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[PMID]: 27984150 [Au] Autor: Kumar R; Banoth L; Banerjee UC; Kaur J [Ad] Endereço: Department of Biotechnology, Sector 25, Panjab University, Chandigarh 160014, India. [Ti] Título: Enantiomeric separation of pharmaceutically important drug intermediates using a Metagenomic lipase and optimization of its large scale production. [So] Source: Int J Biol Macromol;95:995-1003, 2017 Feb. [Is] ISSN: 1879-0003 [Cp] País de publicação: Netherlands [La] Idioma: eng [Ab] Resumo: In the present study, efficient enzymatic methods were developed using a recombinant metagenomic lipase (LipR1) for the synthesis of corresponding esters by the transesterification of five different pharmaceutically important secondary alcohols. The recombinant lipase (specific activity=87m6U/mg) showed maximum conversion in presence of ionic liquid with Naphthyl-ethanol (eeP=99%), Indanol and Methyl-4 pyridine methanol (eeS of 98% and 99%) respectively in 1h. Vinyl acetate was found as suitable acyl donor in transesterification reactions. It was interesting to observe that maximum eeP of 85% was observed in just 15min with 1-indanol. As this enzyme demonstrated pharmaceutical applications, attempts were made to scale up the enzyme production on a pilot scale in a 5litre bioreactor. Different physical parameters affecting enzyme production and biomass concentration such as agitation rate, aeration rate and inoculum concentration were evaluated. Maximum lipase activity of 8463U/ml was obtained at 7h of cultivation at 1 lpm, 300rpm and 1.5% inoculum. [Mh] Termos MeSH primário: Fracionamento Químico/métodos Etanol/análogos & derivados Proteínas Fúngicas/química Indanos/isolamento & purificação Lipase/química Naftalenos/isolamento & purificação Álcool Nicotinílico/isolamento & purificação [Mh] Termos MeSH secundário: Biocatálise Reatores Biológicos Candida/química Candida/enzimologia Clonagem Molecular Escherichia coli/genética Escherichia coli/metabolismo Etanol/química Etanol/isolamento & purificação Fermentação Proteínas Fúngicas/biossíntese Proteínas Fúngicas/genética Expressão Gênica Indanos/química Líquidos Iônicos/química Lipase/biossíntese Lipase/genética Metagenoma Naftalenos/química Álcool Nicotinílico/química Proteínas Recombinantes/biossíntese Proteínas Recombinantes/química Proteínas Recombinantes/genética Estereoisomerismo Compostos de Vinila/química [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (1-(1'-naphthyl)ethanol); 0 (Fungal Proteins); 0 (Indans); 0 (Ionic Liquids); 0 (Naphthalenes); 0 (Recombinant Proteins); 0 (Vinyl Compounds); 3K9958V90M (Ethanol); 6351-10-6 (1-indanol); 9TF312056Y (Nicotinyl Alcohol); EC 3.1.1.3 (Lipase); L9MK238N77 (vinyl acetate) [Em] Mês de entrada: 1704 [Cu] Atualização por classe: 170406 [Lr] Data última revisão: 170406 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 161217 [St] Status: MEDLINE

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[PMID]: 27189143 [Au] Autor: Grabner S; Modec B; Bukovec N; Bukovec P; Cemazar M; Kranjc S; Sersa G; Scancar J [Ad] Endereço: Faculty of Chemistry and Chemical Technology, University of Ljubljana, Vecna pot 113, SI-1000 Ljubljana, Slovenia. Electronic address: sabina.grabner@fkkt.uni-lj.si. [Ti] Título: Cytotoxic trans-platinum(II) complex with 3-hydroxymethylpyridine: Synthesis, X-ray structure and biological activity evaluation. [So] Source: J Inorg Biochem;161:40-51, 2016 Aug. [Is] ISSN: 1873-3344 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: To assess the potential cytostatic properties of Pt(II) complexes with 3-hydroxymethylpyridine (3-hmpy) as the only carrier ligand, novel cis-[PtCl2(3-hmpy)2] (1) and trans-[PtCl2(3-hmpy)2] (2) have been prepared. Elemental analysis, FTIR spectroscopy, multinuclear NMR spectroscopy and X-ray crystallography were used to determine their structures. Based on the results obtained with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay and clonogenic assay on T24 human bladder carcinoma cells (T24), the most potent compound 2 was further tested for cytotoxicity in human ovarian carcinoma cell lines - cisplatin sensitive (IGROV 1) and its resistant subclone (IGROV 1/RDDP). The cytotoxicity of compound 2 in IGROV 1/RDDP is comparable to cisplatin. Furthermore, compound 2 induced severe conformational changes in plasmid DNA, which resulted in a delayed onset of apoptosis in T24 cells, and higher amounts of Pt in tumours and serum compared to cisplatin. In addition, in vivo antitumour effectiveness was comparable to that of cisplatin with a smaller reduction of animals' body weight, thus demonstrating that it is a promising transplatin analogue which deserves further studies. [Mh] Termos MeSH primário: Citotoxinas Álcool Nicotinílico Platina [Mh] Termos MeSH secundário: Linhagem Celular Tumoral Cristalografia por Raios X Citotoxinas/síntese química Citotoxinas/química Citotoxinas/farmacologia Ensaios de Seleção de Medicamentos Antitumorais Seres Humanos Álcool Nicotinílico/síntese química Álcool Nicotinílico/química Álcool Nicotinílico/farmacologia Platina/química Platina/farmacologia [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Cytotoxins); 49DFR088MY (Platinum); 9TF312056Y (Nicotinyl Alcohol) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 170904 [Lr] Data última revisão: 170904 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 160519 [St] Status: MEDLINE

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[PMID]: 25119485 [Au] Autor: Akinwole PO; Lefevre E; Powell MJ; Findlay RH [Ad] Endereço: Department of Biological Sciences, University of Alabama, Tuscaloosa, AL, 35487, USA. [Ti] Título: Unique odd-chain polyenoic phospholipid fatty acids present in chytrid fungi. [So] Source: Lipids;49(9):933-42, 2014 Sep. [Is] ISSN: 1558-9307 [Cp] País de publicação: Germany [La] Idioma: eng [Ab] Resumo: Chytrid fungi are ubiquitous components of aquatic and terrestrial ecosystems yet they remain understudied. To investigate the use of phospholipid fatty acids as phenotypic characteristics in taxonomic studies and biomarkers for ecological studies, 18 chytrid fungi isolated from soil to freshwater samples were grown in defined media and their phospholipid fatty acid profile determined. Gas chromatographic/mass spectral analysis indicated the presence of fatty acids typically associated with fungi, such as 16:1(n-7), 16:0, 18:2(n-6), 18:3(n-3) 18:1(n-9), and 18:0, as well as, a number of odd-chain length fatty acids, including two polyunsaturated C-17 fatty acids. Conversion to their 3-pyridylcarbinol ester facilitated GC-MS determination of double-bond positions and these fatty acid were identified as 6,9-17:2 [17:2(n-8)] and 6,9,12-17:3 [17:3(n-5)]. To the best of our knowledge, this is the first report of polyunsaturated C-17 fatty acids isolated from the phospholipids of chytrid fungi. Cluster analysis of PLFA profiles showed sufficient correlation with chytrid phylogeny to warrant inclusion of lipid analysis in species descriptions and the presence of several phospholipid fatty acids of restricted phylogenetic distributions suggests their usefulness as biomarkers for ecological studies. [Mh] Termos MeSH primário: Ácidos Graxos/análise Fungos/química Fosfolipídeos/análise [Mh] Termos MeSH secundário: Quitridiomicetos/química Quitridiomicetos/metabolismo Análise por Conglomerados Ácidos Graxos/química Ácidos Graxos Insaturados/análise Ácidos Graxos Insaturados/química Água Doce/microbiologia Fungos/metabolismo Álcool Nicotinílico/análise Fosfolipídeos/química Filogenia Microbiologia do Solo [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Fatty Acids); 0 (Fatty Acids, Unsaturated); 0 (Phospholipids); 9TF312056Y (Nicotinyl Alcohol) [Em] Mês de entrada: 1506 [Cu] Atualização por classe: 171105 [Lr] Data última revisão: 171105 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 140815 [St] Status: MEDLINE [do] DOI: 10.1007/s11745-014-3934-3

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[PMID]: 24722816 [Au] Autor: Le Grand B; Letienne R; Dupont-Passelaigue E; Lantoine-Adam F; Longo F; David-Dufilho M; Michael G; Nishida K; Catheline D; Legrand P; Hatem S; Nattel S [Ad] Endereço: Institut de Recherche Pierre Fabre, Castres Cedex, France, bruno.le.grand@pierre-fabre.com. [Ti] Título: F 16915 prevents heart failure-induced atrial fibrillation: a promising new drug as upstream therapy. [So] Source: Naunyn Schmiedebergs Arch Pharmacol;387(7):667-77, 2014 Jul. [Is] ISSN: 1432-1912 [Cp] País de publicação: Germany [La] Idioma: eng [Ab] Resumo: Atrial fibrillation (AF) is a common complication of heart failure. The aim of the present study was to investigate the effects of a new pure docosahexaenoic acid derivative called F 16915 in experimental models of heart failure-induced atria dysfunction. The atrial dysfunction-induced AF was investigated (1) in a dog model of tachypacing-induced congestive heart failure and (2) in a rat model of heart failure induced by occlusion of left descending coronary artery and 2 months reperfusion. F 16915 (5 g/day for 4 weeks) significantly reduced the mean duration of AF induced by burst pacing in the dog model (989 ± 111 s in the vehicle group to 79 ± 59 s with F 16915, P < 0.01). This dose of F 16915 also significantly reduced the incidence of sustained AF (5/5 dogs in the vehicle group versus 1/5 with F 16915, P < 0.05). In the rat model, the percentage of shortening fraction in the F 16915 group (100 mg/kg p.o. daily) was significantly restored after 2 months (32.6 ± 7.4 %, n = 9 vs 17.6 ± 3.4 %, n = 9 in the vehicle group, P < 0.01). F 16915 also reduced the de-phosphorylation of connexin43 from atria tissue. The present results show that treatment with F 16915 reduced the heart dilation, resynchronized the gap junction activity, and reduced the AF duration in models of heart failure. Thus, F 16915 constitutes a promising new drug as upstream therapy for the treatment of AF in patients with heart failure. [Mh] Termos MeSH primário: Antiarrítmicos/uso terapêutico Fibrilação Atrial/tratamento farmacológico Ácidos Docosa-Hexaenoicos/uso terapêutico Insuficiência Cardíaca/tratamento farmacológico Pró-Fármacos/uso terapêutico Piridinas/uso terapêutico [Mh] Termos MeSH secundário: Animais Antiarrítmicos/sangue Antiarrítmicos/farmacocinética Fibrilação Atrial/metabolismo Fibrilação Atrial/patologia Fibrilação Atrial/fisiopatologia Remodelamento Atrial/efeitos dos fármacos Ácidos Docosa-Hexaenoicos/sangue Ácidos Docosa-Hexaenoicos/metabolismo Ácidos Docosa-Hexaenoicos/farmacocinética Cães Átrios do Coração/metabolismo Átrios do Coração/patologia Insuficiência Cardíaca/metabolismo Insuficiência Cardíaca/patologia Insuficiência Cardíaca/fisiopatologia Ventrículos do Coração/patologia Masculino Álcool Nicotinílico/sangue Pró-Fármacos/farmacocinética Piridinas/sangue Piridinas/farmacocinética Ratos Sprague-Dawley Remodelação Ventricular/efeitos dos fármacos [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Anti-Arrhythmia Agents); 0 (F 16915); 0 (Prodrugs); 0 (Pyridines); 25167-62-8 (Docosahexaenoic Acids); 9TF312056Y (Nicotinyl Alcohol) [Em] Mês de entrada: 1502 [Cu] Atualização por classe: 170920 [Lr] Data última revisão: 170920 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 140412 [St] Status: MEDLINE [do] DOI: 10.1007/s00210-014-0975-3

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[PMID]: 20605277 [Au] Autor: Abuhijleh AL; Khalaf J [Ad] Endereço: Chemistry Department, Birzeit University, P.O. Box 14, West Bank, Palestine. latif@birzeit.edu [Ti] Título: Copper (II) complexes of the anti-inflammatory drug naproxen and 3-pyridylmethanol as auxiliary ligand. Characterization, superoxide dismutase and catecholase--mimetic activities. [So] Source: Eur J Med Chem;45(9):3811-7, 2010 Sep. [Is] ISSN: 1768-3254 [Cp] País de publicação: France [La] Idioma: eng [Ab] Resumo: The synthesis and spectral characterization of binary copper (II) complex of the non-steroidal anti-inflammatory drug naproxen (Nap) with formula [Cu(2)(Nap)(4)](n) (1) and its ternary complex with 3-pyridylmethanol (3-pym) of formula [Cu(Nap)(2)(3-pym)(2)](n) (2) were investigated. Complex 1 is polymeric consisting of units of the known paddle-wheel dicopper (II) tetracarboxylates of four naproxenate ions bridging the two copper atoms. The units are axially connected through the neighboring carboxylate oxygen atoms. The X-ray molecular structure measurements of complex 2 showed that it is polymeric consisting of mononuclear units having trans-CuN(2)O(2) + O(2) chromophores which are bridged by 3-pyridylmethanol ligands through their methanolic oxygen atoms. The measured superoxide dismutase (SOD) mimetic activities of the complexes indicated that complexes 1 and 2 are excellent SOD mimics with an IC(50) of 0.30 microM for complex 1 and 0.39 microM for complex 2. The catecholase activities of the complexes toward the aerobic oxidation of 3,5-di-tert-butylcatechol (DTBC) to 3,5-di-tert-butylquinone (DTBQ) showed that both complexes have moderate catalytic oxidase activities. [Mh] Termos MeSH primário: Catecol Oxidase/metabolismo Cobre/química Naproxeno/química Álcool Nicotinílico/química Compostos Organometálicos/química Compostos Organometálicos/metabolismo Superóxido Dismutase/metabolismo [Mh] Termos MeSH secundário: Anti-Inflamatórios/química Materiais Biomiméticos/química Materiais Biomiméticos/metabolismo Cristalografia por Raios X Ligantes [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Anti-Inflammatory Agents); 0 (Ligands); 0 (Organometallic Compounds); 57Y76R9ATQ (Naproxen); 789U1901C5 (Copper); 9TF312056Y (Nicotinyl Alcohol); EC 1.10.3.1 (Catechol Oxidase); EC 1.15.1.1 (Superoxide Dismutase) [Em] Mês de entrada: 1011 [Cu] Atualização por classe: 131121 [Lr] Data última revisão: 131121 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 100708 [St] Status: MEDLINE [do] DOI: 10.1016/j.ejmech.2010.05.031

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[PMID]: 19853978 [Au] Autor: Ramos-Lima FJ; Moneo V; Quiroga AG; Carnero A; Navarro-Ranninger C [Ad] Endereço: Departamento de Química Inorgánica, Universidad Autónoma de Madrid, Francisco Tomas y Valiente 7, 28049 Madrid, Spain. [Ti] Título: The role of p53 in the cellular toxicity by active trans-platinum complexes containing isopropylamine and hydroxymethylpyridine. [So] Source: Eur J Med Chem;45(1):134-41, 2010 Jan. [Is] ISSN: 1768-3254 [Cp] País de publicação: France [La] Idioma: eng [Ab] Resumo: Despite some initial research that reported a lack of activity of trans geometry, complexes with general formula trans-[PtCl2(L)(L')] exhibit an important cytotoxic activity in cisplatin-sensitive and resistant cell lines. Based on the proposed mechanism of action for the trans-platinum compounds, they might form DNA adducts initiating a DNA-damage response and ultimately ending in the activation of the p53 protein. In the present work, we have studied the biochemical properties of the trans-[PtCl2(isopropylamine)(L)] complexes (where L is 3- or 4-(hydroxymethyl)-pyridine) against several cell lines and the relationship between cytotoxicity and the protein p53. Both complexes showed different antitumoral properties depending on the presence or absence of protein p53 in isogenic colon carcinoma HCT116 cell lines. Cell cycle studies with the complexes in these cell lines were performed to investigate their antitumoral activity. Apoptosis was observed to be launched from G1 or G2/M accumulations. Confocal microscopy showed the different behaviour of isogenic tumoral cell lines treated with the trans-platinum complexes. Our data suggest that small differences in the carrier ligands could play an important role in the overall biological effects. The body of the research regarding structure-activity relationships such as the different position of groups in the carrier ligands will provide new rational basis for the design of new platinum antitumor drugs. [Mh] Termos MeSH primário: Álcool Nicotinílico/química Compostos Organoplatínicos/química Compostos Organoplatínicos/farmacologia Propilaminas/química Piridinas/química Proteína Supressora de Tumor p53/metabolismo [Mh] Termos MeSH secundário: Animais Ciclo Celular/efeitos dos fármacos Morte Celular/efeitos dos fármacos Linhagem Celular Tumoral DNA/metabolismo Seres Humanos Compostos Organoplatínicos/metabolismo Estereoisomerismo [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (4-hydroxymethylpyridine); 0 (Organoplatinum Compounds); 0 (Propylamines); 0 (Pyridines); 0 (Tumor Suppressor Protein p53); 9007-49-2 (DNA); 9TF312056Y (Nicotinyl Alcohol); P8W26T4MTD (2-propylamine) [Em] Mês de entrada: 1004 [Cu] Atualização por classe: 131121 [Lr] Data última revisão: 131121 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 091027 [St] Status: MEDLINE [do] DOI: 10.1016/j.ejmech.2009.09.035

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[PMID]: 19660981 [Au] Autor: Singla M; Mathur P [Ad] Endereço: Department of Chemistry, Delhi University, Delhi 110007, India. manishasingla@gmail.com [Ti] Título: Oxidation of alcohols using a manganese (II) complex based on a pentakis benzimidazole amide ligand. [So] Source: Spectrochim Acta A Mol Biomol Spectrosc;74(2):536-43, 2009 Oct 01. [Is] ISSN: 1873-3557 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: A pentakis benzimidazole based penta-amide ligand diethylenetriamine-N,N,N',N',N''-pentakis(2-methyl benzimidazolyl)penta-amide [GBDTPA] has been synthesized and utilized to prepare Mn (II) complexes of general composition [Mn(2)(GBDTPA)X(4)], where X is an exogenous anionic ligand (X = Cl(-), NO(3)(-) and Br(-)). The oxidation of alcohols has been investigated using [Mn(2)(GBDTPA)Cl(4)] as the catalyst and TBHP as an alternate source of oxygen. The respective aldehydic products have been isolated and characterized by (1)H NMR. [Mh] Termos MeSH primário: Álcoois/química Benzimidazóis/química Manganês/química [Mh] Termos MeSH secundário: Amidas/química Catálise Espectroscopia de Ressonância Magnética Álcool Nicotinílico/química Oxirredução Álcool Feniletílico/química Propanóis/química Espectrofotometria Infravermelho [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Alcohols); 0 (Amides); 0 (Benzimidazoles); 0 (Propanols); 42Z2K6ZL8P (Manganese); 9TF312056Y (Nicotinyl Alcohol); ML9LGA7468 (Phenylethyl Alcohol); SS8YOP444F (cinnamyl alcohol) [Em] Mês de entrada: 0912 [Cu] Atualização por classe: 131121 [Lr] Data última revisão: 131121 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 090808 [St] Status: MEDLINE [do] DOI: 10.1016/j.saa.2009.07.001

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[PMID]: 18781728 [Au] Autor: Sípos R; Szabó-Plánka T; Rockenbauer A; Nagy NV; Sima J; Melník M; Nagypál I [Ad] Endereço: Department of Inorganic Chemistry, Slovak Technical University, Bratislava, Slovakia. [Ti] Título: Equilibria of 3-pyridylmethanol with copper(II). A comparative electron spin resonance study by the decomposition of spectra in liquid and frozen solutions. [So] Source: J Phys Chem A;112(41):10280-6, 2008 Oct 16. [Is] ISSN: 1520-5215 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: The copper(II)-3-pyridylmethanol (L) system was investigated in aqueous solution by two-dimensional ESR evaluation at 298 K, and computer simulation of the individual anisotropic spectra at 77 K. The data revealed that the paramagnetic copper(II) complexes [CuL] (2+), [CuL 2] (2+), [CuL 3] (2+), and [CuL 4] (2+) are formed up to pH approximately 7 at a moderate or high excess of ligand. As compared with chelating ligands, two differences were observed for the complexation of 3-pyridylmethanol with copper(II): (1) In contrast with the well-resolved spectra in frozen solution, considerable line-broadening and distortion of the spectral shapes were seen at 298 K, which was interpreted in terms of isomeric equilibria and the medium-rate interconversion of various complexes on the ESR time-scale. (2) At low temperature, there were dramatic changes in the concentration distribution, the minor complexes with higher numbers of coordinating ligands ([CuL 3] (2+) and in particular [CuL 4] (2+)) becoming strongly favored. This phenomenon is explained by the significant differences in the formation enthalpy values of various species, shifting the equilibria according to the van't Hoff equation, and a significant undercooling in the course of fast freezing of the solution, which enhances the changes of the concentration distribution. [Mh] Termos MeSH primário: Cobre/química Álcool Nicotinílico/química Compostos Organometálicos/química [Mh] Termos MeSH secundário: Simulação por Computador Espectroscopia de Ressonância de Spin Eletrônica/métodos Congelamento Concentração de Íons de Hidrogênio Ligantes Modelos Químicos Estrutura Molecular Soluções/química Solventes/química Estereoisomerismo [Pt] Tipo de publicação: COMPARATIVE STUDY; JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Ligands); 0 (Organometallic Compounds); 0 (Solutions); 0 (Solvents); 789U1901C5 (Copper); 9TF312056Y (Nicotinyl Alcohol) [Em] Mês de entrada: 0812 [Cu] Atualização por classe: 131121 [Lr] Data última revisão: 131121 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 080911 [St] Status: MEDLINE [do] DOI: 10.1021/jp805210v

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[PMID]: 17635583 [Au] Autor: de Rosa M; Pennati A; Pandini V; Monzani E; Zanetti G; Aliverti A [Ad] Endereço: Dipartimento di Scienze Biomolecolari e Biotecnologie, Università degli Studi di Milano, Italy. [Ti] Título: Enzymatic oxidation of NADP+ to its 4-oxo derivative is a side-reaction displayed only by the adrenodoxin reductase type of ferredoxin-NADP+ reductases. [So] Source: FEBS J;274(15):3998-4007, 2007 Aug. [Is] ISSN: 1742-464X [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: We have previously shown that Mycobacterium tuberculosis FprA, an NADPH-ferredoxin reductase homologous to mammalian adrenodoxin reductase, promotes the oxidation of NADP(+) to its 4-oxo derivative 3-carboxamide-4-pyridone adenine dinucleotide phosphate [Bossi RT, Aliverti A, Raimondi D, Fischer F, Zanetti G, Ferrari D, Tahallah N, Maier CS, Heck AJ, Rizzi M et al. (2002) Biochemistry41, 8807-8818]. Here, we provide a detailed study of this unusual enzyme reaction, showing that it occurs at a very slow rate (0.14 h(-1)), requires the participation of the enzyme-bound FAD, and is regiospecific in affecting only the C4 of the NADP nicotinamide ring. By protein engineering, we excluded the involvement in catalysis of residues Glu214 and His57, previously suggested to be implicated on the basis of their localization in the three-dimensional structure of the enzyme. Our results substantiate a catalytic mechanism for 3-carboxamide-4-pyridone adenine dinucleotide phosphate formation in which the initial and rate-determining step is the nucleophilic attack of the nicotinamide moiety by an active site water molecule. Whereas plant-type ferredoxin reductases were unable to oxidize NADP(+), the mammalian adrenodoxin reductase also catalyzed this unusual reaction. Thus, the 3-carboxamide-4-pyridone adenine dinucleotide phosphate formation reaction seems to be a peculiar feature of the mitochondrial type of ferredoxin reductases, possibly reflecting conserved properties of their active sites. Furthermore, we showed that 3-carboxamide-4-pyridone adenine dinucleotide phosphate is good ligand and a competitive inhibitor of various dehydrogenases, making this nucleotide analog a useful tool for the characterization of the cosubstrate-binding site of NADPH-dependent enzymes. [Mh] Termos MeSH primário: Ferredoxina-NADP Redutase/metabolismo NADP/metabolismo [Mh] Termos MeSH secundário: Difosfato de Adenosina/análogos & derivados Difosfato de Adenosina/química Difosfato de Adenosina/isolamento & purificação Difosfato de Adenosina/metabolismo Difosfato de Adenosina/farmacologia Animais Catálise Bovinos Crotalus Inibidores Enzimáticos/química Inibidores Enzimáticos/isolamento & purificação Inibidores Enzimáticos/metabolismo Inibidores Enzimáticos/farmacologia Ferredoxina-NADP Redutase/antagonistas & inibidores Ferredoxina-NADP Redutase/classificação Ferredoxina-NADP Redutase/genética Cinética Estrutura Molecular Álcool Nicotinílico/análogos & derivados Álcool Nicotinílico/química Álcool Nicotinílico/isolamento & purificação Álcool Nicotinílico/metabolismo Álcool Nicotinílico/farmacologia Oxirredução Oxigênio/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (3-pyridylcarbinol adenine dinucleotide); 0 (Enzyme Inhibitors); 53-59-8 (NADP); 61D2G4IYVH (Adenosine Diphosphate); 9TF312056Y (Nicotinyl Alcohol); EC 1.18.1.2 (Ferredoxin-NADP Reductase); S88TT14065 (Oxygen) [Em] Mês de entrada: 0709 [Cu] Atualização por classe: 131121 [Lr] Data última revisão: 131121 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 070720 [St] Status: MEDLINE

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[PMID]: 11085408 [Au] Autor: Cui D; Harvison PJ [Ad] Endereço: Department of Pharmaceutical Sciences, University of the Sciences in Philadelphia, PA 19104, USA. [Ti] Título: Determination of the site of glucuronidation in an N-(3,5-dichlorophenyl)succinimide metabolite by electrospray ionization tandem mass spectrometry following derivatization to picolinyl esters. [So] Source: Rapid Commun Mass Spectrom;14(21):1985-90, 2000. [Is] ISSN: 0951-4198 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: Derivatization using 3-pyridylcarbinol coupled with liquid chromatography electrospray ionization tandem mass spectrometry (LC/MS/MS) was used to characterize a novel Phase II metabolite of the nephrotoxic agricultural fungicide, N-(3,5-dichlorophenyl)succinimide (NDPS). A glucuronide conjugate of N-(3,5-dichlorophenyl)-2-hydroxysuccinamic acid (2-NDHSA) was identified in the urine from a rat dosed with [14C]NDPS. However, 2-NDHSA contains an aliphatic hydroxyl group and a carboxylic acid group, both of which are potential sites for glucuronidation. Mass spectrometry alone was unable to distinguish between these possibilities. Since the position of glucuronidation may be important in the mechanism of NDPS-induced nephrotoxicity, chemical derivatization in conjunction with mass spectrometry was used to characterize the glucuronide. The 2-NDHSA glucuronide conjugate was isolated from rat urine, derivatized with 3-pyridylcarbinol, and the derivatized metabolite was then analyzed by LC/MS/MS. Two known NDPS metabolites, 2-NDHSA and N-(3,5-dichlorophenyl)succinamic acid (NDPSA), were also isolated from rat urine and derivatized similarly. 3-Pyridinylcarbinol reacted rapidly with the carboxylic acid groups and formation of the picolinyl esters increased the ionization potential under positive ion conditions. The urinary glucuronide of 2-NDHSA was identified as an alcohol-linked glucuronide by examination of the molecular ions and the collision-induced dissociation (CID) product ion spectra of the derivatized products. When used in combination with mass spectrometry, derivatization of carboxylic acids with 3-pyridylcarbinol provided useful mass fragmentations and is a rapid way to obtain structural information about the position of glucuronidation of NDPS metabolites. [Mh] Termos MeSH primário: Glucuronídeos/análise Glucuronídeos/metabolismo Espectrometria de Massas por Ionização por Electrospray/métodos Succinimidas/metabolismo [Mh] Termos MeSH secundário: Animais Radioisótopos de Carbono Cromatografia Líquida de Alta Pressão Fungicidas Industriais/química Fungicidas Industriais/metabolismo Fungicidas Industriais/farmacologia Fungicidas Industriais/urina Glucuronidase/metabolismo Glucuronídeos/química Glucuronídeos/urina Hidrólise Masculino Estrutura Molecular Álcool Nicotinílico/metabolismo Picolinas/química Picolinas/metabolismo Ratos Ratos Endogâmicos F344 Succinatos/química Succinatos/metabolismo Succinatos/urina Succinimidas/química Succinimidas/farmacologia Succinimidas/urina [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, U.S. GOV'T, P.H.S. [Nm] Nome de substância: 0 (Carbon Radioisotopes); 0 (Fungicides, Industrial); 0 (Glucuronides); 0 (Picolines); 0 (Succinates); 0 (Succinimides); 24096-53-5 (N-(3,5-dichlorophenyl)succinimide); 53219-96-8 (N-(3,5-dichlorophenyl)-2-hydroxysuccinamic acid); 9TF312056Y (Nicotinyl Alcohol); EC 3.2.1.31 (Glucuronidase) [Em] Mês de entrada: 0101 [Cu] Atualização por classe: 131121 [Lr] Data última revisão: 131121 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 001121 [St] Status: MEDLINE

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