Base de dados : MEDLINE
Pesquisa : A11.284.835.540 [Categoria DeCS]
Referências encontradas : 22352 [refinar]
Mostrando: 1 .. 10   no formato [Detalhado]

página 1 de 2236 ir para página                         

  1 / 22352 MEDLINE  
              next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:29235764
[Au] Autor:Marchenko MM; Ketsa OV; Shmarakov IO; Abutnaritsa KH
[Ti] Título:Monooxygenase system in Guerin's carcinoma of rats under conditions of ω-3 polyunsaturated fatty acids administration.
[So] Source:Ukr Biochem J;88(4):48-56, 2016 Jul-Aug.
[Is] ISSN:2409-4943
[Cp] País de publicação:Ukraine
[La] Idioma:eng
[Ab] Resumo:The aim of the study was to determine the variations of function in components of monooxygenase system (MOS) of rat Guerin's carcinoma under ω-3 polyunsaturated fatty acids (PUFAs) administration. The activity of Guerin's carcinoma microsomal NADH-cytochrome b5 reductase, the content and the rate of cytochrome b5 oxidation-reduction, the content and the rate of cytochrome Р450 oxidation-reduction have been investigated in rats with tumor under conditions of ω-3 PUFAs administration. ω-3 PUFAs supplementation before and after transplantation of Guerin's carcinoma resulted in the increase of NADH-cytochrome b5 reductase activity and decrease of cytochrome b5 level in the Guerin's carcinoma microsomal fraction in the logarithmic phases of carcinogenesis as compared to the tumor-bearing rats. Increased activity of NADH-cytochrome b5 reductase facilitates higher electron flow in redox-chain of MOS. Under decreased cytochrome b5 levels the electrons are transferred to oxygen, which leads to heightened generation of superoxide (O2•-) in comparison to control. It was shown, that the decrease of cytochrome P450 level in the Guerin's carcinoma microsomal fraction in the logarithmic phases of oncogenesis under ω-3 PUFAs administration may be associated with its transition into an inactive form ­ cytochrome P420. This decrease in cytochrome P450 coincides with increased generation of superoxide by MOS oxygenase chain.
[Mh] Termos MeSH primário: Carcinoma/tratamento farmacológico
Elétrons
Ácidos Graxos Ômega-3/farmacologia
Expressão Gênica/efeitos dos fármacos
Microssomos/efeitos dos fármacos
Substâncias Protetoras/farmacologia
[Mh] Termos MeSH secundário: Animais
Carcinoma/enzimologia
Carcinoma/patologia
Sistema Enzimático do Citocromo P-450/genética
Sistema Enzimático do Citocromo P-450/metabolismo
Citocromo-B(5) Redutase/genética
Citocromo-B(5) Redutase/metabolismo
Citocromos/genética
Citocromos/metabolismo
Citocromos b5/genética
Citocromos b5/metabolismo
Transporte de Elétrons/efeitos dos fármacos
Feminino
Membro Posterior
Injeções Subcutâneas
Microssomos/enzimologia
Transplante de Neoplasias
Oxirredução/efeitos dos fármacos
Estresse Oxidativo/efeitos dos fármacos
Ratos
Superóxidos/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cytochromes); 0 (Fatty Acids, Omega-3); 0 (Protective Agents); 11062-77-4 (Superoxides); 9035-39-6 (Cytochromes b5); 9035-49-8 (cytochrome P420); 9035-51-2 (Cytochrome P-450 Enzyme System); EC 1.6.2.2 (Cytochrome-B(5) Reductase)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180116
[Lr] Data última revisão:
180116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171214
[St] Status:MEDLINE
[do] DOI:10.15407/ubj88.04.048


  2 / 22352 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28462841
[Au] Autor:Chen L; Chen D; Tang L; Ren J; Chen J; Zhen X; Liu YC; Zhang C; Luo H; Shen J; Xiong B
[Ad] Endereço:School of PharmaceuticalSciences, Nanchang University, Nanchang 330006, China; Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
[Ti] Título:Design and optimization of purine derivatives as in vivo active PDE10A inhibitors.
[So] Source:Bioorg Med Chem;25(13):3315-3329, 2017 07 01.
[Is] ISSN:1464-3391
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Phosphodiesterases are important enzymes regulating signal transduction mediated by second messenger molecules cAMP or cGMP. PDE10A is a unique member in the PDE family because of its selective expression in medium spiny neurons. It is recognized as anti-psychotic drug target. Based on the structural similarity between our previous chemistry work on 8-aminoimidazo[1,2-a]pyrazines and the PDE10A inhibitors reported by Bartolome-Nebreda et al., we initialized a project for developing PDE10A inhibitors. After several rounds of optimization, we were able to obtain a few compounds with good PDE10A enzymatic activity. And after further PDE enzymatic selectivity study, metabolic stability assay and in vivo pharmacological tests we identified two inhibitors as interesting lead compounds with the potential for further PDE10A lead optimizatioin.
[Mh] Termos MeSH primário: Desenho de Drogas
Diester Fosfórico Hidrolases/metabolismo
Purinas/farmacologia
[Mh] Termos MeSH secundário: Animais
Relação Dose-Resposta a Droga
Seres Humanos
Locomoção/efeitos dos fármacos
Masculino
Camundongos
Microssomos/química
Microssomos/metabolismo
Estrutura Molecular
Inibição Pré-Pulso/efeitos dos fármacos
Purinas/síntese química
Purinas/química
Ratos
Ratos Sprague-Dawley
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Purines); EC 3.1.4.- (PDE10A protein, human); EC 3.1.4.- (Phosphoric Diester Hydrolases); W60KTZ3IZY (purine)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171208
[Lr] Data última revisão:
171208
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE


  3 / 22352 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28892748
[Au] Autor:Zhang Z; Lv Z; Wei Z; Li C; Shao Y; Zhang W; Zhao X; Xiong J
[Ad] Endereço:School of Marine Sciences, Ningbo University, Ningbo 315211, PR China.
[Ti] Título:Microsomal glutathione transferase 2 modulates LTC4 synthesis and ROS production in Apostichopus japonicus.
[So] Source:Mol Immunol;91:114-122, 2017 11.
[Is] ISSN:1872-9142
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Microsomal glutathione transferase 2 (mGST2) is an integral membrane protein involved in detoxication of xenobiotics, and has also been suggested to catalyze the biosynthesis of pro-inflammatory mediator leukotriene C4 (LTC4) as homologous to LTC4 synthase (LTC4S) in mammals. In the present study, a novel mGST2 homology was identified from Apostichopus japonicus (designated as AjmGST2) by RACE approaches. The full-length cDNA of AjmGST2 was of 1917bp encoding a polypeptide of 161 amino acids residues. Multiple sequences alignment and phylogenetic analysis together supported that AjmGST2 belonged to a new member in invertebrate mGSTs family and close to mammalian LTC4S. Spatial expression analysis revealed that AjmGST2 was ubiquitously expressed in all examined tissues with the larger magnitude in intestine. AjmGST2 transcripts in coelomocytes were slightly induced post 6h challenge of pathogenic Vibrio splendidus and reached the peak expression at 48h. The increased expression profiles of AjmGST2 were also detected in lipopolysaccharide (LPS) exposed primary coelomocytes. Consistently, LTC4 contents were also induced by a 1.56-fold increase in the same condition. Functional assay further revealed that AjmGST2 might be functioned as LTC4S to promote LTC4 synthesis. AjmGST2 knock-down by specific siRNA significantly depressed LTC4 contents with 27.0% decrease at 24h. Meantime, ROS levels were elevated by 40.1% in vitro. All of these results indicated that AjmGST2 performed dual functions roles as LTC4S and ROS eliminator in sea cucumber immune response.
[Mh] Termos MeSH primário: Glutationa Transferase/imunologia
Leucotrieno C4/imunologia
Microssomos/imunologia
Espécies Reativas de Oxigênio/imunologia
Pepinos-do-Mar/imunologia
[Mh] Termos MeSH secundário: Animais
Glutationa Transferase/genética
Leucotrieno C4/genética
Pepinos-do-Mar/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Reactive Oxygen Species); 2CU6TT9V48 (Leukotriene C4); EC 2.5.1.18 (Glutathione Transferase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171120
[Lr] Data última revisão:
171120
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170912
[St] Status:MEDLINE


  4 / 22352 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28857471
[Au] Autor:Pirali T; Ciraolo E; Aprile S; Massarotti A; Berndt A; Griglio A; Serafini M; Mercalli V; Landoni C; Campa CC; Margaria JP; Silva RL; Grosa G; Sorba G; Williams R; Hirsch E; Tron GC
[Ad] Endereço:Dipartimento di Scienze del Farmaco, Università degli Studi del Piemonte Orientale "A. Avogadro", Largo Donegani 2, 28100, Novara, Italy.
[Ti] Título:Identification of a Potent Phosphoinositide 3-Kinase Pan Inhibitor Displaying a Strategic Carboxylic Acid Group and Development of Its Prodrugs.
[So] Source:ChemMedChem;12(18):1542-1554, 2017 Sep 21.
[Is] ISSN:1860-7187
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Activation of the phosphoinositide 3-kinase (PI3K) pathway is a key signaling event in cancer, inflammation, and other proliferative diseases. PI3K inhibitors are already approved for some specific clinical indications, but their systemic on-target toxicity limits their larger use. In particular, whereas toxicity is tolerable in acute treatment of life-threatening diseases, this is less acceptable in chronic conditions. In the past, the strategy to overcome this drawback was to block selected isoforms mainly expressed in leukocytes, but redundancy within the PI3K family members challenges the effectiveness of this approach. On the other hand, decreasing exposure to selected target cells represents a so-far unexplored alternative to circumvent systemic toxicity. In this manuscript, we describe the generation of a library of triazolylquinolones and the development of the first prodrug pan-PI3K inhibitor.
[Mh] Termos MeSH primário: Ácidos Carboxílicos/química
Inibidores Enzimáticos/química
Fosfatidilinositol 3-Quinases/antagonistas & inibidores
Pró-Fármacos/química
[Mh] Termos MeSH secundário: Animais
Sítios de Ligação
Ácidos Carboxílicos/metabolismo
Ácidos Carboxílicos/farmacologia
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Desenho de Drogas
Inibidores Enzimáticos/metabolismo
Inibidores Enzimáticos/farmacologia
Seres Humanos
Ligações de Hidrogênio
Concentração Inibidora 50
Camundongos
Microssomos/metabolismo
Simulação de Dinâmica Molecular
Fosfatidilinositol 3-Quinases/metabolismo
Pró-Fármacos/metabolismo
Pró-Fármacos/farmacologia
Ligação Proteica
Isoformas de Proteínas/antagonistas & inibidores
Isoformas de Proteínas/metabolismo
Quinolonas/química
Quinolonas/metabolismo
Quinolonas/farmacologia
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Carboxylic Acids); 0 (Enzyme Inhibitors); 0 (Prodrugs); 0 (Protein Isoforms); 0 (Quinolones); EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171009
[Lr] Data última revisão:
171009
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170901
[St] Status:MEDLINE
[do] DOI:10.1002/cmdc.201700340


  5 / 22352 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28815966
[Au] Autor:Mukherjee P; Pettersson M; Dutra JK; Xie L; Am Ende CW
[Ad] Endereço:Pfizer Worldwide Research & Development, Eastern Point Road, Groton, CT, 06340, USA.
[Ti] Título:Trifluoromethyl Oxetanes: Synthesis and Evaluation as a tert-Butyl Isostere.
[So] Source:ChemMedChem;12(19):1574-1577, 2017 Oct 09.
[Is] ISSN:1860-7187
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:The synthesis of a new trifluoromethyl oxetane was developed using a Corey-Chaykovsky epoxidation/ring-expansion reaction of trifluoromethyl ketones. The reaction was shown to proceed under mild conditions and displays a broad substrate scope. The trifluoromethyl oxetane was also evaluated as a tert-butyl isostere in the context of the γ-secretase modulator (GSM) program. We demonstrate that the trifluoromethyl oxetane-containing GSM has decreased lipophilicity, improved lipophilic efficiency (LipE) and metabolic stability relative to the corresponding tert-butyl GSM analogue, thus highlighting several benefits of trifluoromethyl oxetane as a more polar tert-butyl isostere.
[Mh] Termos MeSH primário: Éteres Cíclicos/química
[Mh] Termos MeSH secundário: Secretases da Proteína Precursora do Amiloide/química
Secretases da Proteína Precursora do Amiloide/metabolismo
Peptídeos beta-Amiloides/antagonistas & inibidores
Peptídeos beta-Amiloides/metabolismo
Cristalografia por Raios X
Éteres Cíclicos/síntese química
Éteres Cíclicos/metabolismo
Seres Humanos
Cetonas/química
Microssomos/metabolismo
Conformação Molecular
Fragmentos de Peptídeos/antagonistas & inibidores
Fragmentos de Peptídeos/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amyloid beta-Peptides); 0 (Ethers, Cyclic); 0 (Ketones); 0 (Peptide Fragments); 0 (amyloid beta-protein (1-42)); EC 3.4.- (Amyloid Precursor Protein Secretases); I279Q16FU6 (oxetane)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171030
[Lr] Data última revisão:
171030
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170818
[St] Status:MEDLINE
[do] DOI:10.1002/cmdc.201700333


  6 / 22352 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28623690
[Au] Autor:Siebert MN; Mattos JJ; Toledo-Silva G; Razzera G; Bainy ACD
[Ad] Endereço:Laboratory of Biomarkers of Aquatic Contamination and Immunochemistry - LABCAI, Federal University of Santa Catarina, UFSC, Florianópolis, Santa Catarina, Brazil.
[Ti] Título:Candidate cytochrome P450 genes for ethoxyresorufin O-deethylase activity in oyster Crassostrea gigas.
[So] Source:Aquat Toxicol;189:142-149, 2017 Aug.
[Is] ISSN:1879-1514
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Vertebrate cytochrome P450 1 (CYP1) enzymes metabolize endogenous and xenobiotic compounds and usually demonstrate a substrate-inducible response. Ethoxyresorufin O-deethylase activity (EROD) is a common method to quantify CYP1 enzymes activity in these organisms. Despite the absence of this gene family in protostomes, CYP1-like genes were identified in several species, even though no evolutionary relationship has been established with the vertebrate CYP1 family. In the present study, EROD activity was evaluated in microsomal fraction of gills, digestive gland and mantle of Crassostrea gigas. Enzyme activity was quantified in gills, although no activity was detected in digestive gland and mantle. EROD kinetic characterization in gills using typical Michaelis-Menten equation demonstrated an apparent K of 1.15µM and V of 229.2 fmol.min mg.protein . EROD activity was analyzed in the presence of CYP1 inhibitors, ellipticine (ELP), furafylline (FRF), clotrimazole (CTZ), α-naphthoflavone (ANF), and the non-ionic surfactant Triton X-100. CTZ inhibited EROD activity in all tested concentrations while Triton X-100 (0.5mM) caused 16% inhibition. Transcript levels of four CYP1-like genes were determined in gills, digestive gland and mantle. In general, CYP1-like genes showed higher transcript levels in gills compared to other tissues. The transcript levels of CYP1-like 1 and 2, analyzed together, positively correlated with EROD activity observed in gills, suggesting the possible involvement of these two gene products in EROD activity in this tissue. Homology models of translated CYP1-like 1 and 2 were generated based on human CYP1A1 structure and were similar to the general canonical cytochrome P450 fold. Molecular docking analysis showed that the two putative oyster CYP1-like structures have the potential to metabolize 7-ethoxyresorufin (7-ER), although the contribution of other CYP1-like genes needs to be investigated. Proteins encoded by CYP1-like 1 and 2 genes are plausible candidates for EROD activity observed in gills of C. gigas.
[Mh] Termos MeSH primário: Crassostrea/enzimologia
Crassostrea/genética
Citocromo P-450 CYP1A1
Família 1 do Citocromo P450
Brânquias/enzimologia
Transcrição Genética
[Mh] Termos MeSH secundário: Animais
Crassostrea/efeitos dos fármacos
Citocromo P-450 CYP1A1/antagonistas & inibidores
Citocromo P-450 CYP1A1/genética
Citocromo P-450 CYP1A1/metabolismo
Citocromo P-450 CYP1A2/genética
Citocromo P-450 CYP1A2/metabolismo
Citocromo P-450 CYP1B1/genética
Citocromo P-450 CYP1B1/metabolismo
Inibidores das Enzimas do Citocromo P-450/toxicidade
Família 1 do Citocromo P450/genética
Família 1 do Citocromo P450/metabolismo
Citosol/efeitos dos fármacos
Citosol/enzimologia
Brânquias/efeitos dos fármacos
Seres Humanos
Cinética
Microssomos/efeitos dos fármacos
Microssomos/enzimologia
Simulação de Acoplamento Molecular
Homologia de Sequência de Aminoácidos
Poluentes Químicos da Água/toxicidade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cytochrome P-450 Enzyme Inhibitors); 0 (Water Pollutants, Chemical); EC 1.14.14.1 (CYP1A1 protein, human); EC 1.14.14.1 (CYP1A2 protein, human); EC 1.14.14.1 (CYP1B1 protein, human); EC 1.14.14.1 (Cytochrome P-450 CYP1A1); EC 1.14.14.1 (Cytochrome P-450 CYP1A2); EC 1.14.14.1 (Cytochrome P-450 CYP1B1); EC 1.14.14.1 (Cytochrome P450 Family 1)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171016
[Lr] Data última revisão:
171016
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170618
[St] Status:MEDLINE


  7 / 22352 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28603984
[Au] Autor:Karatas H; Li Y; Liu L; Ji J; Lee S; Chen Y; Yang J; Huang L; Bernard D; Xu J; Townsend EC; Cao F; Ran X; Li X; Wen B; Sun D; Stuckey JA; Lei M; Dou Y; Wang S
[Ad] Endereço:Department of Medicinal Chemistry, ‡Department of Internal Medicine, §Comprehensive Cancer Center, ∥Department of Pathology, ⊥Howard Hughes Medical Institute, #Department of Biological Chemistry, ∇Department of Pharmaceutical Sciences, â—‹Department of Pharmacology, and ¶Life Sciences Inst
[Ti] Título:Discovery of a Highly Potent, Cell-Permeable Macrocyclic Peptidomimetic (MM-589) Targeting the WD Repeat Domain 5 Protein (WDR5)-Mixed Lineage Leukemia (MLL) Protein-Protein Interaction.
[So] Source:J Med Chem;60(12):4818-4839, 2017 Jun 22.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:We report herein the design, synthesis, and evaluation of macrocyclic peptidomimetics that bind to WD repeat domain 5 (WDR5) and block the WDR5-mixed lineage leukemia (MLL) protein-protein interaction. Compound 18 (MM-589) binds to WDR5 with an IC value of 0.90 nM (K value <1 nM) and inhibits the MLL H3K4 methyltransferase (HMT) activity with an IC value of 12.7 nM. Compound 18 potently and selectively inhibits cell growth in human leukemia cell lines harboring MLL translocations and is >40 times better than the previously reported compound MM-401. Cocrystal structures of 16 and 18 complexed with WDR5 provide structural basis for their high affinity binding to WDR5. Additionally, we have developed and optimized a new AlphaLISA-based MLL HMT functional assay to facilitate the functional evaluation of these designed compounds. Compound 18 represents the most potent inhibitor of the WDR5-MLL interaction reported to date, and further optimization of 18 may yield a new therapy for acute leukemia.
[Mh] Termos MeSH primário: Histona-Lisina N-Metiltransferase/metabolismo
Proteína de Leucina Linfoide-Mieloide/metabolismo
Peptídeos Cíclicos/farmacologia
Peptidomiméticos/química
Peptidomiméticos/farmacologia
[Mh] Termos MeSH secundário: Animais
Ligação Competitiva
Linhagem Celular Tumoral
Sobrevivência Celular/efeitos dos fármacos
Técnicas de Química Sintética
Descoberta de Drogas
Estabilidade de Medicamentos
Ensaios de Triagem em Larga Escala/métodos
Histona-Lisina N-Metiltransferase/química
Histona-Lisina N-Metiltransferase/genética
Seres Humanos
Leucemia/tratamento farmacológico
Leucemia/patologia
Compostos Macrocíclicos/síntese química
Compostos Macrocíclicos/química
Compostos Macrocíclicos/farmacologia
Espectroscopia de Ressonância Magnética
Camundongos
Microssomos/efeitos dos fármacos
Simulação de Acoplamento Molecular
Proteína de Leucina Linfoide-Mieloide/genética
Peptídeos Cíclicos/química
Peptidomiméticos/metabolismo
Domínios e Motivos de Interação entre Proteínas
Ratos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (MLL protein, human); 0 (MM-589); 0 (Macrocyclic Compounds); 0 (Peptides, Cyclic); 0 (Peptidomimetics); 0 (WDR5 protein, human); 149025-06-9 (Myeloid-Lymphoid Leukemia Protein); EC 2.1.1.43 (Histone-Lysine N-Methyltransferase)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170811
[Lr] Data última revisão:
170811
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170613
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jmedchem.6b01796


  8 / 22352 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28587824
[Au] Autor:Kumar Biswas B; Malpani YR; Ha N; Kwon DH; Soo Shin J; Kim HS; Kim C; Bong Han S; Lee CK; Jung YS
[Ad] Endereço:Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, 141 Gajeongro, Yuseong, Daejeon 34114, Republic of Korea; Department of Medicinal Chemistry and Pharmacology, University of Science and Technology, 217 Gajeongro, Yuseong, Daejeon 34113, Republic of Korea.
[Ti] Título:Enterovirus inhibitory activity of C-8-tert-butyl substituted 4-aryl-6,7,8,9-tetrahydrobenzo[4,5]thieno[3,2-e][1,2,4]triazolo[4,3-a]pyrimidin-5(4H)-ones.
[So] Source:Bioorg Med Chem Lett;27(15):3582-3585, 2017 08 01.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Members of a series of 4-aryl-6,7,8,9-tetrahydrobenzo[4,5]thieno[3,2-e][1,2,4]triazolo[4,3-a]pyrimidin-5(4H)-ones (1, Fig. 2) were prepared and tested against representative enteroviruses including Human Coxsackievirus B1 (Cox B1), Human Coxsackievirus B3 (Cox B3), human Poliovirus 3 (PV3), human Rhinovirus 14 (HRV14), human Rhinovirus 21 (HRV 21) and human Rhinovirus 71 (HRV 71). The C-8-tert-butyl group on the tetrahydrobenzene ring in these substances was found to be crucial for their enterovirus activity. One member of this group, 1e, showed single digit micromolar activities (1.6-8.85µM) against a spectrum of viruses screened, and the highest selectivity index (SI) values for Cox B1 (>11.2), for Cox B3 (>11.5), and for PV3 (>51.2), respectively. In contrast, 1p, was the most active analog against the selected HRVs (1.8-2.6µM), and showed the highest selectivity indices among the group of compounds tested. The SI values for 1p were 11.5 for HRV14, 8.4 for HRV21, and 12.1 for HRV71, respectively.
[Mh] Termos MeSH primário: Antivirais/química
Antivirais/farmacologia
Enterovirus/efeitos dos fármacos
Pirimidinonas/química
Pirimidinonas/farmacologia
Triazóis/química
Triazóis/farmacologia
[Mh] Termos MeSH secundário: Animais
Antivirais/metabolismo
Enterovirus/fisiologia
Infecções por Enterovirus/tratamento farmacológico
Infecções por Enterovirus/virologia
Células HeLa
Seres Humanos
Microssomos/metabolismo
Pirimidinonas/metabolismo
Ratos
Triazóis/metabolismo
Replicação Viral/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antiviral Agents); 0 (Pyrimidinones); 0 (Triazoles)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171125
[Lr] Data última revisão:
171125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170608
[St] Status:MEDLINE


  9 / 22352 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28538150
[Au] Autor:Sárközi S; Komáromi I; Jóna I; Almássy J
[Ad] Endereço:Department of Physiology, Faculty of Medicine, Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
[Ti] Título:Lanthanides Report Calcium Sensor in the Vestibule of Ryanodine Receptor.
[So] Source:Biophys J;112(10):2127-2137, 2017 May 23.
[Is] ISSN:1542-0086
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Ca regulates ryanodine receptor's (RyR) activity through an activating and an inhibiting Ca -binding site located on the cytoplasmic side of the RyR channel. Their altered sensitivity plays an important role in the pathology of malignant hyperthermia and heart failure. We used lanthanide ions (Ln ) as probes to investigate the Ca sensors of RyR, because they specifically bind to Ca -binding proteins and they are impermeable to the channel. Eu 's and Sm 's action was tested on single RyR1 channels reconstituted into planar lipid bilayers. When the activating binding site was saturated by 50 µM Ca , Ln potently inhibited RyR's open probability (K Eu = 167 ± 5 nM and K Sm = 63 ± 3 nM), but in nominally 0 [Ca ], low [Eu ] activated the channel. These results suggest that Ln acts as an agonist of both Ca -binding sites. More importantly, the voltage-dependent characteristics of Ln 's action led to the conclusion that the activating Ca binding site is located within the electrical field of the channel (in the vestibule). This idea was tested by applying the pore blocker toxin maurocalcine on the cytoplasmic side of RyR. These experiments showed that RyR lost reactivity to changing cytosolic [Ca ] from 50 µM to 100 nM when the toxin occupied the vestibule. These results suggest that maurocalcine mechanically prevented Ca from dissociating from its binding site and support our vestibular Ca sensor-model further.
[Mh] Termos MeSH primário: Cálcio/metabolismo
Elementos da Série dos Lantanídeos/metabolismo
Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo
[Mh] Termos MeSH secundário: Animais
Sítios de Ligação
Cálcio/química
Agonistas dos Canais de Cálcio/química
Agonistas dos Canais de Cálcio/metabolismo
Agonistas dos Canais de Cálcio/farmacologia
Bloqueadores dos Canais de Cálcio/química
Bloqueadores dos Canais de Cálcio/farmacologia
Cátions/química
Cátions/metabolismo
Citosol/química
Citosol/metabolismo
Relação Dose-Resposta a Droga
Elementos da Série dos Lantanídeos/química
Bicamadas Lipídicas/química
Potenciais da Membrana/efeitos dos fármacos
Potenciais da Membrana/fisiologia
Microscopia Eletrônica
Microssomos/química
Microssomos/metabolismo
Modelos Moleculares
Coelhos
Canal de Liberação de Cálcio do Receptor de Rianodina/química
Retículo Sarcoplasmático/química
Retículo Sarcoplasmático/metabolismo
Venenos de Escorpião/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Calcium Channel Agonists); 0 (Calcium Channel Blockers); 0 (Cations); 0 (Lanthanoid Series Elements); 0 (Lipid Bilayers); 0 (Ryanodine Receptor Calcium Release Channel); 0 (Scorpion Venoms); 0 (maurocalcine); SY7Q814VUP (Calcium)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170809
[Lr] Data última revisão:
170809
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170525
[St] Status:MEDLINE


  10 / 22352 MEDLINE  
              first record previous record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28489395
[Au] Autor:Joshi P; McCann GJP; Sonawane VR; Vishwakarma RA; Chaudhuri B; Bharate SB
[Ad] Endereço:Medicinal Chemistry Division, Indian Institute of Integrative Medicine (CSIR) , Canal Road, Jammu-180001, India.
[Ti] Título:Identification of Potent and Selective CYP1A1 Inhibitors via Combined Ligand and Structure-Based Virtual Screening and Their in Vitro Validation in Sacchrosomes and Live Human Cells.
[So] Source:J Chem Inf Model;57(6):1309-1320, 2017 Jun 26.
[Is] ISSN:1549-960X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Target structure-guided virtual screening (VS) is a versatile, powerful, and inexpensive alternative to experimental high-throughput screening (HTS). To discover potent CYP1A1 enzyme inhibitors for cancer chemoprevention, a commercial library of 50 000 small molecules was utilized for VS guided by both ligand and structure-based strategies. For experimental validation, 300 ligands were proposed based on combined analysis of fitness scores from ligand based e-pharmacophore screening and docking score, prime MMGB/SA binding affinity and interaction pattern analysis from structure-based VS. These 300 compounds were screened, at 10 µM concentration, for in vitro inhibition of CYP1A1-Sacchrosomes (yeast-derived microsomal enzyme) in the ethoxyresorufin-O-de-ethylase assay. Thirty-two compounds displayed >50% inhibition of CYP1A1 enzyme activity at 10 µM. 2-Phenylimidazo-[1,2-a]quinoline (5121780, 119) was found to be the most potent with 97% inhibition. It also inhibited ∼95% activity of CYP1B1 and CYP1A2, the other two CYP1 enzymes. The compound 5121780 (119) showed high selectivity toward inhibition of CYP1 enzymes with respect to CYP2 and CYP3 enzymes (i.e., there was no detectable inhibition of CYP2D6/CYP2C9/CYP2C19 and CYP3A4 at 10 µM). It was further investigated in live CYP-expressing human cell system, which confirmed that compound 5121780 (119) potently inhibited CYP1A1, CYP1A2, CYP1B1 enzymes with IC values of 269, 30, and 56 nM, respectively. Like in Sacchrosomes, inhibition of CYP2D6/CYP2C9/CYP2C19 and CYP3A4 enzymes, expressed within live human cells, could hardly be detected at 10 µM. The compound 119 rescued CYP1A1 overexpressing HEK293 cells from CYP1A1 mediated benzo[a]pyrene (B[a]P) toxicity and also overcame cisplatin resistance in CYP1B1 overexpressing HEK293 cells. Molecular dynamics simulations of 5121780 (119) with CYP1 enzymes was performed to understand the interaction pattern to CYP isoforms. Results indicate that VS can successfully be used to identify promising CYP1A1 inhibitors, which may have potential in the development of novel cancer chemo-preventive agents.
[Mh] Termos MeSH primário: Citocromo P-450 CYP1A1/antagonistas & inibidores
Inibidores das Enzimas do Citocromo P-450/farmacologia
Avaliação Pré-Clínica de Medicamentos/métodos
Microssomos/efeitos dos fármacos
Interface Usuário-Computador
Leveduras/genética
[Mh] Termos MeSH secundário: Sobrevivência Celular
Citocromo P-450 CYP1A1/química
Citocromo P-450 CYP1A1/metabolismo
Células HEK293
Seres Humanos
Ligantes
Microssomos/metabolismo
Simulação de Dinâmica Molecular
Conformação Proteica
[Pt] Tipo de publicação:JOURNAL ARTICLE; VALIDATION STUDIES
[Nm] Nome de substância:
0 (Cytochrome P-450 Enzyme Inhibitors); 0 (Ligands); EC 1.14.14.1 (Cytochrome P-450 CYP1A1)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170921
[Lr] Data última revisão:
170921
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170511
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jcim.7b00095



página 1 de 2236 ir para página                         
   


Refinar a pesquisa
  Base de dados : MEDLINE Formulário avançado   

    Pesquisar no campo  
1  
2
3
 
           



Search engine: iAH v2.6 powered by WWWISIS

BIREME/OPAS/OMS - Centro Latino-Americano e do Caribe de Informação em Ciências da Saúde