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Pesquisa : D02.491.567.500 [Categoria DeCS]
Referências encontradas : 268 [refinar]
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[PMID]:28489364
[Au] Autor:Amézqueta S; Ramos-Romero S; Martínez-Guimet C; Moreno A; Hereu M; Torres JL
[Ad] Endereço:Departament d'Enginyeria Química i Química Analítica and Institut de Biomedicina (IBUB), Universitat de Barcelona , Martí i Franquès 1-11, 08028 Barcelona, Spain.
[Ti] Título:Fate of d-Fagomine after Oral Administration to Rats.
[So] Source:J Agric Food Chem;65(22):4414-4420, 2017 Jun 07.
[Is] ISSN:1520-5118
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:d-Fagomine is an iminosugar found in buckwheat that is capable of inhibiting the adhesion of potentially pathogenic bacteria to epithelial mucosa and reducing the postprandial blood glucose concentration. This paper evaluates the excretion and metabolism of orally administered d-fagomine in rats and compares outcomes with the fate of 1-deoxynojirimycin. d-Fagomine and 1-deoxynojirimycin show similar absorption and excretion kinetics. d-Fagomine is partly absorbed (41-84%, dose of 2 mg/kg of body weight) and excreted in urine within 8 h, while the non-absorbed fraction is cleared in feces within 24 h. d-Fagomine is partially methylated (about 10% in urine and 3% in feces). The concentration of d-fagomine in urine from 1 to 6 h after administration is higher than 10 mg/L, the concentration that inhibits adhesion of Escherichia coli. Orally administered d-fagomine is partially absorbed and then rapidly excreted in urine, where it reaches a concentration that may be protective against urinary tract infections.
[Mh] Termos MeSH primário: Fagopyrum/química
Imino Piranoses/farmacocinética
Extratos Vegetais/farmacocinética
[Mh] Termos MeSH secundário: Administração Oral
Animais
Cromatografia Líquida de Alta Pressão
Imino Piranoses/administração & dosagem
Imino Piranoses/urina
Masculino
Espectrometria de Massas
Extratos Vegetais/administração & dosagem
Extratos Vegetais/urina
Ratos
Ratos Sprague-Dawley
Distribuição Tecidual
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Imino Pyranoses); 0 (Plant Extracts); 53185-12-9 (fagomine)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170619
[Lr] Data última revisão:
170619
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170511
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jafc.7b01026


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[PMID]:28288345
[Au] Autor:Lebl R; Thonhofer M; Tysoe C; Pabst BM; Schalli M; Weber P; Paschke E; Stütz AE; Tschernutter M; Windischhofer W; Withers SG
[Ad] Endereço:Glycogroup, Institute of Organic Chemistry, Graz University of Technology, Stremayrgasse 9, A-8010, Graz, Austria.
[Ti] Título:A Morita-Baylis-Hillman based route to C-5a-chain-extended 4-epi-isofagomine type glycosidase inhibitors.
[So] Source:Carbohydr Res;442:31-40, 2017 Apr 10.
[Is] ISSN:1873-426X
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:By Morita-Baylis-Hillman reaction of 2,3-O-isopropylidene-D-glyceraldehyde with α,ß-unsaturated carbonyl as well as hetero analogous carbonyl compounds such as acrylonitrile, suitable precursors of isofagomine and of 4-epi-isofagomine are available. Elaboration of the structures by amine introduction, followed by intramolecular ring closure and subsequent hydroboration of the double bond provides 4-epi-isofagomine derivatives featuring chain extensions at C-5a which are determined by the structures of the carbonyl compounds employed. As an example, the synthesis of C-(5aR)- and C-(5aS)-5a-C-pentyl-4-epi-isofagomines, powerful inhibitors of ß-galactosidases, is outlined. In line with reported data, the (C-5aR) epimer was found a highly potent experimental pharmacological chaperone for G -associated human lysosomal ß-galactosidase mutant R201C.
[Mh] Termos MeSH primário: Inibidores Enzimáticos/farmacologia
Glicosídeo Hidrolases/antagonistas & inibidores
Imino Piranoses/farmacologia
[Mh] Termos MeSH secundário: Relação Dose-Resposta a Droga
Inibidores Enzimáticos/síntese química
Inibidores Enzimáticos/química
Glicosídeo Hidrolases/metabolismo
Seres Humanos
Imino Piranoses/síntese química
Imino Piranoses/química
Lisossomos/enzimologia
Estrutura Molecular
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Enzyme Inhibitors); 0 (Imino Pyranoses); 0 (isofagomine); EC 3.2.1.- (Glycoside Hydrolases)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170417
[Lr] Data última revisão:
170417
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170314
[St] Status:MEDLINE


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[PMID]:27750150
[Au] Autor:Front S; Biela-Banas A; Burda P; Ballhausen D; Higaki K; Caciotti A; Morrone A; Charollais-Thoenig J; Gallienne E; Demotz S; Martin OR
[Ad] Endereço:Université d'Orléans & CNRS, Institut de Chimie Organique et Analytique (ICOA), UMR 7311, Rue de Chartres, 45067 Orléans, France.
[Ti] Título:(5aR)-5a-C-Pentyl-4-epi-isofagomine: A powerful inhibitor of lysosomal ß-galactosidase and a remarkable chaperone for mutations associated with GM1-gangliosidosis and Morquio disease type B.
[So] Source:Eur J Med Chem;126:160-170, 2017 Jan 27.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:This report is about the identification, synthesis and initial biological characterization of derivatives of 4-epi-isofagomine as pharmacological chaperones (PC) for human lysosomal ß-galactosidase. The two epimers of 4-epi-isofagomine carrying a pentyl group at C-5a, namely (5aR)- and (5aS)-5a-C-pentyl-4-epi-isofagomine, were prepared by an innovative procedure involving in the key step the addition of nitrohexane to a keto-pentopyranoside. Both epimers were evaluated as inhibitors of the human ß-galactosidase: the (5aR)-stereoisomer (compound 1) was found to be a very potent inhibitor of the enzyme (IC = 8 nM, 30× more potent than 4-epi-isofagomine at pH 7.3) with a high selectivity for this glycosidase whereas the (5aS) epimer was a much weaker inhibitor. In addition, compound 1 showed a remarkable activity as a PC. It significantly enhanced the residual activity of mutant ß-galactosidase in 15 patient cell lines out of 23, with enhancement factors greater than 3.5 in 10 cell lines and activity restoration up to 91% of normal. Altogether, these results indicated that (5aR)-5a-C-pentyl-4-epi-isofagomine constitutes a promising PC-based drug candidate for the treatment of GM1-gangliosidosis and Morquio disease type B.
[Mh] Termos MeSH primário: Inibidores Enzimáticos/farmacologia
Gangliosidose GM1/genética
Imino Piranoses/farmacologia
Lisossomos/enzimologia
Mucopolissacaridose IV/genética
Mutação
beta-Galactosidase/antagonistas & inibidores
[Mh] Termos MeSH secundário: Desenho de Drogas
Inibidores Enzimáticos/síntese química
Inibidores Enzimáticos/química
Fibroblastos/efeitos dos fármacos
Gangliosidose GM1/enzimologia
Gangliosidose GM1/patologia
Temperatura Alta
Seres Humanos
Concentração de Íons de Hidrogênio
Imino Piranoses/síntese química
Imino Piranoses/química
Mucopolissacaridose IV/enzimologia
Mucopolissacaridose IV/patologia
Desnaturação Proteica
beta-Galactosidase/química
beta-Galactosidase/genética
beta-Galactosidase/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 ((5aR)-5a-C-pentyl-4-epi-isofagomine); 0 (Enzyme Inhibitors); 0 (Imino Pyranoses); 0 (isofagomine); EC 3.2.1.23 (beta-Galactosidase)
[Em] Mês de entrada:1702
[Cu] Atualização por classe:170224
[Lr] Data última revisão:
170224
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161018
[St] Status:MEDLINE


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[PMID]:27474919
[Au] Autor:Cheng WC; Wang JH; Li HY; Lu SJ; Hu JM; Yun WY; Chiu CH; Yang WB; Chien YH; Hwu WL
[Ad] Endereço:Genomics Research Center, Academia Sinica, 128, Academia Road, Section 2, Nankang, Taipei 115, Taiwan; Department of Chemistry, National Cheng-Kung University, 1, University Road, Tainan 701, Taiwan. Electronic address: wcheng@gate.sinica.edu.tw.
[Ti] Título:Bioevaluation of sixteen ADMDP stereoisomers toward alpha-galactosidase A: Development of a new pharmacological chaperone for the treatment of Fabry disease and potential enhancement of enzyme replacement therapy efficiency.
[So] Source:Eur J Med Chem;123:14-20, 2016 Nov 10.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:A unique molecular library consisting of all sixteen synthetic ADMDP (1-aminodeoxy-DMDP) stereoisomers has been prepared and evaluated for inhibitory activity against α-Gal A, and ability to impart thermal stabilization of this enzyme. The results of this testing led us to develop a novel pharmacological chaperone for the treatment of Fabry disease. 3-Epimer ADMDP was found to be an effective pharmacological chaperone, able to rescue α-Gal A activity in the lymphoblast of the N215S Fabry patient-derived cell line, without impairment of cellular ß-galactosidase activity. When 3-epimer ADMDP was administered with rh-α-Gal A (enzyme replacement therapy) for the treatment of Fabry patient-derived cell lines, improvements in the efficacy of rh-α-Gal A was observed, which suggests this small molecule can also provide clinical benefit of enzyme replacement therapy in Fabry disease.
[Mh] Termos MeSH primário: Terapia de Reposição de Enzimas/métodos
Doença de Fabry/tratamento farmacológico
Imino Açúcares/farmacologia
Pirrolidinas/farmacologia
alfa-Galactosidase/efeitos dos fármacos
[Mh] Termos MeSH secundário: Linhagem Celular Tumoral
Inibidores Enzimáticos/química
Estabilidade Enzimática/efeitos dos fármacos
Seres Humanos
Imino Piranoses/química
Imino Piranoses/farmacologia
Imino Piranoses/uso terapêutico
Imino Açúcares/síntese química
Imino Açúcares/uso terapêutico
Manitol/análogos & derivados
Manitol/química
Manitol/farmacologia
Manitol/uso terapêutico
Pirrolidinas/síntese química
Pirrolidinas/uso terapêutico
Bibliotecas de Moléculas Pequenas/química
Bibliotecas de Moléculas Pequenas/farmacologia
Estereoisomerismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (1-aminodeoxy-2,5-dideoxy-2,5-iminomannitol); 0 (Enzyme Inhibitors); 0 (Imino Pyranoses); 0 (Imino Sugars); 0 (Pyrrolidines); 0 (Small Molecule Libraries); 3OWL53L36A (Mannitol); EC 3.2.1.22 (alpha-Galactosidase)
[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:160731
[St] Status:MEDLINE


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[PMID]:27063389
[Au] Autor:Thonhofer M; Weber P; Gonzalez Santana A; Tysoe C; Fischer R; Pabst BM; Paschke E; Schalli M; Stütz AE; Tschernutter M; Windischhofer W; Withers SG
[Ad] Endereço:Glycogroup, Institute of Organic Chemistry, Graz University of Technology, Stremayrgasse 9, A-8010 Graz, Austria.
[Ti] Título:Synthesis of C-5a-substituted derivatives of 4-epi-isofagomine: notable ß-galactosidase inhibitors and activity promotors of GM1-gangliosidosis related human lysosomal ß-galactosidase mutant R201C.
[So] Source:Carbohydr Res;429:71-80, 2016 Jun 24.
[Is] ISSN:1873-426X
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:From an easily available partially protected analog of 1-deoxy-L-gulo-nojirimycin, by chain-branching at C-4 and suitable modification, lipophilic analogs of the powerful ß-D-galactosidase inhibitor 4-epi-isofagomine have been prepared. New compounds exhibit considerably improved inhibitory activities when compared with the unsubstituted parent compound and may serve as leads toward new pharmacological chaperones for GM1-gangliosidosis and Morquio B disease.
[Mh] Termos MeSH primário: 1-Desoxinojirimicina/análogos & derivados
Imino Piranoses/síntese química
beta-Galactosidase/antagonistas & inibidores
[Mh] Termos MeSH secundário: 1-Desoxinojirimicina/química
Gangliosidose GM1/tratamento farmacológico
Seres Humanos
Interações Hidrofóbicas e Hidrofílicas
Imino Piranoses/química
Mucopolissacaridose IV/tratamento farmacológico
beta-Galactosidase/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (1-deoxy-gulonojirimycin); 0 (Imino Pyranoses); 0 (isofagomine); 19130-96-2 (1-Deoxynojirimycin); EC 3.2.1.23 (beta-Galactosidase)
[Em] Mês de entrada:1701
[Cu] Atualização por classe:170119
[Lr] Data última revisão:
170119
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160412
[St] Status:MEDLINE


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[PMID]:26988476
[Au] Autor:Rodríguez-Sánchez S; Martín-Ortiz A; Carrero-Carralero C; Ramos S; Sanz ML; Soria AC
[Ad] Endereço:Instituto de Química Orgánica General (CSIC), Juan de la Cierva, 3, 28006 Madrid, Spain. Electronic address: sonia.rodriguez@iqog.csic.es.
[Ti] Título:Pressurized liquid extraction of Aglaonema sp. iminosugars: Chemical composition, bioactivity, cell viability and thermal stability.
[So] Source:Food Chem;204:62-9, 2016 Aug 01.
[Is] ISSN:0308-8146
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Pressurized liquid extraction of Aglaonema sp. iminosugars has been optimized. A single cycle under optimal conditions (80mg, 100°C, 2min) was enough to extract ⩾96% of most iminosugars. Further incubation with Saccharomyces cerevisiae for 5h removed coextracted interfering low molecular weight carbohydrates from extracts of different Aglaonema cultivars. A complete characterization of these extracts was carried out by gas chromatography-mass spectrometry: three iminosugars were tentatively identified for the first time; α-homonojirimycin and 2,5-dideoxy-2,5-imino-d-mannitol were the major iminosugars determined. α-Glucosidase inhibition activity, cell viability and thermal stability of Aglaonema extracts were also evaluated. Extracts with IC50 for α-glucosidase activity in the 0.010-0.079mgmL(-1) range showed no decrease of Caco-2 cell viability at concentrations lower than 125µgmL(-1) and were stable at 50°C for 30days. These results highlight the potential of Aglaonema extracts as a source of bioactives to be used as functional ingredients.
[Mh] Termos MeSH primário: Araceae/química
Sobrevivência Celular/efeitos dos fármacos
Inibidores de Glicosídeo Hidrolases/análise
Extratos Vegetais/análise
[Mh] Termos MeSH secundário: 1-Desoxinojirimicina/análogos & derivados
1-Desoxinojirimicina/análise
Células CACO-2
Carboidratos/química
Fenômenos Químicos
Cromatografia Gasosa-Espectrometria de Massas
Inibidores de Glicosídeo Hidrolases/farmacologia
Seres Humanos
Imino Piranoses/análise
Manitol/análogos & derivados
Manitol/análise
Peso Molecular
Extratos Vegetais/farmacologia
Pressão
alfa-Glucosidases/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (2,5-dideoxy-2,5-imino-D-mannitol); 0 (Carbohydrates); 0 (Glycoside Hydrolase Inhibitors); 0 (Imino Pyranoses); 0 (Plant Extracts); 119557-99-2 (homonojirimycin); 19130-96-2 (1-Deoxynojirimycin); 3OWL53L36A (Mannitol); EC 3.2.1.20 (alpha-Glucosidases)
[Em] Mês de entrada:1612
[Cu] Atualização por classe:161230
[Lr] Data última revisão:
161230
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160319
[St] Status:MEDLINE


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[PMID]:26838810
[Au] Autor:Thonhofer M; Weber P; Santana AG; Fischer R; Pabst BM; Paschke E; Schalli M; Stütz AE; Tschernutter M; Windischhofer W; Withers SG
[Ad] Endereço:Glycogroup, Institute of Organic Chemistry, Graz University of Technology, Stremayrgasse 9, A-8010 Graz, Austria.
[Ti] Título:Synthesis of C-5a-chain extended derivatives of 4-epi-isofagomine: Powerful ß-galactosidase inhibitors and low concentration activators of GM1-gangliosidosis-related human lysosomal ß-galactosidase.
[So] Source:Bioorg Med Chem Lett;26(5):1438-42, 2016 Mar 01.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:From an easily available partially protected formal derivative of 1-deoxymannojirimycin, by hydroxymethyl chain-branching and further elaboration, lipophilic analogs of the powerful ß-d-galactosidase inhibitor 4-epi-isofagomine have become available. New compounds exhibit improved inhibitory activities comparable to benchmark compound NOEV (N-octyl-epi-valienamine) and may serve as leads towards improved and more selective pharmacological chaperones for GM1-gangliosidosis.
[Mh] Termos MeSH primário: Inibidores Enzimáticos/farmacologia
Gangliosidose GM1/enzimologia
Imino Piranoses/farmacologia
Lisossomos/enzimologia
beta-Galactosidase/antagonistas & inibidores
[Mh] Termos MeSH secundário: Relação Dose-Resposta a Droga
Inibidores Enzimáticos/síntese química
Inibidores Enzimáticos/química
Gangliosidose GM1/patologia
Seres Humanos
Imino Piranoses/síntese química
Imino Piranoses/química
Lisossomos/efeitos dos fármacos
Modelos Moleculares
Estrutura Molecular
Relação Estrutura-Atividade
beta-Galactosidase/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Enzyme Inhibitors); 0 (Imino Pyranoses); 0 (isofagomine); EC 3.2.1.23 (beta-Galactosidase)
[Em] Mês de entrada:1610
[Cu] Atualização por classe:161230
[Lr] Data última revisão:
161230
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160204
[St] Status:MEDLINE


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[PMID]:26717544
[Au] Autor:Thonhofer M; Gonzalez Santana A; Fischer R; Torvisco Gomez A; Saf R; Schalli M; Stütz AE; Withers SG
[Ad] Endereço:Glycogroup, Institute for Organic Chemistry, Graz University of Technology, Stremayrgasse 9, A-8010 Graz, Austria.
[Ti] Título:5-Fluoro derivatives of 4-epi-isofagomine as D-galactosidase inhibitors and potential pharmacological chaperones for GM1-gangliosidosis as well as Fabry's disease.
[So] Source:Carbohydr Res;420:6-12, 2016 Feb.
[Is] ISSN:1873-426X
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Electrophilic fluorination of an exocyclic methoxymethylene enol ether derived from N-tert-butyloxycarbonyl-1,5-dideoxy-1,5-imino-3,4-O-isopropylidene-D-erythro-pent-2-ulose (11) provided the 5-fluoro derivative of the powerful ß-galactosidase inhibitor 4-epi-isofagomine (8). This structural alteration, in combination with N-alkylation, led to considerably improved α-galactosidase selectivity. New compounds may serve as leads en route to new pharmacological chaperones for Fabry's disease.
[Mh] Termos MeSH primário: Inibidores Enzimáticos/síntese química
Galactosidases/antagonistas & inibidores
Imino Piranoses/síntese química
[Mh] Termos MeSH secundário: Inibidores Enzimáticos/química
Inibidores Enzimáticos/farmacologia
Doença de Fabry/tratamento farmacológico
Doença de Fabry/enzimologia
Gangliosidose GM1/tratamento farmacológico
Gangliosidose GM1/enzimologia
Halogenação
Seres Humanos
Imino Piranoses/química
Imino Piranoses/farmacologia
Estrutura Molecular
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Enzyme Inhibitors); 0 (Imino Pyranoses); 0 (isofagomine); EC 3.2.1.- (Galactosidases)
[Em] Mês de entrada:1610
[Cu] Atualização por classe:161230
[Lr] Data última revisão:
161230
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151231
[St] Status:MEDLINE


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[PMID]:26537532
[Au] Autor:Stockwell J; Daniels AD; Windle CL; Harman TA; Woodhall T; Lebl T; Trinh CH; Mulholland K; Pearson AR; Berry A; Nelson A
[Ad] Endereço:School of Chemistry, University of Leeds, Leeds, LS2 9JT, UK. a.s.nelson@leeds.ac.uk.
[Ti] Título:Evaluation of fluoropyruvate as nucleophile in reactions catalysed by N-acetyl neuraminic acid lyase variants: scope, limitations and stereoselectivity.
[So] Source:Org Biomol Chem;14(1):105-12, 2016 Jan 07.
[Is] ISSN:1477-0539
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The catalysis of reactions involving fluoropyruvate as donor by N-acetyl neuraminic acid lyase (NAL) variants was investigated. Under kinetic control, the wild-type enzyme catalysed the reaction between fluoropyruvate and N-acetyl mannosamine to give a 90 : 10 ratio of the (3R,4R)- and (3S,4R)-configured products; after extended reaction times, equilibration occurred to give a 30 : 70 mixture of these products. The efficiency and stereoselectivity of reactions of a range of substrates catalysed by the E192N, E192N/T167V/S208V and E192N/T167G NAL variants were also studied. Using fluoropyruvate and (2R,3S)- or (2S,3R)-2,3-dihydroxy-4-oxo-N,N-dipropylbutanamide as substrates, it was possible to obtain three of the four possible diastereomeric products; for each product, the ratio of anomeric and pyranose/furanose forms was determined. The crystal structure of S. aureus NAL in complex with fluoropyruvate was determined, assisting rationalisation of the stereochemical outcome of C-C bond formation.
[Mh] Termos MeSH primário: Biocatálise
Imino Furanoses/metabolismo
Imino Piranoses/metabolismo
Oxo-Ácido-Liases/metabolismo
Piruvatos/metabolismo
[Mh] Termos MeSH secundário: Imino Furanoses/química
Imino Piranoses/química
Conformação Molecular
Piruvatos/química
Estereoisomerismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Imino Furanoses); 0 (Imino Pyranoses); 0 (Pyruvates); 0 (fluoropyruvate); EC 4.1.3.- (Oxo-Acid-Lyases); EC 4.1.3.3 (N-acetylneuraminate lyase)
[Em] Mês de entrada:1609
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151106
[St] Status:MEDLINE
[do] DOI:10.1039/c5ob02037a


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[PMID]:26361824
[Au] Autor:Mena-Barragán T; García-Moreno MI; Nanba E; Higaki K; Concia AL; Clapés P; García Fernández JM; Ortiz Mellet C
[Ad] Endereço:Department of Organic Chemistry, Faculty of Chemistry, University of Seville, C/ Profesor García González 1, 41012 Seville, Spain.
[Ti] Título:Inhibitor versus chaperone behaviour of d-fagomine, DAB and LAB sp(2)-iminosugar conjugates against glycosidases: A structure-activity relationship study in Gaucher fibroblasts.
[So] Source:Eur J Med Chem;121:880-891, 2016 Oct 04.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:A library of sp(2)-iminosugar conjugates derived from the piperidine iminosugar d-fagomine and the enantiomeric pyrrolidine iminosugars DAB and LAB has been generated in only two steps involving direct coupling of the fully unprotected polyhydroxylated heterocycles with isothiocyanates, to give monocyclic thiourea adducts, and further intramolecular nucleophilic displacement of the δ-located primary hydroxyl group by the thiocarbonyl sulphur atom, affording bicyclic isothioureas. These transformations led to a dramatic shift in the inhibitory selectivity from α- to ß-glucosidases, with inhibition potencies that depended strongly on the nature of the aglycone-type moiety in the conjugates. Some of the new derivatives behaved as potent inhibitors of human ß-glucocerebrosidase (GCase), the lysosomal enzyme whose dysfunction is responsible for Gaucher disease. Moreover, GCase inhibition was 10-fold weaker at pH 5 as compared to pH 7, which is generally considered as a good property for pharmacological chaperones. Surprisingly, most of the compounds strongly inhibited GCase in wild type fibroblasts at rather low concentrations, showing an unfavourable chaperone/inhibitor balance on disease-associated GCase mutants in cellulo. A structure-activity relationship analysis points to the need for keeping a contiguous triol system in the glycone moiety of the conjugates to elicit a chaperone effect. In any case, the results reported here represent a proof of concept of the utmost importance of implementing diversity-oriented strategies for the identification and optimization of potent and specific glycosidase inhibitors and chaperones.
[Mh] Termos MeSH primário: Inibidores Enzimáticos/química
Inibidores Enzimáticos/farmacologia
Fibroblastos/efeitos dos fármacos
Doença de Gaucher/patologia
Glicosídeo Hidrolases/antagonistas & inibidores
Imino Piranoses/química
Imino Açúcares/química
[Mh] Termos MeSH secundário: Seres Humanos
Relação Estrutura-Atividade
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Enzyme Inhibitors); 0 (Imino Pyranoses); 0 (Imino Sugars); 53185-12-9 (fagomine); EC 3.2.1.- (Glycoside Hydrolases)
[Em] Mês de entrada:1702
[Cu] Atualização por classe:171009
[Lr] Data última revisão:
171009
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150913
[St] Status:MEDLINE



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