich-Kister equation parameters have been adjusted on experimental data. In addition, partial molar volumes and partial excess molar volumes at infinite dilution have been calculated for each component

CRYSTAL AND MOLECULAR STRUCTURE OF 5-NITROPIRIDINE PIPERIDINE-SULFENAMIDE

OpenAIRE

Brito, Iván; León, Yasna; Arias, Mauricio; Vargas, Danitza; Carmona, Francisco; Ramírez, Eduardo; Restovic, Ambrosio; Cárdenas, Alejandro; Wittke, Oscar; López-Rodríguez, Matías

2002-01-01

The crystal and molecular structure of 5-nitropiridine piperidine-sulfenamide, C10H13N3O2 S is described and compared with other sulfenamides and with other similar compounds. This structure belongs to a type of divalent sulphur compound and crystallizes in the orthorhombic space group Pnma with a= 27.810(4), b=6.797(1), c=6.110(1)Å, and Dx =1.376 g cm-3 with Z=4. The S-N bond distance of 1.699(4) Å is shorter than a single S-N bond [1.74 Å]. The NO2-(C6H3N)-S-N(C 5H10) molecule lies on a cry...

Systems of pyridine, piperidine, piperazine, morpholine hydrochlorides-terbium (dysprosium) chloride-water

International Nuclear Information System (INIS)

Gajfutdinova, R.K.; Sharafutdinova, A.A.; Murinov, Yu.I.

1988-01-01

The isothermal cross section method at 25 and 50 deg C is applied to study pyridine hydrochloride-terbium chloride-water (1) piperidine hydrochloride-dysprosium chloride-water (2), piperazine dihydrochloride-dysprosium chloride-water (3) and morpholine hydrochloride-terbium chloride (4) systems. Solubility isotherma prove the formation of incongruently soluble compound of the TbCl 3 x6C 5 H 5 NxHCl composition systems (1). The individuality of the new solid phase is proved by the chemical and DTA methods. Systems (2-4) are of a simple eutonic type

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

Science.gov (United States)

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.

Synthesis of fused bicyclic piperidines: potential bioactive templates for medicinal chemistry.

Science.gov (United States)

Zhou, Jinglan; Campbell-Conroy, Erica L; Silina, Alina; Uy, Johnny; Pierre, Fabrice; Hurley, Dennis J; Hilgraf, Nicole; Frieman, Bryan A; DeNinno, Michael P

2015-01-02

An array of six pyridyl-substituted fused bicyclic piperidines was prepared as novel cores for medicinal chemistry. For maximum diversity, the size of the fused ring varied from three to six atoms and contained up to two oxygen atoms. The pyridine ring was incorporated to improve physicochemical properties and to challenge the robustness of the chemistry. The presence of the pyridine did interfere with our initial approaches to these molecules, and in several instances, a blocking strategy had to be employed. These new scaffolds possess high sp3 character and may prove useful in multiple medicinal chemistry applications.

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.

Science.gov (United States)

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 of (R-Dihydropyridones as Key Intermediates for an Efficient Access to Piperidine Alkaloids

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Serkos A Haroutounian

2007-04-01

Full Text Available The efficient transformation of D-glucal to (2R-hydroxymethyldihydro-pyridinone 5 in seven steps and 35 % overall yield is reported. Dihydropyridone 5 constitutes a versatile chiral building block for the synthesis of various piperidine alkaloids. In this regard, 5 was converted to piperidinol 13 and piperidinone 15, that may be further elaborated for the syntheses of (+-desoxoprosophylline (1 and deoxymannojirimycin (3 or D-mannolactam (4, respectively.

Synthesis and study of bio-distribution of a piperidine derivative marked by the technetium 99m

International Nuclear Information System (INIS)

Guizani, Sihem

2008-01-01

With the increase in life expectancy and ageing, the cerebral diseases, became among the first causes of mortality of the population. However, the prevention and the treatment of these diseases depend on the diagnosis and an early and reliable assessment. The radio pharmaceutics used are very few. The object of our work concerns the development of a new radiotracer labelled with the Tc 99m, it's a piperidine derivative (the 1 piperidine-1-yl ferrocene-1-one), then to follow the kinetics and its biodistribution in rats to detect its targets. The follow-up of kinetics and the biodistribution of the lately synthesized molecule after their injection, revealed a cerebral activity of 0.82 pour cent. This value represents a sufficient quantity to be detected by an external device of acquisition of radioactivity like gamma camera without health threatens of the patient. The method of labelling developed opens a new way of synthesis of characterized by radiochemical stability and a very promising biochemical behavior for the cerebral radiodiagnosis. (Author)

Crystal structure of 4-methoxy-N-(piperidine-1-carbonothioylbenzamide

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Khairi Suhud

2017-10-01

Full Text Available 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.

A kryptoracemic salt: 2-{[2,8-bis(trifluoromethylquinolin-4-yl](hydroxymethyl}piperidin-1-ium (+-3,3,3-trifluoro-2-methoxy-2-phenylpropanoate

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James L. Wardell

2016-06-01

Full Text Available The asymmetric unit of the title salt, C17H17F6N2O+·C10H8F3O3−, comprises two piperidin-1-ium cations and two carboxylate 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-enantiomeric. The anions have the same absolute configuration but differ in the relative orientations of the carboxylate, methoxy 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 = methoxy and c = carboxylate. The presence of Oh—H...Oc and Np—H...Oc hydrogen bonds leads to the formation of a supramolecular chain along the a axis (h = hydroxy and p = piperidin-1-ium; weak intramolecular Np—H...Oh hydrogen bonds are also noted. Chains are connected into a three-dimensional architecture by C—H...F interactions. Based on a literature survey, related molecules/cations adopt a uniform conformation in the solid state based on the letter L.

Novel Substituted Heteroaromatic Piperazine and Piperidine Derivatives as Inhibitors of Human Enterovirus 71 and Coxsackievirus A16

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Xian Zhang

2013-04-01

Full Text Available A series of substituted heteroaromatic piperazine and piperidine derivatives were found through virtual screening based on the structure of human enterovirus 71 capsid protein VP1. The preliminary biological evaluation revealed that compounds 8e and 9e have potent activity against EV71 and Coxsackievirus A16 with low cytotoxicity.

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

Science.gov (United States)

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.

Determination of low concentrations of pyridine in piperidine by gas chromatography and infrared spectroscopy; Determinacion de bajas concentraciones de piperidina en piridina por cromatografia de gases y espectroscopia infrarroja

Energy Technology Data Exchange (ETDEWEB)

Perez Garcia, M. M.; Parellada Bellod, R.

1979-07-01

This paper describes the determination of low amounts of piperidine in pyridine in the concentration range of 0-5%. After an exhausting review of the bibliography on the column selection, the chromatographic separation and determination are made on the following column: 27% Pennwalt- 223; 4% KOH on Gas-Chrom R; 80-100 mesh with flame ionization detector. The retention indexes of both compounds and tho Rohrschneider constants of the phase used are calculated. The minimum detection limit achieved for piperidine is 0,25%. (Author) 25 refs.

Nano magnetite (Fe3O4, an efficient and robust catalyst for the one-pot synthesis of 1-(aryl(piperidin-1-ylmethylnaphthalene-2-ol and 1-(α-amido alkyl-2-naphthol under ultrasound irradiation

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Masoud Mokhtary

2017-01-01

Full Text Available The direct three component reaction via condensation of aldehydes, 2-naphthol and piperidine or acetamide to generate 1-(aryl(piperidin-1-ylmethylnaphthalene-2-ol and N-((2-hydroxy naphthalene-1-yl(arylmethylacetamide derivatives has been carried out over Fe3O4 magnetic nanoparticle with high efficiency under ultrasound irradiation. These reactions were studied under different conditions. In terms of reaction time and yield, it was found that optimum results were obtained for the synthesis of 1-(aryl(piperidin-1-ylmethylnaphthalene-2-ol under solvent free condition and for preparation of N-((2-hydroxynaphthalene-1-yl(arylmethylacetamide in acetic acid under ultrasound irradiation at 80 °C. Clean methodologies, easy workup procedure, and high yields are some advantages of this work.

N-(5-Benzylsulfanyl-1,3,4-thiadiazol-2-yl-2-(piperidin-1-ylacetamide

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D. S. Ismailova

2014-03-01

Full Text Available The title compound, C16H20N4OS2, was synthesized by the reaction of 2-benzylsulfanyl-5-chloroacetamido-1,3,4-thiadiazole and piperidine in a 1:2 ratio. The planes of the acetamide and 1,3,4-thiadiazole units are twisted by 10.8 (4°. The thiadiazole S atom and the acetamide O atom are syn-oriented due to a hypervalent S...O interaction of 2.628 (4 Å. In the crystal, molecules form centrosymmetric dimers via N—H...N hydrogen bonds. These dimers are further connected by C—H...O interactions into (100 layers.

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

Science.gov (United States)

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.

Regio- and stereoselective 1,2-dihydropyridine alkylation/addition sequence for the synthesis of piperidines with quaternary centers.

Science.gov (United States)

Duttwyler, Simon; Chen, Shuming; Lu, Colin; Mercado, Brandon Q; Bergman, Robert G; Ellman, Jonathan A

2014-04-07

The first example of C alkylation of 1,2-dihydropyridines with alkyl triflates and Michael acceptors was developed to introduce quaternary carbon centers with high regio- and diastereoselectivity. Hydride or carbon nucleophile addition to the resultant iminium ion also proceeded with high diastereoselectivity. Carbon nucleophile addition results in an unprecedented level of substitution to provide piperidine rings with adjacent tetrasubstituted carbon atoms. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

4-(Phenylsulfonyl)piperidines: novel, selective, and bioavailable 5-HT(2A) receptor antagonists.

Science.gov (United States)

Fletcher, Stephen R; Burkamp, Frank; Blurton, Peter; Cheng, Susan K F; Clarkson, Robert; O'Connor, Desmond; Spinks, Daniel; Tudge, Matthew; van Niel, Monique B; Patel, Smita; Chapman, Kerry; Marwood, Rose; Shepheard, Sara; Bentley, Graham; Cook, Gina P; Bristow, Linda J; Castro, Jose L; Hutson, Peter H; MacLeod, Angus M

2002-01-17

On the basis of a spirocyclic ether screening lead, a series of acyclic sulfones have been identified as high-affinity, selective 5-HT(2A) receptor antagonists. Bioavailability lacking in the parent, 1-(2-(2,4-difluorophenyl)ethyl)-4-(phenylsulfonyl)piperidine (12), was introduced by using stability toward rat liver microsomes as a predictor of bioavailability. By this means, the 4-cyano- and 4-carboxamidophenylsulfonyl derivatives 26 and 31 were identified as orally bioavailable, brain-penetrant analogues suitable for evaluation in animal models. Bioavailability was also attainable by N substitution leading to the N-phenacyl derivative 35. IKr activity detected through counterscreening was reduced to insignificant levels in vivo with the latter compound.

8-{1-[(4′-Fluoro-[1,1′-biphenyl]-4-ylmethyl]piperidin-4-yl}-3,4-dihydroquinolin-2(1H-one chloroform 0.25-solvate

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Nisar Ullah

2014-02-01

Full Text Available In the asymmetric unit of the title compound, C27H27FN2O·0.25CHCl3, there are two independent molecules (A and B together with a partially disordered chloroform molecule situated about an inversion center. The conformation of the two molecules is very similar. The bridging piperidine rings each have a chair conformation while the piperidin-2-one rings of the quinoline moiety have screw-boat conformations. The benzene rings of the biphenyl moiety are inclined to one another by 26.37 (4 and 23.75 (15° in molecules A and B, respectively. The mean plane of the central piperidine ring [r.m.s. deviation = 0.241 (2 Å in both molecules A and B] is inclined to the benzene ring of the quinoline moiety by 80.06 (4 in A and 83.75 (15° in B, while it is inclined to the adjacent benzene ring of the biphenyl group by 73.623 (15 in A and 75.65 (14° in B. In the crystal, individual molecules are linked by pairs of N—H...O hydrogen bonds, forming A–A and B–B inversion dimers with R22(8 ring motifs. The dimers are stabilized by C—H...O hydrogen bonds and linked via C—H...F and C—H...N hydrogen bonds into a three-dimensional network. Several C—H...π interactions are also present.

Ca{sup 2+} ion sensing by a piperidin-4-one derivative and the effect of β-cyclodextrin complexation on the sensing

Energy Technology Data Exchange (ETDEWEB)

Sumithra, M.; Sivaraj, R.; Selvan, G. Tamil; Selvakumar, P. Mosae; Enoch, Israel V.M.V., E-mail: drisraelenoch@gmail.com

2017-05-15

In this paper, we report the turn-on fluorescence based Ca{sup 2+} ion sensing by an anthracene piperidin-4-one derivative. The compound is obtained using a simple two step synthesis. The compound is characterized using NMR and mass spectral methods. The host-guest complex formation of the compound with β-cyclodextrin is prepared and characterized using fluorescence and 2D ROESY spectroscopy. The compound forms the inclusion complex with a 1:1 stoichiometry. The structure of the host-guest complex is proposed. The Ca{sup 2+} ion selectivity of the compound in its free form and cyclodextrin-bound forms are studied. In both the forms, the piperidin-4-one derivative senses Ca{sup 2+} and in the case of the cyclodextrin encapsulated form it shows a better competitive binding of Ca{sup 2+} in the presence of other metal ions. - Highlights: •An anthracene iminoderivative of 3-methyl-2,6-diphenylpiperidin-4-one is synthesized. •The anthracene moiety of the compound is encapsulated by β-Cyclodextrin. •The compound senses Ca{sup 2+} ion both in water and β-CD media. •β-CD molecule does not interrupt the Ca{sup 2+} ion binding.

Synthesis and biological screening of 4-(1-pyrrolidinyl) piperidine derivatives as effective analgesics

International Nuclear Information System (INIS)

Saify, Z.S.; Malick, T.Z.; Mallick, T.Z.

2014-01-01

A variety of 4(1-pyrrolidinyl) piperidine analogs 2-6 with variable substituents on phenyl ring of phenacyl moiety were synthesized and evaluated for their analgesic inhibitory potential by tail flick method revealed significant analgesic activity. The synthetic compounds exhibit analgesic inhibitory potential was ranging from significant to highly significant activity. Compounds were evaluated by thermal stimuli (tail immersion method) at the dose of 50 mg/kg of body weight. The compounds 2-5 showed significant and highly significant analgesic activity. Pethidine was used as reference drug. Same compounds tested at the dose of 75mg/kg of body weight showed toxicity. The size of the substituent, electron donating or withdrawing affect of substituents as well as the position of substituent on phenyl ring affected the activity. These compounds could be considered to develop a new class of analgesics. (author)

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

Science.gov (United States)

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.

Synthesis and Characterization of the Adducts of Morpholinedithioccarbamate Complexes of Oxovanadium (IV, Nickel(II, and Copper(II with Piperidine and Morpholine

Directory of Open Access Journals (Sweden)

Mousami Sharma

2012-01-01

Full Text Available A series of 1:1 adducts of bis(morpholinedithiocarbamato complex of VO(IV, 1:1 and 1:2 adducts of bis(morpholinedithiocarbamato complexes of Ni(II and Cu(II with piperidine and morpholine have been synthesized and characterized by elemental analysis, molar conductance, magnetic susceptibility, IR, UV-Vis, and TGA/DTA techniques. Analytical data reveals that VO(IV complex forms only 1:1 adducts with the formula [VO(morphdtc2L].H2O while Ni(II and Cu(II complexes form both 1:1 and 1:2 adducts with 1:1 adducts having general formula Ni(morphdtc2.L and Cu(morphdtc2.L and 1:2 adducts having general formula Ni(morphdtc2.L2 and Cu(morphdtc2.L2 (morphdtc = morpholinedithiocarbamate, L = morpholine and piperidine. Antifungal activity of some complexes has been carried out against the fungal strain Fusarium oxysporium. Thermal studies indicate a continuous weight loss. A square pyramidal geometry has been proposed for the 1:1 adducts of Ni(II and Cu(II complexes while an octahedral geometry has been proposed for the 1:1 adducts of VO(IV and for the 1:2 adducts of Ni(II and Cu(II complexes.

Convergent Synthesis of Piperidines by the Union of Conjugated Alkynes with Imines: A Unique Regioselective Bond Construction for Heterocycle Synthesis

Science.gov (United States)

Chen, Ming Z.; Micalizio, Glenn C.

2009-01-01

A two-step process is described for the union of aromatic imines, conjugated alkynes and aldehydes that results in a stereoselective synthesis of highly substituted piperidines. This synthetic process has been made possible by defining a unique regioselective functionalization of conjugated alkynes that establishes a suitably functionalized substrate for subsequent heterocycle-forming cationic annulation. Given the flexibility of the coupling process, heterocycles can be accessed through a process that establishes up to four stereogenic centers and four fused rings. PMID:19817447

The synthesis and spectroscopic study of stable free radicals related to piperidine-n-oxyl, including a stable bi-radical

International Nuclear Information System (INIS)

Briere, R.

1965-07-01

A new synthesis of di-tert-butyl nitroxide using the reaction between tert-butyl magnesium chloride and nitro-tert-butane is presented in the first section. Synthesis and investigation of stable free piperidine-N-oxyl radicals are described in the second section. All these nitroxides have been characterised by their I. R., U. V. and E. P. R. absorption spectra. The final section contains a description of the synthesis of a stable bi-radical of the nitroxide type by condensation of 2,2, 6, 6-tetramethyl-piperid-4-one-l-oxyl with hydrazine. (author) [fr

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.

Science.gov (United States)

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.

Synthesis of 3-substituted 4-piperidinones via a one-pot tandem oxidation-cyclization-oxidation process: stereodivergent reduction to 3,4-disubstituted piperidines.

Science.gov (United States)

Bahia, Perdip S; Snaith, John S

2004-04-30

A novel approach to 3-substituted 4-piperidinones is described. The one-pot tandem oxidation-cyclization-oxidation of unsaturated alcohols 1a-e by PCC or PCC and trifluoromethanesulfonic acid affords piperidinones 2a-e in good yield. Reduction of 2a-e by L-Selectride gives the corresponding cis 3,4-disubstituted piperidines with diastereomeric ratios of >99:1. By contrast, reduction of 2a-e by Al-isopropoxydiisobutylalane gives the trans products with diastereomeric ratios of up to 99:1.

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

Science.gov (United States)

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.

Some bromo phenyl piperidine derivatives having plasmepsin inhibition with potent analgesia

International Nuclear Information System (INIS)

Rafiq, K.; Saify, Z.S.

2016-01-01

The present study was conducted to evaluate the synthesized 4-(4?-Bromophenyl)-4-hydroxy piperdine derivatives for plasmepsin inhibition (antimalarial activity) and analgesic response to develop excellent moiety to work in malaria. The plasmepsin II and cathepsin D (Biodesign International, USA) assays were measured using a fluorescence resonance energy transfer (FRET) method. The inhibition of enzyme was done (in triplicates) in 96 well plate format and response were obtained on a Perkin Elmer LS55 Fluorescence spectrometer with an excitation and emission wavelengths of 336 and 490 nm, respectively and analgesic activity of synthesized derivatives of 4-(4-Bromophenyl)-4-hydroxy piperidine was conducted by Eddy's hot plate method in albino mice by providing standard colony conditions using Pethidine as standard drug. These novel compounds having the parent moiety 4-(4-Bromophenyl)-4-hydroxy piperdine were found to prove strong inhibition towards plasmepsin enzyme with 8-10 IC50 in micro M and highly significant analgesic response in albino mice. The current studies suggest that the designed molecules were found to work both on cellular level and also on the symptoms of disease as the headache, fever and muscle aches are the very common and initial symptoms associated with malaria and hence the molecules discovered as excellent analgesics. (author)

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

Directory of Open Access Journals (Sweden)

I. S. Ahmed Farag

2014-01-01

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

Syntheses and biological evaluation of {sup 18}F-labeled 3-(1-benzyl-piperidin-4-yl)-1-(1-methyl-1H-indol-3-yl)propan-1-ones for in vivo mapping of acetylcholinesterase

Energy Technology Data Exchange (ETDEWEB)

Choe, Y.-S. E-mail: yschoe@samsung.co.kr; Oh, S.-J.; Shim, Insop; Naruto, Shunji; Chi, Dae Yoon; Kim, Sang Eun; Lee, Kyung-Han; Choi, Yong; Kim, B.-T

2000-04-01

We synthesized novel {sup 18}F-labeled acetylcholinesterase (AChE) inhibitors, 3-[1-(3- and 4-[{sup 18}F]fluoromethylbenzyl)piperidin-4-yl]-1-(1-methyl-1H-indol-3-yl)propan- 1-ones ([{sup 18}F]1 and [{sup 18}F]2) and 3-[1-(4-[{sup 18}F]fluorobenzyl)piperidin-4-yl]-1-(1-methyl-1H-indol-3-yl)propan- 1-one ([{sup 18}F]3) in high yields (decay-corrected, 25%-40%) and with high effective specific activities (>37 GBq/{mu}mol). Tissue distribution studies of the [{sup 18}F]1 and the [{sup 18}F]3 in mice showed the nonspecific bindings in brain regions, with metabolic defluorination of the [{sup 18}F]1. The result suggests that these radioligands may not be suitable agents for in vivo mapping of AChE, despite their potent in vitro anti-AChE activities.

Neurotoxicity of Prosopis juliflora: from Natural Poisoning to Mechanism of Action of Its Piperidine Alkaloids.

Science.gov (United States)

da Silva, Victor Diogenes Amaral; da Silva, André Mario Mendes; E Silva, Juliana Helena Castro; Costa, Silvia Lima

2018-01-16

Prosopis juliflora was introduced in northeastern Brazil in the 1940s, and since then, it has been available as an alternative for animal nutrition. However, the consumption of P. juliflora as main or sole source of food causes an illness in animals known locally as "cara torta" disease. Cattle and goats experimentally intoxicated presents neurotoxic damage in the central nervous system. Histologic lesions were mainly characterized by vacuolation and loss of neurons in trigeminal motor nuclei. Furthermore, mitochondrial damage in neurons and gliosis was reported in trigeminal nuclei of intoxicated cattle. Studies, using neural cell cultures, have reproduced the main cellular alterations visualized in cara torta disease and contributed to understanding the mechanism of action piperidine alkaloids, the main neurotoxic compound in P. juliflora leaves and pods. Here, we will present aspects of the biological and toxicological properties of P. juliflora and its pharmacologically active compounds.

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

Science.gov (United States)

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...

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

Science.gov (United States)

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

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

Science.gov (United States)

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

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

Science.gov (United States)

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.

5-(Piperidin-4-yl)-3-Hydroxypyrazole: A Novel Scaffold for Probing the Orthosteric γ-Aminobutyric Acid Type A Receptor Binding Site

DEFF Research Database (Denmark)

Krall, Jacob; Kongstad, Kenneth Thermann; Nielsen, Birgitte

2014-01-01

A series of bioisosteric N1- and N2-substituted 5-(piperidin-4-yl)-3-hydroxypyrazole analogues of the partial GABAAR agonists 4-PIOL and 4-PHP have been designed, synthesized, and characterized pharmacologically. The unsubstituted 3-hydroxypyrazole analogue of 4-PIOL (2 a; IC50∼300 μM) is a weak...... indicate that the N1-substituted analogues of 4-PIOL and 4-PHP, 2 a–k, and previously reported 3-substituted 4-PHP analogues share a common binding mode to the orthosteric binding site in the receptor. Interestingly, the core scaffold of the N2-substituted analogues of 4-PIOL and 4-PHP, 3 b...

Synthesis of bromo phenyl piperidine derivatives and the study of their effects on neurotransmitters and strong compatibility with alpha amylase enzyme

International Nuclear Information System (INIS)

Rafiq, K.; Zarreen, T.

2016-01-01

In the last few decades several novel derivatives of piperidine have been synthesized for their CNS potentials and proved to be effective in the treatment of psychiatric and other CNS disorders. The present study is the demonstration of same phenomenon through which a new series of 4-(4-Bromophenyl)-4-hydroxypiperidine derivatives were synthesized via substitution at nitrogen and tested for aectylcholinestrase and butyrylcholinestrase activity by TLC bioautographic method and showed that among these synthesized moieties two were found to produce effects on these neurotransmitters. The synthesized compounds were also assessed further for their interaction with digestive enzymes (alpha-amylase) in vitro by plate method and all the compounds showed good interaction with amylase enzyme. (author)

In vivo evaluation in rats of [18F]1-(2-fluoroethyl)-4-[(4-cyanophenoxy)methyl]piperidine as a potential radiotracer for PET assessment of CNS sigma-1 receptors

International Nuclear Information System (INIS)

Waterhouse, Rikki N.; Chang, Raymond C.; Zhao, Jun; Carambot, Patty E.

2006-01-01

Introduction: Sigma-1 receptors are expressed throughout the mammalian central nervous system (CNS) and are implicated in several psychiatric disorders, including schizophrenia and depression. We have recently evaluated the high-affinity (K D =0.5±0.2 nM, log P=2.9) sigma-1 receptor radiotracer [ 18 F]1-(3-fluoropropyl)-4-(4-cyanophenoxymethyl)piperidine, [ 18 F]FPS, in humans. In contrast to appropriate kinetics exhibited in baboon brain, in the human CNS, [ 18 F]FPS does not reach pseudoequilibrium by 4 h, supporting the development of a lower-affinity tracer [Waterhouse RN, Nobler MS, Chang RC, Zhou Y, Morales O, Kuwabara H, et al. First evaluation of the sigma-1 receptor radioligand [ 18 F]1-3-fluoropropyl-4-((4-cyanophenoxy)-methyl)piperidine ([ 18 F]FPS) in healthy humans. Neuroreceptor Mapping 2004, July 15-18th, Vancouver, BC Canada 2004]. We describe herein the in vivo evaluation in rats of [ 18 F]1-(2-fluoroethyl)-4-[(4-cyanophenoxy)methyl]piperidine ([ 18 F]SFE) (K D =5 nM, log P=2.4), a structurally similar, lower-affinity sigma-1 receptor radioligand. Methods: [ 18 F]SFE was synthesized (n=4) as previously described in good yield (54±6% EOB), high specific activity (2.1±0.6 Ci/μmol EOS) and radiochemical purity (98±1%) and evaluated in awake adult male rats. Results: Similar to [ 18 F]FPS, regional brain radioactivity concentrations [percentage of injected dose per gram of tissue (%ID/g), 15 min] for [ 18 F]SFE were highest in occipital cortex (1.86±0.06 %ID/g) and frontal cortex (1.76±0.38 %ID/g), and lowest in the hippocampus (1.01±0.02%ID/g). Unlike [ 18 F]FPS, [ 18 F]SFE cleared from the brain with ∼40% reduction in peak activity over a 90-min period. Metabolite analysis (1 h) revealed that [ 18 F]SFE was largely intact in the brain. Blocking studies showed a large degree (>80%) of saturable binding for [ 18 F]SFE in discrete brain regions. Conclusions: We conclude that [ 18 F]SFE exhibits excellent characteristics in vivo and may provide

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

Science.gov (United States)

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.

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

OpenAIRE

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

2012-01-01

We here report a study of the intramolecular amination of sp3 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 BF3•OEt2 to effect imine formation and HT-cyclization, leading to 2-aryl-piperidines 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 flexib...

Synthesis, radiofluorination and first evaluation of [{sup 18}F]fluorophenylsulfonyl- and [{sup 18}F]fluorophenylsulfinyl-piperidines as serotonin 5-HT{sub 2A} receptor antagonists for PET

Energy Technology Data Exchange (ETDEWEB)

Muehlhausen, Ute; Sihver, Wiebke [Institute of Neuroscience and Medicine, INM-5: Nuclear Chemistry, Forschungszentrum Juelich GmbH, 52425 Juelich (Germany); Ermert, Johannes, E-mail: j.ermert@fz-juelich.d [Institute of Neuroscience and Medicine, INM-5: Nuclear Chemistry, Forschungszentrum Juelich GmbH, 52425 Juelich (Germany); Coenen, Heinz H. [Institute of Neuroscience and Medicine, INM-5: Nuclear Chemistry, Forschungszentrum Juelich GmbH, 52425 Juelich (Germany)

2010-07-15

In psychiatric disorders, 5-HT{sub 2A} receptors play an important role. In order to study these receptors in vivo by positron emission tomography (PET), there is an increasing interest for subtype selective and high affinity radioligands. Up to now, no optimal radiotracer is available. Thus, 1-(2,4-difluorophenethyl)-4-(4-fluorophenylsulfonyl)piperidine (9), possessing high affinity and sufficient subtype selectivity for 5-HT{sub 2A} receptors, and 1-(2,4-difluorophenethyl)-4-(4-fluorophenylsulfinyl)piperidine (15) have been {sup 18}F-labelled by a nucleophilic one-step reaction. Both radiotracers could be prepared and isolated within 45 min, [{sup 18}F]9 in a radiochemical yield (RCY) of 34.5{+-}8% and [{sup 18}F]15 of 9.5{+-}2.5%. The K{sub i} values of 9 and 15 at 5-HT{sub 2A} receptors towards [{sup 3}H]ketanserin were determined to be 1.9{+-}0.6 and 198{+-}8 nM, respectively. Autoradiography with [{sup 18}F]9 and [{sup 18}F]15 on rat brain sections showed a very high nonspecific binding of >80% for [{sup 18}F]9 and 30% to 40% nonspecific binding for [{sup 18}F]15; however, it is still too high in order to compensate for its lower affinity. Even though the affinity of 9 is more promising compared with 15, the high nonspecific binding of both radiofluorinated tracers in rat brain does not recommend those as an in vivo PET imaging agent for serotonin 5-HT{sub 2A} receptors in humans.

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

Energy Technology Data Exchange (ETDEWEB)

Kim, Kyung Jin [Department of Biomaterials Science and Engineering, Yonsei University, Seoul 120-749 (Korea, Republic of); Lee, Myoung-Su; Jo, Keunae [Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749 (Korea, Republic of); Hwang, Jae-Kwan, E-mail: jkhwang@yonsei.ac.kr [Department of Biomaterials Science and Engineering, Yonsei University, Seoul 120-749 (Korea, Republic of); Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749 (Korea, Republic of); Translational Research Center for Protein Functional Control, Yonsei University, Seoul 120-749 (Korea, Republic of)

2011-07-22

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 remains 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

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

International Nuclear Information System (INIS)

Kim, Kyung Jin; Lee, Myoung-Su; Jo, Keunae; Hwang, Jae-Kwan

2011-01-01

Highlights: → Piperidine alkaloids from Piperretrofractum Vahl. (PRPAs), including piperine, pipernonaline, and dehydropipernonaline, are isolated as the anti-obesity constituents. → PRPA administration significantly reduces body weight gain without altering food intake and fat pad mass. → PRPA reduces high-fat diet-induced triglyceride accumulation in liver. → PRPAs attenuate HFD-induced obesity by activating AMPK and PPARδ, 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 remains 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 δ (PPARδ) transactivation assay. The molecular mechanism was investigated in 3T3-L1 adipocytes and L6 myocytes. PRPA treatment activated AMP-activated protein kinase (AMPK) signaling and PPARδ 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

In vivo evaluation in rats of [{sup 18}F]1-(2-fluoroethyl)-4-[(4-cyanophenoxy)methyl]piperidine as a potential radiotracer for PET assessment of CNS sigma-1 receptors

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Waterhouse, Rikki N. [Department of Psychiatry, Columbia University, New York, NY 10032 (United States) and Department of Radiology, Columbia University, New York, NY 10032 (United States) and Neurobiology and Imaging Program, Department of Biological Psychiatry, New York State Psychiatric Institute, New York, NY 10032 (United States)]. E-mail: rnw7@columbia.edu; Chang, Raymond C. [Department of Psychiatry, Columbia University, New York, NY 10032 (United States); Neurobiology and Imaging Program, Department of Biological Psychiatry, New York State Psychiatric Institute, New York, NY 10032 (United States); Zhao, Jun [Department of Psychiatry, Columbia University, New York, NY 10032 (United States); Neurobiology and Imaging Program, Department of Biological Psychiatry, New York State Psychiatric Institute, New York, NY 10032 (United States); Carambot, Patty E. [Department of Psychiatry, Columbia University, New York, NY 10032 (United States); Neurobiology and Imaging Program, Department of Biological Psychiatry, New York State Psychiatric Institute, New York, NY 10032 (United States)

2006-02-15

Introduction: Sigma-1 receptors are expressed throughout the mammalian central nervous system (CNS) and are implicated in several psychiatric disorders, including schizophrenia and depression. We have recently evaluated the high-affinity (K {sub D}=0.5{+-}0.2 nM, log P=2.9) sigma-1 receptor radiotracer [{sup 18}F]1-(3-fluoropropyl)-4-(4-cyanophenoxymethyl)piperidine, [{sup 18}F]FPS, in humans. In contrast to appropriate kinetics exhibited in baboon brain, in the human CNS, [{sup 18}F]FPS does not reach pseudoequilibrium by 4 h, supporting the development of a lower-affinity tracer [Waterhouse RN, Nobler MS, Chang RC, Zhou Y, Morales O, Kuwabara H, et al. First evaluation of the sigma-1 receptor radioligand [{sup 18}F]1-3-fluoropropyl-4-((4-cyanophenoxy)-methyl)piperidine ([{sup 18}F]FPS) in healthy humans. Neuroreceptor Mapping 2004, July 15-18th, Vancouver, BC Canada 2004]. We describe herein the in vivo evaluation in rats of [{sup 18}F]1-(2-fluoroethyl)-4-[(4-cyanophenoxy)methyl]piperidine ([{sup 18}F]SFE) (K {sub D}=5 nM, log P=2.4), a structurally similar, lower-affinity sigma-1 receptor radioligand. Methods: [{sup 18}F]SFE was synthesized (n=4) as previously described in good yield (54{+-}6% EOB), high specific activity (2.1{+-}0.6 Ci/{mu}mol EOS) and radiochemical purity (98{+-}1%) and evaluated in awake adult male rats. Results: Similar to [{sup 18}F]FPS, regional brain radioactivity concentrations [percentage of injected dose per gram of tissue (%ID/g), 15 min] for [{sup 18}F]SFE were highest in occipital cortex (1.86{+-}0.06 %ID/g) and frontal cortex (1.76{+-}0.38 %ID/g), and lowest in the hippocampus (1.01{+-}0.02%ID/g). Unlike [{sup 18}F]FPS, [{sup 18}F]SFE cleared from the brain with {approx}40% reduction in peak activity over a 90-min period. Metabolite analysis (1 h) revealed that [{sup 18}F]SFE was largely intact in the brain. Blocking studies showed a large degree (>80%) of saturable binding for [{sup 18}F]SFE in discrete brain regions. Conclusions

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.

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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.

Autophagy protects against neural cell death induced by piperidine alkaloids present in Prosopis juliflora (Mesquite).

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Silva, Victor D A; Cuevas, Carlos; Muñoz, Patricia; Villa, Monica; Ahumada-Castro, Ulises; Huenchuguala, Sandro; Santos, Cleonice C Dos; Araujo, Fillipe M DE; Ferreira, Rafael S; Silva, Vanessa B DA; Silva, Juliana H C E; Soares, Érica N; Velozo, Eudes S; Segura-Aguilar, Juan; Costa, Silvia L

2017-01-01

Prosopis juliflora is a shrub that has been used to feed animals and humans. However, a synergistic action of piperidine alkaloids has been suggested to be responsible for neurotoxic damage observed in animals. We investigated the involvement of programmed cell death (PCD) and autophagy on the mechanism of cell death induced by a total extract (TAE) of alkaloids and fraction (F32) from P. juliflora leaves composed majoritary of juliprosopine in a model of neuron/glial cell co-culture. We saw that TAE (30 µg/mL) and F32 (7.5 µg/mL) induced reduction in ATP levels and changes in mitochondrial membrane potential at 12 h exposure. Moreover, TAE and F32 induced caspase-9 activation, nuclear condensation and neuronal death at 16 h exposure. After 4 h, they induced autophagy characterized by decreases of P62 protein level, increase of LC3II expression and increase in number of GFP-LC3 cells. Interestingly, we demonstrated that inhibition of autophagy by bafilomycin and vinblastine increased the cell death induced by TAE and autophagy induced by serum deprivation and rapamycin reduced cell death induced by F32 at 24 h. These results indicate that the mechanism neural cell death induced by these alkaloids involves PCD via caspase-9 activation and autophagy, which seems to be an important protective mechanism.

Autophagy protects against neural cell death induced by piperidine alkaloids present in Prosopis juliflora (Mesquite

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VICTOR D.A. SILVA

Full Text Available ABSTRACT Prosopis juliflora is a shrub that has been used to feed animals and humans. However, a synergistic action of piperidine alkaloids has been suggested to be responsible for neurotoxic damage observed in animals. We investigated the involvement of programmed cell death (PCD and autophagy on the mechanism of cell death induced by a total extract (TAE of alkaloids and fraction (F32 from P. juliflora leaves composed majoritary of juliprosopine in a model of neuron/glial cell co-culture. We saw that TAE (30 µg/mL and F32 (7.5 µg/mL induced reduction in ATP levels and changes in mitochondrial membrane potential at 12 h exposure. Moreover, TAE and F32 induced caspase-9 activation, nuclear condensation and neuronal death at 16 h exposure. After 4 h, they induced autophagy characterized by decreases of P62 protein level, increase of LC3II expression and increase in number of GFP-LC3 cells. Interestingly, we demonstrated that inhibition of autophagy by bafilomycin and vinblastine increased the cell death induced by TAE and autophagy induced by serum deprivation and rapamycin reduced cell death induced by F32 at 24 h. These results indicate that the mechanism neural cell death induced by these alkaloids involves PCD via caspase-9 activation and autophagy, which seems to be an important protective mechanism.

Genetic variation of piperidine alkaloids in Pinus ponderosa: a common garden study.

Science.gov (United States)

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

catena-Poly[lead(II-[μ-2,4-diamino-6-(piperidin-1-ylpyrimidine N-oxide-κ2O:O]di-μ-iodido

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Maryam Ranjbar

2009-07-01

Full Text Available The N-oxide O atom of the minoxidil unit in the 1/1 adduct with lead(II iodide, [PbI2(C9H15N5O]n, bridges two PbII atoms, as do each of the I atoms. The bridging interactions give rise to a linear chain motif that propagates along the a axis of the orthorhombic unit cell. The coordination sphere around the six-coordinate PbII atom is a distorted ψ-monocapped octahedron in which the stereochemically active lone pair caps one of the faces defined by the O and I atoms forming the longer Pb—O or Pb—I bonds. The PbII atom lies on a mirror plane; the mirror plane is perpendicular to the pyrimidine ring and it bisects the piperidine ring. The aromatic ring is disordered about the mirror plane with respect to the 1-nitrogen and 5-carbon atoms.

Synthesis and evaluation of 1-[l brace]1-[5-(2'-[[sup 18]F]fluoroethyl)-2-thienyl]cyclohexyl[r brace]piperidine as a potential in vivo radioligand for the NMDA receptor-channel complex. [N-methyl-D-aspartate receptor

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Orita, Kazuhiro; Sasaki, Shigeki; Maeda, Minoru [Kyushu Univ., Fukuoka (Japan). Faculty of Pharmaceutical Sciences; Hashimoto, Atsushi; Nishikawa, Toru [National Inst. of Neuroscience, Tokyo (Japan); Yugami, Tomoko; Umezu, Kohei [Mitsubishi Kasei Corp., Yokohama (Japan). Research Center

1993-10-01

1-[l brace]1-[5-(2'-[[sup 18]F]Fluoroethyl)-2-thienyl]cyclohexyl[r brace]piperidine ([sup 18]FE-TCP) was prepared a fluorine-substituted analogue of the potent NMDA receptor channel blocker, 1-[1-(2-thienyl)cyclohexyl]piperidine (TCP), by the mesylate displacement with [[sup 18]F]fluoride ion with isolated radiochemical yields of 6-12%, and the synthesis time including a two step HPLC purification was 120 min. The regional distribution in rat brain after i.v. injection of [sup 18]FE-TCP was heterogeneous and similar to the known distribution of phencyclidine recognition sites, with hippocampus-cerebellum, striatum-cerebellum and cerebral cortex-cerebellum concentration ratios of 2.08, 1.7 and 1.54, respectively, 15 min post-injection. Furthermore, this localized regional cerebral distribution was blocked by co-injection with the unlabelled FE-TCP or pretreatment with cis-2-hydroxymethyl-r-1-(N-piperidyl)-1-(2-thienyl)cyclohexane, with the greatest reductions seen in the hippocampus followed by the striatum and cerebral cortex. However, relatively low receptor binding affinity and high non-specific binding due to its high lipophilicity suggest that [sup 18]FE-TCP may not be a suitable radioligand for in vivo PET investigations of the NMDA receptor-channel complex. (Author).

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

Science.gov (United States)

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.

Imino Diels-Alder-Based Construction of a Piperidine A-Ring Unit for Total Synthesis of the Marine Hepatotoxin Cylindrospermopsin.

Science.gov (United States)

Heintzelman, Geoffrey R.; Weinreb, Steven M.; Parvez, Masood

1996-07-12

The synthesis of a piperidine A-ring precursor to the alkaloid cylindrospermopsin (1) is described. The initial approach to the A-ring precursor focused on the imino Diels-Alder reaction of diene 8 with ethyl (N-tosylimino)acetate (9) to form the cycloadduct 10 as a single stereoisomer. However, all attempts to convert ester 10 to a requisite diene such as 5 were unsuccessful. An alternative strategy involved the Diels-Alder cycloaddition of N-tosylimine 9 with oxygenated diene 19 under either thermal or Lewis acid-catalyzed conditions to produce a mixture of cis and trans enones 20 and 21. Although the undesired cis-enone 20 was the major product under all reaction conditions, it could be converted to the desired trans enone 21 by acid-catalyzed isomerization. Copper-mediated conjugate addition of vinylmagnesium bromide to cis-enone 20 followed by stereoselective ketone reduction with L-Selectride produced alcohol 23, whose structure was confirmed by X-ray crystallography. Similarly, trans-enone 21 was converted to alcohol 25 whose structure and stereochemistry were also established by X-ray analysis. Alcohol 25 was then protected as the silyl ether 26, which was hydroborated at the terminal olefin to produce primary alcohol ester 28having the stereochemistry and functionality needed for cylindrospermopsin.

Discovery of novel piperidine-substituted indolylarylsulfones as potent HIV NNRTIs via structure-guided scaffold morphing and fragment rearrangement.

Science.gov (United States)

Li, Xiao; Gao, Ping; Huang, Boshi; Zhou, Zhongxia; Yu, Zhao; Yuan, Zheng; Liu, Huiqing; Pannecouque, Christophe; Daelemans, Dirk; De Clercq, Erik; Zhan, Peng; Liu, Xinyong

2017-01-27

To further explore the chemical space around the entrance channel of HIV-1 reverse transcriptase (RT), a series of novel indolylarylsulfones (IASs) bearing N-substituted piperidine at indole-2-carboxamide were identified as potent HIV NNRTIs by structure-guided scaffold morphing and fragment rearrangement. All the IASs exhibited moderate to excellent potency against wild-type HIV-1 with EC 50 values ranging from 0.62 μM to 0.006 μM 8 (EC 50  = 6 nM) and 18 (EC 50  = 9 nM) were identified as the most potent compounds, which were more active than NVP and DLV, and reached the same order of EFV and ETV. Furthermore, most compounds maintained high activity agaist various single HIV-1 mutants (L100I, K103N, E138K, Y181C) as well as one double mutant (F227L/V106A) with EC 50 values in low-micromolar to double-digit nanomolar concentration ranges. Especially, 8 displayed outstanding potency against L100I (EC 50  = 17 nM with a 2.8-fold resistance ratio) and 18 was relatively more potent to E138K mutant (EC 50  = 43 nM with a 4.7-fold resistance ratio). Preliminary SARs and molecular modeling studies were also discussed in detail, which may provide valuable insights for further optimization. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Leishmanicidal activity of the crude extract, fractions and major piperidine alkaloids from the flowers of Senna spectabilis.

Science.gov (United States)

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.

Synthesis and evaluation of a series of 2-substituted-5-thiopropylpiperazine (piperidine)-1,3,4-oxadiazoles derivatives as atypical antipsychotics.

Science.gov (United States)

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 and evaluation of a series of 2-substituted-5-thiopropylpiperazine (piperidine-1,3,4-oxadiazoles derivatives as atypical antipsychotics.

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Yin Chen

Full Text Available BACKGROUND: 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. METHODOLOGY/PRINCIPAL FINDINGS: 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. CONCLUSIONS/SIGNIFICANCE: 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 of Quinuclidines by Intramolecular Silver-​Catalysed Amine Additions to Alkynes

NARCIS (Netherlands)

Breman, A.C.; Ruiz-Olalla, A.; van Maarseveen, J.H.; Ingemann, S.; Hiemstra, H.

2014-01-01

A new method has been developed for the synthesis of 2-​alkylidenequinuclidines based on a silver triflate catalyzed intramol. hydroamination of 4-​(prop-​2-​ynyl)​piperidines. Monosubstituted piperidines reacted less efficiently than cis-​disubstituted piperidines, and the reaction was selective

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.

Science.gov (United States)

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

Synthesis of bicyclic alkaloids from the iridoid antirrhinoside

DEFF Research Database (Denmark)

Frederiksen, Signe Maria

The present thesis describes the isolation of the iridoid glucoside antirrhinoside from Antirrhinum majus, and the approaches made towards its transformation into analogues of biologically active compounds, with special interest in syntheses of bicyclic alkaloids.A synthetic piperidine monoterpene...... or by reduction using lithium aluminum hydride. The piperidines were subjected to hydrogenation to remove the N-benzyl group. The compounds were tested for hypoglycaemic activity by Novo Nordisk, but no activity was observed.Another approach towards a synthetic piperidine monoterpene was attempted. The strategy...... involved preparation of a diol, which through treatment of its ditosyl derivative with an amine would afford a piperidine monoterpene. Antirrhinoside was protected as its 5,6-O-monoacetonide via its 5,6:4',6'-O-diacetonide. The 5,6-O-isopropylidene-derivative was hydrogenated to give the 3,4-dihydro...

Racemic methyl 3,10-dioxa-2-azatricyclo[6.2.1.02,6]undecane-4- carboxylate

KAUST Repository

Moosa, Basem; Fazal, Atif; Ali, Shaikh A.; Fettouhi, Mohammed

2011-01-01

The structure of the racemic title compound, C10H 15NO4, consists of a tricyclic skeleton comprising a six-membered piperidine ring and five-membered isoxazolidine and tetrahydrofuran rings. The piperidine ring adopts a distorted chair conformation

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

Science.gov (United States)

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.

Racemic methyl 3,10-dioxa-2-azatricyclo[6.2.1.02,6]undecane-4- carboxylate

KAUST Repository

Moosa, Basem

2011-04-29

The structure of the racemic title compound, C10H 15NO4, consists of a tricyclic skeleton comprising a six-membered piperidine ring and five-membered isoxazolidine and tetrahydrofuran rings. The piperidine ring adopts a distorted chair conformation, while the isoxazolidine and tetrahydrofuran rings have envelope conformations.

Racemic methyl 3,10-dioxa-2-azatricyclo[6.2.1.02,6]undecane-4-carboxylate

Directory of Open Access Journals (Sweden)

Basem A. Moosa

2011-05-01

Full Text Available The structure of the racemic title compound, C10H15NO4, consists of a tricyclic skeleton comprising a six-membered piperidine ring and five-membered isoxazolidine and tetrahydrofuran rings. The piperidine ring adopts a distorted chair conformation, while the isoxazolidine and tetrahydrofuran rings have envelope conformations.

Novel selective kappa-opioid ligands.

Science.gov (United States)

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.

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.

Science.gov (United States)

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.

BF2.649 [1-{3-[3-(4-Chlorophenyl)propoxy]propyl}piperidine, hydrochloride], a nonimidazole inverse agonist/antagonist at the human histamine H3 receptor: Preclinical pharmacology.

Science.gov (United States)

Ligneau, X; Perrin, D; Landais, L; Camelin, J-C; Calmels, T P G; Berrebi-Bertrand, I; Lecomte, J-M; Parmentier, R; Anaclet, C; Lin, J-S; Bertaina-Anglade, V; la Rochelle, C Drieu; d'Aniello, F; Rouleau, A; Gbahou, F; Arrang, J-M; Ganellin, C R; Stark, H; Schunack, W; Schwartz, J-C

2007-01-01

Histamine H3 receptor inverse agonists are known to enhance the activity of histaminergic neurons in brain and thereby promote vigilance and cognition. 1-{3-[3-(4-Chlorophenyl)propoxy]propyl}piperidine, hydrochloride (BF2.649) is a novel, potent, and selective nonimidazole inverse agonist at the recombinant human H3 receptor. On the stimulation of guanosine 5'-O-(3-[35S]thio)triphosphate binding to this receptor, BF2.649 behaved as a competitive antagonist with a Ki value of 0.16 nM and as an inverse agonist with an EC50 value of 1.5 nM and an intrinsic activity approximately 50% higher than that of ciproxifan. Its in vitro potency was approximately 6 times lower at the rodent receptor. In mice, the oral bioavailability coefficient, i.e., the ratio of plasma areas under the curve after oral and i.v. administrations, respectively, was 84%. BF2.649 dose dependently enhanced tele-methylhistamine levels in mouse brain, an index of histaminergic neuron activity, with an ED50 value of 1.6 mg/kg p.o., a response that persisted after repeated administrations for 17 days. In rats, the drug enhanced dopamine and acetylcholine levels in microdialysates of the prefrontal cortex. In cats, it markedly enhanced wakefulness at the expense of sleep states and also enhanced fast cortical rhythms of the electroencephalogram, known to be associated with improved vigilance. On the two-trial object recognition test in mice, a promnesiant effect was shown regarding either scopolamine-induced or natural forgetting. These preclinical data suggest that BF2.649 is a valuable drug candidate to be developed in wakefulness or memory deficits and other cognitive disorders.

A method for producing lower olefins

Energy Technology Data Exchange (ETDEWEB)

Lemayev, N.V.; Grigorovich, V.A.; Isayev, V.A.; Liakumovich, A.G.; Mitrofanov, A.I.; Orekhov, A.I.; Trifonov, S.V.; Vernov, P.A.

1983-01-01

In the known method for producing lower olefins by pyrolysis of a hydrocarbon raw material in the presence of an initiator which contains ammonia, in order to increase the output of the target products, morpholine or piperidine are additionally introduced into the initiator in a volume of 0.00001 to 0.1 percent each, converted for the raw material. The compounds to be added may be introduced into the pyrolysis zone by dissolving them in the hydrocarbon raw material or in water, which forms vapors with dilution of the raw material being subjected to pyrolysis. The increase in the outputs of the lower olefins in the process through the use of additives may be explained by the synergistic effect of the mixture of ammonia, morpholine and piperidine used. With benzine pyrolysis without the additives the output of ethylene is 24.1 percent; in comparable conditions with additives of ammonia or morpholine alone, or of piperidine alone, the outputs are 24.0, 26.2 and 25.8 percent, respectively. With the joint presence of ammonia and piperidine, the output of ethylene reaches 27.2 percent and with the addition of ammonia and morpholine, it reaches 27.4 percent.

The synthesis and spectroscopic study of stable free radicals related to piperidine-n-oxyl, including a stable bi-radical; Syntheses et etudes spectroscopiques de radicaux libres piperidiniques et d'un biradical stable, du type nitroxyde

Energy Technology Data Exchange (ETDEWEB)

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

1967-06-01

A new synthesis of di-tert-butyl nitroxide using the reaction between tert-butyl magnesium chloride and nitro-tert-butane is presented in the first section. Synthesis and investigation of stable free piperidine-N-oxyl radicals are described in the second section. All these nitroxides have been characterised by their I. R., U. V. and E. P. R. absorption spectra. The final section contains a description of the synthesis of a stable bi-radical of the nitroxide type by condensation of 2,2, 6, 6-tetramethyl-piperid-4-one-l-oxyl with hydrazine. (author) [French] La premiere partie expose une nouvelle methode de synthase du di-t-butyl nitroxyde, par action d'halogenures de t-butyl magnesium sur le nitro-t-butane (Rdt maximum 45 pour cert, purete 86 pour cent). Une etude de radicaux. libres stables pipericliniques est faite dans une seconde partie. Ces composes sont obtenus par oxydation de derives de la triacetonamine. Les caracteristiques spectroscopiques ultra-violette, infra-rouge, et paramagnetique electronique de ces radicaux sont donnees. La grande inertie chimique du groupement nitroxyde a permis la syn-these d'un biradical stable par formation d'azine d'une cetone radicalaire, ce qui fait 1'objet de la troisieme partie. (auteur)

Identification of N-phenyl-N'-(2,2,6,6-tetramethyl-piperidin-4-yl)-oxalamides as a new class of HIV-1 entry inhibitors that prevent gp120 binding to CD4

International Nuclear Information System (INIS)

Zhao Qian; Ma Liying; Jiang Shibo; Lu Hong; Liu Shuwen; He Yuxian; Strick, Nathan; Neamati, Nouri; Debnath, Asim Kumar

2005-01-01

We have identified two N-phenyl-N'-(2,2,6,6-tetramethyl-piperidin-4-yl)-oxalamide analogs as a novel class of human immunodeficiency virus type 1 (HIV-1) entry inhibitors that block the gp120-CD4 interaction, using database screening techniques. The lead compounds, NBD-556 and NBD-557, are small molecule organic compounds with drug-like properties. These compounds showed potent cell fusion and virus-cell fusion inhibitory activity at low micromolar levels. A systematic study showed that these compounds target viral entry by inhibiting the binding of HIV-1 envelope glycoprotein gp120 to the cellular receptor CD4 but did not inhibit reverse transcriptase, integrase, or protease, indicating that they do not target the later stages of the HIV-1 life cycle to inhibit HIV-1 infection. These compounds were equally potent inhibitors of both X4 and R5 viruses tested in CXCR4 and CCR5 expressing cell lines, respectively, indicating that their anti-HIV-1 activity is not dependent on the coreceptor tropism of the virus. A surface plasmon resonance study, which measures binding affinity, clearly demonstrated that these compounds bind to unliganded HIV-1 gp120 but not to the cellular receptor CD4. NBD-556 and NBD-557 were active against HIV-1 laboratory-adapted strains including an AZT-resistant strain and HIV-1 primary isolates, indicating that these compounds can potentially be further modified to become potent HIV-1 entry inhibitors

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.

Science.gov (United States)

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.

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.

Science.gov (United States)

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.

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

Energy Technology Data Exchange (ETDEWEB)

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

2012-01-15

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

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

International Nuclear Information System (INIS)

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

2012-01-01

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

1,5-Anhydro-D-fructose as Chiral Building Block: A Novel Approach to 1-Deoxymannojirimycin

DEFF Research Database (Denmark)

Maier, Peter; Andersen, Søren Møller; Lundt, Inge

2006-01-01

A novel six-step synthesis of 1-deoxymannojirimycin from 1,5-anhydro-D-fructose in 35% overall yield is reported. The key steps are nucleophilic piperidine ring formation and subsequent Lewis acid induced pyran ether cleavage.......A novel six-step synthesis of 1-deoxymannojirimycin from 1,5-anhydro-D-fructose in 35% overall yield is reported. The key steps are nucleophilic piperidine ring formation and subsequent Lewis acid induced pyran ether cleavage....

Synthesis of deuterium-labelled methylphenidate, p-hydroxy-methylphenidate, ritalinic acid and p-hydroxyritalinic acid

International Nuclear Information System (INIS)

Patrick, K.; Kilts, C.; Breese, G.

1982-01-01

The synthesis of threo-dl-methylphenidate (Ritalin 1), threo-dl-p-hydroxy-methylphenidate (3), threo-dl-ritalinic acid (2), and threo-dl-p-hydroxyritalinic acid (4) with deuterium incorporated in the piperidine ring is described. These compounds were synthesized for use as internal standards for mass fragmentographic assays of methylphenidate and its metabolites. The synthetic scheme described resulted in less than 0.05% 2 H 0 in the piperidine ring in any of the preparations. (author)

5′′-(4-Nitrobenzylidene-7′-(4-nitrophenyl-1′′-methyl-1′,3′,5′,6′,7′,7a′-hexahydrodispiro[acenaphthylene-1,5′-pyrrolo[1,2-c][1,3]thiazole-6′,3′′-piperidine]-2,4′′(1H-dione including an unknown solvate

Directory of Open Access Journals (Sweden)

P. L. Nilantha Lakshman

2013-08-01

Full Text Available The title compound, C35H28N4O6S, crystallizes with two molecules in the asymmetric unit. In both molecules, the piperidine ring adopts a shallow-chair conformation, the thiazole ring adopts a twisted conformation about the Cm—N bond (m = methine and the pyrrole ring adopts an envelope conformation with the C atom shared with the thiazole ring as the flap. In the crystal, inversion dimers linked by pairs of C—H...O interactions generate R22(34 loops for one of the asymmetric molecules. Further C—H...O links also involving the other molecule lead to a three-dimesional network. The contribution of the highly disordered solvent to the scattering was removed with SQUEEZE option of PLATON [Spek (2009. Acta Cryst. D65, 148–155]. The solvent contribution is not included in the reported molecular weight and density.

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

Energy Technology Data Exchange (ETDEWEB)

Goromaru, T.; Matsuura, H.; Furuta, T.; Baba, S.; Yoshimura, N.; Miyawaki, T.; Sameshima, 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, 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.

Syntese af transitionstate analoger til fremstillingen af katalytiske antistoffer med glycosidaseaktivitet

DEFF Research Database (Denmark)

Tagmose, Tina Møller

-5-hydroxymethyl-piperidine was synthesised. Swern oxidation of methyl 2,3,4-tri-O-benzyl-6-deoxy-alfa-D-glucoheptopyranoside gave methyl 2,3,4-tri-O-benzyl-6-deoxy-alfa-D-glucoheptodialdo-1,5-pyranoside which was coupled with the piperidine 9 by reductive amination. This gave methyl 2,3,4-tri...... and periodate cleavage of the carbon chain gave 4-O-benzyl-2-C-deoxy-hydroxymethyl-D-xylo-pentodialdose. Reductive amination with ammonia resulted in (3R,4R,5R)-4-benzyloxy-3-hydroxy-5-hydroxymethyl-piperidine (9). By catalytic hydrogenation under acidic conditions the hydrochloride of (3R,4R,5R)-3,4-dihydroxy......-peroxide resulted in stereoselective formation of the methyl 6,7-dideoxy-7-[(1'S,3'R,4'R,5'R)-3',4'-dihydroxy-5'-hydroxymethylp iperidinyl]-alfa-D-glucoheptopyranoside N-oxide a 2'-deoxy-gentiobiose analogue. N-Alkylation of 1 with methyliodide resulted in two isomers of methyl 6,7-dideoxy-7-[3'R,4'R,5'R...

Stability study on an anti-cancer drug 4-(3,5-bis(2-chlorobenzylidene-4-oxo-piperidine-1-yl-4-oxo-2-butenoic acid (CLEFMA using a stability-indicating HPLC method

Directory of Open Access Journals (Sweden)

Dhawal Raghuvanshi

2017-02-01

Full Text Available CLEFMA, 4-(3,5-bis(2-chlorobenzylidene-4-oxo-piperidine-1-yl-4-oxo-2-butenoic acid, is a new chemical entity with anti-cancer and anti-inflammatory activities. Here, we report its stability in solution against stress conditions of exposure to acid/base, light, oxidant, high temperature, and plasma. The identity of the degradation products was ascertained by mass and proton nuclear magnetic resonance spectroscopy. To facilitate this study, we developed and validated a reverse phase high performance liquid chromatography method for detection of CLEFMA and its degradation. The method was linear over a range of 1–100 µg/mL; the accuracy and precision were within acceptable limits; it was stability-indicating as it successfully separated cis-/trans-isomers of CLEFMA as well as its degradation product. The major degradation product was produced from amide hydrolysis at maleic acid functionality caused by an acidic buffer, oxidant (3% hydrogen peroxide, or temperature stress (40–60 °C. The log k-pH profile showed that CLEFMA was most stable at neutral pH. In accelerated stability study we found that the shelf-life (T90% of CLEFMA at 25 °C and 4 °C was 45 days and 220 days, respectively. Upon exposure to UV-light (365 nm, the normally prevalent trans-CLEFMA attained cis-configuration. This isomerization also involved the maleic acid moiety. CLEFMA was stable in plasma from which it could be efficiently extracted by an acetonitrile precipitation method. These results indicate that CLEFMA is sensitive to hydrolytic cleavage at its maleic acid moiety, and it is recommended that its samples should be stored under refrigerated and light-free conditions, and under inert environment.

In vivo evaluation of [{sup 123}I]-4-(2-(bis(4-fluorophenyl)methoxy)ethyl)-1-(4-iodobenzyl)piperidine, an iodinated SPECT tracer for imaging the P-gp transporter

Energy Technology Data Exchange (ETDEWEB)

De Bruyne, Sylvie; Wyffels, Leonie [Laboratory for Radiopharmacy, Ghent University, 9000 Ghent (Belgium); Boos, Terrence L. [Chemical Biology Research Branch, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD (United States); Staelens, Steven; Deleye, Steven [IBITECH-Medisip, Ghent University-IBBT, 9000 Ghent (Belgium); Rice, Kenner C. [Chemical Biology Research Branch, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD (United States); De Vos, Filip [Laboratory for Radiopharmacy, Ghent University, 9000 Ghent (Belgium)], E-mail: filipx.devos@ugent.be

2010-05-15

Introduction: P-glycoprotein (P-gp) is an energy-dependent transporter that contributes to the efflux of a wide range of xenobiotics at the blood-brain barrier playing a role in drug-resistance or therapy failure. In this study, we evaluated [{sup 123}I]-4-(2-(bis(4-fluorophenyl)methoxy)ethyl)-1-(4-iodobenzyl)piperidine ([{sup 123}I]-FMIP) as a novel single photon emission computed tomography (SPECT) tracer for imaging P-gp at the brain in vivo. Methods: The tissue distribution and brain uptake as well as the metabolic profile of [{sup 123}I]-FMIP in wild-type and mdr1a (-/-) mice after pretreatment with physiological saline or cyclosporin A (CsA) (50 mg/kg) was investigated. The influence of increasing doses CsA on brain uptake of [{sup 123}I]-FMIP was explored. {mu}SPECT images of mice brain after injection of 11.1 MBq [{sup 123}I]-FMIP were obtained for different treatment strategies thereby using the Milabs U-SPECT-II. Results: Modulation of P-gp with CsA (50 mg/kg) as well as mdr1a gene depletion resulted in significant increase in cerebral uptake of [{sup 123}I]-FMIP with only minor effect on blood activity. [{sup 123}I]-FMIP is relative stable in vivo with >80% intact [{sup 123}I]-FMIP in brain at 60 min p.i. in the different treatment regiments. A dose-dependent sigmoidal increase in brain uptake of [{sup 123}I]-FMIP with increasing doses of CsA was observed. In vivo region of interest-based SPECT measurements correlated well with the observations of the biodistribution studies. Conclusions: These findings indicate that [{sup 123}I]-FMIP can be applied to assess the efficacy of newly developed P-gp modulators. It is also suggested that [{sup 123}I]-FMIP is a promising SPECT tracer for imaging P-gp at the blood-brain barrier.

Substitution determination of Fmoc‐substituted resins at different wavelengths

Science.gov (United States)

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

Stereochemical Basis for a Unified Structure Activity Theory of Aromatic and Heterocyclic Rings in Selected Opioids and Opioid Peptides

Directory of Open Access Journals (Sweden)

Joel S. Goldberg

2010-02-01

Full Text Available This paper presents a novel unified theory of the structure activity relationship of opioids and opioid peptides. It is hypothesized that a virtual or known heterocyclic ring exists in all opioids which have activity in humans, and this ring occupies relative to the aromatic ring of the drug, approximately the same plane in space as the piperidine ring of morphine. Since the rings of morphine are rigid, and the aromatic and piperidine rings are critical structural components for morphine’s analgesic properties, the rigid morphine molecule allows for approximations of the aromatic and heterocyclic relationships in subsequent drug models where bond rotations are common. This hypothesis and five propositions are supported by stereochemistry and experimental observations. Proposition #1 The structure of morphine provides a template. Proposition #2 Steric hindrance of some centric portion of the piperidine ring explains antagonist properties of naloxone, naltrexone and alvimopam. Proposition #3 Methadone has an active conformation which contains a virtual heterocyclic ring which explains its analgesic activity and racemic properties. Proposition #4 The piperidine ring of fentanyl can assume the morphine position under conditions of nitrogen inversion. Proposition #5 The first 3 amino acid sequences of beta endorphin (l-try-gly-gly and the active opioid dipeptide, l-tyr-pro, (as a result of a peptide turn and zwitterion bonding form a virtual piperazine-like ring which is similar in size, shape and location to the heterocyclic rings of morphine, meperidine, and methadone. Potential flaws in this theory are discussed. This theory could be important for future analgesic drug design.

Stereoselective synthesis and spectral studies of some benzotriazolylacetyl hydrazones of 3-alkyl-2,6-diarylpiperidin-4-ones

Science.gov (United States)

Pillai, M. Velayutham; Rajeswari, K.; Kumar, C. Udhaya; Krishnan, K. Gokula; Mahendran, S.; Ramalingan, C.; Nagarajan, E. R.; Vidhyasagar, T.

2017-12-01

An effort to include biologically potent benzotriazole nucleus into piperidine ring is achieved through hydrazone formation. The characterization of the synthesized compounds was carried out using FT-IR, 1H &13C NMR, 1H-1H COSY, 1H-13C COSY, NOESY spectral techniques and GC-Mass spectrum. The spectral assignments were done without ambiguity using 2D-NMR techniques. The conformational preference of the piperidine ring deduced from the spectral studies is 'chair'. The diastereotopic nature of the methylene protons/methyl groups present in the molecules is revealed clearly in their spectral pattern observed.

Identification of radiolytic products from N-nitrosodimethylamine and N-nitrosopyrrolidine by gas chromatography and mass spectrometry[Gamma irradiation; N-Nitrosodimethylamine; N-Nitrosopyrrolidine; Radiolysis

Energy Technology Data Exchange (ETDEWEB)

Ahn, H -J; Lee, C -H; Kim, J -H; Han, S -B; Jo, Cheorun; Kim, Sung; Byun, M -W

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.

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

International Nuclear Information System (INIS)

Ahn, H.-J.; Lee, C.-H.; Kim, J.-H.; Han, S.-B.; Jo, Cheorun; Kim, Sung; Byun, M.-W.

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

The discovery of tropane-derived CCR5 receptor antagonists.

Science.gov (United States)

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 2-[4(E-2,6-bis(4-chlorophenyl-3-ethylpiperidin-4-ylidene]acetamide

Directory of Open Access Journals (Sweden)

K. Priya

2015-11-01

Full Text Available In the title piperidine derivative, C21H22Cl2N2O, the piperidine ring adopts a chair conformation. The chlorophenyl rings are oriented at an angle of 45.59 (14° with respect to each other. In the crystal, molecules are linked via N—H...O hydrogen bonds, forming C(4 chains along [100]. The chains are linked by C—H...O hydrogen bonds, forming sheets parallel to the ab plane. Within the sheets, there are N—H...π interactions present. The crystal studied was refined as an inversion twin.

Substitution determination of Fmoc-substituted resins at different wavelengths.

Science.gov (United States)

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.

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

Science.gov (United States)

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.

Spectroscopic properties and antimicrobial activity of dioxomolybdenum(VI complexes with heterocyclic S,S’-ligands

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Sovilj Sofija P.

2012-01-01

Full Text Available Five new dioxomolybdenum(VI complexes of the general formula[MoO2(Rdtc2], 1-5, where Rdtc-refer to piperidine- (Pipdtc, 4-morpholine-(Morphdtc, 4-thiomorpholine-(Timdtc, piperazine- (Pzdtc or Nmethylpiperazine- (N-Mepzdtc dithiocarbamates, respectively, have been prepared. Elemental analysis, conductometric measurements, electronic, IR and NMR spectroscopy have been employed to characterize them. Complexes 1-5 contain a cis-MoO2 group and are of an octahedral geometry. Two dithiocarbamato ions join as bidentates with both the sulphur atoms to the molybdenum atom. The presence of different heteroatom in the piperidinо moiety influences the v(C----N and v(C----S vibrations, which decrease in the order of the complexes with: Pipdtc > N-Mepipdtc > Morphdtc > Pzdtc > Timdtc ligands. On the basis of spectral data, molecular structures of complexes 1-5 were optimized on semiempirical molecular-orbital level, and the geometries, as obtained from calculations, described. Antimicrobial activity was tested against nine different laboratory control strains of bacteria and two strains of yeast Candida albicans. All tested strains were sensitive. Complexes bearing heteroatom in position 4 of piperidine moiety are significantly more potent against bacteria tested comparing to corresponding ligands.

Synthesis and Comparison of In Vitro Leishmanicidal Activity of 5-(Nitroheteroaryl-1, 3, 4-Thiadiazols Containing Cyclic Amine of Piperidin-4-ol at C-2 with Acyclic Amine Analogues against Iranian Strain of Leishmania major (MRHO/IR/75/ER

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Azar Tahghighi

2017-04-01

Full Text Available Background: Cutaneous Leishmaniasis (CL is endemic in many tropical and subtropical regions of the world. Due to the prolonged duration of therapy, adverse effect and resistance to current drugs in the treatment of CL, the dis­covery of novel, efficient, and safe leishmanicidal drugs is required. The aims of the present study was to synthesis of new compounds based on the active compounds of 5-(5-nitrofuran-2-yl- and 5-(5-nitrothiophen-2-yl-1,3,4-thia­diazole bearing the linear amino alcohol of 3-aminopropan-1-ol in the C-2 position of thiadiazole ring and evaluation of their activity against the promastigote and amastigote forms of Leishmania major.Methods: Reaction between the solution of 5-(5-nitro heteroaryl-2-chloro-1, 3, 4-thiadiazole and piperidin-4-ol in absolute ethanol was performed and the resulting products were evaluated against promastigotes form of L. major with MTT assay and amastigote form of L. major in murine peritoneal macrophages. In addition, the toxicity of these compounds was assessed against mouse peritoneal macrophages with MTT assay.Results: New synthetic compounds 5a-b showed moderate in vitro antileishmanial activity against L. major pro­mastigotes with IC50 values of 68.9 and 27 µM, respectively. These compounds have also demonstrated a good antiamastigote activity in terms of amastigote number per macrophage, the percentage of macrophage infectivity and infectivity index.Conclusion: Novel cyclic compounds 5a-b were synthesized and exhibited less antipromastigote and antiamastigote activity compared to linear analogues.

Preparation of phenacylchloride, morpholinophenacyl and N-Piperidinophenacyl oximes and study of their complexation with Copper (II) and Cobalt (II) ions

International Nuclear Information System (INIS)

Ali, Kamal Eldin Ahmed

1999-01-01

The aim of the present work is to prepare phenacyl chloride oxime and phenacyl of N-Piperidine and morpholine derivatives, and mainly to study their complexes with Cu(II) and Co(II) ions with objective ascertaining that one of these ligands can be used in quantitative extraction of these metal ions from the aqueous solution. Copper (II) salts form 1:1 complexes with the phenyacyl oximes of N-piperidine and morpholine and 1:2 complex with phenacyl chloride oxime. However, cobalt(II) salts form 1:2 complexes with phenacyl oxime of N-piperidine and morpholine but does not complex with phenacyl chloride oxime. The stoichiometry of these complexes were determined by UV/VIS spectrophotometry using the mole ratio, continuous variation and slope ratio methods.The stability constants of the five complexes were calculated from aberrances using Job's method. They showed that the copper (II) and cobalt (II) complexes with N-piperidinophenacy oxime are more stable than those with morpholinophenacyl oxime. Copper (II) complexes with any of these two ligands are more stable than those of cobalt (II). IR spectra of the complexes of copper (II) and cobalt (II) with phenacyl oxime of N-piperidine and morpholine show diminished peaks of hydrogen bonds between N and O atoms of the ligand. Specific extractabilities using amylalcohol of copper (II) complexes with the three ligands increase from PH4 to reach its maximum at PH8. The high value for N-piperidinophenacyl oxime ligand (96%-97%) indicates that, this ligand can be used as analytical reagent for the quantitative spectrophotometric determination of copper (II) salts in aqueous media. Cobalt (II) complexes were formed and extracted from solution only at PH6 (specific PH). The extractabilities ranging from 81.6-87.2% warrants the use of these ligands in quantitative spectrophotometric determination of cobalt (II).(Author)

Thermal aromatic Claisen rearrangement and Strecker reaction of alkyl(allyl-aryl ethers under green reaction conditions: Efficient and clean preparation of ortho-allyl phenols (naphthols and alkyl(allyloxyarene-based γ-amino nitriles

Directory of Open Access Journals (Sweden)

Kheila N. Silgado-Gómez

2017-11-01

Full Text Available Chemical transformations of 13 diverse allyl(alkyl-aryl ethers, easily prepared using Williamson reaction of different hydroxyarenes and allyl bromide and alkyl (n-butyl, n-octyl bromides, were studied. Thermal aromatic Claisen rearrangement of allyl-aryl ethers to obtain ortho-allyl phenols (naphthols employing propylene carbonate as a nontoxic and biodegradable solvent was described for the first time. The use of this green solvent allowed to enhance notably product yields and reduce significantly the reaction time comparing with the use of 1,2-dichlorobenzene, toxic solvent, which is traditionally employed in this type of Claisen rearrangement. Three-component Strecker reaction of selected alkyl(allyl-aryl ethers with formyl function on aryl fragment and, piperidine and potassium cyanide in the presence of sulfuric acid supported on silica gel (SSA, SiO2-O-SO3H under mild reaction conditions was used in the preparation of new γ-amino nitriles, analogues of alkaloid girgensohnine [2-(4-hydroxyphenyl-2-(piperidin-1-ylacetonitrile], a perspective biological model in the search for new insecticidal agrochemicals against Aedes aegypti. The use of SSA, an inexpensive and reusable solid catalyst, allowed to obtain new series of 2-[4-alkyl(allyloxyphenyl]-2-(piperidin-1-ylacetonitriles in short time at room temperature with good yields.

Hemlock alkaloids from Socrates to poison aloes.

Science.gov (United States)

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.

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.

Science.gov (United States)

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.

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

Science.gov (United States)

2011-10-07

...-phenethyl-4-piperidine (8333)... II Phenylacetone (8501) II Opium, raw (9600) II Poppy Straw Concentrate... under international treaties, conventions, or protocols in effect on May 1, 1971. DEA has investigated...

Stereoelectronic Substituent Effects

DEFF Research Database (Denmark)

Bols, Mikael; Jensen, Henrik Helligsø

2006-01-01

An investigation was carried Out on the influence of the stereo-chemistry of substituents, particularly hydroxyl groups, on their electronic effects in piperidines, carbohydrates (pyranosides), and related compounds. Polar groups, such as OH, OR, and F, were found in the 3 and 4 position to be much...... more electron-withdrawing when positioned equatorially rather than axially. In contrast, little difference in electronic effects was observed from apolar groups as a result of epimerization. These observations were believed to be caused by differences in charge-dipole interactions and were used...... to explain why stereoisomeric glycosides hydrolyze with different rates. The conformational changes of hydroxylated piperidines and related compounds as a function of pH were likewise explained from the different substituent effects of axial and equatorial OH groups....

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

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Yu Mi Heo

2013-08-01

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

75 FR 38915 - Removal of Thresholds for the List I Chemicals Pseudoephedrine and Phenylpropanolamine

Science.gov (United States)

2010-07-07

... available ``recipes'' and can be accomplished with little or no chemistry expertise. A variety of different... Piperidine and its 500 grams. salts. 8750 Piperonal (also called 4 kilograms. heliotropine). 8328 Propionic...

78 FR 5498 - Importer of Controlled Substances; Notice of Registration; Chattem Chemicals, Inc.

Science.gov (United States)

2013-01-25

...-Anilino-N-phenethyl-4-piperidine (8333).. II Phenylacetone (8501) II Opium, raw (9600) II Poppy Straw... treaties, conventions, or protocols in effect on May 1, 1971. DEA has investigated Chattem Chemicals, Inc...

78 FR 69131 - Importer of Controlled Substances, Notice of Registration, Chattem Chemicals, Inc.

Science.gov (United States)

2013-11-18

...-Anilino-N-phenethyl-4-piperidine (8333).. II Phenylacetone (8501) II Opium, raw (9600) II Poppy Straw..., or protocols in effect on May 1, 1971. DEA has investigated Chattem Chemicals, Inc., to ensure that...

4-Hydroxy-1-naphthaldehydes: proton transfer or deprotonation

DEFF Research Database (Denmark)

Manolova, Y; Kurteva, V; Antonov, L

2015-01-01

A series of naphthaldehydes, including a Mannich base, have been investigated by UV-Vis spectroscopy, NMR and theoretical methods to explore their potential tautomerism. In the case of 4-hydroxy-1-naphthaldehyde concentration dependent deprotonation has been detected in methanol and acetonitrile....... For 4-hydroxy-3-(piperidin-1-ylmethyl)-1-naphthaldehyde (a Mannich base) an intramolecular proton transfer involving the OH group and the piperidine nitrogen occurs. In acetonitrile the equilibrium is predominantly at the OH-form, whereas in methanol the proton transferred tautomer is the preferred form....... In chloroform and toluene, the OH form is completely dominant. Both 4-hydroxy-1-naphthaldehyde and 4-methoxy-1-naphthaldehyde (fixed enol form) show dimerization in the investigated solvents and the crystallographic data, obtained for the latter, confirm the existence of a cyclic dimer...

Synthesis and characterization of oxovanadium (IV) dithiocarbamates with pyridine

Energy Technology Data Exchange (ETDEWEB)

Doadrio, Antonio L.; Sotelo, Jose; Fernandez-Ruano, Ana [Universidad Complutense, Madrid (Spain). Facultad de Farmacia. Dept. de Quimica Inorganica y Bioinorganica]. E-mail: antoniov@farm.ucm.es

2002-07-01

We report the synthesis and study of a new series of oxovanadium (IV) dithiocarbamate adducts and derivatives with pyridine and cyclohexyl, di-iso-butyl, di-n-propyl, aniline, morpholine, piperidine and di-iso-propyl amines. The complexes have been characterized by analytical, magneto chemical, IR, visible-UV spectral and thermal studies, and are assigned the formulas [VO(L){sub 2}].py, where L=cyclohexyl, di-iso-butyl, di-n-propyl, aniline dithiocarbamate and [VO(OH)(L)(py){sub 2}] OH.H{sub 2}O (L=morpholine, piperidine and di-iso-propyl dithiocarbamate). The effect of the adduct formation on the p{sub V=0} bound is discussed in terms of the IR (V=O, V-S and V-N stretching frequencies) and electronic spectra (d-d transitions). (author)

t-3-Benzyl-r-2,c-6-diphenylpiperidin-4-one oxime

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R. Arulraj

2016-12-01

Full Text Available In the title compound, C24H24N2O [systematic name: (E-3-benzyl-2,6-diphenylpiperidin-4-one oxime], the piperidine ring adopts a slightly distorted chair conformation and the phenyl rings and the benzyl group substituents are attached equatorially. The oxime group makes a dihedral angle of 42.88 (12° with the piperidine ring. The dihedral angle between the phenyl rings is 71.96 (8°. The benzyl ring makes dihedral angles of 63.01 (8 and 59.35 (8° with the two phenyl rings. In the crystal, molecules are linked by O—H...N hydrogen bonds, forming C(7 chains along the c axis. The chains are linked by C—H...π interactions, forming slabs lying parallel to the bc plane.

Synthesis of some new derivatives of thiazolopyrimidines and ...

Indian Academy of Sciences (India)

In addition, a new series of thiazole-fused pyrimidines were synthesized and hydrolysis of one of its arylidene derivative studied. ..... ondary amines like morpholine, piperidine and pyrro- ..... Biginelli one pot cyclo-condensation reaction.21 The.

Workers and alate queens of Solenopsis geminata share qualitatively similar but quantitatively different venom alkaloid chemistry

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Qun-Hui eShi

2015-07-01

Full Text Available Solenopsis geminata group (Hymenoptera: Formicidae encompasses ant species commonly called fire ants because of their painful sting. The many physiological effects of the venom are caused by 2-methyl-6-alkyl and/or alkenylpiperidine alkaloids. The variation in piperidine alkaloid structures has useful taxonomic characters. The most well studied Solenopsis species is S. invicta, which was accidentally imported into the USA in the 1930s from South America. It quickly spread throughout the southern USA and is now a major invasive pest ant in the USA and in other parts of the world. Interestingly, the invasive S. invicta has largely displaced a native USA fire ant, S. geminata, from the southern USA. We explore the possibility that differences in venom chemistry could be correlated with this displacement. The cis and trans alkaloids from body extracts of workers and alate queens of S. geminata were separated by silica gel chromatography, identified, and quantitated by GC-MS analysis. Both workers and alate queens produce primarily cis- and trans-2-methyl-6-n-undecyl-piperidines, as well as other minor alkaloid components. Imported fire ant, S. invicta, alate queens produce the same alkaloids as S. geminata alate queens, but in contrast S. invicta workers produce piperidine alkaloids with longer side chains, which are purported to be physiologically more effective. These results are discussed in relation to the evolutionary progression of fire ant venom alkaloids and displacement of S. geminata by S. invicta in the USA.

Mechanism of hydrodenitrogenation on phosphides and sulfides.

Science.gov (United States)

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.

Parallel and four-step synthesis of natural-product-inspired scaffolds through modular assembly and divergent cyclization

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Hiroki Oguri

2012-06-01

Full Text Available By emulating the universal biosynthetic strategy, which employs modular assembly and divergent cyclizations, we have developed a four-step synthetic process to yield a collection of natural-product-inspired scaffolds. Modular assembly of building blocks onto a piperidine-based manifold 6, having a carboxylic acid group, was achieved through Ugi condensation, N-acetoacetylation and diazotransfer, leading to cyclization precursors. The rhodium-catalyzed tandem cyclization and divergent cycloaddition gave rise to tetracyclic and hexacyclic scaffolds by the appropriate choice of dipolarophiles installed at modules 3 and 4. A different piperidine-based manifold 15 bearing an amino group was successfully applied to demonstrate the flexibility and scope of the unified four-step process for the generation of structural diversity in the fused scaffolds. Evaluation of in vitro antitrypanosomal activities of the collections and preliminary structure–activity relationship (SAR studies were also undertaken.

Identification and characterization of potential impurities of donepezil.

Science.gov (United States)

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.

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

Science.gov (United States)

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

2015-09-21

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

Synthesis, NMR spectral and antimicrobial studies of some [N-methyl-3t-alkyl-2r,6c-diarylpiperidin-4-ylidine]-5‧-methylthiazolidine-4-ones

Science.gov (United States)

Prakash, S. M.; Pandiarajan, K.; Kumar, S.

2013-06-01

Four new [N-methyl-3t-alkyl-2r,6c-diaryl-4-ylidine]-5'-methylthiozolidin-4-ones 9-12 have been synthesized by the condensation of N-methyl-3t-alkyl-2r,6c-diarylpiperidin-4-one thiosemicarbazones with ethyl 2-bromopropionate. These compounds have been characterized using FT-IR, 1H NMR, 13C NMR spectral techniques. HOMOCOSY, HSQC and HMBC spectral study have been done for [N-methyl-3,3-dimethyl-2r,6c-bis(p-methoxyphenyl)piperidin-4-ylidine]-5'-methylthiazolidine-4-one (12). Two geometrical isomers are formed in this reaction. In all these compounds piperidin rings adopt chair conformation. The rotation of the aryl group at C-2 is rather slow in 10-12. Antimicrobial activities have also been studied for 9-12. These compounds are active against all the tested bacterial and fungal strains.

Synthesis of sup 14 C-radiolabelled Tilmicosin

Energy Technology Data Exchange (ETDEWEB)

Crouse, G D; Terando, N H [Lilly (Eli) and Co., Indianapolis, IN (USA). Lilly Research Labs.

1989-04-01

Tilmicosin was radiolabelled with carbon-14 on the 3,5-dimethylpiperidinyl sidechain as a requirement for animal metabolism studies. A new radiosynthesis of 3,5-dimethyl-piperidine was developed for this purpose. Incorporation into the desmycosin nucleus was accomplished by a reductive amination reaction. (author).

Asymmetric Hydrogenation of Quinoxalines Catalyzed by Iridium/PipPhos

NARCIS (Netherlands)

Mrsic, Natasa; Jerphagnon, Thomas; Minnaard, Adriaan J.; Feringa, Ben L.; de Vries, Johannes G.

2009-01-01

A catalyst made in situ from the (cyclooctadiene)iridium chloride dimer, [Ir(COD)Cl](2), and the monodentate phosphoramidite ligand (S)-PipPhos was used in the enantioselective hydrogenation of 2- and 2,6-substituted quinoxalines. In the presence of piperidine hydrochloride as additive full

Synthesis of 14C-radiolabelled Tilmicosin

International Nuclear Information System (INIS)

Crouse, G.D.; Terando, N.H.

1989-01-01

Tilmicosin was radiolabelled with carbon-14 on the 3,5-dimethylpiperidinyl sidechain as a requirement for animal metabolism studies. A new radiosynthesis of 3,5-dimethyl-piperidine was developed for this purpose. Incorporation into the desmycosin nucleus was accomplished by a reductive amination reaction. (author)

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

African Journals Online (AJOL)

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

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

Science.gov (United States)

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

NARCIS (Netherlands)

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

2012-01-01

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

Identification and quantification of phencyclidine pyrolysis products formed during smoking.

Science.gov (United States)

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.

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

Science.gov (United States)

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.

Identification and quantification of phencyclidine pyrolysis products formed during smoking

International Nuclear Information System (INIS)

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 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%). 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, α-methylstyrene, naphthalene, 2-methyl-naphthalene, 1-methylnaphthalene, biphenyl, cyclohexylbenzene, acenaphthene, phenanthrene, and anthracene. These compounds were not formed from PCP under smoking conditions

Separação de fases induzida por meio de reação química no sistema éter diglicidílico do bisfenol A e piperidina com poli(metacrilato de metila Phase separation induced by chemical reaction in the system of diglycidyl ether of bisphenol A and piperidine with poly(methyl methacrylate

Directory of Open Access Journals (Sweden)

Filiberto González Garcia

2003-12-01

Full Text Available O comportamento da separação de fases e da gelificação do sistema epoxídico, constituído pelo éter diglicidílico do bisfenol A (DGEBA e a piperidina, modificado com poli(metacrilato de metila (PMMA, foi estudado na faixa de temperatura de 60 °C - 120 °C. A concentração de PMMA e a temperatura de cura causam mudanças significativas na morfologia gerada. A massa molecular de PMMA provoca ligeiras mudanças para a observação da separação de fases e não afeta a velocidade da reação. O sistema modificado com PMMA mostra o efeito de retardação cinético e a velocidade de separação de fases é maior que a velocidade de polimerização.The phase separation and gelification behavior of epoxy system based on diglycidyl ether of bisphenol-A (DGEBA and piperidine modified with poly(methyl methacrylate (PMMA were studied in the range between 60 °C and 120 °C. The morphology is influenced by the PMMA content in the blend and also by the cure temperature. The molecular weight of PMMA provokes slight changes on cloud point and does not affect the reaction rate. The systems modified by PMMA exhibited kinetic retardation effect but the cloud point rate was higher than the polymerization rate.

Fe (III) complex of mefloquine hydrochloride: Synthesis ...

African Journals Online (AJOL)

As part of the ongoing research for more effective antimalarial drug, Fe (III) complex of mefloquine hydrochloride (antimalarial drug) was synthesized using template method. Mefloquine was tentatively found to have coordinated through the hydroxyl and the two nitrogen atoms in the quinoline and piperidine in the structure, ...

Journal of Chemical Sciences | Indian Academy of Sciences

Indian Academy of Sciences (India)

Home; Journals; Journal of Chemical Sciences. P G Aravindan. Articles written in Journal of Chemical Sciences. Volume 123 Issue 4 July 2011 pp 403-409. The role of weak intermolecular C-H…F interactions in supramolecular assembly: Structural investigations on 3,5- dibenzylidene-piperidin-4-one and database ...

A Facile Stereospecific Synthesis of 1, 3-Enynylsulfides via Sonogashira Coupling of (E)-α-Iodovinyl Sulfides with 1-Alkynes

Institute of Scientific and Technical Information of China (English)

Jian Wen JIANG; Ming Zhong CAI

2006-01-01

(E)-α-Iodovinyl sulfides 1 underwent the Sonogashira coupling reactions with terminal alkynes 2 in piperidine at room temperature in the presence of 5 mol % of Pd(PPh3)4 and 10 mol %of CuI to afford the corresponding 1, 3-enynylsulfides 3 stereospecifically in high yields.

Identification of a new psychoactive substance in seized material

DEFF Research Database (Denmark)

Breindahl, Torben; Kimergård, Andreas; Andreasen, Mette Findal

2017-01-01

Among the new psychoactive substances (NPS) that have recently emerged on the market, many of the new synthetic opioids have shown to be particularly harmful. A new synthetic analogue of fentanyl, N-phenyl-N-[1-(2-phenethyl)piperidin-4-yl]prop-2-enamide (acrylfentanyl), was identified in powder...

Pyridoxine-dependent epilepsy owing to antiquitin deficiency - mutation in the ALDH7A1 gene

NARCIS (Netherlands)

Jagadeesh, S.; Suresh, B.; Murugan, V.; Suresh, S.; Salomons, G.S.; Struys, E.A.; Jacobs, C.

2013-01-01

Pyridoxine-dependent epilepsy (PDE) is an inborn error of metabolism resulting from antiquitin deficiency. There is marked elevation of a-amino adipic semi-aldehyde (aAASA), piperidine-6-carboxylate (P6C) and pipecolic acid. The diagnosis can be confirmed by identifying the mutation in the ALDH7A1

Sample list: S0000000259 [jPOST repository metadata[Archive

Lifescience Database Archive (English)

Full Text Available n was reacted with 1 μL of each recombinant kinase (0.5 μg/μL) or distilled water as a control at 37 °C in kinase reaction buffer...elution by 0.5% piperidine. Phosphopeptides were desalted by StageTips and suspended in the loading buffer

Sample list: S0000000260 [jPOST repository metadata[Archive

Lifescience Database Archive (English)

Full Text Available on was reacted with 1 μL of each recombinant kinase (0.5 μg/μL) or distilled water as a control at 37 °C in kinase reaction buffer... elution by 0.5% piperidine. Phosphopeptides were desalted by StageTips and suspended in the loading buffe

Sample list: S0000000262 [jPOST repository metadata[Archive

Lifescience Database Archive (English)

Full Text Available on was reacted with 1 μL of each recombinant kinase (0.5 μg/μL) or distilled water as a control at 37 °C in kinase reaction buffer... elution by 0.5% piperidine. Phosphopeptides were desalted by StageTips and suspended in the loading buffe

Sample list: S0000000261 [jPOST repository metadata[Archive

Lifescience Database Archive (English)

Full Text Available on was reacted with 1 μL of each recombinant kinase (0.5 μg/μL) or distilled water as a control at 37 °C in kinase reaction buffer... elution by 0.5% piperidine. Phosphopeptides were desalted by StageTips and suspended in the loading buffe

Syntese af amino/hydroxypyrrolidines og -piperidiner fra kulhydratderivater

DEFF Research Database (Denmark)

Godskesen, Michael Anders

by methyliodide. The 5-Bromo functionality was then substituted by azid, which was hydrogenated in presence of palladium on carbon. The amino-lactones rearranged to the corresponding lactams, that could be reduced to 1,2,5-trideoxy-1,5-imino-2-C-methyl-D-arabinitol, hydrotosylate and 1,2,5-trideoxy-1,5-imino-2-C...

The systems terbium (holmium) nitrate-piperidine nitrate-water

International Nuclear Information System (INIS)

Khisaeva, D.A.; Zhuravlev, E.F.; Semenova, Eh.B.

1982-01-01

Using the method of cross sections at 25 and 50 deg C solubility in the systems Tb(NO 3 ) 2 -C 5 H 10 NHxHNO 3 -H 2 O and Ho(NO 3 ) 3 -C 5 H 10 NHxHNO 3 -H 2 O has been studied. The systems are characterized by chemical interaction of components. Solubility isotherms have crystallization fields of solid phases of the composition Tb(NO 3 ) 3 x3[C 5 H 10 NHxHNO 3 ]x3H 2 O and Ho(NO 3 ) 3 x2[C 5 H 10 NHxHNO 3 ]. The compounds detected are singled out preparatively, their IR spectra are studied, their thermogravimetric analysis is carried out. Investigation results are compared with similar systems formed by nitrates of other representatives of rare earth group

Comparative tissue distribution of conformationally restricted radioiodinated vesamicol receptor ligands

Energy Technology Data Exchange (ETDEWEB)

Efange, S M.N.; Khare, A B; Langason, R B

1995-05-01

Three conformationally restricted analogs of vesamicol, 1'-[1-(3-iodobenzyl)-4-hydroxypiperidin-3-yl]-spirol[1H-indene-1,4'- piperidine] (5), 1'-[1-(3-iodobenzyl)-4-hydroxypiperidin-3-yl]-3,4-dihydrospiro[indene-1,4'- piperidine] (6) and 1'-[1-(3-iodobenzyl)-4-hydroxypiperidin-3-yl)]-3,4-dihydrospiro[naphthalene- 1(2H),4'-piperidine] (7), were labelled with iodine-125 and evaluated as potential radioligands for mapping vesamicol receptor (VR) density and cholinergic function in vivo. All compounds showed similar kinetics in most tissues. However, differences were observed in the brain. Although comparable levels of each corresponding enantiomeric pair were obtained initially in the brain, the levels of the dextrorotatory enantiomers (+)-5, (+)-6 and (+)-7 were found to decrease by 72-82% over a period of 3 h. In contrast, the brain levels of the corresponding levorotatory isomers were maintained throughout the duration of the experiment. Among the dextrorotatory isomers, (+)-6 showed the highest brain extraction, while (+)-7 showed the lowest. In tissue dissection experiments, the levels of (+)-5, (+)-6 and (+)-7 were highest in the striatum and moderate to low in the cortex and cerebellum. Co-administration of haloperidol with (+)-6 decreased the levels of the latter in the striatum by 27%, while the levels in the cortex and cerebellum were each reduced by 60%. In addition, haloperidol failed to affect the regional distribution of (+)-7 in the brain. However, both haloperidol and spiperone increased the striatal levels of (+)-5 by 67 and 76%, respectively, suggesting that the binding of this radioligand is related to cholinergic function. Furthermore, haloperidol reduced the concentration of (+)-5 in the cortex and cerebellum by 25 and 33%, respectively, thereby implicating the sigma site as a secondary target for this ligand in the cortex.

Comparative tissue distribution of conformationally restricted radioiodinated vesamicol receptor ligands

International Nuclear Information System (INIS)

Efange, S.M.N.; Khare, A.B.; Langason, R.B.

1995-01-01

Three conformationally restricted analogs of vesamicol, 1'-[1-(3-iodobenzyl)-4-hydroxypiperidin-3-yl]-spirol[1H-indene-1,4'- piperidine] (5), 1'-[1-(3-iodobenzyl)-4-hydroxypiperidin-3-yl]-3,4-dihydrospiro[indene-1,4'- piperidine] (6) and 1'-[1-(3-iodobenzyl)-4-hydroxypiperidin-3-yl)-3,4-dihydrospiro[naphthalene- 1(2H),4'-piperidine] (7), were labelled with iodine-125 and evaluated as potential radioligands for mapping vesamicol receptor (VR) density and cholinergic function in vivo. All compounds showed similar kinetics in most tissues. However, differences were observed in the brain. Although comparable levels of each corresponding enantiomeric pair were obtained initially in the brain, the levels of the dextrorotatory enantiomers (+)-5, (+)-6 and (+)-7 were found to decrease by 72-82% over a period of 3 h. In contrast, the brain levels of the corresponding levorotatory isomers were maintained throughout the duration of the experiment. Among the dextrorotatory isomers, (+)-6 showed the highest brain extraction, while (+)-7 showed the lowest. In tissue dissection experiments, the levels of (+)-5, (+)-6 and (+)-7 were highest in the striatum and moderate to low in the cortex and cerebellum. Co-administration of haloperidol with (+)-6 decreased the levels of the latter in the striatum by 27%, while the levels in the cortex and cerebellum were each reduced by 60%. In addition, haloperidol failed to affect the regional distribution of (+)-7 in the brain. However, both haloperidol and spiperone increased the striatal levels of (+)-5 by 67 and 76%, respectively, suggesting that the binding of this radioligand is related to cholinergic function. Furthermore, haloperidol reduced the concentration of (+)-5 in the cortex and cerebellum by 25 and 33%, respectively, thereby implicating the sigma site as a secondary target for this ligand in the cortex

Development of radiotracers for imaging NR2B subtype NMDA receptors with positron emission tomography

International Nuclear Information System (INIS)

Labas, R.

2007-01-01

The aim of this thesis was to develop new radioactive tracers for imaging NR2B subtype NMDA receptors with positron emission tomography. Several compounds including 4-(4-fluoro-benzyl)piperidine and presenting interesting in vivo biological properties were the object of a labelling with a positrons emitter atom ( 11 C or 18 F)

Amine-Controlled Divergent Reaction: Iminolactonization and Olefination in the Presence of a Cu(I) Catalyst.

Science.gov (United States)

Nishikata, Takashi; Itonaga, Kohei; Yamaguchi, Norihiro; Sumimoto, Michinori

2017-05-19

α-Bromoamides and styrenes underwent iminolactonization reactions (carbooxygenation), in which simultaneous C-C and C-O formation occurred in the presence of a copper catalyst with triethylamine as the base. Conversely, olefination reactions occurred in the presence of a Cu catalyst with piperidine as the base. The selectivities in those reactions were very high.

N-(1-Acryloyl-2,2,6,6-tetramethylpiperidin-4-ylacrylamide

Directory of Open Access Journals (Sweden)

Shailesh K. Goswami

2011-11-01

Full Text Available The title compound, C15H24N2O2, crystallizes with two unique molecules, (I and (II, in the asymmetric unit, differing in the orientation of the acryloyl units with respect to the piperidine rings. The acrylamide units are essentially planar in both molecules (r.m.s. deviations = 0.042 and 0.024 Å, respectively, as are the C3N chains of the acryloyl units. The carbonyl O atoms of the acryloyl systems lie significantly out of these planes, viz. by −0.171 (9 Å for molecule (I and by 0.33 (1 Å for molecule (II. The acrylamide and acryloyl planes are inclined at 68.7 (4° and 59.8 (3° in the two molecules. The piperidine rings each adopt twist boat conformations. In the crystal, strong N—H...O hydrogen bonds link the molecules into zigzag C(4 chains along b. Additional C—H...O contacts result in the formation of stacks along a.

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

Science.gov (United States)

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.

The ketamine analogue methoxetamine and 3- and 4-methoxy analogues of phencyclidine are high affinity and selective ligands for the glutamate NMDA receptor.

Directory of Open Access Journals (Sweden)

Bryan L Roth

Full Text Available In this paper we determined the pharmacological profiles of novel ketamine and phencyclidine analogues currently used as 'designer drugs' and compared them to the parent substances via the resources of the National Institute of Mental Health Psychoactive Drug Screening Program. The ketamine analogues methoxetamine ((RS-2-(ethylamino-2-(3-methoxyphenylcyclohexanone and 3-MeO-PCE (N-ethyl-1-(3-methoxyphenylcyclohexanamine and the 3- and 4-methoxy analogues of phencyclidine, (1-[1-(3-methoxyphenylcyclohexyl]piperidine and 1-[1-(4-methoxyphenylcyclohexyl]piperidine, were all high affinity ligands for the PCP-site on the glutamate NMDA receptor. In addition methoxetamine and PCP and its analogues displayed appreciable affinities for the serotonin transporter, whilst the PCP analogues exhibited high affinities for sigma receptors. Antagonism of the NMDA receptor is thought to be the key pharmacological feature underlying the actions of dissociative anaesthetics. The novel ketamine and PCP analogues had significant affinities for the NMDA receptor in radioligand binding assays, which may explain their psychotomimetic effects in human users. Additional actions on other targets could be important for delineating side-effects.

GC/MS analysis of piperidinocyclohexanecarbonitrile (PCC) smoking products

International Nuclear Information System (INIS)

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

1986-01-01

Piperidinocyclohexanecarbonitrile (PCC), an intermediate in phencyclidine (PCP) synthesis, is a major contaminant of illicit PCP. Due to the frequent abuse of PCP by smoking, this study was conducted to determine the PCC pyrolysis products delivered in smoke. Marihuana placebo cigarettes were impregnated with 3 H-piperidino- 14 C-cyano-PCC (synthesized in the lab and recrystallized twice, m.p. 67 0 C) and burned under conditions which simulated smoking. Mainstream smoke was passed through glass wool filters and H 2 SO 4 and NaOH traps. Tritium and 14 C were recovered as 83%, and 56%, respectively, of the starting material. Seventy-six percent of the recovered tritium was found in the glass wool trap followed by 13, 7 and 4% in the acid trap, base trap and in the ash/unburned butt, respectively. Seventy-three percent of the recovered 14 C was found in the glass wool filter and 16 and 8% were found in the acid and base traps, respectively. GC/MS analysis revealed the presence of 1-piperidinocyclohexene (30%), PCC (24%), piperidine (7%), and 1-acetyl-piperidine (5%)

Synthesis and reactions of 4-(p-methoxybenzyl-6-[5,6,7,8-tetrahydro-2-naphthyl]-pyridazin-3(2H-one

Directory of Open Access Journals (Sweden)

NAGWA M.S. EL-DIN HARB

1999-11-01

Full Text Available The condensation of 4-(p-methoxybenzyl-6-[5,6,7,8-tetrahydro-2-naphthyl]-pyridazin-3(2H-one (3, prepared by the reaction of 6-[5,6,7,8-tetrahydro-2-naphthyl]-4,5-dihydropyridazin-3(2H-one (1 and anisaldehyde, with dimethyl sulphate, formaldehyde and acrylonitrile, and also the formation of the Mannich base, proceeded smoothly at the 2-position to give compounds 4,5,6,7, respectively. 4-p-Methoxybenzyl-3-chloro-6-[5,6,7,8-tetrahydro-2-naphthyl]-pyridazine (9 was prepared in law yield by the action of phosphorus oxychloride on 3. The reaction of 9 with benzylamine, aniline and piperidine gave 10a,b,c, respectively. 4-p-Methoxybenzyl-6-[5,6,7,8-tetrahydro-2-napthyl]pyridazine-3(2H-thione (12 was prepared either by the action of thiourea on 9, or by the reaction of 3 with phosphorus pentasulphide. The reaction of these thiones with acrylonitrile, morpholine and piperidine to give 13 and 14 a,b, respectively, were also investigated.

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

Directory of Open Access Journals (Sweden)

Xianglong Wu

2014-01-01

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

Use of cytectrene marked by the technetium 99 to study the activity of Acetylcholinesterase in the rat brain

International Nuclear Information System (INIS)

Mejri, Najoua

2007-01-01

Alzheimer's disease is a degenerative neurological disorder that causes progressive and irreversible loss of mental functions. It is the most common form of dementia and is characterized by a decrease in serotonergic neurons that carry the 5HT1A receptors. Derivatives piperidine with a tertiary amine and ester are similar to acetylcholine [natural substrate of acetylcholinesterase)], we used the cytectrene [molecule based piperidine marked the technetium 99m] as a substrate to investigate the activity of Acetylcholinesterase in the brain. The use of cytectrene for the quantitative measurement of the activity of the Acetylcholinesterase in the brain depends on the rate of hydrolysis and the enzymatic specificity. The results showed that the cytectrene can be used as a substrate for a precise and quantitative determination of the activity of this enzyme. The use of cytectrene as a substrate of Acetylcholinesterase and determination of its activity can use this molecule as an agent for early diagnosis of Alzheimer's disease. The results will, therefore, not only their importance on a fundamental level but also on a plan applied in the medical field. (Author)

Development of radiotracers for imaging NR2B subtype NMDA receptors with positron emission tomography; Developpement de radiotraceurs pour la visualisation des recepteurs NMDA de sous-type NR2B par tomographie par emission de positons

Energy Technology Data Exchange (ETDEWEB)

Labas, R

2007-07-01

The aim of this thesis was to develop new radioactive tracers for imaging NR2B subtype NMDA receptors with positron emission tomography. Several compounds including 4-(4-fluoro-benzyl)piperidine and presenting interesting in vivo biological properties were the object of a labelling with a positrons emitter atom ({sup 11}C or {sup 18}F)

Microwave-Assisted Synthesis and Biological Evaluation of Dihydropyrimidinone Derivatives as Anti-Inflammatory, Antibacterial, and Antifungal Agents

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Anjna Bhatewara

2013-01-01

Full Text Available A simple protocol for the efficient preparation of aryl and heteroaryl substituted dihydropyrimidinone has been achieved via initial Knoevenagel, subsequent addition, and final cyclization of aldehyde, ethylcyanoacetate, and guanidine nitrate in the presence of piperidine as a catalyst in solvent-free under microwave irradiation. The synthesized compounds showed a good anti-inflammatory, antibacterial, and antifungal activity.

Synthesis of acetylene alcohols of heterocyclic type and the acyl derivatives

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Moldir Dyusebaeva

2015-03-01

Full Text Available A synthesis of potentially biologically active heterocyclic amino alcohols of acetylene (Piperidine and Morpholine under the conditions of Mannich reaction accomplished and received their acyl derivatives. Pharmacological activity (antibacterial and antispasmotic of synthesized compounds, also acute toxicological characteristics studied. The study showed that the combination of DMAE-4 has antispasmodic activity with low toxicity.

Enaminonitriles in Heterocyclic Synthesis: A Route to 1,3-Diaryl-4-aminopyrazole Derivatives

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Abdellatif Mohamed Salaheldin

2013-01-01

Full Text Available Benzylcyanide and 4-nitrobenzylcyanide condensed with triethyl orthoformate and piperidine or morpholine to yield 2-aryl-2-piperidinyl or 2-morpholinylacrylonitriles. These coupled with aromatic diazonium salts to yield the 2-arylhydrazno-2-arylethane nitriles in good yields. The latter were converted into 4-aminopyrazoles in good yields using the Thorpe-Ziegler cyclization.

Hydrogen-Bonding Catalysis of Tetraalkylammonium Salts in an Aza-Diels-Alder Reaction.

Science.gov (United States)

Kumatabara, Yusuke; Kaneko, Shiho; Nakata, Satoshi; Shirakawa, Seiji; Maruoka, Keiji

2016-08-05

A piperidine-derived tetraalkylammonium salt with a non-coordinating counteranion worked as an effective hydrogen-bonding catalyst in an aza-Diels-Alder reaction of imines and a Danishefsky diene. The hydrogen-bonding interaction between the ammonium salt and an imine was observed as part of a (1) H NMR titration study. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Ultrasound-Promoted One-Pot, Four-Component Synthesis of Pyridin-2(1H-One Derivatives

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Jinming Yang

2013-11-01

Full Text Available An efficient one-pot synthesis of 1,6-diamino-2-oxo-1,2,3,4-tetrahydro- pyridine-3,5-dicarbonitrile derivatives by four-component piperidine-catalyzed reactions of a ketone, malononitrile, ethyl cyanoacetate and hydrazine hydrate under ultrasound irradiation is described. This method provides several advantages such as shorter reaction times, excellent yields, and a simple workup procedure.

An Expeditious Stereoselective Synthesis of (−)-Pinidinone from Ethyl Acetoacetate

International Nuclear Information System (INIS)

Damodar, Kongara; Jun, Jong-Gab

2016-01-01

An expeditious stereoselective synthesis of a naturally occurring 2,6-disubstituted piperidine alkaloid, (−)-pinidinone, has been accomplished with an overall yield of 31% in total eight steps. The synthesis involves ethyl acetoacetate as the starting material and the stereoselective α-aminoallylation of aldehyde with (S)-tert-butanesulfinamide, allyl bromide, and indium and Grubbs' olefin cross-metathesis as the pivotal steps.

Quenching of excited uranyl ion during its photochemical reduction with triphenyl-phosphine : Part IV - effect of heterocyclic molecules

International Nuclear Information System (INIS)

Sidhu, M.S.; Bhatia, P.V.K.

1994-01-01

The presence of heterocyclic compounds triggers off a competition between photophysical and photochemical annihilation of excited uranyl ion during its photochemical reduction with triphenylphosphine. This competition is used to measure Stern-Volmer constant using UV visible spectrophotometer for quenching the uranyl ion luminescence with a number of heterocyclic molecules viz., pyridine, thiophene bipyridyl, tetrahydrofuran and piperidine. (author). 7 refs., 2 figs., 1 tab

Controlled shift in the tautomeric equilibrium of 4-​((phenylimino)​methyl)​naphthalen-​1-​ol

DEFF Research Database (Denmark)

Kamounah, Fadhil S.; Deneva, V; Manolova, y

2013-01-01

-​((Phenylimino)​methyl)​naphthalen-​1-​ol and 4-​((phenylimino)​methyl)​-​2-​(piperidin-​1-​ylmethyl)​naphthalen-​1-​ol have been synthesized and their tautomeric properties were investigated using mol. spectroscopy (UV-​vis absorption​/emission and NMR)​, X-​ray crystallog. anal. and quantum-​c...

Effects of basic nitrogen poisoning on adsorption of hydrogen on a hydrotreatment catalyst

International Nuclear Information System (INIS)

Entz, R.W.; Seapan, M.

1985-01-01

Activity of a hydrotreatment catalyst depends on the hydrogen adsorption characteristics of the catalyst. In this work, the adsorption of hydrogen on a Ni-Mo/Al/sub 2/O/sub 3/ catalyst (shell 324) has been studied using a TGA at 1 atm pressure and 200-400 0 C temperature. Hydrogen adsorption on a calcined catalyst was shown to be of activated type with a sudden increase in hydrogen adsorption around 350 0 C. When the catalyst is extracted with Tetrahydrofuran (THF), the hydrogen adsorption increases gradually as the temperature is increased, approaching a monolayer coverage of the catalyst surface. It is shown that solvent extraction of catalyst changes its hydrogen adsorption characteristics significantly. Indeed, at 400 0 C, an extracted catalyst adsorbs about four times more hydrogen than an unextracted catalyst. Adsorption of basic nitrogen compounds on the catalyst interferes with the hydrogen adsorption. The adsorption of pyridine, piperidine, n-pentylamine, and ammonia were studied at 400 0 C. It is shown that the strength of adsorption of piperidine and n-pentylamine are relatively similar, however their adsorption strength is higher than pyridine. Ammonia is the weakest adsorbing compound studied. These observations are in agreement with other studies

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

Science.gov (United States)

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

2014-10-15

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

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.

Science.gov (United States)

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.

Reaction of single-standard DNA with hydroxyl radical generated by iron(II)-ethylenediaminetetraacetic acid

International Nuclear Information System (INIS)

Prigodich, R.V.; Martin, C.T.

1990-01-01

This study demonstrates that the reaction of Fe(II)-EDTA and hydrogen peroxide with the single-stranded nucleic acids d(pT) 70 and a 29-base sequence containing a mixture of bases results in substantial damage which is not directly detected by gel electrophoresis. Cleavage of the DNA sugar backbone is enhanced significantly after the samples are incubated at 90 degree C in the presence of piperidine. The latter reaction is used in traditional Maxam-Gilbert DNA sequencing to detect base damage, and the current results are consistent with reaction of the hydroxyl radical with the bases in single-stranded DNA (although reaction with sugar may also produce adducts that are uncleaved but labile to cleavage by piperidine). We the authors propose that hydroxyl radicals may react preferentially with the nucleic acid bases in ssDNA and that reaction of the sugars in dsDNA is dominant because the bases are sequestered within the double helix. These results have implications both for the study of single-stranded DNA binding protein binding sites and for the interpretation of experiments using the hydroxyl radical to probe DNA structure or to footprint double-stranded DNA binding protein binding sites

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

Science.gov (United States)

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

2010-11-15

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

A concise synthesis of (R)-Bgugaine, a pyrrolidine alkaloid from Arisarum vulgare

Digital Repository Service at National Institute of Oceanography (India)

Majik, M.S.; Parameswaran, P.S.; Tilve, S.G.

and conversion of N-carboethoxy group to N-methyl. Keywords: pyrrolidine alkaloids, bgugaine, Wittig reaction Nitrogen containing heterocycles including pyrrolidines, piperidines and related compounds, include important biologically active compounds 1.... 18 The necessary manipulation for the conversion of aldehyde group to tetradecane chain involved application of the Wittig reaction followed by reduction of the double bond and reduction of carboethoxy group to methyl. Thus, freshly...

Prospective, Controlled, Multicentre Study of Loperimide in Pregnancy

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A Einarson

2000-01-01

Full Text Available BACKGROUND: Loperamide is a synthetic piperidine derivative used for the treatment of both acute and chronic diarrhea. Little is known about its safety and risk in pregnancy. Human data are limited to one surveillance study of Michigan Medicaid patients, with 108 women exposed in the first trimester. In this study there were six major birth defects, three of which were cardiovascular anomalies.

Drug Abuse and Criminal Violence in Urban Communities.

Science.gov (United States)

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

Exploring architectures displaying multimeric presentations of a trihydroxypiperidine iminosugar

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Camilla Matassini

2015-12-01

Full Text Available The synthesis of new multivalent architectures based on a trihydroxypiperidine α-fucosidase inhibitor is reported herein. Tetravalent and nonavalent dendrimers were obtained by means of the click chemistry approach involving the copper azide-alkyne-catalyzed cycloaddition (CuAAC between suitable scaffolds bearing terminal alkyne moieties and an azido-functionalized piperidine as the bioactive moiety. A preliminary biological investigation is also reported towards commercially available and human glycosidases.

A facile stereospecific synthesis of (Z)-2-sulfonyl-substituted 1,3-enynes via Sonogashira coupling of (E)-α-iodovinyl sulfones with 1-alkynes

Institute of Scientific and Technical Information of China (English)

无

2007-01-01

(E)-α-Iodovinyl sulfones 1 underwent the Sonogashira coupling reactions with terminal alkynes 2 in piperidine at room temperature in the presence of 5 mol% of Pd(PPh3)4 and 10 mol% of CuI to stereospecifically afford the corresponding (Z)-2-sulfonyl-substituted 1,3-enynes 3 in high yields.(C) 2007 Ming Zhong Cai. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.

4-[3-(4-Methylpiperidin-1-ylpropanamido]benzenesulfonamide monohydrate

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Hasan Türkmen

2012-12-01

Full Text Available In the title compound, C15H23N3O3S·H2O, the piperidine ring has a chair conformation. In the crystal, the sulfonamide molecules are linked by N—H...O hydrogen bonds, forming a layer parallel to (10-1. The layers are interconnected via N—H...Ow, Ow—H...N and Ow—H...O (w = water hydrogen bonds, forming a three-dimensional network.

Genetic variation of alkaloid production in Conium maculatum after reassociation with the specialist moth Agonopterix alstroemeriana

OpenAIRE

Castells Caballé, Eva; Berenbaum, M.R.

2005-01-01

Conium maculatum, a Eurasian weed naturalized in North America, contains high concentrations of piperidine alkaloids. In the United States, C. maculatum was largely free from herbivory until approximately 30 years ago, when it was re-associated via accidental introduction with a monophagous European herbivore, the oecophorid caterpillar Agonopterix alstroemeriana. At present, A. alstroemeriana is found in a continuum of re-association time and intensities with C. maculatum across the continen...

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

International Nuclear Information System (INIS)

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

1988-01-01

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

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

Science.gov (United States)

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.

Pyrolytic fate of piperidinocyclohexanecarbonitrile, a contaminant of phencyclidine, during smoking

International Nuclear Information System (INIS)

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

1988-01-01

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, [ 3 H]piperidino-[ 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 2 SO 4 , or NaOH. Approximately 75% of the 3 H was collected in these traps, and 46, 11, and 5% of the 14 C was found in the glass wool, H 2 SO 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

The effect of heterocyclic S,S’-ligands on the electrochemical properties of some cobalt(III complexes in acid

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V. M. JOVANOVIC

2005-02-01

Full Text Available Eight mixed-ligand cobalt(III complexes with the macrocyclic amine 1,4,8,11-tetraazacyclotetradecane (cyclam and a heterocyclic dithiocarbamate (Rdtc- i.e., morpholine- (Morphdtc, thiomorpholine- (Timdtc, piperazine- (Pzdtc, N-methylpiperazine-(Mepzdtc, piperidine- (Pipdtc, 2-, 3- or 4-methylpiperidine- (2-, 3- and 4-Mepipdtc carbodithionato-S,S ions, of the general formula [Co(cyclamRdtc](ClO42, were investigated in deoxygenated 0.1MHClO4 solutions. Cyclic voltammetry data at a glassy carbon (GC electrode demonstrate a redox reaction of cobalt(III from the complexes at potentials strongly influenced by the presence of different heterocyclic Rdtc- ligands. In this respect, the complexes were separated into two groups: the first, with a heteroatom O, S or N in the heterocyclic ring, and the second, with a methyl group on the piperidine ring of the Rdtc- ligand. Anodic polarization of an Fe electrode in the presence of the complexes shows their influence not only on the dissolution of iron but also on the hydrogen evolution reactions and on this basis complexes the complexes could be divided into the same two groups. It was found that the weaker the inhibiting effect of the free heterocyclic amines is, the significantly higher is the efficiency of the corresponding complexes.

Synthesis, Antifungal and Antitumor Activity of Novel (Z-5-Hetarylmethylidene-1,3-thiazol-4-ones and (Z-5-Ethylidene-1,3-thiazol-4-ones

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Susana A. Zacchino

2013-05-01

Full Text Available New hetaryl- and alkylidenerhodanine derivatives 3a–d, 3e, and 4a–d were prepared from heterocyclic aldehydes 1a–d or acetaldehyde 1e. The treatment of several rhodanine derivatives 3a–d and 3e with piperidine or morpholine in THF under reflux, afforded (Z-5-(hetarylmethylidene-2-(piperidin-1-ylthiazol-4(5H-ones and 2-morpholinothiazol-4(5H-ones 5a–d, 6a–d, and (Z-5-ethylidene-2-morpholinothiazol-4(5H-one (5e, respectively, in good yields. Structures of all compounds were determined by IR, 1D and 2D NMR and mass spectrometry. Several of these compounds were screened by the U.S. National Cancer Institute (NCI to assess their antitumor activity against 60 different human tumor cell lines. Compound 3c showed high activity against HOP-92 (Non-Small Cell Lung Cancer, which was the most sensitive cell line, with GI50 = 0.62 μM and LC50 > 100 μM from the in vitro assays. In vitro antifungal activity of these compounds was also determined against 10 fungal strains. Compound 3e showed activity against all fungal strains tested, but showed high activity against Saccharomyces cerevisiae (MIC 3.9 μg/mL.

Sequence specificity of alkali-labile DNA damage photosensitized by suprofen.

Science.gov (United States)

Starrs, S M; Davies, R J

2000-09-01

On irradiation at UVB wavelengths, in aerated neutral aqueous solution, the anti-inflammatory drug suprofen (SP) photosensitizes the production of alkali-labile cleavage sites in DNA much more efficiently than direct strand breaks. It is active at submillimolar concentrations despite having no significant binding affinity for DNA. Gel sequencing studies utilizing 32P-end-labeled oligonucleotides have revealed that piperidine-sensitive lesions are formed predominantly at the positions of guanine (G) bases, with the extent of modification being UV dose- and SP concentration-dependent. Quite distinct patterns of G-specific damage are observed in single-stranded and duplex DNA molecules. The uniform attack at all G residues in single-stranded DNA, which is enhanced in D2O, is compatible with a Type-II mechanism. SP is a known generator of singlet oxygen whose participation in the reaction is supported by the effects of quenchers and scavengers. In duplex DNA, piperidine-induced cleavage occurs with high selectivity at the 5'-G of GG and (less prominently) GA doublets. This behavior is characteristic of a Type-I process involving electron transfer from DNA to photoexcited SP molecules. The ability of SP to sensitize the formation of Type-I and Type-II photo-oxidation products from 2'-deoxyguanosine attests to the feasibility of competing mechanisms in DNA.

Experimental and theoretical NMR study of 4-(1-pyrrolidinyl)piperidine

African Journals Online (AJOL)

Solvent effects on nuclear magnetic shielding tensors have been investigated using chloroform-d, methanol-d, acetone-d, dimethylsulfoxide-d and water-d. The magnitude of nJ(C,H) (n = 1, 2, 3) coupling constants of 4-pypp have been determined with selective 1H decoupled 13C NMR techniques. 1H, 13C, 15N NMR ...

Actions of piperidine alkaloid teratogens at fetal nicotinic acetylcholine receptors.

Science.gov (United States)

Green, Benedict T; Lee, Stephen T; Panter, Kip E; Welch, Kevin D; Cook, Daniel; Pfister, James A; Kem, William R

2010-01-01

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 cleft palate. A pharmacodynamic comparison of the alkaloids ammodendrine, anabasine, anabaseine, anagyrine, and coniine in SH-SY5Y cells and TE-671 cells was made. These alkaloids and their enantiomers were more effective in depolarizing TE-671 cells which express the human fetal-muscle type nicotinic acetylcholine receptor (nAChR) relative to SH-SY5Y cells which predominately express autonomic nAChRs. The rank order of potency in TE-671 cells was: anabaseine>(+)-anabasine>(-)-anabasine > (+/-)-anabasine>anagyrine>(-)-coniine > (+/-)-coniine>(+)-coniine>(+/-)-ammodendrine>(+)-ammodendrine. The rank order potency in SH-SY5Y cells was: anabaseine>(+)-anabasine>(-)-coniine>(+)-coniine>(+)-ammodendrine>anagyrine>(-)-anabasine>(+/-)-coniine>(+/-)-anabasine>(-)-ammodendrine. The actions of these alkaloids at nAChRs in both cell lines could be distinguished by their maximum effects in depolarizing cell membrane potential. The teratogenic action of these compounds may be related to their ability to activate and subsequently desensitize nAChRs.

Facile and Green Synthesis of Saturated Cyclic Amines

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Arruje Hameed

2017-10-01

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

Piperidinium 3-hydroxy-2-naphthoate

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Wen-Zhu Wan

2008-09-01

Full Text Available The crystals of the title salt, C5H12N+·C11H7O3−, were obtained from a methanol/water solution of 3-hydroxy-2-naphthoic acid and piperidine at room temperature. In the crystal structure, the piperidinium cations display a chair conformation and link with hydroxynaphthoate anions via N—H...O and C—H...O hydrogen bonds. An intramolecular O—H...O interaction is also present.

Carrier-added and no-carrier-added syntheses of (/sup 18/F)spiroperidol and (/sub 18/F)haloperidol

Energy Technology Data Exchange (ETDEWEB)

Kilbourn, M R; Welch, M J; Dence, C S; Tewson, T J; Saji, H; Maeda, M

1984-07-01

Syntheses of (18F)haloperidol and (18F)spiroperidol in both no-carrier-added and carrier-added forms have been accomplished. The no-carrier-added (18F)butyrophenone neuroleptics were prepared in low (less than 2%) yield by acid decomposition of aryl piperidine triazenes. Carrier-added 18F-neuroleptics were prepared in better (5-17%) yields by 18F-for-19F nucleophilic aromatic substitution. The preparation of all synthetic precursors, and procedures for radiolabeling are fully described.

Total synthesis of (-)- and (+)-tedanalactam

Digital Repository Service at National Institute of Oceanography (India)

Majik, M.S.; Parameswaran, P.S.; Tilve, S.G.

: The Journal of Organic Chemistry, vol.74(16); 6378-6381 1 Total Synthesis of (-) and (+)-Tedanalactam Mahesh S. Majik, † Peruninakulath S. Parameswaran, ‡ and Santosh G. Tilve* ,† Department of Chemistry, Goa University, Taleigao Plateau, Goa 403..., displaying a wide range of biological activities. 1 Piperidones are key synthetic intermediates 2 for the synthesis of piperidine ring due to the presence of keto function which allows the introduction of other groups. Piperidones are also known...

Efficient modulation of γ-aminobutyric acid type A receptors by piperine derivatives.

Science.gov (United States)

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.

Carrier-added and no-carrier-added syntheses of (/sup 18/F)spiroperidol and (/sup 18/F)haloperidol

Energy Technology Data Exchange (ETDEWEB)

Kilbourn, M R; Welch, M J; Dence, C S; Tewson, T J; Saji, H; Maeda, M [Washington Univ., St. Louis, MO (USA). Edward Mallinckrodt Inst. of Radiology

1984-07-01

Syntheses of (/sup 18/F)haloperidol and (/sup 18/F)spiroperidol in both no-carrier-added and carrier-added forms have been accomplished. The no-carrier-added (/sup 18/F)butyrophenone neuroleptics were prepared in low (<2%) yield by acid decomposition of aryl piperidine triazenes. Carrier-added /sup 18/F-neuroleptics were prepared in better (5-17%) yields by /sup 18/F-for-/sup 19/F nucleophilic aromatic substitution. The preparation of all synthetic precursors, and procedures for radiolabeling are fully described.

Ultrasound-Promoted One-Pot, Three-Component Synthesis of Spiro[indoline-3,1'-pyrazolo[1,2-b]phthalazine] Derivatives

Directory of Open Access Journals (Sweden)

Daqing Shi

2012-07-01

Full Text Available A series of 3'-aminospiro[indoline-3,1'-pyrazolo[1,2-b]phthalazine]-2,5',10'-trione derivatives have been synthesized by a one-pot three-component reaction of isatin, malononitrile or ethyl cyanoacetate and phthalhydrazide catalyzed by piperidine under ultrasound irradiation. For comparison the reactions were carried out under both conventional and ultrasonic conditions. In general, improvement in rates and yields were observed when the reactions were carried out under sonication compared with classical conditions.

Stereoselective, nitro-Mannich/lactamisation cascades for the direct synthesis of heavily decorated 5-nitropiperidin-2-ones and related heterocycles

Directory of Open Access Journals (Sweden)

Pavol Jakubec

2012-04-01

Full Text Available A versatile nitro-Mannich/lactamisation cascade for the direct stereoselective synthesis of heavily decorated 5-nitropiperidin-2-ones and related heterocycles has been developed. A highly enantioenriched substituted 5-nitropiperidin-2-one was synthesised in a four component one-pot reaction combining an enantioselective organocatalytic Michael addition with the diastereoselective nitro-Mannich/lactamisation cascade. Protodenitration and chemoselective reductive manipulation of the heterocycles was used to install contiguous and fully substituted stereocentres in the synthesis of substituted piperidines.

Study of chemical shifts of the chloroform complexes with cyclic donors of electrons

International Nuclear Information System (INIS)

Blaszkiewicz, B.; Pajak, Z.

1973-01-01

Chemical shifts of chloroform complexes with the heterocyclic electron donors: pyridine, piperidine, alpha-picoline and gamma-picoline have been studied using the high resolution (5.10 -9 ) spectrometer operating at 80 MHz. An attempt has also been made to study the three - component solutions of : chloroform, a heterocyclic donor of electrons and carbon tetrachloride. The results, which have been obtained, indicate that the complex-forming power of pyridine and other electron donors is greater in carbon tetrachloride than in other solvents. (S.B.)

Microwave-assisted rapid synthesis of methyl 2,4,5-trimethoxyphenylpropionate, a metabolite of Cordia alliodora.

Science.gov (United States)

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).

Discovery, synthesis, selectivity modulation and DMPK characterization of 5-azaspiro[2.4]heptanes as potent orexin receptor antagonists.

Science.gov (United States)

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.

Novel derivatives of 5,6-dimethoxy-1-indanone coupled with substituted pyridine as potential antimicrobial agents

OpenAIRE

Vimal M. Patel; Nilay D. Bhatt; Pralav V. Bhatt; Hasmukh D. Joshi

2018-01-01

Synthesis of novel derivatives of 5,6-dimethoxy-1-indanone was carried out via its Schiff’s base using 2-cyanoacetohydrazide followed by cyclization with 2-arylidenemalononitrile in the presence of a catalytical amount of piperidine to get 6-amino-1-(5,6-dimethoxy-2,3-dihydro-1H-inden-1-ylideneamino)-2-oxo-4-aryl-1,2-dihydropyridine-3,5-dicarbonitrile derivatives. The structures of the synthesized compounds were confirmed on the basis of their spectral and elemental analysis. The synthesized ...

A prototypical Sigma-1 receptor antagonist protects against brain ischemia

OpenAIRE

Schetz, John A.; Perez, Evelyn; Liu, Ran; Chen, Shiuhwei; Lee, Ivan; Simpkins, James W.

2007-01-01

Previous studies indicate that the Sigma-1 ligand 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP) protects the brain from ischemia. Less clear is whether protection is mediated by agonism or antagonism of the Sigma-1 receptor, and whether drugs already in use for other indications and that interact with the Sigma-1 receptor might also prevent oxidative damage due to conditions such as cerebral ischemic stroke. The antipsychotic drug haloperidol is an antagonist of Sigma-1 receptors and in this s...

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.

Science.gov (United States)

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

Enzymatic Kinetic Resolution of 2-Piperidineethanol for the Enantioselective Targeted and Diversity Oriented Synthesis

Directory of Open Access Journals (Sweden)

Dario Perdicchia

2015-12-01

Full Text Available 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.

Sub-nanosecond plastic scintillators

International Nuclear Information System (INIS)

Lyons, P.B.; Caldwell, S.E.; Hocker, L.P.; Crandall, D.G.; Zagarino, P.A.; Cheng, J.; Tirsell, G.; Hurlbut, C.R.

1977-01-01

Quenched plastic scintillators have been developed that yield much faster short decay components and greatly reduced long decay components compared to conventional plastic scintillators. The plastics are produced through the addition of selected quench agents to NE111 plastic scintillator that result in reduced total light output. Eight different agents have been studied. Benzophenone and piperidine are two of the most effective quench agents. Data are presented both for short and long decay components. The plastics are expected to make significant contributions in areas of plasma diagnostics

Sub-nanosecond plastic scintillators

International Nuclear Information System (INIS)

Lyons, P.B.; Caldwell, S.E.; Hocker, L.P.; Crandall, D.G.; Zagarino, P.A.; Cheng, J.; Tirsell, G.; Hurlbut, C.R.

1976-01-01

Quenched plastic scintillators have been developed that yield much faster short decay components and greatly reduced long decay components compared to conventional plastic scintillators. The plastics are produced through the addition of selected quench agents to NE111 plastic scintillator that result in reduced total light output. Eight different agents have been studied. Benzophenone and piperidine are two of the most effective quench agents. Data are presented both for short and long decay components. The plastics are expected to make significant contributions in areas of plasma diagnostics

Green synthesis of tetrahydrobenzo[b]Pyrans by microwave assisted multi-component one-pot reactions in PEG-400.

Science.gov (United States)

Feng, Chun; Wang, Qiuyan; Lu, Cuifen; Yang, Guichun; Chen, Zuxing

2012-01-01

Polyethylene glycol is found to be a nontoxic and recyclable reaction medium for the microwave-assisted, multi-component one-pot reactions of aromatic aldehydes with ethyl-2-cyanoacetate and 1,3-cyclohexanedione or 5,5- dimethyl-1,3-cyclohexanedione in the presence of piperidine. This environmentally friendly microwave protocol offers ease of operation and enables recyclability of reaction medium and synthesis of a variety of substituted tetrahydrobenzo[b]pyran derivatives. It is an efficient, promising, and green synthetic strategy to construct tetrahydrobenzo[b]pyran skeleton.

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

Directory of Open Access Journals (Sweden)

K. L. Ameta

2012-01-01

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

Synthesis and characterization of new mixed ligand complexes of ruthenium(II) containing triphenylphosphine and 2'-hydroxychalcones

International Nuclear Information System (INIS)

Dharmaraj, N.; Natarajan, K.

1994-01-01

A few hexacoordinated ruthenium(II) complexes of the type [RuCl(CO) (HLL')(PPh 3 ) 2 ] and [RuCl(CO)(HLL')(B) (PPh 3 )] (where HLL' 2'-hydroxychalcone, 2'-hydroxy-4-methoxychalcone, 2'-hydroxy-3,4-dimethoxychalcone and B=pyridine(Py), piperidine(Pip), morpholine (Morph)) have been synthesised and characterized on the basis of their analytical and spectral data (IR, electronic and 1 H NMR). In all these complexes, the 2'-hydroxychalcones behave as a uninegative bidentate (OO - ) chelating ligand. (author). 17 refs., 1 tab

Curcumin and synthetic analogs induce reactive oxygen species and decreases specificity protein (Sp) transcription factors by targeting microRNAs

International Nuclear Information System (INIS)

Gandhy, Shruti U; Kim, KyoungHyun; Larsen, Lesley; Rosengren, Rhonda J; Safe, Stephen

2012-01-01

Curcumin inhibits growth of several cancer cell lines, and studies in this laboratory in bladder and pancreatic cancer cells show that curcumin downregulates specificity protein (Sp) transcription factors Sp1, Sp3 and Sp4 and pro-oncogenic Sp-regulated genes. In this study, we investigated the anticancer activity of curcumin and several synthetic cyclohexanone and piperidine analogs in colon cancer cells. The effects of curcumin and synthetic analogs on colon cancer cell proliferation and apoptosis were determined using standardized assays. The changes in Sp proteins and Sp-regulated gene products were analysed by western blots, and real time PCR was used to determine microRNA-27a (miR-27a), miR-20a, miR-17-5p and ZBTB10 and ZBTB4 mRNA expression. The IC 50 (half-maximal) values for growth inhibition (24 hr) of colon cancer cells by curcumin and synthetic cyclohexanone and piperidine analogs of curcumin varied from 10 μM for curcumin to 0.7 μM for the most active synthetic piperidine analog RL197, which was used along with curcumin as model agents in this study. Curcumin and RL197 inhibited RKO and SW480 colon cancer cell growth and induced apoptosis, and this was accompanied by downregulation of specificity protein (Sp) transcription factors Sp1, Sp3 and Sp4 and Sp-regulated genes including the epidermal growth factor receptor (EGFR), hepatocyte growth factor receptor (c-MET), survivin, bcl-2, cyclin D1 and NFκB (p65 and p50). Curcumin and RL197 also induced reactive oxygen species (ROS), and cotreatment with the antioxidant glutathione significantly attenuated curcumin- and RL197-induced growth inhibition and downregulation of Sp1, Sp3, Sp4 and Sp-regulated genes. The mechanism of curcumin-/RL197-induced repression of Sp transcription factors was ROS-dependent and due to induction of the Sp repressors ZBTB10 and ZBTB4 and downregulation of microRNAs (miR)-27a, miR-20a and miR-17-5p that regulate these repressors. These results identify a new and highly potent

Curcumin and synthetic analogs induce reactive oxygen species and decreases specificity protein (Sp transcription factors by targeting microRNAs

Directory of Open Access Journals (Sweden)

Gandhy Shruti U

2012-11-01

Full Text Available Abstract Background Curcumin inhibits growth of several cancer cell lines, and studies in this laboratory in bladder and pancreatic cancer cells show that curcumin downregulates specificity protein (Sp transcription factors Sp1, Sp3 and Sp4 and pro-oncogenic Sp-regulated genes. In this study, we investigated the anticancer activity of curcumin and several synthetic cyclohexanone and piperidine analogs in colon cancer cells. Methods The effects of curcumin and synthetic analogs on colon cancer cell proliferation and apoptosis were determined using standardized assays. The changes in Sp proteins and Sp-regulated gene products were analysed by western blots, and real time PCR was used to determine microRNA-27a (miR-27a, miR-20a, miR-17-5p and ZBTB10 and ZBTB4 mRNA expression. Results The IC50 (half-maximal values for growth inhibition (24 hr of colon cancer cells by curcumin and synthetic cyclohexanone and piperidine analogs of curcumin varied from 10 μM for curcumin to 0.7 μM for the most active synthetic piperidine analog RL197, which was used along with curcumin as model agents in this study. Curcumin and RL197 inhibited RKO and SW480 colon cancer cell growth and induced apoptosis, and this was accompanied by downregulation of specificity protein (Sp transcription factors Sp1, Sp3 and Sp4 and Sp-regulated genes including the epidermal growth factor receptor (EGFR, hepatocyte growth factor receptor (c-MET, survivin, bcl-2, cyclin D1 and NFκB (p65 and p50. Curcumin and RL197 also induced reactive oxygen species (ROS, and cotreatment with the antioxidant glutathione significantly attenuated curcumin- and RL197-induced growth inhibition and downregulation of Sp1, Sp3, Sp4 and Sp-regulated genes. The mechanism of curcumin-/RL197-induced repression of Sp transcription factors was ROS-dependent and due to induction of the Sp repressors ZBTB10 and ZBTB4 and downregulation of microRNAs (miR-27a, miR-20a and miR-17-5p that regulate these repressors

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

Science.gov (United States)

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

2012-03-21

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

Radiosynthesis of [11C]brofaromine, a potential tracer for imaging monoamine oxidase A

International Nuclear Information System (INIS)

Ametamey, S.M.; Beer, H.-F.; Guenther, I.; Antonini, A.; Leenders, K.L.; Waldmeier, P.C.; Schubiger, P.A.

1996-01-01

Brofaromine(4-5(-methoxy-7-bromobenzofuranyl)-2-piperidine-HCl) is a potent and selective inhibitor of monoamine oxidase (MAO) A. Two methods for its synthesis and a preliminary positron emission tomography (PET) evaluation in monkey brain are described. The first method, at low carrier concentration of CO 2 , consisted of direct O-methylation of (4-(5-hydroxy-7-bromobenzofuranyl)-2-piperidine). The total radiochemical yield achieved ranged from 30 to 50% (from end of bombardment [EOB] and decay corrected) with an overall synthesis time of 45 min. The second approach, with high carrier amounts of CO 2 arising from inherent target problems, was accomplished in a three-step route involving protection of secondary amino functionality, O-methylation and deprotection. The total radiochemical yield was 10% (from EOB and decay corrected) with a total synthesis time of 70 min. For both methods methylation was achieved using the classical methylating agent [ 11 C]CH 3 I, and radiochemical purity was higher than 98%. PET evaluation of the radioligand in a Rhesus monkey showed a high uptake of radioactivity in the brain. Using the irreversible MAO-A inhibitor clorgyline and reversible MAO-A inhibitors moclobemide and brofaromine, three blockade experiments were designed to determine the extent of specific binding of [ 11 C]brofaromine to MAO-A. No apparent decrease in accumulation of radioactivity in the monkey brain was observed when compared to a baseline scan

Anti-trypanosomal activities and structural chemical properties of selected compound classes.

Science.gov (United States)

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.

Asymmetric Formal Aza-Diels-Alder Reaction of Trifluoromethyl Hemiaminals with Enones Catalyzed by Primary Amines.

Science.gov (United States)

Zhang, Sheng; Cha, Lide; Li, Lijun; Hu, Yanbin; Li, Yanan; Zha, Zhenggen; Wang, Zhiyong

2016-04-15

A primary amine-catalyzed asymmetric formal aza-Diels-Alder reaction of trifluoromethyl hemiaminals with enones was developed via a chiral gem-diamine intermediate. This novel protocol allowed facile access to structurally diverse trifluoromethyl-substituted piperidine scaffolds with high stereoselectivity. The utility of this method was further demonstrated through a concise approach to biologically active 4-hydroxypiperidine. More importantly, a stepwise mechanism involving an asymmetric induction process was proposed to rationalize the positive correlation between the chirality of the gem-diamine intermediate and the formal aza-Diels-Alder product.

Preparation of iodine-123 labeled AM251: a potential SPECT radioligand for the brain cannabinoid CB1 receptor

International Nuclear Information System (INIS)

Lan, Ruoxi; Makriyannis, Alexandros; Gatley, S.J.

1996-01-01

We report the synthesis and labeling with iodine-123 of N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2, 4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251). This compound is an analog of the recently described cannabinoid receptor antagonist, SR141716A, in which a 4-chlorophenyl group is replaced by 4-iodophenyl. Labeling in good yield (62%) and radiochemical purity (> 95%), and high specific activity (> 2500 Ci/mmol) was achieved by an iododestannylation reaction using the tributyltin precursor, no carrier added I-123 iodide, and chloramine-T. (author)

(-)-7-hydroxycassine: a new 2,6-dialkylpiperidin-3-ol alkaloid and other constituents isolated from flowers and fruits of Senna spectabilis (Fabaceae)

International Nuclear Information System (INIS)

Viegas Junior, Claudio; Pivatto, Marcos; Rezende, Amanda de; Hamerski, Lidilhone; Silva, Dulce Helena Siqueira; Bolzani, Vanderlan da Silva

2013-01-01

The phytochemical study of flowers and green fruits of Senna spectabilis furnished a new substituted 2,6-dialkylpiperidin-3-ol alkaloid, named (–)-7-hydroxycassine, along with five known piperidine alkaloids: (–)-cassine, (–)-spectaline, (–)-3-O-acetylspectaline, (–)-7-hydroxyspectaline and (–)-iso-6-spectaline. In addition to non-alkaloidal, chemical constituents from other chemical classes were also identified, including the steroid β-sitosterol, the flavonoids luteolin and 3-methoxyluteolin, the triterpene betulinic acid and trans-cinnamic acid. To our knowledge, compounds are being reported for the first time in this species. (author)

Probing Framework-Restricted Metal Axial Ligation and Spin State Patterns in a Post-Synthetically Reduced Iron-Porphyrin-Based Metal–Organic Framework

Energy Technology Data Exchange (ETDEWEB)

Kucheryavy, Pavel; Lahanas, Nicole; Velasco, Ever; Sun, Cheng-Jun; Lockard, Jenny V.

2016-04-07

An iron porphyrin-based metal organic framework, PCN-222(Fe) is investigated upon post-synthetic reduction with piperidine. Fe K-edge X-ray absorption and Kβ mainline emission spectroscopy measurements reveal the local coor-dination geometry, oxidation and spin state changes experi-enced by the Fe sites upon reaction with this axially coordi-nating reducing agent. Analysis and fitting of these data con-firm the binding pattern predicted by a space filling model of the structurally constrained pore environments. These results are further support by UV-vis diffuse reflectance, IR and Raman spectroscopy data.

(-)-7-hydroxycassine: a new 2,6-dialkylpiperidin-3-ol alkaloid and other constituents isolated from flowers and fruits of Senna spectabilis (Fabaceae)

Energy Technology Data Exchange (ETDEWEB)

Viegas Junior, Claudio, E-mail: viegas@unifal-mg.edu.br, E-mail: cvjviegas@gmail.com [Universidade Federal de Alfenas (UNIFAL), MG (Brazil). Instituto de Quimica. Laboratorio de Fitoquimica e Quimica Medica; Pivatto, Marcos [Universidade Federal de Uberlandia, MG (Brazil). Instituto de Quimica; Rezende, Amanda de; Hamerski, Lidilhone; Silva, Dulce Helena Siqueira; Bolzani, Vanderlan da Silva [Universidade Estadual Paulista Julio de Mesquita Filho (NuBBE/UNESP), Araraquara, SP (Brazil). Instituto de Quimica. Nucleo de Bioensaios, Biossintese e Ecofiologia de Produtos Naturais

2013-02-15

The phytochemical study of flowers and green fruits of Senna spectabilis furnished a new substituted 2,6-dialkylpiperidin-3-ol alkaloid, named (-)-7-hydroxycassine, along with five known piperidine alkaloids: (-)-cassine, (-)-spectaline, (-)-3-O-acetylspectaline, (-)-7-hydroxyspectaline and (-)-iso-6-spectaline. In addition to non-alkaloidal, chemical constituents from other chemical classes were also identified, including the steroid {beta}-sitosterol, the flavonoids luteolin and 3-methoxyluteolin, the triterpene betulinic acid and trans-cinnamic acid. To our knowledge, compounds are being reported for the first time in this species. (author)

Oxidation of the Primary Alcoholic Moiety Selectively in the Presence of the Secondary Alcoholic Moieties

International Nuclear Information System (INIS)

Tin Myint Htwe

2011-12-01

Both primary and secondary alcoholic moieties are very sensitive to oxidation reactions. But sometimes it is necessary to oxidized only the primary alcoholic moiety. Such cases are usually found in Food Industries. In this situation, TEMPO (1, 1, 6, 6-Tetramethyl-1-Piperidine Oxoammonium) was used as an oxidizing agent. In this paper, Alpha starch was successfully oxidized using TEMPO as the oxidizing agent in combination with sodium hypochlorite with and without sodium bromide. The oxidation of primary alcoholic moiety only and the remaining untouched secondary alcoholic moiety were proved by infrared spectroscopy method.

Homoserine as an Aspartic Acid Precursor for Synthesis of Proteoglycan Glycopeptide Containing Aspartic Acid and a Sulfated Glycan Chain.

Science.gov (United States)

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.

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

Science.gov (United States)

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.

Preparation of iodine-123 labeled AM251: a potential SPECT radioligand for the brain cannabinoid CB1 receptor

Energy Technology Data Exchange (ETDEWEB)

Lan, Ruoxi; Makriyannis, Alexandros [Connecticut Univ., Molecular and Cell Biology Dept., Storrs, CT (United States); Gatley, S.J. [Brookhaven National Lab., Medical Dept., Upton, NY (United States)

1996-10-01

We report the synthesis and labeling with iodine-123 of N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2, 4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251). This compound is an analog of the recently described cannabinoid receptor antagonist, SR141716A, in which a 4-chlorophenyl group is replaced by 4-iodophenyl. Labeling in good yield (62%) and radiochemical purity (> 95%), and high specific activity (> 2500 Ci/mmol) was achieved by an iododestannylation reaction using the tributyltin precursor, no carrier added I-123 iodide, and chloramine-T. (author).

Aspiperidine oxide, a piperidine N-oxide from the filamentous fungus Aspergillus indologenus

DEFF Research Database (Denmark)

Petersen, Lene Maj; Kildgaard, Sara; Jaspars, Marcel

2015-01-01

A novel secondary metabolite, aspiperidine oxide, was isolated from the filamentous fungus, Aspergillus indologenus. The structure of aspiperidine oxide was determined from extensive 1D and 2D NMR spectroscopic analysis supported by high-resolution mass spectrometry. The structure revealed a rare...

Coal conversion processes. Quarterly report, December 13, 1983-March 12, 1984

Energy Technology Data Exchange (ETDEWEB)

Cobb, J.T. Jr.; Biloen, P.; Holder, G.D.; Klinzing, G.E.; Tierney, J.W.

1984-05-01

Experimental work is continuing on four separate projects related to coal conversion processes. The direct digital control of exothermic multiphase reactions is being studied in an experimental adiabatic flow reactor. The existence of two stable steady states for the Fischer-Tropsch reaction network at the same temperature and feed condition has been verified and quantified. Various absorbents for SO/sub 2/ and NO/sub X/ are being studied. The absorption of NO/sub 2/ by methanol and N-cyclohexyl-2-pyrrolidone has been extensively examined. Preliminary data have been obtained with triethylene-tetraamine. Hindered amines will be studied next. Procedures for the preparation of liquid membranes have been tested and the incorporation of hindered amines in them will now be examined. Isotopic switching is being used to study the way in which promoters affect supported metal catalysts. With improved resolution from the mass spectrometer, early quantitative results give indications of three different surface species and of non-statistical ingrowth of /sup 13/C into the product molecules. A program for the study of the extraction of coal and oil shale using supercritical fluids is being carried out. The effect of the presence of piperidine on the amount of toluene solubles produced by supercritical extraction of coal with toluene/piperidine mixture has been determined. A new kinetic model for the extraction/liquefaction of coal by supercritical toluene and THF has been developed and proven satisfactory. Bruceton coal and Hi Na lignite have been extracted with supercritical water. 3 references, 7 figures, 6 tables.

Molecular and crystal structure of 3,4-dihydroxy-2-oxo-1-methyl-4-phenylpiperidine

International Nuclear Information System (INIS)

Kuleshova, L.N.; Khrustalev, V.N.; Struchkov, Yu.T.; Soldatenkov, A.T.; Bekro, I.A.; Mamyrbekova, Zh.A.; Soldatova, S.A.

1996-01-01

The molecular and crystal structure of 3,4-dihydroxy-2-oxo-1-methyl-4-phenylpiperidine was determined. The crystal is orthorhombic: sp. gr. Pca21; a=15.764, b=5.635, and c=25.536 A; and Z=8. The structure was solved by direct methods; R1=0.051, for 2643 unique refections. Symmetry-independent molecules are related by a pseudocenter of symmetry. The piperidine cycle has an asymmetric half-chair conformation. The orientation of substituents is determined. In the crystal, intermolecular OH...O hydrogen bonds link the molecules into chains parallel to the Y-axis

Opportunities and challenges for direct C–H functionalization of piperazines

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Zhishi Ye

2016-04-01

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

3-(4-Chlorobenzoyl-4-(4-chlorophenyl-1-phenethylpiperidin-4-ol

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Abdullah Aydın

2011-06-01

Full Text Available In the title compound, C26H25Cl2NO2, the piperidine ring adopts a chair conformation with a cis configuration of the carbonyl and hydroxy substituents. The dihedral angle between the aromatic rings of the chlorobenzene groups is 24.3 (2°. The phenyl ring forms dihedral angles of 59.4 (3 and 44.1 (3° with the benzene rings. In the crystal, molecules are linked by intermolecular O—H...N and C—H...O hydrogen bonds and C—H...π interactions into layers parallel to the bc plane.

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

Science.gov (United States)

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.

Tert-butyl 3-oxo-2,3,4,5,6,7-hexahydro-1H-pyrazolo[4,3-c]pyridine-5-carboxylate

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Tara Shahani

2010-01-01

Full Text Available In the title compound, C11H17N3O3, the pyrazole ring is approximately planar, with a maximum deviation of 0.005 (2 Å, and forms a dihedral angle of 5.69 (13° with the plane through the six atoms of the piperidine ring. In the crystal, pairs of intermolecular N—H...O hydrogen bonds form dimers with neighbouring molecules, generating R22(8 ring motifs. These dimers are further linked into two-dimensional arrays parallel to the bc plane by intermolecular N—H...O and C—H...O hydrogen bonds.

Electrochemistry of norcocaine nitroxide and related compounds: implications for cocaine hepatotoxicity.

Science.gov (United States)

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.

New enamine derivatives of lapachol and biological activity

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OLIVEIRA MAILCAR F.

2002-01-01

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

Novel derivatives of 5,6-dimethoxy-1-indanone coupled with substituted pyridine as potential antimicrobial agents

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Vimal M. Patel

2018-01-01

Full Text Available Synthesis of novel derivatives of 5,6-dimethoxy-1-indanone was carried out via its Schiff’s base using 2-cyanoacetohydrazide followed by cyclization with 2-arylidenemalononitrile in the presence of a catalytical amount of piperidine to get 6-amino-1-(5,6-dimethoxy-2,3-dihydro-1H-inden-1-ylideneamino-2-oxo-4-aryl-1,2-dihydropyridine-3,5-dicarbonitrile derivatives. The structures of the synthesized compounds were confirmed on the basis of their spectral and elemental analysis. The synthesized compounds were also screened for antimicrobial activity and found to have promising antibacterial activity.

A simple and efficient in vitro method for metabolism studies of radiotracers

International Nuclear Information System (INIS)

Lee, Sang-Yoon; Choe, Yearn Seong; Kim, Dong Hyun; Park, Bok-Nam; Kim, Sang Eun; Choi, Yong; Lee, Kyung-Han; Lee, Jeewoo; Kim, Byung-Tae

2001-01-01

In vitro metabolism of acetylcholinesterase inhibitors containing 3-[ 18 F]fluoromethylbenzyl- ([ 18 F]1) and 4-[ 18 F]fluorobenzyl-piperidine moieties ([ 18 F]2) was studied and compared with the in vivo metabolism. Defluorination of the [ 18 F]1 mainly occurred to generate [ 18 F]fluoride ion both in vitro and in vivo. In contrast, the [ 18 F]2 was converted into an unknown polar metabolite in both metabolism methods and another metabolite, 4-[ 18 F]fluorobenzoic acid in vitro. These results demonstrated that the in vitro method can be used to predict the in vivo metabolism of both radiotracers

DNA lability induced by nimustine and ramustine in rat glioma cells.

Science.gov (United States)

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

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

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Mikołaj Piekarski

2014-01-01

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

N-Cyano-7α-methoxycarbonyl-6,14-endo-ethenotetrahydronorthebaine

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Mustafa Odabaşoğlu

2009-09-01

Full Text Available In the title compound (systematic name: methyl 17-cyano-3,6-dimethoxy-4,5α-epoxy-6,14-endo-ethenomorphinan-7-carboxylate, C23H24N2O5, the dihydrofuran ring adopts a twist conformation, while the piperidine ring is in a chair conformation. The benzene-fused cyclohexene ring adopts an envelope conformation. An intramolecular C—H...O hydrogen bond is observed. Intermolecular C—H...N and C—H...O hydrogen bonds form C(5 chains along the a and b axes, respectively, and together they form a three-dimensional network.

In vivo labeling of phencyclidine (PCP) receptors with 3H-TCP in the mouse brain

International Nuclear Information System (INIS)

Maurice, T.; Vignon, J.

1990-01-01

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) 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

Anti-inflammatory, antibacterial and molecular docking studies of novel spiro-piperidine quinazolinone derivatives

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Subba Poojari

2017-05-01

Full Text Available A series of novel substituted quinazolinone derivatives was synthesized and characterized by 1H NMR and LC–MS spectral techniques. The overall results of the antibacterial tests showed that these compounds had better bacteriostatic activity against Gram-positive bacteria than their parent compounds. Furthermore, compounds 5f, 6b and 6f showed potent activity against Enterococcus faecalis (ATCC 51299, with MIC values <0.2 μg/mL. Compounds 4e, 5g, 5e and 6c showed excellent activity, with MIC values <0.4 μg/mL. Gram-negative bacteria Escherichia coli (ATCC 35218 and Klebsiella (ATCC 700603 are more resistant to lower concentrations of the synthesized compounds. The anti-inflammatory activities of the synthesized compounds were evaluated using the Carrageenan-induced rat Paw oedema method and ibuprofen as a standard drug. Compounds 4a and 4b exhibited good activity. Additionally, docking stimulations were performed to position compounds 4e, 4g, 5e, 5f, 6a and 6f into the EGFR kinase domain and human oestrogen receptor active site to determine probable binding information. This study indicated that compounds 6a and 6f have significant binding activities of 58.36 and 57.67 kJ mol−1, respectively.

Synthesis and the crystal and molecular structures of 4-(piperidyl-1)-2-phenylpyrido[2,3-a]anthraquinone-7,12 Mono- and dibromohydrates (HL)Br . 3H2O and (H2L)Br2 . 3H2O

International Nuclear Information System (INIS)

Kovalchukova, O. V.; Stash, A. I.; Belsky, V. K.; Strashnova, S. B.; Zaitsev, B. E.; Ryabov, M. A.

2009-01-01

4-(Piperidyl-1)-2-phenylpyrido[2,3-a]anthraquinone-7,12 monobromohydrate (HL)Br . 3H 2 O (I) and 4-(piperidyl-1)-2-phenylpyrido[2,3-a]anthraquinone-7,12 dibromohydrate (H 2 L)Br 2 . 3H 2 O (II) are isolated in the crystalline state. The crystal structures of compounds I and II are determined using X-ray diffraction. It is established that the protonation of 4-(piperidyl-1)-2-phenylpyrido[2,3-a]anthraquinone-7,12 proceeds primarily through the pyridine atom at pH 2-3. The attachment of the second proton occurs through the piperidine nitrogen atom at pH ∼ 1.

The Brønsted Acid-Catalyzed, Enantioselective Aza-Diels-Alder Reaction for the Direct Synthesis of Chiral Piperidones.

Science.gov (United States)

Weilbeer, Claudia; Sickert, Marcel; Naumov, Sergei; Schneider, Christoph

2017-01-12

We disclose herein the first enantioselective aza-Diels-Alder reaction of β-alkyl-substituted vinylketene silyl-O,O-acetals and imines furnishing a broad range of optically highly enriched 4-alkyl-substituted 2-piperidones. As a catalyst for this one-pot reaction we employed a chiral phosphoric acid which effects a vinylogous Mannich reaction directly followed by ring-closure to the lactam. Subsequent fully diastereoselective transformations including hydrogenation, enolate alkylation, and lactam alkylation/reduction processes converted the cycloadducts into various highly substituted piperidines of great utility for the synthesis of natural products and medicinally active compounds. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Identification of nitrogen compounds and amides from spent hydroprocessing catalyst

Energy Technology Data Exchange (ETDEWEB)

Choi, J.H.K.; Gray, M.R. (University of Alberta, Edmonton, AB (Canada). Dept. of Chemical Engineering)

1991-06-01

A spent commercial naphtha hydrotreating catalyst was analyzed to identify compounds which had accumulated on the catalyst surface during its active life. The catalyst was extracted with methylene chloride, methanol and pyridine to remove adsorbed organic material, which was rich in nitrogen and oxygen. A series of quinolones were identified in the methanol extract after enrichment with HCl-modified silica gel adsorption and subsequent silica gel chromatography. Tetra- and hexahydroquinolones with alkyl substituents up to C{sub 3} were identified. Similar amides have been identified in asphaltenes, and are very resistant to hydrogenation. Tetrahydroquinolines and piperidines were detected in the pyridine extract. 36 refs., 8 figs., 2 tabs.

Synthesis of Schiff and Mannich Bases of Isatin Derivatives with 4-Amino-4,5-Dihydro-1H-1,2,4-Triazole-5-Ones

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Hakan Bektas

2008-09-01

Full Text Available Ethyl imidate hydrochlorides 1 were prepared by passing HCl gas through solutions of substituted benzyl cyanides and absolute ethanol. Ethoxycarbonylhydrazones 2 were synthesized from the reaction of compounds 1 with ethyl carbazate. Treatment of 2 with hydrazine hydrate leads to the formation of substituted 4-amino-4,5-dihydro-1H-1,2,4-triazole-5-ones 3. Isatin and 5-chloroisatin were added to 3 to form Schiff bases 4 and N-Mannich bases 5 of these compounds were synthesized by reacting with formaldehyde and piperidine. Their chemical structures were confirmed by means of IR, 1H- and 13C-NMR data and by elemental analysis.

Effect of gamma irradiation on mechanical and thermal properties of DGEBA/cycloaliphatic amine networks with potential for medical applications; Efeito da irradiacao gama nas propriedades mecanicas e termicas de redes DGEBA/amina cicloalifatica com potencial para aplicacoes medicas

Energy Technology Data Exchange (ETDEWEB)

Neves, Juliana C.; Silva, Glaura G., E-mail: glaura@qui.ufmg.br [Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG (Brazil); Mendes, Marcio W. Duarte; Bressiani, Ana H.; Bressiani, Jose C. [Instituto de Pesquisas Energeticas e Nucleares (IPEN/CNEN-SP), Sao Paulo, SP (Brazil); Garcia, Filiberto Gonzalez [Universidade Federal de Itajuba (UNIFEI), MG (Brazil)

2013-07-01

Two epoxy polymers based on diglycidyl ether of bisphenol A (DGEBA), cured with piperidine (Pip) and 4,4'-diamino-3,3'-dimethyldicyclohexylmethane (3DCM), were characterized before and after treatment with γ irradiation. The changes in the mechanical and thermal properties were studied by elastic modulus, glass transition temperature and degradation temperature measurements. A dose of 50 kGy of irradiation caused subtle variations in properties such as rigidity and stability, which are relevant from the fundamental point of view. The variations do not imply on negative impact when considering the stage of sterilization during the use of these systems as a biomaterial in the medical area. (author)

A simple and efficient in vitro method for metabolism studies of radiotracers

Energy Technology Data Exchange (ETDEWEB)

Lee, Sang-Yoon; Choe, Yearn Seong E-mail: yschoe@samsung.co.krjeewoo@snu.ac.kr; Kim, Dong Hyun; Park, Bok-Nam; Kim, Sang Eun; Choi, Yong; Lee, Kyung-Han; Lee, Jeewoo E-mail: yschoe@samsung.co.krjeewoo@snu.ac.kr; Kim, Byung-Tae

2001-05-01

In vitro metabolism of acetylcholinesterase inhibitors containing 3-[{sup 18}F]fluoromethylbenzyl- ([{sup 18}F]1) and 4-[{sup 18}F]fluorobenzyl-piperidine moieties ([{sup 18}F]2) was studied and compared with the in vivo metabolism. Defluorination of the [{sup 18}F]1 mainly occurred to generate [{sup 18}F]fluoride ion both in vitro and in vivo. In contrast, the [{sup 18}F]2 was converted into an unknown polar metabolite in both metabolism methods and another metabolite, 4-[{sup 18}F]fluorobenzoic acid in vitro. These results demonstrated that the in vitro method can be used to predict the in vivo metabolism of both radiotracers.

Synthesis of high specific activity tritium labelled compounds

International Nuclear Information System (INIS)

Parent, P.

1986-01-01

Tritiated methyl iodide of high specific activity is synthetized by Fischer-Tropsch reaction of tritium with carbon monoxide, tritiated methanol obtained is reacted with hydriodic acid. It is used for the synthesis of S-adenosyl L-methionine 3 H-methyl and of diazepam 3 H-methyl derivatives. Synthesis of 3-PPP 3 H: (hydroxy-3 phenyl)-3N-n propyl [ 3 H-2.3] piperidine [ 3 H-2.3] with a specific activity of 4.25 T Bq/mM (115 Ci/mM) and of baclofene 3 H with a specific activity of 0.925 TBq (25 Ci/mM) are also described [fr

Anticonvulsant effects of isomeric nonimidazole histamine H3 receptor antagonists

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Sadek B

2016-11-01

Full Text Available Bassem Sadek,1 Ali Saad,1 Johannes Stephan Schwed,2,3 Lilia Weizel,2 Miriam Walter,2 Holger Stark2,3 1Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates; 2Biocenter, Institute of Pharmaceutical Chemistry, Goethe University, Frankfurt, Germany; 3Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University, Düsseldorf, Germany Abstract: 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-ylpropoxybenzylaminopropanamide (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-ylpropoxybenzylaminopropaneamide (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

A study of the conformation and stability of nitroxide free radicals

International Nuclear Information System (INIS)

Briere, R.

1969-03-01

The first part of this study is an application of nuclear magnetic resonance to the determination of the sign and magnitude of the long range nuclear-electron spin-spin couplings in the free radical nitroxide derived from piperidine. It has been shown that the coupling constants of the protons γ to the nitrogen atom have a pronounced spatial dependence as do the protons in the β position, a point which has not been brought out by previous investigations. Conformational analysis of these compounds has been carried out by measurement of the effect of temperature on the NMR spectra at 310 MHz. The synthesis of di-t-Bu nitroxide labelled with C 13 in the α-position made possible the unambiguous determination of the corresponding 13 C nuclear-electron spin-spin coupling constant, a parameter which had not previously been measured. The coupling constants measured in the 2,2,6,6-tetramethyl piperidine series could then be attributed to the 13 C atoms in the β-position and their variation related to the conformations of the heterocycles. This constitutes the second part of the work reported here. The final section is devoted to a study of the decomposition of an unstable nitroxide having a hydrogen atom in the p-position. This decomposition is bimolecular and the primary isotope effect shows that the rupture. of the C-H bond is involved. From this one can conclude that a nitroxide is stable when the different groups attached to the nitrogen atom cannot give rise to a decomposition either intra molecularly, if the molecular geometry is suitable, or inter molecularly by dimerisation through attack on a different center of a neighbouring molecule thus leading to a fragmentation or a disproportionation. (author) [fr

Synthesis, characterization and biodistribution of neutral and lipid-soluble 99mTc-bisaminoethanethiol spiperone derivatives: Possible ligands for receptor imaging with SPECT

International Nuclear Information System (INIS)

Samnick, Samuel; Brandau, Wolfgang; Sciuk, Joachim; Steinstrasser, Axel; Schober, Otmar

1995-01-01

Using parts of the molecular structure of spiperone, two new ligand systems for complexation with [ 99m Tc]technetium were prepared in order to develop potential receptor imaging agents for single photon emission computer tomography (SPECT). The bis-aminoethanethiols (BAT): 1-benzyl-4-(2-mercapto-2-methyl-4-aza-pentyl)-4-(2-mercapto-2-methyl- propylamino)-piperidine (benzylpiperidyl-BAT, BP-BAT) and 1-[3-(4-fluorobenzoyl)-propyl]-4-(2-mercapto-2-methyl-4-aza-pentyl)-4-(2- mercapto-2-methyl-propylamino)-piperidine (butyrophenoylpiperidyl-BAT, BUP-BAT) form stable, neutral and lipid soluble complexes with [ 99m Tc]technetium at pH ≥ 11 using SnCl 2 as reducing agent in nearly quantitative radiochemical yields. Biodistribution of 99m Tc-BP-BAT and 99m Tc-BUP-BAT in rats showed a moderate clearance from blood and low uptake and retention in the liver, whereas brain uptake was moderate, however with prolonged brain retention. On the other hand, significant accumulations and retentions were observed in heart, kidney and lung with increasing oxygen/blood ratios up to 24 h. Within 24 h p.i. 22 and 29% of the injected dose (i.d.) of 99m Tc-BP-BAT and 99m Tc-BUP-BAT were eliminated by hepatobiliary excretion whereas 22% i.d. of both 99m Tc-BAT complexes were excreted into the urine. Although first biodistribution studies of 99m Tc-BP-BAT and 99m Tc-BUP-BAT in rats showed relatively low brain uptake, the high uptake in peripheral, receptor rich organs indicates that compounds of this type may be used as a basis for further structural modification to develop agents with optimal properties for cerebral or peripheral receptor imaging with SPECT

Juliprosopine and juliprosine from prosopis juliflora leaves induce mitochondrial damage and cytoplasmic vacuolation on cocultured glial cells and neurons.

Science.gov (United States)

Silva, Victor Diogenes A; Pitanga, Bruno P S; Nascimento, Ravena P; Souza, Cleide S; Coelho, Paulo Lucas C; Menezes-Filho, Noélio; Silva, André Mário M; Costa, Maria de Fátima D; El-Bachá, Ramon S; Velozo, Eudes S; Costa, Silvia L

2013-12-16

Prosopis juliflora is a shrub largely used for animal and human consumption. However, ingestion has been shown to induce intoxication in animals, which is characterized by neuromuscular alterations induced by mechanisms that are not yet well understood. In this study, we investigated the cytotoxicity of a total alkaloid extract (TAE) and one alkaloid fraction (F32) obtained from P. juliflora leaves to rat cortical neurons and glial cells. Nuclear magnetic resonance characterization of F32 showed that this fraction is composed of a mixture of two piperidine alkaloids, juliprosopine (majority constituent) and juliprosine. TAE and F32 at concentrations between 0.3 and 45 μg/mL were tested for 24 h on neuron/glial cell primary cocultures. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide test revealed that TAE and F32 were cytotoxic to cocultures, and their IC50 values were 31.07 and 7.362 μg/mL, respectively. Exposure to a subtoxic concentration of TAE or F32 (0.3-3 μg/mL) induced vacuolation and disruption of the astrocyte monolayer and neurite network, ultrastructural changes, characterized by formation of double-membrane vacuoles, and mitochondrial damage, associated with changes in β-tubulin III and glial fibrillary acidic protein expression. Microglial proliferation was also observed in cultures exposed to TAE or F32, with increasing levels of OX-42-positive cells. Considering that F32 was more cytotoxic than TAE and that F32 reproduced in vitro the main morphologic and ultrastructural changes of "cara torta" disease, we can also suggest that piperidine alkaloids juliprosopine and juliprosine are primarily responsible for the neurotoxic damage observed in animals after they have consumed the plant.

Screening of Potential Lead Molecule as Novel MurE Inhibitor: Virtual Screening, Molecular Dynamics and In Vitro Studies.

Science.gov (United States)

Zaveri, Kunal; Kiranmayi, Patnala

2017-01-01

The prevalence of multi-drug resistance S. aureus is one of the most challenging tasks for the treatment of nosocomial infections. Proteins and enzymes of peptidoglycan biosynthesis pathway are one among the well-studied targets, but many of the enzymes are unexplored as targets. MurE is one such enzyme featured to be a promising target. As MurE plays an important role in ligating the L-lys to stem peptide at third position that is crucial for peptidoglycan synthesis. To screen the potential MurE inhibitor by in silico approach and evaluate the best potential lead molecule by in vitro methods. In the current study, we have employed structure based virtual screening targeting the active site of MurE, followed by Molecular dynamics and in vitro studies. Virtual screening resulted in successful screening of potential lead molecule ((2R)-2-[[1-[(2R)- 2-(benzyloxycarbonylamino) propanoyl] piperidine-4-carbonyl]amino]-5-guanidino-pentan). The molecular dynamics of the MurE and Lead molecule complex emphasizes that lead molecule has shown stable interactions with active site residues Asp 406 and with Glu 460. In vitro studies demonstrate that the lead molecule shows antibacterial activity close to standard antibiotic Vancomycin and higher than that of Ampicillin, Streptomycin and Rifampicin. The MIC of lead molecule at 50μg/mL was observed to be 3.75 μg/mL, MBC being bactericidal with value of 6.25 μg/mL, cytotoxicity showing 34.44% and IC50 of 40.06μg/mL. These results suggest ((2R)-2-[[1-[(2R)-2-(benzyloxycarbonylamino) propanoyl] piperidine-4-carbonyl]amino]-5-guanidino-pentan) as a promising lead molecule for developing a MurE inhibitor against treatment of S. aureus infections. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Crystal structure of (3S*,4R*-4-fluoro-3-(4-methoxyphenyl-1-oxo-2-phenyl-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid

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Anna Lehmann

2017-06-01

Full Text Available The title compound, C23H18FNO4, 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 methoxyphenyl ring and the phenyl ring are inclined to the mean plane of the isoquinoline ring system by 89.85 (4 and 46.62 (5°, respectively, and by 78.15 (5° to one another. In the crystal, molecules 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.

Mixed ligand complexes of uranyl lactate with some simple and heterocyclic amines

International Nuclear Information System (INIS)

Jaiswal, S.R.; Rupainwar, D.C.

1984-01-01

Mixed ligand complexes of uranyl lactate with simple and heterocyclic amines having a general formula UO 2 (C 3 H 5 O 3 ).nL.xH 2 O, were prepared, where n=1 and x=1 for L=ethylenediamine (En), dimethyl aniline (DMAn), diethyl amine (DEA), orthophenylenediamine (OPDA), pyridine (Py), 2-picoline(2-Pic), 3-picoline(3-Pic), 4-Picoline(4-Pic), piperidine (Pipy), 2,4-lutidine (2,4 Lut), 2-Aminopyridine (2 APy), quinoline (Quin), isoquinoline (Isoquin) but x=0 for the ligands 2,2'-bipyrldyl (Bipy) and 1,10-phenenthroline (Phen). All the compounds are bright yellow coloured with high decomposition temp. (>200deg) and were characterized by electronic and infrared spectral data. (author)

Stereochemistry of nitrogenous heterocycles. 61. Synthesis and configuration of an eighth isomer of 2-methyl-4-hydroxydecahydroquinoline

International Nuclear Information System (INIS)

Litvinenko, G.S.; Voronenko, L.A.

1987-01-01

Reduction of 1-benzoyl-2α-methyl-4-oxo-cis-decahydroquinoline with dodium borohydride and sodium in alcohol has given 1-benzoyl-2α-methyl-4β-hydroxy-cis-decahydroquinoline, which exists in the steroidal conformation with diaxial α, α'-substituents in the piperidine ring and with an equatorial hydroxy-group. Debenzoylation of this has given the last of the eight theoretically possible isomers of 2-methyl-4-hydroxydecahydroquinoline, namely 2α-methyl-4β-hydroxy-cis-decahydroquinoline, which exists in the nonsteroidal conformation with an axial hydroxy-group. IR spectra were obtained on a UR-20 spectrometer in KBr disks, and PMR spectra on a BS487 instrument (80 MHz), internal standard HMDS

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

Science.gov (United States)

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.

Synthesis of 1-amino-2-[3-(3-[2,6-14C]piperidinomethylphenoxy) propylamino]-1-cyclobutene-3,4-dione hydrochloride

International Nuclear Information System (INIS)

Swigor, J.E.; Algieri, A.A.; Standridge, R.T.; Pittman, K.A.

1985-01-01

The synthesis of the title compound is described. The condensation of 3-aminopropanol with phthalic anhydride and subsequent treatment with phosphorous tribromide produced N-[3-bromopropyl] phthalimide. Acylation with 3-hydroxybenzaldehyde, reduction with hydrogen over Raney nickel and subsequent treatment with thionyl chloride gave N-[3-(3-chloromethylphenoxy) propyl] phthalimide. Treatment with [2,6 - 14 C] piperidine introduced the radiolabel. Deprotection of the amino group with hydrazine and treatment with 3-methoxy-4-amino-3-cyclobutene-1,2-dione produced 1-amino-2-[3-(3-[2,6- 14 C]piperidinomethylphenoxy) propylamino]-1-cyclobutene-3, 4-dione. Treatment with hydrochloric acid yielded the title compound in an overall chemical yield of 22%. (author)

Biologically important radiation damage in DNA

International Nuclear Information System (INIS)

Ward, J.F.

1994-01-01

Most DNA damage by the hydroxyl radical is confined to the bases, and this base damage represents an important component of locally multiply demanded sites (LMOS). The yields of the major damaged bases have been determined by gas chromatography mass spectrometry. For our propose, it was necessary to convert a known fraction of these damaged bases to strand breaks and then assay these labile sites as the increase in strand break yield over the normally observed level. Three potential agents by which this strategy of conversion of base damage to strand break could be implemented were identified in the original application: 1, Sl nuclease; 2, piperidine; and 3, base damage specific enzymes

Design, Synthesis, Antibacterial and Antifungal Activity of Novel 2-[(E-2-aryl-1-ethenyl]-3-(2-sulfanyl-1H-benzo[d]imidazole-5-yl-3,4- dihydro-4-quinolinones

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Anisetti Ravinder Nath

2012-01-01

Full Text Available The novel 2-[(E-2-aryl-1-ethenyl]-3-(2-sulfanyl-1H-benzo[d]imidazole-5-yl-3,4- dihydro-4-quinolinones (4a-j analogs were synthesized by Knoevenagel condensation of a solution of 2-methyl-3-(2-sulfanyl-1H-benzo[d]imidazole-5-yl-3,4-dihydro-4-quinazolinone (3 with aromatic aldehyde in presence of catalytic amount of piperidine. Compounds (4a-j showed significant biological activity against all the standard strains. All the synthesized compounds were characterized on the basis of their IR, 1H NMR, MASS spectroscopic data and elemental analyses. All the compounds have been tested for antimicrobial and antifungal activity by the cup-plate method.

Bromido(2-{1-[2-(piperidin-1-yl)ethyl?imino]?eth?yl}phenolato)copper(II)

OpenAIRE

Zhao, Xiao-Fan; Li, Fang

2010-01-01

In the title complex, [CuBr(C15H21N2O)], the CuII atom is coordinated by one phenolate O, one imine N and one amine N atom of the tridentate Schiff base ligand and by one bromide ion, resulting in a distorted CuBrN2O square-planar geometry for the metal ion, with the N atoms in a cis conformation.

Complexes of lanthanum(III), cerium(III), samarium(III) and dysprosium(III) with substituted piperidines

Energy Technology Data Exchange (ETDEWEB)

Manhas, B S; Trikha, A K; Singh, H; Chander, M

1983-11-01

Complexes of the general formulae M/sub 2/Cl/sub 6/(L)/sub 3/.C/sub 2/H/sub 5/OH and M/sub 2/(NO/sub 3/)/sub 6/(L)/sub 2/.CH/sub 3/OH have been synthesised by the reactions of chlorides and nitrates of La(III), Ce(III), Sm(III) and Dy(III) with 2-methylpiperidine, 3-methylpiperidine and 4-methylpiperidine. These complexes have been characterised on the basis of their elemental analysis, and IR and electronic reflectance spectra. IR spectral data indicate the presence of coordinated ethanol and methanol molecules and bidentate nitrate groups. Coordination numbers of the metal ions vary from 5 to 8. 19 refs.

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

Science.gov (United States)

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.

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

Energy Technology Data Exchange (ETDEWEB)

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

2017-10-01

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

Congenital skeletal malformations and cleft palate induced in goats by ingestion of Lupinus, Conium and Nicotiana species.

Science.gov (United States)

Panter, K E; Keeler, R F; Bunch, T D; Callan, R J

1990-01-01

Three piperidine alkaloid containing plants, Conium maculatum (poison-hemlock), Nicotiana glauca (tree tobacco) and Lupinus formosus (lunara lupine), induced multiple congenital contractures (MCC) and palatoschisis in goat kids when their dams were gavaged with the plant during gestation days 30-60. The skeletal abnormalities included fixed extension or flexure of the carpal, tarsal, and fetlock joints, scoliosis, lordosis, torticollis and rib cage abnormalities. Clinical signs of toxicity included those reported in sheep, cattle and pigs--ataxia, incoordination, muscular weakness, prostration and death. One quinolizidine alkaloid containing plant, Lupinus caudatus (tailcup lupine), on the other hand, which is also known to cause MCC in cows, caused only slight signs of toxicity in pregnant goats and no teratogenic effects in their offspring.

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

Directory of Open Access Journals (Sweden)

Raju Suresh Kumar

2012-07-01

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

Antimycobacterial and cytotoxicity activity of synthetic and natural compounds

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Ana O. de Souza

2007-01-01

Full Text Available Antimycobacterial and cytotoxicity activity of synthetic and natural compounds. Secondary metabolites from Curvularia eragrostidis and Drechslera dematioidea, Clusia sp. floral resin, alkaloids from Pilocarpus alatus, salicylideneanilines, piperidine amides, the amine 1-cinnamylpiperazine and chiral pyridinium salts were assayed on Mycobacterium tuberculosis H37Rv. N-(salicylidene-2-hydroxyaniline was the most effective compound with a minimal inhibitory concentration (MIC of 8 µmol/L. Dihydrocurvularin was moderately effective with a MIC of 40 µmol/L. Clusia sp. floral resin and a gallocatechin-epigallocatechin mixture showed MIC of 0.02 g/L and 38 µmol/L, respectively. The cytotoxicity was evaluated for N-(salicylidene-2-hydroxyaniline, curvularin, dihydrocurvularin and Clusia sp. floral resin, and the selectivity indexes were > 125, 0.47, 0.75 and 5, respectively.

Temporal characteristics and saturation effects of organic scintillators to low-energy X-rays

International Nuclear Information System (INIS)

Pronko, J.G.; Chase, L.F.

1979-01-01

Rise time, short and long term decay characteristics and possible saturation effects of the fluorescence of NE102, NE111, and doped NE111 organic scintillators were investigated using low-energy X-rays from a laser produced plasma. The laser system consisted of a pulsed Nd:glass facility operating at a pulse width of 0.2 ns at levels up to 10 J. The NE111 samples consisted of a matrix of scintillators with benzophenone, acetophenone, and piperidine each at concentrations of 0, 1, 2, 5, and 10 percent. The rise time of NE102 was measured at (640+-50) ps while that of both the doped and undoped NE111 was 2 ns) of irradiance used in this investigation. (Auth.)

Cyclopentadienyl tricarbonyl complexes of 99mTc for the in vivo imaging of the serotonin 5-HT 1a receptor in the brain

International Nuclear Information System (INIS)

Saidi, Mouldi; Trabelsi, Adel; MEKNI, Abdelkader; Kretzschmar, M.; Sefert, S.; Bergmann, R.; Pietzsch, H.-J.

2005-01-01

The present interest in the 5-HT 1a receptor is due to its implicated role in several major neuropsychiatric disorders such as depression, eating disorders and anxiety. For the diagnosis of these pathophysiological processes it is important to have radioligands in hand able to specifically bind on the 5-HT 1a receptor in order to allow brain imaging. due to the optimal radiation properties of 99mTc there is a considerable interest in the development of 99mTc radiopharmaceuticals for imaging serotonergic CNS receptors using single-photon emission tomography (SPET). Here we introduce two cyclopentadienyl technitium tricarbonyl conjugates of piperidine derivatives which show high accumulation of radioactivity in brain areas rich in 5-HT 1a receptors

Titanocene(III)-Catalyzed Three-Component Reaction of Secondary Amides, Aldehydes, and Electrophilic Alkenes.

Science.gov (United States)

Zheng, Xiao; He, Jiang; Li, Heng-Hui; Wang, Ao; Dai, Xi-Jie; Wang, Ai-E; Huang, Pei-Qiang

2015-11-09

An umpolung Mannich-type reaction of secondary amides, aliphatic aldehydes, and electrophilic alkenes has been disclosed. This reaction features the one-pot formation of C-N and C-C bonds by a titanocene-catalyzed radical coupling of the condensation products, from secondary amides and aldehydes, with electrophilic alkenes. N-substituted γ-amido-acid derivatives and γ-amido ketones can be efficiently prepared by the current method. Extension to the reaction between ketoamides and electrophilic alkenes allows rapid assembly of piperidine skeletons with α-amino quaternary carbon centers. Its synthetic utility has been demonstrated by a facile construction of the tricyclic core of marine alkaloids such as cylindricine C and polycitorol A. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Synthesis of 3-[18F]fluoromethyl-BTCP and evaluation as a potential PET radioligand for the dopamine transporter in baboons

International Nuclear Information System (INIS)

Ponchant, M.; Crouzel, C.; Varastet, M.; Hantraye, P.;

1993-01-01

In an attempt to visualize in vivo the dopamine transporter and evaluate its potential as an imaging tool for monitoring dopamine fiber degeneration by positron emission tomography, the 18 F-positron-emitting analogue of 3-fluoromethyl-1-[2-benzothienyl)-cyclohexyl]-piperidine, [ 18 F]BTCP, was synthesized and tested in a primate model of hemiparkinsonism. When comparing binding ratios between the intact and the dopamine-denervated striatum, there was a modest loss of binding in denervated striatum, suggesting that degeneration of dopaminergic fibers could be detected using 3-[ 18 F]fluoromethyl-BTCP. However due to a high non-specific binding in vivo, the interest of 3-[ 18 F]fluoromethyl-BTCP to image the dopamine reuptake system in vivo appears limited. (author)

Effect of DNA sequence, ionic strength, and cationic DNA affinity binders on the methylation of DNA by N-methyl-N-nitrosourea

International Nuclear Information System (INIS)

Wurdeman, R.L.; Gold, B.

1988-01-01

DNA alkylation by N-alkyl-N-nitrosoureas is generally accepted to be responsible for their mutagenic, carcinogenic, and antineoplastic activities. The exact nature of the ultimate alkylating intermediate is still controversial, with a variety of species having been nominated. The sequence specificity for DNA alkylation by simple N-alkyl-N-nitrosoureas has not been reported, although such information is basic in understanding the specific point mutations induced by these compounds in oncogene targets. These two points are addressed by using N-methyl-N-nitrosourea methylation of a 576 base-pair 32 P-end-labeled DNA restriction fragment and high-resolution polyacrylamide sequencing gels. This method provides information on the formation of N 7 -methylguanine, by the generation of single-strand breaks upon exposure to piperidine

CB1 receptor antagonism increases hippocampal acetylcholine release: site and mechanism of action.

Science.gov (United States)

Degroot, Aldemar; Köfalvi, Attila; Wade, Mark R; Davis, Richard J; Rodrigues, Ricardo J; Rebola, Nelson; Cunha, Rodrigo A; Nomikos, George G

2006-10-01

Evidence indicates that blockade of cannabinoid receptors increases acetylcholine (ACh) release in brain cortical regions. Although it is assumed that this type of effect is mediated through CB1 receptor (CB1R) antagonism, several in vitro functional studies recently have suggested non-CB1R involvement. In addition, neither the precise neuroanatomical site nor the exact mechanisms underlying this effect are known. We thoroughly examined these issues using a combination of systemic and local administration of CB1R antagonists, different methods of in vivo microdialysis, CB1R knockout (KO) mice, tissue measurements of ACh, and immunochemistry. First, we showed that systemic injections of the CB1R antagonists N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide hydrochloride (SR-141716A) and N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2, 4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251) dose-dependently increased hippocampal ACh efflux. Likewise, local hippocampal, but not septal, infusions of SR141716A or AM251 increased hippocampal ACh release. It is noteworthy that the stimulatory effects of systemically administered CB1R antagonists on hippocampal ACh release were completely abolished in CB1R KO mice. CB1R KO mice had similar basal but higher stress-enhanced hippocampal ACh levels compared with wild-type controls. It is interesting that dopamine D1 receptor antagonism counteracted the stimulatory effect of CB1R blockade on hippocampal ACh levels. Finally, immunohistochemical methods revealed that a high proportion of CB1R-positive nerve terminals were found in hippocampus and confirmed the colocalization of CB1 receptors with cholinergic and dopaminergic nerve terminals. In conclusion, hippocampal ACh release may specifically be controlled through CB1Rs located on both cholinergic and dopaminergic neuronal projections, and CB1R antagonism increases hippocampal ACh release, probably through both a direct

The synthesis and pharmacological evaluation of (±-2,3-seco-fentanyl analogues

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LJ. DOSEN-MICOVIC

2004-11-01

Full Text Available An efficient, five-step synthetic approach to various acyclic 1,3-diamines has been developed and applied to the preparation of a novel class of open-chained fentanyl analogues. The acyclic derivatives 5.1–5.5 (all new compounds were synthesized with the aim of estimating the significance of the piperidine ring for the opioid analgesic activity of anilido-piperidines. The starting b-keto-amide 1.1, prepared by the aminolysis of methyl acetoacetate with methylphenethylamine, (93 % yield, was successively reacted with NaH and BuLi, to form the highly reactive a,g-dienolate anion 1.1a. Regio and chemoselective g-alkylation of the dienolate with various primary and secondary alkyl halides furnished the b-keto-amides 1.2–1.5 (76–91 %. Reductive amination of the keto-amides 1.1–1.5 with aniline and Zn powder in acetic acid, via the enamine intermediates 2.1–2.5, afforded the b-anilino amides 3.1–3.5 (74–85 %. After reductive deoxygenation of the tertiary amide group, using in situ generated diborane, the corresponding 1,3-diamines 4.1–4.5 were obtained (87–97 %. The synthesis of (±-2,3-seco-fentanyls 5.1–5.5 was completed by N-acylation of the diamines 4.1–4.5 with propionyl chloride, followed by precipitation of the monooxalate salts (86–95 %. The parent compound, 2,3-seco-fentanyl 5.1, was found to be a 40 times less potent narcotic analgesic than fentanyl but still 5–6 times more active than morphine in rats, while i-Pr derivative 5.3 was inactive. Apart from the pharmacological significance, the general procedure described herein may afford various functionalized, 1,3-diamines as potential complexing agents and building blocks for the synthesis of aza-crown ethers.

Pharmacological aspects of application of 1,2,4-triazole-3-thiol furan derivatives

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O. A. Bihdan

2016-12-01

Full Text Available Introduction. Nowadays 1,2,4-triazole-3-thiol furan derivatives have established themselves as a separate class of promising bioactive compounds. Presented substance is practically non-toxic and exhibits various kinds of pharmacological activity. New original drug «Tryfuzol» in two dosage forms (1% injectable solution and 1% solution for oral administration triumphantly entered the practice of the national veterinary. The most attractive in pharmacological aspects are water-soluble compounds 5-(furan-2-yl-4R-1,2,4-triazole-3-thiols. Other classes of 1,2,4-triazole-3-thiol furan derivatives are also in considerable scientific interest. However, despite the presence of a sufficiently large number of publications, the issue of pharmacological tests systematization of the 1,2,4-triazole-3-thiol furan derivatives is still open. In this way the aim of our work was the systematization of the available sources of domestic authors. Materials and methods. Our work presents the results of systematic analysis of the available domestic literature related to the study of pharmacological properties of 1,2,4-triazole-3-thiol furan derivatives. Research results. It is known that 1,2,4-triazole-3-thiol furan derivatives have wide range of properties and biological activities. Thioacetate salts of corresponding acids show the highest results. The authors investigated the properties of water-soluble compounds of 1,2,4-triazole-3-thiol furan derivatives. Another group of compounds was investigated on hypoglycemic activity. It was established that the most active were piperidine 2-(5-(furan-2-yl-4-(3-methylphenyl-1,2,4-triazol-3-ylthio acetate and piperidine 2-(5-(furan-2-yl-4-phenyl-1,2,4-triazol-3-ylthio acetate. Conclusion. The scientific potential of the domestic pharmaceutical industry has no doubts for today. The literature analysis of Russian authors proves the obvious prospect of further research of biologically active compounds among 1,2,4-triazole-3-thiol

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

Energy Technology Data Exchange (ETDEWEB)

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

2008-04-15

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

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

International Nuclear Information System (INIS)

Zeng Zhizhen; O'Brien, Julie A.; Lemaire, Wei; O'Malley, Stacey S.; Miller, Patricia J.; Zhao Zhijian; Wallace, Michael A.; Raab, Conrad; Lindsley, Craig W.; Sur, Cyrille; Williams, David L.

2008-01-01

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

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

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Goti Andrea

2007-12-01

Full Text Available Abstract 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.

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

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Amir E. Wahba

2010-08-01

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

Bis(morpholino-1,3,5-triazine) derivatives: potent adenosine 5'-triphosphate competitive phosphatidylinositol-3-kinase/mammalian target of rapamycin inhibitors: discovery of compound 26 (PKI-587), a highly efficacious dual inhibitor.

Science.gov (United States)

Venkatesan, Aranapakam M; Dehnhardt, Christoph M; Delos Santos, Efren; Chen, Zecheng; Dos Santos, Osvaldo; Ayral-Kaloustian, Semiramis; Khafizova, Gulnaz; Brooijmans, Natasja; Mallon, Robert; Hollander, Irwin; Feldberg, Larry; Lucas, Judy; Yu, Ker; Gibbons, James; Abraham, Robert T; Chaudhary, Inder; Mansour, Tarek S

2010-03-25

The PI3K/Akt signaling pathway is a key pathway in cell proliferation, growth, survival, protein synthesis, and glucose metabolism. It has been recognized recently that inhibiting this pathway might provide a viable therapy for cancer. A series of bis(morpholino-1,3,5-triazine) derivatives were prepared and optimized to provide the highly efficacious PI3K/mTOR inhibitor 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea 26 (PKI-587). Compound 26 has shown excellent activity in vitro and in vivo, with antitumor efficacy in both subcutaneous and orthotopic xenograft tumor models when administered intravenously. The structure-activity relationships and the in vitro and in vivo activity of analogues in this series are described.

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

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Pilli Ronaldo A.

2001-01-01

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

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

International Nuclear Information System (INIS)

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

1975-01-01

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

Synthesis and study of the biodistribution of a new molecule labeled by technetium 99M

International Nuclear Information System (INIS)

Ben alaya, Monia

2008-01-01

Cytectrenes are stable complexes, neutral, low-weight molecular and lipophilic, that's allowing them to be able to cross the intact BBB. These piperidinic molecules are synthesized by atomic exchange between tricarbonyl technetium with the Fe-Cyclopentadienyl fragment. The labelling reaction is carried out classically in oil bath at a temperature of 150 C during one hour. The reaction can be optimized using microwave. The study of the biodistribution in rat of these complexes after there purification shows high cerebral uptake. Cytectrenes can be used as a potential cerebral radiotracers for the early diagnosis of neuropsychiatric diseases. Cytectrene are able to cross the BBB regarding there lipophilicity. These characteristic allow them to cross the membrane of the white cells and to be used us a potential agent for the diagnosis of infection. (Author). 44 refs

Technetium-99m labeled 1-(4-fluorobenzyl)-4-(2-mercapto-2-methyl-4-azapentyl)-4- (2-mercapto-2-methylp ropylamino)-piperidine and iodine-123 metaiodobenzylguanidine for studying cardiac adrenergic function: a comparison of the uptake characteristics in vascular smooth muscle cells and neonatal cardiac myocytes, and an investigation in rats

International Nuclear Information System (INIS)

Samnick, Samuel; Scheuer, Claudia; Muenks, Sven; El-Gibaly, Amr M.; Menger, Michael D.; Kirsch, Carl-Martin

2004-01-01

In developing technetium-99m-based radioligands for in vivo studies of cardiac adrenergic neurons, we compared the uptake characteristics of the 99m Tc-labeled 1-(4-fluorobenzyl)-4-(2-mercapto-2-methyl-4-azapentyl)-4- (2-mercapto-2-methylpropylamino)-piperidine ( 99m Tc-FBPBAT) with those of the clinically established meta-[ 123 I]iodobenzylguanidine ( 123 I-MIBG) in rat vascular smooth muscle cells and neonatal cardiac myocytes. Furthermore, the cardiac and extracardiac uptake of both radiopharmaceuticals was assessed in intact rats and in rats pretreated with various α- and β-adrenoceptor drugs, and adrenergic reuptake blocking agents. The uptake of 99m Tc-FBPBAT and 123 I-MIBG into vascular smooth muscle cells and neonatal cardiac myocytes was rapid; more than 85% of the radioactivity accumulation into the cells occurring within the first 3 minutes. Radioactivity uptake after a 60-minute incubation at 37 degree sign C (pH 7.4) varied from 15% to 65% of the total loaded activity per million cells. In all cases, 99m Tc-FBPBAT showed the higher uptake, relative to 123 I-MIBG, at any given cell concentration. The cellular uptake of 99m Tc-FBPBAT was lower at 4 degree sign C and 20 degree sign C than at 37 degree sign C. In contrast, the 123 I-MIBG uptake was only slightly temperature dependent. Inhibition experiments confirmed that the cellular uptake of 123 I-MIBG is mediated by the uptake-I carrier, whereas α 1 - and β 1 -adrenoceptors were predominantly involved in the uptake of 99m Tc-FBPBAT into the cardiovascular tissues. Biodistribution studies in rats showed that 99m Tc-FBPBAT accumulated in myocardium after intravenous injection. Radioactivity in rat heart amounted to 2.32% and 1.91% of the injected dose per gram at 15 and 60 minutes postinjection, compared with 3.10% and 2.21% injected dose per gram of tissue (%ID/g) in the experiment with 123 I-MIBG, respectively. Prazosin, urapidil, and metoprolol were as effective as treatment with other adrenergic

Technetium-99m labeled 1-(4-fluorobenzyl)-4-(2-mercapto-2-methyl-4-azapentyl)-4- (2-mercapto-2-methylp ropylamino)-piperidine and iodine-123 metaiodobenzylguanidine for studying cardiac adrenergic function: a comparison of the uptake characteristics in vascular smooth muscle cells and neonatal cardiac myocytes, and an investigation in rats

Energy Technology Data Exchange (ETDEWEB)

Samnick, Samuel E-mail: rassam@uniklinik-saarland.de; Scheuer, Claudia; Muenks, Sven; El-Gibaly, Amr M.; Menger, Michael D.; Kirsch, Carl-Martin

2004-05-01

In developing technetium-99m-based radioligands for in vivo studies of cardiac adrenergic neurons, we compared the uptake characteristics of the {sup 99m}Tc-labeled 1-(4-fluorobenzyl)-4-(2-mercapto-2-methyl-4-azapentyl)-4- (2-mercapto-2-methylpropylamino)-piperidine ({sup 99m}Tc-FBPBAT) with those of the clinically established meta-[{sup 123}I]iodobenzylguanidine ({sup 123}I-MIBG) in rat vascular smooth muscle cells and neonatal cardiac myocytes. Furthermore, the cardiac and extracardiac uptake of both radiopharmaceuticals was assessed in intact rats and in rats pretreated with various {alpha}- and {beta}-adrenoceptor drugs, and adrenergic reuptake blocking agents. The uptake of {sup 99m}Tc-FBPBAT and {sup 123}I-MIBG into vascular smooth muscle cells and neonatal cardiac myocytes was rapid; more than 85% of the radioactivity accumulation into the cells occurring within the first 3 minutes. Radioactivity uptake after a 60-minute incubation at 37 degree sign C (pH 7.4) varied from 15% to 65% of the total loaded activity per million cells. In all cases, {sup 99m}Tc-FBPBAT showed the higher uptake, relative to {sup 123}I-MIBG, at any given cell concentration. The cellular uptake of {sup 99m}Tc-FBPBAT was lower at 4 degree sign C and 20 degree sign C than at 37 degree sign C. In contrast, the {sup 123}I-MIBG uptake was only slightly temperature dependent. Inhibition experiments confirmed that the cellular uptake of {sup 123}I-MIBG is mediated by the uptake-I carrier, whereas {alpha}{sub 1}- and {beta}{sub 1}-adrenoceptors were predominantly involved in the uptake of {sup 99m}Tc-FBPBAT into the cardiovascular tissues. Biodistribution studies in rats showed that {sup 99m}Tc-FBPBAT accumulated in myocardium after intravenous injection. Radioactivity in rat heart amounted to 2.32% and 1.91% of the injected dose per gram at 15 and 60 minutes postinjection, compared with 3.10% and 2.21% injected dose per gram of tissue (%ID/g) in the experiment with {sup 123}I

Chemical cleavage reactions of DNA on solid support: application in mutation detection

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Cotton Richard GH

2003-05-01

Full Text Available Abstract Background The conventional solution-phase Chemical Cleavage of Mismatch (CCM method is time-consuming, as the protocol requires purification of DNA after each reaction step. This paper describes a new version of CCM to overcome this problem by immobilizing DNA on silica solid supports. Results DNA test samples were loaded on to silica beads and the DNA bound to the solid supports underwent chemical modification reactions with KMnO4 (potassium permanganate and hydroxylamine in 3M TEAC (tetraethylammonium chloride solution. The resulting modified DNA was then simultaneously cleaved by piperidine and removed from the solid supports to afford DNA fragments without the requirement of DNA purification between reaction steps. Conclusions The new solid-phase version of CCM is a fast, cost-effective and sensitive method for detection of mismatches and mutations.

Crosslinking in the diglycidyl ether oligoepichlorhydrin-piperazine

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Konstantyn E. Varlan

2014-03-01

Full Text Available The possibility of acquiring film material from a mixture of oligoepichlorhydrin diglycidylether and piperazyne discussed. The process involves elongation of the chain by means of reaction of the oligomer terminal oxyran cycles with piperazine aminogrups, and the subsequent formation of crosslinked by tertiary amine alongthe chainsalkylation whis chlorometyl dand groups of macromolecules. With this purpose, the model system investigated: epichlorohydrin−piperidine, epichlorohydrin−piperazine, oligoetylenglikol glicidyl ether−piperazine. The possibility of regulating the contributions of reactions of epoxy group and alkylation on crosslinking primary stage is disclosed, as well as material properties. Taking into account the found regularities receive elastic film structured materials with quaternary nitrogen atoms in the nodes. The ratio of tertiary and quaternary structure of nitrogen depends on the process conditions. Films swell in polar solvents and has ion-exchange properties.

Synthesis and Biological Evaluation of Some Novel Dithiocarbamate Derivatives

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Begüm Nurpelin Sağlık

2014-01-01

Full Text Available 18 novel dithiocarbamate derivatives were synthesized in order to investigate their inhibitory potency on acetylcholinesterase enzyme and antimicrobial activity. Structures of the synthesized compounds were elucidated by spectral data and elemental analyses. The synthesized compounds showed low enzyme inhibitory activity. However, they displayed good antimicrobial activity profile. Antibacterial activity of compounds 4a, 4e, and 4p (MIC = 25 μg/mL was equal to that of chloramphenicol against Klebsiella pneumoniae (ATCC 700603 and Escherichia coli (ATCC 35218. Most of the compounds exhibited notable antifungal activity against Candida albicans (ATCC 10231, Candida glabrata (ATCC 90030, Candida krusei (ATCC 6258, and Candida parapsilosis (ATCC 7330. Moreover, compound 4a, which carries piperidin-1-yl substituent and dimethylthiocarbamoyl side chain as variable group, showed twofold better anticandidal effect against all Candida species than reference drug ketoconazole.

Synthesis and characterization of a series of diarylguanidines that are noncompetitive N-methyl-D-aspartate receptor antagonists with neuroprotective properties

International Nuclear Information System (INIS)

Keana, J.F.W.; McBurney, R.N.; Scherz, M.W.

1989-01-01

Four diarylguanidine derivatives were synthesized. These compounds were found to displace, at submicromolar concentrations, 3 H-labeled 1-[1-(2-thienyl)cyclohexyl]piperidine and (+)-[ 3 H]MK-801 from phencyclidine receptors in brain membrane preparations. In electrophysiological experiments the diarylguanidines blocked N-methyl-D-aspartate (NMDA)-activated ion channels. These dairylguanidines also protected rat hippocampal neurons in vitro from glutamate-induced cell death. The results show that some diarylguanidines are noncompetitive antagonists of NMDA receptor-mediated responses and have the neuroprotective property that is commonly associated with blockers of the NMDA receptor-gated cation channel. Diarylguanidines are structurally unrelated to known blockers of NMDA channels and, therefore, represent a new compound series for the development of neuroprotective agents with therapeutic value in patients suffering from stroke, from brain or spinal cord trauma, from hypoglycemia, and possibly from brain ischemia due to heart attack

A simple, enaminone-based approach to some bicyclic pyridazinium tetrafluoroborates

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František Josefík

2013-07-01

Full Text Available Easily obtainable cyclic enaminones (piperidin-2-ylidenealkanones can be transformed into substituted bicyclic pyridazinium tetrafluoroborates upon treatment with corresponding diazonium salts. The transformation can be performed either in a one-pot way or in a two-step process with the isolation of single azo-coupled enaminone as the intermediate. The former method is superior. Under the optimized conditions, a number of pyridazinium salts substituted with both electron-donating and electron-withdrawing substituents was easily synthesized. A mechanism of the formation of the pyridazinium salts is suggested. A partial drawback is the possibility of the formation of a mixture of products when using a different diazonium salt in each step due to a reversibility of the azo coupling. This can be suppressed by using a more reactive diazonium salt before a less reactive one.

Calculations of optical rotation: Influence of molecular structure

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Yu Jia

2012-01-01

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

Structure-activity relationship of 9-methylstreptimidone, a compound that induces apoptosis selectively in adult T-cell leukemia cells.

Science.gov (United States)

Takeiri, Masatoshi; Ota, Eisuke; Nishiyama, Shigeru; Kiyota, Hiromasa; Umezawa, Kazuo

2012-01-01

We previously reported that 9-methylstreptimidone, a piperidine compound isolated from a culture filtrate of Streptomyces, induces apoptosis selectively in adult T-cell leukemia cells. It was screened for a compound that inhibits LPS-induced NF-kappaB and NO production in mouse macrophages. However, 9-methystreptimidone is poorly obtained from the producing microorganism and difficult to synthesize. Therefore, in the present research, we studied the structure-activity relationship to look for new selective inhibitors. We found that the structure of the unsaturated hydrophobic portion of 9-methylstreptimidone was essential for the inhibition of LPS-induced NO production. Among the 9-methylstreptimidone-related compounds tested, (+/-)-4,alpha-diepi-streptovitacin A inhibited NO production in macrophage-like cells as potently as 9-methylstreptimidone and without cellular toxicity. Moreover, this compound selectively induced apoptosis in adult T-cell leukemia MT-1 cells.

Anomalous H/D isotope effect on 35Cl NQR frequencies in piperidinium p-chlorobenzoate

International Nuclear Information System (INIS)

Nakano, Ryo; Honda, Hisashi; Kimura, Taiki; Nakata, Eiichi; Takamizawa, Satoshi; Noro, Sumiko; Ishimaru, Shin'ichi

2008-01-01

Anomalous isotope effects were detected in the 35 Cl nuclear quadrupole resonance (NQR) frequency of piperidinium p-chlrobenzoate (C 5 H 10 NH. ClC 6 H 4 COOH) by deuteration of hydrogen atoms. The atoms were determined to form two kinds of N-H...O type H-bonds in the crystal structure. Large frequency shifts of the 35 Cl resonance lines reaching 288 kHz at 77 K and 278 kHz at room temperature were caused upon deuteration, in spite of the fact that the Cl atoms in the molecule do not form hydrogen bonds in the crystal. Results of single crystal X-ray diffraction measurements and density-functional-theorem calculations suggest that a dihedral-angle change of 1.8 o between benzene and the piperidine ring contributes to 35 Cl NQR anomalous frequency shifts.

A Rapid Selection Procedure for Simple Commercial Implementation of omega-Transaminase Reactions

DEFF Research Database (Denmark)

Gundersen Deslauriers, Maria; Tufvesson, Pär; Rackham, Emma J.

2016-01-01

A stepwise selection procedure is presented to quickly evaluate whether a given omega-transaminase reaction is suitable for a so-called "simple" scale-up for fast industrial implementation. Here "simple" is defined as a system without the need for extensive process development or specialized......, and (3) determination of product inhibition. The method is exemplified with experimental work focused on two products: 1-(4-bromophenyl)ethylamine and (S)-(+)3-amino-1-Boc-piperidine, synthesized from their corresponding pro-chiral ketones each with two alternative amine donors, propan-2-amine, and 1......-phenylethylamine. Each step of the method has a threshold value, which must be surpassed to allow "simple" implementation, helping select suitable combinations of substrates, enzymes, and donors. One reaction pair, 1-Boc-3-piperidone with propan-2-amine, met the criteria of the three-step selection procedure...

Interaction of organic solvent with a subbituminous coal below pyrolysis temperature

Energy Technology Data Exchange (ETDEWEB)

Lindsey, D.; Grens, E.A.

1978-06-01

The interactions of a subbituminous coal with certain binary organic solvent mixtures have been studied at 250/sup 0/C. Mixtures of pyridine, quinoline, piperidine, tetrahydroquinoline, and ethylenediamine with either toluene or tetralin were contacted with coal in a successive batch, stirred reactor, the extractions being carried to near completion. Two distinct behaviors of extraction yield as a function of composition have been identified. In the majority of the solvent mixtures the extraction yield increases linearly with increasing concentration of the more active solvent. When the active solvent is ethylenediamine, however, the extraction yield increases rapidly when small concentrations of ethylenediamine are used but then levels out close to its maximum value in a 50 to 50 mix. This behavior is an indication that, except in the case of ethylenediamine, the activity of solvent mixtures is a function of bulk solution properties.

Antioxidant activity of salts of 2-(5-R-4-amino-1,2,4-triazole-3-ylthioacetic acid

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Ye. S. Pruglo

2017-12-01

that the most active substances among the studied substances were the initial 2-(4-amino-5-(2-bromophenyl-1,2,4-triasole-3-ylthioacetic acid (1b which reduced TBK-AP level at 91,95% (p˂0,001 and its magnesium salt (3a which suppressed the formation of this final product of LPO at 94,13% (p˂0,001. Some regularities of the chemical structure and AOA of the investigated substances were established after analyzing the data of experimental studies. Replacement of the morpholine cation in the morpholine molecule of 2-(4-amino-5-phenyl-1,2,4-triazole-3-ylthioacetic acid (2d on piperidine (2c is accompanied by the appearance of AOA from 18,18% to 74,95%. Replacement of the same piperidine cation on the morpholine cation in the piperidine molecule of 2-(4-amino-5-(2-bromophenyl-1,2,4-triazole-3-ylthioacetic acid is accompanied by the expressive appearance of AOA, which is 90,27% (3f. Conclusions 8 compounds among the 12 which were studied were able to suppress the generation of free radicals in varying degrees of severity and possessed a distinct AOA. It was established that the introduction in the molecule of 2-(4-amino-5-phenyl-1,2,4-triazole-3-ylthioacetic acid by С2 carbon atom of the phenyl nucleus of bromine atom was accompanied by an increase in the AOA of the studied substances.

Syntheses of New Unsymmetrical and Symmetrical Diarylsulphides and Diarylsulphones Containing Thiazolinyl and Thiazolidinonyl Moieties Using 4,4'-Diacetyldiphenylsulphide

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M. I. Abdel-Monem

2003-07-01

Full Text Available Condensation of 4,4’-diacetyldiphenyl sulphide (2 with variable amounts of thiosemicarbazide (3 in refluxing ethanol and in the presence of catalytic amounts of dry piperidine afforded only 4-acetylthiosemicarbazone-4’-acetyldiphenyl sulphide (5. Condensation of 2 with excess semicarbazide hydrochloride (4 in the presence of fused sodium acetate and/or piperidine yielded 4,4’-diacetylsemicarbazone diphenyl sulphide (6, whereas use of equimolar amounts of 2 and 4 afforded 4-acetyl-semicarbazone-4’-acetyldiphenyl sulphide (7. 4-Acetylsemicarbazone-4’-acetylthiosemicarbazone diphenyl sulphide (8 was also obtained via two different routes. The effect of tautomeric structure 5d is discussed. 4-(4"-phenyl-Δ3-thiazoline-2"-acetylazino-4’-acetyldiphenyl sulphide (9, 4-(5"-carboxyethyl-4"-thiazolidinone-2"-acetylazino-4’-acetyldiphenyl sulphide (10, 4-(4"-thiazolidinone-2’-acetylazino-4’-acetyldiphenyl sulphide (11 and 4-(4"-methyl-Δ3-thiazoline-2"-acetylazino-4’-acetyldiphenyl sulphide (12 were prepared by interaction of 5 with phenacylbromide, bromodiethylmalonate, chloro ethylacetate and chloroacetone, respectively. Sulphides 9-12 were easily condensed with 3 to afford the corresponding 4-(heterocyclic moiety-2"-acetylazino-4’-acetylthiosemicarbazone diphenyl sulphides 23-26. Oxidation of the prepared sulphides 5-7, 9-12, 23 and 25-26 using H2O2/glacial AcOH mixtures yielded only 4,4’-diacetyldiphenyl sulphone (13 as the main product in every case, besides 3 and 4 in certain cases. Unsymmetrical and symmetrical sulphones 14-22 were obtained starting from 13. The structures of the synthesized compounds are based on IR, 1H-NMR, 13C-NMR and mass spectral data. A theoretical study on some of the prepared compounds using molecular modeling was carried out.

``In silico'' study of the binding of two novel antagonists to the nociceptin receptor

Science.gov (United States)

Della Longa, Stefano; Arcovito, Alessandro

2018-02-01

Antagonists of the nociceptin receptor (NOP) are raising interest for their possible clinical use as antidepressant drugs. Recently, the structure of NOP in complex with some piperidine-based antagonists has been revealed by X-ray crystallography. In this study, a multi-flexible docking (MF-docking) procedure, i.e. docking to multiple receptor conformations extracted by preliminary molecular dynamics trajectories, together with hybrid quantum mechanics/molecular mechanics (QM/MM) simulations have been carried out to provide the binding mode of two novel NOP antagonists, one of them selective (BTRX-246040, formerly named LY-2940094) and one non selective (AT-076), i.e. able to inactivate NOP as well as the classical µ- k- and δ-opioid receptors (MOP KOP and DOP). According to our results, the pivotal role of residue D1303,32 (upper indexes are Ballesteros-Weinstein notations) is analogous to that enlighten by the already known X-ray structures of opioid receptors: binding of the molecules are predicted to require a slight readjustment of the hydrophobic pocket (residues Y1313,33, M1343,36, I2195,43, Q2806,52 and V2836,55) in the orthosteric site of NOP, accommodating either the pyridine-pyrazole (BTRX-246040) or the isoquinoline (AT-076) moiety of the ligand, in turn allowing the protonated piperidine nitrogen to maximize interaction (salt-bridge) with residue D1303,32 of the NOP, and the aromatic head to be sandwiched in optimal π-stacking between Y1313,33 and M1343,36. The QM/MM optimization after the MF-docking procedure has provided the more likely conformations for the binding to the NOP receptor of BTRX-246040 and AT-076, based on different pharmacophores and exhibiting different selectivity profiles. While the high selectivity for NOP of BTRX-246040 can be explained by interactions with NOP specific residues, the lack of selectivity of AT-076 could be associated to its ability to penetrate into the deep hydrophobic pocket of NOP, while retaining a

Oxidation and N-alkylation of galactomannan extracted from Caesalpinia ferrea var. ferrea seeds;Oxidacao e N-alquilacao de galactomanana de sementes de Caesalpina ferrea var. ferrea

Energy Technology Data Exchange (ETDEWEB)

Souza, Clayton F. de; Lucyszyn, Neoli; Ferraz, Fernando A.; Sierakowski, Maria Rita, E-mail: clayton@quimica.ufpr.b [Universidade Federal do Parana (UFPR), Curitiba, PR (Brazil). Dept. de Quimica

2009-07-01

The objective of this work was the synthesis and characterization of carboxyl (polyelectrolyte, GMPFOXT) and amino alkylate (amphiphilic, GMPFOXD) derivatives of the galactomannan extracted from the seeds of native specie Pau-ferro (Caesalpinia ferrea - GMPF). The derivatives were obtained by selective modification of GMPF at C-6 in the presence of TEMPO reagent (N-oxil-2,2,6,6-tetramethyl-piperidine) and dodecylamine showed high yields (approx 77 and 94% for GMPFOXT and GMPFOXD, respectively). The characteristics of the derivatives were confirmed by spectroscopic techniques of FTIR and {sup 13}C-NMR. By gel permeation chromatography (GPC), was observed a decrease of molar mass values and increase in polydispersity after derivatization, indicating change in the aggregation state in solution, caused by modification on the superficial structure. The development of these products can expand the use of them in different areas such as cosmetics and pharmaceutics, among others. (author)

Anomalous H/D isotope effect on {sup 35}Cl NQR frequencies in piperidinium p-chlorobenzoate

Energy Technology Data Exchange (ETDEWEB)

Nakano, Ryo; Honda, Hisashi, E-mail: hhonda@yokohama-cu.ac.jp [Yokohama City University, Graduate School of Integrated Science (Japan); Kimura, Taiki [Yokohama City University, Faculty of Science (Japan); Nakata, Eiichi; Takamizawa, Satoshi; Noro, Sumiko [Yokohama City University, Graduate School of Integrated Science (Japan); Ishimaru, Shin' ichi [Tokyo Denki University, Department of Green and Sustainable Chemistry (Japan)

2008-01-15

Anomalous isotope effects were detected in the {sup 35}Cl nuclear quadrupole resonance (NQR) frequency of piperidinium p-chlrobenzoate (C{sub 5}H{sub 10}NH. ClC{sub 6}H{sub 4}COOH) by deuteration of hydrogen atoms. The atoms were determined to form two kinds of N-H...O type H-bonds in the crystal structure. Large frequency shifts of the {sup 35}Cl resonance lines reaching 288 kHz at 77 K and 278 kHz at room temperature were caused upon deuteration, in spite of the fact that the Cl atoms in the molecule do not form hydrogen bonds in the crystal. Results of single crystal X-ray diffraction measurements and density-functional-theorem calculations suggest that a dihedral-angle change of 1.8{sup o} between benzene and the piperidine ring contributes to {sup 35}Cl NQR anomalous frequency shifts.

Nitroxide-Mediated Radical Polymerization of Styrene Initiated from the Surface of Titanium Oxide Nanoparticles

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M. Abbasian

2016-01-01

Full Text Available Titanium dioxide (TiO2 nanoparticles, with an average size of about 45 nm, were encapsulated by polystyrene using in situ nitroxide mediated radical polymerization   in the presence of 3-aminopropyl triethoxy silane (APTES as a coupling agent and 2, 2, 6, 6-tetramethylpiperidinyl-1-oxy  as a initiator. First, the initiator for NMRP was covalently bonded onto the surface of Titanium dioxide nanoparticles through our novel method. For this purpose, the surface of TiO2 nanoparticle was treated with 3-aminopropyl triethoxy silane, a silane coupling agent, and then these functionalized nanoparticles was reacted with ±-chloro phenyl acetyl chloride. The chlorine groups were converted to nitroxide mediated groups by coupling with 1-hydroxy-2, 2, 6, 6-tetramethyl piperidine. These modified TiO2 nanoparticles were then dispersed in styrene (St monomers to carry out the in situ free radical polymerization.

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

DEFF Research Database (Denmark)

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

2007-01-01

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

Is subnanomolar binding affinity required for the in vivo imaging of acetylcholinesterase? Studies on 18F-labeled G379

International Nuclear Information System (INIS)

Lee, Sang-Yoon; Choe, Yearn Seong; Ryu, Eun Kyoung; Iimura, Yoichi; Choi, Yong; Lee, Kyung-Han; Kim, Byung-Tae

2006-01-01

Acetylcholinesterase (AChE) is an important cholinergic marker of Alzheimer's disease (AD) and shows reduced activity in postmortem AD brain tissues. 1-(4-Fluorobenzyl)-4-[(5,6-dimethoxy-1-oxoindan-2-fluoro-2-yl)methyl] piperidine (G379, ), an AChE inhibitor with a subnanomolar IC 5 (0.56 nM), was prepared as a 18 F-labeled radioligand ([ 18 F]) and evaluated in mice. Metabolism studies of [ 18 F] showed no metabolites in the mouse brain. Tissue distribution studies demonstrated its uniform regional distribution in the mouse brain, suggesting that this radioligand is not suitable for the in vivo imaging of AChE. This result along with reports on radiolabeled N-benzylpiperidine lactam benzisoxazole (IC 5 5 >1 nM) suggested that a subnanomolar IC 5 may not be the only important factor in determining the suitability of a radioligand for in vivo studies of AChE

Oxidation and N-alkylation of galactomannan extracted from Caesalpinia ferrea var. ferrea seeds

International Nuclear Information System (INIS)

Souza, Clayton F. de; Lucyszyn, Neoli; Ferraz, Fernando A.; Sierakowski, Maria Rita

2009-01-01

The objective of this work was the synthesis and characterization of carboxyl (polyelectrolyte, GMPFOXT) and amino alkylate (amphiphilic, GMPFOXD) derivatives of the galactomannan extracted from the seeds of native specie Pau-ferro (Caesalpinia ferrea - GMPF). The derivatives were obtained by selective modification of GMPF at C-6 in the presence of TEMPO reagent (N-oxil-2,2,6,6-tetramethyl-piperidine) and dodecylamine showed high yields (∼ 77 and 94% for GMPFOXT and GMPFOXD, respectively). The characteristics of the derivatives were confirmed by spectroscopic techniques of FTIR and 13 C-NMR. By gel permeation chromatography (GPC), was observed a decrease of molar mass values and increase in polydispersity after derivatization, indicating change in the aggregation state in solution, caused by modification on the superficial structure. The development of these products can expand the use of them in different areas such as cosmetics and pharmaceutics, among others. (author)

Acid- and base-catalysis in the mononuclear rearrangement of some (Z)-arylhydrazones of 5-amino-3-benzoyl-1,2,4-oxadiazole in toluene: effect of substituents on the course of reaction.

Science.gov (United States)

D'Anna, Francesca; Frenna, Vincenzo; Ghelfi, Franco; Marullo, Salvatore; Spinelli, Domenico

2011-04-15

The reaction rates for the rearrangement of eleven (Z)-arylhydrazones of 5-amino-3-benzoyl-1,2,4-oxadiazole 3a-k into the relevant (2-aryl-5-phenyl-2H-1,2,3-triazol-4-yl)ureas 4a-k in the presence of trichloroacetic acid or of piperidine have been determined in toluene at 313.1 K. The results have been related to the effect of the aryl substituent by using Hammett and/or Ingold-Yukawa-Tsuno correlations and have been compared with those previously collected in a protic polar solvent (dioxane/water) as well as with those on the analogous rearrangement of the corresponding (Z)-arylhydrazones of 3-benzoyl-5-phenyl-1,2,4-oxadiazole 1a-k in benzene. Some light can thus be shed on the general differences of chemical reactivity between protic polar (or dipolar aprotic) and apolar solvents.

Toxicosis by Plant Alkaloids in Humans and Animals in Colombia

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Gonzalo J. Diaz

2015-12-01

Full Text Available Due to its tropical location, chains of mountains, inter-Andean valleys, Amazon basin area, eastern plains and shores on both the Atlantic and Pacific Oceans, Colombia has many ecosystems and the second largest plant biodiversity in the world. Many plant species, both native and naturalized, are currently recognized as toxic for both animals and humans, and some of them are known to cause their toxic effects due to their alkaloid content. Among these, there are plants containing the hepatotoxic pyrrolizidine alkaloids, neurotoxins such as the indolizidine alkaloid swainsonine and the piperidine alkaloids coniine and γ-coniceine and tropane alkaloids. Unfortunately, the research in toxic plants in Colombia is not nearly proportional to its plant biodiversity and the scientific information available is only very scarce. The present review aims at summarizing the scarce information about plant alkaloid toxicosis in animals and humans in Colombia.

Toxicosis by Plant Alkaloids in Humans and Animals in Colombia

Science.gov (United States)

Diaz, Gonzalo J.

2015-01-01

Due to its tropical location, chains of mountains, inter-Andean valleys, Amazon basin area, eastern plains and shores on both the Atlantic and Pacific Oceans, Colombia has many ecosystems and the second largest plant biodiversity in the world. Many plant species, both native and naturalized, are currently recognized as toxic for both animals and humans, and some of them are known to cause their toxic effects due to their alkaloid content. Among these, there are plants containing the hepatotoxic pyrrolizidine alkaloids, neurotoxins such as the indolizidine alkaloid swainsonine and the piperidine alkaloids coniine and γ-coniceine and tropane alkaloids. Unfortunately, the research in toxic plants in Colombia is not nearly proportional to its plant biodiversity and the scientific information available is only very scarce. The present review aims at summarizing the scarce information about plant alkaloid toxicosis in animals and humans in Colombia. PMID:26690479

FT-IR, NMR spectroscopic and quantum mechanical investigations of two ferrocene derivatives

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Ö. Alver

2017-07-01

Full Text Available New ferrocene derivatives as N-(3-piperidin-1-ylpropylferrocenamide (Fc-3ppa and N-(pyridine-3-ylmethylferrocenamide (Fc-3pica and structural investigations were carried out with 1H, 13C, DEPT 45 or 135, HETCOR, COSY NMR and FT-IR spectroscopic techniques. Characterization of Fc-3ppa (FeC19H26N2O and Fc-3pica (FeC17H16N2O was also supported by density functional theory (DFT used by B3LYP functional and 6-31G(d or 6-311++G(d,p basis sets. From the combination of all the results, it can be clearly seen that syntheses of Fc-3ppa and Fc-3pica have been successfully achieved. Theoretical values are successfully compared against experimental data and B3LYP method is able to provide satisfactory results for predicting NMR properties and vibrational frequencies of the synthesized ferrocene based systems.

Homologation of methanol catalyzed by transition metal complexes in the presence of tertiary amines

Energy Technology Data Exchange (ETDEWEB)

Tanaka, Masato; Ogata, Ikuei

1987-12-18

This paper describes the homologation of methanol by transition metal carbonyl catalysts in the presence of tertiary amines. Methanol was reacted with amine using a catalyst at 180/sup 0/C under 100 atm in the atmosphere of CO and H/sub 2/ mixed at the ratio of 4 in an autoclave. The reaction activities and selectivities of ethanol using iron carbonyl and Co carbonyl catalysts are superior. Only the iron catalyst was used hereafter because phosphine is required for the latter catalyst. N-methyl- piperidine, a cyclic amine, is superior to the other amines. The selectivity of ethanol is higher under higher partial pressure of H/sub 2/ and lower partial pressure of CO. The conversion rate is optimum at 180/sup 0/ and it goes down with increasing the temperature from it. Since the selectivity is markedly decreased with increasing amine, the reaction activity must be balanced with the amount of amine. The presence of solvent affects it. (3 figs, 6 tabs, 15 refs)

Antioxidant properties of MitoTEMPOL and its hydroxylamine.

Science.gov (United States)

Trnka, Jan; Blaikie, Frances H; Logan, Angela; Smith, Robin A J; Murphy, Michael P

2009-01-01

Piperidine nitroxides such as TEMPOL have been widely used as antioxidants in vitro and in vivo. MitoTEMPOL is a mitochondria-targeted derivative of TEMPOL designed to protect mitochondria from the oxidative damage that they accumulate, but once there is rapidly reduced to its hydroxylamine, MitoTEMPOL-H. As little is known about the antioxidant efficacy of hydroxylamines, this study has assessed the antioxidant activity of both MitoTEMPOL and MitoTEMPOL-H. The hydroxylamine was more effective at preventing lipid-peroxidation than MitoTEMPOL and decreased oxidative damage to mitochondrial DNA caused by menadione. In contrast to MitoTEMPOL, MitoTEMPOL-H has no superoxide dismutase activity and its antioxidant actions are likely to be mediated by hydrogen atom donation. Therefore, even though MitoTEMPOL is rapidly reduced to MitoTEMPOL-H in cells, it remains an effective antioxidant. Furthermore, as TEMPOL is also reduced to a hydroxylamine in vivo, many of its antioxidant effects may also be mediated by its hydroxylamine.

Characterization of glutamate-induced formation of N- acylphosphatidylethanolamine and N-acylethanolamine in cultured neocortical neurons

DEFF Research Database (Denmark)

Hansen, Harald S.; Lauritzen, L.; Strand, A.M.

1997-01-01

) assay). The increase in NAPE and NAE could be detected earlier than the neuronal death. Neither cyclic AMP, cyclic GMP, nitric oxide, protein kinase C, nor peroxidation appears to be involved in the formation of NAPE and NAE, as assessed by the use of different pharmacological agents. Exposure to 5 m...... receptors as seen by the inhibitory action of the NMDA-selective receptor antagonists D(-)-2-amino-5-phosphonovalerate and N- (1-(2-thienyl)-cyclohexyl)piperidine and the lack of effect of the a-amino- 3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate-receptor antagonist 6-cyano-7-nitro......-quinoxaline-2,3-dione (CNQX). In 6-day-old cultures, exposure to NMDA (100 µM for 24 h) induced a linear increase in the formation of NAPE and NAE as well as a 40-50% neuronal death, as measured by a decrease in cellular formazan formation [3-(4,5-dimethylthiazol-2-yl)- 2,5-diphenyltetrazolium bromide (MTT...

Unique interaction pattern for a functionally biased ghrelin receptor agonist

DEFF Research Database (Denmark)

Sivertsen, Bjørn Behrens; Lang, Manja; Frimurer, Thomas M.

2011-01-01

Based on the conformationally constrained D-Trp-Phe-D-Trp (wFw) core of the prototype inverse agonist [D-Arg(1),D-Phe(5),D-Trp(7,9),Leu(11)]substance P, a series of novel, small, peptide-mimetic agonists for the ghrelin receptor were generated. By using various simple, ring-constrained spacers...... connecting the D-Trp-Phe-D-Trp motif with the important C-terminal carboxyamide group, 40 nm agonism potency was obtained and also in one case (wFw-Isn-NH(2), where Isn is isonipecotic acid) ~80% efficacy. However, in contrast to all previously reported ghrelin receptor agonists, the piperidine-constrained w......Fw-Isn-NH(2) was found to be a functionally biased agonist. Thus, wFw-Isn-NH(2) mediated potent and efficacious signaling through the Ga(q) and ERK1/2 signaling pathways, but in contrast to all previous ghrelin receptor agonists it did not signal through the serum response element, conceivably the Ga(12...

An In-Silico Investigation of Phytochemicals as Antiviral Agents Against Dengue Fever.

Science.gov (United States)

Powers, Chelsea N; Setzer, William N

2016-01-01

A virtual screening analysis of our library of phytochemical structures with dengue virus protein targets has been carried out using a molecular docking approach. A total of 2194 plant-derived secondary metabolites have been docked. This molecule set comprised of 290 alkaloids (68 indole alkaloids, 153 isoquinoline alkaloids, 5 quinoline alkaloids, 13 piperidine alkaloids, 14 steroidal alkaloids, and 37 miscellaneous alkaloids), 678 terpenoids (47 monoterpenoids, 169 sesquiterpenoids, 265 diterpenoids, 81 steroids, and 96 triterpenoids), 20 aurones, 81 chalcones, 349 flavonoids, 120 isoflavonoids, 74 lignans, 58 stilbenoids, 169 miscellaneous polyphenolic compounds, 100 coumarins, 28 xanthones, 67 quinones, and 160 miscellaneous phytochemicals. Dengue virus protein targets examined included dengue virus protease (NS2B-NS3pro), helicase (NS3 helicase), methyltransferase (MTase), RNA-dependent RNA polymerase (RdRp), and the dengue virus envelope protein. Polyphenolic compounds, flavonoids, chalcones, and other phenolics were the most numerous of the strongly docking ligands for dengue virus protein targets.

Design, synthesis, and biological testing of thiosalicylamides as a novel class of calcium channel blockers.

Science.gov (United States)

Mehanna, Ahmed S; Kim, Jin Yung

2005-07-01

The current research aimed to investigate the importance of the heterocyclic ring system in the structure of the cardiovascular drug diltiazem for its calcium channel blocking activity. The manuscript describes the design, synthesis, and biological testing of a total of 10 S-(p-methoxybenzyl), N-substituted thiosalicylamides as a series of non-cyclic compounds derived from diltiazem's structure. The new compounds maintained all diltiazem pharmacophores except the thiazepine ring system. In vitro evaluation of the new series for calcium channel blocking effects revealed moderate activities with IC50 values in the range of 4.8-56.0 microM. The data suggest that the ring system is not essential for activity; however, its absence leads to a considerable drop of activity relative to that of diltiazem (IC50=0.3 microM). Compounds of the current series showed optimum activity when the aliphatic alkyl chain on the salicylamide nitrogen is part of a piperidine or piperazine ring system substituted at the terminal nitrogen with a benzyl group.

Some laws governing the electrosynthesis of organic compounds with a solid polymetric electrolyte

Energy Technology Data Exchange (ETDEWEB)

Rodionova, N.A.; Avrutskaya, I.A.; Fioshin, M. Ya.; Khrizolitova, M.A.

1986-01-01

The electrosynthesis of organic compounds with a solid polymetric electrolyte (SPE) makes it possible to carry out the process in the absence of a supporting electrolyte. This facilitates the recovery of the desired product, eliminates the inorganic waste products, and allows a small interelectrode distance, and the absence of the accumulation of gases lowers the voltage in the cell. Some laws governing syntheses of SPE were studied in the example cases of the electrochemical reduction of 2,2,6,6-tetramethyl-4-oxopiperidine to 2,2,6,6-tetramethyl-4-hydroxy-piperidine, the reduction of triacetonamine oxime and triacetonamine azine to 2,2,6,6-tetramethyl-4- aminopiperidine and the oxidation of isobutanol to isobutyric acid. The electrolysis with an SPE was carried out under galvanostatic conditions in an electrolyzer of the filter-press type with forced circulation of the catholyte and anolyte. Low reaction rates are found to be characteristic of all the compounds investigated when the electrolysis is carried out with an SPE.

Ropizine concurrently enhances and inhibits [3H] dextromethorpan binding to different structures of the guinea pig brain: Autoradiographic evidence for multiple binding sites

International Nuclear Information System (INIS)

Canoll, P.D.; Smith, P.R.; and Musacchio, J.M.

1990-01-01

Ropizine produces a simultaneous enhancement and inhibition of [ 3 H] dextromethorphan (DM) high-affinity binding to different areas of the guinea pig brain. These results imply that there are two distinct types of high-affinity [ 3 H]DM binding sites, which are present in variable proportions in different brain structures. The ropizine-enhances [ 3 H]DM binding type was preferentially inhibited by (+)-pentazocine. This is consistent with the presumption that the (+)-pentazocine-sensitive site is identical with the common site for DM and 3-(-3-Hydroxphenyl)-N-(1-propyl)piperidine ((+)-3-PPP). The second binding type, which is inhibited by ropizine and is not so sensitive to (+)- pentazocine, has not been fully characterized. This study demonstrates that the biphasic effects to ropizine are due, at least in part, to the effects of ropizine on two different types of [ 3 H]DM binding sites. However, this study does not rule out that the common DM/(+)-3-PPP site also might be inhibited by higher concentrations of ropizine

Quantitative localization of (/sup 3/H)TCP binding in rat brain by light microscopy autoradiography

Energy Technology Data Exchange (ETDEWEB)

Sircar, R; Zukin, S R

1985-09-30

The anatomical localization of phencyclidine (PCP)/sigma-opiate receptors in rat brain was determined by quantitative light microscopy autoradiography using the new ligand N-(1-(2-thienyl) cyclohexyl(/sup 3/H) piperidine ((/sup 3/H)TCP). TCP is a potent analog of PCP which possesses a higher affinity for PCP/sigma-opiate receptor than does PCP itself. The highest level of (/sup 3/H)TCP binding was detected in the hippocampus. Intermediate levels were found in frontal cortex, striatum, amygdala and cerebellum. Specific (/sup 3/H)TCP binding was undetectable in anterior commissure and corpus callosum. The distribution pattern of (/sup 3/H)TCP binding sites is similar to the pattern obtained with (/sup 3/H)PCP but more sharply defined. On the basis of its greater potency and specificity, (/sup 3/H)TCP may prove superior to (/sup 3/H)PCP as a molecular probe for the study of brain sigma opiate/phencyclidine receptors. 13 refs.; 1 figure; 1 table.

Coulometric titrations of bases in propylene carbonate and g-butyrolactone using hydroquinone as the depolarizer and a quinhydrone indicator electrode

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Z. D. STANIC

2000-08-01

Full Text Available The application of hydroquinone for the coulometric generation of hydrogen ions in propylene carbonate (PC and g-butyrolactone (GBL is described. The current-potential curves recorded for theid sepolarizer, titrated bases, indicator and the solvents used showed that the investigated depolarizer is oxidized at lower potentials than the oxidation potentials of other components in the solution. the hydrogen ions generated by the oxidation of hydroquinone were used for the titration of organic bases (triethylamine, n-butylamine, pyridine, quinoline, aniline, N,N’-diphenylguanidine, piperidine, and 2,2’-bipiridine in PC and GBL with visual (Crystal Violet as indicator and potentiometric end-point detection using a quinhydrone electrode as the indicator electrode. The quinhydrone added to the to be analyzed solution served both as a source of hydrogen ions and, together with the immersed platinum electrode, as a quinhydrone electrode. The relative error of the determination of the bases was about 1 %.

Alkaloids as Cyclooxygenase Inhibitors in Anticancer Drug Discovery.

Science.gov (United States)

Hashmi, Muhammad Ali; Khan, Afsar; Farooq, Umar; Khan, Sehroon

2018-01-01

Cancer is the leading cause of death worldwide and anticancer drug discovery is a very hot area of research at present. There are various factors which control and affect cancer, out of which enzymes like cyclooxygenase-2 (COX-2) play a vital role in the growth of tumor cells. Inhibition of this enzyme is a very useful target for the prevention of various types of cancers. Alkaloids are a diverse group of naturally occurring compounds which have shown great COX-2 inhibitory activity both in vitro and in vivo. In this mini-review, we have discussed different alkaloids with COX-2 inhibitory activities and anticancer potential which may act as leads in modern anticancer drug discovery. Different classes of alkaloids including isoquinoline alkaloids, indole alkaloids, piperidine alkaloids, quinazoline alkaloids, and various miscellaneous alkaloids obtained from natural sources have been discussed in detail in this review. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

One-pot synthesis and sigma receptor binding studies of novel spirocyclic-2,6-diketopiperazine derivatives.

Science.gov (United States)

Ghandi, Mehdi; Sherafat, Fatemeh; Sadeghzadeh, Masoud; Alirezapour, Behrouz

2016-06-01

New spirocyclic-2,6-diketopiperazine derivatives containing benzylpiperidine and cycloalkane moieties were synthesized by a one-pot two-step sequential Ugi/intramolecular N-amidation process in moderate to good yields. The in vitro ligand-binding profile studies performed on the sigma-1 and sigma-2 receptors revealed that the σ1 affinities and subtype selectivities of three spirocyclic piperidine derivatives are generally comparable to those of spirocycloalkane analogues. Compared to the low σ1 affinities obtained for cycloalkyl-substituted spirocyclic-2,6-diketopiperazines with n=2, those with n=1 proved to have optimal fitting with σ2 subtype by exhibiting higher affinities. Moreover, the best binding affinity and subtype selectivity was identified for compound 3c with Kiσ1=5.9±0.5nM and Kiσ2=563±21nM as well as 95-fold σ1/σ2 selectivity ratio, respectively. Copyright © 2016. Published by Elsevier Ltd.

Biotransformation and bioactivation reactions of alicyclic amines in drug molecules.

Science.gov (United States)

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

2014-08-01

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

(2,2′-Bipyridine-κ2N,N′iodido(piperidine-1-carbodithioato-κ2S,S′copper(II

Directory of Open Access Journals (Sweden)

Le-Qing Fan

2009-01-01

Full Text Available In the title compound, [Cu(C6H10NS2I(C10H8N2], the CuII ion is coordinated by one iodide ion, two N atoms of the bipyridine ligand and two S atoms from the piperidinecarbodithioate ligand in a distorted square-pyramidal environment. π–π stacking interactions, with centroid–centroid distances of 3.643 (4 Å, between pyridyl rings of the bipyridyl ligands of neighbouring molecules lead to chains propagating parallel to the a axis.

Synthesis of n.c.a. {sup 18}F-fluorinated NMDA- and D{sub 4}-receptor ligands via [{sup 18}F]fluorobenzenes; Traegerarme Synthese {sup 18}F-markierter, ausgewaehlter NMDA- und D{sub 4}-Rezeptorliganden durch Einsatz geeigneter [{sup 18}F]Fluorbenzolderivate

Energy Technology Data Exchange (ETDEWEB)

Ludwig, T

2005-11-01

In this thesis new strategies were developed and evaluated for the no-carrier-added (n.c.a.) {sup 18}F-labelling of receptor ligands as radiodiagnostics for characterization of brain receptors using positron-emission-tomography (PET). Special emphasis was placed on the synthesis of n.c.a. ({+-})-3-(4-hydroxy-4-(4-[{sup 18}F]fluorophenyl)-piperidin-l-yl)chroman-4,7-diol, a ligand with high affinity for the NR2B subtype of NMDA receptors and n.c.a. (3-(4-[{sup 18}F]fluorphenoxy)propyl)-(2-(4-tolylphenoxy)ethyl)amine ([{sup 18}F]FPTEA) a dopamine D{sub 4} receptor ligand. In order to synthesize n.c.a. ({+-})-3-(4-hydroxy-4-(4-[{sup 18}F]fluorophenyl)-piperidin-l-yl)chroman-4,7-diol the {sup 18}F-fluoroarylation method via metallorganic intermediates was modified and improved. The suitability of the organometallic {sup 18}F-fluoroarylation agents was proven with several model compounds. High radiochemical yields of 20-30% were obtained also with piperidinone-derivatives. The preparation of a suitable precursor for the synthesis of the NMDA receptor ligand, however, could not be achieved by synthesis of appropriate 1,3-dioxolane protected piperidinone derivatives. Further, the synthesis of n.c.a. ([{sup 18}F]fluoroaryloxy)alkylamines via n.c.a. 4-[{sup 18}F]fluorophenol was developed and evaluated. The synthesis of n.c.a. [{sup 18}F]fluoroarylethers with corresponding model compounds was optimized and led to a radiochemical yield of 25-60%, depending on the alkylhalide used. The preparation of n.c.a. 1-(3-bromopropoxy)-4-[{sup 18}F]fluorobenzene proved advantageous in comparison to direct use of 4-[{sup 18}]fluorophenol for coupling with a corresponding N-protected precursor for the synthesis of n.c.a. [{sup 18}F]FPTEA. With regard to the radiochemical yields and the loss of activity during the synthesis and isolation of n.c.a. 4-[{sup 18}F]fluorophenol and n.c.a. 1-(3-bromopropoxy)-4-[{sup 18}F]fluorobenzene, [{sup 18}F]FPTEA was obtained by reaction with 2-(4-tolyloxy

Synthesis of n.c.a. 18F-fluorinated NMDA- and D4-receptor ligands via [18F]fluorobenzenes

International Nuclear Information System (INIS)

Ludwig, T.

2005-11-01

In this thesis new strategies were developed and evaluated for the no-carrier-added (n.c.a.) 18 F-labelling of receptor ligands as radiodiagnostics for characterization of brain receptors using positron-emission-tomography (PET). Special emphasis was placed on the synthesis of n.c.a. (±)-3-(4-hydroxy-4-(4-[ 18 F]fluorophenyl)-piperidin-l-yl)chroman-4,7-diol, a ligand with high affinity for the NR2B subtype of NMDA receptors and n.c.a. (3-(4-[ 18 F]fluorphenoxy)propyl)-(2-(4-tolylphenoxy)ethyl)amine ([ 18 F]FPTEA) a dopamine D 4 receptor ligand. In order to synthesize n.c.a. (±)-3-(4-hydroxy-4-(4-[ 18 F]fluorophenyl)-piperidin-l-yl)chroman-4,7-diol the 18 F-fluoroarylation method via metallorganic intermediates was modified and improved. The suitability of the organometallic 18 F-fluoroarylation agents was proven with several model compounds. High radiochemical yields of 20-30% were obtained also with piperidinone-derivatives. The preparation of a suitable precursor for the synthesis of the NMDA receptor ligand, however, could not be achieved by synthesis of appropriate 1,3-dioxolane protected piperidinone derivatives. Further, the synthesis of n.c.a. ([ 18 F]fluoroaryloxy)alkylamines via n.c.a. 4-[ 18 F]fluorophenol was developed and evaluated. The synthesis of n.c.a. [ 18 F]fluoroarylethers with corresponding model compounds was optimized and led to a radiochemical yield of 25-60%, depending on the alkylhalide used. The preparation of n.c.a. 1-(3-bromopropoxy)-4-[ 18 F]fluorobenzene proved advantageous in comparison to direct use of 4-[ 18 ]fluorophenol for coupling with a corresponding N-protected precursor for the synthesis of n.c.a. [ 18 F]FPTEA. With regard to the radiochemical yields and the loss of activity during the synthesis and isolation of n.c.a. 4-[ 18 F]fluorophenol and n.c.a. 1-(3-bromopropoxy)-4-[ 18 F]fluorobenzene, [ 18 F]FPTEA was obtained by reaction with 2-(4-tolyloxy)ethylamine in radiochemical yields of about 25-30% in ethanol or 2-butanone

Studies on low-carrier radiofluorination of non-active aromatics with no-carrier-added [18F]fluoride

International Nuclear Information System (INIS)

Cardinale, Jens

2013-01-01

In vivo imaging with positron emission tomography generally demands radiotracers with a high specific activity. In case of fluorine-18 the required no-carrier-added (n.c.a.) starting material is only available in form of fluoride. This and the short half-life of 109.7 minutes of the radionuclide lead to the demand of special methods for radiosyntheses. The only practical procedure for manufacturing n.c.a. [ 18 F]fluoro-compounds is therefore nucleophilic substitution. There is, however, still a lack of effective procedures for the labelling of electron rich aromatic molecules starting from n.c.a. [ 18 F]fluoride. A process for n.c.a. radiofluorination of these compounds is offered by the reaction of iodonium compounds as starting materials. In this study modern procedures for the synthesis of iodoniumsalts and -ylides were investigated. Several precursor molecules for the versatile synthetic building block 4-[ 18 F]fluoroiodobenzene were synthesised. In this course, a new one-pot procedure for the synthesis of iodoniumylides was developed. Further on, the syntheses of suitable iodonium precursors for two fluorophenoxy-derivatives, which are possible antidepressants, were investigated. Due to their binding profile these compounds can be considered as ligands for the serotonin reuptake transporter (SERT) and the norepinephrin reuptake transporter (NET), respectively. The preparation of appropriate iodonium salts proved to be too problematic, while the synthesis of suitable iodoniumylides could be accomplished with satisfactory yields of about 30% and 40 %, respectively. Both compounds were labelled with n.c.a. [ 18 F]fluoride and deprotected to the desired target compounds 4-((3-[ 18 F]fluorophenoxy)(phenyl)methyl)piperidine and 4-((4-[ 18 F]fluorophenoxy)(phenyl)methyl)piperidine in radiochemical yields of about 40 % and 25 %, respectively. Those are now available for preclinical evaluation studies. Furthermore, a process for the palladium catalysed synthesis of 18

Synthesis and receptor binding studies of (+/-)1-iodo-MK-801

International Nuclear Information System (INIS)

Yang, D.J.; Ciliax, B.J.; Van Dort, M.E.; Gildersleeve, D.; Pirat, J.L.; Young, A.B.; Wieland, D.M.

1989-01-01

The glutamate analogue N-methyl-D-aspartate (NMDA) binds to a subset of glutamate receptors that are coupled to a voltage-sensitive cation channel. This NMDA-linked channel is the likely binding locus of the potent anticonvulsant MK-801. To develop single-photon emission computed tomography (SPECT) probes of this brain channel, we synthesized (+/)1-iodo-MK-801 and (+/-)1-[ 125 I]iodo-MK-801. The effect of (+/-)1-iodo-MK-801 on ligand binding to the NMDA-linked glutamate receptor site was assessed using a rat brain homogenate assay. (+/-)1-Iodo-MK-801 displaced the dissociative anesthetic ligand [ 3 H]N-[1-(2-thienyl)cyclohexyl]piperidine ([ 3 H]TCP) binding with an IC50 of 1 microM, which is a 10-fold lower binding affinity than that of (+/-)MK-801. In in vivo autoradiographic studies, (+/-)MK-801 failed to block selective uptake of (+/-)1-iodo-MK-801 in rat brain. These results suggest that (+/-)1-iodo-MK-801 may not be a suitable ligand for mapping NMDA-linked glutamate receptor channels

Membrane Inlet Mass Spectrometry for Homeland Security and Forensic Applications

Science.gov (United States)

Giannoukos, Stamatios; Brkić, Boris; Taylor, Stephen; France, Neil

2015-02-01

A man-portable membrane inlet mass spectrometer has been built and tested to detect and monitor characteristic odors emitted from the human body and also from threat substances. In each case, a heated membrane sampling probe was used. During human scent monitoring experiments, data were obtained for inorganic gases and volatile organic compounds emitted from human breath and sweat in a confined space. Volatile emissions were detected from the human body at low ppb concentrations. Experiments with compounds associated with narcotics, explosives, and chemical warfare agents were conducted for a range of membrane types. Test compounds included methyl benzoate (odor signature of cocaine), piperidine (precursor in clandestine phencyclidine manufacturing processes), 2-nitrotoluene (breakdown product of TNT), cyclohexanone (volatile signature of plastic explosives), dimethyl methylphosphonate (used in sarin and soman nerve agent production), and 2-chloroethyl ethyl sulfide (simulant compound for sulfur mustard gas). Gas phase calibration experiments were performed allowing sub-ppb LOD to be established. The results showed excellent linearity versus concentration and rapid membrane response times.

Synthesis, characterization and physiological activity of some novel isoxazoles.

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NITIN G. GHODILE

2012-07-01

Full Text Available Hushare VJ, Rajput PR, Malpani MO, Ghodile NG. 2012. Synthesis, characterization and physiological activity of some novel isoxazoles. Nusantara Bioscience 4: 81-85. A series of chlorosubstituted 4-aroylisoxazoles have been synthesized by refluxing chlorosubstituted-3-aroylflavones and 3-alkoylchromone with hydroxylamine hydrochloride in dioxane medium containing 0.5 mL piperidine. Chlorosubstituted-3-aroylflavones and chlorosubstituted-3-alkoylchromone were prepared by refluxing them separately with iodine crystal in ethanol. Initially chlorosubstituted-3-aroylflavanones and 3-alkoylchromanone were prepared by the interaction of different aromatic and aliphatic aldehydes with 1-(2’-hydroxy-3’,5’-dichlorophenyl-3-phenyl-1,3-propanedione. Constitutions of synthesized compounds were confirmed on the basis of elemental analysis, molecular weight determination, UV-Visible, I.R. and 1H-NMR spectral data. The titled compounds were evaluated for their growth promoting activity on some flowering plants viz. Papaver rhoeas, Calendula officinalise, Gladiola tristis, Gaillardia aristata, Dianthus chinensis, and Iberis sp. (candytuft. The results indicate that applicated plants had higher shoots and more number of leaves.

Alkaloids as important scaffolds in therapeutic drugs for the treatments of cancer, tuberculosis, and smoking cessation.

Science.gov (United States)

Kittakoop, Prasat; Mahidol, Chulabhorn; Ruchirawat, Somsak

2014-01-01

Alkaloid molecules can act, depending on a type of amine functionality present in alkalods, as either hydrogenacceptor or hydrogen-donor for hydrogen bonding that is critically important for the interaction (binding) between targets (enzymes, proteins and receptors) and drugs (ligands). Because of this unique property, alkaloid scaffolds are therefore present in several drugs and lead compounds. This review highlights alkaloid scaffolds in drugs, particularly those recently approved in 2012; it also covers the scaffolds in leads and drug candidates which are in clinical trials and preclinical pipeline. The review focuses on three therapeutic areas including treatments of cancer, tuberculosis, and tobacco cessation. Alkaloid scaffolds in drugs and leads are inspired by those of naturally occurring alkaloids, and these scaffolds include pyridine, piperidine, quinoline, quinolinone, quinazoline, isoquinoline, indole, indolinone, isoindole, isoxazole, imidazole, indazole, thiazole, pyrazole, oxazolidinone, oxadiazole, and benzazepine. In addition to medicinal chemistry aspects, natural products possessing an individual alkaloid scaffold, as well as the mechanism of action of drugs and leads, are also discussed in this review.

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

Energy Technology Data Exchange (ETDEWEB)

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

1970-07-01

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

Flexible synthetic routes to poison-frog alkaloids of the 5,8-disubstituted indolizidine-class I: synthesis of common lactam chiral building blocks and application to the synthesis of (--203A, (--205A, and (--219F

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Spande Thomas F

2007-09-01

Full Text Available Abstract Background The 5,8-disubstituted indolizidines are the largest class of poison-frog alkaloids found in anuran skin, and are of considerable interest because of their inhibitory effects on the neuronal nicotinic acetylcholine receptors. Many synthetic strategies for the construction of this nucleus have been reported: however, a flexible route has not been reported to date. Results Synthesis of lactam chiral building blocks for the flexible synthesis of the title alkaloids has been achieved using a Michael-type conjugate addition reaction to a chiral cyclic enamine ester as the key step in constructing the trisubstituted piperidine ring system. To demonstrate the usefulness of these chiral building blocks, syntheses of (--203A, (--205A from 1, and (--219F from 2 have been achieved. Conclusion The total synthesis of (--203A, (--205A, and (--219F was achieved, and the absolute stereochemistry of natural 203A was determined to be 5S, 8R, 9S. In addition, the relative stereochemistry of natural 219F was determined.

Volatiles from roasted byproducts of the poultry-processing industry.

Science.gov (United States)

Wettasinghe, M; Vasanthan, T; Temelli, F; Swallow, K

2000-08-01

Volatiles of roasted chicken breast muscle and byproducts, such as backbones, breastbones, spent bones, and skin, were investigated. Total volatile concentrations ranged from 2030 ppb in the roasted backbones to 4049 ppb in the roasted skin. The major classes of volatile compounds detected in roasted samples were aldehydes (648-1532 ppb) and alcohols (336-1006 ppb). Nitrogen- and/or sulfur-containing compounds were also detected in appreciable quantities (161-706 ppb) in all samples. For all samples, hexanal and 2-methyl-2-buten-1-ol were dominant among the aldehydes and alcohols, respectively. Among the nitrogen- and sulfur-containing compounds, Maillard reaction products, such as tetrahydropyridazines, piperidines, and thiazoles, were the major contributors to the total volatile content in all samples. The composition of volatiles observed in roasted byproducts was markedly different from that of the roasted breast muscle. Therefore, the blending of the byproducts in appropriate proportions or blending of volatile flavor extracts from different byproducts may be necessary to obtain an aroma that mimics roasted chicken aroma.

Pharmacophore modeling, virtual screening and molecular docking of ATPase inhibitors of HSP70.

Science.gov (United States)

Sangeetha, K; Sasikala, R P; Meena, K S

2017-10-01

Heat shock protein 70 is an effective anticancer target as it influences many signaling pathways. Hence the study investigated the important pharmacophore feature required for ATPase inhibitors of HSP70 by generating a ligand based pharmacophore model followed by virtual based screening and subsequent validation by molecular docking in Discovery studio V4.0. The most extrapolative pharmacophore model (hypotheses 8) consisted of four hydrogen bond acceptors. Further validation by external test set prediction identified 200 hits from Mini Maybridge, Drug Diverse, SCPDB compounds and Phytochemicals. Consequently, the screened compounds were refined by rule of five, ADMET and molecular docking to retain the best competitive hits. Finally Phytochemical compounds Muricatetrocin B, Diacetylphiladelphicalactone C, Eleutheroside B and 5-(3-{[1-(benzylsulfonyl)piperidin-4-yl]amino}phenyl)- 4-bromo-3-(carboxymethoxy)thiophene-2-carboxylic acid were obtained as leads to inhibit the ATPase activity of HSP70 in our findings and thus can be proposed for further in vitro and in vivo evaluation. Copyright © 2017 Elsevier Ltd. All rights reserved.

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

Science.gov (United States)

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

2009-01-01

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

Ultrasound studies of the effects of certain poisonous plants on uterine function and fetal development in livestock.

Science.gov (United States)

Bunch, T D; Panter, K E; James, L F

1992-05-01

Ingestion of locoweed (Astragalus spp. and Oxytropis spp.) by pregnant livestock may result in fetal malformations, delayed placentation, reduced placental and uterine vascular development, hydrops amnii, hydrops allantois, abnormal cotyledonary development, interruption of fetal fluid balance, and abortion. Ultrasonography of pregnant sheep fed locoweed demonstrated that abortion was first preceded by changes in fetal heart rate and strength of contraction and structural changes of the cotyledons, followed by increased accumulation of fetal fluid within the placental membranes and death of the fetus. During pregnancy the toxic agent in locoweed (swainsonine) apparently passes through the placental barrier to the fetus and during lactation through the milk to the neonate. Poison-hemlock (Conium maculatum), wild tree tobacco (Nicotiana glauca), and lunara lupine (Lupinus formosus) all contain piperidine alkaloids and induce fetal malformations, including multiple congenital contractures and cleft palate in livestock. Ultrasonography studies of pregnant sheep and goats gavaged with these plants during 30 to 60 d of gestation suggests that the primary cause of multiple congenital contractures and cleft palate is the degree and the duration of the alkaloid-induced fetal immobilization.

Poison hemlock (Conium maculatum L.).

Science.gov (United States)

Vetter, J

2004-09-01

One of the most poisonous species amongst higher plants is Conium maculatum. It is a very common nitrophile weed species, belonging to the Apiaceae (formerly Umbelliferae) family. It contains some piperidine alkaloids (coniine, N-methyl-coniine, conhydrine, pseudoconhydrine, gamma-coniceine), which are formed by the cyclisation of an eight-carbon chain derived from four acetate units. gamma-Coniceine is the precursor of the other hemlock alkaloids. All vegetative organs, flowers and fruits contain alkaloids. The concentrations (both absolute and relative) of the different alkaloids depend on plant varieties, on ecological conditions and on the age of the plant. The characteristic biological effects of the plants are summarised on cattle, sheep, goat, swine, rabbit, elk, birds and insects and the symptoms of the human toxicosis (some cases of poisonings) are discussed according to the literature data. The general symptoms of hemlock poisoning are effects on nervous system (stimulation followed by paralysis of motor nerve endings and CNS stimulation and later depression), vomiting, trembling, problems in movement, slow and weak later rapid pulse, rapid respiration, salivation, urination, nausea, convulsions, coma and death.

Stereoselective potencies and relative toxicities of γ-coniceine and N-methylconiine enantiomers.

Science.gov (United States)

Lee, Stephen T; Green, Benedict T; Welch, Kevin D; Jordan, Glenn T; Zhang, Qian; Panter, Kip E; Hughes, David; Chang, Cheng-Wei Tom; Pfister, James A; Gardner, Dale R

2013-04-15

γ-Coniceine, coniine, and N-methylconiine are toxic alkaloids present in poison hemlock (Conium maculatum). We previously reported the comparison of the relative potencies of (+)- and (-)-coniine enantiomers. In this study, we synthesized γ-coniceine and the enantiomers of N-methylconiine and determined the biological activity of γ-coniceine and each of the N-methylconiine enantiomers in vitro and in vivo. The relative potencies of these piperidine alkaloids on cells expressing human fetal muscle-type nicotinic acetylcholine receptors had the rank order of γ-coniceine > (-)-N-methylconiine > (±)-N-methylconiine > (+)-N-methylconiine. The relative lethalities of γ-coniceine and (-)-, (±)-, and (+)-N-methylconiine in vivo using a mouse bioassay were 4.4, 16.1, 17.8, and 19.2 mg/kg, respectively. The results from this study suggest γ-coniceine is a more potent agonist than the enantiomers of N-methylconiine and that there is a stereoselective difference in the in vitro potencies of the enantiomers of N-methylconiine that correlates with the relative toxicities of the enantiomers in vivo.

Aromatic C-nitrosation of a bioactive molecule. Nitrosation of minoxidil.

Science.gov (United States)

González-Jiménez, Mario; Arenas-Valgañón, Jorge; Calle, Emilio; Casado, Julio

2011-10-26

Minoxidil (2,4-diamino-6-(piperidin-1'-yl)pyrimidine N(3)-oxide; CASRN 38304-91-5) is a bioactive molecule with several nitrosatable groups widely used as an antihypertensive and antialopecia agent. Here the nitrosation of minoxidil was investigated. The conclusions drawn are as follows: (i) In the pH = 2.3-5.0 range, the minoxidil molecule undergoes aromatic C-nitrosation by nitrite. The dominant reaction was C-5 nitrosation through a mechanism that appears to consist of an electrophilic attack on the nitrosatable substrate by H(2)NO(2)(+)/NO(+), followed by a slow proton transfer; (ii) the reactivity of minoxidil as a C-nitrosatable substrate proved to be 7-fold greater than that of phenol, this being attributed to the preferred para- and ortho-orientations of the two -NH(2) groups at positions 2 and 4 of the minoxidil molecule, which activate electrophilic substitution in the C-5 position through their mesomeric effect. The N-nitrosominoxidil resulting from the nitrosation could be potentially harmful to the minoxidil users.

Alkaline polymer electrolyte fuel cells stably working at 80 °C

Science.gov (United States)

Peng, Hanqing; Li, Qihao; Hu, Meixue; Xiao, Li; Lu, Juntao; Zhuang, Lin

2018-06-01

Alkaline polymer electrolyte fuel cells are a new class of polymer electrolyte fuel cells that fundamentally enables the use of nonprecious metal catalysts. The cell performance mostly relies on the quality of alkaline polymer electrolytes, including the ionic conductivity and the chemical/mechanical stability. For a long time, alkaline polymer electrolytes are thought to be too weak in stability to allow the fuel cell to be operated at elevated temperatures, e.g., above 60 °C. In the present work, we report a progress in the state-of-the-art alkaline polymer electrolyte fuel cell technology. By using a newly developed alkaline polymer electrolyte, quaternary ammonia poly (N-methyl-piperidine-co-p-terphenyl), which simultaneously possesses high ionic conductivity and excellent chemical/mechanical stability, the fuel cell can now be stably operated at 80 °C with high power density. The peak power density reaches ca. 1.5 W/cm2 at 80 °C with Pt/C catalysts used in both the anode and the cathode. The cell works stably in a period of study over 100 h.

Synthesis of 9,9,9-trideutero-1,4-dihydroxynonane mercapturic acid (d3-DHN-MA), a useful internal standard for DHN-MA urinalysis.

Science.gov (United States)

Chantegrel, B; Deshayes, C; Doutheau, A; Steghens, J P

2002-10-01

Racemic 1,4-dihydroxynonane mercapturic acid (DHN-MA) and 9,9,9-trideutero-1,4-dihydroxynonane mercapturic acid (d3-DHN-MA) are synthesized on a 400-mg scale (overall yield approximately 40%) by a two-step sequence involving Michael addition of N-acetyl-L-cysteine to methyl 4-hydroxynon-2(E)-enoate or methyl 9,9,9-trideutero-4-hydroxynon-2 (E)-enoate, followed by reduction of the intermediate adducts with lithium borohydride. The requisite starting methyl esters are obtained, respectively, from heptanal or 7,7,7-trideuteroheptanal and methyl 4-chlorophenylsulfinylacetate via a sulfoxide piperidine and carbonyl reaction described in the literature. The 7,7,7-trideuteroheptanal is easily prepared by classical methods in four steps from 6-bromo-1-hexanol. 13C NMR data indicate that DHN-MA as well as d3-DHN-MA are obtained as mixtures of four diastereomers. Preliminary results show that d3-DHN-MA could be used as an internal standard for mass spectrometric quantification of DHN-MA in human urine.

Development of local radio protectors and adaptogens

International Nuclear Information System (INIS)

Praliev, K.; Seitkazina, G.; Karabalin, V.Yu.

1996-01-01

The works in the field of search and study of new highly efficient and safe preparations for prevention and treatment of many diseases are most important in this country because of the grievous ecological situation some of its regions. In particular, essential territorial contamination by radionuclides causing a threat of people radioactive poisoning and total absence of radioprotectors aggravate the above-stated problem, as it is known, that many medicinal prepared lions are low efficient in conditions .of beam affection. Besides there is another problem - it concerns elaboration of efficient adaptogens - medicinal means that help a diseased organism to manage the illness more fast.Taking into account that the problem is most vital and significant research experience on new domestic radioprotectors and adaptogens is available, we have determined the forthcoming research main tasks: - Ynthetic investigations for the piperidine derivative series, purposed to the synthesis methods development, total substances identification and elaboration of experimental samples for pharmacological research. - The synthesized substances pharmacological tests according to the principles of radioprotector and adaptogen primary selection. - Selected preparations biochemical tests on radionuclide-affected experimental animals

Structure of Prolyl-tRNA Synthetase-Halofuginone Complex Provides Basis for Development of Drugs against Malaria and Toxoplasmosis.

Science.gov (United States)

Jain, Vitul; Yogavel, Manickam; Oshima, Yoshiteru; Kikuchi, Haruhisa; Touquet, Bastien; Hakimi, Mohamed-Ali; Sharma, Amit

2015-05-05

The Chinese herb Dichroa febrifuga has traditionally treated malaria-associated fever. Its active component febrifugine (FF) and derivatives such as halofuginone (HF) are potent anti-malarials. Here, we show that FF-based derivatives arrest parasite growth by direct interaction with and inhibition of the protein translation enzyme prolyl-tRNA synthetase (PRS). Dual administration of inhibitors that target different tRNA synthetases suggests high utility of these drug targets. We reveal the ternary complex structure of PRS-HF and adenosine 5'-(β,γ-imido)triphosphate where the latter facilitates HF integration into the PRS active site. Structural analyses also highlight spaces within the PRS architecture for HF derivatization of its quinazolinone, but not piperidine, moiety. We also show a remarkable ability of HF to kill the related human parasite Toxoplasma gondii, suggesting wider HF efficacy against parasitic PRSs. Hence, our cell-, enzyme-, and structure-based data on FF-based inhibitors strengthen the case for their inclusion in anti-malarial and anti-toxoplasmosis drug development efforts. Copyright © 2015 Elsevier Ltd. All rights reserved.

New method to measure the carbamoylating activity of nitrosoureas by electron paramagnetic resonance spectroscopy.

Science.gov (United States)

Gadzheva, V; Ichimori, K; Raikov, Z; Nakazawa, H

1997-08-01

A new method for measuring the carbamoylating activity of nitrosoureas and isocyanates using electron paramagnetic resonance (EPR) spectroscopy is described. The extent and time course of carbamoylation reaction of chloroethyl isocyanate and a series of 9 nitrosoureas toward amino group of 4-amino-2,2,6,6-tetramethyl-piperidine-1-oxyl were examined with both the EPR method and the HPLC method which has been proposed by Brubaker et al. [Biochem. Pharmacol. 35:2359 (1986)]. Spin-labeled nitrosoureas we synthesized are included in this study since they have less toxicity or more efficiency than commercially available drug in some cases. The concentration of carbamoylated product was easily determined with the EPR spectra. There is a very high correlation (r = 0.982, t = 2.58, N = 10, p nitrosoureas showed lower carbamoylating activity than non-labeled analogues. The carbamoylating activity for these nitrosourea depended on the reactivity of isocyanate intermediate and almost independent of their half life. This rapid and simple EPR method is suitable for the detailed investigation of the rate and extent of carbamoylation reaction.

Synthesis of N-methyl-N-nitrosourea linked to a methidium chloride analogue and its reactions with 32P-end-labeled DNA

International Nuclear Information System (INIS)

Konakahara, T.; Wurdeman, R.L.; Gold, B.

1988-01-01

The synthesis and characterization of an N-methyl-N-nitrosourea (MNU) analogue that is covalently linked to methidium nucleus (9) is described. At 37/degrees/C in pH 8.0 buffer 9 hydrolyzes via pseudo-first-order kinetics, with a calculated t/sub 1/2/ = 77 min. By use of polyacrylamide sequencing gels the formation of piperidine-labile N 7 -methylguanine adducts from the reaction of 9 and MNU with 5'- 32 P-end-labeled DNA restriction fragments is reported. DNA methylation by 9 in 10 mM Tris buffer is enhanced with increasing ionic strength (50-200 mM NaCl), which contrasts to the inhibition of MNU-induced cleavage with increasing salt. In addition, 9 methylates all G sites equally, while MNU shows a clear preference for d(G)/sub n/ (n ≥ 3) runs and an asymmetrical methylation pattern within these G-rich regions. The results are discussed in terms of the delivery of the MNU moiety to the DNA target by a non-sequence-specific intercalation process and the subsequent hydrolytic generation of a nondiffusible alkylating intermediate

Synthesis and biological investigation of PIM mimics carrying biotin or a fluorescent label for cellular imaging.

Science.gov (United States)

Front, Sophie; Bourigault, Marie-Laure; Rose, Stéphanie; Noria, Ségueni; Quesniaux, Valérie F J; Martin, Olivier R

2013-01-16

Phosphatidyl inositol mannosides (PIMs) are constituents of the mycobacterial cell wall; these glycolipids are known to exhibit potent inhibitory activity toward the LPS-induced production of cytokines by macrophages, and therefore have potential as anti-inflammatory agents. Recently, heterocyclic analogues of PIMs in which the inositol is replaced by a piperidine (aza-PIM mimics) or a tetrahydropyran moiety (oxa-PIM mimics) have been prepared by short synthetic sequences and shown to retain the biological activity of the parent PIM structures. In this investigation, the aza-PIM analogue was used as a convenient scaffold to link biotin or a fluorescent label (tetramethyl-rhodamine) by way of an aminocaproyl spacer, with the goal of using these conjugates for intracellular localization and for the study of the mechanism of their antiinflammatory action. The synthesis of these compounds is reported, as well as the evaluation of their activities as inhibitors of LPS-induced cytokine production by macrophages (TNFα, IL12p40); preliminary investigations by FACS and confocal microscopy indicated that PIM-biotin conjugate binds to macrophage membranes with rapid kinetics.

A tentative characterization of volatile compounds from Iberian Dry-Cured Ham according to different anatomical locations. A detailed study

Directory of Open Access Journals (Sweden)

Narváez-Rivas, Mónica

2010-12-01

Full Text Available The aim of this work was to carry out a characterization of the volatile fraction of 23 Iberian dry-cured hams by GC-iontrap- MS. Two different locations –subcutaneous fat and musclefrom the slices taken parallel to the femur from each ham were analyzed. The analyses were done by Gas Chromatography- Mass Spectrometry with a polar capillary column and after a previous extraction using the Purge and Trap method. A total of 109 volatile compounds were identified, twenty-eight of which for the first time in Iberian dry-cured ham (isopropanol, 4-methyl-5-decanol, 2-butyl-1-octanol, 2-etoxy-ethanol, 2-ethyl-phenol, 2-hexen-1-ol, 3,5-octadien-2-ol, 2-decen- 1-ol, 5-ethylcyclopent-1-enecarboxaldehyde, 2,4-heptadienal, 6-nonenal, cyclopentanone, 3-ethenyl-cyclohexanone, 2-methyl-cyclopentanone, 6-octen-2-one, 5-methyl-2-(1-methylethyl- cyclopentanone, 3,5-octadien-2-one, 2-hydroxymethyl- 2,3,3-trimethyl-oxirane, 2-ethyl-hexyl 2-propenoate, 1-methoxypentane, 2,3-dihydrofurane, 2-D-2-pentadecyl-1,3-dioxolane, hexyl octyl eter, eucalyptol, di-(3-methyl-buthyl eter, piperidine, isopropylamine and 2-ethenyl-pyridine.

El objetivo de este trabajo fue llevar a cabo una caracterización de la fracción volátil de 23 jamones curados de cerdo ibérico mediante GC-ion-trap-MS. Se analizaron dos zonas diferentes de las lonchas tomadas paralelas al fémur de cada jamón, Grasa subcutánea y magro. El análisis se realizó mediante cromatografía gaseosa en columna capilar de alta polaridad con detección de espectrometría de masas y extracción previa de la fracción volátil mediante purga y trampa. Un total de 109 compuestos volátiles fueron identificados, veintiocho de ellos descritos por primera vez en Jamón ibérico curado (isopropanol, 4-methyl-5-decanol, 2-butyl-1-octanol, 2-etoxy-ethanol, 2-ethyl-phenol, 2-hexen-1-ol, 3,5-octadien-2- ol, 2-decen-1-ol, 5-ethylcyclopent-1-enecarboxaldehyde, 2,4-heptadienal, 6-nonenal, cyclopentanone, 3-ethenyl

Studies on low-carrier radiofluorination of non-active aromatics with no-carrier-added [{sup 18}F]fluoride; Untersuchungen zur traegerarmen Radiofluorierung nicht-aktiver Aromaten mit n.c.a. [{sup 18}F]Fluorid

Energy Technology Data Exchange (ETDEWEB)

Cardinale, Jens

2013-01-15

In vivo imaging with positron emission tomography generally demands radiotracers with a high specific activity. In case of fluorine-18 the required no-carrier-added (n.c.a.) starting material is only available in form of fluoride. This and the short half-life of 109.7 minutes of the radionuclide lead to the demand of special methods for radiosyntheses. The only practical procedure for manufacturing n.c.a. [{sup 18}F]fluoro-compounds is therefore nucleophilic substitution. There is, however, still a lack of effective procedures for the labelling of electron rich aromatic molecules starting from n.c.a. [{sup 18}F]fluoride. A process for n.c.a. radiofluorination of these compounds is offered by the reaction of iodonium compounds as starting materials. In this study modern procedures for the synthesis of iodoniumsalts and -ylides were investigated. Several precursor molecules for the versatile synthetic building block 4-[{sup 18}F]fluoroiodobenzene were synthesised. In this course, a new one-pot procedure for the synthesis of iodoniumylides was developed. Further on, the syntheses of suitable iodonium precursors for two fluorophenoxy-derivatives, which are possible antidepressants, were investigated. Due to their binding profile these compounds can be considered as ligands for the serotonin reuptake transporter (SERT) and the norepinephrin reuptake transporter (NET), respectively. The preparation of appropriate iodonium salts proved to be too problematic, while the synthesis of suitable iodoniumylides could be accomplished with satisfactory yields of about 30% and 40 %, respectively. Both compounds were labelled with n.c.a. [{sup 18}F]fluoride and deprotected to the desired target compounds 4-((3-[{sup 18}F]fluorophenoxy)(phenyl)methyl)piperidine and 4-((4-[{sup 18}F]fluorophenoxy)(phenyl)methyl)piperidine in radiochemical yields of about 40 % and 25 %, respectively. Those are now available for preclinical evaluation studies. Furthermore, a process for the palladium

Novel pyridylmethylamines as highly selective 5-HT(1A) superagonists.

Science.gov (United States)

Bollinger, Stefan; Hübner, Harald; Heinemann, Frank W; Meyer, Karsten; Gmeiner, Peter

2010-10-14

To further improve the maximal serotonergic efficacy and better understand the configurational requirements for 5-HT(1A) binding and activation, we generated and biologically investigated structural variants of the lead structure befiradol. For a bioisosteric replacement of the 3-chloro-4-fluoro moiety, a focused library of 63 compounds by solution phase parallel synthesis was developed. Target binding of our compound collection was investigated, and their affinities for 5-HT(2), α(1), and α(2)-adrenergic as well as D(1)-D(4) dopamine receptors were compared. For particularly interesting test compounds, intrinsic activities at 5-HT(1A) were examined in vitro employing a GTPγS assay. The investigation guided us to highly selective 5HT(1A) superagonists. The benzothiophene-3-carboxamide 8bt revealed almost exclusive 5HT(1A) recognition with a K(i) value of 2.7 nM and a maximal efficacy of 124%. To get insights into the bioactive conformation of our compound collection, we synthesized conformationally constrained bicyclic scaffolds when SAR data indicated a chair-type geometry and an equatorially dispositioned aminomethyl substituent for the 4,4-disubstituted piperidine moiety.

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

Science.gov (United States)

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.

Pressure effect of the 1H NMR spectra of organic compounds in the presence of lanthanide shift reagents. A formally associative process characterized by volume expansion

International Nuclear Information System (INIS)

Schulman, E.M.; Cheung, C.K.; Merbach, A.E.; Yamada, H.; le Noble, W.J.

1987-01-01

Following the successful application of hydrostatic pressure in mechanistic investigations of organic reactions, chemists have launched a vigorous effort to apply this tool to substitution reactions of coordination compounds. The authors began to study pressure effects in the NMR spectra of keton-lanthanide combination with the hope that the increase shifts anticipated might enhance the utility of the method, perhaps even expand its applicability to new classes of compounds. 5-Phenyl- and 5-tert-butyladamantan-2-one, piperidine, tetrahydrofuran, and cyclopentanol exhibited pressure-reduced lanthanide-induced shifts with Eu(fod) 3 ; Yb(fob) 3 and the shielding reagent Pr(fod) 3 showed the same effect with adamantanone. Solvent variations (CD 2 Cl 2 , CCl 4 ) caused minor changes in the magnitude of these shifts but did not reverse any. With the objective of learning whether these effects are due to a suppressed equilibrium population or to a reduction in the bound shift of the complex, they measured the spectra for a series or equimolar solutions of adamantanone and Eu(fod) 3 in CDCl 3 and used the Bouquant-Chuche equation to calculate both. Reasonable agreement with known atmosphere pressure data was obtained

SCH-C (SCH 351125), an orally bioavailable, small molecule antagonist of the chemokine receptor CCR5, is a potent inhibitor of HIV-1 infection in vitro and in vivo.

Science.gov (United States)

Strizki, J M; Xu, S; Wagner, N E; Wojcik, L; Liu, J; Hou, Y; Endres, M; Palani, A; Shapiro, S; Clader, J W; Greenlee, W J; Tagat, J R; McCombie, S; Cox, K; Fawzi, A B; Chou, C C; Pugliese-Sivo, C; Davies, L; Moreno, M E; Ho, D D; Trkola, A; Stoddart, C A; Moore, J P; Reyes, G R; Baroudy, B M

2001-10-23

We describe here the identification and properties of SCH-C (SCH 351125), a small molecule inhibitor of HIV-1 entry via the CCR5 coreceptor. SCH-C, an oxime-piperidine compound, is a specific CCR5 antagonist as determined in multiple receptor binding and signal transduction assays. This compound specifically inhibits HIV-1 infection mediated by CCR5 in U-87 astroglioma cells but has no effect on infection of CXCR4-expressing cells. SCH-C has broad and potent antiviral activity in vitro against primary HIV-1 isolates that use CCR5 as their entry coreceptor, with mean 50% inhibitory concentrations ranging between 0.4 and 9 nM. Moreover, SCH-C strongly inhibits the replication of an R5-using HIV-1 isolate in SCID-hu Thy/Liv mice. SCH-C has a favorable pharmacokinetic profile in rodents and primates with an oral bioavailability of 50-60% and a serum half-life of 5-6 h. On the basis of its novel mechanism of action, potent antiviral activity, and in vivo pharmacokinetic profile, SCH-C is a promising new candidate for therapeutic intervention of HIV infection.

Identification of Unique Metabolites of the Designer Opioid Furanyl Fentanyl.

Science.gov (United States)

Goggin, Melissa M; Nguyen, An; Janis, Gregory C

2017-06-01

The illicit drug market has seen an increase in designer opioids, including fentanyl and methadone analogs, and other structurally unrelated opioid agonists. The designer opioid, furanyl fentanyl, is one of many fentanyl analogs clandestinely synthesized for recreational use and contributing to the fentanyl and opioid crisis. A method has been developed and validated for the analysis of furanyl fentanyl and furanyl norfentanyl in urine specimens from pain management programs. Approximately 10% of samples from a set of 500 presumptive heroin-positive urine specimens were found to contain furanyl fentanyl, with an average concentration of 33.8 ng/mL, and ranging from 0.26 to 390 ng/mL. Little to no furanyl norfentanyl was observed; therefore, the furanyl fentanyl specimens were further analyzed by untargeted high-resolution mass spectrometry to identify other metabolites. Multiple metabolites, including a dihydrodiol metabolite, 4-anilino-N-phenethyl-piperidine (4-ANPP) and a sulfate metabolite were identified. The aim of the presented study was to identify the major metabolite(s) of furanyl fentanyl and estimate their concentrations for the purpose of toxicological monitoring. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Spectrochemical investigation of neodymium fluorinated #betta#-diketonates

International Nuclear Information System (INIS)

Khomenko, V.S.; Rasshinina, T.A.; Lozinskij, M.O.; Fialkov, Yu.A.

1982-01-01

A spectrochemical study is carried out on neodymium complexes with #betta#-diketonates of the following contents: Nd(tdh) 4 xHP, Nd(tdh) 3 xbipy, Nd(tdh) 3 xC 10 D 8 N 2 , Nd(tdh) 3 xphen, Nd(fod) 4 xHP, Nd(fod) 3 xbipy, Nd(fod) 3 xphen, where tdh - 1, 1, 1,-trifluoro-5, 5 dimethylhexanedione-2, 4; fod - 1, 1, 1, 2, 2, 3, 3-heptafluoro-7, 7-dimethyloctanedione-4, 6; bipy - 2, 2'-dipyridyl- phen - 1, 10-phenanthroline; p - piperidine; C 10 D 8 N 2 - deuterated 2, 2'-dipyridyl. A change in the metal-ligand bond character was determined by means of the nepheloxetic effect (band shift in absorption spectra at the expense of an interelectron repulsion decrease in the 4f-electron shell due to its expansion during the formation of partially covalent metal-ligand bonds). Mutual ligand effect on the complex properties was also studied using the mass spectrometric method. It is established that an extra addition of a bisheterocycle to a triligand rare-earth complex makes an average bond in a complex more covalent

MS-377, a novel selective sigma(1) receptor ligand, reverses phencyclidine-induced release of dopamine and serotonin in rat brain.

Science.gov (United States)

Takahashi, S; Horikomi, K; Kato, T

2001-09-21

A novel selective sigma(1) receptor ligand, (R)-(+)-1-(4-chlorophenyl)-3-[4-(2-methoxyethyl)piperazin-1-yl]methyl-2-pyrrolidinone L-tartrate (MS-377), inhibits phencyclidine (1-(1-phenylcyclohexyl)piperidine; PCP)-induced behaviors in animal models. In this study, we measured extracellular dopamine and serotonin levels in the rat brain after treatment with MS-377 alone, using in vivo microdialysis. We also examined the effects of MS-377 on extracellular dopamine and serotonin levels in the rat medial prefrontal cortex after treatment with PCP. MS-377 itself had no significant effects on dopamine release in the striatum (10 mg/kg, p.o.) nor on dopamine or serotonin release in the medial prefrontal cortex (1 and 10 mg/kg, p.o.). PCP (3 mg/kg, i.p.) markedly increased dopamine and serotonin release in the medial prefrontal cortex. MS-377 (1 mg/kg, p.o.), when administered 60 min prior to PCP, significantly attenuated this effect of PCP. These results suggest that the inhibitory effects of MS-377 on PCP-induced behaviors are partly mediated by inhibition of the increase in dopamine and serotonin release in the rat medial prefrontal cortex caused by PCP.

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

International Nuclear Information System (INIS)

Tudose, Madalina; Constantinescu, Titus; Balaban, Alexandru T.; Ionita, Petre

2008-01-01

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

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

Energy Technology Data Exchange (ETDEWEB)

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

2008-01-30

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

Can effective atomic polarizability {alpha}{sub d} determine the ionization of {sup 99}tc{sup m} - diaminedithiol alkylamine radioligand derivatives?; Polarizabilidade atomica efetiva {alpha}{sub d} pode ditar a ionizacao de radioligantes {sup 99}Tc{sup m} - diaminoditiol alquilaminicos?

Energy Technology Data Exchange (ETDEWEB)

Goncalves, Marcos Moises; Fraceto, Leonardo Fernandes; Vila, Marta Maria Duarte Carvalho; Oliveira, Robson Vicente Machado de [Universidade de Sorocaba, SP (Brazil). Curso de Farmacia]. E-mail: marcos.goncalves@uniso.br

2006-09-15

Polarizability correlates well with organic ion stabilization in solution and can be defined as a measure of the relative ease of the distortion of the electronic cloud of a dipolar system exposed to an external electric field. The effective atomic polarizability, {alpha}{sub d}, has a fundamental influence on chemical reactivity in the gas phase and in solution. In terms of chemical reactivity the charge is generated within the molecule as a positive charge due to protonation, ionization or resulting from the attack of a nucleophilic anion. In this paper, lipoidal diaminedithiol (DADT) perfusion radioligands based on {sup 99}Tc{sup m} and possessing an alkylamine side chain have been used to check the influence of {alpha}{sub d} on their brain uptake. Some new DADT derivatives, respectively DADT-DIPA (diaminedithiol-diisopropylamine), DADT DIBA (diaminedithiol - diisobutylamine), DADT-PR (diaminedithiol-branched piperidine), have been designed to have high nitrogen alkylamine {alpha}{sub d} values. In spite of the fact of higher {alpha}{sub d} values having been correlated to higher brain uptakes, there is not a clear mechanism able to trap these radioligands into the brain space. (author)

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

Science.gov (United States)

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

2015-06-01

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

Nontoxic piperamides and their synthetic analogues as novel antifouling reagents

KAUST Repository

Huang, Xiang-Zhong

2014-03-25

Bioassay-guided isolation of an acetone extract from a terrestrial plant Piper betle produced four known piperamides with potent antifouling (AF) activities, as evidenced by inhibition of settlement of barnacle cypris larvae. The AF activities of the four piperamides and 15 synthesized analogues were compared and their structure-activity relationships were probed. Among the compounds, piperoleine B and 1-[1-oxo-7-(3′,4′-methylenedioxyphenyl)-6E-heptenyl]-piperidine (MPHP) showed strong activity against settlement of cyprids of the barnacle Balanus amphitrite, having EC50 values of 1.1 ± 0.3 and 0.5 ± 0.2 μg ml-1, respectively. No toxicity against zebra fish was observed following incubation with these two compounds. Besides being non-toxic, 91% of piperoleine B-treated cyprids and 84% of MPHP-treated cyprids at a concentration of 100 μM completed normal metamorphosis in recovery bioassays, indicating that the anti-settlement effect of these two compounds was reversible. Hydrolysis and photolysis experiments indicated that MPHP could be decomposed in the marine environment. It is concluded that piperamides are promising compounds for use in marine AF coatings. © 2014 © 2014 Taylor & Francis.

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

Energy Technology Data Exchange (ETDEWEB)

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

1970-07-01

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

Brain uptake of pipecolic acid, amino acids, amines following intracarotid injection in the mouse

International Nuclear Information System (INIS)

Nishio, H.; Giacobini, E.

1981-01-01

The uptake of pipecolic acid by the mouse brain was compared to that of several amino acids and amines, following an injection of a double-labeled mixture into the carotid artery. In general, BUI (brain uptake index) values were lower in the mouse than those previously reported in the rat. The only exception was proline. Lysine, a precursor of pipecolic acid biosynthesis in brain, showed a higher BUI than pipecolic acid. The BUI of D,L-[3H]pipecolic acid was found to be 3.39 (at 0.114 mM). This was saturable between a concentration of 0.114 and 3.44 mM. Kinetic analysis suggests the presence of two kinds of transport systems. Substances structurally related to pipecolic acid, such as nipecotic acid, isonipecotic acid, L-proline, and piperidine show a significant inhibitory effect. Amont the amino acids tested, only GABA showed an inhibitory effect. Data are reported which, when considered with other findings present evidence that pipecolic acid is (1) synthesized both in vitro and in vivo in the mouse brain, (2) actively transported in vivo into the brain, and (3) taken up in vitro by synaptosomal preparations

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

Science.gov (United States)

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

2013-01-01

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

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

Science.gov (United States)

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...

Clinical toxicology of newer recreational drugs.

Science.gov (United States)

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

Novel, high-activity hydroprocessing catalysts: Iron group phosphides

Science.gov (United States)

Wang, Xianqin

A series of iron, cobalt and nickel transition metal phosphides was synthesized by means of temperature-programmed reduction (TPR) of the corresponding phosphates. The same materials, Fe2P, CoP and NO, were also prepared on a silica (SiO2) support. The phase purity of these catalysts was established by x-ray diffraction (XRD), and the surface properties were determined by N2 BET specific surface area (Sg) measurements and CO chemisorption. The activities of the silica-supported catalysts were tested in a three-phase trickle bed reactor for the simultaneous hydrodenitrogenation (HDN) of quinoline and hydrodesulfurization (HDS) of dibenzothiophene using a model liquid feed at realistic conditions (30 atm, 370°C). The reactivity studies showed that the nickel phosphide (Ni2P/SiO2) was the most active of the catalysts. Compared with a commercial Ni-Mo-S/gamma-Al 2O3 catalyst at the same conditions, Ni2P/silica had a substantially higher HDS activity (100% vs. 76%) and HDN activity (82% vs. 38%). Because of their good hydrotreating activity, an extensive study of the preparation of silica supported nickel phosphides, Ni2P/SiO 2, was carried out. The parameters investigated were the phosphorus content and the weight loading of the active phase. The most active composition was found to have a starting synthesis Ni/P ratio close to 1/2, and the best loading of this sample on silica was observed to be 18 wt.%. Extended x-ray absorption fine structure (EXAFS) and x-ray absorption near edge spectroscopy (XANES) measurements were employed to determine the structures of the supported samples. The main phase before and after reaction was found to be Ni2P, but some sulfur was found to be retained after reaction. A comprehensive scrutiny of the HDN reaction mechanism was also made over the Ni2P/SiO2 sample (Ni/P = 1/2) by comparing the HDN activity of a series of piperidine derivatives of different structure. It was found that piperidine adsorption involved an alpha-H activation

Multi-residue determination of 210 drugs in pork by ultra-high-performance liquid chromatography-tandem mass spectrometry.

Science.gov (United States)

Yin, Zhiqiang; Chai, Tingting; Mu, Pengqian; Xu, Nana; Song, Yue; Wang, Xinlu; Jia, Qi; Qiu, Jing

2016-09-09

This paper presents a multi-residue analytical method for 210 drugs in pork using ultra-high-performance liquid chromatography-Q-Trap tandem mass spectrometry (UPLC-MS/MS) within 20min via positive ESI in scheduled multi-reaction monitoring (MRM) mode. The 210 drugs, belonging to 21 different chemical classes, included macrolides, sulfonamides, tetracyclines, β-lactams, β-agonists, aminoglycosides, antiviral drugs, glycosides, phenothiazine, protein anabolic hormones, non-steroidal anti-inflammatory drugs (NSAIDs), quinolones, antifungal drugs, corticosteroids, imidazoles, piperidines, piperazidines, insecticides, amides, alkaloids and others. A rapid and simple preparation method was applied to process the animal tissues, including solvent extraction with an acetonitrile/water mixture (80/20, v/v), defatting and clean-up processes. The recoveries ranged from 52% to 130% with relative standard deviations (RSDs)<20% for spiked concentrations of 10, 50 and 250μg/kg. More than 90% of the analytes achieved low limits of quantification (LOQs)<10μg/kg. The decision limit (CCα), detection capability (CCβ) values were in the range of 2-502μg/kg and 4-505μg/kg, respectively. This method is significant for food safety monitoring and controlling veterinary drug use. Copyright © 2016 Elsevier B.V. All rights reserved.

(3aS,7aS-5-[(S-3,3,3-Trifluoro-2-methoxy-2-phenylpropanoyl]-2,3,4,5,6,7-hexahydro-1H-pyrrolo[3,4-c]pyridin-3(2H-one monohydrate

Directory of Open Access Journals (Sweden)

Huichun Zhu

2010-01-01

Full Text Available rac-Benzyl 3-oxohexahydro-1H-pyrrolo[3,4-c]pyridine-5(6H-carboxylate was separated by chiral chromatography, and one of the enantiomers ([α]22D = +10° was hydrogenated in the presence of Pd/C in methanol, producing octahydro-3H-pyrrolo[3,4-c]pyridin-3-one. The latter was reacted with (2R-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl chloride [(R-(−-Mosher acid chloride], giving rise to the title compound, C17H19F3N2O3·H2O. The present structure established the absolute configuration of the pyrrolopiperidine fragment based on the known configuration of the (R-Mosher acid chloride. The piperidine ring has a somewhat distorted chair conformation and is cis-fused with the five-membered envelope-shaped ring; the plane of the exocyclic amide bond is approximately orthogonal to the plane of the phenyl ring, making a dihedral angle of 82.31 (3°. The water molecule acts as an acceptor to the proton of the amino group in an N—H...O interaction, and as a double proton donor in O—H...O hydrogen bonds, generating infinite bands along the a axis.

Application of stable, nitroxide free radicals in solution to low magnetic fields measurements

International Nuclear Information System (INIS)

Besson, Rene

1973-01-01

The first attempts to use the Overhauser-Abragam effect for measuring low magnetic fields date back to 1956. However, the instability of the free radical used, PREMY'S Salt, as well as its virtual insolubility in solvents other than water, hampered the development of the nuclear magnetic resonance magnetometer realized in accordance to this principle: dynamic polarization of protons. New free radicals stable and soluble in many solvents, will enhanced the interest in the device. In particular, the use of 2,2,6,6, tetramethyl- piperidine-4-one-1-oxide (TANO or TANONE) leads to a high sensitivity, low field magnetometer. The methods of measurements, the required apparatus and sample preparation are first described. Next the results of measurements made both in high and low magnetic fields with various free radicals in different solvents are presented in tabular and graphical form. These measurements have determined which radical-solvent couple will yield a high dynamic polarization coefficient. In addition, the improvement obtained by complete deuteration of the free radical has been demonstrated. Problems connected with the application of such radicals in solution to the 'double effect probe' of the magnetometer built by LETI at CEN Grenoble and the solutions reached are discussed. (author) [fr

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

Science.gov (United States)

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.

Determination of perfluoroalkyl carboxylic, sulfonic, and phosphonic acids in food.

Science.gov (United States)

Ullah, Shahid; Alsberg, Tomas; Vestergren, Robin; Berger, Urs

2012-11-01

A sensitive and accurate method was developed and validated for simultaneous analysis of perfluoroalkyl carboxylic acids, sulfonic acids, and phosphonic acids (PFPAs) at low picograms per gram concentrations in a variety of food matrices. The method employed extraction with acetonitrile/water and cleanup on a mixed-mode co-polymeric sorbent (C8 + quaternary amine) using solid-phase extraction. High-performance liquid chromatographic separation was achieved on a C18 column using a mobile phase gradient containing 5 mM 1-methyl piperidine for optimal chromatographic resolution of PFPAs. A quadrupole time-of-flight high-resolution mass spectrometer operating in negative ion mode was used as detector. Method detection limits were in the range of 0.002 to 0.02 ng g(-1) for all analytes. Sample preparation (extraction and cleanup) recoveries at a spiking level of 0.1 ng g(-1) to a baby food composite were in the range of 59 to 98 %. A strong matrix effect was observed in the analysis of PFPAs in food extracts, which was tentatively assigned to sorption of PFPAs to the injection vial in the solvent-based calibration standard. The method was successfully applied to a range of different food matrices including duplicate diet samples, vegetables, meat, and fish samples.

Formation of a covalent complex between the terminal protein of pneumococcal bacteriophage Cp-1 and 5'-dAMP

International Nuclear Information System (INIS)

Garcia, P.; Hermoso, J.M.; Garcia, J.A.; Garcia, E.; Lopez, R.; Salas, M.

1986-01-01

Incubation of extracts of Cp-1-infected Streptococcus pneumoniae with [α- 32 P]dATP produced a labeled protein with the electrophoretic mobility of the Cp-1 terminal protein. The reaction product was resistant to treatment with micrococcal nuclease and sensitive to treatment with proteinase K. Incubation of the 32 P-labeled protein with 5 M piperidine for 4 h at 50 0 C released 5'-dAMP, indicating that a covalent complex between the terminal protein and 5'-dAMP was formed in vitro. When the four deoxynucleoside triphosphates were included in the reaction mixture, a labeled complex of slower electrophoretic mobility in sodium dodecyl sulfate-polyacrylamide gels than the terminal protein-dAMP complex was also found, indicating that the Cp-1 terminal protein-dAMP complex can be elongated and, therefore, that it is an initiation complex. Treatment of the 32 P-labeled terminal protein-dAMP complex with 5.8 M HCl at 110 0 C for 2 h yielded phosphothreonine. These results, together with the resistance of the terminal protein-DNA linkage to hydroxylamine, suggest that the Cp-1 terminal protein is covalently linked to the DNA through a phosphoester bond between L-threonine and 5'-dAMP, namely, a O-5'-deoxyadenylyl-L-threonine bond

1-[3-(4-Butylpiperidin-1-yl)propyl]-1,2,3,4-tetrahydroquinolin-2-one (77-LH-28-1) as a Model for the Rational Design of a Novel Class of Brain Penetrant Ligands with High Affinity and Selectivity for Dopamine D4 Receptor.

Science.gov (United States)

Del Bello, Fabio; Bonifazi, Alessandro; Giorgioni, Gianfabio; Cifani, Carlo; Micioni Di Bonaventura, Maria Vittoria; Petrelli, Riccardo; Piergentili, Alessandro; Fontana, Stefano; Mammoli, Valerio; Yano, Hideaki; Matucci, Rosanna; Vistoli, Giulio; Quaglia, Wilma

2018-04-26

In the present article, the M 1 mAChR bitopic agonist 1-[3-(4-butylpiperidin-1-yl)propyl]-1,2,3,4-tetrahydroquinolin-2-one (77-LH-28-1, 1) has been demonstrated to show unexpected D 4 R selectivity over D 2 R and D 3 R and to behave as a D 4 R antagonist. To better understand the structural features required for the selective interaction with the D 4 R and to obtain compounds unable to activate mAChRs, the aliphatic butyl chain and the piperidine nucleus of 1 were modified, affording compounds 2-14. The 4-benzylpiperidine 9 and the 4-phenylpiperazine 12 showed high D 4 R affinity and selectivity not only over the other D 2 -like subtypes, but also over M 1 -M 5 mAChRs. Derivative 12 was also highly selective over some selected off-targets. This compound showed biased behavior, potently and partially activating G i protein and inhibiting β-arrestin2 recruitment in functional studies. Pharmacokinetic studies demonstrated that it was characterized by a relevant brain penetration. Therefore, 12 might be a useful tool to better clarify the role played by D 4 R in disorders in which this subtype is involved.

Synthesis and in vivo testing of a bromobutyl substituted 1,2-dithia-5,9-diazacycloundecane: a versatile precursor for new sup 99m Tc-bis(aminoethanethiol) complexes

Energy Technology Data Exchange (ETDEWEB)

Eisenhut, M.; Brandau, W.; Missfeldt, M. (Heidelberg Univ. (Germany, F.R.). Radiologisches Zentrum)

1989-01-01

7-(4'Bromobutyl)-3,3,11,11-tetramethyl-1,2-dithia-5,9-diazacycloundecane (6) an intermediate for the preparation of new {sup 99m}Tc-bis(aminoethanethiol) complexes ({sup 99m}Tc-BAT) was synthesized from the corresponding 7-(4'-phenoxybutyl) derivative (5) by ether cleavage with HBr/AcOH. To demonstrate its versatility as an alkylating agent, 6 was reacted with the amines piperidine, morpholine, NH{sub 3} and 1-phenyl-1,3,8-triazaspiro(4,5)decan-4-one, yielding the corresponding N-alkylated amines. Mild ring opening affording the BAT-ligands was achieved by reductive cleavage of the disulphide bonds with threo-2,3-dihydroxy-1,4-dimercaptobutane. The {sup 99m}Tc-BAT complexes prepared by the tin-reduction method proved to be stable under in vitro conditions. With the exception of the 7-(4'-aminobutyl) substituted one, the {sup 99m}Tc-BAT complexes revealed octanol-buffer partition coefficients (P) of log P > 1 at physiological pH. The complexes proved to be neutral and the amount of ultrafiltrable {sup 99m}Tc-BAT complex varied between 8-18%. In contrast to the good in vitro characteristics, the brain uptake values in CD-1 mice were comparably low. (author).

4-Ferrocenylpyridine- and 4-Ferrocenyl-3-ferrocenylmethyl-3,4-dihydropyridine-3,5-dicarbonitriles: Multi-Component Synthesis, Structures and Electrochemistry

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Luis Ortiz-Frade

2012-08-01

Full Text Available The reactions of 2-cyano-3-ferrocenylacrylonitrile (1 with malononitrile (2 in a MeOH/H₂O or 2-PrOH/H₂O medium in the presence of Na₂CO₃ afforded 6-alkoxy-2-amino-4-ferrocenylpyridine-3,5-dicarbonitriles 3a,b (multi-component condensation and 6-alkoxy-2-amino-4-ferrocenyl-3-ferrocenylmethyl-3,4-dihydropyridine-3,5-dicarbonitriles 4a,b (multi-component cyclodimerization. Analogous reactions of 1 with 2 in an MeOH/H₂O medium in the presence of NaOH, piperidine, or morpholine gave compounds 3a, 4a and 2-amino-4-ferrocenyl-6-hydroxy-, 6-piperidino- and 6-morpholinopyridine-3,5-dicarbonitriles 3c–e, respectively. The structures of the compounds 3b, 4a and 4b were established by the spectroscopic data and X-ray diffraction analysis. The electrochemical behaviour of compounds 3b, 3d and 4b was investigated by means of cyclic voltammetry.

Spectrochemical investigation of neodymium fluorinated. beta. -diketonates

Energy Technology Data Exchange (ETDEWEB)

Khomenko, V.S.; Rasshinina, T.A.; Lozinskij, M.O.; Fialkov, Yu.A.

1982-10-01

A spectrochemical study is carried out on neodymium complexes with ..beta..-diketonates of the following contents: Nd(tdh)/sub 4/xHP, Nd(tdh)/sub 3/xbipy, Nd(tdh)/sub 3/xC/sub 10/D/sub 8/N/sub 2/, Nd(tdh)/sub 3/xphen, Nd(fod)/sub 4/xHP, Nd(fod)/sub 3/xbipy, Nd(fod)/sub 3/xphen, where tdh - 1, 1, 1,-trifluoro-5, 5 dimethylhexanedione-2, 4; fod - 1, 1, 1, 2, 2, 3, 3-heptafluoro-7, 7-dimethyloctanedione-4, 6; bipy - 2, 2'-dipyridyl- phen - 1, 10-phenanthroline; p - piperidine; C/sub 10/D/sub 8/N/sub 2/ - deuterated 2, 2'-dipyridyl. A change in the metal-ligand bond character was determined by means of the nepheloxetic effect (band shift in absorption spectra at the expense of an interelectron repulsion decrease in the 4f-electron shell due to its expansion during the formation of partially covalent metal-ligand bonds). Mutual ligand effect on the complex properties was also studied using the mass spectrometric method. It is established that an extra addition of a bisheterocycle to a triligand rare-earth complex makes an average bond in a complex more covalent.

Investigation of long-term retention of unchanged (-)-N-{2-[(R)-3-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidino]ethyl}-4-fluorobenzamide, a novel "funny" If current channel inhibitor, and its metabolites in the eyeball and thoracic aorta of rats.

Science.gov (United States)

Umehara, Ken-ichi; Nakada, Naoyuki; Noguchi, Kiyoshi; Iwatsubo, Takafumi; Usui, Takashi; Kamimura, Hidetaka

2009-11-01

(-)-N-{2-[(R)-3-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidino]ethyl}-4-fluorobenzamide (YM758), a novel "funny" If current channel inhibitor, was being developed as a treatment for stable angina and atrial fibrillation. After a single oral administration of (14)C-YM758, extensive accumulation and long-term retention of radioactivity were observed in the eyeballs of nonalbino rats and in the thoracic aorta of albino/nonalbino rats. Radioluminograms of the eyeballs of nonalbino rats indicated that the radioactivity was localized to the uveal tract, which suggests that the radioactivity may be positively charged and bound mainly to the melanins. Treatment with a mixture of 2 mol/l hydrochloric acid and methanol (5:95, v/v) allowed for the recovery of the major portion of radioactivity from the eyeball, which suggests reversible binding. The radioactive constituents in eyeballs consisted of the unchanged drug (YM758) and three metabolites [mainly 6,7-dimethoxy-2-[(3R)-piperidin-3-ylcarbonyl]-1,2,3,4-tetrahydroisoquinoline (YM-252124)]. Using the organic solvent mixture described above, almost all of the radioactivity was not collected from the thoracic aorta, and approximately 90% was recovered by treatment with elastase, which suggests that some metabolites covalently bind to the elastin fiber localized in the tunica media.

Multitarget-directed tricyclic pyridazinones as G protein-coupled receptor ligands and cholinesterase inhibitors.

Science.gov (United States)

Pau, Amedeo; Catto, Marco; Pinna, Giovanni; Frau, Simona; Murineddu, Gabriele; Asproni, Battistina; Curzu, Maria M; Pisani, Leonardo; Leonetti, Francesco; Loza, Maria Isabel; Brea, José; Pinna, Gérard A; Carotti, Angelo

2015-06-01

By following a multitarget ligand design approach, a library of 47 compounds was prepared, and they were tested as binders of selected G protein-coupled receptors (GPCRs) and inhibitors of acetyl and/or butyryl cholinesterase. The newly designed ligands feature pyridazinone-based tricyclic scaffolds connected through alkyl chains of variable length to proper amine moieties (e.g., substituted piperazines or piperidines) for GPCR and cholinesterase (ChE) molecular recognition. The compounds were tested at three different GPCRs, namely serotoninergic 5-HT1A, adrenergic α1A, and dopaminergic D2 receptors. Our main goal was the discovery of compounds that exhibit, in addition to ChE inhibition, antagonist activity at 5-HT1A because of its involvement in neuronal deficits typical of Alzheimer's and other neurodegenerative diseases. Ligands with nanomolar affinity for the tested GPCRs were discovered, but most of them behaved as dual antagonists of α1A and 5-HT1A receptors. Nevertheless, several compounds displaying this GPCR affinity profile also showed moderate to good inhibition of AChE and BChE, thus deserving further investigations to exploit the therapeutic potential of such unusual biological profiles. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Pituitary and brain D2 receptor density measured in vitro and in vivo in EEDQ treated male rats

International Nuclear Information System (INIS)

Ekman, A.; Eriksson, E.

1991-01-01

The effect of the alkylating compound N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) on dopamine D2 receptor density in rat pituitary and brain was measured using in vitro and in vivo radioligand binding techniques. In the in vitro radioligand binding experiments EEDQ was found to reduce the density (B max ) of [ 3 H]-spiperone binding sites in the striatum by 86% while in the pituitary the corresponding decrease was only 37%. The affinity (K D ) of the remaining striatal and pituitary D2 receptors was not different in EEDQ treated animals as compared to controls. When D2 receptor density was measured in vivo the effect of EEDQ was less pronounced. Thus, in rats given EEDQ the specific binding of either of the two D2 ligands [ 3 H]-raclopride or [ 3 H]-spiperone in striatum and in the limbic forebrain was reduced by 45-62%; moreover, no significant decrease in pituitary D2 receptor density was observed. The data are discussed in relation to the finding that the same dose of EEDQ that failed to influence pituitary D2 receptor density as measured in vivo effectively antagonizes the prolactin decreasing effect of the partial D2 agonist (-)-3-(3-hydroxyphenyl)-N-n-propyl-piperidine [(-)-3-PPP

Identification of small molecules that disrupt signaling between ABL and its positive regulator RIN1.

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Pamela Y Ting

Full Text Available Constitutively active BCR-ABL kinase fusions are causative mutations in the pathogenesis of hematopoietic neoplasias including chronic myelogenous leukemia (CML. Although these fusions have been successfully targeted with kinase inhibitors, drug-resistance and relapse continue to limit long-term survival, highlighting the need for continued innovative drug discovery. We developed a time-resolved Förster resonance energy transfer (TR-FRET -based assay to identify compounds that disrupt stimulation of the ABL kinase by blocking its ability to bind the positive regulator RIN1. This assay was used in a high throughput screen (HTS of two small molecule libraries totaling 444,743 compounds. 708 confirmed hits were counter-screened to eliminate off-target inhibitors and reanalyzed to prioritize compounds with IC50 values below 10 μM. The CML cell line K562 was then used to identify five compounds that decrease MAPK1/3 phosphorylation, which we determined to be an indicator of RIN1-dependent ABL signaling. One of these compounds is a thiadiazole, and the other four are structurally related acyl piperidine amides. Notably, these five compounds lower cellular BCR-ABL1 kinase activity by blocking a positive regulatory interaction rather than directly inhibiting ABL catalytic function.

Fluoroethoxy-1,4-diphenethylpiperidine and piperazine derivatives: Potent and selective inhibitors of [3H]dopamine uptake at the vesicular monoamine transporter-2.

Science.gov (United States)

Hankosky, Emily R; Joolakanti, Shyam R; Nickell, Justin R; Janganati, Venumadhav; Dwoskin, Linda P; Crooks, Peter A

2017-12-15

A small library of fluoroethoxy-1,4-diphenethyl piperidine and fluoroethoxy-1,4-diphenethyl piperazine derivatives were designed, synthesized and evaluated for their ability to inhibit [ 3 H]dopamine (DA) uptake at the vesicular monoamine transporter-2 (VMAT2) and dopamine transporter (DAT), [ 3 H]serotonin (5-HT) uptake at the serotonin transporter (SERT), and [ 3 H]dofetilide binding at the human-ether-a-go-go-related gene (hERG) channel. The majority of the compounds exhibited potent inhibition of [ 3 H]DA uptake at VMAT2, Ki changes in the nanomolar range (K i  = 0.014-0.073 µM). Compound 15d exhibited the highest affinity (K i  = 0.014 µM) at VMAT2, and had 160-, 5-, and 60-fold greater selectivity for VMAT2 vs. DAT, SERT and hERG, respectively. Compound 15b exhibited the greatest selectivity (>60-fold) for VMAT2 relative to all the other targets evaluated, and 15b had high affinity for VMAT2 (K i  = 0.073 µM). Compound 15b was considered the lead compound from this analog series due to its high affinity and selectivity for VMAT2. Copyright © 2017 Elsevier Ltd. All rights reserved.

A novel selective prostaglandin E2 synthesis inhibitor relieves pyrexia and arthritis in Guinea pigs inflammatory models

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Ryusuke Sugita

2016-02-01

Full Text Available Prostaglandin E2 (PGE2, one of the terminal products in the cyclooxygenase pathway, plays an important role in various inflammatory responses. To determine whether selective inhibition of PGE2 may relieve these inflammatory symptoms, we synthesized a selective PGE2 synthesis inhibitor, compound A [1-(6-fluoro-5,7-dimethyl-1,3-benzothiazol-2-yl-N-[(1S,2R-2-(hydroxymethylcyclohexyl]piperidine-4-carboxamide], then investigated the effects on pyrexia, arthritis and inflammatory pain in guinea pigs. In LPS-stimulated guinea pig macrophages, compound A selectively inhibited inducible PGE2 biosynthesis in a dose-dependent manner whereas enhanced the formation of thromboxane B2 (TXB2. Compound A suppressed yeast-evoked PGE2 production selectively and enhanced the production of TXB2 and 6-keto PGF1α in vivo. In addition, compound A relieved yeast-induced pyrexia and also suppressed paw swelling in an adjuvant-induced arthritis model. The effect on gastrointestinal (GI ulcer formation was also evaluated and compound A showed a lower GI adverse effect than indomethacin. However, compound A failed to relieve yeast-induced thermal hyperalgesia. These results suggest that selective inhibition of PGE2 synthesis may have anti-pyretic and anti-inflammatory properties without GI side effect, but lack the analgesic efficacy.

Synthesis of some pyridine and pyrimidine derivatives via Michael-Addition

International Nuclear Information System (INIS)

El-Baih, Fatma E.M.; Al-Rasheed, Hessa H.; Al-Hazimi, Hassan M.

2006-01-01

Synthesis of pyridine and pyrimidine analogues 4 and 6-9 were achieved by Michael-addition of compounds containing either active methylene groups like, malononitrile , ethyl cyanoacetate and 1-tetralone or compounds containing active hydrogen atoms like, guanidine in the presence of an oxidizing agent and thiourea to 2-arylmethylidine-1-tetralone and 2-arylmethylidine-6-methoxy-1-tetralone (2) (enones). Addition of malononitrile in piperidine at room temperature to 2-amino-3-cyno-naphtho [1, 2-malonoitrile in sodium alkoxide or sodium hydroxide to 2 gave 4. Cyclization of 3a with acetic anhydride in the presence of conc. H2sO4 gave the naphtha-pyrano[2, 3-d]pyrimidin-8-one (5). Condensation of the pyrimidine thione derivatives 9 with chloroacetic acid gave the 3-oxobenzo[h]thiazoladino[2, 3-b]quinazoline derivatives (10), which were reacted through their active methylene groups with aromatic aldehydes to give the arylidine derivatives 11. These compounds were also prepared in one step by reacting 9 with chloroacetic acid and aromatic aldehydes. Condensation of 9 with 3-bromopropanoic acid gave 4-oxo-benzo[h]1, 3-thiazino[2, 3-b]quinazoline derivatives (12). The structures of the prepared compounds were mainly confirmed on the basis of spectroscopic methods. (author)

Vibrational spectroscopic study of cationic phosphorus dendrimers with aminoethylpiperidine terminal groups

Science.gov (United States)

Furer, V. L.; Vandyukov, A. E.; Tripathi, V.; Majoral, J. P.; Caminade, A. M.; Kovalenko, V. I.

2018-04-01

Two generations of phosphoric dendrimers with piperidine functional groups were synthesized for use in biology and medicine. Neutral samples are soluble in organic solvents but after protonation these dendrimers become water soluble and can be used for biological experiments. The FTIR and FT Raman spectra of two generations of dendrimers Gi constructed from the cyclotriphosphazene core, repeating units sbnd Osbnd C6H4sbnd CHdbnd Nsbnd N(CH3)sbnd P(S)molecular structure and vibrational spectra of the first generation dendrimer was performed by the method of DFT. This molecule has flat, repeating units and a plane of symmetry passing through the core. The calculation of the distribution of potential energy made it possible to classify the bands in the experimental spectra of dendrimers. Amine groups are manifested in the form of a band of NH stretching vibrations at 3389 cm-1 in the IR spectrum of G1. NH+ stretching bands located at 2646 and 2540 cm-1 in the IR spectrum of G2. The stretching vibrations of NH+ groups are noticeably shifted to low frequencies due to the formation of a hydrogen bond with the chlorine atom. The line at 1575 cm-1 in the Raman spectrum of G1 is characteristic for repeating units.

The 3,3,5,5[2H4]-4-methacrylamido-2,2,6,6-tetra([2H3]methyl)piperidin-1-yloxyl radical

Czech Academy of Sciences Publication Activity Database

Dušková, Jarmila; Labský, Jiří; Dušek, Michal; Hašek, Jindřich

2006-01-01

Roč. 62, č. 2 (2006), o811-o813 ISSN 1600-5368 R&D Projects: GA AV ČR 1ET400500402 Institutional research plan: CEZ:AV0Z40500505; CEZ:AV0Z10100521 Keywords : structure determination * spin label * x-ray diffraction Subject RIV: CD - Macromolecular Chemistry Impact factor: 0.567, year: 2006

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

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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...

Crystal structure of [propane-1,3-diylbis(piperidine-4,1-diyl]bis[(pyridin-4-ylmethanone]–4,4′-oxydibenzoic acid (1/1

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Emily M. Low

2014-09-01

Full Text Available In the title co-crystal, C25H32N4O2·C14H10O5, molecules are connected into supramolecular chains aligned along [102] by O—H...N hydrogen bonding. These aggregate into supramolecular layers oriented parallel to (20-1 by C—H...O interactions. 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 carboxylic acid group.

Synthesis, Characterization and Photophysical Properties of Pyridine-Carbazole Acrylonitrile Derivatives

Science.gov (United States)

Pérez-Gutiérrez, Enrique; Percino, M. Judith; Chapela, Víctor M.; Cerón, Margarita; Maldonado, José Luis; Ramos-Ortiz, Gabriel

2011-01-01

We synthesized three novel highly fluorescent compounds, 2-(2’-pyridyl)-3-(N-ethyl-(3’-carbazolyl))acrylonitrile, 2-(3”-pyridyl)-3-(N-ethyl-(3’-carbazolyl))acrylonitrile, and 2-(4-pyridyl)-3-(N-ethyl-(3’-carbazolyl))acrylonitrile by Knoevenagel condensation. The first two were synthesized without solvent in the presence of piperidine as a catalyst; the third was synthesized without a catalyst and with N,N-dimethylformamide as a solvent. In solution, the molar absorption coefficients showed absorptions at 380, 378, and 396 nm, respectively; in solid state, absorptions were at 398, 390, and 442 nm, respectively. The fluorescence emission was at 540, 540 and 604 nm, respectively, the 2-(4-pyridyl)-3-(N-ethyl-(3’-carbazolyl))acrylonitrile showed a red shift in the emission of 64 nm compared to the other two compounds. The fluorescence quantum yield for the compounds in powder form showed values of 0.05, 0.14, and 0.006, respectively; compared with the value measured for the Alq3 reference, 2-(3”-pyridyl)-3-(N-ethyl-(3’-carbazolyl))acrylonitrile had a lightly higher value. The third harmonic generation measurement for 2-(2’-pyridyl)-3-(N-ethyl-(3’-carbazolyl))acrylonitrile yielded a χ(3) value of 5.5 × 10−12 esu, similar to that reported for commercial polymers. PMID:28880006

Synthesis, Characterization and Photophysical Properties of Pyridine-Carbazole Acrylonitrile Derivatives

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Gabriel Ramos-Ortiz

2011-03-01

Full Text Available We synthesized three novel highly fluorescent compounds, 2-(2’-pyridyl-3-(N-ethyl-(3’-carbazolylacrylonitrile, 2-(3”-pyridyl-3-(N-ethyl-(3’-carbazolylacrylonitrile, and 2-(4-pyridyl-3-(N-ethyl-(3’-carbazolylacrylonitrile by Knoevenagel condensation. The first two were synthesized without solvent in the presence of piperidine as a catalyst; the third was synthesized without a catalyst and with N,N-dimethylformamide as a solvent. In solution, the molar absorption coefficients showed absorptions at 380, 378, and 396 nm, respectively; in solid state, absorptions were at 398, 390, and 442 nm, respectively. The fluorescence emission was at 540, 540 and 604 nm, respectively, the 2-(4-pyridyl-3-(N-ethyl-(3’-carbazolylacrylonitrile showed a red shift in the emission of 64 nm compared to the other two compounds. The fluorescence quantum yield for the compounds in powder form showed values of 0.05, 0.14, and 0.006, respectively; compared with the value measured for the Alq3 reference, 2-(3”-pyridyl-3-(N-ethyl-(3’-carbazolylacrylonitrile had a lightly higher value. The third harmonic generation measurement for 2-(2’-pyridyl-3-(N-ethyl-(3’-carbazolylacrylonitrile yielded a χ(3 value of 5.5 × 10−12 esu, similar to that reported for commercial polymers.

Evaluation and Modeling of Vapor-Liquid Equilibrium and CO2 Absorption Enthalpies of Aqueous Designer Diamines for Post Combustion Capture Processes.

Science.gov (United States)

Luo, Weiliang; Yang, Qi; Conway, William; Puxty, Graeme; Feron, Paul; Chen, Jian

2017-06-20

Novel absorbents with improved characteristics are required to reduce the existing cost and environmental barriers to deployment of large scale CO 2 capture. Recently, bespoke absorbent molecules have been specifically designed for CO 2 capture applications, and their fundamental properties and suitability for CO 2 capture processes evaluated. From the study, two unique diamine molecules, 4-(2-hydroxyethylamino)piperidine (A4) and 1-(2-hydroxyethyl)-4-aminopiperidine (C4), were selected for further evaluation including thermodynamic characterization. The solubilities of CO 2 in two diamine solutions with a mass fraction of 15% and 30% were measured at different temperatures (313.15-393.15 K) and CO 2 partial pressures (up to 400 kPa) by thermostatic vapor-liquid equilibrium (VLE) stirred cell. The absorption enthalpies of reactions between diamines and CO 2 were evaluated at different temperatures (313.15 and 333.15 K) using a CPA201 reaction calorimeter. The amine protonation constants and associated protonation enthalpies were determined by potentiometric titration. The interaction of CO 2 with the diamine solutions was summarized and a simple mathematical model established that could make a preliminary but good prediction of the VLE and thermodynamic properties. Based on the analyses in this work, the two designer diamines A4 and C4 showed superior performance compared to amines typically used for CO 2 capture and further research will be completed at larger scale.

Quantitation and identification of organic N-chloramines formed in stomach fluid on ingestion of aqueous hypochlorite

Energy Technology Data Exchange (ETDEWEB)

Scully, F.E. Jr.; Mazina, K.; Sonenshine, D.; Kopfler, F.

1986-11-01

The chemical reactions that hypochlorite undergoes in the body when chlorinated water is ingested have received very little attention. Because amino nitrogen compounds are important components of the average diet, the reactions of hypochlorite with amino compounds in the stomach were investigated. Stomach fluid was recovered from Sprague-Dawley rats that had been fasted for 48 hr and administered 4 mL deionized water. The chlorine demand of the stomach fluid was determined. At least part of the chlorine demand is associated with amino acids present in the stomach fluid. Amino acids were identified and quantified in the stomach fluid by precolumn derivatization with o-phthalaldehyde and high-pressure liquid chromatography (HPLC). When stomach fluid is chlorinated to concentrations of chlorine between 200 and 1000 mg/L, organic N-chloramines are formed. After derivatization of chlorinated stomach fluid with dansyl sulfinic acid, fluorescent derivatives of chloramines were separated by HPLC. Three chloramino acid derivatives, N-chloroalanine, N-chloroglycine, and N-chlorophenylalanine, were identified by cochromatography with known standards using two chromatographic methods. The yield of a chloramine that would form in stomach fluid on administration of hypochlorite to animals as determined using tritiated piperidine and doses of 200 and 1000 mg/L chlorine. Yields of tritiated N-chloropiperidine in recovered stomach fluid were 70% and 42%, respectively, of the theoretical amount expected.

Formation of a covalent complex between the terminal protein of pneumococcal bacteriophage Cp-1 and 5'-dAMP

Energy Technology Data Exchange (ETDEWEB)

Garcia, P.; Hermoso, J.M.; Garcia, J.A.; Garcia, E.; Lopez, R.; Salas, M.

1986-04-01

Incubation of extracts of Cp-1-infected Streptococcus pneumoniae with (..cap alpha..-/sup 32/P)dATP produced a labeled protein with the electrophoretic mobility of the Cp-1 terminal protein. The reaction product was resistant to treatment with micrococcal nuclease and sensitive to treatment with proteinase K. Incubation of the /sup 32/P-labeled protein with 5 M piperidine for 4 h at 50/sup 0/C released 5'-dAMP, indicating that a covalent complex between the terminal protein and 5'-dAMP was formed in vitro. When the four deoxynucleoside triphosphates were included in the reaction mixture, a labeled complex of slower electrophoretic mobility in sodium dodecyl sulfate-polyacrylamide gels than the terminal protein-dAMP complex was also found, indicating that the Cp-1 terminal protein-dAMP complex can be elongated and, therefore, that it is an initiation complex. Treatment of the /sup 32/P-labeled terminal protein-dAMP complex with 5.8 M HCl at 110/sup 0/C for 2 h yielded phosphothreonine. These results, together with the resistance of the terminal protein-DNA linkage to hydroxylamine, suggest that the Cp-1 terminal protein is covalently linked to the DNA through a phosphoester bond between L-threonine and 5'-dAMP, namely, a O-5'-deoxyadenylyl-L-threonine bond.

Evaluation of spiropiperidine hydantoins as a novel class of antimalarial agents.

Science.gov (United States)

Meyers, Marvin J; Anderson, Elizabeth J; McNitt, Sarah A; Krenning, Thomas M; Singh, Megh; Xu, Jing; Zeng, Wentian; Qin, Limei; Xu, Wanwan; Zhao, Siting; Qin, Li; Eickhoff, Christopher S; Oliva, Jonathan; Campbell, Mary A; Arnett, Stacy D; Prinsen, Michael J; Griggs, David W; Ruminski, Peter G; Goldberg, Daniel E; Ding, Ke; Liu, Xiaorong; Tu, Zhengchao; Tortorella, Micky D; Sverdrup, Francis M; Chen, Xiaoping

2015-08-15

Given the rise of parasite resistance to all currently used antimalarial drugs, the identification of novel chemotypes with unique mechanisms of action is of paramount importance. Since Plasmodium expresses a number of aspartic proteases necessary for its survival, we have mined antimalarial datasets for drug-like aspartic protease inhibitors. This effort led to the identification of spiropiperidine hydantoins, bearing similarity to known inhibitors of the human aspartic protease β-secretase (BACE), as new leads for antimalarial drug discovery. Spiropiperidine hydantoins have a dynamic structure-activity relationship profile with positions identified as being tolerant of a variety of substitution patterns as well as a key piperidine N-benzyl phenol pharmacophore. Lead compounds 4e (CWHM-123) and 12k (CWHM-505) are potent antimalarials with IC50 values against Plasmodium falciparum 3D7 of 0.310 μM and 0.099 μM, respectively, and the former features equivalent potency on the chloroquine-resistant Dd2 strain. Remarkably, these compounds do not inhibit human aspartic proteases BACE, cathepsins D and E, or Plasmodium plasmepsins II and IV despite their similarity to known BACE inhibitors. Although the current leads suffer from poor metabolic stability, they do fit into a drug-like chemical property space and provide a new class of potent antimalarial agents for further study. Copyright © 2015 Elsevier Ltd. All rights reserved.

SKF 525-A and cytochrome P-450 ligands inhibit with high affinity the binding of [3H]dextromethorphan and σligands to guinea pig brain

International Nuclear Information System (INIS)

Klein, M.; Canoll, P.D.; Musacchio, J.M.

1991-01-01

The DM 1 /σ 1 site binds dextromethorphan (DM) and σ receptor ligands. The broad binding specificity of this site and its peculiar subcellular distribution prompted us to explore the possibility that this site is a member of the cytochrome P-450 superfamily of enzymes. We tested the effects of the liver microsomal monooxygenase inhibitor SKF 525-A (Proadifen), and other P-450 substrates on the binding of [ 3 H]dextromethorphan, [ 3 H]3-(3-Hydroxyphenyl)-N-(1-propyl)piperidine and (+)-[ 3 H]1,3-Di-o-tolyl-guanidine ([ 3 H]DTG) to the guinea pig brain. SKF 525-A, l-lobeline and GBR-12909 inhibited the binding of the three labeled ligands with nM affinity. Each drug has identical nM K i values for the high-affinity site labeled by the three ligands. This indicated that they displaced the labeled ligands from the common DM 1 σ 1 site. Debrisoquine and sparteine, prototypical substrates for liver debrisoquine 4-hydroxylase, displayed K i values of 9-13 and 3-4 μM respectively against the three labeled ligands. These results, the broad specificity of the DM 1 /σ 1 binding site, and its peculiar subcellular distribution, raises the possibility that this binding site is a member of the cytochrome P-450 superfamily of isozymes, rather than a neurotransmitter receptor

Essential Oils and Pure Volatile Compounds as Potential Drugs in Alzheimer's Disease Therapy: An Updated Review of the Literature.

Science.gov (United States)

Maggio, Antonella; Rosselli, Sergio; Bruno, Maurizio

2016-01-01

The use of aromatic plants to relief different illness is not a new therapy. Actually aromatic plants have been used for many centuries by different cultures around the world. Pharmacological studies provide scientific support to the traditional use of aromatic medicinal plants and aromatherapy; nevertheless, more clinical trials are required regarding to their effectiveness in order to establish a guidance for their use in routine healthcare. Moreover, modern medicine in studies about olfactory function has attained great achievements and got Nobel Prize in 2004. These new searches have obviously fueled interest in the essential oils and volatile compounds of natural origin. Several reviews on the newly discovered AChEi obtained from plants, fungus and marine organisms have also been published over the last years. The majority of these AChEi belong to the alkaloid group, including indole, isoquinoline, quinolizidine, piperidine and steroidal alkaloids. Probably the interest in the essential oils and volatile compounds will be fueled from the new available scientific data about receptor on olfactory mucosa of nasal cavity. It can receive and distinguish different odor molecules, which produce nerve impulse and transmit into olfactory bulb via olfactory nerves. The nerve cells in the olfactory bulb transmit the signals into hippocampus. Because hippocampus is closely related with learning and memory functions, the volatile compounds can be potential drugs in AD therapies.

Estradiol-induced increase in the magnitude of long-term potentiation is prevented by blocking NR2B-containing receptors.

Science.gov (United States)

Smith, Caroline C; McMahon, Lori L

2006-08-16

Estradiol, through activation of genomic estrogen receptors, induces changes in synaptic morphology and function in hippocampus, a brain region important for memory acquisition. Specifically, this hormone increases CA1 pyramidal cell dendritic spine density, NMDA receptor (NMDAR)-mediated transmission, and the magnitude of long-term potentiation (LTP) at CA3-CA1 synapses. We recently reported that the estradiol-induced increase in LTP magnitude occurs only when there is a simultaneous increase in the fractional contribution of NMDAR-mediated transmission relative to AMPA receptor transmission, suggesting a direct role for the increase in NMDAR transmission to the heightened LTP magnitude. Estradiol has been shown to increase expression of the NMDAR subunit NR2B, but whether this translates into an increase in function of NR2B-containing receptors remains to be determined. Here we show that not only is the estradiol-induced increase in NMDAR transmission mediated by NR2B-containing receptors, but blocking these receptors using RO25-6981 [R-(R,S)-alpha-(4-hydroxyphenyl)-beta-methyl-4-(phenylmethyl)-1-piperidine propranol] (0.5 microM), an NR2B selective antagonist, prevents the estradiol-induced increase in LTP magnitude. Thus, our data show a causal link between the estradiol-induced increase in transmission mediated by NR2B-containing NMDARs and the increase in LTP magnitude.

Sedoanalgesia in interventional radiology

International Nuclear Information System (INIS)

Linsenmaier, U.; Pfeifer, K.J.; Reiser, M.

2002-01-01

Purpose: Development of a save and effective protocol for analgosedation of patients undergoing painful interventional procedures. Material and Methods: In a prospective trial a consecutive series of 72 adult patients underwent analgosedation during painful interventions. A radiologist performed the analgosedation, the patients received a combination of a shortly effective piperidine derivative (Alfentanil [Rapifen trademark ]; 7.5-15 μg/kg body weight) and Benzodiazepine (midazolam [Dormicum trademark ]; 20 μg/kg body weight). After pre-procedure oxygenation patients were continuously monitored. Pain and discomfort were scored using an established visual-analog pain score (0-10). A control group (n=24) had received midazolam, pentazocine or fentanyl according to the study protocol. Results: All procedures could be carried out by an interventional radiologist and a nurse and/or technologist only. In 69/72 cases adequate analgosedation could be achieved. Injection of alfentanil was titrated, with a rapid onset and short acting effect of the analgesia. Patients reported an average pain score of 2.6 vs. 4.5 in the control group. Over 55% experienced no or mild pain (score 0-3), in the control group only 8% reached this level. Conclusion: A combination of shortly effective alfentanil and midazolam allows interventional radiologists to perform major procedures alone under effective analgosedation. This medication scheme is superior to the medication upon demand. (orig.) [de

Synthesis and biological evaluation of radioiodinated N-2-(4-piperidyl)ethyl benzamides

International Nuclear Information System (INIS)

Efange, S.M.N.; Michelson, R.H.; Boudreau, R.J.; Thomas, J.R.; Knusel, B.; Hefti, F.; Tennison, J.R.

1993-01-01

Three iodinated benzamides, 5-7, analogues of the potent acetylcholinesterase inhibitor 1-benzyl-4-[N-[4'-(benzylsulfonyl) benzoyl-N-methylamino]ethyl]piperidine (2), were synthesized and evaluated as potential anticholinesterase agents. All three compounds were found to be three orders of magnitude less potent than the parent compound. However, receptor screening revealed that compounds 5-7 exhibit nanomolar affinity for the sigma binding site. Both [ 125 I]5 and [ 125 I]7 were synthesized and evaluated in rats. Following the intravenous administration of [ 125 I]5 into rats, 1.59% of the injected dose was found in the rat brain within 5 min. The level of radioactivity in the brain remained steady for 2 h, the duration of the study. In contrast, 0.42% of the injected dose was detected in the rat brain following the i.v. injection of [ 125 I]7. Coadministration of either [ 125 I]5 or [ 125 I]7 with 0.5 μmol/kg of haloperidol resulted in a 56-73% reduction in the level of radioactivity in the rat brain, suggesting that these compounds bind to the sigma binding site in vivo. Planar imaging studies with [ 123 I]5 revealed significant accumulation of radioactivity within the monkey brain, with a half-life of 6 h. Compound [ 123 I]5 may be potentially useful for studying sigma receptor distribution in the human brain. (author)

Synthesis and biological evaluation of radioiodinated N-2-(4-piperidyl)ethyl benzamides

International Nuclear Information System (INIS)

Efange, S.M.N.; Michelson, R.H.; Boudreau, R.J.; Thomas, J.R.; Knusel, B.; Hefti, F.; Tennison, J.R.

1993-01-01

Three iodinated benzamides, 5-7, analogues of the potent acetylcholinesterase inhibitor 1-benzyl-4[N-[4'-(benzylsulfonyl) benzoyl-N-methylamino]ethyl]piperidine were synthesized and evaluated as potential anticholinesterase agents. All three compounds were found to be three orders of magnitude less potent than the parent compound. However, receptor screening revealed that compounds 5-7 exhibit nanomolar affinity for the sigma binding site. Both [ 125 I]5 and [ 125 I]7 were synthesized and evaluated in rats. Following the intravenous administration of [ 125 I]5 into rats, 1.59% of the injected dose was found in the rat brain within 5 min. The level of radioactivity in the brain remained steady for 2 h, the duration of the study. In contrast, 0.42% of the injected dose was detected in the rat brain following the i.v. injection of [ 125 I]7. Coadministration of either [ 125 I]5 or [ 125 I]7 with 0.5 μmol/kg of haloperidol resulted in a 56-73% reduction in the level of radioactivity in the rat brain, suggesting that these compounds bind to the sigma binding site in vivo. Planar imaging studies with [ 123 I]5 revealed significant accumulation of radioactivity within the monkey brain, with a half-life of 6 h. Compound [ 123 I]5 may be potentially useful for studying sigma receptor distribution in the human brain. (Author)

Preparation and characterization of nanocomposite films from oil palm pulp nanocellulose/poly (Vinyl alcohol) by casting method.

Science.gov (United States)

Asad, Mohammad; Saba, Naheed; Asiri, Abdullah M; Jawaid, M; Indarti, Eti; Wanrosli, W D

2018-07-01

TEMPO-oxidize nanocellulose (TONC) suspension has been obtained from total chlorine free (TCF) oil palm empty-fruit-bunches (OPEFB) pulp using 4-acetamido-TEMPO (2,2,6,6-tetramethyl piperidin-1-oxyl) mediated oxidation with sodium hypochlorite and sodium bromide in water at 25 °C and pH 10. TONC suspension with varied content from 0.5 to 6% (w/w) reinforced polyvinyl alcohol (PVA) polymer based nanocomposite films were prepared by the casting method. The structural interaction between the TONC and PVA was characterized by the Fourier transform infrared (FT-IR) spectroscopy, nuclear magnetic resonance (NMR) spectroscopy, X-ray diffraction (XRD) and scanning electron microscopy (SEM). It was found that the 4% (w/w) TONC content reinforced nanocomposite exhibited the highest tensile strength and modulus with an increase of 122% and 291% respectively, compared to PVA while the elongation at break decreased about 42.7%. Thermal stability of PVA based nanocomposite films was improved after incorporation of TONC. Incorporation of TONC in PVA film increases its crystallinity due to strongly linking between the hydroxyl groups of materials however considerable decreases beyond 2 wt% loading are observed. TONC incorporation beyond 2 wt% also reduces the melting temperature peaks and enthalpy of nanocomposite films. FT-IR spectra, NMR and SEM indicate that there is interaction between the TONC and PVA. Copyright © 2018 Elsevier Ltd. All rights reserved.

A Small Molecule that Targets r(CGG)exp and Improves Defects in Fragile X-Associated Tremor Ataxia Syndrome

Science.gov (United States)

Disney, Matthew D.; Liu, Biao; Yang, Wang-Yong; Sellier, Chantal; Tran, Tuan; Charlet-Berguerand, Nicolas; Childs-Disney, Jessica L.

2012-01-01

The development of small molecule chemical probes or therapeutics that target RNA remains a significant challenge despite the great interest in such compounds. The most significant barrier to compound development is a lack of knowledge of the chemical and RNA motif spaces that interact specifically. Herein, we describe a bioactive small molecule probe that targets expanded r(CGG) repeats, or r(CGG)exp , that causes Fragile X-associated Tremor Ataxia Syndrome (FXTAS). The compound was identified by using information on the chemotypes and RNA motifs that interact. Specifically, 9-hydroxy-5,11-dimethyl-2-(2-(piperidin-1-yl)ethyl)-6H-pyrido[4,3-b]carbazol-2-ium, binds the 5’CGG/3’GGC motifs in r(CGG)exp and disrupts a toxic r(CGG)exp -protein complex in vitro. Structure-activity relationships (SAR) studies determined that the alkylated pyridyl and phenolic side chains are important chemotypes that drive molecular recognition to r(CGG)exp . Importantly, the compound is efficacious in FXTAS model cellular systems as evidenced by its ability to improve FXTAS-associated pre-mRNA splicing defects and to reduce the size and number of r(CGG)exp -protein aggregates. This approach may establish a general strategy to identify lead ligands that target RNA while also providing a chemical probe to dissect the varied mechanisms by which r(CGG)exp promotes toxicity. PMID:22948243

Characterization of the allergen Sol gem 2 from the fire ant venom, Solenopsis geminata

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S Sukprasert

2012-01-01

Full Text Available Sol i 2 is a potent allergen in Solenopsis invicta venom, and most humans exhibit reactivity to it. The Sol gem 2 allergen found in the venom of the Thai tropical fire ant Solenopsis geminata was analysed in the present study. The protein was present in higher amounts than other proteins, as determined by SDS-PAGE, and presumably has allergenic properties similar to those of Sol i 2. Sol gem 2 molecular weight is 28 and 15 kDa, respectively, under non-reducing and reducing conditions, indicating that its native form is a dimer. LC-MS/MS analysis confirmed its similarity to Sol i 2. The mono/dimeric form of Sol gem 2 was determined to be relevant by proteomic approach and immunoblotting. An anti-Sol gem 2 antibody was produced in mice, with a titer greater than 1:800 according to the Western blotting analysis. The Sol gem 2-neutralising activity of this antibody was determined in crickets. The paralytic dose 50 (PD50 of crude S. geminata venom was elevated from 0.18 mg/g of body weight to more than 0.90 mg/g of body weight after preincubation with antibody at a ratio of 1:1. These results suggest that Sol gem 2 plays an important role in mediating the effects of the piperidine derivatives in the venom.

Synthesis and biological evaluation of radioiodinated N-2-(4-piperidyl)ethyl benzamides

Energy Technology Data Exchange (ETDEWEB)

Efange, S M.N.; Michelson, R H; Boudreau, R J; Thomas, J R [Minnesota Univ., Minneapolis, MN (United States); Knusel, B; Hefti, F [Minnesota Univ., Minneapolis, MN (United States). Hospitals; Tennison, J R [University of Southern Cailfornia, Los Angeles, CA (United States). Andrus Gerontology Center

1993-05-01

Three iodinated benzamides, 5-7, analogues of the potent acetylcholinesterase inhibitor 1-benzyl-4-[N-[4'-(benzylsulfonyl) benzoyl-N-methylamino]ethyl]piperidine (2), were synthesized and evaluated as potential anticholinesterase agents. All three compounds were found to be three orders of magnitude less potent than the parent compound. However, receptor screening revealed that compounds 5-7 exhibit nanomolar affinity for the sigma binding site. Both [[sup 125]I]5 and [[sup 125]I]7 were synthesized and evaluated in rats. Following the intravenous administration of [[sup 125]I]5 into rats, 1.59% of the injected dose was found in the rat brain within 5 min. The level of radioactivity in the brain remained steady for 2 h, the duration of the study. In contrast, 0.42% of the injected dose was detected in the rat brain following the i.v. injection of [[sup 125]I]7. Coadministration of either [[sup 125]I]5 or [[sup 125]I]7 with 0.5 [mu]mol/kg of haloperidol resulted in a 56-73% reduction in the level of radioactivity in the rat brain, suggesting that these compounds bind to the sigma binding site in vivo. Planar imaging studies with [[sup 123]I]5 revealed significant accumulation of radioactivity within the monkey brain, with a half-life of 6 h. Compound [[sup 123]I]5 may be potentially useful for studying sigma receptor distribution in the human brain. (author).

Repeated Dose 28-Days Oral Toxicity Study of Carica papaya L. Leaf Extract in Sprague Dawley Rats

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Hussin Muhammad

2012-04-01

Full Text Available Carica papaya L. leaves have been used in ethnomedicine for the treatment of fevers and cancers. Despite its benefits, very few studies on their potential toxicity have been described. The aim of the present study was to characterize the chemical composition of the leaf extract from ‘Sekaki’ C. papaya cultivar by UPLC-TripleTOF-ESI-MS and to investigate the sub-acute oral toxicity in Sprague Dawley rats at doses of 0.01, 0.14 and 2 g/kg by examining the general behavior, clinical signs, hematological parameters, serum biochemistry and histopathology changes. A total of twelve compounds consisting of one piperidine alkaloid, two organic acids, six malic acid derivatives, and four flavonol glycosides were characterized or tentatively identified in the C. papaya leaf extract. In the sub-acute study, the C. papaya extract did not cause mortality nor were treatment-related changes in body weight, food intake, water level, and hematological parameters observed between treatment and control groups. Some biochemical parameters such as the total protein, HDL-cholesterol, AST, ALT and ALP were elevated in a non-dose dependent manner. Histopathological examination of all organs including liver did not reveal morphological alteration. Other parameters showed non-significant differences between treatment and control groups. The present results suggest that C. papaya leaf extract at a dose up to fourteen times the levels employed in practical use in traditional medicine in Malaysia could be considered safe as a medicinal agent.

Positive inotropic effects of RP 62719, a new pure class III antiarrhythmic agent, on guinea pig myocardium.

Science.gov (United States)

Beregi, J P; Escande, D; Coudray, N; Mery, P; Mestre, M; Chemla, D; Lecarpentier, Y

1992-12-01

The mechanical effects of RP 62719 [(-)1-[-2-(3,4-dihydro-2H-1- benzopyran-4-yl)ethyl]-4-(3,4-dimethoxyphenyl)-piperidine] were tested in vitro on guinea pig left ventricular papillary muscle. RP 62719 is a novel pure class III antiarrhythmic agent known to prolong the cardiac action potential duration by selectively blocking the inward rectifying K+ current. Mechanical parameters were determined from contraction and relaxation phases under isotonic and isometric conditions. At a concentration of 0.02 microM, RP 62719 did not produce significant effects on inotropy or lusitropy. At 0.2 and 2 microM, the drug improved contraction under both heavy and low loading conditions, as evidenced by a 30% increase in maximum unloaded shortening velocity (Vmax, P delta L, P force normalized per cross-sectional area (AF/s, P force derivative per mm2 (+dF/s, P force derivative per mm2 (-dF/s, P < .001). At a higher concentration (20 microM), effects of RP 62719 on inotropy and lusitropy were less marked, thus accounting for the bell-shaped form of the dose-response curve. An increase in the extracellular Ca++ concentration from 2.5 to 3.75 mM improved inotropy to a similar extent (+30-50%) as did 2 microM RP 62719. However, lusitropy and mechanical coupling between contraction and relaxation were not modified in the same proportion under RP 62719 and under 3.75 mM Ca++.(ABSTRACT TRUNCATED AT 250 WORDS)

Evaluation of Novel Dual Acetyl- and Butyrylcholinesterase Inhibitors as Potential Anti-Alzheimer’s Disease Agents Using Pharmacophore, 3D-QSAR, and Molecular Docking Approaches

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Xiaocong Pang

2017-07-01

Full Text Available DL0410, containing biphenyl and piperidine skeletons, was identified as an acetylcholinesterase (AChE and butyrylcholinesterase (BuChE inhibitor through high-throughput screening assays, and further studies affirmed its efficacy and safety for Alzheimer’s disease treatment. In our study, a series of novel DL0410 derivatives were evaluated for inhibitory activities towards AChE and BuChE. Among these derivatives, compounds 6-1 and 7-6 showed stronger AChE and BuChE inhibitory activities than DL0410. Then, pharmacophore modeling and three-dimensional quantitative structure activity relationship (3D-QSAR models were performed. The R2 of AChE and BuChE 3D-QSAR models for training set were found to be 0.925 and 0.883, while that of the test set were 0.850 and 0.881, respectively. Next, molecular docking methods were utilized to explore the putative binding modes. Compounds 6-1 and 7-6 could interact with the amino acid residues in the catalytic anionic site (CAS and peripheral anionic site (PAS of AChE/BuChE, which was similar with DL0410. Kinetics studies also suggested that the three compounds were all mixed-types of inhibitors. In addition, compound 6-1 showed better absorption and blood brain barrier permeability. These studies provide better insight into the inhibitory behaviors of DL0410 derivatives, which is beneficial for rational design of AChE and BuChE inhibitors in the future.

Oxidation of cyclic amines by molybdenum(II and tungsten(II halocarbonyls, [M(CO4X2]2 (M = Mo, W; X = Cl, Br

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H.M. Mbuvi

2013-05-01

Full Text Available The molybdenum(II and tungsten(II halocarbonyls, [M(CO4X2]2 (M = Mo, W; X = Cl, Br react with a large excess of the nitrogen bases, 1-methylpyrrolidine, 1-methylpiperidine, 1-ethylpiperidine and 2-ethylpiperidine to give aminecarbonyl complexes of the type M(CO3L3 (L= alkylamine. Excess piperidine reacts with the tungsten halocarbonyls, [W(CO4X2]2 (X = Cl, Br, to give the trans isomer of the complex, W(CO3(C5H11N3. The halogens were recovered as the amminium salts, amine, HX. The oxidized amine dimerized to form a yellow product which was recovered as an oily liquid but in very small amounts. However, in the reaction between Mo(CO4Br2 and 1-ethylpiperidine, a yellow crystalline solid, with a melting point of 224 oC was recovered in sufficient amounts for elemental analysis, melting point and spectral data. Its mass spectrum showed a molecular ion peak at m+/z = 222, a clear evidence that the oxidized amine dimerizes. The cyclic dibasic amine piperazine, C4H10N2 is not, however, oxidized by these halocarbonyls but rather it reacts by substituting some CO groups to form products of the type, M(CO3(C4H10N22X2 (M = Mo, W; X = Cl, Br. Products were characterized by elemental analysis, IR, UV, 1H NMR and mass spectrometry.

Modulation of Antimalarial Activity at a Putative Bisquinoline Receptor In Vivo Using Fluorinated Bisquinolines.

Science.gov (United States)

Fielding, Alistair J; Lukinović, Valentina; Evans, Philip G; Alizadeh-Shekalgourabi, Said; Bisby, Roger H; Drew, Michael G B; Male, Verity; Del Casino, Alessio; Dunn, James F; Randle, Laura E; Dempster, Nicola M; Nahar, Lutfun; Sarker, Satyajit D; Cantú Reinhard, Fabián G; de Visser, Sam P; Dascombe, Mike J; Ismail, Fyaz M D

2017-05-17

Antimalarials can interact with heme covalently, by π⋅⋅⋅π interactions or by hydrogen bonding. Consequently, the prototropy of 4-aminoquinolines and quinoline methanols was investigated by using quantum mechanics. Calculations showed mefloquine protonated preferentially at the piperidine and was impeded at the endocyclic nitrogen because of electronic rather than steric factors. In gas-phase calculations, 7-substituted mono- and bis-4-aminoquinolines were preferentially protonated at the endocyclic quinoline nitrogen. By contrast, compounds with a trifluoromethyl substituent on both the 2- and 8-positions, reversed the order of protonation, which now favored the exocyclic secondary amine nitrogen at the 4-position. Loss of antimalarial efficacy by CF 3 groups simultaneously occupying the 2- and 8-positions was recovered if the CF 3 group occupied the 7-position. Hence, trifluoromethyl groups buttressing the quinolinyl nitrogen shifted binding of antimalarials to hematin, enabling switching from endocyclic to the exocyclic N. Both theoretical calculations (DFT calculations: B3LYP/BS1) and crystal structure of (±)-trans-N 1 ,N 2 -bis-(2,8-ditrifluoromethylquinolin-4-yl)cyclohexane-1,2-diamine were used to reveal the preferred mode(s) of interaction with hematin. The order of antimalarial activity in vivo followed the capacity for a redox change of the iron(III) state, which has important implications for the future rational design of 4-aminoquinoline antimalarials. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Characterization of GABA/sub A/ receptor-mediated 36chloride uptake in rat brain synaptoneurosomes

International Nuclear Information System (INIS)

Luu, M.D.; Morrow, A.L.; Paul, S.M.; Schwartz, R.D.

1987-01-01

γ-Aminobutyric acid (GABA) receptor-mediated 36 chloride ( 36 Cl - ) uptake was measured in synaptoneurosomes from rat brain. GABA and GABA agonists stimulated 36 Cl - uptake in a concentration-dependent manner with the following order of potency: Muscimol>GABA>piperidine-4-sulfonic acid (P4S)>4,5,6,7-tetrahydroisoxazolo-[5,4-c]pyridin-3-ol (THIP)=3-aminopropanesulfonic acid (3APS)>>taurine. Both P4S and 3APS behaved as partial agonists, while the GABA/sub B/ agonist, baclofen, was ineffective. The response to muscimol was inhibited by bicuculline and picrotoxin in a mixed competitive/non-competitive manner. Other inhibitors of GABA receptor-opened channels or non-neuronal anion channels such as penicillin, picrate, furosemide and disulfonic acid stilbenes also inhibited the response to muscimol. A regional variation in muscimol-stimulated 36 Cl - uptake was observed; the largest responses were observed in the cerebral cortex, cerebellum and hippocampus, moderate responses were obtained in the striatum and hypothalamus and the smallest response was observed in the pons-medulla. GABA receptor-mediated 36 Cl - uptake was also dependent on the anion present in the media. The muscinol response varied in media containing the following anions: Br - >Cl - ≥NO 3 - >I - ≥SCN - >>C 3 H 5 OO - ≥ClO 4 - >F - , consistent with the relative anion permeability through GABA receptor-gated anion channels and the enhancement of convulsant binding to the GABA receptor-gated Cl - channel. 43 references, 4 figures, 3 tables

Synthesis, Structural Characterization and Catalytic Activity of A Cu(II Coordination Polymer Constructed from 1,4-Phenylenediacetic Acid and 2,2’-Bipyridine

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Wang Li-Hua

2017-04-01

Full Text Available In order to study the catalytic activity of Cu(II coordination polymer material, a novel 1D chained Cu(II coordination polymer material, [CuL(bipy(H2O5]n (A1 (H2L = 1,4-phenylenediacetic acid, bipy = 2,2’-bipyridine, has been prepared by the reaction of 1,4-phenylenediacetic acid, 2,2’-bipyridine, Cu(CH3COO2·H2O and NaOH. The composition of A1 was determined by elemental analysis, IR spectra and single crystal X-ray diffraction. The results of characterization show that each Cu(II atom adopts six-coordination and forms a distorted octahedral configuration. The catalytic activity and reusability of A1 catalyst for A3 coupling reaction of benzaldehyde, piperidine, and phenylacetylene have been investigated. And the results show that the Cu(II complex catalyst has good catalytic activity with a maximum yield of 54.3% and stability. Copyright © 2017 BCREC GROUP. All rights reserved Received: 21st October 2016; Revised: 17th November 2016; Accepted: 22nd November 2016 How to Cite: Li-Hua, W., Lei, L., Xin, W. (2017. Synthesis, Structural Characterization and Catalytic Activity of A Cu(II Coordination Polymer Constructed from 1,4-Phenylenediacetic Acid and 2,2’-Bipyridine. Bulletin of Chemical Reaction Engineering & Catalysis, 12 (1: 113-118 (doi:10.9767/bcrec.12.1.735.113-118 Permalink/DOI: http://dx.doi.org/10.9767/bcrec.12.1.735.113-118

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

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Mohamed I. Attia

2013-12-01

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

Synthesis and biological evaluation of radioiodinated N-2-(4-piperidyl)ethyl benzamides

Energy Technology Data Exchange (ETDEWEB)

Efange, S.M.N.; Michelson, R.H.; Boudreau, R.J.; Thomas, J.R. (Minnesota Univ., Minneapolis, MN (United States)); Knusel, B.; Hefti, F. (Minnesota Univ., Minneapolis, MN (United States). Hospitals); Tennison, J.R. (University of Southern Cailfornia, Los Angeles, CA (United States). Andrus Gerontology Center)

1993-05-01

Three iodinated benzamides, 5-7, analogues of the potent acetylcholinesterase inhibitor 1-benzyl-4-[N-[4'-(benzylsulfonyl) benzoyl-N-methylamino]ethyl]piperidine (2), were synthesized and evaluated as potential anticholinesterase agents. All three compounds were found to be three orders of magnitude less potent than the parent compound. However, receptor screening revealed that compounds 5-7 exhibit nanomolar affinity for the sigma binding site. Both [[sup 125]I]5 and [[sup 125]I]7 were synthesized and evaluated in rats. Following the intravenous administration of [[sup 125]I]5 into rats, 1.59% of the injected dose was found in the rat brain within 5 min. The level of radioactivity in the brain remained steady for 2 h, the duration of the study. In contrast, 0.42% of the injected dose was detected in the rat brain following the i.v. injection of [[sup 125]I]7. Coadministration of either [[sup 125]I]5 or [[sup 125]I]7 with 0.5 [mu]mol/kg of haloperidol resulted in a 56-73% reduction in the level of radioactivity in the rat brain, suggesting that these compounds bind to the sigma binding site in vivo. Planar imaging studies with [[sup 123]I]5 revealed significant accumulation of radioactivity within the monkey brain, with a half-life of 6 h. Compound [[sup 123]I]5 may be potentially useful for studying sigma receptor distribution in the human brain. (author).

Hypoxia inhibits colonic ion transport via activation of AMP kinase.

LENUS (Irish Health Repository)

Collins, Danielle

2012-02-01

BACKGROUND AND AIMS: Mucosal hypoxia is a common endpoint for many pathological processes including ischemic colitis, colonic obstruction and anastomotic failure. Previous studies suggest that hypoxia modulates colonic mucosal function through inhibition of chloride secretion. However, the molecular mechanisms underlying this observation are poorly understood. AMP-activated protein kinase (AMPK) is a metabolic energy regulator found in a wide variety of cells and has been linked to cystic fibrosis transmembrane conductance regulator (CFTR) mediated chloride secretion in several different tissues. We hypothesized that AMPK mediates many of the acute effects of hypoxia on human and rat colonic electrolyte transport. METHODS: The fluorescent chloride indicator dye N-(ethoxycarbonylmethyl)-6-methoxyquinolinium bromide was used to measure changes in intracellular chloride concentrations in isolated single rat colonic crypts. Ussing chamber experiments in human colonic mucosa were conducted to evaluate net epithelial ion transport. RESULTS: This study demonstrates that acute hypoxia inhibits electrogenic chloride secretion via AMPK mediated inhibition of CFTR. Pre-treatment of tissues with the AMPK inhibitor 6-[4-(2-piperidin-1-yl-ethoxy)-phenyl)]-3-pyridin-4-yl-pyyrazolo [1,5-a] pyrimidine (compound C) in part reversed the effects of acute hypoxia on chloride secretion. CONCLUSION: We therefore suggest that AMPK is a key component of the adaptive cellular response to mucosal hypoxia in the colon. Furthermore, AMPK may represent a potential therapeutic target in diseased states or in prevention of ischemic intestinal injury.

Effects of hypoxia-ischemia and MK-801 treatment on the binding of a phencyclidine analogue in the developing rat brain

International Nuclear Information System (INIS)

Silverstein, F.S.; McDonald, J.W. III; Bommarito, M.; Johnston, M.V.

1990-01-01

The phencyclidine analogue [ 3 H](1-[2-thienyl]cyclohexyl)piperidine ( 3 H-TCP) binds to the ion channel associated with the N-methyl-D-aspartate receptor channel complex. In vitro autoradiography indicates that the distribution of 3 H-TCP binding in brain closely parallels that of [ 3 H]glutamate binding to the N-methyl-D-aspartate receptor. In nine 7-day-old rats, an acute focal hypoxic-ischemic insult produced by unilateral carotid artery ligation and subsequent exposure to 8% oxygen acutely reduced 3 H-TCP binding ipsilateral to the ligation by 30% in the CA1, by 27% in the CA3, by 26% in the dentate gyrus, and by 17% in the striatum compared with values from the contralateral hemisphere. In 10 littermates that received 1 mg/kg of the neuroprotective noncompetitive N-methyl-D-aspartate antagonist MK-801 immediately before hypoxic exposure, the regional distribution of 3 H-TCP binding in hypoxic-ischemic brain was relatively preserved and there were no interhemispheric asymmetries in 3 H-TCP binding densities. In addition, in three unoperated rats decapitated 24 hours after MK-801 treatment, 3 H-TCP binding was reduced by 15-35%; similar bilateral suppression of 3 H-TCP binding was detected in MK-801-treated ligates. Our data indicate that 3 H-TCP autoradiography can be used to assay the efficacy of neuroprotective agents in this experimental model of perinatal stroke

A study of the conformation and stability of nitroxide free radicals; Etude de la conformation et de la stabilite de radicaux libres nitroxydes

Energy Technology Data Exchange (ETDEWEB)

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

1969-03-01

The first part of this study is an application of nuclear magnetic resonance to the determination of the sign and magnitude of the long range nuclear-electron spin-spin couplings in the free radical nitroxide derived from piperidine. It has been shown that the coupling constants of the protons {gamma} to the nitrogen atom have a pronounced spatial dependence as do the protons in the {beta} position, a point which has not been brought out by previous investigations. Conformational analysis of these compounds has been carried out by measurement of the effect of temperature on the NMR spectra at 310 MHz. The synthesis of di-t-Bu nitroxide labelled with C{sup 13} in the {alpha}-position made possible the unambiguous determination of the corresponding {sup 13}C nuclear-electron spin-spin coupling constant, a parameter which had not previously been measured. The coupling constants measured in the 2,2,6,6-tetramethyl piperidine series could then be attributed to the {sup 13}C atoms in the {beta}-position and their variation related to the conformations of the heterocycles. This constitutes the second part of the work reported here. The final section is devoted to a study of the decomposition of an unstable nitroxide having a hydrogen atom in the p-position. This decomposition is bimolecular and the primary isotope effect shows that the rupture. of the C-H bond is involved. From this one can conclude that a nitroxide is stable when the different groups attached to the nitrogen atom cannot give rise to a decomposition either intra molecularly, if the molecular geometry is suitable, or inter molecularly by dimerisation through attack on a different center of a neighbouring molecule thus leading to a fragmentation or a disproportionation. (author) [French] La premiere partie est une application de la resonance magnetique nucleaire a la determination du signe et de la grandeur des couplages a longue distance dans des radicaux libres nitroxydes piperidiniques. Il est montre que

Specific labelling of serotonin 5-HT(1B) receptors in rat frontal cortex with the novel, phenylpiperazine derivative, [3H]GR125,743. A pharmacological characterization.

Science.gov (United States)

Millan, M J; Newman-Tancredi, A; Lochon, S; Touzard, M; Aubry, S; Audinot, V

2002-04-01

-(1,4-benzodioxan-5-yl)piperidin-4-yl]N-(indan-2yl)amine (S18127; 7.9), metergoline (7.8), (-)-pindolol (7.6), 1'-methyl-5-[2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-biphenyl-4-ylcarbonyl]-2,3,6,7-tetrahydro-5H-spiro[furo[2,3-f]indole-3,4'-piperidine] (SB224,289; 7.5) and ketanserin (<5.0). These rank orders of affinity correspond to the binding profile of 5-HT(1B) rather than 5-HT(1D) receptors. The low affinities of L775,066 and PNU109,291 versus L694,247 should be noted, as well as the low affinity of ketanserin as compared to SB224,289. Finally, in line with species differences, the affinities of several ligands including CP93,129, RU24,969, (-)-pindolol and (-)-propanolol in rat 5-HT(1B) sites were markedly different to guinea pig 5-HT(1B) sites labelled with [3H]GR125,743. In conclusion, [3H]GR125,743 is an appropriate tool for the radiolabelling of native, rat 5-HT(1B) receptors and permitted determination of the affinities of an extensive series of ligands at these sites.

Modulation of oxidative damage by nitroxide free radicals.

Science.gov (United States)

Dragutan, Ileana; Mehlhorn, Rolf J

2007-03-01

Piperidine nitroxides like 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) are persistent free radicals in non-acidic aqueous solutions and organic solvents that may have value as therapeutic agents in medicine. In biological environments, they undergo mostly reduction to stable hydroxylamines but can also undergo oxidation to reactive oxoammonium compounds. Reactions of the oxoammonium derivatives could have adverse consequences including chemical modification of vital macromolecules and deleterious effects on cell signaling. An examination of their reactivity in aqueous solution has shown that oxoammonium compounds can oxidize almost any organic as well as many inorganic molecules found in biological systems. Many of these reactions appear to be one-electron transfers that reduce the oxoammonium to the corresponding nitroxide species, in contrast to a prevalence of two-electron reductions of oxoammonium in organic solvents. Amino acids, alcohols, aldehydes, phospholipids, hydrogen peroxide, other nitroxides, hydroxylamines, phenols and certain transition metal ions and their complexes are among reductants of oxoammonium, causing conversion of this species to the paramagnetic nitroxide. On the other hand, thiols and oxoammonium yield products that cannot be detected by ESR even under conditions that would oxidize hydroxylamines to nitroxides. These products may include hindered secondary amines, sulfoxamides and sulfonamides. Thiol oxidation products other than disulfides cannot be restored to thiols by common enzymatic reduction pathways. Such products may also play a role in cell signaling events related to oxidative stress. Adverse consequences of the reactions of oxoammonium compounds may partially offset the putative beneficial effects of nitroxides in some therapeutic settings.

The Protective Role of Tempol Against Oxidative Stress-Related Renal Impairment Induced by Gamma Rays in Rats

International Nuclear Information System (INIS)

Mekawy, H.M.S.; Elkhouly, W.A.; Tawfik, S.S.

2015-01-01

Tempol (4-hydroxy-2,2,6,6-tetramethyl-piperidine-1 oxyl) is a naturally occurring substance that counteracts the harmful and damaging effects of oxidation in animal tissues and has been reported to permeate the biological membranes. In this study, tempol with dose of 18 mg/kg/day for 2 weeks has been shown to be effective in preventing several of the adverse consequences of oxidative stress and inflammation that underlie radiation damage. Adult rats were exposed to a total dose of 6 Gy gamma rays to determine the protective role of tempol on the biochemistry of the injured kidney because gamma rays displayed significant augmentation in renal oxidative modifications markers.The results indicated that plasma renal function tests; urea (Ur), creatinine (Cr), uric acid (UA) and sodium (Na), and plasma renal tubular injury markers; γ -glutamyltransferase ( γ -GT), aspartate aminotransferase (AST), creatine phosphokinase (CPK) and lactate dehydrogenase (LDH), were increased significantly in gamma rays group. In addition, the renal oxidative stress parameters; malondialdehyde (MDA), total cholesterol (TC) and protein carbonyl (PC), were increased significantly, and reduced glutathione (GSH) was decreased significantly in gamma rays group. Moreover, the levels of renal antioxidant enzymes; superoxide dismutase (SOD) and catalase (CAT), were decreased significantly, and myeloperoxidase (MPO) was in creased significantly in gamma rays group.The antioxidant treatment with tempol ameliorates gamma rays-induced biochemical alterations and dysfunction of kidney.Tempol, at levels within tolerable nutritional strategy, reduced the oxidative modification-related renal impairment induced by gamma radiation in rats.

Kinetic Study on Nucleophilic Substitution Reactions of 4-Chloro-2-nitrophenyl X-Substituted-benzoates with Cyclic Secondary Amines: Effect of Substituent X on Reactivity and Reaction Mechanism

Energy Technology Data Exchange (ETDEWEB)

Jeon, Seong Hoon; Kim, Hyun Soo; Han, Young Joon [Sejong Science High School, Seoul (Korea, Republic of); Kim, Minyoung; Um, Ikhwan [Ewha Woman' s Univ., Seoul (Korea, Republic of)

2013-10-15

Second-order rate constants (k{sub N}) have been measured spectrophotometrically for the reactions of 4-chloro-2-nitrophenyl X-substituted-benzoates (1a-1h) with a series of cyclic secondary amines in 80 mol % H{sub 2}O/20 mol % DMSO at 25.0 ± 0.1 .deg. C. The Hammett plot for the reactions of 1a-1h with piperidine consists of two intersecting straight lines, while the Yukawa-Tsuno plot exhibits an excellent linear correlation with ρ{sub X} = 1.25 and r = 0.58, indicating that the nonlinear Hammett plot is not due to a change in the rate-determining step (RDS) but is caused by ground-state stabilization through resonance interactions for substrates possessing an electron-withdrawing group in the benzoyl moiety. The Brφnsted-type plot for the reactions of 4-chloro-2-nitrophenyl benzoate (1d) with a series of cyclic secondary amines curves downward with β{sub 2} = 0.85, β{sub 1} = 0.24, and pK{sub a}{sup o} = 10.5, implying that a change in RDS occurs from the k{sub 2} step to the k{sub 1} process as the pK{sub a} of the conjugate acid of the amine exceeds 10.5. Dissection of k{sub N} into the microscopic rate constants k{sub 1} and k{sub 2}/k{sub -1} ratio associated with the reaction of 1d reveals that k{sub 2} is dependent on the amine basicity, which is contrary to generally held views.

Evaluation of developmental toxicity of coniine to rats and rabbits.

Science.gov (United States)

Forsyth, C S; Frank, A A

1993-07-01

Conium maculatum (poison hemlock, CM) is teratogenic in several domestic species, presumably due to its piperidine alkaloids, including coniine, which has been verified to be teratogenic in cattle. Coniine/CM teratogenicity culminates in production of arthrogryposis. The purpose of this study was to evaluate coniine-induced teratogenicity in two laboratory animal species, Sprague-Dawley rats and New Zealand white rabbits. Pregnant rats were given coniine (25 mg/kg body weight) by oral gavage at 8-hour intervals on gestation days 16-18. Pregnant rabbits were given coniine (40 mg/kg body weight) by oral gavage at 8-hour intervals on gestation days 20-24. Rats were killed on day 19 and rabbits on day 29. Fetuses were immediately removed, weighed, and examined for external abnormalities. Alternate fetuses were either stained for skeletal examinations with alizarin red-S or fixed in Bouin's solution for visceral examination. Symptoms of maternal intoxication due to coniine administration were observed in both the rat and the rabbit, and higher doses were uniformly lethal. Rabbits treated with coniine appeared to lose more weight and eat less than controls, but there was no statistically significant difference between groups. Fetal weights were significantly lower in coniine-exposed rat and rabbit fetuses indicating fetotoxicity. The only statistically significant treatment-related visceral or skeletal malformation was a reduction of cranial ossification of rabbit fetuses, probably related to maternal toxicity. Coniine-exposed rabbit litters tended to be affected by arthrogryposis (no bony deformities noted on skeletal exam) more than controls (2/6 vs. 0/9).

DAT/SERT Selectivity of Flexible GBR 12909 Analogs Modeled Using 3D-QSAR Methods

Science.gov (United States)

Gilbert, Kathleen M.; Boos, Terrence L.; Dersch, Christina M.; Greiner, Elisabeth; Jacobson, Arthur E.; Lewis, David; Matecka, Dorota; Prisinzano, Thomas E.; Zhang, Ying; Rothman, Richard B.; Rice, Kenner C.; Venanzi, Carol A.

2007-01-01

The dopamine reuptake inhibitor GBR 12909 (1-{2-[bis(4-fluorophenyl)methoxy]ethyl}-4-(3-phenylpropyl)piperazine, 1) and its analogs have been developed as tools to test the hypothesis that selective dopamine transporter (DAT) inhibitors will be useful therapeutics for cocaine addiction. This 3D-QSAR study focuses on the effect of substitutions in the phenylpropyl region of 1. CoMFA and CoMSIA techniques were used to determine a predictive and stable model for the DAT/serotonin transporter (SERT) selectivity (represented by pKi (DAT/SERT)) of a set of flexible analogs of 1, most of which have eight rotatable bonds. In the absence of a rigid analog to use as a 3D-QSAR template, six conformational families of analogs were constructed from six pairs of piperazine and piperidine template conformers identified by hierarchical clustering as representative molecular conformations. Three models stable to y-value scrambling were identified after a comprehensive CoMFA and CoMSIA survey with Region Focusing. Test set correlation validation led to an acceptable model, with q2 = 0.508, standard error of prediction = 0.601, two components, r2 = 0.685, standard error of estimate = 0.481, F value = 39, percent steric contribution = 65, and percent electrostatic contribution = 35. A CoMFA contour map identified areas of the molecule that affect pKi (DAT/SERT). This work outlines a protocol for deriving a stable and predictive model of the biological activity of a set of very flexible molecules. PMID:17127069

Synthesis and biological activity of novel series of 4-methoxy, and 4,9-dimethoxy-5-substituted furo[2,3-g]-1,2,3-benzoxathiazine-7,7-dioxide derivatives.

Science.gov (United States)

El-Sawy, Eslam R; Ebaid, Manal S; Abo-Salem, Heba M; El-Hallouty, Salwa; Kassem, Emad M; Mandour, Adel H

2014-05-01

A novel series of 4-methoxy, and 4,9-dimethoxy-5-substituted furo[2,3-g]-1,2,3-benzoxathiazine-7,7-dioxide derivatives 3a,b, 10a-g and 11a-g were prepared in good yields via the reaction of 4-methoxy (1a) and 4,7-dimethoxy-5-acetyl-6-hydroxybenzofurans (1b) and their α,β-unsaturated keto derivatives 6a-g and 7a-g with chlorosulfonyl isocyanate (CSI). On the other hand, N-chlorosulfonyl carbamate derivatives 4a,b, 12a,b and 13a,b were prepared and allowed to react with piperidine to give the corresponding N-piperidinosulfonyl carbamate derivatives 5a,b, 14a,b and 15a,b, respectively. Sixteen new target compounds 3a,b, 10a-g, and 11a-g were tested for their DPPH radical-scavenging, and in vitro antiproliferative activity against A-549, MCF7 and HCT-116 cancer cell lines. Compounds 10a, 11c, 11e, and 11g showed moderate DPPH radical-scavenging activity compared to ascorbic acid at 100 μg/mL. 4,9-Dimethoxy-5-substituted styrylfuro[3,2-g]-1,2,3-benzoxathiazine-7,7-dioxides 11a, 11b, and 11c were found to be highly active against A-549 and HCT-116 cancer cell lines with IC50 values ranging from 0.02 to 0.08 μmol/mL compared to doxorubicin with IC50 = 0.04 and 0.06 μmol/mL, respectively.

Triazole derivatives with improved in vitro antifungal activity over azole drugs

Directory of Open Access Journals (Sweden)

Yu S

2014-04-01

Full Text Available Shichong Yu,1,* Xiaoyun Chai,1,* Yanwei Wang,1 Yongbing Cao,2 Jun Zhang,3 Qiuye Wu,1 Dazhi Zhang,1 Yuanying Jiang,2 Tianhua Yan,4 Qingyan Sun11Department of Organic Chemistry, School of Pharmacy, Second Military Medical University, Shanghai, People's Republic of China; 2Drug Research Center, School of Pharmacy, Second Military Medical University, Shanghai, People's Republic of China; 3Overseas Education Faculty of the Second Military Medical University, Shanghai, People's Republic of China; 4Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing, People's Republic of China*These authors contributed equally to this workAbstract: A series of triazole antifungal agents with piperidine side chains was designed and synthesized. The results of antifungal tests against eight human pathogenic fungi in vitro showed that all the compounds exhibited moderate-to-excellent activities. Molecular docking between 8d and the active site of Candida albicans CYP51 was provided based on the computational docking results. The triazole interacts with the iron of the heme group. The difluorophenyl group is located in the S3 subsite and its fluorine atom (2-F can form H-bonds with Gly307. The side chain is oriented into the S4 subsite and formed hydrophobic and van der Waals interactions with the amino residues. Moreover, the phenyl group in the side chain interacts with the phenol group of Phe380 through the formation of π–π face-to-edge interactions.Keywords: synthesis, CYP51, molecular docking, azole agents

[Research on source profile of aerosol organic compounds in leather plant].

Science.gov (United States)

Wang, Bo-Guang; Zhou, Yan; Feng, Zhi-Cheng; Liu, Hui-Xuan

2009-04-15

Through investigating current air pollution condition for PM10 in every factories of different style leather plants in Pearl River Delta, characteristic profile of semi-volatile organic compounds in PM10 emitted from leather factories and their contents were researched by using ultrasonic and gas chromatography and mass spectrum technology. The 6 types of organic compounds containing 46 species in total were found in the collected samples, including phenyl compounds, alcohols, PAHs, acids, esters and amides. The concentrations of PM10 in leather tanning plant, leather dying plant and man-made leather plant were 678.5, 454.5, 498.6 microgm x m(-3) respectively, and concentration of organic compounds in PM10 were 10.04, 6.89, 14.21 microg x m(-3) in sequence. The more important type of pollutants in each leather plants had higher contribution to total organic mass as follows, esters and amides in tanning plants profile account for 43.47% and 36.51% respectively; esters and alcohols in dying plants profiles account for 52.52% and 16.16% respectively; esters and amide in man-made leather plant have the highest content and account for 57.07% and 24.17% respectively. In the aerosol organic source profiles of tested leather plants, 9-octadecenamide was the abundant important species with the weight of 26.15% in tanning plant, and Bis(2-ethylhexyl) phthalate was up to 44.19% in the dying plant, and Bis(2-ethylhexyl) maleate and 1-hydroxy-piperidine had obviously higher weight in man-made plant than the other two plants.

In vitro Activation of heme oxygenase-2 by menadione and its analogs.

Science.gov (United States)

Vukomanovic, Dragic; Rahman, Mona N; Bilokin, Yaroslav; Golub, Andriy G; Brien, James F; Szarek, Walter A; Jia, Zongchao; Nakatsu, Kanji

2014-02-18

Previously, we reported that menadione activated rat, native heme oxygenase-2 (HO-2) and human recombinant heme oxygenase-2 selectively; it did not activate spleen, microsomal heme oxygenase-1. The purpose of this study was to explore some structure-activity relationships of this activation and the idea that redox properties may be an important aspect of menadione efficacy. Heme oxygenase activity was determined in vitro using rat spleen and brain microsomes as the sources of heme oxygenase-1 and -2, respectively, as well as recombinant, human heme oxygenase-2. Menadione analogs with bulky aliphatic groups at position-3, namely vitamins K1 and K2, were not able to activate HO-2. In contrast, several compounds with similar bulky but less lipophilic moieties at position-2 (and -3) were able to activate HO-2 many fold; these compounds included polar, rigid, furan-containing naphthoquinones, furan-benzoxazine naphthoquinones, 2-(aminophenylphenyl)-3-piperidin-1-yl naphthoquinones. To explore the idea that redox properties might be involved in menadione efficacy, we tested analogs such as 1,4-dimethoxy-2-methylnaphthalene, pentafluoromenadione, monohalogenated naphthoquinones, α-tetralone and 1,4-naphthoquinone. All of these compounds were inactive except for 1,4-naphthoquinone. Menadione activated full-length recombinant human heme oxygenase-2 (FL-hHO-2) as effectively as rat brain enzyme, but it did not activate rat spleen heme oxygenase. These observations are consistent with the idea that naphthoquinones such as menadione bind to a receptor in HO-2 and activate the enzyme through a mechanism that may involve redox properties.

Discovery of biaryl-4-carbonitriles as antihyperglycemic agents that may act through AMPK-p38 MAPK pathway.

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Goel, Atul; Nag, Pankaj; Rahuja, Neha; Srivastava, Rohit; Chaurasia, Sumit; Gautam, Sudeep; Chandra, Sharat; Siddiqi, Mohammad Imran; Srivastava, Arvind K

2014-08-25

A series of functionalized biaryl-4-carbonitriles was synthesized in three steps and evaluated for PTP-1B inhibitory activity. Among the synthesized compounds, four biaryls 6a-d showed inhibition (IC50 58-75 μM) against in vitro PTP-1B assay possibly due to interaction with amino acid residues Lys120, Tyr46 through hydrogen bonding and aromatic-aromatic interactions, respectively. Two biaryl-4-carbonitriles 6b and 6c showed improved glucose tolerance, fasting as well as postprandial blood glucose, serum total triglycerides, and increased high-density lipoprotein-cholesterol in SLM, STZ, STZ-S and C57BL/KsJ-db/db animal models. The bioanalysis of 4'-bromo-2,3-dimethyl-5-(piperidin-1-yl)biphenyl-4-carbonitrile (6b) revealed that like insulin, it increased 2-deoxyglucose uptake in skeletal muscle cells (L6 and C2C12 myotubes). The compound 6b significantly up-regulated the genes related to the insulin signaling pathways like AMPK, MAPK including glucose transporter-4 (GLUT-4) gene in muscle tissue of C57BL/KsJ-db/db mice. Furthermore, it was observed that the compound 6b up-regulated PPARα, UCP2 and HNF4α, which are key regulator of glucose, lipid, and fatty acid metabolism. Western blot analysis of the compound 6b showed that it significantly increased the phosphorylation of AMPK and p38 MAPK and ameliorated glucose uptake in C57BL/KsJ-db/db mice through the AMPK-p38 MAPK pathway. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

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..

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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,...

Identification of a Glycogen Synthase Kinase-3[beta] Inhibitor that Attenuates Hyperactivity in CLOCK Mutant Mice

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Kozikowski, Alan P.; Gunosewoyo, Hendra; Guo, Songpo; Gaisina, Irina N.; Walter, Richard L.; Ketcherside, Ariel; McClung, Colleen A.; Mesecar, Andrew D.; Caldarone, Barbara (Psychogenics); (Purdue); (UIC); (UTSMC)

2012-05-02

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 exhibits 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.

Pre-synaptic glycine GlyT1 transporter--NMDA receptor interaction: relevance to NMDA autoreceptor activation in the presence of Mg2+ ions.

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Musante, Veronica; Summa, Maria; Cunha, Rodrigo A; Raiteri, Maurizio; Pittaluga, Anna

2011-05-01

Rat hippocampal glutamatergic terminals possess NMDA autoreceptors whose activation by low micromolar NMDA elicits glutamate exocytosis in the presence of physiological Mg(2+) (1.2 mM), the release of glutamate being significantly reduced when compared to that in Mg(2+)-free condition. Both glutamate and glycine were required to evoke glutamate exocytosis in 1.2 mM Mg(2+), while dizocilpine, cis-4-[phosphomethyl]-piperidine-2-carboxylic acid and 7-Cl-kynurenic acid prevented it, indicating that occupation of both agonist sites is needed for receptor activation. D-serine mimicked glycine but also inhibited the NMDA/glycine-induced release of [(3H]D-aspartate, thus behaving as a partial agonist. The NMDA/glycine-induced release in 1.2 mM Mg(2+) strictly depended on glycine uptake through the glycine transporter type 1 (GlyT1), because the GlyT1 blocker N-[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl])sarcosine hydrochloride, but not the GlyT2 blocker Org 25534, prevented it. Accordingly, [(3)H]glycine was taken up during superfusion, while lowering the external concentration of Na(+), the monovalent cation co-transported with glycine by GlyT1, abrogated the NMDA-induced effect. Western blot analysis of subsynaptic fractions confirms that GlyT1 and NMDA autoreceptors co-localize at the pre-synaptic level, where GluN3A subunits immunoreactivity was also recovered. It is proposed that GlyT1s coexist with NMDA autoreceptors on rat hippocampal glutamatergic terminals and that glycine taken up by GlyT1 may permit physiological activation of NMDA pre-synaptic autoreceptors. © 2011 The Authors. Journal of Neurochemistry © 2011 International Society for Neurochemistry.

Exposure to marijuana smoke impairs memory retrieval in mice.

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Niyuhire, Floride; Varvel, Stephen A; Martin, Billy R; Lichtman, Aron H

2007-09-01

Marijuana (Cannabis sativa) and its primary psychoactive component, delta-9-tetrahydrocannabinol (Delta(9)-THC), have long been known to disrupt cognition in humans. Although Delta(9)-THC and other cannabinoids disrupt performance in a wide range of animal models of learning and memory, few studies have investigated the effects of smoked marijuana in these paradigms. Moreover, in preclinical studies, cannabinoids are generally administered before acquisition, and because retention is generally evaluated soon afterward, it is difficult to distinguish between processes related to acquisition and retrieval. In the present study, we investigated the specific effects of marijuana smoke and injected Delta(9)-THC on acquisition versus memory retrieval in a mouse repeated acquisition Morris water-maze task. To distinguish between these processes, subjects were administered Delta(9)-THC or they were exposed to marijuana smoke either 30 min before acquisition or 30 min before the retention test. Inhalation of marijuana smoke or injected Delta(9)-THC impaired the ability of the mice to learn the location of the hidden platform and to recall the platform location once learning had already taken place. In contrast, neither drug impaired performance in a cued task in which the platform was made visible. Finally, the cannabinoid-1 (CB(1)) receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide HCl (rimonabant) blocked the memory disruptive effects of both Delta(9)-THC and marijuana. These data represent the first evidence demonstrating that marijuana impairs memory retrieval through a CB(1) receptor mechanism of action and independently of its effects on sensorimotor performance, motivation, and initial acquisition.

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

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

2005-02-01

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

Geographic variation in alkaloid production in Conium maculatum populations experiencing differential herbivory by Agonopterix alstroemeriana.

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Castells, Eva; Berhow, Mark A; Vaughn, Steven F; Berenbaum, May R

2005-08-01

Conium maculatum, a Eurasian weed naturalized in North America, contains high concentrations of piperidine alkaloids that act as chemical defenses against herbivores. C. maculatum was largely free from herbivory in the United States, until approximately 30 yr ago, when it was reassociated via accidental introduction with a monophagous European herbivore, the oecophorid caterpillar Agonopterix alstroemeriana. At present, A. alstroemeriana is found in a continuum of reassociation time and intensities with C. maculatum across the continent; in the Pacific Northwest, A. alstroemeriana can cause severe damage, resulting in some cases in complete defoliation. Studies in biological control and invasion biology have yet to determine whether plants reassociated with a significant herbivore from the area of indigeneity increase their chemical defense investment in areas of introduction. In this study, we compared three locations in the United States (New York, Washington, and Illinois) where C. maculatum experiences different levels of herbivory by A. alstroemeriana to determine the association between the intensity of the interaction, as measured by damage, and chemical defense production. Total alkaloid production in C. maculatum was positively correlated with A. alstroemeriana herbivory levels: plants from New York and Washington, with higher herbivory levels, invested two and four times more N to alkaloid synthesis than did plants from Illinois. Individual plants with lower concentrations of alkaloids from a single location in Illinois experienced more damage by A. alstroemeriana, indicative of a preference on the part of the insect for plants with less chemical defense. These results suggest that A. alstroemeriana may act either as a selective agent or inducing agent for C. maculatum and increase its toxicity in its introduced range.

Tempol moderately extends survival in a hSOD1(G93A ALS rat model by inhibiting neuronal cell loss, oxidative damage and levels of non-native hSOD1(G93A forms.

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Edlaine Linares

Full Text Available Amyotrophic lateral sclerosis (ALS is a fatal neurodegenerative disease characterized by the progressive dysfunction and death of motor neurons by mechanisms that remain unclear. Evidence indicates that oxidative mechanisms contribute to ALS pathology, but classical antioxidants have not performed well in clinical trials. Cyclic nitroxides are an alternative worth exploring because they are multifunctional antioxidants that display low toxicity in vivo. Here, we examine the effects of the cyclic nitroxide tempol (4-hydroxy-2,2,6,6-tetramethyl piperidine-1-oxyl on ALS onset and progression in transgenic female rats over-expressing the mutant hSOD1(G93A . Starting at 7 weeks of age, a high dose of tempol (155 mg/day/rat in the rat´s drinking water had marginal effects on the disease onset but decelerated disease progression and extended survival by 9 days. In addition, tempol protected spinal cord tissues as monitored by the number of neuronal cells, and the reducing capability and levels of carbonylated proteins and non-native hSOD1 forms in spinal cord homogenates. Intraperitoneal tempol (26 mg/rat, 3 times/week extended survival by 17 days. This group of rats, however, diverted to a decelerated disease progression. Therefore, it was inconclusive whether the higher protective effect of the lower i.p. dose was due to higher tempol bioavailability, decelerated disease development or both. Collectively, the results show that tempol moderately extends the survival of ALS rats while protecting their cellular and molecular structures against damage. Thus, the results provide proof that cyclic nitroxides are alternatives worth to be further tested in animal models of ALS.

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

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

2012-01-01

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

[Inhibitory mechanism of ifenprodil tartrate on rabbit platelet aggregation].

Science.gov (United States)

Irino, O; Saitoh, K; Hayashi, T; Ohkubo, K

1985-05-01

The effects of dl-erythro-4-benzyl-alpha-(4-hydroxyphenyl)-beta-methyl-l-piperidine-eth anol tartrate (ifenprodil tartrate) on rabbit platelet aggregation in vitro and ex vivo were studied. Ifenprodil tartrate inhibited platelet aggregation in vitro induced by ADP, collagen and epinephrine. It also inhibited 5-hydroxytryptamine (5-HT) uptake into platelets and 5-HT release from platelets. Since these inhibitory effects of ifenprodil tartrate on the functions of rabbit platelets were similar to the effects of imipramine, the effects of ifenprodil tartrate may be due to the stabilizing action of ifenprodil tartrate on the platelet membrane. The platelet aggregation by ADP was significantly inhibited in rabbits after oral administration of ifenprodil tartrate, the maximal plasma level of ifenprodil being reached at 20 ng/ml ex vivo, while the maximal level was only 1/40 of the minimal concentration of ifenprodil tartrate necessary to inhibit platelet aggregation in vitro. These results indicate that factors other than ifenprodil tartrate acting directly on the platelets (e.g., PGI2 which is an endogenous inhibitor of platelet aggregation) are involved in inducing the inhibitory effects of ifenprodil tartrate on platelet aggregation ex vivo. The effects of ifenprodil tartrate on both PGI2 release from the aorta and the inhibitory effects of PGI2 on platelet aggregation in vitro were investigated: PGI2 was found to intensify the inhibitory effects of ifenprodil tartrate on platelet aggregation in vitro, but there was little effect, if any, on PGI2 release. Therefore, it is considered that the ex vivo effects of ifenprodil tartrate might be due to its interaction with endogenous PGI2 in the blood.

Radiation dosimetry of [(18)F]VAT in nonhuman primates.

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Karimi, Morvarid; Tu, Zhude; Yue, Xuyi; Zhang, Xiang; Jin, Hongjun; Perlmutter, Joel S; Laforest, Richard

2015-12-01

The objective of this study is to determine the radiation dosimetry of a novel radiotracer for vesicular acetylcholine transporter (-)-(1-((2R,3R)-8-(2-[(18)F]fluoro-ethoxy)-3-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)piperidin-4-yl)(4-fluorophenyl)-methanone ([(18)F]VAT) based on PET imaging in nonhuman primates. [(18)F]VAT has potential for investigation of neurological disorders including Alzheimer's disease, Parkinson's disease, and dystonia. Three macaque fascicularis (two males, one female) received 185.4-198.3 MBq [(18)F]VAT prior to whole-body imaging in a MicroPET-F220 scanner. Time activity curves (TACs) were created from regions of interest (ROIs) that encompassed the entire small organs or samples with the highest activity within large organs. Organ residence times were calculated based on the TACs. We then used OLINDA/EXM 1.1 to calculate human radiation dose estimates based on scaled organ residence times. Measurements from directly sampled arterial blood yielded a residence time of 0.30 h in agreement with the residence time of 0.39 h calculated from a PET-generated time activity curve measured in the left ventricle. Organ dosimetry revealed the liver as the critical organ (51.1 and 65.4 μGy/MBq) and an effective dose of 16 and 19 μSv/MBq for male and female, respectively. The macaque biodistribution data showed high retention of [(18)F]VAT in the liver consistent with hepatobiliary clearance. These dosimetry data support that relatively safe doses of [(18)F]VAT can be administered to obtain imaging in humans.

Digital gene expression analysis of Microsporum canis exposed to berberine chloride.

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Chen-Wen Xiao

Full Text Available Berberine, a natural isoquinoline alkaloid of many medicinal herbs, has an active function against a variety of microbial infections including Microsporum canis (M. canis. However, the underlying mechanisms are poorly understood. To study the effect of berberine chloride on M. canis infection, a Digital Gene Expression (DGE tag profiling was constructed and a transcriptome analysis of the M. canis cellular responses upon berberine treatment was performed. Illumina/Hisseq sequencing technique was used to generate the data of gene expression profile, and the following enrichment analysis of Gene Ontology (GO and Pathway function were conducted based on the data of transcriptome. The results of DGE showed that there were 8476945, 14256722, 7708575, 5669955, 6565513 and 9303468 tags respectively, which was obtained from M. canis incubated with berberine or control DMSO. 8,783 genes were totally mapped, and 1,890 genes have shown significant changes between the two groups. 1,030 genes were up-regulated and 860 genes were down-regulated (P<0.05 in berberine treated group compared to the control group. Besides, twenty-three GO terms were identified by Gene Ontology functional enrichment analysis, such as calcium-transporting ATPase activity, 2-oxoglutarate metabolic process, valine catabolic process, peroxisome and unfolded protein binding. Pathway significant enrichment analysis indicated 6 signaling pathways that are significant, including steroid biosynthesis, steroid hormone biosynthesis, Parkinson's disease, 2,4-Dichlorobenzoate degradation, and tropane, piperidine and Isoquinoline alkaloid biosynthesis. Among these, eleven selected genes were further verified by qRT-PCR. Our findings provide a comprehensive view on the gene expression profile of M. canis upon berberine treatment, and shed light on its complicated effects on M. canis.

Brain redox imaging in the pentylenetetrazole (PTZ)-induced kindling model of epilepsy by using in vivo electron paramagnetic resonance and a nitroxide imaging probe.

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Emoto, Miho C; Yamato, Mayumi; Sato-Akaba, Hideo; Yamada, Ken-ichi; Fujii, Hirotada G

2015-11-03

Much evidence supports the idea that oxidative stress is involved in the pathogenesis of epilepsy, and therapeutic interventions with antioxidants are expected as adjunct antiepileptic therapy. The aims of this study were to non-invasively obtain spatially resolved redox data from control and pentylenetetrazole (PTZ)-induced kindled mouse brains by electron paramagnetic resonance (EPR) imaging and to visualize the brain regions that are sensitive to oxidative damage. After infusion of the redox-sensitive imaging probe 3-methoxycarbonyl-2,2,5,5-tetramethyl-piperidine-1-oxyl (MCP), a series of EPR images of PTZ-induced mouse heads were measured. Based on the pharmacokinetics of the reduction reaction of MCP in the mouse heads, the pixel-based rate constant of its reduction reaction was calculated as an index of redox status in vivo and mapped as a redox map. The obtained redox map showed heterogeneity in the redox status in PTZ-induced mouse brains compared with control. The co-registered image of the redox map and magnetic resonance imaging (MRI) for both control and PTZ-induced mice showed a clear change in the redox status around the hippocampus after PTZ. To examine the role of antioxidants on the brain redox status, the levels of antioxidants were measured in brain tissues of control and PTZ-induced mice. Significantly lower concentrations of glutathione in the hippocampus of PTZ-kindled mice were detected compared with control. From the results of both EPR imaging and the biochemical assay, the hippocampus was found to be susceptible to oxidative damage in the PTZ-induced animal model of epilepsy. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Mechanism of hydrodenitrogenation. Final report, September 1, 1989--August 31, 1992

Energy Technology Data Exchange (ETDEWEB)

Miranda, R.

1992-11-30

In this project it was proposed that the selectivity of the HDN reaction can be affected by an alteration of the catalyst acidity since it is possible that an acidic Hofmann-like deamination C--N--C bonds. Such a possibility was verified in this work by studying the denitrogenation of piperidine over acidic catalysts, and it was demonstrated that Bronsted acid sites are active for the denitrogenation of N-heterocycles, whereas Lewis sites are not. To better understand the role of acidic sites in the presence of hydrogenation and hydrogenolysis sites, molybdena was supposed on a series of acidic aluminas, and the resulting new acidity and molybdic phases were characterized. The oxidized catalysts supported on silica-aluninas showed increases from 3 to 150% of weak, medium and strong acid sites, which were produced by the molybdena phases. The new acidity was both of Lewis and Bronsted type, the predominance of one over the other depending upon support composition, as well as on loading and state of oxidation of Mo. High-alumina supports and low Mo loading favor dispersed Mo species, in particular bidentate and monodentate di-oxo Mo species. The latter is responsible for the new Bronsted acidity. Coordinative unsaturation of polymolybdates is responsible for the new Lewis acidity, which is increased upon reduction of Mo. High-silica supports favor monodentate species (high Bronsted acidity) up to 4 wt % MoO{sub 3}. Beyond that, polymolybdate species and Lewis acidity predominate. The nature of the reduced molybdena phases is obviously affected by support composition. The HDN reaction of pyridine was utilized to assess the variation in activity and selectivity produced by the nature of the support.

Mechanism of hydrodenitrogenation

Energy Technology Data Exchange (ETDEWEB)

Miranda, R.

1992-11-30

In this project it was proposed that the selectivity of the HDN reaction can be affected by an alteration of the catalyst acidity since it is possible that an acidic Hofmann-like deamination C--N--C bonds. Such a possibility was verified in this work by studying the denitrogenation of piperidine over acidic catalysts, and it was demonstrated that Bronsted acid sites are active for the denitrogenation of N-heterocycles, whereas Lewis sites are not. To better understand the role of acidic sites in the presence of hydrogenation and hydrogenolysis sites, molybdena was supposed on a series of acidic aluminas, and the resulting new acidity and molybdic phases were characterized. The oxidized catalysts supported on silica-aluninas showed increases from 3 to 150% of weak, medium and strong acid sites, which were produced by the molybdena phases. The new acidity was both of Lewis and Bronsted type, the predominance of one over the other depending upon support composition, as well as on loading and state of oxidation of Mo. High-alumina supports and low Mo loading favor dispersed Mo species, in particular bidentate and monodentate di-oxo Mo species. The latter is responsible for the new Bronsted acidity. Coordinative unsaturation of polymolybdates is responsible for the new Lewis acidity, which is increased upon reduction of Mo. High-silica supports favor monodentate species (high Bronsted acidity) up to 4 wt % MoO[sub 3]. Beyond that, polymolybdate species and Lewis acidity predominate. The nature of the reduced molybdena phases is obviously affected by support composition. The HDN reaction of pyridine was utilized to assess the variation in activity and selectivity produced by the nature of the support.

In vitro evaluation of the schistosomicidal effect of the extracts, fractions and major 3-hydroxy-2,6-dialkyl-substituted piperidine alkaloids from the flowers of Senna spectabilis (Fabaceae).

Science.gov (United States)

de Castro, Andreísa Teixeira; Castro, Aline Pereira; Silva, Matheus Siqueira; de Souza, Isabella Maria Monteiro; Martins-Souza, Raquel Lopes; Chagas-Paula, Daniela Aparecida; Coelho, Luiz Felipe Leomil; da Silva Bolzani, Vanderlan; Pivatto, Marcos; Viegas, Claudio; Marques, Marcos José

2016-09-01

In this work, we present the in vitro schistosomicidal activity evaluation of the most active dichloromethane fraction (FDm) (ED50=83.5μg/mL) and of a mixture of the major alkaloids ((-)-cassine/(-)-spectaline, C/E) (ED50=37.4μg/mL) from the flowers of Senna spectabilis against adult worms and cercariae. We also demonstrate other toxic effects including paralysis of the adult worms, inhibition of the secretory activity, tegument lesions and cercaricidal activity. In the association test of Praziquantel (PZQ)-C/E, we observed up to 80% mortality of Schistosoma mansoni in comparison to PZQ monotherapy. Due to the diversity of the toxic effects, the schistosomicidal activity of C/E is likely a result of a multitarget mechanism involving the tegument, secretory system and neuromotor action. Copyright © 2016 Elsevier Ltd. All rights reserved.

Radiosynthesis of an opiate receptor-binding radiotracer for positron emission tomography: (C-11 methyl)-methyl-4-(N-(1-oxopropyl)-N-phenylamino)-4-piperidine carboxylate (C-11 4-carbomethoxyfentanyl)

Energy Technology Data Exchange (ETDEWEB)

Dannals, R.F.; Ravert, H.T.; Frost, J.J.; Wilson, A.A.; Burns, H.D.; Wagner, H.N. Jr.

1984-01-01

The development of high affinity, high specific activity tritium-labeled neurotransmitter receptor ligands has made it possible to determine the spatial distribution and relative regional concentration of several neuroreceptors by means of in vivo receptor labeling techniques in animals. This development made possible the biochemical identification of opiate receptors by autoradiographic visualization in experimental animals. The quantitation and localization of opiate receptors in man using non-invasive methods, such as positron emission tomography, could provide a means of obtaining information about a variety of receptor-linked neuropsychiatric diseases as well as normal brain mechanisms regulating pain and emotions. As part of a continuing program to identify and radiolabel high affinity, highly specific ligands for the opiate receptor, the authors have selected two derivatives of fentanyl, a well-known analgesic, as candidates for radiolabeling: R-31,833 (4-carbomethoxy-fentanyl) and R-34,995 (lofentanil). Carbon-11 labeled R-31,833 was synthesized by the methylation of the appropriate carboxylate with C-11 methyl iodide in dimethylformamide at room temperature and purified by high performance liquid chromatography. The average synthesis time from end-of-bombardment (E.O.B.) was 30 minutes. The average specific activity was determined by ultraviolet spectroscopy to be 890 mCi/..mu..mole end-of-synthesis (approx. 2500 mCi/..mu..mole E.O.B.).

Radiosynthesis of an opiate receptor-binding radiotracer for positron emission tomography: [C-11 methyl]-methyl-4-[N-(1-oxopropyl)-N-phenylamino]-4-piperidine carboxylate (C-11 4-carbomethoxyfentanyl)

International Nuclear Information System (INIS)

Dannals, R.F.; Ravert, H.T.; Frost, J.J.; Wilson, A.A.; Burns, H.D.; Wagner, H.N. Jr.

1984-01-01

The development of high affinity, high specific activity tritium-labeled neurotransmitter receptor ligands has made it possible to determine the spatial distribution and relative regional concentration of several neuroreceptors by means of in vivo receptor labeling techniques in animals. This development made possible the biochemical identification of opiate receptors by autoradiographic visualization in experimental animals. The quantitation and localization of opiate receptors in man using non-invasive methods, such as positron emission tomography, could provide a means of obtaining information about a variety of receptor-linked neuropsychiatric diseases as well as normal brain mechanisms regulating pain and emotions. As part of a continuing program to identify and radiolabel high affinity, highly specific ligands for the opiate receptor, the authors have selected two derivatives of fentanyl, a well-known analgesic, as candidates for radiolabeling: R-31,833 (4-carbomethoxy-fentanyl) and R-34,995 (lofentanil). Carbon-11 labeled R-31,833 was synthesized by the methylation of the appropriate carboxylate with C-11 methyl iodide in dimethylformamide at room temperature and purified by high performance liquid chromatography. The average synthesis time from end-of-bombardment (E.O.B.) was 30 minutes. The average specific activity was determined by ultraviolet spectroscopy to be 890 mCi/μmole end-of-synthesis (approx. 2500 mCi/μmole E.O.B.)

Synthesis, physical-chemical and biological properties of 1,8-disubstituted compounds of theobromine. III. 8-Amino-p-chlorobenzyltheobromines

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D. G. Ivanchenko

2014-08-01

Full Text Available Introduction. This work is a follow-up to a series of research activities dedicated to the search of biologically active compounds among the xanthine derivatives. Aim of the Work.Development of simple laboratory-based methods for 8-amino-1-p-chlorobenzyltheobromines synthesis and the study of antioxidant, antimicrobial and antifungal effect of the synthesized compounds. Materials and Methods of Research.The melting point has been determined with the help of an open capillary method with TAP device (M. Elemental analysis has been performed with the helpof the instrument ElementarVario L cube, NMR-spectra have been taken on a spectrometer Bruker SF-400 (operating frequency of 400 MHz, solvent DMSO-d6 or DMSO-d6 + CDCl3, internal standard – TMS. These data correspond to thecalculated elemental analysis. The synthesis of 8-aminosubstituted 1-p-chlorobenzyltheobromine (2,3.Mixture 0.01 mole of8-bromo-1-p-chlorobenzyltheobromine (1, 0.03 mole of pyrrolidine (2 or piperidine (3, 40 ml of cellosolve is boiled during 4 hours, then it is allowed to steam out dry in a vacuum. Dry residue is processed with water, then residual matter which has been formed is filtered out, washed with water and recrystallized from the aqueous ethanol. The synthesis of 8-amino-1-p-chlorobenzyltheobromines (4-7. Mixture 0.01 mole of initial compound (1, 0.03 mole of the respective amine and 40 ml of cellosolve is boiled during 4 hours, thenit is allowed to cool down and is diluted with water. After this, residual matter which has been formed is filtered out, washed with water and aqueous propanol-2 and recrystallized from the water ethanol. Molecular descriptors have been calculated using the computer programs ALOGPS and DRAGON, whereas biological properties of the synthesized compounds have been calculated with the help of GUSAR and ACD / Percepta Platform. Antioxidant activity (AOA has been studied in vitro applying the method of nonenzymic initiation of free

Radiosynthesis and biodistribution of a histamine H3 receptor antagonist 4-[3-(4-piperidin-1-yl-but-1-ynyl)-[11C]benzyl]-morpholine: evaluation of a potential PET ligand

International Nuclear Information System (INIS)

Airaksinen, Anu J.; Jablonowski, Jill A.; Mey, Margreet van der; Barbier, Ann J.; Klok, Rob P.; Verbeek, Joost; Schuit, Robert; Herscheid, Jacobus D.M.; Leysen, Josee E.; Carruthers, Nicholas I.; Lammertsma, Adriaan A.; Windhorst, Albert D.

2006-01-01

The potent histamine H 3 receptor antagonist JNJ-10181457 () was successfully labeled with 11 C in a novel one-pot reaction sequence, with high chemical yield (decay-corrected yield, 28±8%) and high specific radioactivity (56±26 GBq/μmol). The binding of [ 11 C] to H 3 receptors was studied in vitro in rat brain and in vivo in rats and mice. The in vitro binding of [ 11 C] in rat coronal brain slices showed high binding in the striatum, and this binding was blocked by histamine and by two known H 3 antagonists, JNJ-5207852 () and unlabeled Compound (), in a concentration-dependent manner. The biodistribution of [ 11 C] in rats was measured at 5, 10, 30 and 60 min. The uptake of [ 11 C] in regions rich in H 3 receptors was highest at 30 min, giving 0.98%, 1.41%, 1.28% and 1.72% dose/g for the olfactory bulb, hippocampus, striatum and cerebral cortex, respectively. However, the binding of [ 11 C] in the rat brain could not be blocked by pretreatment with either Compound () (30 min or 24 h pretreatment) or cold Compound () (30-min pretreatment). The biodistribution of [ 11 C] in a second species (Balb/c mice) showed a higher overall uptake of the radioligand with an average brain uptake of 8.9% dose/g. In C57BL/6-H 3 (-/-) knockout mice, a higher brain uptake was also observed. Analyses of metabolites and plasma protein binding were also undertaken. It appeared that [ 11 C] could not specifically label H 3 receptors in rodent brain in vivo. Possible causes are discussed

Preclinical acute toxicity studies and rodent-based dosimetry estimates of the novel sigma-1 receptor radiotracer [18F]FPS

International Nuclear Information System (INIS)

Waterhouse, Rikki N.; Stabin, Michael G.; Page, John G.

2003-01-01

[ 18 F]1-(Fluoropropyl)-4-[(4-cyanophenoxy)methyl]piperidine ([ 18 F]FPS) is a novel high affinity (KD = 0.5 nM) sigma receptor radioligand that exhibits saturable and selective in vivo binding to sigma receptors in rats, mice and non-human primates. In order to support an IND application for the characterization of [ 18 F]FPS through PET imaging studies in humans, single organ and whole body radiation adsorbed doses associated with [ 18 F]FPS injection were estimated from distribution data obtained in rats. In addition, acute toxicity studies were conducted in rats and rabbits and limited toxicity analyses were performed in dogs. Radiation dosimetry estimates obtained using rat biodistribution analysis of [ 18 F]FPS suggest that most organs would receive around 0.012-0.015 mGy/MBq. The adrenal glands, brain, kidneys, lungs, and spleen would receive slightly higher doses (0.02-0.03 mGy/MBq). The adrenal glands were identified as the organs receiving the greatest adsorbed radiation dose. The total exposure resulting from a 5 mCi administration of [ 18 F]FPS is well below the FDA defined limits for yearly cumulative and per study exposures to research participants. Extended acute toxicity studies in rats and rabbits, and limited acute toxicity studies in beagle dogs suggest at least a 175-fold safety margin in humans at a mass dose limit of 2.8 μg per intravenous injection. This estimate is based on the measured no observable effect doses (in mg/m 2 ) in these species. These data support the expectation that [ 18 F]FPS will be safe for use in human PET imaging studies at a maximum administration of 5 mCi and a mass dose equal to or less than 2.8 μg FPS per injection

5-Hydroxytryptamine (serotonin)2A receptors in rat anterior cingulate cortex mediate the discriminative stimulus properties of d-lysergic acid diethylamide.

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Gresch, Paul J; Barrett, Robert J; Sanders-Bush, Elaine; Smith, Randy L

2007-02-01

d-Lysergic acid diethylamide (LSD), an indoleamine hallucinogen, produces profound alterations in mood, thought, and perception in humans. The brain site(s) that mediates the effects of LSD is currently unknown. In this study, we combine the drug discrimination paradigm with intracerebral microinjections to investigate the anatomical localization of the discriminative stimulus of LSD in rats. Based on our previous findings, we targeted the anterior cingulate cortex (ACC) to test its involvement in mediating the discriminative stimulus properties of LSD. Rats were trained to discriminate systemically administered LSD (0.085 mg/kg s.c.) from saline. Following acquisition of the discrimination, bilateral cannulae were implanted into the ACC (AP, +1.2 mm; ML, +/-1.0 mm; DV, -2.0 mm relative to bregma). Rats were tested for their ability to discriminate varying doses of locally infused LSD (0.1875, 0.375, and 0.75 microg/side) or artificial cerebrospinal fluid (n = 3-7). LSD locally infused into ACC dose-dependently substituted for systemically administered LSD, with 0.75 microg/side LSD substituting completely (89% correct). Systemic administration of the selective 5-hydroxytryptamine (serotonin) (5-HT)(2A) receptor antagonist R-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine-methanol (M100907; 0.4 mg/kg) blocked the discriminative cue of LSD (0.375 microg/side) infused into ACC (from 68 to 16% drug lever responding). Furthermore, M100907 (0.5 microg/microl/side) locally infused into ACC completely blocked the stimulus effects of systemic LSD (0.04 mg/kg; from 80 to 12% on the LSD lever). Taken together, these data indicate that 5-HT(2A) receptors in the ACC are a primary target mediating the discriminative stimulus properties of LSD.

Ultrarapid mutation detection by multiplex, solid-phase chemical cleavage

Energy Technology Data Exchange (ETDEWEB)

Rowley, G.; Saad, S.; Giannelli, F.; Green, P.M. [Guy`s & St. Thomas`s Hospitals, London (United Kingdom)

1995-12-10

The chemical cleavage of mismatches in heteroduplexes formed by probe and test DNA detects and locates any sequence change in long DNA segments ({approximately}1.8 kb), and its efficiency has been well tested in the analysis of both average (e.g., coagulation factor IX) and large, complex genes (e.g., coagulation factor VIII and dystrophin). In the latter application RT/PCR products allow the examination of all essential sequences of the gene in a minimum number of reactions. We use two specific chemical reactants (hydroxylamine and osmium tetroxide) and piperidine cleavage of the above procedure to develop a very fast mutation screening method. This is based on: (1) 5{prime} or internal fluorescent labeling to allow concurrent screening of three to four DNA fragments and (2) solid-phase chemistry to use a microliter format and reduce the time required for the procedure, from amplification of sequence to gel loading inclusive, to one person-working-day. We test the two variations of the method, one entailing 5{prime} labeling of probe DNA and the other uniform labeling of both probe and target DNA, by detecting 114 known hemophilia B (coagulation factor IX) mutations and by analyzing 129 new patients. Uniform labeling of both probe and target DNA prior to formation of the heteroduplexes leads to almost twofold redundancy in the ability to detect mutations. Alternatively, the latter procedure may offer very efficient though less than 100% screening for sequence changes with only hydroxylamine. The full method with two chemical reactions (hydroxylamine and osmium tetroxide) should allow one person to screen with virtually 100% accuracy more than 300 kb of sequence in three ABI 373 gels in 1 day. 26 refs., 7 figs., 1 tab.

Antitumor effects of cannabidiol, a nonpsychoactive cannabinoid, on human glioma cell lines.

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Massi, Paola; Vaccani, Angelo; Ceruti, Stefania; Colombo, Arianna; Abbracchio, Maria P; Parolaro, Daniela

2004-03-01

Recently, cannabinoids (CBs) have been shown to possess antitumor properties. Because the psychoactivity of cannabinoid compounds limits their medicinal usage, we undertook the present study to evaluate the in vitro antiproliferative ability of cannabidiol (CBD), a nonpsychoactive cannabinoid compound, on U87 and U373 human glioma cell lines. The addition of CBD to the culture medium led to a dramatic drop of mitochondrial oxidative metabolism [3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H tetrazolium bromide test] and viability in glioma cells, in a concentration-dependent manner that was already evident 24 h after CBD exposure, with an apparent IC(50) of 25 microM. The antiproliferative effect of CBD was partially prevented by the CB2 receptor antagonist N-[(1S)-endo-1,3,3-trimethylbicyclo[2,2,1]heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide (SR144528; SR2) and alpha-tocopherol. By contrast, the CB1 cannabinoid receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide hydrochloride (SR141716; SR1), capsazepine (vanilloid receptor antagonist), the inhibitors of ceramide generation, or pertussis toxin did not counteract CBD effects. We also show, for the first time, that the antiproliferative effect of CBD was correlated to induction of apoptosis, as determined by cytofluorimetric analysis and single-strand DNA staining, which was not reverted by cannabinoid antagonists. Finally, CBD, administered s.c. to nude mice at the dose of 0.5 mg/mouse, significantly inhibited the growth of subcutaneously implanted U87 human glioma cells. In conclusion, the nonpsychoactive CBD was able to produce a significant antitumor activity both in vitro and in vivo, thus suggesting a possible application of CBD as an antineoplastic agent.

Behavior of detoxifying enzymes of Aedes aegypti exposed to girgensohnine alkaloid analog and Cymbopogon flexuosus essential oil.

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Carreño Otero, Aurora L; Palacio-Cortés, Angela Maria; Navarro-Silva, Mario Antonio; Kouznetsov, Vladimir V; Duque L, Jonny E

2018-01-01

Because mosquito control depend on the use of commercial insecticides and resistance has been described in some of them, there is a need to explore new molecules no resistant. In vivo effects of girgensohnine analog 2-(3,4-dimethoxyphenyl)-2-(piperidin-1-yl)acetonitrile DPPA and Cymbopogon flexuosus essential oil CFEO, on the detoxifying enzymes acetylcholinesterase (AChE), glutathione-S-transferase (GST), nonspecific esterases (α- and β-), mixed function oxidases (MFO) and p-NPA esterases were evaluated on a Rockefeller (Rock) and wild Aedes aegypti population from Santander, Colombia (WSant). The action was tested after 24h of exposure at concentrations of 20.10, 35.18 and 70.35mgL -1 of DPPA and 18.45, 30.75 and 61.50mgL -1 of CFEO, respectively. It was found that AChE activity of Rock and WSant was not influenced by the evaluated concentration of DPPA and CFEO (p>0.05), while MFO activity was significantly affected by all CFEO concentrations in WSant (p<0.05). GST, α- and β-esterase activities were affected in Rock exposed at the highest CFEO concentration, this concentration also modified β-esterases activity of WSant. DPPA and CFEO sublethal doses induced inhibition of AChE activity on untreated larvae homogenate from 12 to 20% and 18 to 26%, respectively. For untreated adult homogenate, the inhibition activity raised up to 14 to 27% for DPPA and 26 to 34% for CFEO. Elevated levels of detoxifying enzymes, found when CFEO was evaluated, showed a larval sensitivity not observed by the pure compound suggesting that DPPA, contrary to CFEO, was not recognized, transformed or eliminated by the evaluated detoxifying enzymes. Copyright © 2017 Elsevier Inc. All rights reserved.

In vivo growth-inhibition of Sarcoma 180 by piplartine and piperine, two alkaloid amides from Piper

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D.P. Bezerra

2006-06-01

Full Text Available Piplartine {5,6-dihydro-1-[1-oxo-3-(3,4,5-trimethoxyphenyl-2-propenyl]-2(1Hpyridinone} and piperine {1-5-(1,3-benzodioxol-5-yl-1-oxo-2,4-pentadienyl]piperidine} are alkaloid amides isolated from Piper. Both have been reported to show cytotoxic activity towards several tumor cell lines. In the present study, the in vivo antitumor activity of these compounds was evaluated in 60 female Swiss mice (N = 10 per group transplanted with Sarcoma 180. Histopathological and morphological analyses of the tumor and the organs, including liver, spleen, and kidney, were performed in order to evaluate the toxicological aspects of the treatment with these amides. Administration of piplartine or piperine (50 or 100 mg kg-1 day-1 intraperitoneally for 7 days starting 1 day after inoculation inhibited solid tumor development in mice transplanted with Sarcoma 180 cells. The inhibition rates were 28.7 and 52.3% for piplartine and 55.1 and 56.8% for piperine, after 7 days of treatment, at the lower and higher doses, respectively. The antitumor activity of piplartine was related to inhibition of the tumor proliferation rate, as observed by reduction of Ki67 staining, a nuclear antigen associated with G1, S, G2, and M cell cycle phases, in tumors from treated animals. However, piperine did not inhibit cell proliferation as observed in Ki67 immunohistochemical analysis. Histopathological analysis of liver and kidney showed that both organs were reversibly affected by piplartine and piperine treatment, but in a different way. Piperine was more toxic to the liver, leading to ballooning degeneration of hepatocytes, accompanied by microvesicular steatosis in some areas, than piplartine which, in turn, was more toxic to the kidney, leading to discrete hydropic changes of the proximal tubular and glomerular epithelium and tubular hemorrhage in treated animals.

Development of novel arginase inhibitors for therapy of endothelial dysfunction

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Jochen eSteppan

2013-09-01

Full Text Available Endothelial dysfunction and resulting vascular pathology have been identified as an early hallmark of multiple diseases, including diabetes mellitus. One of the major contributors to endothelial dysfunction is a decrease in nitric oxide (NO bioavailability, impaired NO signaling and an increase in the amount of reactive oxygen species (ROS. In the endothelium NO is produced by eNOS (endothelial nitric oxide synthase, for which L-arginine is a substrate. Arginase, an enzyme critical in the urea cycle also metabolizes L-arginine, thereby directly competing with eNOS for their common substrate and constraining its bioavailability for eNOS, thereby compromising NO production. Arginase expression and activity is upregulated in many cardiovascular diseases including ischemia reperfusion injury, hypertension, atherosclerosis, and diabetes mellitus. More importantly, since the 1990s, specific arginase inhibitors such as N-hydroxy-guanidinium or N-hydroxy-nor-L-arginine, and boronic acid derivatives, such as, 2(S-amino-6-boronohexanoic acid, and S-(2-boronoethyl-L-cysteine (BEC, that can bridge the binuclear manganese cluster of arginase have been developed. These highly potent and specific inhibitors can now be used to probe arginase function and thereby modulate the redox milieu of the cell by changing the balance between NO and ROS. Inspired by this success, drug discovery programs have recently led to the identification of α-α-disubstituted amino acid based arginase inhibitors (such as (R-2-amino-6-borono-2-(2-(piperidin-1-ylethylhexanoic acid, that are currently under early investigation as therapeutics. Finally, some investigators concentrate on identification of plant derived compounds with arginase inhibitory capability, such as piceatannol-3'-O-β-D-glucopyranoside (PG. All of these synthesized or naturally derived small molecules may represent novel therapeutics for vascular disease particularly that associated with diabetes.

Application of Physiologically-Based Pharmacokinetic Modeling for the Prediction of Tofacitinib Exposure in Japanese.

Science.gov (United States)

Suzuki, Misaki; Tse, Susanna; Hirai, Midori; Kurebayashi, Yoichi

2017-05-09

Tofacitinib (3-[(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl]-3 -oxopropanenitrile) is an oral Janus kinase inhibitor that is approved in countries including Japan and the United States for the treatment of rheumatoid arthritis, and is being developed across the globe for the treatment of inflammatory diseases. In the present study, a physiologically-based pharmacokinetic model was applied to compare the pharmacokinetics of tofacitinib in Japanese and Caucasians to assess the potential impact of ethnicity on the dosing regimen in the two populations. Simulated plasma concentration profiles and pharmacokinetic parameters, i.e. maximum concentration and area under plasma concentration-time curve, in Japanese and Caucasian populations after single or multiple doses of 1 to 30 mg tofacitinib were in agreement with clinically observed data. The similarity in simulated exposure between Japanese and Caucasian populations supports the currently approved dosing regimen in Japan and the United States, where there is no recommendation for dose adjustment according to race. Simulated results for single (1 to 100 mg) or multiple doses (5 mg twice daily) of tofacitinib in extensive and poor metabolizers of CYP2C19, an enzyme which has been shown to contribute in part to tofacitinib elimination and is known to exhibit higher frequency in Japanese compared to Caucasians, were also in support of no recommendation for dose adjustment in CYP2C19 poor metabolizers. This study demonstrated a successful application of physiologically-based pharmacokinetic modeling in evaluating ethnic sensitivity in pharmacokinetics at early stages of development, presenting its potential value as an efficient and scientific method for optimal dose setting in the Japanese population.

Role of protein sulfation in vasodilation induced by minoxidil sulfate, a K+ channel opener

International Nuclear Information System (INIS)

Meisheri, K.D.; Oleynek, J.J.; Puddington, L.

1991-01-01

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 of 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

Preclinical acute toxicity studies and rodent-based dosimetry estimates of the novel sigma-1 receptor radiotracer [(18)F]FPS.

Science.gov (United States)

Waterhouse, Rikki N; Stabin, Michael G; Page, John G

2003-07-01

[(18)F]1-(Fluoropropyl)-4-[(4-cyanophenoxy)methyl]piperidine ([(18)F]FPS) is a novel high affinity (KD = 0.5 nM) sigma receptor radioligand that exhibits saturable and selective in vivo binding to sigma receptors in rats, mice and non-human primates. In order to support an IND application for the characterization of [(18)F]FPS through PET imaging studies in humans, single organ and whole body radiation adsorbed doses associated with [(18)F]FPS injection were estimated from distribution data obtained in rats. In addition, acute toxicity studies were conducted in rats and rabbits and limited toxicity analyses were performed in dogs. Radiation dosimetry estimates obtained using rat biodistribution analysis of [(18)F]FPS suggest that most organs would receive around 0.012-0.015 mGy/MBq. The adrenal glands, brain, kidneys, lungs, and spleen would receive slightly higher doses (0.02-0.03 mGy/MBq). The adrenal glands were identified as the organs receiving the greatest adsorbed radiation dose. The total exposure resulting from a 5 mCi administration of [(18)F]FPS is well below the FDA defined limits for yearly cumulative and per study exposures to research participants. Extended acute toxicity studies in rats and rabbits, and limited acute toxicity studies in beagle dogs suggest at least a 175-fold safety margin in humans at a mass dose limit of 2.8 microg per intravenous injection. This estimate is based on the measured no observable effect doses (in mg/m(2)) in these species. These data support the expectation that [(18)F]FPS will be safe for use in human PET imaging studies at a maximum administration of 5 mCi and a mass dose equal to or less than 2.8 microg FPS per injection.

5D-QSAR for spirocyclic sigma1 receptor ligands by Quasar receptor surface modeling.

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Oberdorf, Christoph; Schmidt, Thomas J; Wünsch, Bernhard

2010-07-01

Based on a contiguous and structurally as well as biologically diverse set of 87 sigma(1) ligands, a 5D-QSAR study was conducted in which a quasi-atomistic receptor surface modeling approach (program package Quasar) was applied. The superposition of the ligands was performed with the tool Pharmacophore Elucidation (MOE-package), which takes all conformations of the ligands into account. This procedure led to four pharmacophoric structural elements with aromatic, hydrophobic, cationic and H-bond acceptor properties. Using the aligned structures a 3D-model of the ligand binding site of the sigma(1) receptor was obtained, whose general features are in good agreement with previous assumptions on the receptor structure, but revealed some novel insights since it represents the receptor surface in more detail. Thus, e.g., our model indicates the presence of an H-bond acceptor moiety in the binding site as counterpart to the ligands' cationic ammonium center, rather than a negatively charged carboxylate group. The presented QSAR model is statistically valid and represents the biological data of all tested compounds, including a test set of 21 ligands not used in the modeling process, with very good to excellent accuracy [q(2) (training set, n=66; leave 1/3 out) = 0.84, p(2) (test set, n=21)=0.64]. Moreover, the binding affinities of 13 further spirocyclic sigma(1) ligands were predicted with reasonable accuracy (mean deviation in pK(i) approximately 0.8). Thus, in addition to novel insights into the requirements for binding of spirocyclic piperidines to the sigma(1) receptor, the presented model can be used successfully in the rational design of new sigma(1) ligands. Copyright (c) 2010 Elsevier Masson SAS. All rights reserved.

NESS06SM reduces body weight with an improved profile relative to SR141716A.

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Mastinu, Andrea; Pira, Marilena; Pinna, Gérard Aimè; Pisu, Carla; Casu, Maria Antonietta; Reali, Roberta; Marcello, Stefania; Murineddu, Gabriele; Lazzari, Paolo

2013-08-01

We have recently synthesized a new series of 4,5-dihydrobenzo-oxa-cycloheptapyrazole derivatives with the aim to discover novel CB1 antagonist agents characterized by anti-obesity activity comparable to that of SR141716A but with reduced adverse effects such as anxiety and depression. Within the novel class, the CB1 antagonist 8-chloro-1-(2,4-dichlorophenyl)-N-piperidin-1-yl-4,5-dihydrobenzo-1H-6-oxa-cyclohepta(1,2-c)pyrazole-3-carboxamide (NESS06SM) has been selected as lead compound. We found that NESS06SM is a CB1 neutral antagonist, characterized by poor blood-brain barrier permeability. Moreover, NESS06SM chronic treatment determined both anti-obesity effect and cardiovascular risk factor improvement in C57BL/6N Diet Induced Obesity (DIO) mice fed with fat diet (FD mice). In fact, the mRNA gene expression in Central Nervous System (CNS) and peripheral tissues by real time PCR, showed a significant increase of orexigenic peptides and a decrease of anorexigenic peptides elicited by NESS06SM treatment, compared to control mice fed with the same diet. Moreover, in contrast to SR141716A treatment, the chronic administration of NESS06SM did not change mRNA expression of both monoaminergic transporters and neurotrophins highly related with anxiety and mood disorders. Our results suggest that NESS06SM reduces body weight and it can restore the disrupted expression profile of genes linked to the hunger-satiety circuit without altering monoaminergic transmission probably avoiding SR141716A side effects. Therefore the novel CB1 neutral antagonist could represent a useful candidate agent for the treatment of obesity and its metabolic complications. Copyright © 2013 Elsevier Ltd. All rights reserved.

Organic-inorganic hybrid rare earth complexes based on polymolybdates with intrinsic photosensitive properties.

Science.gov (United States)

Wang, Yuan; Ma, Pengtao; Niu, Jingyang

2015-03-14

A series of organic–inorganic hybrid rare earth complexes {[RE2(PO)2(H2O)10][H2Mo36O112(OH2)12(PO)4]}·5PO·2(CH3CN)·nH2O [n = 23–42, RE(III) = Nd(III), 1; Sm(III), 2; Eu(III), 3; Gd(III), 4; Dy(III), 5; Er(III), 6; Tm(III), 7; Yb(III), 8; Lu(III), 9; Y(III), 10; PO = piperidin-2-one] have been synthesized and fully characterized by single-crystal X-ray diffraction, powder X-ray diffraction, elemental analysis, IR spectra, thermogravimetric analysis and UV-vis spectra. Structural analysis reveals that compounds 1-10 are isostructural and crystallize in the monoclinic P2(1)/n space group. Each compound contains a centrosymmetric anionic cluster [Mo36O112(OH2)12(PO)4](8-), which could be described as the derivative of [Mo36O112(OH2)16](8-) with four water molecules substituted by organic PO molecules. Each {Mo18} subunit connects with one RE(III) ion via its two terminal O atoms from two independent {MoO6} octahedra. The eight coordinated RE(III) ion with a distorted tetragonal antiprism coordination geometry is also surrounded by another six oxygen atoms, five of them from five water molecules and the final one from one PO molecule. Compounds 1-10 show considerable photosensitive behavior under visible light excitation. In addition, compound 3 exhibits three emission bands at 580, 595 and 617 nm in the solid state, which could be assigned to (5)D0→(7)F0, (5)D0→(7)F1 and (5)D0→(7)F2 transitions of Eu(III) ions, respectively.

Stereochemical features of unsaturated aminodiesters - intermediates in the synthesis of Richlocaine

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Meyrambek Ospanov

2014-10-01

Full Text Available The article provides information on the methods for synthesis of unsaturated aminodiesters, which are the key intermediates in the synthesis of N-substituted 2,5-dimethyl-piperidin-4-ones, including 1,2,5-trimetilpieridin-3-one. The developed method includes reaction of methyl ester of methacrylic acid with alkyl (alkenyl amines. The obtained N-alkyl(alkenyl-(2-methyl-2- carbmetoxyethyl methylamine are attached to acetoacetic ester being in the enol form. The optimal conditions for synthesis of N-alkyl(alkenyl-(2-methyl-2-carbethoxyethenemethylamines have been established. Results of gas chromatographic analysis has showed that, at room temperature, the reaction in polar solvents is delayed for two days. In non-polar solvents, the reaction runs with simultaneous distillation of water as an azeotrope with the solvent. Increase of the radical size at N atom has little effect on the reaction rate. Introduction of allyl radical at the nitrogen atom, apparently due to steric hindrance, resulted in lower reactivity of the monoester with allyl radical by condensation with acetoacetic ester. The structure of (1-methyl-2-carbethoxyethene-(2-methyl-2-carbmethoxyethyl methylamine has been studied by PMR spectroscopy. Study of the effect of chirality on the NMR spectra showed that, if the molecule of the organic compound has an asymmetric carbon atom, it may lead to the disappearance of the magnetic equivalence of neighboring protons or group of protons. Presence of an asymmetric carbon atom in b-position to the amino group of enamine leads to the disappearance of the magnetic equivalence of the neighboring protons is observed in the form of two quartets. For enaminodiesters, equilibrium is shifted toward the trans-S-cis conformer where less steric hindrance is pronounced.

Nitroxides protect horseradish peroxidase from H2O2-induced inactivation and modulate its catalase-like activity.

Science.gov (United States)

Samuni, Amram; Maimon, Eric; Goldstein, Sara

2017-08-01

Horseradish peroxidase (HRP) catalyzes H 2 O 2 dismutation while undergoing heme inactivation. The mechanism underlying this process has not been fully elucidated. The effects of nitroxides, which protect metmyoglobin and methemoglobin against H 2 O 2 -induced inactivation, have been investigated. HRP reaction with H 2 O 2 was studied by following H 2 O 2 depletion, O 2 evolution and heme spectral changes. Nitroxide concentration was followed by EPR spectroscopy, and its reactions with the oxidized heme species were studied using stopped-flow. Nitroxide protects HRP against H 2 O 2 -induced inactivation. The rate of H 2 O 2 dismutation in the presence of nitroxide obeys zero-order kinetics and increases as [nitroxide] increases. Nitroxide acts catalytically since its oxidized form is readily reduced to the nitroxide mainly by H 2 O 2 . The nitroxide efficacy follows the order 2,2,6,6-tetramethyl-piperidine-N-oxyl (TPO)>4-OH-TPO>3-carbamoyl proxyl>4-oxo-TPO, which correlates with the order of the rate constants of nitroxide reactions with compounds I, II, and III. Nitroxide catalytically protects HRP against inactivation induced by H 2 O 2 while modulating its catalase-like activity. The protective role of nitroxide at μM concentrations is attributed to its efficient oxidation by P940, which is the precursor of the inactivated form P670. Modeling the dismutation kinetics in the presence of nitroxide adequately fits the experimental data. In the absence of nitroxide the simulation fits the observed kinetics only if it does not include the formation of a Michaelis-Menten complex. Nitroxides catalytically protect heme proteins against inactivation induced by H 2 O 2 revealing an additional role played by nitroxide antioxidants in vivo. Copyright © 2017 Elsevier B.V. All rights reserved.

Pet imaging of human pituitary 5-HT2 receptors with F-18 setoperone

Energy Technology Data Exchange (ETDEWEB)

Fischman, A.J.; Bonab, A.A.; Babich, J.W. [Massachusetts General Hospital, Boston, MA (United States)] [and others

1995-05-01

Serotonin (5-HT) receptors play an important role in the regulation of pituitary function. In particular, 5HT agonists stimulate ACTH, {beta}-endorphin, prolactin and growth hormone secretion but inhibit TSH release. 5-HT binding sites have been identified by autoradiographic studies of rat and human pituitary. In the present investigation, we used PET with F-18 setoperone to image 5-HT2 receptors in normal humans. Setoperone, a piperidine derivative with potent 5-HT2 receptor blocking properties was labelled with F-18 by nucleophilic substitution on the nitro derivative. After HPLC purification, specific activity was between 10,000 and 15,000 mCi/{mu} mole and radiochemical purity was >98%. Six healthy male volunteers were injected with 5-7 mCi of F-18. Setoperone and serial PET images and arterial blood samples were collected over 2 hrs. Specific binding to 5-HT2 receptors in the frontal cortex (FC), striatum (ST) and pituitary (P) was quantitated using the cerebellum (C) as reference. The tracer showed clear retention in FC, ST and P (known to contain a high density of 5-HT2 receptors) relative to C (known to be devoid of 5-HT2 receptors). In all subjects, FC/C, ST/C and P/C ratios increased during the first hr. and remained stable thereafter. For FC and ST, the ratios reached similar values; 3.92{plus_minus}0.73 and 3.53{plus_minus}0.32. For pituitary, a significantly higher ratio, was measured at all times; 6.53{plus_minus}1.82 (p<0.01). These results indicate that F-18 setoperone is an effective PET radiopharmaceutical for imaging 5-HT2 receptors in the human pituitary. Future applications of this agent could provide important new insights into neuroendocrine function.

Interactions of CB1 and mGlu5 receptor antagonists in food intake, anxiety and memory models in rats.

Science.gov (United States)

Varga, Balázs; Kassai, Ferenc; Gyertyán, István

2012-12-01

CB(1) receptor antagonists proved to be effective anti-obesity drugs, however, their depressive and anxiogenic effects became also evident. Finding solution to overcome these psychiatric side effects is still in focus of research. Based on the available clinical and preclinical results we hypothesized that the combination of CB(1) and mGlu(5) receptor antagonisms may result in a pharmacological intervention, where the anxiolytic mGlu(5) receptor inhibition may counteract the anxiogenic psychiatric side effects of CB(1) antagonism, while CB(1) antagonism may ameliorate the memory impairing effect of mGlu(5) receptor antagonism. Further, the two components will synergistically interact in blocking food-intake and reducing obesity. For testing the interaction of mGlu(5) and CB(1) receptor antagonism MTEP [3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pridine; SIB-1757, 6-methyl-2-(phenylazo)-3-pyridinol)] (mGlu(5) antagonist) and rimonabant [(5-(4-Chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide)hydrochloride] (CB(1) antagonist) were used. All experiments were carried out in rats. Effects of the compounds on anxiety were tested in two foot shock induced ultrasonic vocalization paradigms, appetite suppression was assessed in the food intake test, while memory effects were tested in a context conditioned ultrasonic vocalization setup. MTEP abolished the anxiogenic effect of rimonabant, while there was an additive cooperation in suppressing appetite. However, rimonabant did not ameliorate the memory impairing effect of MTEP. By combination of CB(1) and mGluR5 antagonism, anxiety related side effects might be attenuated, appetite suppression maintained, nevertheless, the possible emergence of unwanted memory impairments can overshadow its therapeutic success. Copyright © 2012 Elsevier Inc. All rights reserved.

Pharmacological characterization of LY233053: A structurally novel tetrazole-substituted competitive N-methyl-D-aspartic acid antagonist with a short duration of action

International Nuclear Information System (INIS)

Schoepp, D.D.; Ornstein, P.L.; Leander, J.D.; Lodge, D.; Salhoff, C.R.; Zeman, S.; Zimmerman, D.M.

1990-01-01

This study reports the activity of a structurally novel excitatory amino acid receptor antagonist, LY233053 [cis-(+-)-4-[(2H-tetrazol-5-yl)methyl]piperidine-2-carboxylic acid], the first tetrazole-containing competitive N-methyl-D-aspartic acid (NMDA) antagonist. LY233053 potently inhibited NMDA receptor binding to rat brain membranes as shown by the in vitro displacement of [3H] CGS19755 (IC50 = 107 +/- 7 nM). No appreciable affinity in [3H]alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) or [3H]kainate binding assays was observed (IC50 values greater than 10,000 nM). In vitro NMDA receptor antagonist activity was further demonstrated by selective inhibition of NMDA-induced depolarization in cortical wedges (IC50 = 4.2 +/- 0.4 microM vs. 40 microM NMDA). LY233053 was effective after in vivo systemic administration in a number of animal models. In neonatal rats, LY233053 selectively blocked NMDA-induced convulsions (ED50 = 14.5 mg/kg i.p.) with a relatively short duration of action (2-4 hr). In pigeons, LY233053 potently antagonized (ED50 = 1.3 mg/kg i.m.) the behavioral suppressant effects of 10 mg/kg of NMDA. However, a dose of 160 mg/kg, i.m., was required to produce phencyclidine-like catalepsy in pigeons. In mice, LY233053 protected against maximal electroshock-induced seizures at lower doses (ED50 = 19.9 mg/kg i.p.) than those that impaired horizontal screen performance (ED50 = 40.9 mg/kg i.p.). Cholinergic and GABAergic neuronal degenerations after striatal infusion of NMDA were prevented by single or multiple i.p. doses of LY233053. In summary, the antagonist activity of LY233053 after systemic administration demonstrates potential therapeutic value in conditions of neuronal cell loss due to NMDA receptor excitotoxicity

Presynaptic selectivity of a ligand for serotonin 1A receptors revealed by in vivo PET assays of rat brain.

Science.gov (United States)

Saijo, Takeaki; Maeda, Jun; Okauchi, Takashi; Maeda, Jun-ichi; Morio, Yasunori; Kuwahara, Yasuhiro; Suzuki, Masayuki; Goto, Nobuharu; Fukumura, Toshimitsu; Suhara, Tetsuya; Higuchi, Makoto

2012-01-01

A novel investigational antidepressant with high affinity for the serotonin transporter and the serotonin 1A (5-HT(1A)) receptor, called Wf-516 (structural formula: (2S)-1-[4-(3,4-dichlorophenyl)piperidin-1-yl]-3-[2-(5-methyl-1,3,4-oxadiazol-2-yl)benzo[b]furan-4-yloxy]propan-2-ol monohydrochloride), has been found to exert a rapid therapeutic effect, although the mechanistic basis for this potential advantage remains undetermined. We comparatively investigated the pharmacokinetics and pharmacodynamics of Wf-516 and pindolol by positron emission tomographic (PET) and autoradiographic assays of rat brains in order to elucidate their molecular interactions with presynaptic and postsynaptic 5-HT(1A) receptors. In contrast to the full receptor occupancy by pindolol in PET measurements, the binding of Wf-516 to 5-HT(1A) receptors displayed limited capacity, with relatively high receptor occupancy being achieved in regions predominantly containing presynaptic receptors. This selectivity was further proven by PET scans of neurotoxicant-treated rats deficient in presynaptic 5-HT(1A) receptors. In addition, [(35)S]guanosine 5'-O-[γ-thio]triphosphate autoradiography indicated a partial agonistic ability of Wf-516 for 5-HT(1A) receptors. This finding has lent support to reports that diverse partial agonists for 5-HT(1A) receptors exert high sensitivity for presynaptic components. Thus, the present PET data suggest a relatively high capacity of presynaptic binding sites for partial agonists. Since our in vitro and ex vivo autoradiographies failed to illustrate these distinct features of Wf-516, in vivo PET imaging is considered to be, thus far, the sole method capable of pharmacokinetically demonstrating the unique actions of Wf-516 and similar new-generation antidepressants.

Impact on creatinine renal clearance by the interplay of multiple renal transporters: a case study with INCB039110.

Science.gov (United States)

Zhang, Yan; Warren, Mark S; Zhang, Xuexiang; Diamond, Sharon; Williams, Bill; Punwani, Naresh; Huang, Jane; Huang, Yong; Yeleswaram, Swamy

2015-04-01

Serum creatinine is commonly used as a marker of renal function, but increases in serum creatinine might not represent changes in glomerular filtration rate (GFR). INCB039110 (2-(3-(4-(7H-pyrrolo[2,3-day]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile) is an inhibitor of the Janus kinases (JAKs) with selectivity for JAK1. In a phase 1 study, a modest and reversible increase in serum creatinine was observed after treatment with INCB039110. However, a dedicated renal function study with INCB039110, assessed by iohexol plasma clearance, conducted in healthy volunteers indicated no change in GFR. In vitro studies were therefore conducted to investigate the interaction of INCB039110 with five transporters that are likely involved in the renal clearance of creatinine. Cell systems expressing individual or multiple transporters were used, including a novel quintuple-transporter model OAT2/OCT2/OCT3/MATE1/MATE2-K. INCB039110 potently inhibited OCT2-mediated uptake of creatinine as well as MATE1-/MATE2-K-mediated efflux of creatinine. Given the interactions of INCB039110 with multiple transporters affecting creatinine uptake and efflux, an integrated system expressing all five transporters was sought; in that system, INCB039110 caused a dose-dependent decrease in transcellular transport of creatinine with weaker net inhibition compared with the effects on individual transporters. In summary, a molecular mechanism for the increase in serum creatinine by INCB039110 has been established. These studies also underline the limitations of using serum creatinine as a marker of renal function. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

Professor Eugen Cerkovnikov (1904-1985): the founder of the Chemical and Biochemical Institute of the Rijeka University School of Medicine.

Science.gov (United States)

Milin, Cedomila

2008-01-01

Professor Eugen Cerkovnikov, PhD (Kamenska, Russia, 1904- Rijeka, Croatia 1985) graduated in chemical technology from the Faculty of Engineering in Zagreb in 1929. His first job was at the School of Medicine in Paris in 1930, and then he moved to Zagreb to the Department of Organic Chemistry of the Faculty of Engineering run by our Nobel Prize winner Vladimir Prelog (1935-1938). There he took his PhD degree with a dissertation on piperidine gamma derivatives. From 1938 to 1947 he was a research associate at an institute established by the pharmaceutical company Kastel (later Pliva). This is when he became a lecturer at the Faculty of Pharmacy in Zagreb and the first director of the Institute of Organic Chemistry, established in 1946/47. In 1948 he became reader, and in 1956 (full) professor. In 1957 he moved to the newly established School of Medicine in Rijeka, and set up the Institute of Chemistry and Biochemistry. He ran the Institute until retirement in 1975. He was the second dean of the Rijeka University School of Medicine and a pioneer of quantum chemistry and medical cybernetics in undergraduate and (post)graduate courses. His scientific work consists of over 200 papers published at home and abroad, 60 professional papers, 20 book reviews, three works of translation, and 27 volumes of lecture notes. In 1958, professor Cerkovnikov established the Croatian Chemical Society and the Rijeka and Istria branches of the nation's Association of Chemists and Chemical Engineers, chairing them until 1974. In addition, he was one of the founding fathers, and the first chair of the Health Culture Studies Association in Rijeka (that preceded today's Croatian Scientific Society for the History of Health Culture), established in 1965.

Preclinical acute toxicity studies and rodent-based dosimetry estimates of the novel sigma-1 receptor radiotracer [{sup 18}F]FPS

Energy Technology Data Exchange (ETDEWEB)

Waterhouse, Rikki N. E-mail: rn27@columbia.edu; Stabin, Michael G.; Page, John G

2003-05-01

[{sup 18}F]1-(Fluoropropyl)-4-[(4-cyanophenoxy)methyl]piperidine ([{sup 18}F]FPS) is a novel high affinity (KD = 0.5 nM) sigma receptor radioligand that exhibits saturable and selective in vivo binding to sigma receptors in rats, mice and non-human primates. In order to support an IND application for the characterization of [{sup 18}F]FPS through PET imaging studies in humans, single organ and whole body radiation adsorbed doses associated with [{sup 18}F]FPS injection were estimated from distribution data obtained in rats. In addition, acute toxicity studies were conducted in rats and rabbits and limited toxicity analyses were performed in dogs. Radiation dosimetry estimates obtained using rat biodistribution analysis of [{sup 18}F]FPS suggest that most organs would receive around 0.012-0.015 mGy/MBq. The adrenal glands, brain, kidneys, lungs, and spleen would receive slightly higher doses (0.02-0.03 mGy/MBq). The adrenal glands were identified as the organs receiving the greatest adsorbed radiation dose. The total exposure resulting from a 5 mCi administration of [{sup 18}F]FPS is well below the FDA defined limits for yearly cumulative and per study exposures to research participants. Extended acute toxicity studies in rats and rabbits, and limited acute toxicity studies in beagle dogs suggest at least a 175-fold safety margin in humans at a mass dose limit of 2.8 {mu}g per intravenous injection. This estimate is based on the measured no observable effect doses (in mg/m{sup 2}) in these species. These data support the expectation that [{sup 18}F]FPS will be safe for use in human PET imaging studies at a maximum administration of 5 mCi and a mass dose equal to or less than 2.8 {mu}g FPS per injection.

Radiosynthesis and biodistribution of a histamine H{sub 3} receptor antagonist 4-[3-(4-piperidin-1-yl-but-1-ynyl)-[{sup 11}C]benzyl]-morpholine: evaluation of a potential PET ligand

Energy Technology Data Exchange (ETDEWEB)

Airaksinen, Anu J. [Department of Nuclear Medicine and PET Research, Location Radionuclide Center, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam (Netherlands); Jablonowski, Jill A. [Johnson and Johnson Pharmaceutical Research and Development LLC, San Diego, CA 92121 (United States); Mey, Margreet van der [Department of Nuclear Medicine and PET Research, Location Radionuclide Center, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam (Netherlands); Barbier, Ann J. [Johnson and Johnson Pharmaceutical Research and Development LLC, San Diego, CA 92121 (United States); Klok, Rob P. [Department of Nuclear Medicine and PET Research, Location Radionuclide Center, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam (Netherlands); Verbeek, Joost [Department of Nuclear Medicine and PET Research, Location Radionuclide Center, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam (Netherlands); Schuit, Robert [Department of Nuclear Medicine and PET Research, Location Radionuclide Center, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam (Netherlands); Herscheid, Jacobus D.M. [Department of Nuclear Medicine and PET Research, Location Radionuclide Center, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam (Netherlands); Leysen, Josee E. [Department of Nuclear Medicine and PET Research, Location Radionuclide Center, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam (Netherlands); Carruthers, Nicholas I. [Johnson and Johnson Pharmaceutical Research and Development LLC, San Diego, CA 92121 (United States); Lammertsma, Adriaan A. [Department of Nuclear Medicine and PET Research, Location Radionuclide Center, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam (Netherlands); Windhorst, Albert D. [Department of Nuclear Medicine and PET Research, Location Radionuclide Center, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam (Netherlands)]. E-mail: bwindhorst@rnc.vu.nl

2006-08-15

The potent histamine H{sub 3} receptor antagonist JNJ-10181457 () was successfully labeled with {sup 11}C in a novel one-pot reaction sequence, with high chemical yield (decay-corrected yield, 28{+-}8%) and high specific radioactivity (56{+-}26 GBq/{mu}mol). The binding of [{sup 11}C] to H{sub 3} receptors was studied in vitro in rat brain and in vivo in rats and mice. The in vitro binding of [{sup 11}C] in rat coronal brain slices showed high binding in the striatum, and this binding was blocked by histamine and by two known H{sub 3} antagonists, JNJ-5207852 () and unlabeled Compound (), in a concentration-dependent manner. The biodistribution of [{sup 11}C] in rats was measured at 5, 10, 30 and 60 min. The uptake of [{sup 11}C] in regions rich in H{sub 3} receptors was highest at 30 min, giving 0.98%, 1.41%, 1.28% and 1.72% dose/g for the olfactory bulb, hippocampus, striatum and cerebral cortex, respectively. However, the binding of [{sup 11}C] in the rat brain could not be blocked by pretreatment with either Compound () (30 min or 24 h pretreatment) or cold Compound () (30-min pretreatment). The biodistribution of [{sup 11}C] in a second species (Balb/c mice) showed a higher overall uptake of the radioligand with an average brain uptake of 8.9% dose/g. In C57BL/6-H{sub 3}(-/-) knockout mice, a higher brain uptake was also observed. Analyses of metabolites and plasma protein binding were also undertaken. It appeared that [{sup 11}C] could not specifically label H{sub 3} receptors in rodent brain in vivo. Possible causes are discussed.

Heterogeneous binding of sigma radioligands in the rat brain and liver

International Nuclear Information System (INIS)

Ross, S.B.

1991-01-01

The binding of four sigma receptor ligands, 3 H-(+)-N-allyl-N-normetazocine ( 3 H-(+)-SKF 10,047), 3 H-(+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ( 3 H-(+)-3-PPP), 3 H-haloperidol and 3 H-N,N'-di(o-totyl)guanidine ( 3 H-DTG), and the cytochrome P450IID6 ligand and dopamine uptake inhibitor 3 H-1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine ( 3 H-GBR 12935) to membranal preparations of rat liver or whole rat brain was examined regarding kinetical properties and inhibition by various compounds with affinity for sigma binding sites or cytochrome P-450. In rat brain the density of binding sites was increased in order (+)-SKF 10,047 3 H-(+)-SKF 10,047 there were quite marked differences between the ligands studied. Multiple binding sites were also indicated by the low Hill coefficients found for most of the compounds studied. It was found that the cytochrome P-450 inhibitor proadifen (SKF 525A), like haloperidol, was a potent inhibitor of the binding of 3 H-(+)-SKF 10,047, 3 H-(+)-3-PPP and 3 H-haloperidol to the liver and brain preparations, less active in inhibiting the binding of 3 H-DTG and least effective on the binding of 3 H-GBR 12935. Another cytochrome P-450 inhibitor, L-lobeline, was particularly potent in inhibiting the binding of 3 H-DTG but was also quite potent inhibitor of the binding of the other sigma ligands. It was less potent in inhibiting the binding of 3 H-GBR 12935. The binding of the latter ligand was potently inhibited by the analogous compound GBR 12909 but of the other compounds examined only L-lobeline, proadifen, haloperidol, DTG and (+)-3-PPP had IC50 values below 10 μM. The possibility that the sigma binding sites are identical with some subforms of cytochrome P-450 is discussed. (author)

R+-methanandamide inhibits tracheal response to endogenously released acetylcholine via capsazepine-sensitive receptors.

Science.gov (United States)

Nieri, Paola; Martinotti, Enrica; Testai, Lara; Adinolfi, Barbara; Calderone, Vincenzo; Breschi, Maria Cristina

2003-01-10

The effects of cannabinoid drugs on the cholinergic response evoked by electrical field stimulation (0.2 ms pulse width, 20 V amplitude, 10 Hz, 7.5 s train duration) in guinea-pig tracheal preparations were investigated. The stable analogue of the endocannabinoid anandamide, R(+)-methanandamide (10(-7)-10(-4) M), produced a dose-dependent inhibition (up to 27+/-5% of control) of electrical field stimulation-mediated atropine-sensitive response. This effect was not blocked by the selective cannabinoid CB(1) receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3 carboxamide hydrochloride (SR 141716A; 10(-6) M), and was not reproduced with the cannabinoid CB(1)/CB(2) receptor agonist R(+)-[2,3-dihydro-5-methyl-[(morpholinyl)methyl]pyrrolo [1,2,3-de]-1,4-benzoxazin-6-yl]-(1-naphthalenyl)methanone mesylate) (WIN 55,212-2; 10(-8)-10(-5) M) or the cannabinoid CB(2) receptor selective agonist 1-propyl-2-methyl-3-(1-naphthoyl)indole (JWH-015; 10(-8)-10(-5) M); it was, on the contrary, antagonized by the vanilloid antagonist 2-[2-(4-chlorophenyl)ethyl-amino-thiocarbonyl]-7,8-dihydroxy-2,3,4,5-tetrahydro-1H-2 benzazepine (capsazepine; 10(-6) M). At the postjunctional level, neither R(+)-methanandamide nor WIN 55,212-2 nor JWH-015 did affect tracheal contractions induced by exogenous acetylcholine (10(-6) M). An inhibitory vanilloid receptor-mediated effect on the cholinergic response evoked by electrical stimulation was confirmed with the vanilloid agonist capsaicin, at doses (3-6 x 10(-8) M) which poorly influenced the basal smooth muscle tone of trachea. In conclusion, our data indicate that in guinea-pig trachea (a) neither CB(1) nor CB(2) cannabinoid receptor-mediated modulation of acetylcholine release occurs; (b) vanilloid VR1-like receptors appear involved in R(+)-methanandamide inhibitory activity on the cholinergic response to electrical field stimulation.

New approach for determination of the degradation products of fenspiride hydrochloride found in oral liquid formulations.

Science.gov (United States)

Cioroiu, Bogdan I; Caba, Ioana C; Prisăcaru, Irina; Cioroiu, Mona E; Lazar, Mihai I; Niculaua, Marius

2018-05-01

Fenspiride hydrochloride (FNS) is used in treating chronic inflammatory diseases, most commonly as a liquid oral solution. FNS produces degradation products along with fenspiride N-oxide (FNO) and 1-phenylethyl-4-hydroxy-4-aminomethyl piperidine hydrochloride (PHAP). We aimed to develop and validate a chromatographic method in order to identify the main degradation products in the presence of other compounds from a liquid preparation. The method used a dual gradient using two buffer solutions: the first with pH 4.5 (buffer 1, pH 4.5-MeOH 90:10%, v/v) and the second with pH 2.9 (buffer 2, pH 2.9-acetronitrile-methanol, 65:15:10%, v/v/v). As mentioned, there was a modification of the organic mixture, starting with 10% methanol and ending with a mixture of acetonitrile-methanol (15:10%, v/v). The flow-rate was 1.5 mL/min. According to the elution program, experimental conditions started with 100% solution S1, which decreased to 0% and, simultaneously, solution S2 increased to 100% during the first 10 min and was maintained for a further 5 min. After 15 min, initial conditions were re-established. The linearity interval was 0.5-2 μg/mL and the minimum correlation coefficient was 0.999. The recovery factor was 100.47-103.17% and the limit of quantification was 0.19-0.332 μg/mL. Intra-day maximum precision was 4.08% for FNS and 2.65% for PHAP. This double-gradient mobile phase produced good specificity in relation to the degradation products of FNS and other constituents of the oral liquid formulation. Forced degradation studies revealed other related substances that were confirmed in mass balance analyses. Degradation products were confirmed in acidic, basic and oxidative media. Copyright © 2017 John Wiley & Sons, Ltd.

Synthesis and characterization of CdS nanocrystallites and OMWCNT-supported cadmium sulfide composite and their photocatalytic activity under visible light irradiation

International Nuclear Information System (INIS)

Pawar, Amol S.; Garje, Shivram S.; Revaprasadu, Neerish

2016-01-01

CdS nanocrystallites and CdS- oxidized multiwalled carbon nanotubes (OMWCNT) composite were prepared by the solvothermal decomposition of a single-source molecular precursor, [Cd(pip.dtc) 2 ] (pip.dtc = piperidine dithiocarbamate) in the presence of ethylene glycol. The as prepared CdS nanocrystallites and CdS-OMWCNT composite were characterized by powder X-ray diffraction (XRD), scanning electron microscopy (SEM), energy dispersive X-ray analysis (EDX), transmission electron microscopy (TEM), UV-vis and Raman spectroscopy. Peak broadening in the XRD shows the formation of nanocrystalline CdS. TEM images of CdS nanocrystallites revealed the nearly spherical shape morphology of the particles, whereas, TEM images of composite showed the deposition of CdS nanocrystallites on the OMWCNT. EDX measurements matches with a 1:1 stoichiometry of Cd and S in CdS nanocrystallites, whereas, that of the composite showed the presence of Cd and S along with C. The vibrational properties of CdS nanocrystallites and their composite with OMWCNT were studied by Raman spectroscopy. Furthermore, the photocatalytic activity studies for the degradation of methylene blue under visible light irradiation using these materials were carried out. The surface area calculated using BET surface analyzer for CdS-OMWCNT composite (148.31 m 2 /g) was found to be more compared to bare CdS nanocrystallites (56.78 m 2 /g). The CdS-OMWCNT composite exhibited very good photocatalytic activity for the degradation of methylene blue under visible light irradiation which has been attributed to the increased surface area and synergistic effect in the composite compared to bare CdS nanocrystallites. - Highlights: • The carbon based nanocomposite of CdS (CdS-OMWCNT) have been prepared. • Simple solvothermal decomposition method has been used. • Single-source molecular precursor in presence of carbon nanotubes has been employed. • The photocatalytic activity of CdS NPs and CdS-OMWCNT composite have been

Evidence for a role of 5-HT2C receptors in the motor aspects of performance, but not the efficacy of food reinforcers, in a progressive ratio schedule.

Science.gov (United States)

Bezzina, G; Body, S; Cheung, T H C; Hampson, C L; Bradshaw, C M; Glennon, J C; Szabadi, E

2015-02-01

5-Hydroxytryptamine2C (5-HT2C) receptor agonists reduce the breakpoint in progressive ratio schedules of reinforcement, an effect that has been attributed to a decrease of the efficacy of positive reinforcers. However, a reduction of the breakpoint may also reflect motor impairment. Mathematical models can help to differentiate between these processes. The effects of the 5-HT2C receptor agonist Ro-600175 ((αS)-6-chloro-5-fluoro-α-methyl-1H-indole-1-ethanamine) and the non-selective 5-HT receptor agonist 1-(m-chlorophenyl)piperazine (mCPP) on rats' performance on a progressive ratio schedule maintained by food pellet reinforcers were assessed using a model derived from Killeen's Behav Brain Sci 17:105-172, 1994 general theory of schedule-controlled behaviour, 'mathematical principles of reinforcement'. Rats were trained under the progressive ratio schedule, and running and overall response rates in successive ratios were analysed using the model. The effects of the agonists on estimates of the model's parameters, and the sensitivity of these effects to selective antagonists, were examined. Ro-600175 and mCPP reduced the breakpoint. Neither agonist significantly affected a (the parameter expressing incentive value), but both agonists increased δ (the parameter expressing minimum response time). The effects of both agonists could be attenuated by the selective 5-HT2C receptor antagonist SB-242084 (6-chloro-5-methyl-N-{6-[(2-methylpyridin-3-yl)oxy]pyridin-3-yl}indoline-1-carboxamide). The effect of mCPP was not altered by isamoltane, a selective 5-HT1B receptor antagonist, or MDL-100907 ((±)2,3-dimethoxyphenyl-1-(2-(4-piperidine)methanol)), a selective 5-HT2A receptor antagonist. The results are consistent with the hypothesis that the effect of the 5-HT2C receptor agonists on progressive ratio schedule performance is mediated by an impairment of motor capacity rather than by a reduction of the incentive value of the food reinforcer.

The selective dopamine uptake inhibitor, D-84, suppresses cocaine self-administration, but does not occasion cocaine-like levels of generalization.

Science.gov (United States)

Batman, Angela M; Dutta, Aloke K; Reith, Maarten E A; Beardsley, Patrick M

2010-12-01

A successful replacement pharmacotherapy for treating cocaine dependency would likely reduce cocaine's abuse, support a low abuse liability, overlap cocaine's subjective effects, and have a long duration of action. Inhibitors with varying selectivity at the dopamine transporter (DAT) have approximated these properties. The objective of the present study was to characterize the behavioural effects of an extremely selective DAT inhibitor, (+) trans-4-(2-Benzhydryloxyethyl)-1-(4-fluorobenzyl) piperadin-3-ol (D-84), a 3-hydroxy substituted piperidine derivative of GBR-12935, for its cocaine-like discriminative stimulus effects, its effects on cocaine self-administration, and for its own self-administration. During cocaine discrimination tests, cocaine occasioned the 10 mg/kg cocaine training stimulus with an ED(50) value of 3.13 (1.54-6.34) mg/kg, and reduced response rates with an ED(50) value of 20.39 (7.24-57.44) mg/kg. D-84 incompletely generalized to the cocaine stimulus occasioning a maximal 76% cocaine-lever responding, while reducing response rates with lower potency than cocaine (ED(50)=30.94 (12.34-77.60) mg/kg). Pretreatment with D-84 (9.6-30.4 mg/kg) significantly (P<0.05) reduced cocaine intake at 17.1 mg/kg D-84 when cocaine was self-administered at 0.5 mg/kg/infusion, and at 30.4 mg/kg D-84 when cocaine was self-administered at 0.1, 0.5 .and 1.0 mg/kg/infusion. During self-administration tests with D-84 (0.1-1 mg/kg/infusion), numbers of infusions significantly exceeded vehicle levels at 0.3 mg/kg/infusion. These results show that D-84 pretreatment can decrease cocaine intake especially when high doses of cocaine are being self-administered. This observation, combined with its incomplete generalization to the cocaine discriminative stimulus and its reported long duration of action, provides a profile consistent with a potential replacement therapy for treating cocaine-abusing patients. Copyright © 2010 Elsevier B.V. All rights reserved.

The efficacy of repellents against Aedes, Anopheles, Culex and Ixodes spp. - a literature review.

Science.gov (United States)

Lupi, Eleonora; Hatz, Christoph; Schlagenhauf, Patricia

2013-01-01

Travellers are confronted with a variety of vector-borne threats. Is one type of repellent effective against all biting vectors? The aim of this review is to examine the literature, up to December 31st, 2012, regarding repellent efficacy. We searched PubMed for relevant papers. Repellents of interest were DEET, Icaridin as well as other piperidine-derived products (SS220), Insect Repellent (IR) 3535 (ethyl-butylacetyl-amino-propionat, EBAAP) and plant-derived products, including Citriodora (para-menthane-3,8-diol). As vectors, we considered the mosquito species Anopheles, Aedes and Culex as well as the tick species Ixodes. We selected only studies evaluating the protective efficacy of repellents on human skin. We reviewed a total of 102 publications. Repellents were evaluated regarding complete protection time or as percentage efficacy [%] in a time interval. We found no standardized study for tick bite prevention. Regarding Aedes, DEET at concentration of 20% or more, showed the best efficacy providing up to 10 h protection. Citriodora repellency against this mosquito genus was lower compared to the other products. Also between subspecies a difference could be observed: Ae. aegypti proved more difficult to repel than Ae. Albopictus. Fewer studies have been conducted on mosquito species Anopheles and Culex. The repellency profile against Anopheles species was similar for the four principal repellents of interest, providing on average 4-10 h of protection. Culex mosquitoes are easier to repel and all four repellents provided good protection. Few studies have been conducted on the tick species Ixodes. According to our results, the longest protection against Ixodes scapularis was provided by repellents containing IR3535, while DEET and commercial products containing Icaridin or PMD showed a better response than IR3535 against Ixodes ricinus. Many plant-based repellents provide only short duration protection. Adding vanillin 5% to plant-based repellents and to DEET

Moving Synergistically Acting Drug Combinations to the Clinic by Comparing Sequential versus Simultaneous Drug Administrations.

Science.gov (United States)

Dinavahi, Saketh S; Noory, Mohammad A; Gowda, Raghavendra; Drabick, Joseph J; Berg, Arthur; Neves, Rogerio I; Robertson, Gavin P

2018-03-01

Drug combinations acting synergistically to kill cancer cells have become increasingly important in melanoma as an approach to manage the recurrent resistant disease. Protein kinase B (AKT) is a major target in this disease but its inhibitors are not effective clinically, which is a major concern. Targeting AKT in combination with WEE1 (mitotic inhibitor kinase) seems to have potential to make AKT-based therapeutics effective clinically. Since agents targeting AKT and WEE1 have been tested individually in the clinic, the quickest way to move the drug combination to patients would be to combine these agents sequentially, enabling the use of existing phase I clinical trial toxicity data. Therefore, a rapid preclinical approach is needed to evaluate whether simultaneous or sequential drug treatment has maximal therapeutic efficacy, which is based on a mechanistic rationale. To develop this approach, melanoma cell lines were treated with AKT inhibitor AZD5363 [4-amino- N -[(1 S )-1-(4-chlorophenyl)-3-hydroxypropyl]-1-(7 H -pyrrolo[2,3- d ]pyrimidin-4-yl)piperidine-4-carboxamide] and WEE1 inhibitor AZD1775 [2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1 H -pyrazolo[3,4- d ]pyrimidin-3(2 H )-one] using simultaneous and sequential dosing schedules. Simultaneous treatment synergistically reduced melanoma cell survival and tumor growth. In contrast, sequential treatment was antagonistic and had a minimal tumor inhibitory effect compared with individual agents. Mechanistically, simultaneous targeting of AKT and WEE1 enhanced deregulation of the cell cycle and DNA damage repair pathways by modulating transcription factors p53 and forkhead box M1, which was not observed with sequential treatment. Thus, this study identifies a rapid approach to assess the drug combinations with a mechanistic basis for selection, which suggests that combining AKT and WEE1 inhibitors is needed for maximal efficacy. Copyright © 2018 by The American

Tensor algebra-based geometric methodology to codify central chirality on organic molecules.

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García-Jacas, C R; Marrero-Ponce, Y; Hernández-Ortega, T; Martinez-Mayorga, K; Cabrera-Leyva, L; Ledesma-Romero, J C; Aguilera-Fernández, I; Rodríguez-León, A R

2017-06-01

A novel mathematical procedure to codify chiral features of organic molecules in the QuBiLS-MIDAS framework is introduced. This procedure constitutes a generalization to that commonly used to date, where the values 1 and -1 (correction factor) are employed to weight the molecular vectors when each atom is labelled as R (rectus) or S (sinister) according to the Cahn-Ingold-Prelog rules. Therefore, values in the range [Formula: see text] with steps equal to 0.25 may be accounted for. The atoms labelled R or S can have negative and positive values assigned (e.g. -3 for an R atom and 1 for an S atom, or vice versa), opposed values (e.g. -3 for an R atom and 3 for an S atom, or vice versa), positive values (e.g. 3 for an R atom and 1 for an S atom) or negative values (e.g. -3 for an R atom and -1 for an S atom). These proposed Chiral QuBiLS-MIDAS 3D-MDs are real numbers, non-symmetric and reduced to 'classical' (non-chiral) QuBiLS-MIDAS 3D-MDs when symmetry is not codified (correction factor equal to zero). In this report, only the factors with opposed values were considered with the purpose of demonstrating the feasibility of this proposal. From QSAR modelling carried out on four chemical datasets (Cramer's steroids, fenoterol stereoisomer derivatives, N-alkylated 3-(3-hydroxyphenyl)-piperidines, and perindoprilat stereoisomers), it was demonstrated that the use of several correction factors contributes to the building of models with greater robustness and predictive ability than those reported in the literature, as well as with respect to the models exclusively developed with QuBiLS-MIDAS 3D-MDs based on the factor 1 | -1. In conclusion, it can be stated that this novel strategy constitutes a suitable alternative to computed chirality-based descriptors, contributing to the development of good models to predict properties depending on symmetry.

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

Science.gov (United States)

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

Full Fatty Acid Amide Hydrolase Inhibition Combined with Partial Monoacylglycerol Lipase Inhibition: Augmented and Sustained Antinociceptive Effects with Reduced Cannabimimetic Side Effects in Mice.

Science.gov (United States)

Ghosh, Sudeshna; Kinsey, Steven G; Liu, Qing-Song; Hruba, Lenka; McMahon, Lance R; Grim, Travis W; Merritt, Christina R; Wise, Laura E; Abdullah, Rehab A; Selley, Dana E; Sim-Selley, Laura J; Cravatt, Benjamin F; Lichtman, Aron H

2015-08-01

Inhibition of fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MAGL), the primary hydrolytic enzymes for the respective endocannabinoids N-arachidonoylethanolamine (AEA) and 2-arachidonylglycerol (2-AG), produces antinociception but with minimal cannabimimetic side effects. Although selective inhibitors of either enzyme often show partial efficacy in various nociceptive models, their combined blockade elicits augmented antinociceptive effects, but side effects emerge. Moreover, complete and prolonged MAGL blockade leads to cannabinoid receptor type 1 (CB1) receptor functional tolerance, which represents another challenge in this potential therapeutic strategy. Therefore, the present study tested whether full FAAH inhibition combined with partial MAGL inhibition would produce sustained antinociceptive effects with minimal cannabimimetic side effects. Accordingly, we tested a high dose of the FAAH inhibitor PF-3845 (N-​3-​pyridinyl-​4-​[[3-​[[5-​(trifluoromethyl)-​2-​pyridinyl]oxy]phenyl]methyl]-​1-​piperidinecarboxamide; 10 mg/kg) given in combination with a low dose of the MAGL inhibitor JZL184 [4-nitrophenyl 4-(dibenzo[d][1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate] (4 mg/kg) in mouse models of inflammatory and neuropathic pain. This combination of inhibitors elicited profound increases in brain AEA levels (>10-fold) but only 2- to 3-fold increases in brain 2-AG levels. This combination produced significantly greater antinociceptive effects than single enzyme inhibition and did not elicit common cannabimimetic effects (e.g., catalepsy, hypomotility, hypothermia, and substitution for Δ(9)-tetrahydrocannabinol in the drug-discrimination assay), although these side effects emerged with high-dose JZL184 (i.e., 100 mg/kg). Finally, repeated administration of this combination did not lead to tolerance to its antiallodynic actions in the carrageenan assay or CB1 receptor functional tolerance. Thus, full FAAH inhibition

Recognition and repair of 2-aminofluorene- and 2-(acetylamino)fluorene-DNA adducts by UVRABC nuclease

International Nuclear Information System (INIS)

Pierce, J.R.; Case, R.; Tang, Moonshong

1989-01-01

Recognition of damage induced by N-hydroxy-2-aminofluorene (N-OH-AF) and N-acetoxy-2-(acetylamino)fluorene (NAAAF) in both φX174 RFI supercoiled DNA and a linear DNA fragment by purified UVRA, UVRB, and UVRC proteins was investigated. The authors have previously demonstrated that N-OH-AF and NAAAF treatments produce N-(deoxyguanosin-8-yl)-2-aminofluorene (dG-C8-AF) and N-(deoxyguanosin-8-yl)-2-(acetylamino)fluorene (dG-C8-AAF), respectively, in DNA. Using a piperidine cleavage method and DNA sequence analysis, they have found that all guanine residues can be modified by N-OH-AF and NAAAF. These two kinds of adducts have different impacts on the DNA helix structure; while dG-C8-AF maintains the anti configuration, dG-C8-AAF is in the syn form. φX174 RF DNA-Escherichia coli transfection results indicate that while the uvrA, uvrB, and uvrC gene products are needed to repair dG-C8-AAF, the uvrC, but not the uvrA or uvrB gene products, is needed for repair of dG-C8-Af. However, they have found that in vitro the UVRA, UVRB, and UVRC proteins must work in concert to nick both dG-C8-AF and dG-C8-AAF. In general, the reactions of UVRABC nuclease toward dG-C8-AF are similar to those toward dG-C8-AAF; it incises seven to eight nucleotides from the 5' side and three to four nucleotides from the 3' side of the DNA adduct. Evidence is presented to suggest that hydrolysis on the 3' and 5' sides of the damaged base by UVRABC nuclease is not simultaneous and that at least occasionally hydrolysis occurs only on the 3' side or on the 5' side of the damage site. The possible mechanisms of UVRABC nuclease incision for AF-DNA are discussed

Cooperative electrocatalytic alcohol oxidation with electron-proton-transfer mediators

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Badalyan, Artavazd; Stahl, Shannon S.

2016-07-01

The electrochemical oxidation of alcohols is a major focus of energy and chemical conversion efforts, with potential applications ranging from fuel cells to biomass utilization and fine-chemical synthesis. Small-molecule electrocatalysts for processes of this type are promising targets for further development, as demonstrated by recent advances in nickel catalysts for electrochemical production and oxidation of hydrogen. Complexes with tethered amines that resemble the active site of hydrogenases have been shown both to catalyse hydrogen production (from protons and electrons) with rates far exceeding those of such enzymes and to mediate reversible electrocatalytic hydrogen production and oxidation with enzyme-like performance. Progress in electrocatalytic alcohol oxidation has been more modest. Nickel complexes similar to those used for hydrogen oxidation have been shown to mediate efficient electrochemical oxidation of benzyl alcohol, with a turnover frequency of 2.1 per second. These compounds exhibit poor reactivity with ethanol and methanol, however. Organic nitroxyls, such as TEMPO (2,2,6,6-tetramethyl-1-piperidine N-oxyl), are the most widely studied electrocatalysts for alcohol oxidation. These catalysts exhibit good activity (1-2 turnovers per second) with a wide range of alcohols and have great promise for electro-organic synthesis. Their use in energy-conversion applications, however, is limited by the high electrode potentials required to generate the reactive oxoammonium species. Here we report (2,2‧-bipyridine)Cu/nitroxyl co-catalyst systems for electrochemical alcohol oxidation that proceed with much faster rates, while operating at an electrode potential a half-volt lower than that used for the TEMPO-only process. The (2,2‧-bipyridine)Cu(II) and TEMPO redox partners exhibit cooperative reactivity and exploit the low-potential, proton-coupled TEMPO/TEMPOH redox process rather than the high-potential TEMPO/TEMPO+ process. The results show how

In-vitro antimicrobial screening and molecular docking studies of synthesized 2-chloro-N-(4-phenylthiazol-2-ylacetamide derivatives

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Rahmat Ali

2015-01-01

Full Text Available Introduction: Glucosamine-6-phosphate (GlcN6P synthase biosynthetic pathway has been identified as potential targets for the development of new antimicrobial agents. Aim: A series of 2-chloro-N-(42-phenylthiazol-25-ylacetamide derivatives (3a-r was synthesized and evaluated their antimicrobial activity. Materials and Methods: The 2-chloro-N-(Para substituted phenylthiazol-25-yl acetamide (2a-c were synthesized by stirring intermediates (1a-c with 2-chloroacetylchloride in dichloromethane in the presence of K2CO3. The intermediate (2a-c were further reacted with different secondary amine such as pyrrolidine, N-methyl piperazine, N-ethyl piperazine, thiomorpholine, morpholine, piperidine etc in ethanol in presence of TEA Triethylamine (TEA to get desired compounds (3a-r. Compounds were characterized by a spectroscopic technique such as Fourier transform infraredFTIR, 1 H-NMR, 13 C-NMR, and mass spectrometry. The synthesized thiazole derivatives (3a-r were screened for anti-bacterial and anti-fungal activity against Escherichia coli, Staphylococcus aureus NCTC 6571, Pseudomonas aeruginosa NCTC 10662, CandidaC. albicans (MTCC-183, AspergillusA. niger (MTCC 281 NCTC 10418 and AspergillusA. flavus (MTCC 277. Result and Conclusion: The results of anti-bacterial screening revealed that among all the screened compounds, eight compounds viz. 3b, 3c, 3d, 3e, 3i, 3j, 3k, and 3p showed moderate to good anti-bacterial and antifungal activity having minimum inhibitory concentration (MIC between 6.25- and 25 µg/ml. While compound 3d showed the most promising antibacterial activity against E. coli and S. aureus, while the compound 3j showed promising antifungal activity with MIC value 6.25 µg/ml against C. albicans, A. niger and A. flavus. In addition, all these eight potential molecules were also examined for possible binding on enzyme GlcN6Pglucosamine-6-phosphate synthase by molecular docking studies on (PDB ID 1JXA.

Novel Profluorescent Nitroxides for Monitoring Alkyl Radical Reactions During Radiation Degradation

International Nuclear Information System (INIS)

George, G.

2006-01-01

Hindered amine stabilizers (HAS) are effective at retarding the photo-oxidative and high energy radiation degradation of PP and in certain circumstances, also thermo-oxidative degradation. The effectiveness of HAS as retarders of oxidation relies on the oxidation of the N-C bond by polymer hydroperoxide, ROOH, to form the nitroxyl group -NO which is the scavenger of polymer alkyl radicals, R. This reaction, which produces the alkoxy amine: -NO-R, must be competitive with the reaction of R with oxygen (which gives the chain-carrying peroxy radical, RO 2 ) if this stabilization mechanism is to be important in the inhibition of radiation-induced oxidative degradation of polyolefins by HAS. The rate of this reaction is high and in solution the rate coefficient is from 1 to 9x10 8 l mol - 1 s - 1. The efficient radical trapping by nitroxides has been widely employed in spin-trapping studies by electron spin resonance (esr) spectroscopy]. In addition to the hindered piperidine structure of commercial HAS, more rigid aromatic systems have been studied that are more stable to oxidative degradation and are more efficient at scavenging alkyl radicals. One such family is the iso-indoline nitroxide system, TMDBIO, shown below which, as it contains the phenanthrene fluorophore, is termed phenanthrene nitroxide. This nitroxide only becomes fluorescent when it reacts with alkyl radicals or is reduced and is termed profluorescent. TMDBIO has a vanishingly small fluorescence quantum yield (φ∼10 - 4) due to the enhanced intersystem crossing from the first excited singlet state to the ground state due to electron exchange interactions of the nitroxyl radical. When the nitroxide traps an alkyl radical, R, the resulting alkoxy amine is fluorescent (φ∼10 - 1) and the emission intensity is a measure of the number of reactions that have occurred. This property may be exploited by using quantitative fluorescence spectroscopy to follow the reaction of the nitroxide with alkyl radicals

Development and evaluation of a novel radioiodinated vesamicol analog as a sigma receptor imaging agent.

Science.gov (United States)

Ogawa, Kazuma; Kanbara, Hiroya; Shiba, Kazuhiro; Kitamura, Yoji; Kozaka, Takashi; Kiwada, Tatsuto; Odani, Akira

2012-09-28

Sigma receptors are highly expressed in human tumors and should be appropriate targets for developing tumor imaging agents. Previously, we synthesized a vesamicol analog, (+)-2-[4-(4-iodophenyl)piperidino]cyclohexanol ((+)-pIV), with a high affinity for sigma receptors and prepared radioiodinated (+)-pIV. As a result, (+)-[125I]pIV showed high tumor uptake in biodistribution experiments. However, the accumulation of radioactivity in normal tissues, such as the liver, was high. We supposed that some parts of the accumulation of (+)-pIV in the liver should be because of its high lipophilicity, and prepared and evaluated a more hydrophilic radiolabeled vesamicol analog, (+)-4-[1-(2-hydroxycyclohexyl)piperidine-4-yl]-2-iodophenol ((+)-IV-OH). (+)-[125I]IV-OH was prepared by the chloramine T method from the precursor. The partition coefficient of (+)-[125I]IV-OH was measured. Biodistribution experiments were performed by intravenous administration of a mixed solution of (+)-[125I]IV-OH and (+)-[131I]pIV into DU-145 tumor-bearing mice. Blocking studies were performed by intravenous injection of (+)-[125I]IV-OH mixed with an excess amount of ligand into DU-145 tumor-bearing mice. The hydrophilicity of (+)-[125I]IV-OH was much higher than that of (+)-[125I]pIV. In biodistribution experiments, (+)-[125I]IV-OH and (+)-[131I]pIV showed high uptake in tumor tissues at 10-min post-injection. Although (+)-[131I]pIV tended to be retained in most tissues, (+)-[125I]IV-OH was cleared from most tissues. In the liver, the radioactivity level of (+)-[125I]IV-OH was significantly lower at all time points compared to those of (+)-[131I]pIV. In the blocking studies, co-injection of an excess amount of sigma ligands resulted in significant decreases of tumor/blood uptake ratios after injection of (+)-[125I]IV-OH. The results indicate that radioiodinated (+)-IV-OH holds a potential as a sigma receptor imaging agent.

Identification and characterization of trans-3-hydroxy-l-proline dehydratase and Δ1-pyrroline-2-carboxylate reductase involved in trans-3-hydroxy-l-proline metabolism of bacteria

Directory of Open Access Journals (Sweden)

Seiya Watanabe

2014-01-01

Full Text Available trans-4-Hydroxy-l-proline (T4LHyp and trans-3-hydroxy-l-proline (T3LHyp occur mainly in collagen. A few bacteria can convert T4LHyp to α-ketoglutarate, and we previously revealed a hypothetical pathway consisting of four enzymes at the molecular level (J Biol Chem (2007 282, 6685–6695; J Biol Chem (2012 287, 32674–32688. Here, we first found that Azospirillum brasilense has the ability to grow not only on T4LHyp but also T3LHyp as a sole carbon source. In A. brasilense cells, T3LHyp dehydratase and NAD(PH-dependent Δ1-pyrroline-2-carboxylate (Pyr2C reductase activities were induced by T3LHyp (and d-proline and d-lysine but not T4LHyp, and no effect of T3LHyp was observed on the expression of T4LHyp metabolizing enzymes: a hypothetical pathway of T3LHyp → Pyr2C → l-proline was proposed. Bacterial T3LHyp dehydratase, encoded to LhpH gene, was homologous with the mammalian enzyme. On the other hand, Pyr2C reductase encoded to LhpI gene was a novel member of ornithine cyclodeaminase/μ-crystallin superfamily, differing from known bacterial protein. Furthermore, the LhpI enzymes of A. brasilense and another bacterium showed several different properties, including substrate and coenzyme specificities. T3LHyp was converted to proline by the purified LhpH and LhpI proteins. Furthermore, disruption of LhpI gene from A. brasilense led to loss of growth on T3LHyp, d-proline and d-lysine, indicating that this gene has dual metabolic functions as a reductase for Pyr2C and Δ1-piperidine-2-carboxylate in these pathways, and that the T3LHyp pathway is not linked to T4LHyp and l-proline metabolism.

Effects of piperidine and piperideine alkaloids from the venom of red imported fire ants, Solenopsis invicta Buren, on Pythium ultimum Trow growth in vitro and the application of piperideine alkaloids to control cucumber..

Science.gov (United States)

Pythium ultimum Trow is a plant pathogen that causes significant yield losses on many economically important crops. Chemical seed treatment has been used for disease control. In searching for alternatives, the venom alkaloids from red imported fire ant were tested against P. ultimum in vitro and to ...

DNA binding mode of the cis and trans geometries of new antitumor nonclassical platinum complexes containing piperidine, piperazine or 4-picoline ligand in cell-free media. Relations to their activity in cancer cell lines

Czech Academy of Sciences Publication Activity Database

Kašpárková, Jana; Marini, Victoria; Najajreh, Y.; Gibson, D.; Brabec, Viktor

2003-01-01

Roč. 42, č. 20 (2003), s. 6321-6332 ISSN 0006-2960 R&D Projects: GA AV ČR IAA5004101; GA AV ČR KJB5004301; GA ČR GA305/01/0418 Institutional research plan: CEZ:AV0Z5004920 Keywords : cross links * DNA * nonclassical platinum complexes Subject RIV: BO - Biophysics Impact factor: 3.922, year: 2003

Heterogeneous binding of sigma radioligands in the rat brain and liver; Possible relationship to subforms of cytochrome P-450

Energy Technology Data Exchange (ETDEWEB)

Ross, S B [Research Laboratories, Astra Research Centre AB, Soedertaejle (Sweden)

1991-01-01

The binding of four sigma receptor ligands, {sup 3}H-(+)-N-allyl-N-normetazocine ({sup 3}H-(+)-SKF 10,047), {sup 3}H-(+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ({sup 3}H-(+)-3-PPP), {sup 3}H-haloperidol and {sup 3}H-N,N'-di(o-totyl)guanidine ({sup 3}H-DTG), and the cytochrome P450IID6 ligand and dopamine uptake inhibitor {sup 3}H-1-(2-(diphenylmethoxy)ethyl)-4-(3-phenylpropyl)piperazine ({sup 3}H-GBR 12935) to membranal preparations of rat liver or whole rat brain was examined regarding kinetical properties and inhibition by various compounds with affinity for sigma binding sites or cytochrome P-450. In rat brain the density of binding sites was increased in order (+)-SKF 10,047<(+)-3-PPP

Effects of melanocortin-4 receptor agonists and antagonists on expression of genes related to reproduction in spotted scat, Scatophagus argus.

Science.gov (United States)

Jiang, Dong-Neng; Li, Jian-Tao; Tao, Ya-Xiong; Chen, Hua-Pu; Deng, Si-Ping; Zhu, Chun-Hua; Li, Guang-Li

2017-05-01

Melanocortin-4 receptor (Mc4r) function related to reproduction in fish has not been extensively investigated. Here, we report on gene expression changes by real-time PCR following treatment with Mc4r agonists and antagonists in the spotted scat (Scatophagus argus). Using in vitro incubated hypothalamus, the Mc4r nonselective agonist NDP-MSH ([Nle 4 , D-Phe 7 ]-α-melanocyte stimulating hormone; 10 -6 M) and selective agonist THIQ (N-[(3R)-1, 2, 3, 4-Tetrahydroisoquinolinium-3-ylcarbonyl]- (1R)-1-(4-chlorobenzyl)-2-[4-cyclohexyl-4-(1H-1,2,4-triazol-1-ylmethyl) piperidin-1-yl]-2-oxoethylamine; 10 -7 M) significantly increased the expression of gnrh (Gonadotropin releasing hormone), while the Mc4r nonselective antagonist SHU9119 (Ac-Nle-[Asp-His-DPhe/DNal(2')-Arg-Trp-Lys]-NH2; 10 -6 M) and selective antagonist Ipsen 5i (compound 5i synthesized in Ipsen Research Laboratories; 10 -6 M) significantly inhibited gnrh expression after 3 h of incubation. In incubated pituitary tissue, NDP-MSH and THIQ significantly increased the expression of fshb (Follicle-stimulating hormone beta subunit) and lhb (Luteinizing hormone beta subunit), while SHU9119 and Ipsen 5i significantly decreased fshb and lhb expression after 3 h of incubation. During the in vivo experiment, THIQ (1 mg/kg bw) significantly increased gnrh expression in hypothalamic tissue, as well as the fshb and lhb expression in pituitary tissue 12 h after abdominal injection. Furthermore, Ipsen 5i (1 mg/kg bw) significantly inhibited gnrh expression in hypothalamic tissue, as well as fshb and lhb gene expression in pituitary tissue 12 h after abdominal injection. In summary, Mc4r singling appears to stimulate gnrh expression in the hypothalamus, thereby modulating the synthesis of Fsh and Lh in the pituitary. In addition, Mc4r also appears to directly regulate fshb and lhb levels in the pituitary in spotted scat. Our study suggests that Mc4r, through the hypothalamus and pituitary, participates in reproductive

Synthesis and antitumor activity of some novel thiophene, pyrimidine, coumarin, pyrazole and pyridine derivatives

Directory of Open Access Journals (Sweden)

Albratty Mohammed

2017-03-01

Full Text Available 2-Cyano-N-(thiazol-2-yl acetamide (2a and 2-cyano-N-(oxazol- 2-yl acetamide (2b were obtained via the reaction of ethyl cyanoacetate with either 2-aminothiazole (1a or 2-aminooxazole (1b. The formed products were directed toward the reaction with cyclopentanone and elemental sulfur in the presence of triethylamine to give cyclopenta[b]thiophene derivatives (3a,b. The latter products were reacted with either ethyl cyanoacetate or malononitrile to form compounds 4a,b and 5a,b, respectively. Compounds 4a,b were aimed at synthesizing some heterocyclic compounds; thus internal cyclization reactions were introduced to form compounds 6a,b. Also, compounds 4a,b reacted with salicylaldehyde, hydrazine derivatives and either urea or thiourea to produce coumarin derivatives (7a,b, pyrazole derivatives (8a-d and pyrimidine derivatives (9a-d, respectively. Reaction of either benzaldehyde or benzene diazonium chloride (11 with compounds 4a,b afforded compounds 10a,b and 12a,b, respectively. On the other hand, compounds 5a,b underwent internal cyclization to form pyrimidine derivatives 13a,b. Also, when compounds 5a,b reacted with either ethyl cyanoacetate or malononitrile, they gave pyridine derivatives (15a-d through the formation of intermediates (14a-d. Finally, formation of fused pyrimidine derivatives (17a,b was achieved through the reaction of compounds 5a,b and salicylaldehyde applying two different pathways. The first pathway used a catalytic amount of piperidine to form compounds 16a,b; the latter products underwent cyclization to give compounds 17a,b. The second pathway, using a catalytic amount of sodium ethoxide solution directly in one step, afforded compounds 17a,b. Structures of the newly synthesized compounds were established using IR, 1H NMR, 13C NMR and mass spectrometry and their antitumor activity was investigated. Some of these compounds showed promising inhibitory effects on three different cell lines. However, fused pyrimidine

Prospective Evaluation of 68Ga-RM2 PET/MRI in Patients with Biochemical Recurrence of Prostate Cancer and Negative Findings on Conventional Imaging.

Science.gov (United States)

Minamimoto, Ryogo; Sonni, Ida; Hancock, Steven; Vasanawala, Shreyas; Loening, Andreas; Gambhir, Sanjiv S; Iagaru, Andrei

2018-05-01

68 Ga-labeled DOTA-4-amino-1-carboxymethyl-piperidine-d-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH 2 ( 68 Ga-RM2) is a synthetic bombesin receptor antagonist that targets gastrin-releasing peptide receptor (GRPr). GRPr proteins are highly overexpressed in several human tumors, including prostate cancer (PCa). We present data from the use of 68 Ga-RM2 in patients with biochemical recurrence (BCR) of PCa and negative findings on conventional imaging. Methods: We enrolled 32 men with BCR of PCa, who were 59-83 y old (mean ± SD, 68.7 ± 6.4 y). Imaging started at 40-69 min (mean, 50.5 ± 6.8 min) after injection of 133.2-151.7 MBq (mean, 140.6 ± 7.4 MBq) of 68 Ga-RM2 using a time-of-flight-enabled simultaneous PET/MRI scanner. T1-weighted, T2-weighted, and diffusion-weighted images were acquired. Results: All patients had a rising level of prostate-specific antigen (PSA) (range, 0.3-119.0 ng/mL; mean, 10.1 ± 21.3 ng/mL) and negative findings on conventional imaging (CT or MRI, and a 99m Tc-methylene diphosphonate bone scan) before enrollment. The observed 68 Ga-RM2 PET detection rate was 71.8%. 68 Ga-RM2 PET identified recurrent PCa in 23 of the 32 participants, whereas the simultaneous MRI scan identified findings compatible with recurrent PCa in 11 of the 32 patients. PSA velocity was 0.32 ± 0.59 ng/mL/y (range, 0.04-1.9 ng/mL/y) in patients with negative PET findings and 2.51 ± 2.16 ng/mL/y (range, 0.13-8.68 ng/mL/y) in patients with positive PET findings ( P = 0.006). Conclusion: 68 Ga-RM2 PET can be used for assessment of GRPr expression in patients with BCR of PCa. High uptake in multiple areas compatible with cancer lesions suggests that 68 Ga-RM2 is a promising PET radiopharmaceutical for localization of disease in patients with BCR of PCa and negative findings on conventional imaging. © 2018 by the Society of Nuclear Medicine and Molecular Imaging.