- Yeast supported gold nanoparticles: an efficient catalyst for the synthesis of commercially important aryl amines
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Candida parapsilosisATCC 7330 supported gold nanoparticles (CpGNP), prepared by a simple and green method can selectively reduce nitroarenes and substituted nitroarenes with different functional groups like halides (-F, -Cl, -Br), olefins, esters and nitriles using sodium borohydride. The product aryl amines which are useful for the preparation of pharmaceuticals, polymers and agrochemicals were obtained in good yields (up to >95%) using CpGNP catalyst under mild conditions. The catalyst showed high recyclability (≥10 cycles) and is a robust free flowing powder, stored and used after eight months without any loss in catalytic activity.
- Krishnan, Saravanan,Patel, Paresh N.,Balasubramanian, Kalpattu K.,Chadha, Anju
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supporting information
p. 1915 - 1923
(2021/02/06)
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- The conversion of 2-cyano cyanothioformanilides into 3-aminoindole-2- carbonitriles using triphenylphosphine
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2-Cyano cyanothioformanilide 3a reacts with triphenylphosphine in the presence of water to give 2-(cyanomethyleneamino)benzonitrile 4a, 2-(cyanomethylamino)benzonitrile 5, 3-aminoindole-2-carbonitrile 2a and (2-cyanoindol-3-yl)iminotriphenylphosphorane 6a. In the presence of p-toluenesulfonic acid in MeOH the reaction between 2-cyano cyanothioformanilide 3a and triphenylphosphine (2 equiv) gives 3-aminoindole-2-carbonitrile 2a in 90% yield. Under the same conditions 2-(cyanomethyleneamino)benzonitrile 4a gives anthranilonitrile 8a, 3-aminoindole-2-carbonitrile 2a and N-(2-cyanophenyl)formamide 9. In addition, substituted 2-cyano cyanothioformanilides 3b-f react with triphenylphosphine and p-toluenesulfonic acid in MeOH to give 3-aminoindole-2-carbonitriles 2b-f in 63-75% yields. Under analogous conditions 2-cyano-4,5-dimethoxyphenyl cyanothioformanilide 2g gives only 4,5-dimethoxyanthranilonitrile 8g and 4,6,7-trimethoxyquinazoline-2- carbonitrile 14g, but in refluxing dry PhMe in the absence of p-toluenesulfonic acid 2-cyano-4,5-dimethoxyphenyl cyanothioformanilide 3g, (2-cyano-5,6- dimethoxyindol-3-yl)iminotriphenylphosphorane 6g and 2-(cyanomethyleneamino)-4, 5-dimethoxybenzonitrile 4g are obtained. The structure of 2- (cyanomethyleneamino)-4,5-dimethoxybenzonitrile 4g is supported unambiguously via independent synthesis and comparison to the isomeric 6,7- dimethoxyquinazoline-2-carbonitrile 15. All new compounds are fully characterised and a tentative mechanism for the transformation of 2-cyano cyanothioformanilides to indoles is proposed.
- Koutentis, Panayiotis A.,Michaelidou, Sophia S.
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scheme or table
p. 6032 - 6039
(2010/09/11)
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- The conversion of 2-(4-chloro-5H-1,2,3-dithiazolylideneamino)benzonitriles into 3-aminoindole-2-carbonitriles using triphenylphosphine
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2-(4-Chloro-5H-1,2,3-dithiazolylideneamino)benzonitrile 1a reacts with triphenylphosphine (4 equiv) in the presence of water (2 equiv) to afford anthranilonitrile 2a, 3-aminoindole-2-carbonitrile 3a and (2-cyanoindol-3-yl)iminotriphenylphosphorane 4a, tog
- Michaelidou, Sophia S.,Koutentis, Panayiotis A.
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experimental part
p. 8428 - 8433
(2009/12/26)
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- Evaluation and biological properties of reactive ligands for the mapping of the glycine site on the N-methyl-D-aspartate (NMDA) receptor
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The glycine-binding site of the N-methyl-D-aspartate (NMDA) receptor, given its potential as pharmacological target, has been thoroughly studied by structure-activity relationships, which has made possible its description in terms of spatial limits and interactions of various types. A structural model, based on mutational analysis and sequence alignments, has been proposed. Yet, the amino acid residues responsible for the interactions with the ligand have not been unambiguously characterized. To evidence nucleophilic pocket-lining residues, we have designed and synthesized reactive glycine-site ligands derived from 3-substituted 4-hydroxy-quinolin- 2(1H)-ones by introducing various electrophilic groups at different positions of the molecule. These ligands were found to have high affinity at the glycine site and to be functional antagonists by inhibiting glycine/glutamate-induced currents in transfected oocytes. The correlation between their potency and their substitution pattern was strictly consistent with previously established structure-activity relationships. Most ligands displayed intrinsic reactivity toward cysteine, but none inactivated wild- type receptors. This is consistent with the model since it indicates the absence of exposed cysteine in the glycine-binding site. A strategy of cysteine incorporation by point mutations at selected polypeptide positions will create unambiguously localized targets for our reactive probes.
- Kreimeyer, Annett,Laube, Bodo,Sturgess, Mike,Goeldner, Maurice,Foucaud, Bernard
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p. 4394 - 4404
(2007/10/03)
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- Effect of plasma protein binding-on in vivo activity and brain penetration of glycine/NMDA receptor antagonists
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A major issue in designing drugs as antagonists at the glycine site of the NMDA receptor has been to achieve good in vivo activity. A series of 4- hydroxyquinolone glycine antagonists was found to be active in the DBA/2 mouse anticonvulsant assay, but improvements in in vitro affinity were not mirrored by corresponding increases in anticonvulsant activity. Here we show that binding of the compounds to plasma protein limits their brain penetration. Relative binding to the major plasma protein, albumin, was measured in two different ways: by a radioligand binding experiment or using an HPLC assay, for a wide structural range of glycine/NMDA site ligands. These measures of plasma protein binding correlate well (r = 0.84), and the HPLC assay has been used extensively to quantify plasma protein binding. For the 4-hydroxyquinolone series, binding to plasma protein correlates (r = 0.92) with log P (octanol/pH 7.4 buffer) over a range of log P values from 0 to 5. The anticonvulsant activity increases with in vitro affinity, but the slope of a plot of pED50 versus pIC50 is low (0.40); taking plasma protein binding into account in this plot increases the slope to 0.60. This shows that binding to albumin in plasma reduces the amount of compound free to diffuse across the blood-brain barrier. Further evidence comes from three other experiments: (a) Direct measurements of brain/blood ratios for three compounds (2, 16, 26) show the ratio decreases with increasing log P. (b) Warfarin, which compotes for albumin binding sites dose-dependently, decreased the ED50 of 26 for protection against seizures induced by NMDLA. (c) Direct measurements of brain penetration using an in situ brain perfusion model in rat to measure the amount of drug crossing the blood-brain barrier showed that compounds 2, 26, and 32 penetrate the brain well in the absence of plasma protein, but this is greatly reduced when the drug is delivered in plasma. In the 4-hydroxyquinolones glycine site binding affinity increases with lipophilicity of the 3-substituent up to a maximum at a log P around 3, then does not improve further. When combined with increasing protein binding, this gives a parabolic relationship between predicted in vivo activity and log P, with a maximum log P value of 2.39. Finally, the plasma protein binding studies have been extended to other series of glycine site antagonists, and it is shown that for a given log P these have similar protein binding to the 4-hydroxyquinolones, except for compounds that are not acidic. The results have implications for the design of novel glycine site antagonists, and it is suggested that it is necessary to either keep log P low or pK(a) high to obtain good central nervous system activity.
- Rowley, Michael,Kulagowski, Janusz J.,Watt, Alan P.,Rathbone, Denise,Stevenson, Graeme I.,Carling, Robert W.,Baker, Raymond,Marshall, George R.,Kemp, John A.,Foster, Alan C.,Grimwood, Sarah,Hargreaves, Richard,Hurley, Catherine,Saywell, Kay L.,Tricklebank, Mark D.,Leeson, Paul D.
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p. 4053 - 4068
(2007/10/03)
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- 4-Substituted-3-phenylquinolin-2(1H)-ones: Acidic and nonacidic glycine site N-methyl-D-aspartate antagonists with in vivo activity
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4-Substituted-3-phenylquinolin-2(1H)-ones have been synthesized and evaluated in vitro for antagonist activity at the glycine sits on the NMDA (N-methyl-D-aspartate) receptor and in vivo for anticonvulsant activity in the DBA/2 strain of mouse in an audiogenic seizure model. 4-Amino-3- phenylquinolin-2(1H)-one (3) is 40-fold lower in binding affinity but only 4- fold weaker as an anticonvulsant than the acidic 4-hydroxy compound 1. Methylsulfonylation at the 4-position of 3 gives an acidic compound (6, pK(a) = 6.0) where affinity is fully restored but in vivo potency is significantly reduced (Table 1). Methylation at the 4-position of 1 to give 18 results in the abolition of measurable affinity, but the attachment of neutral hydrogen bond-accepting groups to the methyl group of 18 produces compounds with comparable in vitro and in vivo activity to 1 (e.g., 23 and 28, Table 2). Replacement of the 4-hydroxy group of 1 with an ethyl group abolishes activity (42), but again, incorporation of neutral hydrogen bond acceptors to the terminal carbon atom restores affinity (e.g., 36, 39, and 40, Table 3). Replacement of the 4-hydroxy group of the high-affinity compound 2 with an amino group produces a compound with 200-fold reduced affinity (43, IC50 = 0.42 μM, Table 4) which is nevertheless still 10-fold higher in affinity than 3. The results in this paper indicate that anionic functionality is not an absolute requirement for good affinity at the glycine/NMDA site and provide compelling evidence for the existence of a ligand/receptor hydrogen bond interaction between an acceptor attached to the 4-position of the ligand and a hydrogen bond donor attached to the receptor.
- Carling, Robert W.,Leeson, Paul D.,Moore, Kevin W.,Moyes, Christopher R.,Duncton, Matthew,Hudson, Martin L.,Baker, Raymond,Foster, Alan C.,Grimwood, Sarah,Kemp, John A.,Marshall, George R.,Tricklebank, Mark D.,Saywell, Kay L.
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p. 754 - 765
(2007/10/03)
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- 3H-azepines and related systems. Part 5. Photo-induced ring expansions of o-azidobenzonitriles to 3-cyano- and 7-cyano-3H-azepin-2(1H)-ones
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Unlike other aryl azides bearing electron-withdrawing ortho-substituents, o-azidobenzonitriles on photolysis in aqueous-tetrahydrofuran yield mixtures of the expected 3-cyano- and the unexpected 7-cyano-3H-azepin-2(1H)-ones. In one instance ring contraction to a 2-azabicyclo[3.2.0]hept-6-ene-3-one is noted. X-ray crystallographic data for 7-cyano- and 4-chloro-7-cyano-3H-azepin-2-one, and for the azabicycloheptenone, are presented.
- Lamara,Redhouse,Smalley,Thompson
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p. 5515 - 5525
(2007/10/02)
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