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[PMID]:29324339
[Au] Autor:Azzouz R; Peauger L; Gembus V; Tîntas ML; Sopková-de Oliveira Santos J; Papamicaël C; Levacher V
[Ad] Endereço:VFP Therapies, 15 rue François Couperin, 76000 Rouen, France.
[Ti] Título:Novel donepezil-like N-benzylpyridinium salt derivatives as AChE inhibitors and their corresponding dihydropyridine "bio-oxidizable" prodrugs: Synthesis, biological evaluation and structure-activity relationship.
[So] Source:Eur J Med Chem;145:165-190, 2018 Feb 10.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:As an extension of our previous work on donepezil-based "bio-oxidizable" prodrug approach, two new classes of N-benzylpyridinium donepezil analogues in tetralone B2 and acetophenone B3 series and a new set of indanone derivatives B1 were investigated along with the corresponding dihydropyridine prodrugs A1-3. A total of fifty one N-benzylpyridinium quaternary donepezil analogues B1-3 and twenty two prodrugs A1-3 were synthesized and evaluated for their inhibitory activities against hAChE and eqBuChE. While most prodrugs A1-3 were demonstrated to be inactive against AChE (IC > 10 µM), a large number of the corresponding N-benzylpyridinium salt B1-3 exhibited appealing three-to-one-digit nanomolar hAChE inhibitory activities and even reaching subnanomolar activity (IC = 0.36 nM). In addition, in silico docking studies were conducted for several compounds to explain the more relevant in vitro results. Lastly, the influence of the two stereogenic centers in prodrugs A was also evaluated, highlighting not only marked differences in residual AChE inhibitory activity of the four separated isomers of prodrug 23h (IC ranging from 173 nM to 10 µM) but also significant variations of the oxidation rate between two separated diastereoisomers of prodrug 24a. This work provides useful information in the search of a preclinical candidate to conduct further development of this attractive "bio-oxidizable" prodrug strategy.
[Mh] Termos MeSH primário: Acetilcolinesterase/metabolismo
Inibidores da Colinesterase/farmacologia
Di-Hidropiridinas/farmacologia
Pró-Fármacos/farmacologia
Compostos de Piridínio/farmacologia
[Mh] Termos MeSH secundário: Animais
Butirilcolinesterase/metabolismo
Inibidores da Colinesterase/síntese química
Inibidores da Colinesterase/química
Di-Hidropiridinas/química
Relação Dose-Resposta a Droga
Electrophorus
Cavalos
Simulação de Acoplamento Molecular
Estrutura Molecular
Pró-Fármacos/síntese química
Pró-Fármacos/química
Compostos de Piridínio/síntese química
Compostos de Piridínio/química
Sais/síntese química
Sais/química
Sais/farmacologia
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cholinesterase Inhibitors); 0 (Dihydropyridines); 0 (Prodrugs); 0 (Pyridinium Compounds); 0 (Salts); 7M8K3P6I89 (1,4-dihydropyridine); EC 3.1.1.7 (Acetylcholinesterase); EC 3.1.1.8 (Butyrylcholinesterase)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180227
[Lr] Data última revisão:
180227
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180112
[St] Status:MEDLINE


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[PMID]:28457669
[Au] Autor:Kamens HM; Peck C; Garrity C; Gechlik A; Jenkins BC; Rajan A
[Ad] Endereço:Department of Biobehavioral Health, Penn State University, University Park, PA, USA; Center for Brain, Behavior, and Cognition, Penn State University, University Park, PA, USA. Electronic address: hmk123@psu.edu.
[Ti] Título:α6ß2 nicotinic acetylcholine receptors influence locomotor activity and ethanol consumption.
[So] Source:Alcohol;61:43-49, 2017 Jun.
[Is] ISSN:1873-6823
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Nicotinic acetylcholine receptors (nAChRs) in the mesolimbic dopamine system have been implicated in ethanol behaviors. In particular, work in genetically engineered mice has demonstrated that α6-containing nAChRs are involved in ethanol consumption and sedation. A limitation of these studies is that the alteration in the receptor was present throughout development. The recently described α6ß2 antagonist, N,N-decane-1,10-diyl-bis-3-picolinium diiodide (bPiDI), now makes it possible to test for the involvement of these receptors using a pharmacological approach. The aim of this study was to examine the role of α6ß2 nAChRs in ethanol behaviors using a pharmacological approach. Adolescent C57BL/6J mice were treated with bPiDI 30 min prior to testing the mice for binge-like ethanol consumption in the drinking-in-the-dark (DID) test, ethanol-induced motor incoordination using the balance beam, and ethanol-induced sedation using the Loss of Righting Reflex (LORR) paradigm. Adolescent animals were chosen because they express a high amount of α6 mRNA relative to adult animals. Control studies were also performed to determine the effect of bPiDI on locomotor activity and ethanol metabolism. Female mice treated with 20 mg/kg bPiDI had reduced locomotor activity compared to saline-treated animals during the first 30 min following an acute injection. Pretreatment with the α6ß2 antagonist reduced adolescent ethanol consumption but also reduced saccharin consumption. No significant effects were observed on ethanol-induced ataxia, sedation, or metabolism. This study provides evidence that α6ß2 nAChRs are involved in locomotor activity as well as ethanol and saccharin consumption in adolescent animals.
[Mh] Termos MeSH primário: Consumo de Bebidas Alcoólicas/fisiopatologia
Etanol/administração & dosagem
Locomoção/efeitos dos fármacos
Receptores Nicotínicos/fisiologia
[Mh] Termos MeSH secundário: Consumo de Bebidas Alcoólicas/prevenção & controle
Animais
Bebedeira/fisiopatologia
Etanol/efeitos adversos
Feminino
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Antagonistas Nicotínicos/farmacologia
Picolinas/farmacologia
Compostos de Piridínio/farmacologia
Sacarina/administração & dosagem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (N,N-decane-1,10-diyl-bis-3-picolinium); 0 (Nicotinic Antagonists); 0 (Picolines); 0 (Pyridinium Compounds); 0 (Receptors, Nicotinic); 0 (alpha6beta2 nicotinic acetylcholine receptor); 3K9958V90M (Ethanol); FST467XS7D (Saccharin)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180227
[Lr] Data última revisão:
180227
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170502
[St] Status:MEDLINE


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[PMID]:28470883
[Au] Autor:Schardon CL; Tuley A; Er JAV; Swartzel JC; Fast W
[Ad] Endereço:Biochemistry Graduate Program, The University of Texas, Austin, TX, 78712, USA.
[Ti] Título:Selective Covalent Protein Modification by 4-Halopyridines through Catalysis.
[So] Source:Chembiochem;18(15):1551-1556, 2017 08 04.
[Is] ISSN:1439-7633
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:We have investigated 4-halopyridines as selective, tunable, and switchable covalent protein modifiers for use in the development of chemical probes. Nonenzymatic reactivity of 4-chloropyridine with amino acids and thiols was ranked with respect to common covalent protein-modifying reagents and found to have reactivity similar to that of acrylamide, but could be switched to a reactivity similar to that of iodoacetamide upon stabilization of the positively charged pyridinium. Diverse, fragment-sized 4-halopyridines inactivated human dimethylarginine dimethylaminohydrolase-1 (DDAH1) through covalent modification of the active site cysteine, acting as quiescent affinity labels that required off-pathway catalysis through stabilization of the protonated pyridinium by a neighboring aspartate residue. A series of 2-fluoromethyl-substituted 4-chloropyridines demonstrated that the pK and k /K values could be predictably varied over several orders of magnitude. Covalent labeling of proteins in an Escherichia coli lysate was shown to require folded proteins, indicating that alternative proteins can be targeted, and modification is likely to be catalysisdependent. 4-Halopyridines, and quiescent affinity labels in general, represent an attractive strategy to develop reagents with switchable electrophilicity as selective covalent protein modifiers.
[Mh] Termos MeSH primário: Amidoidrolases/química
Piridinas/química
[Mh] Termos MeSH secundário: Acrilamida/química
Marcadores de Afinidade/química
Cisteína/química
Escherichia coli/metabolismo
Glutationa/química
Seres Humanos
Iodoacetamida/química
Fenóis/química
Proteoma/química
Proteoma/metabolismo
Compostos de Piridínio/química
Compostos de Sulfidrila/química
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Affinity Labels); 0 (Phenols); 0 (Proteome); 0 (Pyridines); 0 (Pyridinium Compounds); 0 (Sulfhydryl Compounds); 20R035KLCI (Acrylamide); 7K011JR4T0 (thiophenol); EC 3.5.- (Amidohydrolases); EC 3.5.3.18 (dimethylargininase); GAN16C9B8O (Glutathione); K848JZ4886 (Cysteine); ZRH8M27S79 (Iodoacetamide)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:180122
[Lr] Data última revisão:
180122
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170505
[St] Status:MEDLINE
[do] DOI:10.1002/cbic.201700104


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[PMID]:29199489
[Au] Autor:Alterio V; Esposito D; Monti SM; Supuran CT; De Simone G
[Ad] Endereço:a Istituto di Biostrutture e Bioimagini-CNR , Naples , Italy.
[Ti] Título:Crystal structure of the human carbonic anhydrase II adduct with 1-(4-sulfamoylphenyl-ethyl)-2,4,6-triphenylpyridinium perchlorate, a membrane-impermeant, isoform selective inhibitor.
[So] Source:J Enzyme Inhib Med Chem;33(1):151-157, 2018 Dec.
[Is] ISSN:1475-6374
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Pyridinium containing sulfonamides have been largely investigated as carbonic anhydrase inhibitors (CAIs), showing interesting selectivity features. Nevertheless, only few structural studies are so far available on adducts that these compounds form with diverse CA isoforms. In this paper, we report the structural characterization of the adduct that a triphenylpyridinium derivative forms with hCA II, showing that the substitution of the pyridinium ring plays a key role in determining the conformation of the inhibitor in the active site and consequently the binding affinity to the enzyme. These findings open new perspectives on the basic structural requirements for designing sulfonamide CAIs with a selective inhibition profile.
[Mh] Termos MeSH primário: Anidrase Carbônica II/antagonistas & inibidores
Inibidores da Anidrase Carbônica/farmacologia
Compostos de Piridínio/farmacologia
Sulfonamidas/farmacologia
[Mh] Termos MeSH secundário: Anidrase Carbônica II/metabolismo
Inibidores da Anidrase Carbônica/química
Cristalografia por Raios X
Relação Dose-Resposta a Droga
Seres Humanos
Modelos Moleculares
Estrutura Molecular
Compostos de Piridínio/síntese química
Compostos de Piridínio/química
Relação Estrutura-Atividade
Sulfonamidas/síntese química
Sulfonamidas/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (1-(4-sulfamoylphenylethyl)-2,4,6-triphenylpyridinium); 0 (Carbonic Anhydrase Inhibitors); 0 (Pyridinium Compounds); 0 (Sulfonamides); EC 4.2.1.- (Carbonic Anhydrase II)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171219
[Lr] Data última revisão:
171219
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171205
[St] Status:MEDLINE
[do] DOI:10.1080/14756366.2017.1405263


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[PMID]:28939337
[Au] Autor:Zuzek MC; Grandic M; Benoit E; Frangez R
[Ad] Endereço:Institute of Preclinical Sciences, Veterinary Faculty, University of Ljubljana, Gerbiceva 60, 1000 Ljubljana, Slovenia.
[Ti] Título:Natural polymeric 3-alkylpyridinium salt affects vertebrate skeletal muscle contractility by preferentially blocking neuromuscular transmission.
[So] Source:Toxicol Lett;281:95-101, 2017 Nov 05.
[Is] ISSN:1879-3169
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:The effects of natural polymeric alkylpyridinium salt (nPoly-3-APS), a potent acetylcholinesterase inhibitor isolated from the marine sponge Reniera sarai, were studied on isolated mouse phrenic nerve-hemidiaphragm muscle preparations using electrophysiological approaches. nPoly-3-APS inhibited nerve-evoked isometric muscle twitch and tetanic contraction in a concentration-dependent manner (IC =29.4µM and 18.5µM, respectively) and produced a 30-44% decrease of directly muscle-elicited twitch and tetanus amplitudes at 54.4µM. Additionally, nPoly-3-APS (9.1-27.2µM) markedly decreased the amplitude of miniature endplate potentials, while their frequency was only affected at the highest concentration used. Endplate potentials were also inhibited by nPoly-3-APS in a concentration-dependent manner (IC =20.1µM), without significant change in the resting membrane potential of muscle fibers (up to 54.4µM). In conclusion, our results show, for the first time, that nPoly-3-APS preferentially blocks the neuromuscular transmission, in vitro, by a non-depolarizing mechanism. This strongly suggests that the in vivo toxicity of nPoly-3-APS mainly occurs through an antagonist action of the compound on nicotinic acetylcholine receptors of skeletal muscles.
[Mh] Termos MeSH primário: Contração Muscular/efeitos dos fármacos
Músculo Esquelético/efeitos dos fármacos
Polímeros/toxicidade
Compostos de Piridínio/toxicidade
Transmissão Sináptica/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Inibidores da Colinesterase/toxicidade
Diafragma/efeitos dos fármacos
Modelos Animais de Doenças
Concentração Inibidora 50
Masculino
Potenciais da Membrana/efeitos dos fármacos
Camundongos
Camundongos Endogâmicos BALB C
Músculo Esquelético/metabolismo
Junção Neuromuscular/efeitos dos fármacos
Nervo Frênico/efeitos dos fármacos
Receptores Nicotínicos/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cholinesterase Inhibitors); 0 (Polymers); 0 (Pyridinium Compounds); 0 (Receptors, Nicotinic); 0 (poly-APS)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171106
[Lr] Data última revisão:
171106
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170924
[St] Status:MEDLINE


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[PMID]:28859059
[Au] Autor:Mita MM; Mita AC; Moseley JL; Poon J; Small KA; Jou YM; Kirschmeier P; Zhang D; Zhu Y; Statkevich P; Sankhala KK; Sarantopoulos J; Cleary JM; Chirieac LR; Rodig SJ; Bannerji R; Shapiro GI
[Ad] Endereço:Institute for Drug Development, Cancer Therapy and Research Center at University of Texas Health Science Center, San Antonio, TX 78229, USA.
[Ti] Título:Phase 1 safety, pharmacokinetic and pharmacodynamic study of the cyclin-dependent kinase inhibitor dinaciclib administered every three weeks in patients with advanced malignancies.
[So] Source:Br J Cancer;117(9):1258-1268, 2017 Oct 24.
[Is] ISSN:1532-1827
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Dinaciclib is a potent inhibitor of cell cycle and transcriptional cyclin-dependent kinases. This Phase 1 study evaluated the safety, tolerability and pharmacokinetics of various dosing schedules of dinaciclib in advanced solid tumour patients and assessed pharmacodynamic and preliminary anti-tumour activity. METHODS: In part 1, patients were enrolled in escalating cohorts of 2-h infusions administered once every 3 weeks, utilising an accelerated titration design until a recommended phase 2 dose (RP2D) was defined. In part 2, 8- and 24-h infusions were evaluated. Pharmacokinetic parameters were determined for all schedules. Pharmacodynamic effects were assessed with an ex vivo stimulated lymphocyte proliferation assay performed in whole blood.Effects of dinaciclib on retinoblastoma (Rb) phosphorylation and other CDK targets were evaluated in skin and tumour biopsies. In addition to tumour size, metabolic response was evaluated by 18F-fluorodeoxyglucose-positron emission tomography. RESULTS: Sixty-one patients were enrolled to parts 1 and 2. The RP2Ds were 50, 7.4 and 10.4 mg m as 2- 8- and 24-hour infusions, respectively. Dose-limiting toxicities included pancytopenia, neutropenic fever, elevated transaminases, hyperuricemia and hypotension. Pharmacokinetics demonstrated rapid distribution and a short plasma half-life. Dinaciclib suppressed proliferation of stimulated lymphocytes. In skin and tumour biopsies, dinaciclib reduced Rb phosphorylation at CDK2 phospho-sites and modulated expression of cyclin D1 and p53, suggestive of CDK9 inhibition. Although there were no RECIST responses, eight patients had prolonged stable disease and received between 6 and 30 cycles. Early metabolic responses occurred. CONCLUSIONS: Dinaciclib is tolerable at doses demonstrating target engagement in surrogate and tumour tissue.
[Mh] Termos MeSH primário: Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico
Quinases Ciclina-Dependentes/antagonistas & inibidores
Neoplasias/tratamento farmacológico
Inibidores de Proteínas Quinases/uso terapêutico
Compostos de Piridínio/uso terapêutico
[Mh] Termos MeSH secundário: Adolescente
Adulto
Idoso
Compostos Bicíclicos Heterocíclicos com Pontes/farmacocinética
Esquema de Medicação
Feminino
Seguimentos
Seres Humanos
Masculino
Meia-Idade
Estadiamento de Neoplasias
Neoplasias/patologia
Prognóstico
Inibidores de Proteínas Quinases/farmacocinética
Compostos de Piridínio/farmacocinética
Distribuição Tecidual
Adulto Jovem
[Pt] Tipo de publicação:CLINICAL TRIAL, PHASE I; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bridged Bicyclo Compounds, Heterocyclic); 0 (Protein Kinase Inhibitors); 0 (Pyridinium Compounds); 4V8ECV0NBQ (dinaciclib); EC 2.7.11.22 (Cyclin-Dependent Kinases)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171111
[Lr] Data última revisão:
171111
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170901
[St] Status:MEDLINE
[do] DOI:10.1038/bjc.2017.288


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[PMID]:28843708
[Au] Autor:Wang PY; Fang HS; Shao WB; Zhou J; Chen Z; Song BA; Yang S
[Ad] Endereço:State Key Laboratory Breeding Base of Green Pesticide and Agricultural Bioengineering, Key Laboratory of Green Pesticide and Agricultural Bioengineering, Ministry of Education, Center for R&D of Fine Chemicals of Guizhou University, Guiyang 550025, China.
[Ti] Título:Synthesis and biological evaluation of pyridinium-functionalized carbazole derivatives as promising antibacterial agents.
[So] Source:Bioorg Med Chem Lett;27(18):4294-4297, 2017 09 15.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Various pyridinium-functionalized carbazole derivatives were constructed by coupling the key fragments of carbazole skeleton and pyridinium nucleus in a single molecular architecture. Antibacterial bioassays revealed that some of the title compounds displayed impressive bioactivities against plant pathogens such as Xanthomonas oryzae pv. oryzae, Ralstonia solanacearum, and Xanthomonas axonopodis pv. citri with minimal EC values of up to 0.4, 0.3, and 0.3mg/L, respectively. These bioactivities were achieved by systematically tuning and optimizing bridging linker, alkyl length of the tailor, and substituents on the carbazole scaffold. Compared with the bioactivity of the lead compound (AP-10), antibacterial efficacy dramatically increased by approximately 13-, 104- and 21-fold. This finding suggested that these compounds can serve as new lead compounds in research on antibacterial chemotherapy.
[Mh] Termos MeSH primário: Antibacterianos/farmacologia
Carbazóis/farmacologia
Compostos de Piridínio/farmacologia
Ralstonia solanacearum/efeitos dos fármacos
Xanthomonas/efeitos dos fármacos
[Mh] Termos MeSH secundário: Antibacterianos/síntese química
Antibacterianos/química
Carbazóis/síntese química
Carbazóis/química
Relação Dose-Resposta a Droga
Testes de Sensibilidade Microbiana
Estrutura Molecular
Compostos de Piridínio/química
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Anti-Bacterial Agents); 0 (Carbazoles); 0 (Pyridinium Compounds); 0P2197HHHN (carbazole)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171125
[Lr] Data última revisão:
171125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170828
[St] Status:MEDLINE


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[PMID]:28797883
[Au] Autor:Lan JS; Ding Y; Liu Y; Kang P; Hou JW; Zhang XY; Xie SS; Zhang T
[Ad] Endereço:Experiment Center of Teaching & Learning, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
[Ti] Título:Design, synthesis and biological evaluation of novel coumarin-N-benzyl pyridinium hybrids as multi-target agents for the treatment of Alzheimer's disease.
[So] Source:Eur J Med Chem;139:48-59, 2017 Oct 20.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:Combining N-benzyl pyridinium moiety and coumarin into in a single molecule, novel hybrids with ChE and MAO-B inhibitory activities were designed and synthesized. The biological screening results indicated that most of compounds displayed potent inhibitory activity for ChE and Aß (1-42) self-aggregation, and clearly selective inhibition to MAO-B over MAO-A. Of these compounds, compound 7f was the most potent inhibitor for hMAO-B, and it was also a good and balanced inhibitor to ChEs and hMAO-B (0.0373 µM for eeAChE; 2.32 µM for eqBuChE; 1.57 µM for hMAO-B). Molecular modeling and kinetic studies revealed that compound 7f was a mixed-type inhibitor, which bond simultaneously to CAS and PAS of AChE, and it was also a competitive inhibitor, which occupied the active site of MAO-B. In addition, compound 7f with no toxicity on PC12 neuroblastoma cells, showed good ability to inhibit Aß (1-42) self-aggregation and cross the BBB. Collectively, all these results suggested that compound 7f might be a promising multi-target lead candidate worthy of further pursuit.
[Mh] Termos MeSH primário: Doença de Alzheimer/tratamento farmacológico
Inibidores da Colinesterase/farmacologia
Cumarínicos/farmacologia
Desenho de Drogas
Inibidores da Monoaminoxidase/farmacologia
Compostos de Piridínio/farmacologia
[Mh] Termos MeSH secundário: Acetilcolinesterase/metabolismo
Doença de Alzheimer/metabolismo
Peptídeos beta-Amiloides/antagonistas & inibidores
Peptídeos beta-Amiloides/metabolismo
Animais
Inibidores da Colinesterase/química
Cumarínicos/química
Relação Dose-Resposta a Droga
Seres Humanos
Estrutura Molecular
Monoaminoxidase/metabolismo
Inibidores da Monoaminoxidase/síntese química
Inibidores da Monoaminoxidase/química
Células PC12
Agregados Proteicos/efeitos dos fármacos
Compostos de Piridínio/química
Ratos
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amyloid beta-Peptides); 0 (Cholinesterase Inhibitors); 0 (Coumarins); 0 (Monoamine Oxidase Inhibitors); 0 (Protein Aggregates); 0 (Pyridinium Compounds); EC 1.4.3.4 (Monoamine Oxidase); EC 1.4.3.4. (monoamine oxidase A, human); EC 3.1.1.7 (Acetylcholinesterase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171031
[Lr] Data última revisão:
171031
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170812
[St] Status:MEDLINE


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[PMID]:28756008
[Au] Autor:Moharram SA; Shah K; Khanum F; Marhäll A; Gazi M; Kazi JU
[Ad] Endereço:Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund, Sweden; Lund Stem Cell Center, Department of Laboratory Medicine, Lund University, Lund, Sweden.
[Ti] Título:Efficacy of the CDK inhibitor dinaciclib in vitro and in vivo in T-cell acute lymphoblastic leukemia.
[So] Source:Cancer Lett;405:73-78, 2017 Oct 01.
[Is] ISSN:1872-7980
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:T-cell acute lymphoblastic leukemia (T-ALL) is a heterogeneous disease of the blood affecting children, adolescents and adults. Although current treatment protocols for T-ALL have improved overall survival, a portion of T-ALL patients still experiences treatment failure. Thus, the development of novel therapies is needed. In this study, we used several patient-derived T-ALL cell lines to screen for an effective drug for T-ALL. Using a panel of 378 inhibitors against different kinases, we identified the CDK inhibitor dinaciclib as a potential drug for T-ALL. Dinaciclib treatment significantly reduced cell viability and completely blocked colony formation. Furthermore, cells treated with dinaciclib showed decreased expression of several pro-survival proteins including survivin, cyclin T1 and c-MYC. Dinaciclib treatment also increased accumulation of cells in G2/M phase and significantly induced apoptosis. Finally, dinaciclib extended survival of mice in a T-ALL cell xenograft model. Collectively, these data suggest that the CDK inhibitor dinaciclib is an active drug for T-ALL in the preclinical settings.
[Mh] Termos MeSH primário: Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia
Terapia de Alvo Molecular/métodos
Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico
Inibidores de Proteínas Quinases/farmacologia
Compostos de Piridínio/farmacologia
[Mh] Termos MeSH secundário: Adulto
Animais
Apoptose/efeitos dos fármacos
Pontos de Checagem do Ciclo Celular/efeitos dos fármacos
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Sobrevivência Celular/efeitos dos fármacos
Quinases Ciclina-Dependentes/metabolismo
Modelos Animais de Doenças
Seres Humanos
Camundongos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bridged Bicyclo Compounds, Heterocyclic); 0 (Protein Kinase Inhibitors); 0 (Pyridinium Compounds); 4V8ECV0NBQ (dinaciclib); EC 2.7.11.22 (Cyclin-Dependent Kinases)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170920
[Lr] Data última revisão:
170920
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170731
[St] Status:MEDLINE


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[PMID]:28734604
[Au] Autor:Corazza G; Merib J; Magosso HA; Bittencourt OR; Carasek E
[Ad] Endereço:Departamento de Química, Universidade Federal de Santa Catarina, Florianópolis, 88040-900, SC, Brazil.
[Ti] Título:A hybrid material as a sorbent phase for the disposable pipette extraction technique enhances efficiency in the determination of phenolic endocrine-disrupting compounds.
[So] Source:J Chromatogr A;1513:42-50, 2017 Sep 01.
[Is] ISSN:1873-3778
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:In this study, the hybrid material 3-n-propyl(3-methylpyridinium) silsesquioxane chloride (Si3Py Cl ) was synthesized and investigated as a novel sorbent phase for the disposable pipette extraction (DPX) technique coupled to high-performance liquid chromatography-florescence detection. This sorbent phase was characterized by scanning electron microscopy (SEM) and Fourier transform infrared spectroscopy (FTIR). Aqueous samples containing the phenolic endocrine-disrupting compounds bisphenol A (BPA), 17α-ethynylestradiol (EE2), 4-tert-octylphenol (4-t-OP), 4-octylphenol (4-OP) and 4-nonylphenol (4-NP) were subjected to DPX procedures and a series of optimizations was performed to determine the ideal extraction conditions using this approach. The proposed sorbent phase exhibited higher extraction efficiency than DPX-RP (reversed phase tips containing styrene-divinylbenzene), commonly used for the determination of the phenolic endocrine- disrupting-compounds under study. Satisfactory analytical performance was achieved with linear ranges from 2 to 100µgL for 4-t-OP and 1-100µgL for the other analytes. Limits of detection of 0.60µgL for 4-t-OP and 0.30µgL for other analytes, RSDs ranging from 1 to 20% and relative recoveries of 83-116% were obtained. Based on these satisfactory results, this sorbent phase represents a valuable alternative for the extraction of compounds with polar moieties in their structure.
[Mh] Termos MeSH primário: Disruptores Endócrinos/análise
Fenol/análise
Compostos de Piridínio/síntese química
Siloxanas/síntese química
Poluentes Químicos da Água/análise
[Mh] Termos MeSH secundário: Adsorção
Cromatografia Líquida de Alta Pressão
Concentração de Íons de Hidrogênio
Limite de Detecção
Microscopia Eletrônica de Varredura
Sensibilidade e Especificidade
Extração em Fase Sólida
Espectroscopia de Infravermelho com Transformada de Fourier
Propriedades de Superfície
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (3-n-propyl(3-methylpyridinium)silsesquioxane); 0 (Endocrine Disruptors); 0 (Pyridinium Compounds); 0 (Siloxanes); 0 (Water Pollutants, Chemical); 339NCG44TV (Phenol)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170825
[Lr] Data última revisão:
170825
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170724
[St] Status:MEDLINE



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