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[PMID]:29049732
[Au] Autor:Wang K; Peng B; Xiao J; Weinreb O; Youdim MBH; Lin B
[Ad] Endereço:Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China.
[Ti] Título:Iron-Chelating Drugs Enhance Cone Photoreceptor Survival in a Mouse Model of Retinitis Pigmentosa.
[So] Source:Invest Ophthalmol Vis Sci;58(12):5287-5297, 2017 Oct 01.
[Is] ISSN:1552-5783
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Purpose: Retinitis pigmentosa (RP) is a group of hereditary retinal degeneration in which mutations commonly result in the initial phase of rod cell death followed by gradual cone cell death. The mechanisms by which the mutations lead to photoreceptor cell death in RP have not been clearly elucidated. There is currently no effective treatment for RP. The purpose of this work was to explore iron chelation therapy for improving cone survival and function in the rd10 mouse model of RP. Methods: Two iron-chelating drugs, 5-(4-(2-hydroxyethyl) piperazin-1-yl (methyl)-8-hydroxyquinoline (VK28) and its chimeric derivative 5-(N-methyl-N-propargyaminomethyl)-quinoline-8-oldihydrochloride (VAR10303), were injected intraperitoneally to rd10 mice every other day starting from postnatal day 14. We investigate the effects of the two compounds on cone rescue at three time points, using a combination of immunocytochemistry, RT-PCR, Western blot analysis, and a series of visual function tests. Results: VK28 and VAR10303 treatments partially rescued cones, and significantly improved visual function in rd10 mice. Moreover, we showed that the neuroprotective effects of VK28 and VAR10303 were correlated to inhibition of neuroinflammation, oxidative stress, and apoptosis. Furthermore, we demonstrated that downregulation of NF-kB and p53 is likely to be the mechanisms by which proinflammatory mediators and apoptosis are reduced in the rd10 retina, respectively. Conclusions: VK28 and VAR10303 provided partial histologic and functional rescue of cones in RD10 mice. Our study demonstrated that iron chelation therapy might represent an effective therapeutic strategy for RP patients.
[Mh] Termos MeSH primário: Modelos Animais de Doenças
Quelantes de Ferro/uso terapêutico
Fármacos Neuroprotetores/uso terapêutico
Células Fotorreceptoras Retinianas Cones/fisiologia
Retinite Pigmentosa/tratamento farmacológico
[Mh] Termos MeSH secundário: Animais
Apoptose/efeitos dos fármacos
Western Blotting
Sobrevivência Celular/fisiologia
Eletrorretinografia
Hidroxiquinolinas/uso terapêutico
Imuno-Histoquímica
Injeções Intraperitoneais
Camundongos
Camundongos Endogâmicos C57BL
NF-kappa B/metabolismo
Estresse Oxidativo/efeitos dos fármacos
Piperazinas/uso terapêutico
Quinolinas/uso terapêutico
Reação em Cadeia da Polimerase em Tempo Real
Retinite Pigmentosa/metabolismo
Retinite Pigmentosa/patologia
Proteína Supressora de Tumor p53/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (5-(2-(methylprop-2-ynylamino)ethyl)quinolin-8-ol); 0 (5-(4-(2-hydroxyethyl)piperazine-1-ylmethyl)quinoline-8-ol); 0 (Hydroxyquinolines); 0 (Iron Chelating Agents); 0 (NF-kappa B); 0 (Neuroprotective Agents); 0 (Piperazines); 0 (Quinolines); 0 (Tumor Suppressor Protein p53)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171027
[Lr] Data última revisão:
171027
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171020
[St] Status:MEDLINE
[do] DOI:10.1167/iovs.17-22096


  2 / 1565 MEDLINE  
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[PMID]:28708374
[Au] Autor:Thierbach S; Birmes FS; Letzel MC; Hennecke U; Fetzner S
[Ad] Endereço:Institute for Molecular Microbiology and Biotechnology, University of Münster , 48149 Münster, Germany.
[Ti] Título:Chemical Modification and Detoxification of the Pseudomonas aeruginosa Toxin 2-Heptyl-4-hydroxyquinoline N-Oxide by Environmental and Pathogenic Bacteria.
[So] Source:ACS Chem Biol;12(9):2305-2312, 2017 Sep 15.
[Is] ISSN:1554-8937
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:2-Heptyl-4-hydroxyquinoline N-oxide (HQNO), a major secondary metabolite and virulence factor produced by the opportunistic pathogen Pseudomonas aeruginosa, acts as a potent inhibitor of respiratory electron transfer and thereby affects host cells as well as microorganisms. In this study, we demonstrate the previously unknown capability of environmental and pathogenic bacteria to transform and detoxify this compound. Strains of Arthrobacter and Rhodococcus spp. as well as Staphylococcus aureus introduced a hydroxyl group at C-3 of HQNO, whereas Mycobacterium abscessus, M. fortuitum, and M. smegmatis performed an O-methylation, forming 2-heptyl-1-methoxy-4-oxoquinoline as the initial metabolite. Bacillus spp. produced the glycosylated derivative 2-heptyl-1-(ß-d-glucopyranosydyl)-4-oxoquinoline. Assaying the effects of these metabolites on cellular respiration and on quinol oxidase activity of membrane fractions revealed that their EC values were up to 2 orders of magnitude higher than that of HQNO. Furthermore, cellular levels of reactive oxygen species were significantly lower in the presence of the metabolites than under the influence of HQNO. Therefore, the capacity to transform HQNO should lead to a competitive advantage against P. aeruginosa. Our findings contribute new insight into the metabolic diversity of bacteria and add another layer of complexity to the metabolic interactions which likely contribute to shaping polymicrobial communities comprising P. aeruginosa.
[Mh] Termos MeSH primário: Bactérias/metabolismo
Toxinas Bacterianas/metabolismo
Hidroxiquinolinas/metabolismo
Pseudomonas aeruginosa/metabolismo
[Mh] Termos MeSH secundário: Bactérias/química
Toxinas Bacterianas/química
Biotransformação
Seres Humanos
Hidroxiquinolinas/química
Infecções por Pseudomonas/microbiologia
Pseudomonas aeruginosa/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bacterial Toxins); 0 (Hydroxyquinolines); 1FU5S5CG6A (2-(n-heptyl)-4-hydroxyquinoline N-oxide)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171010
[Lr] Data última revisão:
171010
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170715
[St] Status:MEDLINE
[do] DOI:10.1021/acschembio.7b00345


  3 / 1565 MEDLINE  
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[PMID]:28698673
[Au] Autor:Nair DR; Chen J; Monteiro JM; Josten M; Pinho MG; Sahl HG; Wu J; Cheung A
[Ad] Endereço:Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, NH, USA.
[Ti] Título:A quinolinol-based small molecule with anti-MRSA activity that targets bacterial membrane and promotes fermentative metabolism.
[So] Source:J Antibiot (Tokyo);70(10):1009-1019, 2017 Oct.
[Is] ISSN:0021-8820
[Cp] País de publicação:Japan
[La] Idioma:eng
[Ab] Resumo:In a loss-of-viability screen of small molecules against methicillin-resistant Staphylococcus aureus (MRSA) USA300, we found a small molecule, designated DNAC-2, which has an MIC of 8 µg ml . DNAC-2 is a quinolinol derivative that is bactericidal at 2X MIC. Macromolecular synthesis assays at 2 × MIC of DNAC-2 revealed inhibition of DNA, cell wall, RNA and protein synthesis within fifteen to thirty minutes of treatment when compared to the untreated control. Transmission electron microscopy of DNAC-2-treated cells revealed a significantly thicker cell wall and impaired daughter cell separation. Exposure of USA300 cells to 1 × MIC of DNAC-2 resulted in mislocalization of PBP2 away from the septum in an FtsZ-independent manner. In addition, membrane localization with FM4-64, as well as depolarization study with DiOC and lipophilic cation TPP+ displayed membrane irregularities and rapid membrane depolarization, respectively, in DNAC-2-treated cells vs -untreated control. However, DNAC-2 exhibited almost no toxicity toward eukaryotic membranes. Notably, DNAC-2 drives energy generation toward substrate level phosphorylation and the bacteria become more sensitive to DNAC-2 under anaerobic conditions. We propose that DNAC-2 affects USA300 by targeting the membrane, leading to partial membrane depolarization and subsequently affecting aerobic respiration and energy-dependent functional organization of macromolecular biosynthetic pathways. The multiple effects may have the desirable consequence of limiting the emergence of resistance to DNAC-2.
[Mh] Termos MeSH primário: Antibacterianos/farmacologia
Membrana Celular/efeitos dos fármacos
Hidroxiquinolinas/farmacologia
Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos
[Mh] Termos MeSH secundário: Anaerobiose
Parede Celular/ultraestrutura
Fermentação
Potenciais da Membrana
Staphylococcus aureus Resistente à Meticilina/fisiologia
Staphylococcus aureus Resistente à Meticilina/ultraestrutura
Testes de Sensibilidade Microbiana
Viabilidade Microbiana/efeitos dos fármacos
Microscopia Eletrônica de Transmissão
Fatores de Tempo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-Bacterial Agents); 0 (Hydroxyquinolines)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171010
[Lr] Data última revisão:
171010
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170713
[St] Status:MEDLINE
[do] DOI:10.1038/ja.2017.79


  4 / 1565 MEDLINE  
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[PMID]:28182987
[Au] Autor:Rogolino D; Cavazzoni A; Gatti A; Tegoni M; Pelosi G; Verdolino V; Fumarola C; Cretella D; Petronini PG; Carcelli M
[Ad] Endereço:Dipartimento di Scienze Chimiche, della Vita e della Sostenibilità Ambientale and Consorzio Interuniversitario di Ricerca in Chimica dei Metalli nei Sistemi Biologici, Università di Parma, Parco Area delle Scienze 17/A, 43124 Parma, Italy. Electronic address: dominga.rogolino@unipr.it.
[Ti] Título:Anti-proliferative effects of copper(II) complexes with hydroxyquinoline-thiosemicarbazone ligands.
[So] Source:Eur J Med Chem;128:140-153, 2017 Mar 10.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:The possibility to influence the physiological concentration of copper ions through the careful choice of ligands is emerging as a novel intriguing strategy in the treatment of pathologies such as cancer and Alzheimer. Thiosemicarbazones play an important role in this field, because they offer a wide variety of potential functionalizations and different kinds of coordination modes. Here we report the synthesis of some 8-hydroxyquinoline thiosemicarbazone ligands containing an ONN'S donor set and their Zn(II) and Cu(II) complexes. The metal complexes were characterized in solution and in the solid state and the X-ray structure of one of the copper(II) complex is reported. The Cu(II) complexes were characterized also by means of quantum mechanical calculations. The Cu(II) complexes displayed cytostatic activity in different cancer cell models. In particular, the most active Cu(II) complex significantly inhibited cell proliferation with an IC value lower than 1 µM; this effect was associated with a block of the cell cycle in the G /M phase. This Cu(II) complex induced neither the production of reactive oxygen species (ROS) nor the accumulation of p53 protein, suggesting the lack of DNA damage.
[Mh] Termos MeSH primário: Antineoplásicos/química
Antineoplásicos/farmacologia
Proliferação Celular/efeitos dos fármacos
Complexos de Coordenação/química
Cobre/química
Hidroxiquinolinas/química
Tiossemicarbazonas/química
[Mh] Termos MeSH secundário: Western Blotting
Ciclo Celular/efeitos dos fármacos
Cristalografia por Raios X
Seres Humanos
Ligantes
Modelos Moleculares
Estrutura Molecular
Neoplasias/tratamento farmacológico
Neoplasias/patologia
Espécies Reativas de Oxigênio/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Coordination Complexes); 0 (Hydroxyquinolines); 0 (Ligands); 0 (Reactive Oxygen Species); 0 (Thiosemicarbazones); 789U1901C5 (Copper)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170418
[Lr] Data última revisão:
170418
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170210
[St] Status:MEDLINE


  5 / 1565 MEDLINE  
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[PMID]:28151463
[Au] Autor:Sargenti A; Farruggia G; Zaccheroni N; Marraccini C; Sgarzi M; Cappadone C; Malucelli E; Procopio A; Prodi L; Lombardo M; Iotti S
[Ad] Endereço:Department of Pharmacy and Biotechnologies, University of Bologna, Bologna, Italy.
[Ti] Título:Synthesis of a highly Mg -selective fluorescent probe and its application to quantifying and imaging total intracellular magnesium.
[So] Source:Nat Protoc;12(3):461-471, 2017 Mar.
[Is] ISSN:1750-2799
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Magnesium plays a crucial role in many physiological functions and pathological states. Therefore, the evolution of specific and sensitive tools capable of detecting and quantifying this element in cells is a very desirable goal in biological and biomedical research. We developed a Mg -selective fluorescent dye that can be used to selectively detect and quantify the total magnesium pool in a number of cells that is two orders of magnitude smaller than that required by flame atomic absorption spectroscopy (F-AAS), the reference analytical method for the assessment of cellular total metal content. This protocol reports itemized steps for the synthesis of the fluorescent dye based on diaza-18-crown-6-hydroxyquinoline (DCHQ5). We also describe its application in the quantification of total intracellular magnesium in mammalian cells and the detection of this ion in vivo by confocal microscopy. The use of in vivo confocal microscopy enables the quantification of magnesium in different cellular compartments. As an example of the sensitivity of DCHQ5, we studied the involvement of Mg in multidrug resistance in human colon adenocarcinoma cells sensitive (LoVo-S) and resistant (LoVo-R) to doxorubicin, and found that the concentration was higher in LoVo-R cells. The time frame for DCHQ5 synthesis is 1-2 d, whereas the use of this dye for total intracellular magnesium quantification takes 2.5 h and for ion bioimaging it takes 1-2 h.
[Mh] Termos MeSH primário: Técnicas de Química Sintética/métodos
Corantes Fluorescentes/síntese química
Corantes Fluorescentes/metabolismo
Espaço Intracelular/metabolismo
Magnésio/metabolismo
Microscopia de Fluorescência
[Mh] Termos MeSH secundário: Linhagem Celular Tumoral
Corantes Fluorescentes/química
Seres Humanos
Hidroxiquinolinas/síntese química
Hidroxiquinolinas/química
Hidroxiquinolinas/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Fluorescent Dyes); 0 (Hydroxyquinolines); I38ZP9992A (Magnesium)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170529
[Lr] Data última revisão:
170529
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170203
[St] Status:MEDLINE
[do] DOI:10.1038/nprot.2016.183


  6 / 1565 MEDLINE  
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[PMID]:28137423
[Au] Autor:Minnow YV; Goldberg R; Tummalapalli SR; Rotella DP; Goodey NM
[Ad] Endereço:Department of Chemistry and Biochemistry, Montclair State University, Montclair, NJ, 07043, USA.
[Ti] Título:Mechanism of inhibition of botulinum neurotoxin type A light chain by two quinolinol compounds.
[So] Source:Arch Biochem Biophys;618:15-22, 2017 Mar 15.
[Is] ISSN:1096-0384
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Quinolinol-based compounds are a promising starting point for discovery of effective inhibitors of the clostridial neurotoxin, botulinum neurotoxin type A light chain (BoNT/A LC). Insights into the mechanism of inhibition by quinolinol compounds facilitate interpretation of docking data and inhibitor optimization. In this study, a fluorogenic substrate of BoNT/A, SNAPtide, was used to study the mechanism by which two new quinolinol compounds, MSU58 and MSU84, with IC values of 3.3 µM and 5.8 µM, respectively, inhibit BoNT/A LC. Kinetic studies and model discrimination analysis showed both compounds to be competitive inhibitors of BoNT/A LC with inhibition constants (K ) 3.2 µM and 6.2 µM for MSU58 and MSU84, respectively. These data indicate that the inhibitors bind in the BoNT/A LC active site and that inhibitor binding is mutually exclusive with the binding of the substrate. This is the first study to report the competitive inhibition of BoNT/A LC by quinolinol compounds. These data help define the inhibitor binding pocket and, along with structure activity relationship studies, provide immediate direction for further compound synthesis.
[Mh] Termos MeSH primário: Toxinas Botulínicas Tipo A/antagonistas & inibidores
Hidroxiquinolinas/química
[Mh] Termos MeSH secundário: Ligação Competitiva
Toxinas Botulínicas Tipo A/química
Catálise
Domínio Catalítico
Concentração Inibidora 50
Cinética
Luz
Peptídeos/química
Ligação Proteica
Proteínas Recombinantes/química
Relação Estrutura-Atividade
Água/química
Zinco/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Hydroxyquinolines); 0 (Peptides); 0 (Recombinant Proteins); 059QF0KO0R (Water); EC 3.4.24.69 (Botulinum Toxins, Type A); J41CSQ7QDS (Zinc)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170523
[Lr] Data última revisão:
170523
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170201
[St] Status:MEDLINE


  7 / 1565 MEDLINE  
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[PMID]:28043798
[Au] Autor:Harrell WA; Vieira RC; Ensel SM; Montgomery V; Guernieri R; Eccard VS; Campbell Y; Roxas-Duncan V; Cardellina JH; Webb RP; Smith LA
[Ad] Endereço:Division of Molecular and Translational Sciences, U.S. Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, United States.
[Ti] Título:A matrix-focused structure-activity and binding site flexibility study of quinolinol inhibitors of botulinum neurotoxin serotype A.
[So] Source:Bioorg Med Chem Lett;27(3):675-678, 2017 02 01.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Our initial discovery of 8-hydroxyquinoline inhibitors of BoNT/A and separation/testing of enantiomers of one of the more active leads indicated considerable flexibility in the binding site. We designed a limited study to investigate this flexibility and probe structure-activity relationships; utilizing the Betti reaction, a 36 compound matrix of quinolinol BoNT/A LC inhibitors was developed using three 8-hydroxyquinolines, three heteroaromatic amines, and four substituted benzaldehydes. This study has revealed some of the most effective quinolinol-based BoNT/A inhibitors to date, with 7 compounds displaying IC values ⩽1µM and 11 effective at ⩽2µM in an ex vivo assay.
[Mh] Termos MeSH primário: Toxinas Botulínicas Tipo A/antagonistas & inibidores
Hidroxiquinolinas/química
[Mh] Termos MeSH secundário: Animais
Sítios de Ligação
Toxinas Botulínicas Tipo A/metabolismo
Hidroxiquinolinas/metabolismo
Hidroxiquinolinas/toxicidade
Concentração Inibidora 50
Camundongos
Nervo Frênico/efeitos dos fármacos
Nervo Frênico/metabolismo
Ligação Proteica
Sorogrupo
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.
[Nm] Nome de substância:
0 (Hydroxyquinolines); EC 3.4.24.69 (Botulinum Toxins, Type A)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171124
[Lr] Data última revisão:
171124
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170104
[St] Status:MEDLINE


  8 / 1565 MEDLINE  
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[PMID]:27987700
[Au] Autor:Weerasuriya DRK; Wijesinghe WPSL; Rajapakse RMG
[Ad] Endereço:Department of Chemistry, Faculty of Science, University of Peradeniya, Peradeniya 20400, Sri Lanka.
[Ti] Título:Encapsulation of anticancer drug copper bis(8-hydroxyquinoline) in hydroxyapatite for pH-sensitive targeted delivery and slow release.
[So] Source:Mater Sci Eng C Mater Biol Appl;71:206-213, 2017 Feb 01.
[Is] ISSN:1873-0191
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:There is a conspicuous progress in increasing anticancer drug delivery through the utilization of nanoparticles (NPs) as drug delivery agents. Hydroxyapatite (HA) gives improved clinical effectiveness of drugs by reducing systemic toxicity and broadening the spectrum of drug delivery since it is biocompatible and it can be targeted towards tumor cells. Herein, investigation of the potential of enhancing controlled drug release of the template model drug, copper bis-(8-hydroxyquinoline), by encapsulating it in hollow hydroxyapatite nano-carriers, is presented. Hydroxyapatite nanoparticles are synthesized by following four different routes to optimize its efficacy of drug loading. Copper bis-(8-hydroxyquinoline) is encapsulated by Method (a) which was effected by stirring the model drug and porous HA NPs in colloidal solution and Method (b) which was done during synthesis of hydroxyapatite nanoparticles in a solution of the model drug. In synthesizing nanoporous HA NPs, calcium carbonate is used as a template to create voids in HA. In each method, Ca/P ratio was ensured to be kept at 1.67:1. Appealing results are reported for the encapsulated product which was prepared by Method (a2). Method (a) was done at three different molar ratios of PO :CO and best result was obtained for that utilized 2.003:1 molar ratio (Method (a2).). It produced 98.67% of encapsulation efficiency and 2.9522mg/g of drug loading capacity. Release kinetics was studied at a range of pH values; the lower the pH of the medium the higher is the drug release. For instance, when considering the product which exhibited high encapsulation efficiency and high drug loading capacity, at pH3.5 during the first 8h it elicited about 13% of release, at pH5.0 about 8% release while at pH6.0 it was just 2.5%. During the 24-hour span, pH3.5 exhibited about 23.8%, at pH5.0 approximately 9% with an increasing trend of release and at pH6.0 showed a value just above 2.5%. As such, acidity of the cancerous cells can be made use to increase the drug slow-release kinetics at the vicinity of the cancer cells.
[Mh] Termos MeSH primário: Antineoplásicos
Durapatita
Hidroxiquinolinas
Compostos Organometálicos
[Mh] Termos MeSH secundário: Animais
Antineoplásicos/química
Antineoplásicos/farmacocinética
Antineoplásicos/farmacologia
Preparações de Ação Retardada/química
Preparações de Ação Retardada/farmacocinética
Preparações de Ação Retardada/farmacologia
Durapatita/química
Durapatita/farmacocinética
Durapatita/farmacologia
Seres Humanos
Hidroxiquinolinas/química
Hidroxiquinolinas/farmacocinética
Hidroxiquinolinas/farmacologia
Compostos Organometálicos/química
Compostos Organometálicos/farmacocinética
Compostos Organometálicos/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Delayed-Action Preparations); 0 (Hydroxyquinolines); 0 (Organometallic Compounds); 91D9GV0Z28 (Durapatite)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170926
[Lr] Data última revisão:
170926
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161219
[St] Status:MEDLINE


  9 / 1565 MEDLINE  
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[PMID]:27966961
[Au] Autor:Bremer PT; Adler M; Phung CH; Singh AK; Janda KD
[Ad] Endereço:Departments of Chemistry and Immunology, The Skaggs Institute for Chemical Biology, Worm Institute of Research and Medicine (WIRM), The Scripps Research Institute , 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
[Ti] Título:Newly Designed Quinolinol Inhibitors Mitigate the Effects of Botulinum Neurotoxin A in Enzymatic, Cell-Based, and ex Vivo Assays.
[So] Source:J Med Chem;60(1):338-348, 2017 Jan 12.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Botulinum neurotoxin A (BoNT/A) is one of the most deadly toxins and is the etiological agent of the potentially fatal condition, botulism. Herein, we investigated 8-hydroxyquinoline (quinolin-8-ol) as a potential inhibitor scaffold for preventing the deadly neurochemical effects of the toxin. Quinolinols are known chelators that can disrupt the BoNT/A metalloprotease zinc-containing active site, thus impeding its proteolysis of the endogenous protein substrate, synaptosomal-associated protein 25 (SNAP-25). By use of this information, the structure-activity relationship (SAR) of the quinolinol-5-sulfonamide scaffold was explored through preparation of a crude sulfonamide library and evaluation of the library in a BoNT/A LC enzymatic assay. Potency optimization of the sulfonamide hit compounds was undertaken as informed by docking studies, granting a lead compound with a submicromolar K . These quinolinol analogues demonstrated inhibitory activity in a cell-based model for SNAP-25 cleavage and an ex vivo assay for BoNT/A-mediated muscle paralysis.
[Mh] Termos MeSH primário: Toxinas Botulínicas Tipo A/antagonistas & inibidores
Hidroxiquinolinas/farmacologia
[Mh] Termos MeSH secundário: Animais
Toxinas Botulínicas Tipo A/metabolismo
Células Cultivadas
Hidroxiquinolinas/química
Masculino
Camundongos
Simulação de Acoplamento Molecular
Proteólise
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE; VALIDATION STUDIES
[Nm] Nome de substância:
0 (Hydroxyquinolines); EC 3.4.24.69 (Botulinum Toxins, Type A)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170807
[Lr] Data última revisão:
170807
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161215
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jmedchem.6b01393


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[PMID]:27910702
[Au] Autor:Ma YM; Qiao K; Kong Y; Li MY; Guo LX; Miao Z; Fan C
[Ad] Endereço:a Key Laboratory of Auxiliary Chemistry & Technology for Chemical Industry, Ministry of Education , Shaanxi University of Science and Technology , Shaanxi Xi'an , China.
[Ti] Título:A new isoquinolone alkaloid from an endophytic fungus R22 of Nerium indicum.
[So] Source:Nat Prod Res;31(8):951-958, 2017 Apr.
[Is] ISSN:1478-6427
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:A new isoquinolone alkaloid named 5-hydroxy-8-methoxy-4-phenylisoquinolin-1(2H)-one (3), together with two known quinolinone alkaloids 3-O-methylviridicatin (1) and viridicatol (2) were isolated from the fermentation of an endophytic fungus Penicillium sp. R22 in Nerium indicum. Their structures were elucidated by NMR, IR and MS data, and were also confirmed by comparing with the reported data in the literature. Meanwhile, the antibacterial and antifungal activities of all compounds were tested, and the results showed that three compounds had strong antifungal activity. Among them, compound 2 revealed potent antibacterial activity against Staphylococcus aureus with MIC value of 15.6 µg/mL.
[Mh] Termos MeSH primário: Alcaloides/química
Antibacterianos/farmacologia
Antifúngicos/farmacologia
Isoquinolinas/isolamento & purificação
Nerium/microbiologia
Penicillium/química
[Mh] Termos MeSH secundário: Alcaloides/isolamento & purificação
Alcaloides/farmacologia
Antibacterianos/química
Antifúngicos/química
Avaliação Pré-Clínica de Medicamentos/métodos
Endófitos/química
Hidroxiquinolinas/química
Hidroxiquinolinas/isolamento & purificação
Isoquinolinas/química
Isoquinolinas/farmacologia
Testes de Sensibilidade Microbiana
Estrutura Molecular
Penicillium/fisiologia
Quinolonas/química
Quinolonas/isolamento & purificação
Staphylococcus aureus/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (3-O-methylviridicatin); 0 (5-hydroxy-8-methoxy-4-phenylisoquinolin-1(2H)-one); 0 (Alkaloids); 0 (Anti-Bacterial Agents); 0 (Antifungal Agents); 0 (Hydroxyquinolines); 0 (Isoquinolines); 0 (Quinolones); 45P12JNE0L (viridicatol)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170817
[Lr] Data última revisão:
170817
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161203
[St] Status:MEDLINE
[do] DOI:10.1080/14786419.2016.1258556



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