- Inhibition of nitric oxide synthase with pyrazole-1-carboxamidine and related compounds
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Guanidines, amidines, S-alkylisothioureas, and other compounds containing the amidine function (-C(=NH)NH2) have been described as inhibitors of the generation of nitric oxide (NO) by NO synthase (NOS). Mere we report on the inhibition of the activity of NOS isoforms by compounds in which the amidine function is attached to a nitrogen of 1,2 diazo heterocycles to form N-carboxamidines and related compounds. 1H-Pyrazole-1-carboxamidine HCl (PCA) inhibited the activity of purified inducible NOS (iNOS), endothelial NOS (eNOS), and neuronal NOS (nNOS) isoforms to a similar extent (IC50 = 0.2 μM). 3-Methyl-PCA and 4-methyl-PCA showed reduced potencies, but a preference for iNOS [IC50 = 5 and 2.4 μM, respectively; cf. N(G)-methyl-L-arginine (NMA) IC50 = 6 μM]. Inhibition of purified iNOS by PCAs could be reversed completely by excess L arginine, while their inhibition of NO production by stimulated RAW macrophages could be reversed by transfer to a drug-free medium. This suggests a competitive mode of inhibition. PCA caused potent concentration dependent inhibition of the acetylcholine-induced, endothelium-dependene relaxations of precontracted rat thoracic aorta (IC50 = 30 μM). 4-Methyl-PCA inhibited the relaxations only at ≤300 μM. In contrast, 4-methyl-PCA was more effective than both PCA and NMA in restoring the ex vivo contractility of aortic rings taken from lipopolysaccharide-treated rats. PCA and NMA, but not 4-methyl-PCA, caused marked increases in mean arterial pressure when administered i.v. to anesthetized rats. In conclusion, PCA and related compounds caused potent inhibition of NOS. Substitution of the pyrazole ring reduced potency, but improved selectivity towards iNOS as exemplified by 4-methyl-PCA.
- Southan, Garry J.,Gauld, Douglas,Lubeskie, Andrew,Zingarelli, Basilia,Cuzzocrea, Salvatore,Salzman, Andrew L.,Szabo, Csaba,Wolff, Donald J.
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Read Online
- Iron-mediated desulphurization approach: synthesis of cyanamides and their conversions
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The iron-mediated efficient multi-component method has been demonstrated for the synthesis of substituted cyanamides from isothiocyanates under mild reaction conditions. Subsequent nucleophilic addition and desulfurization are involved in this proposed synthetic methodology. All the reactions are rapid, facile, and accomplished at room temperature. A variety of substrates readily underwent the optimized reaction conditions to provide their respective target products in good to excellent yields. Furthermore, we have confirmed that no other by-products could be identified during our experimental reaction process. Graphical abstract: Iron-mediated efficient multi-component method has been demonstrated for the synthesis of substituted cyanamides from isothiocyanates under mild reaction conditions. Subsequent nucleophilic addition and desulfurization are involved in this proposed synthetic methodology.[Figure not available: see fulltext.].
- Nannapaneni, Madhavi,Pendem, Venkata Bhavanarushi,Tamminana, Ramana
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- SO2F2-Mediated one-pot cascade process for transformation of aldehydes (RCHO) to cyanamides (RNHCN)
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A simple, mild and practical cascade process for the direct conversion of aldehydes to cyanamides was developed featuring a wide substrate scope and great functional group tolerability. This method allows for transformations of readily available, inexpensive, and abundant aldehydes to highly valuable cyanamides in a pot, atom, and step-economical manner with a green nitrogen source. This protocol will serve as a robust tool for the installation of the cyanamide moiety in various complicated molecules.
- Ding, Chengrong,Ge, Shuting,Wei, Junjie,Zhang, Guofu,Zhao, Yiyong
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p. 17288 - 17292
(2020/05/18)
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- A cascade process for directly converting nitriles (RCN) to cyanamides (RNHCN) via SO2F2-activated Tiemann rearrangement
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A simple, mild and practical process for the direct conversion of nitriles to cyanamides was newly discovered and exhibited a wide substrate scope as well as great functional group-tolerability (36 examples). In this efficient strategy, the in situ generated amidoximes obtained from the reaction of nitriles with hydroxylamine subsequently underwent Tiemann rearrangement, producing the corresponding cyanamides with great isolated yields under SO2F2. Additionally, the control experiments reportedly shed light on the tentative mechanism involved in the formation and elimination of the key intermediate: a sulfonyl ester.
- Zhang, Guofu,Zhao, Yiyong,Ding, Chengrong
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supporting information
p. 7684 - 7688
(2019/08/30)
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- One-pot three-component tandem reaction: Synthesis of aryl/alkyl cyanamides libraries and their further conversion into tetrazole derivatives
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We have developed methodology for the synthesis of aryl/alkyl cyanamides from amines in one-pot four steps reaction using cheap, readily available and air stable copper source as catalyst under mild reaction conditions. We have also studied the application of cyanamides. In this connection, we could construct aryl tetrazolamine from cyanamides using click reaction.
- Mandapati, Usharani,Mandapati, Pavan,Pinapati, Srinivasarao,Tamminana, Ramana,Rudraraju, Rameshraju
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p. 500 - 510
(2018/02/06)
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- Cobalt-promoted one-pot reaction of isothiocyanates toward the synthesis of aryl/alkylcyanamides and substituted tetrazoles
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[Figure not available: see fulltext.] The synthesis of cyanamides and tetrazoles from isothiocyanates through tandem reaction using cobalt catalyst has been demonstrated. In the case of tetrazole preparation, the reaction involved addition/desulfurization/nucleophilic addition/electrocyclization, whereas aromatic cyanamides were constructed from isothiocyanates through addition/desulfurization. Cheap cobalt sulfate was used for the synthesis of various cyanamides and tetrazoles. In addition, cobalt catalyst was found to be desulfurization reagent that has not been previously reported. The final products have been obtained from starting precursors in good to high yield.
- Seelam, Mohan,Kammela, Prasada Rao,Shaikh, Bajivali,Tamminana, Ramana,Bogiri, Sujatha
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p. 535 - 544
(2018/07/05)
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- A novel one-pot synthesis of isothiocyanates and cyanamides from dithiocarbamate salts using environmentally benign reagent tetrapropylammonium tribromide
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A highly efficient and simple protocol for the synthesis of isothiocyanates and cyanamides from their respective amines in the presence of a mild, efficient, and non-toxic reagent tetrapropylammonium tribromide is described. High environmental acceptability of the reagents, cost effectiveness and high yields are the important attributes of this methodology.
- Kuotsu, Neivotsonuo Bernadette,Jamir, Latonglila,Phucho, Tovishe,Sinha, Upasana Bora
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p. 832 - 841
(2018/01/17)
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- One-Pot Synthesis of N-Monosubstituted Ureas from Nitriles via Tiemann Rearrangement
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Amidoximes, obtained from the reaction of nitriles with hydroxylamine, underwent Tiemann rearrangement in the presence of benzenesulfonyl chlorides (TsCl or o-NsCl) to form the N-substituted cyanamides. Subsequently, acidic hydrolysis of the cyanamides afforded the corresponding N-monosubstituted ureas. The synthesis of N-monosubstituted ureas from nitriles was accomplished by three steps in one pot, which provides a direct access to versatile N-monosubstituted urea derivatives from a wide variety of nitriles.
- Wang, Chien-Hong,Hsieh, Tsung-Han,Lin, Chia-Chi,Yeh, Wen-Hsiung,Lin, Chih-An,Chien, Tun-Cheng
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supporting information
p. 1823 - 1826
(2015/08/06)
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- Synthesis, structure activity relationship, radiolabeling and preclinical evaluation of high affinity ligands for the ion channel of the N-methyl-d-aspartate receptor as potential imaging probes for positron emission tomography
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The N-methyl-d-aspartate receptor (NMDAr) is involved in many neurological and psychiatric disorders including Alzheimer's disease and schizophrenia. Currently, it is not possible to assess NMDAr availability in vivo. The purpose of this study was to develop a positron emission tomography (PET) ligand for the NMDAr ion channel. A series of di- and tri-N-substituted diarylguanidines was synthesized. In addition, in vitro binding affinity for the NMDAr ion channel in rat forebrain membrane fractions was assessed. Compounds 10, 11 and 32 were radiolabeled with either carbon-11 or fluorine-18. Ligands [11C]10 and [18F]32 were evaluated ex vivo in B6C3 mice. Biodistribution studies showed higher uptake of [11C]10 and [18F]32 in forebrain regions compared with cerebellum. In addition, for [11C]10 54% and for [18F]32 70% of activity in the brain at 60 min was due to intact tracer. Pre-treatment with MK-801 (0.6 mg·kg-1, ip) slightly decreased uptake in NMDAr-specific regions for [18F]32, but not for [11C]10. As such [18F]32 has the best characteristics as a PET tracer for the ion channel of the NMDAr.
- Klein, Pieter J.,Christiaans, Johannes A.M.,Metaxas, Athanasios,Schuit, Robert C.,Lammertsma, Adriaan A.,Van Berckel, Bart N.M.,Windhorst, Albert D.
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p. 1189 - 1206
(2015/03/04)
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- Practical synthesis of N -substituted cyanamides via tiemann rearrangement of amidoximes
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A facile and general synthesis of various N-substituted cyanamides was accomplished by the Tiemann rearrangement of amidoximes with benzenesulfonyl chlorides (TsCl or o-NsCl) and DIPEA.
- Lin, Chia-Chi,Hsieh, Tsung-Han,Liao, Pen-Yuan,Liao, Zhen-Yuan,Chang, Chih-Wei,Shih, Yu-Chiao,Yeh, Wen-Hsiung,Chien, Tun-Cheng
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supporting information
p. 892 - 895
(2014/03/21)
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- Copper-catalyzed oxidative three-component synthesis of N, N′, N′-trisubstituted guanidines
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A copper-catalyzed three-component synthesis of trisubstituted N-aryl guanidines involving cyanamides, arylboronic acids, and amines has been developed. This operationally simple oxidative process, which is performed in the presence of K2CO3, a catalytic amount of CuCl 2·2H2O, bipyridine, and oxygen (1 atm), allows the rapid assembly of N,N′,N″-trisubstituted aryl guanidines.
- Li, Jihui,Neuville, Luc
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supporting information
p. 6124 - 6127
(2014/01/17)
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- An efficient transformation of ethers to N,N′-disubstituted ureas in a Ritter type reaction
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A simple, mild, and an alternative protocol for the preparation of N,N′-disubstituted ureas from readily available ethers and cyanamides as starting materials is described. The protocol explores the reactivity of ether in a Ritter type reaction with cyanamide in the presence of BF 3·Et2O and resulting in the formation of N,N′-disubstituted urea. Divinyl ether as well as MTBE (methyl tert-butyl ether) can be employed as ether components to afford allyl and tert-butyl ureas respectively.
- Panduranga, Veladi,Basavaprabhu,Sureshbabu, Vommina V.
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p. 975 - 979
(2013/04/10)
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- Some practical methods for the application of 5-metallo-1-benzyl-1H- tetrazoles in synthesis
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Nucleophilic reagents such as 5-lithiotetrazoles are synthetically powerful tools for the installation of tetrazole functional groups, but they are of limited utility due to the instability of tetrazole-derived carbanions. Herein, we report practical methods for the generation and use of new 5-metallo-1-benzyl-1H-tetrazoles (M=K, MgX, ZnX) derived from either 1-benzyl-1H-tetrazole or 1-benzyl-5-bromo-1H-tetrazole. By varying the metal counterion, the tetrazole carbanion stability was improved. Potassium- and magnesium-derived reagents underwent additions to carbonyl compounds at -30 and -20°C, respectively. The isolated yields (41-85%) from these and other reactions were comparable to those reported for 5-lithiotetrazoles at much lower temperatures (-78 to -98 °C). Georg Thieme Verlag Stuttgart ? New York.
- Wiedemann, Sean H.,Bio, Matthew M.,Brown, Liane M.,Hansen, Karl B.,Langille, Neil F.
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supporting information
p. 2231 - 2236
(2012/11/13)
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- Environmentally benign one-pot synthesis of cyanamides from dithiocarbamates using I2 and H2O2
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An environmentally benign reaction is devised for the synthesis of cyanamides from dithiocarbamate salts using iodine and H2O 2. Taylor & Francis Group, LLC.
- Jamir, Latonglila,Sinha, Upasana Bora,Nath, Jayashree,Patel, Bhisma K.
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p. 951 - 958
(2012/02/01)
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- Iron(III) catalysed synthesis of unsymmetrical di and trisubstituted ureas - A variation of classical Ritter reaction
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An application of the classical Ritter reaction for the synthesis of unsymmetrical di and trisubstituted ureas catalyzed by FeCl3 is described. The protocol is of significant interest in view of the easy availability of precursors, mild reaction conditions employed and interestingly its applicability for the alkylation of alcohols capable of forming stable carbocationic intermediates even to the sterically hindered moieties. The Royal Society of Chemistry 2012.
- Basavaprabhu, Hosamani,Sureshbabu, Vommina V.
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supporting information; experimental part
p. 2528 - 2533
(2012/04/23)
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- Palladium-catalyzed arylation of cyanamides
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The cross-coupling of alkyl cyanamides with a number of aryl, heteroaryl, and vinyl halide and pseudohalide coupling partners has been developed via a modification of Pd-catalyzed amidation methods. The reactions proceed selectively under mild conditions with reasonable reaction times in moderate to excellent yields.
- Stolley, Ryan M.,Guo, Wenxing,Louie, Janis
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supporting information; experimental part
p. 322 - 325
(2012/02/04)
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- Novel and green protocol for the synthesis of 2-iminohydantoins
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A novel and green protocol for the synthesis of N-1 and C-5 substituted 2-iminohydantoins has been developed. Methyl N-cyano-N-alkyl/aryl-aminoacetate reacts with aqueous ammonia at room temperature in 10-30 min. The developed protocol does not require any work-up for the isolation or purification of the products; simple filtration can lead to the pure products in good to excellent yields.
- Kumar, Vinod,Rana, Hemlata,Kaushik, M. P.
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p. 6423 - 6425,3
(2012/12/12)
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- Desulfurization and transformation of isothiocyanates to cyanamides by using sodium bis(trimethylsilyl)amide
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Sodium bis(trimethylsilyl)amide was first used as the desulfurizing agent for the conversion of isothiocyanates to cyanamides in a 'one-flask' reaction. Crown Copyright
- Chen, Chun-Yen,Wong, Fung Fuh,Huang, Jiann-Jyh,Lin, Shao-Kai,Yeh, Mou-Yung
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supporting information; scheme or table
p. 6505 - 6507
(2009/04/06)
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- An efficient approach for the synthesis of N-1 substituted hydantoins
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An efficient three-step route for the synthesis of N-1 alkyl/aryl- substituted hydantoins was developed from inexpensive commercially available substrates. The reaction of amines with cyanogen bromide takes place to give monoalkyl/aryl cyanamides. This on treatment with methyl bromoacetate in the presence of sodium hydride in tetrahydrofuran affords methyl N-cyano-N-alkyl/arylaminoacetate, which undergoes hydrolysis and cyclization in the presence of 50% H2SO4 to afford N-1 substituted hydantoins in very good-to-excellent yields. Wide varieties of final products having primary, secondary, tertiary, and aryl substituents at the N-1 position were successfully synthesized by this method. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.
- Kumar, Vinod,Kaushik,Mazumdar, Avik
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experimental part
p. 1910 - 1916
(2009/04/04)
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- Sodium bis(trimethylsilyl)amide in the 'one-flask' transformation of isocyanates to cyanamides
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Cyanamides were successfully prepared in a 'one-flask' reaction from isocyanates by use of sodium bis(trimethylsilyl)amide as the deoxygenating agents in THF at room temperature. Georg Thieme Verlag Stuttgart.
- Wong, Fung Fuh,Chen, Chun-Yen,Yeh, Mou-Yung
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p. 559 - 562
(2007/10/03)
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- Novel alkylpolyaminoguanidines and alkylpolyaminobiguanides with potent antitrypanosomal activity
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A series of polyaminoguanidines and polyaminobiguanides were synthesized and evaluated as potential antitrypanosomal agents. These analogues inhibit trypanothione reductase (TR) with IC50 values as low as 0.95 μM, but do not inhibit the closely related human enzyme glutathione reductase (GR). The most effective analogues, 7a, 7b and 8d, inhibited parasitic growth in vitro with IC50 values of 0.18, 0.09 and 0.18 μM, respectively. These agents represent a promising new class of potential antitrypanosomal agents.
- Bi, Xiangdong,Lopez, Christina,Bacchi, Cyrus J.,Rattendi, Donna,Woster, Patrick M.
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p. 3229 - 3232
(2007/10/03)
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- 2-Cyanopyridazin-3(2H)-ones: Effective and chemoselective electrophilic cyanating agents
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2-Cyanopyridazin-3(2H)-ones are novel, effective, selective and electrophilic cyanating agents. A variety of amino, thiol and carbon nucleophiles are chemoselectively N-, S- or C-cyanated in excellent yield using 2-cyanopyridanzin-3(2H)-ones in water or tetrahydrofuran.
- Kim, Jeum-Jong,Kweon, Deok-Heon,Cho, Su-Dong,Kim, Ho-Kyun,Jung, Eun-Young,Lee, Sang-Gyeong,Falck,Yoon, Yong-Jin
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p. 5889 - 5894
(2007/10/03)
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- Construction of previously inaccessible 2-amino-4-benzyl substituted oxazoles
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A process for the synthesis of 2-amino-4-benzyl-oxazoles is reported.
- Lindsey, Christopher C.,O'Boyle, Brendan M.,Mercede, Stephanie J.,Pettus, Thomas R. R.
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p. 867 - 868
(2007/10/03)
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- Design of novel N-(2,4-dioxo-1,2,3,4-tetrahydro-thieno[3,2-d]pyrimidin-7-yl)-guanidines as thymidine phosphorylase inhibitors, and flexible docking to a homology model.
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A novel class of thymidine phosphorylase (TP) inhibitors has been designed based on analogy to the enzyme substrate as well as known inhibitors. Flexible docking studies, using a homology model of human TP, of the designed N-(2,4-dioxo-1,2,3,4-tetrahydro-thieno[3,2-d]pyrimidin-7-yl)-guanidines as well as their synthetic precursors provide insight into the observed experimental trends in binding affinity.
- Price, Melissa L P,Guida, Wayne C,Jackson, Tara E,Nydick, Jason A,Gladstone, Patricia L,Juarez, Jose C,Donate, Fernando,Ternansky, Robert J
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p. 107 - 110
(2007/10/03)
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- Electrochemical and peroxidase oxidation study of N'-hydroxyguanidine derivatives as NO donors.
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The electrochemical properties of a series of N-substituted-N'-hydroxyguanidines were studied. Two oxidation potentials of each compound were obtained by cyclic voltammetry. The E(ox1) values were from 0.51 to 0.62V, while the E(ox2) values were from 1.14 to 1.81V in acetonitrile solution. Next, their enzymatic controlled NO release abilities were evaluated. All N'-hydroxyguanidines exhibited efficient NO release abilities under the oxidation by horseradish peroxidase in the presence of H(2)O(2).
- Cai, Tingwei,Xian, Ming,Wang, Peng George
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p. 1507 - 1510
(2007/10/03)
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- Novel substrates for nitric oxide synthases.
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Enzymatic generation of nitric oxide (NO) by nitric oxide synthase (NOS) consists of two oxidation steps. The first step converts L-arginine to N(G)-hydroxy-L-arginine (NOHA), a key intermediate, and the second step converts NOHA to NO and L-citrulline. To fully probe the substrate specificity of the second enzymatic step, an extensive structural screening was carried out using a series of N-alkyl (and N-aryl) substituted-N'-hydroxyguanidines (1-14). Among the eleven N-alkyl-N'-hydroxyguanidines evaluated, N-n-propyl (2), N-iso-propyl (3), N-n-butyl (4), N-s-butyl (5), N-iso-butyl (6), N-pentyl (8) and N-iso-pentyl (9) derivatives were efficiently oxidized by the three isoenzymes of NOS (nNOS, iNOS and eNOS) to generate NO. N-Butyl-N'-hydroxyguanidine (4) was the best substrate for iNOS (K(m)=33 microM) and N-iso-propyl-N'-hydroxyguanidine (3) was the best substrate for nNOS (K(m)=56 microM). When the alkyl substituents were too small (such as ethyl 1) or too large (such as hexyl 10 and cyclohexyl 11), the activity decreased significantly. This suggests that the van der Waals interaction between the alkyl group and the hydrophobic cavity in the NOS active site contributes significantly to the relative reactivity of compounds 3-11. Moreover, five N-aryl-N'-hydroxyguanidines were found to be good substrates for iNOS, but not substrates for eNOS and nNOS. N-phenyl-N'-hydroxyguanidine was the best substrate among them (K(m)=243 microM). This work demonstrates that N-alkyl substituted hydroxyguanidine compounds are novel NOS substrates which 'short-circuit' the first oxidation step of NOS, and N-aryl substituted hydroxyguanidine compounds are isoform selective NOS substrate.
- Xian, Ming,Fujiwara, Noriko,Wen, Zhong,Cai, Tingwei,Kazuma, Satoshi,Janczuk, Adam J,Tang, Xiaoping,Telyatnikov, Vladislav V,Zhang, Yingxin,Chen, Xinchao,Miyamoto, Yasuhide,Taniguchi, Naoyuki,Wang, Peng George
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p. 3049 - 3055
(2007/10/03)
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- Modification of the Tiemann rearrangement: One-pot synthesis of N,N-disubstituted cyanamides from amidoximes
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A three-stage one-pot synthetic procedure for transformation of amidoximes to N,N-disubstituted cyanamides in 70-92% yield is described.
- Bakunov, Stanislav A.,Rukavishnikov, Alexey V.,Tkachev, Alexey V.
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p. 1148 - 1159
(2007/10/03)
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- 1-Cyanoimidazole as a mild and efficient electrophilic cyanating agent
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formula presented A mild and high-yielding cyanating reaction of amine, sulfur, and carbanion nucleophiles is reported here using 1-cyanoimidazole as an electrophilic cyanating agent.
- Wu, Yong-Qian,Limburg, David C.,Wilkinson, Douglas E.,Hamilton, Gregory S.
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p. 795 - 797
(2007/10/03)
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- Synthesis of isomelamines and isocyanurates and their biological evaluation
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The reaction of cyanogen bromide (1) with primary amines (2a-p), including arylmethylamines (21-p), gave the corresponding cyanamides (3a- p). Trimerization of 3a-p gave 1,3,5-trisubstituted 2,4,6-triiminohexahydro- 1,3,5-triazines (isomelamines) (4a-p), which were treated with hydrochloric acid to give the corresponding 1,3,5-trisubstituted 2,4,6-trioxohexahydro- 1,3,5-triazines (isocyanurates) (5a-c, f) and 1,3,5-trisubstituted 2-imino- 4,6-dioxohexahydro-1,3,5- triazines (5b'-e'). Biological evaluation of 4a- p, 5a-c, f, and 5b'-e' was carried out, and some of these compounds showed bronchodilator and positive inotropic activities.
- Niwa, Ryuji,Kamada, Hitoshi,Shitara, Eiki,Horiuchi, Jiro,Kibushi, Nobuyuki,Kato, Tetsuzo
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p. 2314 - 2317
(2007/10/03)
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