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1.
Curr Genet ; 64(5): 1043-1056, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29492587

RESUMO

Aspergillus nidulans produces sterigmatocystin (ST), a precursor of a carcinogenic secondary metabolite aflatoxin (AF), during its developmental process. ST biosynthesis has been shown to be affected by various regulatory factors. In this study, we investigated the involvement of O-mannosyltransferases (PmtA, PmtB, PmtC), in ST production and morphological development. Deletion of pmtA (ΔpmtA), pmtB (ΔpmtB) or pmtC (ΔpmtC) caused no spore production and a significant decline of vegetative growth. A tremendous decline of ST level was observed in all Δpmt mutants at the third day after inoculation. By extending the growth period, ST production of ΔpmtA and ΔpmtB increased to the wild-type level 7 days after inoculation. On the other hand, ST was not detected from 7- or 14-day cultures in ΔpmtC. Expression levels of aflR gene, an essential regulator of the ST biosynthesis pathway, were also down-regulated in the Δpmt strains. By introducing the aflR overexpression cassette, ST production in the ΔpmtA and ΔpmtB significantly increased to levels comparable to the wild type. However, the presence of the aflR overexpression cassette could not improve ST production in the ΔpmtC mutant. These data suggest that the PMT family is a new endogenous factor that is required for ST biosynthesis in A. nidulans. These findings provide better understanding of the regulatory mechanisms of AF/ST biosynthesis, which can ultimately contribute to our ability to control aflatoxin contamination.


Assuntos
Aspergillus nidulans/metabolismo , Carcinógenos/metabolismo , Isoenzimas/metabolismo , Manosiltransferases/metabolismo , Esterigmatocistina/biossíntese , Aspergillus nidulans/enzimologia , Aspergillus nidulans/genética , Aspergillus nidulans/crescimento & desenvolvimento , Deleção de Genes , Regulação Fúngica da Expressão Gênica , Técnicas de Silenciamento de Genes , Genes Fúngicos , Teste de Complementação Genética , Isoenzimas/genética , Manosiltransferases/genética , Mutação
2.
Pediatrics ; 137(6)2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27230765

RESUMO

CONTEXT: Half of children experience wheezing by age 6 years, and optimal strategies for preventing severe exacerbations are not well defined. OBJECTIVE: Synthesize the evidence of the effects of daily inhaled corticosteroids (ICS), intermittent ICS, and montelukast in preventing severe exacerbations among preschool children with recurrent wheeze. DATA SOURCES: Medline (1946, 2/25/15), Embase (1947, 2/25/15), CENTRAL. STUDY SELECTION: Studies were included based on design (randomized controlled trials), population (children ≤6 years with asthma or recurrent wheeze), intervention and comparison (daily ICS vs placebo, intermittent ICS vs placebo, daily ICS vs intermittent ICS, ICS vs montelukast), and outcome (exacerbations necessitating systemic steroids). DATA EXTRACTION: Completed by 2 independent reviewers. RESULTS: Twenty-two studies (N = 4550) were included. Fifteen studies (N = 3278) compared daily ICS with placebo and showed reduced exacerbations with daily medium-dose ICS (risk ratio [RR] 0.70; 95% confidence interval [CI], 0.61-0.79; NNT = 9). Subgroup analysis of children with persistent asthma showed reduced exacerbations with daily ICS compared with placebo (8 studies, N = 2505; RR 0.56; 95% CI, 0.46-0.70; NNT = 11) and daily ICS compared with montelukast (1 study, N = 202; RR 0.59; 95% CI, 0.38-0.92). Subgroup analysis of children with intermittent asthma or viral-triggered wheezing showed reduced exacerbations with preemptive high-dose intermittent ICS compared with placebo (5 studies, N = 422; RR 0.65; 95% CI, 0.51-0.81; NNT = 6). LIMITATIONS: More studies are needed that directly compare these strategies. CONCLUSIONS: There is strong evidence to support daily ICS for preventing exacerbations in preschool children with recurrent wheeze, specifically in children with persistent asthma. For preschool children with intermittent asthma or viral-triggered wheezing, there is strong evidence to support intermittent ICS for preventing exacerbations.


Assuntos
Antiasmáticos/uso terapêutico , Asma/tratamento farmacológico , Sons Respiratórios , Prevenção Secundária , Asma/prevenção & controle , Pré-Escolar , Humanos , Recidiva
3.
J Med Chem ; 55(7): 3036-48, 2012 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-22409629

RESUMO

Previously disclosed dihydropyrazolopyrimidines are potent and selective blockers of I(Kur) current. A potential liability with this chemotype is the formation of a reactive metabolite which demonstrated covalent binding to protein in vitro. When substituted at the 2 or 3 position, this template yielded potent I(Kur) inhibitors, with selectivity over hERG which did not form reactive metabolites. Subsequent optimization for potency and PK properties lead to the discovery of ((S)-5-(methoxymethyl)-7-(1-methyl-1H-indol-2-yl)-2-(trifluoromethyl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)((S)-2-(3-methylisoxazol-5-yl)pyrrolidin-1-yl)methanone (13j), with an acceptable PK profile in preclinical species and potent efficacy in the preclinical rabbit atrial effective refractory period (AERP) model.


Assuntos
Canal de Potássio Kv1.5/antagonistas & inibidores , Pirazóis/síntese química , Pirimidinas/síntese química , Animais , Cães , Coração/efeitos dos fármacos , Coração/fisiologia , Humanos , Pirazóis/farmacocinética , Pirazóis/farmacologia , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Coelhos , Ratos , Período Refratário Eletrofisiológico/efeitos dos fármacos , Estereoisomerismo , Relação Estrutura-Atividade
4.
J Med Chem ; 53(23): 8241-51, 2010 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-21073190

RESUMO

A series of 2,2-dimethyl-3,3-diphenyl-propanamides as novel glucocorticoid receptor modulators is reported. SAR exploration led to the identification of 4-hydroxyphenyl propanamide derivatives displaying good agonist activity in GR-mediated transrepression assays and reduced agonist activity in GR-mediated transactivation assays. Compounds 17 and 30 showed anti-inflammatory activity comparable to prednisolone in the rat carrageenan-induced paw edema model, with markedly decreased side effects with regard to increases in blood glucose and expression of hepatic tyrosine aminotransferase. A hypothetical binding mode accounting for the induction of the functional activity by a 4-hydroxyl group is proposed.


Assuntos
Amidas/farmacologia , Receptores de Glucocorticoides/agonistas , Amidas/química , Animais , Modelos Moleculares , Ratos
5.
Bioorg Med Chem Lett ; 19(18): 5469-73, 2009 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-19665893

RESUMO

Dihydropyrazolopyrimidines with a C6 heterocycle substituent were found to have high potency for block of K(V)1.5. Investigation of the substitution in the benzimidazole ring and the substituent in the 5-position of the dihydropyrazolopyrimidine ring produced 31a with an IC50 for K(V)1.5 block of 0.030muM without significant block of other cardiac ion channels. This compound also showed good bioavailability in rats and robust pharmacodynamic effects in a rabbit model.


Assuntos
Canal de Potássio Kv1.5/antagonistas & inibidores , Bloqueadores dos Canais de Potássio/farmacologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , Animais , Fibrilação Atrial/tratamento farmacológico , Linhagem Celular , Humanos , Canal de Potássio Kv1.5/metabolismo , Camundongos , Bloqueadores dos Canais de Potássio/química , Bloqueadores dos Canais de Potássio/farmacocinética , Pirazóis/química , Pirazóis/farmacocinética , Pirimidinas/química , Pirimidinas/farmacocinética , Coelhos , Ratos , Relação Estrutura-Atividade
8.
Bioorg Med Chem Lett ; 19(8): 2139-43, 2009 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-19321341

RESUMO

A series of dihydro-9,10-ethano-anthracene-11-carboxamides as novel glucocorticoid receptor modulators is reported. SAR exploration identified compounds from this series displaying a promising dissociation profile in discriminating between transrepression and transactivation activities. 17a is a partial agonist of GR-mediated transactivation which elicits potent and efficacious transrepression in reporter gene assays. A hypothetical binding mode is provided which accounts for the induction of functional activity by a bridgehead methyl group.


Assuntos
Antracenos/farmacologia , Descoberta de Drogas , Receptores de Glucocorticoides/metabolismo , Antracenos/química , Linhagem Celular , Cristalografia por Raios X , Descoberta de Drogas/métodos , Glucocorticoides/química , Glucocorticoides/farmacologia , Humanos , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/fisiologia , Receptores de Glucocorticoides/agonistas , Receptores de Glucocorticoides/fisiologia , Relação Estrutura-Atividade
10.
Bioorg Med Chem Lett ; 18(15): 4438-41, 2008 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-18619839

RESUMO

This study reports the identification and Hits to Leads optimization of inhibitors of coactivator associated arginine methyltransferase (CARM1). Compound 7b is a potent, selective inhibitor of CARM1.


Assuntos
Proteína-Arginina N-Metiltransferases/antagonistas & inibidores , Pirazóis/síntese química , Pirazóis/farmacologia , Técnicas de Química Combinatória , Estrutura Molecular , Pirazóis/química , Estereoisomerismo , Relação Estrutura-Atividade
11.
Bioorg Med Chem Lett ; 18(6): 1945-51, 2008 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-18289854

RESUMO

An amide library derived from the pyrrolo[2,1-f][1,2,4]triazine scaffold led to the identification of modest inhibitors of Met kinase activity. Introduction of polar side chains at C-6 of the pyrrolotriazine core provided significant improvements in in vitro potency. The amide moiety could be replaced with acylurea and malonamide substituents to give compounds with improved potency in the Met-driven GTL-16 human gastric carcinoma cell line. Acylurea pyrrolotriazines with substitution at C-5 demonstrated single digit nanomolar kinase activity. X-ray crystallography revealed that the C-5 substituted pyrrolotriazines bind to the Met kinase domain in an ATP-competitive manner.


Assuntos
Inibidores Enzimáticos/farmacologia , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Pirróis/química , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores de Fatores de Crescimento/antagonistas & inibidores , Neoplasias Gástricas/tratamento farmacológico , Triazinas/química , Animais , Células CACO-2/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas/efeitos dos fármacos , Cristalografia por Raios X , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Glutationa Transferase/antagonistas & inibidores , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Camundongos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Conformação Proteica , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-met , Receptores Proteína Tirosina Quinases/metabolismo , Receptores de Fatores de Crescimento/metabolismo , Neoplasias Gástricas/sangue , Neoplasias Gástricas/enzimologia , Relação Estrutura-Atividade
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