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Pesquisa : E05.599.595 [Categoria DeCS]
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  1 / 221225 MEDLINE  
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[PMID]:29482394
[Au] Autor:Marcinkowska M; Kotanska M; Zagórska A; Sniecikowska J; Kubacka M; Siwek A; Bucki A; Pawlowski M; Bednarski M; Sapa J; Starek M; Dabrowska M; Kolaczkowski M
[Ad] Endereço:a Department of Medicinal Chemistry , Jagiellonian University Medical College , Kraków , Poland.
[Ti] Título:Synthesis and biological evaluation of N-arylpiperazine derivatives of 4,4-dimethylisoquinoline-1,3(2H,4H)-dione as potential antiplatelet agents.
[So] Source:J Enzyme Inhib Med Chem;33(1):536-545, 2018 Dec.
[Is] ISSN:1475-6374
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Despite the substantial clinical success of aspirin and clopidogrel in secondary prevention of ischemic stroke, up to 40% of patients remain resistant to the available antiplatelet treatment. Therefore, there is an urgent clinical need to develop novel antiplatelet agents with a novel mechanism of action. Recent studies revealed that potent alpha 2B-adrenergic receptor (alpha 2B-ARs) antagonists could constitute alternative antiplatelet therapy. We have synthesized a series of N-arylpiperazine derivatives of 4,4-dimethylisoquinoline-1,3(2H,4H)-dione as potential alpha 2B receptor antagonists. The most potent compound 3, effectively inhibited the platelet-aggregation induced both by collagen and ADP/adrenaline with IC of 26.9 µM and 20.5 µM respectively. Our study confirmed that the alpha 2B-AR antagonists remain an interesting target for the development of novel antiplatelet agents with an alternative mechanism of action.
[Mh] Termos MeSH primário: Isoquinolinas/farmacologia
Piperazinas/farmacologia
Inibidores da Agregação de Plaquetas/farmacologia
Receptores Adrenérgicos alfa 2/metabolismo
[Mh] Termos MeSH secundário: Relação Dose-Resposta a Droga
Seres Humanos
Isoquinolinas/síntese química
Isoquinolinas/química
Modelos Moleculares
Estrutura Molecular
Piperazinas/síntese química
Piperazinas/química
Agregação Plaquetária/efeitos dos fármacos
Inibidores da Agregação de Plaquetas/síntese química
Inibidores da Agregação de Plaquetas/química
Testes de Função Plaquetária
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ADRA2B protein, human); 0 (Isoquinolines); 0 (Piperazines); 0 (Platelet Aggregation Inhibitors); 0 (Receptors, Adrenergic, alpha-2); 1RTM4PAL0V (piperazine)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180228
[St] Status:MEDLINE
[do] DOI:10.1080/14756366.2018.1437155


  2 / 221225 MEDLINE  
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[PMID]:29482389
[Au] Autor:Elzahabi HSA; Nossier ES; Khalifa NM; Alasfoury RA; El-Manawaty MA
[Ad] Endereço:a Department of Pharmaceutical Chemistry , Faculty of Pharmacy (Girls), Al-Azhar University , Cairo , Egypt.
[Ti] Título:Anticancer evaluation and molecular modeling of multi-targeted kinase inhibitors based pyrido[2,3-d]pyrimidine scaffold.
[So] Source:J Enzyme Inhib Med Chem;33(1):546-557, 2018 Dec.
[Is] ISSN:1475-6374
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:An efficient synthesis of substituted pyrido[2,3-d]pyrimidines was carried out and evaluated for in vitro anticancer activity against five cancer cell lines, namely hepatic cancer (HepG-2), prostate cancer (PC-3), colon cancer (HCT-116), breast cancer (MCF-7), and lung cancer (A-549) cell lines. Regarding HepG-2, PC-3, HCT-116 cancer cell lines, 7-(4-chlorophenyl)-2-(3-methyl-5-oxo-2,3-dihydro-1H-pyrazol-1-yl)-5-(p-tolyl)- pyrido[2,3-d]pyrimidin-4(3H)-one (5a) exhibited strong, more potent anticancer (IC : 0.3, 6.6 and 7 µM) relative to the standard doxorubicin (IC : 0.6, 6.8 and 12.8 µM), respectively. Kinase inhibitory assessment of 5a showed promising inhibitory activity against three kinases namely PDGFR ß, EGFR, and CDK4/cyclin D1 at two concentrations 50 and 100 µM in single measurements. Further, a molecular docking study for compound 5a was performed to verify the binding mode towards the EGFR and CDK4/cyclin D1 kinases.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Quinase 4 Dependente de Ciclina/antagonistas & inibidores
Inibidores de Proteínas Quinases/farmacologia
Piridinas/farmacologia
Pirimidinas/farmacologia
Receptor do Fator de Crescimento Epidérmico/antagonistas & inibidores
Receptor beta de Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores
[Mh] Termos MeSH secundário: Antineoplásicos/síntese química
Antineoplásicos/química
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Quinase 4 Dependente de Ciclina/metabolismo
Relação Dose-Resposta a Droga
Ensaios de Seleção de Medicamentos Antitumorais
Seres Humanos
Modelos Moleculares
Estrutura Molecular
Inibidores de Proteínas Quinases/síntese química
Inibidores de Proteínas Quinases/química
Piridinas/síntese química
Piridinas/química
Pirimidinas/síntese química
Pirimidinas/química
Receptor do Fator de Crescimento Epidérmico/metabolismo
Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Protein Kinase Inhibitors); 0 (Pyridines); 0 (Pyrimidines); 0 (pyrido(3,2-d)pyrimidine); EC 2.7.10.1 (Receptor, Epidermal Growth Factor); EC 2.7.10.1 (Receptor, Platelet-Derived Growth Factor beta); EC 2.7.11.22 (CDK4 protein, human); EC 2.7.11.22 (Cyclin-Dependent Kinase 4)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180228
[St] Status:MEDLINE
[do] DOI:10.1080/14756366.2018.1437729


  3 / 221225 MEDLINE  
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[PMID]:29355528
[Au] Autor:Zhu J; Li S; Ramelot TA; Kennedy MA; Liu M; Yang Y
[Ad] Endereço:State Key Laboratory of Magnetic Resonance and Atomic Molecular Physics, Wuhan Center for Magnetic Resonance, Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan 430071, China.
[Ti] Título:Structural insights into the impact of two holoprosencephaly-related mutations on human TGIF1 homeodomain.
[So] Source:Biochem Biophys Res Commun;496(2):575-581, 2018 02 05.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Human protein TGIF1 is an essential regulator of cell fate with broad roles in different tissues, and has been implicated in holoprosencephaly (HPE) and many cancers. The function of TGIF1 in transcriptional regulation depends on its three-amino acid loop extension (TALE) type of homeodomain (HD). Two missense mutations that led to P192A and R219C substitutions in TGIF1-HD were previously found in HPE patients and suggested to be the causes for these cases. However, how these mutations affected TGIF1 function has not been investigated from a structural view. Here, we investigated the roles of P192 and R219 in TGIF1-HD structure packing through determining the NMR structure of TGIF1-HD. Surprisingly, P192 and R219 were found to play roles in packing α1 and α2 to α3 together with A190 and F215 through side-chain interactions. Circular dichroism (CD) showed that P192A and R219C mutants displayed structural change and less folding compared with wild-type TGIF1-HD, and H- N HSQC spectrum of P192A mutant exhibited chemical shift perturbations in all three helices of TGIF1-HD. Thus, it is suggested that P192A and R219C mutations led to structure disturbances of TGIF1-HD, which subsequently reduced the DNA-binding affinity of TGIF1-HD by 23-fold and 10-fold respectively, as revealed by the isothermal titration calorimetry (ITC) experiments. Our study provides structural insights of the probable pathogenesis mechanism of two TGIF1-related HPE cases, and evidences for the roles of P192 and R219 in HD folding.
[Mh] Termos MeSH primário: Holoprosencefalia/genética
Proteínas de Homeodomínio/química
Proteínas de Homeodomínio/genética
Mutação Puntual
Proteínas Repressoras/química
Proteínas Repressoras/genética
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
DNA/metabolismo
Holoprosencefalia/metabolismo
Proteínas de Homeodomínio/metabolismo
Seres Humanos
Modelos Moleculares
Mutação de Sentido Incorreto
Ressonância Magnética Nuclear Biomolecular
Conformação Proteica
Dobramento de Proteína
Proteínas Repressoras/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Homeodomain Proteins); 0 (Repressor Proteins); 0 (TGIF1 protein, human); 9007-49-2 (DNA)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180123
[St] Status:MEDLINE


  4 / 221225 MEDLINE  
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[PMID]:29330050
[Au] Autor:Tanabe A; Nakano K; Nakakido M; Nagatoishi S; Tanaka Y; Tsumoto K; Uchimaru K; Watanabe T
[Ad] Endereço:Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
[Ti] Título:Production and characterization of a novel site-specific-modifiable anti-OX40-receptor single-chain variable fragment for targeted drug delivery.
[So] Source:Biochem Biophys Res Commun;496(2):614-620, 2018 02 05.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OX40 receptor (tumor necrosis factor receptor superfamily, member 4; CD134) is a T-cell co-stimulatory molecule that plays an important role in T-cell activation and survival. OX40 receptor is activated by its ligand, OX40L; and modulation of the OX40-OX40L interaction is a promising target for the treatment of autoimmune diseases and cancers. Here, we generated a high-affinity anti-OX40 single-chain variable fragment carrying a C-terminal cysteine residue (scFvC). Physicochemical and functional analyses revealed that the scFvC bound to OX40-expressing cells and was internalized via OX40-mediated endocytosis without inducing phosphorylation of IκBα (nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha), an important complex in the classical NFκB (nuclear factor kappa-light-chain-enhancer of activated B cells) signaling pathway. In addition, mutation of the 36th cysteine residue in variable region of light chain enabled site-specific chemical modification to carboxy terminal cysteine and improved the thermal stability of the scFvC. These results suggest that this novel high-affinity anti-OX40 scFvC may be useful as a transporter for targeted delivery of small compounds, proteins, peptides, liposomes, and nanoparticles, into OX40-expressing cells for the treatment of autoimmune diseases and cancers.
[Mh] Termos MeSH primário: Imunoconjugados/imunologia
Receptores OX40/imunologia
Anticorpos de Cadeia Única/imunologia
[Mh] Termos MeSH secundário: Linhagem Celular
Sistemas de Liberação de Medicamentos
Escherichia coli/genética
Expressão Gênica
Seres Humanos
Imunoconjugados/química
Imunoconjugados/genética
Células Jurkat
Modelos Moleculares
Mutação Puntual
Estabilidade Proteica
Anticorpos de Cadeia Única/química
Anticorpos de Cadeia Única/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Immunoconjugates); 0 (Receptors, OX40); 0 (Single-Chain Antibodies)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180114
[St] Status:MEDLINE


  5 / 221225 MEDLINE  
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[PMID]:29288668
[Au] Autor:Groves MR; Schroer CFE; Middleton AJ; Lunev S; Danda N; Ali AM; Marrink SJ; Williams C
[Ad] Endereço:Department of Drug Design, Groningen Research Institute of Pharmacy, University of Groningen, 9713AV, The Netherlands.
[Ti] Título:Structural insights into K48-linked ubiquitin chain formation by the Pex4p-Pex22p complex.
[So] Source:Biochem Biophys Res Commun;496(2):562-567, 2018 02 05.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Pex4p is a peroxisomal E2 involved in ubiquitinating the conserved cysteine residue of the cycling receptor protein Pex5p. Previously, we demonstrated that Pex4p from the yeast Saccharomyces cerevisiae binds directly to the peroxisomal membrane protein Pex22p and that this interaction is vital for receptor ubiquitination. In addition, Pex22p binding allows Pex4p to specifically produce lysine 48 linked ubiquitin chains in vitro through an unknown mechanism. This activity is likely to play a role in targeting peroxisomal proteins for proteasomal degradation. Here we present the crystal structures of Pex4p alone and in complex with Pex22p from the yeast Hansenula polymorpha. Comparison of the two structures demonstrates significant differences to the active site of Pex4p upon Pex22p binding while molecular dynamics simulations suggest that Pex22p binding facilitates active site remodelling of Pex4p through an allosteric mechanism. Taken together, our data provide insights into how Pex22p binding allows Pex4p to build K48-linked Ub chains.
[Mh] Termos MeSH primário: Proteínas Fúngicas/metabolismo
Peroxinas/metabolismo
Pichia/metabolismo
[Mh] Termos MeSH secundário: Domínio Catalítico
Cristalografia por Raios X
Proteínas Fúngicas/química
Modelos Moleculares
Peroxinas/química
Pichia/química
Ligação Proteica
Conformação Proteica
Ubiquitinação
Ubiquitinas/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Fungal Proteins); 0 (Peroxins); 0 (Ubiquitins)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171231
[St] Status:MEDLINE


  6 / 221225 MEDLINE  
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[PMID]:29247860
[Au] Autor:Schulz-Fincke J; Hau M; Barth J; Robaa D; Willmann D; Kürner A; Haas J; Greve G; Haydn T; Fulda S; Lübbert M; Lüdeke S; Berg T; Sippl W; Schüle R; Jung M
[Ad] Endereço:Institute of Pharmaceutical Sciences, University of Freiburg, Germany; German Cancer Consortium (DKTK), Freiburg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany.
[Ti] Título:Structure-activity studies on N-Substituted tranylcypromine derivatives lead to selective inhibitors of lysine specific demethylase 1 (LSD1) and potent inducers of leukemic cell differentiation.
[So] Source:Eur J Med Chem;144:52-67, 2018 Jan 20.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:FAD-dependent lysine-specific demethylase 1 (LSD1) is overexpressed or deregulated in many cancers such as AML and prostate cancer and hence is a promising anticancer target with first inhibitors in clinical trials. Clinical candidates are N-substituted derivatives of the dual LSD1-/monoamine oxidase-inhibitor tranylcypromine (2-PCPA) with a basic amine function in the N-substituent. These derivatives are selective over monoamine oxidases. So far, only very limited information on structure-activity studies about this important class of LSD1 inhibitors is published in peer reviewed journals. Here, we show that N-substituted 2-PCPA derivatives without a basic function or even a polar group are still potent inhibitors of LSD1 in vitro and effectively inhibit colony formation of leukemic cells in culture. Yet, these lipophilic inhibitors also block the structurally related monoamine oxidases (MAO-A and MAO-B), which may be of interest for the treatment of neurodegenerative disorders, but this property is undesired for applications in cancer treatment. The introduction of a polar, non-basic function led to optimized structures that retain potent LSD1 inhibitors but exhibit selectivity over MAOs and are highly potent in the suppression of colony formation of cultured leukemic cells. Cellular target engagement is shown via a Cellular Thermal Shift Assay (CETSA) for LSD1.
[Mh] Termos MeSH primário: Inibidores Enzimáticos/química
Inibidores Enzimáticos/farmacologia
Histona Desmetilases/antagonistas & inibidores
Tranilcipromina/análogos & derivados
Tranilcipromina/farmacologia
[Mh] Termos MeSH secundário: Animais
Antineoplásicos/química
Antineoplásicos/farmacologia
Diferenciação Celular/efeitos dos fármacos
Linhagem Celular Tumoral
Histona Desmetilases/metabolismo
Seres Humanos
Leucemia/tratamento farmacológico
Leucemia/metabolismo
Leucemia/patologia
Camundongos
Modelos Moleculares
Inibidores da Monoaminoxidase/química
Inibidores da Monoaminoxidase/farmacologia
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Enzyme Inhibitors); 0 (Monoamine Oxidase Inhibitors); 3E3V44J4Z9 (Tranylcypromine); EC 1.14.11.- (Histone Demethylases); EC 1.5.- (KDM1A protein, human)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171217
[St] Status:MEDLINE


  7 / 221225 MEDLINE  
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[PMID]:29247859
[Au] Autor:Zhao S; Li K; Jin Y; Lin J
[Ad] Endereço:Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, School of Chemical Science and Technology, Yunnan University, Kunming 650091, PR China.
[Ti] Título:Synthesis and biological evaluation of novel 1-(aryl-aldehyde-oxime)uracil derivatives as a new class of thymidine phosphorylase inhibitors.
[So] Source:Eur J Med Chem;144:41-51, 2018 Jan 20.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:A novel series of 1-(aryl aldehyd oxime) uracil derivatives were synthesized, characterized and evaluated for its inhibitory activity against thymidine phosphorylase. Among them, the compound 8d, 8e, 8f, 8g and 8l displayed potent thymidine phosphorylase inhibitory activities with the IC values ranging between 0.12 ± 0.05 and 7.2 ± 1.4 µM. And the compounds 8a, 8h, 8i, 8j, 8m, 8n, 8o, 8q, 8s, 8t and 8u (IC is from 10.7 to 39.9 µM) showed a good thymidine phosphorylase inhibition when compared to the standard 7DX and TPI. The most biologically active compound 8l was demonstrated to be a competition mode of enzyme inhibition. The Molecular docking analysis showed the interaction of these newly synthesized compounds at the active binding site of thymidine phosphorylase based on the experimental results. In general, these results indicated these compounds are promising inhibitors of thymidine phosphorylase for the potential treatment of anti-angiogenesis.
[Mh] Termos MeSH primário: Inibidores Enzimáticos/química
Inibidores Enzimáticos/farmacologia
Timidina Fosforilase/antagonistas & inibidores
Uracila/análogos & derivados
Uracila/farmacologia
[Mh] Termos MeSH secundário: Inibidores da Angiogênese/síntese química
Inibidores da Angiogênese/química
Inibidores da Angiogênese/farmacologia
Inibidores Enzimáticos/síntese química
Células Endoteliais da Veia Umbilical Humana
Seres Humanos
Concentração Inibidora 50
Modelos Moleculares
Oximas/síntese química
Oximas/química
Oximas/farmacologia
Relação Estrutura-Atividade
Timidina Fosforilase/metabolismo
Uracila/síntese química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Angiogenesis Inhibitors); 0 (Enzyme Inhibitors); 0 (Oximes); 56HH86ZVCT (Uracil); EC 2.4.2.4 (Thymidine Phosphorylase)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171217
[St] Status:MEDLINE


  8 / 221225 MEDLINE  
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[PMID]:29247858
[Au] Autor:Palace-Berl F; Pasqualoto KFM; Zingales B; Moraes CB; Bury M; Franco CH; da Silva Neto AL; Murayama JS; Nunes SL; Silva MN; Tavares LC
[Ad] Endereço:Department of Biochemical and Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, University of São Paulo, SP, Brazil. Electronic address: palaceberlf@usp.br.
[Ti] Título:Investigating the structure-activity relationships of N'-[(5-nitrofuran-2-yl) methylene] substituted hydrazides against Trypanosoma cruzi to design novel active compounds.
[So] Source:Eur J Med Chem;144:29-40, 2018 Jan 20.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:Chagas disease, caused by the protozoan Trypanosoma cruzi, is a neglected chronic tropical infection endemic in Latin America. New and effective treatments are urgently needed because the two available drugs - benznidazole (BZD) and nifurtimox (NFX) - have limited curative power in the chronic phase of the disease. We have previously reported the design and synthesis of N'-[(5-nitrofuran-2-yl) methylene] substituted hydrazides that showed high trypanocidal activity against axenic epimastigote forms of three T. cruzi strains. Here we show that these compounds are also active against a BZD- and NFX-resistant strain. Herein, multivariate approaches (hierarchical cluster analysis and principal component analysis) were applied to a set of thirty-six formerly characterized compounds. Based on the findings from exploratory data analysis, novel compounds were designed and synthesized. These compounds showed two-to three-fold higher trypanocidal activity against epimastigote forms than the previous set and were 25-30-fold more active than BZD. Their activity was also evaluated against intracellular amastigotes by high content screening (HCS). The most active compounds (BSF-38 to BSF-40) showed a selective index (SI') greater than 200, in contrast to the SI' values of reference drugs (NFX, 16.45; BZD, > 3), and a 70-fold greater activity than BZD. These findings indicate that nitrofuran compounds designed based on the activity against epimastigote forms show promising trypanocidal activity against intracellular amastigotes, which correspond to the predominant parasite stage in the chronic phase of Chagas disease.
[Mh] Termos MeSH primário: Nitrofuranos/química
Nitrofuranos/farmacologia
Tripanossomicidas/química
Tripanossomicidas/farmacologia
Trypanosoma cruzi/efeitos dos fármacos
[Mh] Termos MeSH secundário: Linhagem Celular
Doença de Chagas/tratamento farmacológico
Desenho de Drogas
Seres Humanos
Modelos Moleculares
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Nitrofurans); 0 (Trypanocidal Agents)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171217
[St] Status:MEDLINE


  9 / 221225 MEDLINE  
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[PMID]:29051067
[Au] Autor:Wang Y; Ryu BH; Yoo W; Lee CW; Kim KK; Lee JH; Kim TD
[Ad] Endereço:Department of Chemistry, College of Natural Science, Sookmyung Women's University, Seoul 04310, Republic of Korea.
[Ti] Título:Identification, characterization, immobilization, and mutational analysis of a novel acetylesterase with industrial potential (LaAcE) from Lactobacillus acidophilus.
[So] Source:Biochim Biophys Acta;1862(1):197-210, 2018 01.
[Is] ISSN:0006-3002
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Lactic acid bacteria, which are involved in the fermentation of vegetables, meats, and dairy products, are widely used for the productions of small organic molecules and bioactive peptides. Here, a novel acetylesterase (LaAcE) from Lactobacillus acidophilus NCFM was identified, functionally characterized, immobilized, and subjected to site-directed mutagenesis for biotechnological applications. The enzymatic properties of LaAcE were investigated using biochemical and biophysical methods including native polyacrylamide gel electrophoresis, acetic acid release, biochemical assays, enzyme kinetics, and spectroscopic methods. Interestingly, LaAcE exhibited the ability to act on a broad range of substrates including glucose pentaacetate, glyceryl tributyrate, fish oil, and fermentation-related compounds. Furthermore, immobilization of LaAcE showed good recycling ability and high thermal stability compared with free LaAcE. A structural model of LaAcE was used to guide mutational analysis of hydrophobic substrate-binding region, which was composed of Leu , Phe , and Val . Five mutants (L156A, F164A, V204A, L156A/F164A, and L156A/V204A) were generated and investigated to elucidate the roles of these hydrophobic residues in substrate specificity. This work provided valuable insights into the properties of LaAcE, and demonstrated that LaAcE could be used as a model enzyme of acetylesterase in lactic acid bacteria, making LaAcE a great candidate for industrial applications.
[Mh] Termos MeSH primário: Acetilesterase
Proteínas de Bactérias
Enzimas Imobilizadas
Lactobacillus acidophilus
Modelos Moleculares
Mutação de Sentido Incorreto
[Mh] Termos MeSH secundário: Acetilesterase/química
Acetilesterase/genética
Substituição de Aminoácidos
Proteínas de Bactérias/química
Proteínas de Bactérias/genética
Enzimas Imobilizadas/química
Enzimas Imobilizadas/genética
Lactobacillus acidophilus/enzimologia
Lactobacillus acidophilus/genética
Especificidade por Substrato/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Bacterial Proteins); 0 (Enzymes, Immobilized); EC 3.1.1.6 (Acetylesterase)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171021
[St] Status:MEDLINE


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[PMID]:28466911
[Au] Autor:Scheller JS; Irvine GW; Wong DL; Hartwig A; Stillman MJ
[Ad] Endereço:Department of Chemistry, The University of Western Ontario, London, Ontario, N6A 5B7, Canada. martin.stillman@uwo.ca.
[Ti] Título:Stepwise copper(i) binding to metallothionein: a mixed cooperative and non-cooperative mechanism for all 20 copper ions.
[So] Source:Metallomics;9(5):447-462, 2017 May 24.
[Is] ISSN:1756-591X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Copper is a ubiquitous trace metal of vital importance in that it serves as a cofactor in many metalloenzymes. Excess copper becomes harmful if not sequestered appropriately in the cell. As a metal ion chaperone, metallothionein (MT) has been proposed as a key player in zinc and copper homeostasis within the cell. The underlying mechanisms by which MT sequesters and transfers copper ions, and subsequently achieves its proposed biological function remain unknown. Using a combination of electrospray ionization mass spectrometry (ESI-MS), circular dichroism (CD), and emission spectroscopy, we report that the Cu(i) to human apo-MT1a binding mechanism is highly pH-dependent. The 20 relative K -values for the binding of 1 to 20 Cu(i) to the 20 cysteines of MT were obtained from computational simulation of the experimental mass spectral results. These data identified the pH-dependent formation of three sequential but completely different Cu-S clusters, as a function of Cu(i) loading. These data provide the first overall sequence for Cu(i) binding in terms of domain specificity and transient binding site structures. Under cooperative binding at pH 7.4, a series of four clusters form: Cu S , followed by Cu S (ß), then a second Cu S (α), and finally Cu S (α) (x = up to 11). Upon further addition of Cu(i), a mixture of species is formed in a non-cooperative mechanism, saturating the 20 cysteines of MT1a. Using benzoquinone, a cysteine modifier, we were able to confirm that Cu S formed solely in the N-terminal ß-domain, as well as confirming the existence of the presumed Cu S cluster in the α-domain. Based on the results of ESI-MS and computational simulation we were able to identify Cu:MT speciation that resulted in specific emission and CD spectral properties.
[Mh] Termos MeSH primário: Cobre/metabolismo
Metalotioneína/metabolismo
[Mh] Termos MeSH secundário: Sítios de Ligação
Dicroísmo Circular
Cobre/química
Seres Humanos
Concentração de Íons de Hidrogênio
Metalotioneína/química
Modelos Moleculares
Ligação Proteica
Proteínas Recombinantes/química
Proteínas Recombinantes/metabolismo
Espectrometria de Massas por Ionização por Electrospray
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (MT1A protein, human); 0 (Recombinant Proteins); 789U1901C5 (Copper); 9038-94-2 (Metallothionein)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170504
[St] Status:MEDLINE
[do] DOI:10.1039/c7mt00041c



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