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1.
Nat Prod Res ; 31(24): 2836-2841, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28281360

RESUMO

The ethanolic extract of the leaves of Eriobotrya japonica exhibited inhibitory activity against phosphodiesterase-4D (PDE4D), which is a therapeutic target of inflammatory disease. Subsequent bioassay-guided fractionation led to the isolation of a new triterpene (1), together with seven known triterpenoids, methyl corosolate (2), ursolic acid (3), oleanolic acid (4), methyl maslinate (5), α-amyin (6), 3ß,19α,23-trihydroxy-urs-12-ene (7) and uvaol (8). The structure of compound 1 was established as 3ß-hydroxyl-21ß-acetoxyl-urs-12-en-28-carboxylate on the basis of interpretation of its 1D and 2D NMR and HR-ESI-MS spectroscopic data. The bioassay results verified compounds 2, 3 and 8 inhibited PDE4D2 effectively with the IC50 values of 3.06, 2.18 and 5.17 µM, respectively, which may provide a novel mechanism for the anti-inflammatory activity of the leaves of E. japonica.


Assuntos
Eriobotrya/química , Inibidores da Fosfodiesterase 4/isolamento & purificação , Animais , Anti-Inflamatórios/isolamento & purificação , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Ácido Oleanólico/análogos & derivados , Ácido Oleanólico/isolamento & purificação , Folhas de Planta/química , Triterpenos/isolamento & purificação , Triterpenos/farmacologia
2.
Nat Prod Res ; 31(6): 734-737, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27531418

RESUMO

In this study, a series of novel ferulic and caffeic acid dimers was designed and synthesised, and their multifunctional properties against Alzheimer's disease (AD) were evaluated. Results showed that our multifunctional strategy was great supported by enhancing the inhibition of Aß1-42 self-induced aggregation. Moreover, 7b also had potent protective effects against glutamate-induced cell death without significant cell toxicity in mouse hippocampal neuronal HT22 cells and 10c effectively scavenged diphenylpicrylhydrazyl free radicals. Collectively, these data strongly encourage further optimisation of 7b as a new hit to develop multifunctional agents for the treatment of AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Ácidos Cafeicos/síntese química , Ácidos Cafeicos/uso terapêutico , Ácidos Cumáricos/síntese química , Ácidos Cumáricos/uso terapêutico , Peptídeos beta-Amiloides/antagonistas & inibidores , Animais , Antioxidantes/farmacologia , Compostos de Bifenilo/química , Morte Celular/efeitos dos fármacos , Linhagem Celular , Depuradores de Radicais Livres/química , Depuradores de Radicais Livres/farmacologia , Ácido Glutâmico/toxicidade , Humanos , Camundongos , Neurônios/efeitos dos fármacos , Fragmentos de Peptídeos/antagonistas & inibidores , Picratos/química
3.
J Ethnopharmacol ; 193: 133-139, 2016 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-27497639

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Sophora flavescens Aiton (Radix Sophorae Flavescentis, Kushen) is used in traditional Chinese medicine to treat chronic hepatitis B (CHB), and has the ability to clear heat and dampness from the body. Oxymatrine is one of the major bioactive compounds extracted from Sophora flavescens Aiton and constitutes more than 90% of the oxymatrine injection commonly used for CHB treatment in clinics in China. AIM OF THE STUDY: We aim to analyze the protein binding target of oxymatrine in treating CHB by screening a T7 phage display cDNA library of human CHB and examine the biochemistry of protein-ligand binding between oxymatrine and its ligands. MATERIALS AND METHODS: A T7 phage cDNA library of human CHB was biopanned by affinity selection using oxymatrine as bait. The interaction of oxymatrine with its candidate binding protein was investigated by affinity assay, molecular docking, Isothermal Titration Calorimetry (ITC) and Surface Plasmon Resonance (SPR). RESULTS: A library of potential oxymatrine binding peptides was generated. Ubiquinol-cytochrome c reductase binding protein (UQCRB) was one of the candidate binding proteins of oxymatrine. UQCRB-displaying T7 phage binding numbers in the oxymatrine group were significantly higher than that in the control group, biotin group, and matrine group (p<0.05 or p<0.01). Three-dimensional structure modeling of the UQCRB with oxymatrine showed that their binding interfaces matched and oxymatrine inserted into a deeper pocket of UQCRB, which mainly involved amino acid residues Tyr21, Arg33, Tyr83, Glu84, Asp86, Pro88, and Glu91. The binding affinity constant (Kb) from SPR was 4.2mM. The Kb from ITC experiment was 3.9mM and stoichiometry was fixed as 1, which fit very well with the result of SPR. The binding of oxymatrine to UQCRB was driven by strong enthalpy forces such as hydrogen bonds and polar interactions as the heat released was about 157kcal/mol and ΔG was less than zero. CONCLUSIONS: In this study, using the T7 phage display system, we have identified UQCRB as a direct binding protein of oxymatrine. Furthermore, the specificity and molecular interaction of oxymatrine with UQCRB were also determined. The binding of UQCRB to oxymatrine suggests that UQCRB is a potential target of oxymatrine in treating CHB. These results provide new understanding into the mechanism of oxymatrine and insights into the strategy on the treatment of CHB.


Assuntos
Alcaloides/farmacologia , Bacteriófago T7 , Hepatite B Crônica/tratamento farmacológico , Quinolizinas/farmacologia , Sophora , Alcaloides/metabolismo , Bacteriófago T7/genética , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Hepatite B Crônica/metabolismo , Humanos , Ligação Proteica , Quinolizinas/metabolismo
4.
Nat Prod Res ; 30(1): 7-12, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26214049

RESUMO

One new cyclic tetrapeptide cyclic-(Tyr-Ala-Leu-Ser) (1) along with four natural compounds firstly obtained 3H-imidazole-4-carboxylic acid (2), 2-methyl-3H-imidazole-4-carboxylic acid (3), 3-ethylidene-6-isopropyl-piperazine-2,5-dione (4), and 3-isobutylidene-6-methyl piperazine-2,5-dione (5) have been isolated from the coral derived endophytic bacteria Brevibacterium sp. L-4 collected from the South China Sea. Their structures were elucidated through spectroscopic techniques including NMR (1D and 2D), MS, and EA, and their relative configurations were also assigned by NMR analysis.


Assuntos
Antozoários/microbiologia , Brevibacterium/química , Peptídeos Cíclicos/química , Animais , Endófitos/química , Imidazóis/química , Imidazóis/isolamento & purificação , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Oceanos e Mares , Peptídeos Cíclicos/isolamento & purificação , Piperazinas/química , Piperazinas/isolamento & purificação
5.
Eur J Med Chem ; 101: 525-33, 2015 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-26188908

RESUMO

In our previous work, indolizinoquinolinedione derivative 1 was identified as a Top1 catalytic inhibitor. Herein, a series of 6-substituted indolizinoquinolinedione derivatives were synthesized through modification of the parent compound 1. Top1 cleavage and relaxation assays indicate that none of these novel compounds act as classical Top1 poison, and that the compounds with alkylamino terminus at C-6 side chain, including 8, 11-16, 18-21, 25, 26 and 28-30, are the most potent Top1 catalytic inhibitors. Top1-mediated unwinding assay demonstrated that 14, 22 and 26 were Top1 catalytic inhibitors without Top1-mediated unwinding effect. Moreover, MTT results showed that compounds 26, 28-30 exhibit significant cytotoxicity against human leukemia HL-60 cells, and that compound 26 exerts potent cytotoxicity against A549 lung cancer cells at nanomolar range.


Assuntos
Antineoplásicos/farmacologia , DNA Topoisomerases Tipo I/metabolismo , Indolizinas/farmacologia , Quinolonas/farmacologia , Inibidores da Topoisomerase I/farmacologia , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Biocatálise/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Indolizinas/síntese química , Indolizinas/química , Estrutura Molecular , Quinolonas/síntese química , Quinolonas/química , Relação Estrutura-Atividade , Inibidores da Topoisomerase I/síntese química , Inibidores da Topoisomerase I/química , Células Tumorais Cultivadas
6.
CNS Neurosci Ther ; 20(9): 840-50, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24922524

RESUMO

AIMS: Oxidative stress (OS) plays an important role in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD). This study was designed to uncover the cellular and biochemical mechanisms underlying the neuroprotective effects of tacrine-3-caffeic acid (T3CA), a novel promising multifunctional anti-Alzheimer's dimer, against OS-induced neuronal death. METHODS AND RESULTS: T3CA protected HT22 cells against high-concentration-glutamate-induced cell death in time- and concentration-dependent manners and potently attenuated glutamate-induced intracellular reactive oxygen species (ROS) production as well as mitochondrial membrane-potential (ΔΨ) disruption. Besides, T3CA significantly induced nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear translocation and increased its transcriptional activity, which were demonstrated by Western blotting, immunofluorescence, and antioxidant response element (ARE)-luciferase reporter gene assay. Further studies showed that T3CA potently up-regulated heme oxygenase-1 (HO-1), an endogenous antioxidative enzyme and a downstream effector of Nrf2, at both mRNA and protein levels. The neuroprotective effects of T3CA were partially reversed by brusatol, which reduced protein level of Nrf2, or by inhibiting HO-1 with siRNA or ZnPP-IX, a specific inhibitor of HO-1. CONCLUSIONS: Taken together, these results clearly demonstrate that T3CA protects neurons against OS-induced cell death partially through Nrf2/ARE/HO-1 signaling pathway, which further supports that T3CA might be a promising novel therapeutic agent for OS-associated diseases.


Assuntos
Ácidos Cafeicos/farmacologia , Heme Oxigenase-1/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Neurônios/efeitos dos fármacos , Nootrópicos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Tacrina/farmacologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Morte Celular/efeitos dos fármacos , Linhagem Celular Transformada , Proteínas do Citoesqueleto/metabolismo , Ácido Glutâmico/farmacologia , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Transfecção
7.
Nat Prod Res ; 28(9): 680-2, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24597911

RESUMO

One new imidazole derivative alkaloid pelopuradazole (1), together with three known alkaloids as in 3H-imidazole-4-carboxylic acid (2), 1H-pyrrole-2-carboxylic acid (3) and 2-methyl-3H-imidazole-4-carboxylic acid (4) and two known cyclo-dipeptides pelopurin A (5) and pelopurin B (6), has been isolated from the marine bacterium Pelomonas puraquae sp. nov. Pelopuradazole (1) was a new imidazole derivative alkaloid, while compounds 2, 3, 5 and 6 were firstly obtained as natural products. Compounds 1-6 were isolated from P. puraquae sp. nov. for the first time.


Assuntos
Alcaloides/isolamento & purificação , Comamonadaceae/química , Imidazóis/isolamento & purificação , Alcaloides/química , Imidazóis/química , Biologia Marinha , Peptídeos Cíclicos/química , Peptídeos Cíclicos/isolamento & purificação , Prolina/análogos & derivados , Prolina/isolamento & purificação
8.
Planta Med ; 79(11): 978-86, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23804040

RESUMO

Six new triterpenoid saponins, psychotrianosides A-F (1-6), and two known triterpenoid saponins, psychotrianoside G (7) and ardisianoside D (8), were isolated from Psychotria sp. Their structures were determined mainly by spectroscopic methods. The cytotoxic activities of 1-8 against five human cancer cell lines (MDA-MB-231, MCF-7, MCF-7/ADM, HepG2, and HepG2/ADM) are reported for the first time. Psychotrianoside C (3) showed the most potent antiproliferative activity among these saponins, and the IC50 value of 3 against MDA-MB-231 was 2.391 ± 0.161 µM. Compound 3 was also found to induce apoptosis.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Psychotria/química , Saponinas/farmacologia , Triterpenos/farmacologia , Antineoplásicos Fitogênicos/química , Apoptose , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Caules de Planta/química , Saponinas/química , Saponinas/isolamento & purificação , Análise Espectral , Triterpenos/química , Triterpenos/isolamento & purificação
9.
Nat Prod Res ; 27(9): 782-6, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-22889207

RESUMO

One new precursor of tetraterpenoids, Sarglaucol (1), along with eight known compounds have been isolated from the soft coral Sarcophyton glaucum collected from the Sanya Bay, Hainan Island, China. Their structures were elucidated through spectroscopic techniques including 1D- and 2D-NMR, and their relative configurations were also assigned by NMR and NOESY analysis. Compounds 1 showed weak antitumour activities.


Assuntos
Antozoários/química , Terpenos/química , Animais , Antozoários/metabolismo , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral/efeitos dos fármacos , China , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Terpenos/isolamento & purificação , Terpenos/farmacologia
11.
Nat Prod Res ; 26(20): 1864-8, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22007603

RESUMO

Chemical study of the Psychotria sp. led to the isolation of a new type of ceramide named psychotramide (1). HR-FAB-MS analysis revealed that psychotramide consists of four new sphingolipids. Their structures were determined on the basis of the spectroscopic data and chemical methods to be psychotramide A (1-a), psychotramide B (1-b), psychotramide C (1-c) and psychotramide D (1-d).


Assuntos
Caules de Planta/química , Psychotria/química , Esfingolipídeos/química , Ceramidas/química , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Estrutura Molecular
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