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Pesquisa : D02.241.223.100.050.300 [Categoria DeCS]
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[PMID]:28699740
[Au] Autor:Okawa T; Aramaki Y; Yamamoto M; Kobayashi T; Fukumoto S; Toyoda Y; Henta T; Hata A; Ikeda S; Kaneko M; Hoffman ID; Sang BC; Zou H; Kawamoto T
[Ad] Endereço:Shonan Research Center, Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd. , 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
[Ti] Título:Design, Synthesis, and Evaluation of the Highly Selective and Potent G-Protein-Coupled Receptor Kinase 2 (GRK2) Inhibitor for the Potential Treatment of Heart Failure.
[So] Source:J Med Chem;60(16):6942-6990, 2017 Aug 24.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:A novel class of therapeutic drug candidates for heart failure, highly potent and selective GRK2 inhibitors, exhibit potentiation of ß-adrenergic signaling in vitro studies. Hydrazone derivative 5 and 1,2,4-triazole derivative 24a were identified as hit compounds by HTS. New scaffold generation and SAR studies of all parts resulted in a 4-methyl-1,2,4-triazole derivative with an N-benzylcarboxamide moiety with highly potent activity toward GRK2 and selectivity over other kinases. In terms of subtype selectivity, these compounds showed enough selectivity against GRK1, 5, 6, and 7 with almost equipotent inhibition to GRK3. Our medicinal chemistry efforts led to the discovery of 115h (GRK2 IC = 18 nM), which was obtained the cocrystal structure with human GRK2 and an inhibitor of GRK2 that potentiates ß-adrenergic receptor (ßAR)-mediated cAMP accumulation and prevents internalization of ßARs in ß2AR-expressing HEK293 cells treated with isoproterenol. Therefore, 115h appears to be a novel class of therapeutic for heart failure treatment.
[Mh] Termos MeSH primário: Quinase 2 de Receptor Acoplado a Proteína G/antagonistas & inibidores
Insuficiência Cardíaca/tratamento farmacológico
Inibidores de Proteínas Quinases/farmacologia
Piridinas/farmacologia
Triazóis/farmacologia
meta-Aminobenzoatos/farmacologia
[Mh] Termos MeSH secundário: Cristalografia por Raios X
Citocromo P-450 CYP3A/metabolismo
Inibidores do Citocromo P-450 CYP3A/síntese química
Inibidores do Citocromo P-450 CYP3A/química
Inibidores do Citocromo P-450 CYP3A/farmacologia
Desenho de Drogas
Células HEK293
Ensaios de Triagem em Larga Escala
Seres Humanos
Hidrazonas/síntese química
Hidrazonas/química
Hidrazonas/farmacologia
Proteína Quinase C-alfa/antagonistas & inibidores
Inibidores de Proteínas Quinases/síntese química
Inibidores de Proteínas Quinases/química
Piridinas/síntese química
Piridinas/química
Receptores Adrenérgicos beta/metabolismo
Relação Estrutura-Atividade
Triazóis/síntese química
Triazóis/química
meta-Aminobenzoatos/síntese química
meta-Aminobenzoatos/química
Quinases Associadas a rho/antagonistas & inibidores
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (3-(((4-methyl-5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl)methyl)amino)-N-(2-(trifluoromethyl)benzyl)benzamide); 0 (Cytochrome P-450 CYP3A Inhibitors); 0 (Hydrazones); 0 (Protein Kinase Inhibitors); 0 (Pyridines); 0 (Receptors, Adrenergic, beta); 0 (Triazoles); 0 (meta-Aminobenzoates); EC 1.14.13.67 (CYP3A4 protein, human); EC 1.14.14.1 (Cytochrome P-450 CYP3A); EC 2.7.11.1 (ROCK2 protein, human); EC 2.7.11.1 (rho-Associated Kinases); EC 2.7.11.13 (Protein Kinase C-alpha); EC 2.7.11.15 (ADRBK1 protein, human); EC 2.7.11.16 (G-Protein-Coupled Receptor Kinase 2)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170926
[Lr] Data última revisão:
170926
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170713
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jmedchem.7b00443


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[PMID]:28118359
[Au] Autor:Asiedu MN; Han C; Dib-Hajj SD; Waxman SG; Price TJ; Dussor G
[Ad] Endereço:University of Arizona, Department of Pharmacology, Tucson, Arizona, United States of America.
[Ti] Título:The AMPK Activator A769662 Blocks Voltage-Gated Sodium Channels: Discovery of a Novel Pharmacophore with Potential Utility for Analgesic Development.
[So] Source:PLoS One;12(1):e0169882, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Voltage-gated sodium channels (VGSC) regulate neuronal excitability by governing action potential (AP) generation and propagation. Recent studies have revealed that AMP-activated protein kinase (AMPK) activators decrease sensory neuron excitability, potentially by preventing sodium (Na+) channel phosphorylation by kinases such as ERK or via modulation of translation regulation pathways. The direct positive allosteric modulator A769662 displays substantially greater efficacy than other AMPK activators in decreasing sensory neuron excitability suggesting additional mechanisms of action. Here, we show that A769662 acutely inhibits AP firing stimulated by ramp current injection in rat trigeminal ganglion (TG) neurons. PT1, a structurally dissimilar AMPK activator that reduces nerve growth factor (NGF) -induced hyperexcitability, has no influence on AP firing in TG neurons upon acute application. In voltage-clamp recordings, application of A769662 reduces VGSC current amplitudes. These findings, based on acute A769662 application, suggest a direct channel blocking effect. Indeed, A769662 dose-dependently blocks VGSC in rat TG neurons and in Nav1.7-transfected cells with an IC50 of ~ 10 µM. A769662 neither displayed use-dependent inhibition nor interacted with the local anesthetic (LA) binding site. Popliteal fossa administration of A769662 decreased noxious thermal responses with a peak effect at 5 mins demonstrating an analgesic effect. These data indicate that in addition to AMPK activation, A769662 acts as a direct blocker/modulator of VGSCs, a potential mechanism enhancing the analgesic property of this compound.
[Mh] Termos MeSH primário: Proteínas Quinases Ativadas por AMP/efeitos dos fármacos
Analgésicos/farmacologia
Canal de Sódio Disparado por Voltagem NAV1.7/efeitos dos fármacos
Pironas/farmacologia
Células Receptoras Sensoriais/efeitos dos fármacos
Bloqueadores dos Canais de Sódio/farmacologia
Tiofenos/farmacologia
[Mh] Termos MeSH secundário: Anestésicos Locais/metabolismo
Animais
Sítios de Ligação/genética
Avaliação Pré-Clínica de Medicamentos
Células HEK293
Temperatura Alta/efeitos adversos
Seres Humanos
Masculino
Metformina/farmacologia
Canal de Sódio Disparado por Voltagem NAV1.7/genética
Condução Nervosa/efeitos dos fármacos
Dor/tratamento farmacológico
Técnicas de Patch-Clamp
Ratos
Ratos Sprague-Dawley
Tempo de Reação/efeitos dos fármacos
Proteínas Recombinantes de Fusão/efeitos dos fármacos
Proteínas Recombinantes de Fusão/metabolismo
Células Receptoras Sensoriais/enzimologia
Estilbenos/farmacologia
Tiazóis/farmacologia
Gânglio Trigeminal/efeitos dos fármacos
meta-Aminobenzoatos/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (2-chloro-5-((5-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-4-oxo-2-thiazolyl)amino)benzoic acid); 0 (A 769662); 0 (Analgesics); 0 (Anesthetics, Local); 0 (NAV1.7 Voltage-Gated Sodium Channel); 0 (Pyrones); 0 (Recombinant Fusion Proteins); 0 (SCN9A protein, human); 0 (Sodium Channel Blockers); 0 (Stilbenes); 0 (Thiazoles); 0 (Thiophenes); 0 (meta-Aminobenzoates); 9100L32L2N (Metformin); EC 2.7.11.31 (AMP-Activated Protein Kinases); Q369O8926L (resveratrol)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170125
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0169882


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[PMID]:27517812
[Au] Autor:Agharbaoui FE; Hoyte AC; Ferro S; Gitto R; Buemi MR; Fuchs JR; Kvaratskhelia M; De Luca L
[Ad] Endereço:Dipartimento di Scienze Chimiche, Biologiche, Farmaceutiche e Ambientali (CHIBIOFARAM), Polo Universitario SS. Annunziata, Università di Messina, Viale Annunziata, I-98168, Messina, Italy; Center for Retrovirus Research and College of Pharmacy, The Ohio State University, Columbus, OH, 43210, USA; Di
[Ti] Título:Computational and synthetic approaches for developing Lavendustin B derivatives as allosteric inhibitors of HIV-1 integrase.
[So] Source:Eur J Med Chem;123:673-683, 2016 Nov 10.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:Through structure-based virtual screening and subsequent activity assays of selected natural products, Lavendustin B was previously identified as an inhibitor of HIV-1 integrase (IN) interaction with its cognate cellular cofactor, lens epithelium-derived growth factor (LEDGF/p75). In order to improve the inhibitory potency we have employed in silico-based approaches. Particularly, a series of new analogues was designed and docked into the LEDGF/p75 binding pocket of HIV-1 IN. To identify promising leads we used the Molecular Mechanics energies combined with the Generalized Born and Surface Area continuum solvation (MM-GBSA) method, molecular dynamics simulations and analysis of hydrogen bond occupancies. On the basis of these studies, six analogues of Lavendustine B, containing the benzylamino-hydroxybenzoic scaffold, were selected for synthesis and structure activity-relationship (SAR) studies. Our results demonstrated a good correlation between computational and experimental data, and all six analogues displayed an improved potency for inhibiting IN binding to LEDGF/p75 in vitro to respect to the parent compound Lavendustin B. Additionally, these analogs show to inhibit weakly LEDGF/p75-independent IN catalytic activity suggesting a multimodal allosteric mechanism of action. Nevertheless, for the synthesized compounds similar profiles for HIV-1 inhibition and cytoxicity were highlighted. Taken together, our studies elucidated the mode of action of Lavendustin B analogs and provided a path for their further development as a new promising class of HIV-1 integrase inhibitors.
[Mh] Termos MeSH primário: Desenho de Drogas
Integrase de HIV/metabolismo
Simulação de Acoplamento Molecular
Simulação de Dinâmica Molecular
Salicilatos/síntese química
Salicilatos/farmacologia
meta-Aminobenzoatos/síntese química
meta-Aminobenzoatos/farmacologia
[Mh] Termos MeSH secundário: Regulação Alostérica/efeitos dos fármacos
Fármacos Anti-HIV/síntese química
Fármacos Anti-HIV/química
Fármacos Anti-HIV/metabolismo
Fármacos Anti-HIV/farmacologia
Técnicas de Química Sintética
Integrase de HIV/química
HIV-1/efeitos dos fármacos
HIV-1/enzimologia
Células HeLa
Seres Humanos
Conformação Proteica
Salicilatos/química
Salicilatos/metabolismo
meta-Aminobenzoatos/química
meta-Aminobenzoatos/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-HIV Agents); 0 (Salicylates); 0 (meta-Aminobenzoates); 0 (p31 integrase protein, Human immunodeficiency virus 1); 125697-91-8 (lavendustin B); EC 2.7.7.- (HIV Integrase)
[Em] Mês de entrada:1702
[Cu] Atualização por classe:170811
[Lr] Data última revisão:
170811
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160813
[St] Status:MEDLINE


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[PMID]:27168529
[Au] Autor:Zhang H; Stephanopoulos G
[Ad] Endereço:Department of Chemical and Biochemical Engineering, Rutgers, The State University of New Jersey, Piscataway, NJ, USA. Haoran.Zhang@rutgers.edu.
[Ti] Título:Co-culture engineering for microbial biosynthesis of 3-amino-benzoic acid in Escherichia coli.
[So] Source:Biotechnol J;11(7):981-7, 2016 Jul.
[Is] ISSN:1860-7314
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:3-amino-benzoic acid (3AB) is an important building block molecule for production of a wide range of important compounds such as natural products with various biological activities. In the present study, we established a microbial biosynthetic system for de novo 3AB production from the simple substrate glucose. First, the active 3AB biosynthetic pathway was reconstituted in the bacterium Escherichia coli, which resulted in the production of 1.5 mg/L 3AB. In an effort to improve the production, an E. coli-E. coli co-culture system was engineered to modularize the biosynthetic pathway between an upstream strain and an downstream strain. Specifically, the upstream biosynthetic module was contained in a fixed E. coli strain, whereas a series of E. coli strains were engineered to accommodate the downstream biosynthetic module and screened for optimal production performance. The best co-culture system was found to improve 3AB production by 15 fold, compared to the mono-culture approach. Further engineering of the co-culture system resulted in biosynthesis of 48 mg/L 3AB. Our results demonstrate co-culture engineering can be a powerful new approach in the broad field of metabolic engineering.
[Mh] Termos MeSH primário: Técnicas de Cocultura/métodos
Escherichia coli/genética
meta-Aminobenzoatos/metabolismo
[Mh] Termos MeSH secundário: Proteínas de Bactérias/genética
Proteínas de Bactérias/metabolismo
Reatores Biológicos
Vias Biossintéticas
Escherichia coli/metabolismo
Engenharia Metabólica/métodos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bacterial Proteins); 0 (meta-Aminobenzoates); G2X3B3O37U (3-aminobenzoic acid)
[Em] Mês de entrada:1701
[Cu] Atualização por classe:170117
[Lr] Data última revisão:
170117
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160512
[St] Status:MEDLINE
[do] DOI:10.1002/biot.201600013


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[PMID]:25868658
[Au] Autor:Huang L; Dai K; Chen M; Zhou W; Wang X; Chen J; Zhou W
[Ad] Endereço:Department of Cardiology, The Central Hospital of Wuhan, Wuhan, China huangling@whu.edu.cn.
[Ti] Título:The AMPK Agonist PT1 and mTOR Inhibitor 3HOI-BA-01 Protect Cardiomyocytes After Ischemia Through Induction of Autophagy.
[So] Source:J Cardiovasc Pharmacol Ther;21(1):70-81, 2016 Jan.
[Is] ISSN:1940-4034
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Myocardial ischemia has become one of the main causes of sudden cardiac death worldwide. Autophagy has been demonstrated to protect cardiomyocytes from ischemia/reperfusion (I/R)-induced damage. A novel small molecule compound 2-Chloro-5-[[5-[[5-(4,5-Dimethyl-2-nitrophenyl)-2-furanyl]methylene]-4,5-dihydro-4-oxo-2-thiazolyl]amino]benzoic acid (PT1) has been previously shown to specifically activate 5'-adenosine monophosphate-activated protein kinase (AMPK). Because AMPK activation effectively induces autophagy, we tested the protective efficacy of PT1 on cardiomyocytes after oxygen glucose deprivation/reoxygenation (OGD/R) in vitro. Mouse neonatal cardiomyocytes were treated with PT1 after OGD/R. 3-[4-(1,3-benzodioxol-5-yl)-2-oxo-3-buten-1-yl]-3-hydroxy-1,3-dihydro-2H-indol-2-one (3HOI-BA-01), a novel small compound showing potent inhibitory effect on mammalian target of rapamycin (mTOR) activation, was also tested for its cardioprotective effect, based on the established relationship between mTOR signaling and autophagy. Cell survival and autophagy-related signal pathways were examined after treatment with these agents. Our data indicate that both PT1 and 3HOI-BA-01 enhance cell survival after OGD/R. As expected, both PT1 and 3HOI-BA-01 induced autophagy in cardiomyocytes through activating AMPK pathway and inhibiting mTOR signaling, respectively. Induction of autophagy by PT1 and 3HOI-BA-01 was responsible for their cardioprotective effect, since inhibition of autophagy abolished the protective efficacy. Furthermore, simultaneous administration of PT1 and 3HOI-BA-01 profoundly upregulated autophagy after OGD/R and significantly promoted survival of cardiomyocytes. In vivo administration of PT1 and 3HOI-BA-01 in a murine myocardial (I/R injury model remarkably reduced infarct size and induced autophagy. Taken together, our research suggests that PT1 and 3HOI-BA-01 could be promising therapeutic agents for myocardial ischemia.
[Mh] Termos MeSH primário: Proteínas Quinases Ativadas por AMP/antagonistas & inibidores
Autofagia/efeitos dos fármacos
Benzodioxóis/farmacologia
Indóis/farmacologia
Infarto do Miocárdio/prevenção & controle
Traumatismo por Reperfusão Miocárdica/prevenção & controle
Miócitos Cardíacos/efeitos dos fármacos
Inibidores de Proteínas Quinases/farmacologia
Serina-Treonina Quinases TOR/antagonistas & inibidores
Tiazóis/farmacologia
meta-Aminobenzoatos/farmacologia
[Mh] Termos MeSH secundário: Proteínas Quinases Ativadas por AMP/metabolismo
Animais
Animais Recém-Nascidos
Apoptose/efeitos dos fármacos
Hipóxia Celular
Células Cultivadas
Citoproteção
Modelos Animais de Doenças
Glucose/deficiência
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Infarto do Miocárdio/enzimologia
Infarto do Miocárdio/patologia
Traumatismo por Reperfusão Miocárdica/enzimologia
Traumatismo por Reperfusão Miocárdica/patologia
Miócitos Cardíacos/enzimologia
Miócitos Cardíacos/patologia
Oxigênio/metabolismo
Transdução de Sinais/efeitos dos fármacos
Serina-Treonina Quinases TOR/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (2-chloro-5-((5-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-4-oxo-2-thiazolyl)amino)benzoic acid); 0 (3-(4-(benzo(d)(1,3)dioxol-5-yl)-2-oxobut-3-en-1-yl)-3-hydroxyindolin-2-one); 0 (Benzodioxoles); 0 (Indoles); 0 (Protein Kinase Inhibitors); 0 (Thiazoles); 0 (meta-Aminobenzoates); EC 2.7.1.1 (TOR Serine-Threonine Kinases); EC 2.7.1.1 (mTOR protein, mouse); EC 2.7.11.31 (AMP-Activated Protein Kinases); IY9XDZ35W2 (Glucose); S88TT14065 (Oxygen)
[Em] Mês de entrada:1609
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150415
[St] Status:MEDLINE
[do] DOI:10.1177/1074248415581177


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[PMID]:26426567
[Au] Autor:Hirayama A; Miyanaga A; Kudo F; Eguchi T
[Ad] Endereço:Department of Chemistry and Materials Science, Tokyo Institute of Technology, 2-12-1 O-okayama, Meguro-ku, Tokyo, 152-8551, Japan.
[Ti] Título:Mechanism-Based Trapping of the Quinonoid Intermediate by Using the K276R Mutant of PLP-Dependent 3-Aminobenzoate Synthase PctV in the Biosynthesis of Pactamycin.
[So] Source:Chembiochem;16(17):2484-90, 2015 Nov.
[Is] ISSN:1439-7633
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Mutational analysis of the pyridoxal 5'-phosphate (PLP)-dependent enzyme PctV was carried out to elucidate the multi-step reaction mechanism for the formation of 3-aminobenzoate (3-ABA) from 3-dehydroshikimate (3-DSA). Introduction of mutation K276R led to the accumulation of a quinonoid intermediate with an absorption maximum at 580 nm after the reaction of pyridoxamine 5'-phosphate (PMP) with 3-DSA. The chemical structure of this intermediate was supported by X-ray crystallographic analysis of the complex formed between the K276R mutant and the quinonoid intermediate. These results clearly show that a quinonoid intermediate is involved in the formation of 3-ABA. They also indicate that Lys276 (in the active site of PctV) plays multiple roles, including acid/base catalysis during the dehydration reaction of the quinonoid intermediate.
[Mh] Termos MeSH primário: Oxirredutases/metabolismo
Pactamicina/biossíntese
[Mh] Termos MeSH secundário: Sítios de Ligação
Biocatálise
Domínio Catalítico
Cristalografia por Raios X
Cinética
Simulação de Dinâmica Molecular
Mutagênese Sítio-Dirigida
Oxirredutases/química
Oxirredutases/genética
Pactamicina/química
Fosfato de Piridoxal/química
Ácido Chiquímico/análogos & derivados
Ácido Chiquímico/química
Ácido Chiquímico/metabolismo
Espectrofotometria Ultravioleta
meta-Aminobenzoatos/química
meta-Aminobenzoatos/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (meta-Aminobenzoates); 23668-11-3 (Pactamycin); 27655-56-7 (3-dehydroshikimate); 29MS2WI2NU (Shikimic Acid); 5V5IOJ8338 (Pyridoxal Phosphate); EC 1.- (Oxidoreductases); EC 1.- (benzoate synthase); G2X3B3O37U (3-aminobenzoic acid)
[Em] Mês de entrada:1610
[Cu] Atualização por classe:170103
[Lr] Data última revisão:
170103
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151002
[St] Status:MEDLINE
[do] DOI:10.1002/cbic.201500426


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[PMID]:25938266
[Au] Autor:Minegishi H; Futamura Y; Fukashiro S; Muroi M; Kawatani M; Osada H; Nakamura H
[Ad] Endereço:†Chemical Resources Laboratory, Tokyo Institute of Technology, Nagatsuta-cho, Midori-ku, Yokohama 226-8503, Japan.
[Ti] Título:Methyl 3-((6-methoxy-1,4-dihydroindeno[1,2-c]pyrazol-3-yl)amino)benzoate (GN39482) as a tubulin polymerization inhibitor identified by MorphoBase and ChemProteoBase profiling methods.
[So] Source:J Med Chem;58(10):4230-41, 2015 May 28.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:A series of indenopyrazoles was synthesized from the corresponding indanones and phenyl isothiocyanates in two steps. Among the compounds synthesized, methyl 3-((6-methoxy-1,4-dihydroindeno[1,2-c]pyrazol-3-yl)amino)benzoate 6m (GN39482) was found to possess a promising antiproliferative activity toward human cancer cells without affecting any antimicrobial and antimalarial activities at 100 nM. Both a methoxy group at R(1) position and a methoxycarbonyl group at R(2) position of the anilinoquinazoline framework are essential for the high cell growth inhibition. Both MorphoBase and ChemProteoBase profiling analyses suggested that compound 6m was classified as a tubulin inhibitor. Indeed, compound 6m inhibited the acetylated tubulin accumulation and the microtubule formation and induced G2/M cell cycle arrest in HeLa cells, revealing that a promising antiproliferative activity of compound 6m toward human cancer cells is probably caused by the tubulin polymerization inhibition.
[Mh] Termos MeSH primário: Avaliação Pré-Clínica de Medicamentos/métodos
Pirazóis/farmacologia
Relação Estrutura-Atividade
Moduladores de Tubulina/farmacologia
meta-Aminobenzoatos/farmacologia
[Mh] Termos MeSH secundário: Anti-Infecciosos/química
Anti-Infecciosos/farmacologia
Antimaláricos/química
Antimaláricos/farmacologia
Antineoplásicos/química
Antineoplásicos/farmacologia
Técnicas de Química Sintética
Células HeLa/efeitos dos fármacos
Seres Humanos
Testes de Sensibilidade Microbiana
Microtúbulos/efeitos dos fármacos
Microtúbulos/metabolismo
Plasmodium falciparum/efeitos dos fármacos
Inibidores de Proteínas Quinases/química
Inibidores de Proteínas Quinases/farmacologia
Pirazóis/química
Moduladores de Tubulina/química
meta-Aminobenzoatos/química
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Anti-Infective Agents); 0 (Antimalarials); 0 (Antineoplastic Agents); 0 (GN39482); 0 (Protein Kinase Inhibitors); 0 (Pyrazoles); 0 (Tubulin Modulators); 0 (meta-Aminobenzoates)
[Em] Mês de entrada:1509
[Cu] Atualização por classe:150528
[Lr] Data última revisão:
150528
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150505
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jmedchem.5b00035


  8 / 80 MEDLINE  
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[PMID]:25572106
[Au] Autor:Hermane J; Bulyszko I; Eichner S; Sasse F; Collisi W; Poso A; Schax E; Walter JG; Scheper T; Kock K; Herrmann C; Aliuos P; Reuter G; Zeilinger C; Kirschning A
[Ad] Endereço:Institute of Organic Chemistry, Center of Biomolecular Drug Research (BMWZ), Leibniz University Hannover, Schneiderberg 1B, 30167 Hannover (Germany).
[Ti] Título:New, non-quinone fluorogeldanamycin derivatives strongly inhibit Hsp90.
[So] Source:Chembiochem;16(2):302-11, 2015 Jan 19.
[Is] ISSN:1439-7633
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Streptomyces hygroscopicus is a natural producer of geldanamycin. Mutasynthetic supplementation of an AHBA-blocked mutant with all possible monofluoro 3-aminobenzoic acids provided new fluorogeldanamycins. These showed strong antiproliferative activity and inhibitory effects on human heat shock protein Hsp90. Binding to Hsp90 in the low nanomolar range was determined from molecular modelling, AFM analysis and by calorimetric studies.
[Mh] Termos MeSH primário: Antineoplásicos/química
Antineoplásicos/farmacologia
Benzoquinonas/química
Proteínas de Choque Térmico HSP90/antagonistas & inibidores
Lactamas Macrocíclicas/química
Streptomyces/metabolismo
[Mh] Termos MeSH secundário: Antineoplásicos/metabolismo
Calorimetria/métodos
Linhagem Celular Tumoral/efeitos dos fármacos
Proliferação Celular/efeitos dos fármacos
Fluorbenzenos/metabolismo
Fluorbenzenos/farmacologia
Proteínas de Choque Térmico HSP90/metabolismo
Seres Humanos
Espectroscopia de Ressonância Magnética
Microscopia de Força Atômica
Modelos Moleculares
Quinonas/química
Streptomyces/genética
meta-Aminobenzoatos/metabolismo
meta-Aminobenzoatos/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Benzoquinones); 0 (Fluorobenzenes); 0 (HSP90 Heat-Shock Proteins); 0 (Lactams, Macrocyclic); 0 (Quinones); 0 (meta-Aminobenzoates); Z3K3VJ16KU (geldanamycin)
[Em] Mês de entrada:1509
[Cu] Atualização por classe:150113
[Lr] Data última revisão:
150113
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150110
[St] Status:MEDLINE
[do] DOI:10.1002/cbic.201402375


  9 / 80 MEDLINE  
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[PMID]:25517927
[Au] Autor:Nudnova MM; Sigg J; Wallimann P; Zenobi R
[Ad] Endereço:Department of Chemistry and Applied Biosciences, ETH Zurich , CH-8093 Zurich, Switzerland.
[Ti] Título:Plasma ionization source for atmospheric pressure mass spectrometry imaging using near-field optical laser ablation.
[So] Source:Anal Chem;87(2):1323-9, 2015 Jan 20.
[Is] ISSN:1520-6882
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Mass spectrometry imaging (MSI) at ambient pressures with submicrometer resolution is challenging, due to the very low amount of material available for mass spectrometric analysis. In this work, we present the development and characterization of a method for MSI based on pulsed laser ablation via a scanning near-field optical microscopy (SNOM) aperture tip. SNOM allows laser ablation of material from surfaces with submicrometer spatial resolution, which can be ionized for further chemical analysis with MS. Efficient ionization is realized here with a custom-built capillary plasma ionization source. We show the applicability of this setup for mass spectrometric analysis of three common MALDI matrices, α-4-hydroxycyanocinnamic acid, 3-aminobenzoic acid, and 2,5-dihydroxybenzoic acid. Although the ultimate goal has been to optimize sensitivity for detecting material ablated from submicrometer diameter craters, the effective lateral resolution is currently limited by the sensitivity of the MS detection system. In our case, the sensitivity of the MS was about 1 fmol, which allowed us to achieve a spatial resolution of 2 µm. We also characterize the analytical figures of merit of our method. In particular, we demonstrate good reproducibility, a repetition rate in the range of only a few seconds, and we determined the amount of substance required to achieve optimal resolution and sensitivity. Moreover, the sample topography is available from SNOM scans, a parameter that is missing in common MSI methods.
[Mh] Termos MeSH primário: Terapia a Laser
Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/instrumentação
[Mh] Termos MeSH secundário: Pressão Atmosférica
Cinamatos/química
Desenho de Equipamento
Gentisatos/química
Lasers
Microscopia
meta-Aminobenzoatos/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cinnamates); 0 (Gentisates); 0 (meta-Aminobenzoates); 1011-92-3 (alpha-cyanocinnamate); G2X3B3O37U (3-aminobenzoic acid); VP36V95O3T (2,5-dihydroxybenzoic acid)
[Em] Mês de entrada:1511
[Cu] Atualização por classe:161125
[Lr] Data última revisão:
161125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:141218
[St] Status:MEDLINE
[do] DOI:10.1021/ac504039w


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[PMID]:25486442
[Au] Autor:Poncet-Montange G; Zhan Y; Bardenhagen JP; Petrocchi A; Leo E; Shi X; Lee GR; Leonard PG; Geck Do MK; Cardozo MG; Andersen JN; Palmer WS; Jones P; Ladbury JE
[Ad] Endereço:*Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Unit 1954, 1515 Holcombe Blvd, Houston, TX 77030, U.S.A.
[Ti] Título:Observed bromodomain flexibility reveals histone peptide- and small molecule ligand-compatible forms of ATAD2.
[So] Source:Biochem J;466(2):337-46, 2015 Mar 01.
[Is] ISSN:1470-8728
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Preventing histone recognition by bromodomains emerges as an attractive therapeutic approach in cancer. Overexpression of ATAD2 (ATPase family AAA domain-containing 2 isoform A) in cancer cells is associated with poor prognosis making the bromodomain of ATAD2 a promising epigenetic therapeutic target. In the development of an in vitro assay and identification of small molecule ligands, we conducted structure-guided studies which revealed a conformationally flexible ATAD2 bromodomain. Structural studies on apo-, peptide-and small molecule-ATAD2 complexes (by co-crystallization) revealed that the bromodomain adopts a 'closed', histone-compatible conformation and a more 'open' ligand-compatible conformation of the binding site respectively. An unexpected conformational change of the conserved asparagine residue plays an important role in driving the peptide-binding conformation remodelling. We also identified dimethylisoxazole-containing ligands as ATAD2 binders which aided in the validation of the in vitro screen and in the analysis of these conformational studies.
[Mh] Termos MeSH primário: Adenosina Trifosfatases/química
Proteínas de Ligação a DNA/química
Desenho de Drogas
Inibidores Enzimáticos/química
Histonas/química
Isoxazóis/química
Fragmentos de Peptídeos/química
Processamento de Proteína Pós-Traducional
[Mh] Termos MeSH secundário: ATPases Associadas a Diversas Atividades Celulares
Adenosina Trifosfatases/antagonistas & inibidores
Adenosina Trifosfatases/genética
Adenosina Trifosfatases/metabolismo
Antineoplásicos/síntese química
Antineoplásicos/química
Antineoplásicos/farmacologia
Sítios de Ligação
Biotinilação
Proteínas de Ligação a DNA/antagonistas & inibidores
Proteínas de Ligação a DNA/genética
Proteínas de Ligação a DNA/metabolismo
Inibidores Enzimáticos/síntese química
Inibidores Enzimáticos/farmacologia
Histonas/antagonistas & inibidores
Histonas/metabolismo
Seres Humanos
Isoxazóis/síntese química
Isoxazóis/farmacologia
Cinética
Ligantes
Proteínas Mutantes/antagonistas & inibidores
Proteínas Mutantes/química
Proteínas Mutantes/metabolismo
Fragmentos de Peptídeos/antagonistas & inibidores
Fragmentos de Peptídeos/metabolismo
Maleabilidade
Conformação Proteica
Domínios e Motivos de Interação entre Proteínas
Proteínas Recombinantes/química
Proteínas Recombinantes/metabolismo
Sulfonamidas/síntese química
Sulfonamidas/química
Sulfonamidas/farmacologia
meta-Aminobenzoatos/síntese química
meta-Aminobenzoatos/química
meta-Aminobenzoatos/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (DNA-Binding Proteins); 0 (Enzyme Inhibitors); 0 (Histones); 0 (Isoxazoles); 0 (Ligands); 0 (Mutant Proteins); 0 (Peptide Fragments); 0 (Recombinant Proteins); 0 (Sulfonamides); 0 (meta-Aminobenzoates); EC 3.6.1.- (Adenosine Triphosphatases); EC 3.6.1.3 (ATAD2 protein, human); EC 3.6.4.- (ATPases Associated with Diverse Cellular Activities)
[Em] Mês de entrada:1504
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:141209
[St] Status:MEDLINE
[do] DOI:10.1042/BJ20140933



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