Base de dados : MEDLINE
Pesquisa : D03.605 [Categoria DeCS]
Referências encontradas : 154 [refinar]
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[PMID]:28675829
[Au] Autor:Liu R; Su Y; Yang J; Wang A
[Ad] Endereço:State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
[Ti] Título:Polyprenylated acylphloroglucinols from Hypericum scabrum.
[So] Source:Phytochemistry;142:38-50, 2017 Oct.
[Is] ISSN:1873-3700
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Fourteen phloroglucinols, named hyperciumoxide A-N, and a known compound were isolated from air-dried aerial parts of Hypericum scabrum. The structures of these compounds were deduced on the basis of extensive 1D- and 2D-NMR experiments. Hepatoprotective properties against D-galactosamine-induced HL-7702 cell damage of isolated compounds were evaluated. Meanwhile, these compounds were also tested for antidepressant activity by inhibiting reuptake of tritiated serotonin ([ H]-5-HT) and Noradrenalinet ([ H]-NE) in rat brain synaptosomes.
[Mh] Termos MeSH primário: Antidepressivos/isolamento & purificação
Medicamentos de Ervas Chinesas/isolamento & purificação
Compostos Heterocíclicos de Anel em Ponte/farmacologia
Hypericum/química
Floroglucinol/isolamento & purificação
Componentes Aéreos da Planta/química
Antagonistas da Serotonina/isolamento & purificação
[Mh] Termos MeSH secundário: Animais
Antidepressivos/química
Antidepressivos/farmacologia
Encéfalo/efeitos dos fármacos
Cicloexanonas/química
Cicloexanonas/isolamento & purificação
Cicloexanonas/farmacologia
Medicamentos de Ervas Chinesas/química
Medicamentos de Ervas Chinesas/farmacologia
Células HL-60
Compostos Heterocíclicos de Anel em Ponte/química
Seres Humanos
Fígado/efeitos dos fármacos
Estrutura Molecular
Ressonância Magnética Nuclear Biomolecular
Floroglucinol/análogos & derivados
Floroglucinol/química
Floroglucinol/farmacologia
Ratos
Antagonistas da Serotonina/química
Antagonistas da Serotonina/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antidepressive Agents); 0 (Cyclohexanones); 0 (Drugs, Chinese Herbal); 0 (Heterocyclic Compounds, Bridged-Ring); 0 (Serotonin Antagonists); 0 (hyperciumoxide N); 5QOR3YM052 (cyclohexanone); DHD7FFG6YS (Phloroglucinol)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170915
[Lr] Data última revisão:
170915
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170705
[St] Status:MEDLINE


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[PMID]:28522254
[Au] Autor:Hayashida K; Hirayama S; Iwai T; Watanabe Y; Takahashi T; Sakai J; Nakata E; Yamakawa T; Fujii H; Nagase H
[Ad] Endereço:Laboratory of Medicinal Chemistry, School of Pharmacy, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan; Discovery Research Laboratories, Nippon Chemiphar Co., Ltd., 1-22, Hikokawado, Misato, Saitama 341-0005, Japan.
[Ti] Título:Novel delta opioid receptor agonists with oxazatricyclodecane structure showing potent agonistic activities.
[So] Source:Bioorg Med Chem Lett;27(12):2742-2745, 2017 06 15.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:We recently reported oxazatricyclodecane derivatives 1 as δ opioid receptor (DOR) agonists having a novel chemotype, but their DOR agonistic activities were relatively low. Based on the working hypothesis that the dioxamethylene moiety in 1 may be an accessory site and that it may interfere with the sufficient conformational change of the receptor required for exerting the full agonistic responses, we designed and synthesized new oxazatricyclodecane derivatives 2-4 lacking the dioxamethylene moiety. As we expected, the designed compounds 2-4 showed pronouncedly improved agonistic activities for the DOR. Compound 2a with the 17-cyclopropylmethyl substituent was a potent agonist with the highest selectivity for the DOR and was expected to be a lead compound for novel and selective DOR agonists.
[Mh] Termos MeSH primário: Compostos Heterocíclicos de Anel em Ponte/farmacologia
Receptores Opioides delta/agonistas
[Mh] Termos MeSH secundário: Relação Dose-Resposta a Droga
Compostos Heterocíclicos de Anel em Ponte/síntese química
Compostos Heterocíclicos de Anel em Ponte/química
Seres Humanos
Estrutura Molecular
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Heterocyclic Compounds, Bridged-Ring); 0 (Receptors, Opioid, delta)
[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:170520
[St] Status:MEDLINE


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[PMID]:28440736
[Au] Autor:Zhao ZM; Liu HL; Sun X; Guo T; Shen L; Tao YY; Liu CH
[Ad] Endereço:1 Institute of Liver Diseases, Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
[Ti] Título:Levistilide A inhibits angiogenesis in liver fibrosis via vascular endothelial growth factor signaling pathway.
[So] Source:Exp Biol Med (Maywood);242(9):974-985, 2017 May.
[Is] ISSN:1535-3699
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Levistilide A (C H O , molecular weight = 380.48) derived from Angelica sinensis (Danggui) has been reported to inhibit hepatic stellate cell proliferation. This study investigated the effects of levistilide A on liver fibrosis relating to angiogenesis, particularly on the characteristic change in liver sinusoidal endothelial cells. LX-2 cells were activated by TGF-ß1, and the human hepatic sinusoidal endothelial cells (HHSECs) were induced by endothelial cell growth supplement. Cell viability was detected using a methylthiazoldiphenyl-tetrazolium bromide assay; F-actin was visualized through the fluorescence probe method; cell proliferation was examined using the EdU kit; antiangiogenesis activity was assessed using the tube formation assay and transgenic zebrafish model. To verify the results in vivo, rats were subcutaneously injected with CCl twice a week for six weeks to duplicate the liver fibrosis model and then treated with 10 mL/kg of normal saline, 4 mg/kg of sorafenib, and 3 and 6 mg/kg of levistilide A for three weeks from the fourth week. Collagen deposition was detected through Sirius Red staining; liver microvasculature was examined through vWF labeling and X-ray 2D imaging; sinusoidal fenestrations were observed through scanning electron microscopy; collagen I, α-SMA, CD31, vascular endothelial growth factor (VEGF), and VEGF-R2 were detected through Western blotting. Our results indicated that levistilide A attenuated LX-2 cell activation and HHSEC proliferation. The ability of HHSECs to form tubelike structures in Matrigel was inhibited, and the number of functional vessels in transgenic zebrafish decreased. In in vivo experiments, levistilide A reduced collagen deposition and the number of new microvessels; ameliorated sinusoid capillarization; and downregulated the expression of CD31, VEGF, and VEGF-R2. These findings suggest that levistilide A can inhibit liver fibrosis through antiangiogenesis by alleviating sinusoid capillarization via the VEGF signaling pathway. Impact statement Levistilide A has been reported to inhibit hepatic stellate cell (HSC) proliferation. In this study, we further investigated the mechanisms of levistilide A on liver fibrosis relating to angiogenesis, particularly on the characteristic change in liver sinusoidal endothelial cells. The cell models of HSC and liver sinusoidal endothelial cell and CCl induced liver fibrosis model were used. These results suggest that levistilide A can inhibit liver fibrosis through antiangiogenesis by alleviating sinusoid capillarization via the vascular endothelial growth factor signaling pathway. The effect of levistilide A on liver fibrosis was confirmed, and its detailed mechanism was also discussed. These findings suggest that levistilide A may be a great potential drug for treating liver fibrosis through antiangiogenesis, and this effect will be verified in other fibrotic animal model studies or by clinical trials.
[Mh] Termos MeSH primário: Fármacos Gastrointestinais/administração & dosagem
Compostos Heterocíclicos de Anel em Ponte/administração & dosagem
Cirrose Hepática/tratamento farmacológico
Cirrose Hepática/patologia
Neovascularização Patológica/patologia
[Mh] Termos MeSH secundário: Animais
Modelos Animais de Doenças
Fígado/patologia
Cirrose Hepática/induzido quimicamente
Niacinamida/administração & dosagem
Niacinamida/análogos & derivados
Compostos de Fenilureia/administração & dosagem
Ratos
Resultado do Tratamento
Peixe-Zebra
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Gastrointestinal Agents); 0 (Heterocyclic Compounds, Bridged-Ring); 0 (Phenylurea Compounds); 0 (levistilide A); 25X51I8RD4 (Niacinamide); 9ZOQ3TZI87 (sorafenib)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:171101
[Lr] Data última revisão:
171101
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170426
[St] Status:MEDLINE
[do] DOI:10.1177/1535370217701005


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[PMID]:28152480
[Au] Autor:Chen YC; Chang JG; Liu TY; Jong YJ; Cheng WL; Yuo CY
[Ad] Endereço:Graduate Institute of Medicine, College of medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
[Ti] Título:Securinine enhances SMN2 exon 7 inclusion in spinal muscular atrophy cells.
[So] Source:Biomed Pharmacother;88:708-714, 2017 Apr.
[Is] ISSN:1950-6007
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:Spinal muscular atrophy (SMA) is an autosomal recessive disease characterized by the degeneration of motor neurons in the spinal cord, leading to muscular atrophy. SMA is caused by deletions or mutations in the survival motor neuron gene (SMN1) on chromosome 5q13. A second copy of the SMN gene (SMN2) also exists on chromosome 5, and both genes can produce functional protein. However, due to alternative splicing of the exon 7, the majority of SMN protein produced by SMN2 is truncated and unable to compensate for the loss of SMN1. Increasing full-length SMN protein production by promoting the exon 7 inclusion in SMN2 mRNA or increasing SMN2 gene transcription could be a therapeutic approach for SMA. In this study, we screened for the compounds that enhance SMN2 exon 7 inclusion by using SMN2 minigene-luciferase reporter system. We found that securinine can increase luciferase activity, indicating that securinine promoted SMN2 exon 7 inclusion. In addition, securinine increased full-length SMN2 mRNA and SMN protein expression in SMA patient-derived lymphoid cell lines. To investigate the mechanism of securinine effect on SMN2 splicing, we compared the protein levels of relevant splicing factors between securinine-treated and untreated cells. We found that securinine downregulated hnRNP A1 and Sam68 and upregulated Tra2-ß1 expression. However, securinine, unlike HDAC inhibitors, did not enhance tra2-ß1 gene transcription, indicating a post-transcriptional mechanism for Tra2-ß1 upregulation. Furthermore, we treated SMA-like mice with securinine by i.p. injection and found that securinine treatment increased SMN2 exon 7 inclusion and SMN protein expression in the brain and spinal cord. According to our results, securinine might have the potential to become a therapeutic drug for SMA disease.
[Mh] Termos MeSH primário: Azepinas/farmacologia
Estimulantes do Sistema Nervoso Central/farmacologia
Éxons/genética
Compostos Heterocíclicos de Anel em Ponte/farmacologia
Lactonas/farmacologia
Atrofia Muscular Espinal/genética
Piperidinas/farmacologia
Proteína 2 de Sobrevivência do Neurônio Motor/genética
[Mh] Termos MeSH secundário: Animais
Linhagem Celular
Ribonucleoproteínas Nucleares Heterogêneas/biossíntese
Ribonucleoproteínas Nucleares Heterogêneas/genética
Tecido Linfoide/metabolismo
Camundongos
Atrofia Muscular Espinal/fisiopatologia
Processamento de Proteína
RNA Mensageiro/biossíntese
RNA Mensageiro/genética
Fatores de Processamento de Serina-Arginina/biossíntese
Fatores de Processamento de Serina-Arginina/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Azepines); 0 (Central Nervous System Stimulants); 0 (Heterocyclic Compounds, Bridged-Ring); 0 (Heterogeneous-Nuclear Ribonucleoproteins); 0 (Lactones); 0 (Piperidines); 0 (RNA, Messenger); 0 (SMN2 protein, mouse); 0 (Survival of Motor Neuron 2 Protein); 0 (Tra2b protein, mouse); 170974-22-8 (Serine-Arginine Splicing Factors); G4VS580P5E (securinine)
[Em] Mês de entrada:1703
[Cu] Atualização por classe:170313
[Lr] Data última revisão:
170313
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170203
[St] Status:MEDLINE


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[PMID]:28005357
[Au] Autor:Castanedo GM; Blaquiere N; Beresini M; Bravo B; Brightbill H; Chen J; Cui HF; Eigenbrot C; Everett C; Feng J; Godemann R; Gogol E; Hymowitz S; Johnson A; Kayagaki N; Kohli PB; Knüppel K; Kraemer J; Krüger S; Loke P; McEwan P; Montalbetti C; Roberts DA; Smith M; Steinbacher S; Sujatha-Bhaskar S; Takahashi R; Wang X; Wu LC; Zhang Y; Staben ST
[Ad] Endereço:Genentech, Inc. 1 DNA Way, South San Francisco, California 94080, United States.
[Ti] Título:Structure-Based Design of Tricyclic NF-κB Inducing Kinase (NIK) Inhibitors That Have High Selectivity over Phosphoinositide-3-kinase (PI3K).
[So] Source:J Med Chem;60(2):627-640, 2017 Jan 26.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:We report here structure-guided optimization of a novel series of NF-κB inducing kinase (NIK) inhibitors. Starting from a modestly potent, low molecular weight lead, activity was improved by designing a type 11/2 binding mode that accessed a back pocket past the methionine-471 gatekeeper. Divergent binding modes in NIK and PI3K were exploited to dampen PI3K inhibition while maintaining NIK inhibition within these series. Potent compounds were discovered that selectively inhibit the nuclear translocation of NF-κB2 (p52/REL-B) but not canonical NF-κB1 (REL-A/p50).
[Mh] Termos MeSH primário: Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia
Compostos Heterocíclicos de Anel em Ponte/farmacologia
Isoxazóis/farmacologia
Oxazepinas/farmacologia
Oxazóis/farmacologia
Fosfatidilinositol 3-Quinase/antagonistas & inibidores
Inibidores de Proteínas Quinases/farmacologia
Proteínas Serina-Treonina Quinases/antagonistas & inibidores
[Mh] Termos MeSH secundário: Transporte Ativo do Núcleo Celular
Animais
Sítios de Ligação
Núcleo Celular/metabolismo
Cães
Células HEK293
Células HeLa
Compostos Heterocíclicos de 4 ou mais Anéis/síntese química
Compostos Heterocíclicos de 4 ou mais Anéis/química
Compostos Heterocíclicos de Anel em Ponte/síntese química
Compostos Heterocíclicos de Anel em Ponte/química
Seres Humanos
Imidazóis/farmacologia
Isoxazóis/síntese química
Isoxazóis/química
Camundongos
Subunidade p50 de NF-kappa B/metabolismo
Subunidade p52 de NF-kappa B/metabolismo
Oxazepinas/síntese química
Oxazepinas/química
Oxazóis/síntese química
Oxazóis/química
Inibidores de Proteínas Quinases/síntese química
Inibidores de Proteínas Quinases/química
Transdução de Sinais/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (10-(3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-ynyl)-N3-methyl-5,6-dihydroimidazo(1,2-d)(1,4)benzoxazepine-2,3-dicarboxamide); 0 (10-fluoro-9-(3-hydroxy-3-(5-methyl-1,2-oxazol-3-yl)but-1-yn-1-yl)-2,5-diazatetracyclo(11.1.1.0(2,6).0(7,12))pentadeca-3,5,7(12),8,10-pentaene-4-carboxamide); 0 (2-(3-(2-(1-isopropyl-3-methyl-1H-1,2-4-triazol-5-yl)-5,6-dihydrobenzo(f)imidazo(1,2-d)(1,4)oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanamide); 0 (Heterocyclic Compounds, 4 or More Rings); 0 (Heterocyclic Compounds, Bridged-Ring); 0 (Imidazoles); 0 (Isoxazoles); 0 (NF-kappa B p50 Subunit); 0 (NF-kappa B p52 Subunit); 0 (Oxazepines); 0 (Oxazoles); 0 (Protein Kinase Inhibitors); EC 2.7.1.137 (Phosphatidylinositol 3-Kinase); EC 2.7.11.1 (Protein-Serine-Threonine Kinases); EC 2.7.11.25 (NF-kappa B kinase)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170704
[Lr] Data última revisão:
170704
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161223
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jmedchem.6b01363


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[PMID]:27792748
[Au] Autor:Stefanowicz-Hajduk J; Sparzak-Stefanowska B; Krauze-Baranowska M; Ochocka JR
[Ad] Endereço:Department of Biology and Pharmaceutical Botany, Medical University of Gdansk, Gdansk, Poland.
[Ti] Título:Securinine from Phyllanthus glaucus Induces Cell Cycle Arrest and Apoptosis in Human Cervical Cancer HeLa Cells.
[So] Source:PLoS One;11(10):e0165372, 2016.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: The Securinega-type alkaloids occur in plants belonging to Euphorbiaceae family. One of the most widely distributed alkaloid of this group is securinine, which was identified next to allosecurinine in Phyllanthus glaucus (leafflower). Recently, some Securinega-type alkaloids have paid attention to its antiproliferative potency towards different cancer cells. However, the cytotoxic properties of allosecurinine have not yet been evaluated. METHODS: The cytotoxicity of the extract, alkaloid fraction obtained from P. glaucus, isolated securinine and allosecurinine against HeLa cells was evaluated by real-time xCELLigence system and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Apoptosis was detected by annexin V and 7-amino-actinomycin (7-AAD) staining and confirmed with fluorescent Hoechst 33342 dye. The assessment of mitochondrial membrane potential (MMP), reactive oxygen species (ROS) generation, the level of extracellular signal-regulated protein kinases 1 and 2 (ERK1/2), caspase-3/7 activity and cell cycle analysis were measured by flow cytometry. The enzymatic activity of caspase-9 was assessed by a luminometric assay. The expression of apoptosis associated genes was analyzed by real-time PCR. RESULTS: The experimental data revealed that securinine and the alkaloid fraction were significantly potent on HeLa cells growth inhibition with IC50 values of 7.02 ± 0.52 µg/ml (32.3 µM) and 25.46 ± 1.79 µg/ml, respectively. The activity of allosecurinine and Phyllanthus extract were much lower. Furthermore, our study showed that the most active securinine induced apoptosis in a dose-dependent manner in the tested cells, increased the percentage of ROS positive cells and depolarized cells as well as stimulated the activity of ERK1/2, caspase-9 and -3/7. Securinine also induced cell cycle arrest in S phase. Real-time PCR analysis showed high expression of TNFRSF genes in the cells stimulated with securinine. CONCLUSIONS: Securinine induces apoptosis and activates cell cycle checkpoints in HeLa cells which is associated with oxidative stress. The results indicate that the mitochondrial pathway is involved in the programmed cell death.
[Mh] Termos MeSH primário: Apoptose/efeitos dos fármacos
Azepinas/farmacologia
Ciclo Celular/efeitos dos fármacos
Células HeLa/efeitos dos fármacos
Compostos Heterocíclicos de Anel em Ponte/farmacologia
Lactonas/farmacologia
Phyllanthus
Piperidinas/farmacologia
Extratos Vegetais/farmacologia
[Mh] Termos MeSH secundário: Proliferação Celular/efeitos dos fármacos
Seres Humanos
Potencial da Membrana Mitocondrial/efeitos dos fármacos
Phyllanthus/química
Reação em Cadeia da Polimerase em Tempo Real
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Azepines); 0 (Heterocyclic Compounds, Bridged-Ring); 0 (Lactones); 0 (Piperidines); 0 (Plant Extracts); G4VS580P5E (securinine)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170613
[Lr] Data última revisão:
170613
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161030
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0165372


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[PMID]:27518479
[Au] Autor:Ramesh P; Rao TP
[Ad] Endereço:Division of Natural Products Chemistry and ‡Centre for NMR and Structural Chemistry, Indian Institute of Chemical Technology , Tarnaka, Hyderabad-500007, India.
[Ti] Título:Biosynthesis-Inspired Total Synthesis of Bioactive Styryllactones (+)-Goniodiol, (6S,7S,8S)-Goniodiol, (-)-Parvistone D, and (+)-Parvistone E.
[So] Source:J Nat Prod;79(8):2060-5, 2016 Aug 26.
[Is] ISSN:1520-6025
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:A protecting-group-free total synthesis of (+)-goniodiol (1), (6S,7S,8S)-goniodiol (2), (-)-parvistone D (4), and (+)-parvistone E (6) was efficiently achieved in five steps from commercially available trans-cinnamaldehyde with high overall yields (72-75%). The synthesis strategy was inspired from the proposed biosynthesis pathway of styryllactones. Key transformations of the strategy include a one-pot conversion of goniothalamin oxide to goniodiol or 9-deoxygoniopypyrone in aqueous media, stereoselective epoxidation, ring-closing metathesis, and stereoselective Maruoka allylation. The route is amenable to synthesis of various analogues for biological evaluation.
[Mh] Termos MeSH primário: Compostos Heterocíclicos de Anel em Ponte/síntese química
Pironas/síntese química
[Mh] Termos MeSH secundário: Compostos Heterocíclicos de Anel em Ponte/química
Lactonas/síntese química
Lactonas/metabolismo
Conformação Molecular
Estrutura Molecular
Pironas/química
Estereoisomerismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Heterocyclic Compounds, Bridged-Ring); 0 (Lactones); 0 (Pyrones); 0 (goniodiol); 0 (parvistone D); 136685-37-5 (9-deoxygoniopypyrone); 34W9GO6B2Z (goniothalamin)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170502
[Lr] Data última revisão:
170502
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160813
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jnatprod.6b00386


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[PMID]:27467236
[Au] Autor:Tang G; Liu X; Ma N; Huang X; Wu ZL; Zhang W; Wang Y; Zhao BX; Wang ZY; Ip FC; Ip NY; Ye WC; Shi L; Chen WM
[Ti] Título:Design and Synthesis of Dimeric Securinine Analogues with Neuritogenic Activities.
[So] Source:ACS Chem Neurosci;7(10):1442-1451, 2016 Oct 19.
[Is] ISSN:1948-7193
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Neurite outgrowth is crucial during neuronal development and regeneration, and strategies that aim at promoting neuritogenesis are beneficial for reconstructing synaptic connections after neuronal degeneration and injury. Using a bivalent analogue strategy as a successful approach, the current study identifies a series of novel dimeric securinine analogues as potent neurite outgrowth enhancers. Compounds 13, 14, 17-19, and 21-23, with different lengths of carbon chain of N,N-dialkyl substituting diacid amide linker between two securinine molecules at C-15 position, exhibited notable positive effects on both neuronal differentiation and neurite extension of neuronal cells. Compound 14, one of the most active compounds, was used as a representative compound for mechanistic studies. Its action on neurite outgrowth was through phosphorylation/activation of multiple signaling molecules including Ca /calmodulin-dependent protein kinase II (CaMKII), extracellular signal-regulated kinase (ERK) and Akt. These findings collectively identify a new group of beneficial compounds for neuritogenesis, and may provide insights on drug discovery of neural repair and regeneration.
[Mh] Termos MeSH primário: Azepinas/síntese química
Azepinas/farmacologia
Crescimento Celular/efeitos dos fármacos
Compostos Heterocíclicos de Anel em Ponte/síntese química
Compostos Heterocíclicos de Anel em Ponte/farmacologia
Neuritos/efeitos dos fármacos
Fármacos Neuroprotetores/síntese química
Fármacos Neuroprotetores/farmacologia
[Mh] Termos MeSH secundário: Animais
Azepinas/química
Western Blotting
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo
Linhagem Celular Tumoral
Desenho de Drogas
Avaliação Pré-Clínica de Medicamentos
MAP Quinases Reguladas por Sinal Extracelular/metabolismo
Compostos Heterocíclicos de Anel em Ponte/química
Imuno-Histoquímica
Lactonas/química
Sistema de Sinalização das MAP Quinases/efeitos dos fármacos
Sistema de Sinalização das MAP Quinases/fisiologia
Camundongos
Estrutura Molecular
Neuritos/fisiologia
Fármacos Neuroprotetores/química
Fosforilação/efeitos dos fármacos
Piperidinas/química
Proteínas Proto-Oncogênicas c-akt/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Azepines); 0 (Heterocyclic Compounds, Bridged-Ring); 0 (Lactones); 0 (Neuroprotective Agents); 0 (Piperidines); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt); EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinase Type 2); EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases); G4VS580P5E (securinine)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170621
[Lr] Data última revisão:
170621
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160729
[St] Status:MEDLINE


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[PMID]:27344492
[Au] Autor:Hou W; Wang ZY; Peng CK; Lin J; Liu X; Chang YQ; Xu J; Jiang RW; Lin H; Sun PH; Chen WM
[Ad] Endereço:College of Pharmacy, Jinan University, Guangzhou 510632, PR China.
[Ti] Título:Novel securinine derivatives as topoisomerase I based antitumor agents.
[So] Source:Eur J Med Chem;122:149-163, 2016 Oct 21.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:DNA topoisomerase I (Topo I) has been validated as a target for anticancer agents. In this study, a series of novel securinine derivatives bearing ß'-hydroxy-α,ß-unsaturated ketone moiety were designed and synthesized via a Baylis-Hillman reaction for screening as Topo I inhibitors and antitumor agents. Their topoisomerase I inhibitory activity as well as their cytotoxicity against four human cancer cell lines (A549, HeLa, HepG2, SH-SY5Y) were evaluated, and two pairs of diastereomers 4a-1 and 4a-6 with significant Topo I inhibitory activity and potent anti-proliferative activity against cancer cell lines were identified. The diastereomers were separated, and absolute configurations of five pairs of diastereomers were identified based on X-ray crystallographic analysis and circular dichroism (CD) spectra analysis. Further mechanism studies of the most active compounds 4a-1-R and 4a-1-S indicated that this kind of securinine derivative exhibits a different inhibitory mechanism from that of camptothecin, an established Topo I inhibitor. Unlike camptothecin, compounds 4a-1-R and 4a-1-S specifically inhibits the combination of Topo I and DNA rather than forming the drug-enzyme-DNA covalent ternary complex. In addition, molecular docking and molecular dynamic studies revealed the binding patterns of these compounds with Topo I.
[Mh] Termos MeSH primário: Antineoplásicos/química
Antineoplásicos/farmacologia
Azepinas/química
Azepinas/farmacologia
DNA Topoisomerases Tipo I/metabolismo
Compostos Heterocíclicos de Anel em Ponte/química
Compostos Heterocíclicos de Anel em Ponte/farmacologia
Lactonas/química
Lactonas/farmacologia
Piperidinas/química
Piperidinas/farmacologia
Inibidores da Topoisomerase I/química
Inibidores da Topoisomerase I/farmacologia
[Mh] Termos MeSH secundário: Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Clivagem do DNA/efeitos dos fármacos
DNA Topoisomerases Tipo I/química
Desenho de Drogas
Seres Humanos
Modelos Moleculares
Conformação Proteica
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Azepines); 0 (Heterocyclic Compounds, Bridged-Ring); 0 (Lactones); 0 (Piperidines); 0 (Topoisomerase I Inhibitors); EC 5.99.1.2 (DNA Topoisomerases, Type I); G4VS580P5E (securinine)
[Em] Mês de entrada:1702
[Cu] Atualização por classe:170807
[Lr] Data última revisão:
170807
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160627
[St] Status:MEDLINE


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[PMID]:27216998
[Au] Autor:Chaiyakunvat P; Anantachoke N; Reutrakul V; Jiarpinitnun C
[Ad] Endereço:Department of Chemistry and Center for Innovation in Chemistry (PERCH-CIC), Faculty of Science, Mahidol University, Rama VI Road, Bangkok 10400, Thailand.
[Ti] Título:Caged xanthones: Potent inhibitors of global predominant MRSA USA300.
[So] Source:Bioorg Med Chem Lett;26(13):2980-2983, 2016 07 01.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Total of 22 caged xanthones were subjected to susceptibility testing of global epidemic MRSA USA300. Natural morellic acid showed the strongest potency (MIC of 12.5µM). However, its potent toxicity diminishes MRSA therapeutic potential. We synthetically modified natural morellic acid to yield 13 derivatives (3a-3m). Synthetically modified 3b retained strong potency in MRSA growth inhibition, yet the toxicity was 20-fold less than natural morellic acid, permitting the possibility of using caged xanthones for MRSA therapeutic.
[Mh] Termos MeSH primário: Antibacterianos/farmacologia
Compostos Heterocíclicos de Anel em Ponte/farmacologia
Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos
Xantonas/farmacologia
[Mh] Termos MeSH secundário: Células A549
Aminoácidos/síntese química
Aminoácidos/farmacologia
Aminoácidos/toxicidade
Ampicilina/farmacologia
Antibacterianos/síntese química
Antibacterianos/toxicidade
Aderência Bacteriana/efeitos dos fármacos
Garcinia
Células HEK293
Compostos Heterocíclicos/síntese química
Compostos Heterocíclicos/isolamento & purificação
Compostos Heterocíclicos/farmacologia
Compostos Heterocíclicos/toxicidade
Compostos Heterocíclicos de Anel em Ponte/síntese química
Compostos Heterocíclicos de Anel em Ponte/isolamento & purificação
Compostos Heterocíclicos de Anel em Ponte/toxicidade
Seres Humanos
Staphylococcus aureus Resistente à Meticilina/fisiologia
Testes de Sensibilidade Microbiana
Oxacilina/farmacologia
Xantonas/síntese química
Xantonas/química
Xantonas/isolamento & purificação
Xantonas/toxicidade
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Amino Acids); 0 (Anti-Bacterial Agents); 0 (Heterocyclic Compounds); 0 (Heterocyclic Compounds, Bridged-Ring); 0 (Xanthones); 0 (forbesione); 0 (morellic acid); 7C782967RD (Ampicillin); 8N585K83U2 (gambogic acid); UH95VD7V76 (Oxacillin)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171122
[Lr] Data última revisão:
171122
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160525
[St] Status:MEDLINE



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