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1.
J Nat Prod ; 84(7): 1954-1966, 2021 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-34170694

RESUMO

Cdc37 associates kinase clients to Hsp90 and promotes the development of cancers. Celastrol, a natural friedelane triterpenoid, can disrupt the Hsp90-Cdc37 interaction to provide antitumor effects. In this study, 31 new celastrol derivatives, 2a-2d, 3a-3g, and 4a-4t, were designed and synthesized, and their Hsp90-Cdc37 disruption activities and antiproliferative activities against cancer cells were evaluated. Among these compounds, 4f, with the highest tumor cell selectivity (15.4-fold), potent Hsp90-Cdc37 disruption activity (IC50 = 1.9 µM), and antiproliferative activity against MDA-MB-231 cells (IC50 = 0.2 µM), was selected as the lead compound. Further studies demonstrated 4f has strong antitumor activities both in vitro and in vivo through disrupting the Hsp90-Cdc37 interaction and inhibiting angiogenesis. In addition, 4f exhibited less toxicity than celastrol and showed a good pharmacokinetics profile in vivo. These findings suggest that 4f may be a promising candidate for development of new cancer therapies.


Assuntos
Antineoplásicos/farmacologia , Proteínas de Ciclo Celular/antagonistas & inibidores , Chaperoninas/antagonistas & inibidores , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Triterpenos Pentacíclicos/farmacologia , Animais , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos Nus , Simulação de Acoplamento Molecular , Estrutura Molecular , Ensaios Antitumorais Modelo de Xenoenxerto , Peixe-Zebra
2.
Chin J Nat Med ; 18(5): 379-384, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32451095

RESUMO

Phytochemical investigation of the aerial parts of Baeckea frutescens resulted in the isolation of three new mono- or sesquiterpene-based meroterpenoids, frutescones S-U (1-3), and one pair of new (±)-5,7-dihydroxy-8-isobutyryl-6-methyldihydroflavonol (4). Their structures and absolute configurations were established by HR-ESI-MS, 1D and 2D NMR, and quantum chemical ECD calculation. Compound 1 exhibited inhibitory effect on NO production in LPS-activated RAW 264.7 macrophages with an IC50 value being 0.81 µmol·L-1.


Assuntos
Medicamentos de Ervas Chinesas/química , Flavonoides/química , Myrtaceae/química , Terpenos/química , Animais , Medicamentos de Ervas Chinesas/isolamento & purificação , Medicamentos de Ervas Chinesas/farmacologia , Flavonoides/isolamento & purificação , Flavonoides/farmacologia , Espectrometria de Massas , Camundongos , Estrutura Molecular , Componentes Aéreos da Planta/química , Células RAW 264.7 , Terpenos/isolamento & purificação , Terpenos/farmacologia
3.
Org Biomol Chem ; 18(6): 1135-1139, 2020 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-31967630

RESUMO

Biomimetic total syntheses of baefrutones A-D (1-4), baeckenon B (5), and frutescones A, D-F (6-9), isolated from the leaves of Baeckea frutescens, were achieved in 9, 8, and 5 steps, respectively, in moderate to good yields (72-83%). The synthetic routes feature the Michael addition, oxidative [4 + 2] cycloaddition, and water-promoted Diels-Alder click reactions as the key steps. This study helped gain thorough mechanistic insights into the biosynthetic origins and provided a facile approach for the construction of a library of natural tasmanone-based meroterpenoid analogues. Moreover, compounds 1-9 show potent inhibitory effects against S. paratyphi and/or C. albicans with MIC values of 3.125-25 µg mL-1, and they could be promising lead molecules for the design of new antibiotic agents.


Assuntos
Materiais Biomiméticos/farmacologia , Monoterpenos/farmacologia , Terpenos/farmacologia , Materiais Biomiméticos/síntese química , Materiais Biomiméticos/química , Candida albicans/efeitos dos fármacos , Reação de Cicloadição , Teoria da Densidade Funcional , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Estrutura Molecular , Monoterpenos/síntese química , Monoterpenos/química , Oxirredução , Pseudomonas aeruginosa/efeitos dos fármacos , Salmonella/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Estereoisomerismo , Relação Estrutura-Atividade , Terpenos/síntese química , Terpenos/química
4.
J Nat Prod ; 82(12): 3267-3278, 2019 12 27.
Artigo em Inglês | MEDLINE | ID: mdl-31738062

RESUMO

Psiguadiols A-J (1-10), new meroterpenoids with rearranged skeletons, were isolated from the leaves of Psidium guajava. Compounds 1-3 represent the first examples of 6,8-diformyl-5,7-dihydroxy-4-phenylchromane-coupled sesquiterpenoids with an unprecedented C-8-spiro-fused 6/6/9/4 tetracyclic ring system. Compounds 4 and 5 represent two unusual scaffolds featuring 1ß,6ß- and 3α,5α-epoxy rings, respectively. The combination of spectroscopic data analyses, comparison of experimental and calculated ECD data, and single-crystal X-ray diffraction data of 1, 6, and 8 allowed for the assignment of the structures. A putative biosynthetic pathway for 1-10 is discussed. Compounds 1, 7, and 8 exhibited inhibitory activities against PTP1B with IC50 values of 4.7, 6.2, and 9.2 µM, respectively. In addition, molecular docking was performed to investigate the mechanism of action.


Assuntos
Inibidores Enzimáticos/farmacologia , Monoterpenos/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Psidium/química , Cristalografia por Raios X , Inibidores Enzimáticos/química , Inibidores Enzimáticos/isolamento & purificação , Humanos , Monoterpenos/química , Monoterpenos/isolamento & purificação , Análise Espectral/métodos
5.
J Nat Prod ; 82(4): 859-869, 2019 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-30848923

RESUMO

Five new phloroglucinol derivatives, eucalyptins C-G (1-5), together with 13 known analogues (6-18) were isolated from the fruits of Eucalyptus globulus. The structures and absolute configurations of 1-5 were established by means of spectroscopic data analysis, computational calculation methods, and single-crystal X-ray diffraction. Compounds 1-18 were investigated for their immunosuppressive effects in vitro, and 1, 2, 6, and 7 displayed moderate inhibitory activities with IC50 values of 11.8, 10.2, 18.2, and 19.1 µM, respectively. The stimulation index (SI) of 1 was 64.2 and was compared to that of cyclosporine A (SI = 149.57). Further study demonstrated that 1 exhibited an immunosuppressive effect through inducing apoptosis and inhibiting cytokine secretion.


Assuntos
Eucalyptus/química , Imunossupressores/farmacologia , Floroglucinol/farmacologia , Animais , Células Cultivadas , Cristalografia por Raios X , Citocinas/metabolismo , Humanos , Imunossupressores/química , Concentração Inibidora 50 , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Floroglucinol/química
6.
ACS Chem Neurosci ; 10(2): 996-1007, 2019 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-29944335

RESUMO

Glycogen synthase kinase-3ß (GSK-3ß) is a key enzyme in hyperphosphorylation of tau proteins and is a promising therapeutic target in Alzheimer's disease (AD). Here, we reported, for the first time, that the stereoisomers of Schisandrin B (Sch B), (+)-1, (-)-1, (+)-2, and (-)-2, were potent GSK-3ß inhibitors. They were demonstrated to selectively target GSK-3ß in an orthosteric binding mode, with IC50 values of 340, 290, 80, and 70 nM, respectively. Further study showed that these stereoisomers can significantly increase the expression of p-GSK-3ß (Ser9) and decrease the expressions of p-GSK-3ß (Tyr216) and p-GSK-3ß (Tyr279). Finally, these compounds can alleviate the cell injury induced by Aß, and the cognitive disorders in AD mice, especially (+)-2 and (-)-2. Collectively, the stereoisomers of Sch B, especially (+)-2 and (-)-2, were found to be potential selective ATP-competitive GSK-3ß inhibitors, which further affected their anti-AD effects. These promising findings explained the biological target of Sch B in AD, and bring a new understanding in the stereochemistry and bioactivities of Sch B.


Assuntos
Trifosfato de Adenosina/metabolismo , Doença de Alzheimer/enzimologia , Inibidores Enzimáticos/uso terapêutico , Glicogênio Sintase Quinase 3 beta/metabolismo , Lignanas/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Compostos Policíclicos/uso terapêutico , Doença de Alzheimer/prevenção & controle , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Ciclo-Octanos/isolamento & purificação , Ciclo-Octanos/farmacologia , Ciclo-Octanos/uso terapêutico , Inibidores Enzimáticos/isolamento & purificação , Inibidores Enzimáticos/farmacologia , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Hipocampo/efeitos dos fármacos , Hipocampo/enzimologia , Humanos , Lignanas/isolamento & purificação , Lignanas/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Simulação de Acoplamento Molecular/métodos , Fármacos Neuroprotetores/isolamento & purificação , Fármacos Neuroprotetores/farmacologia , Compostos Policíclicos/isolamento & purificação , Compostos Policíclicos/farmacologia , Estereoisomerismo , Resultado do Tratamento
7.
Org Biomol Chem ; 16(44): 8513-8524, 2018 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-30357224

RESUMO

Baefrutones A-F (1-6), six new meroterpenoids with rare triketone-phloroglucinol-monoterpene/sesquiterpene frameworks, together with their biosynthetically related intermediate (±)-baeckenon B (7), were isolated from the aerial part of Baeckea frutescens under the guidance of HPLC-Q/TOF-MS2 investigation. Compounds 1-4 represent the first examples of natural meroterpenoids existing as four pairs of inseparable diastereomeric atropisomers (2 : 1, 1H NMR integration) caused by the restricted rotation around the C-6-C-7-C-1' bonds arising from the intramolecular hydrogen bond between C-1 carbonyl and 2'-OH. The discovery of these architectures not only largely enriched the chemodiversity of the meroterpenoid and atropisomer library, but also might be exciting and challenging for asymmetric organic synthesis. Their structures and absolute configurations were established by extensive spectroscopic analysis, X-ray diffraction, and ECD calculations. Compounds 5 and 6 were biomimetically synthesized from 7 and ß-caryophyllene via a regioselective oxidative hetero-Diels-Alder reaction, thus providing access to the construction of the 6/6/9/4 tetracyclic ring system. The anti-inflammatory activities of these meroterpenoids were also discussed.

8.
Chin J Nat Med ; 16(8): 615-620, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30197127

RESUMO

In the present study, we carried out a phytochemical investigation of the ethanol extract of the aerial parts of Baeckea frutescens, which resulted in the isolation of two new flavonoid glycosides, myricetin 3-O-(5″-O-galloyl)-α-L-arabinofuranoside (1), 6-methylquercetin 7-O-ß-D-glucopyranoside (2), one new methylchromone glycoside, 7-O-(4', 6'-digalloyl)-ß-D-glucopyranosyl-5-hydroxy-2-methylchromone (3), together with three known compounds (4-6). The structures of these isolated compounds were established on the basis of 1D and 2D NMR techniques and chemical methods. The anti-inflammatory activities of the compounds 1-6 were evaluated for their inhibitory effects against cyclooxygenases-1 and -2 in vitro. Compounds 1-6 showed potent COX-1 and COX-2 inhibiting activities in vitro with IC50 values ranging from 1.95 to 5.54 µmol·L-1 and ranging from 1.01 to 2.27 µmol·L-1, respectively.


Assuntos
Inibidores de Ciclo-Oxigenase/química , Flavonoides/química , Myrtaceae/química , Extratos Vegetais/química , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Ciclo-Oxigenase 1/química , Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase/isolamento & purificação , Flavonoides/isolamento & purificação , Estrutura Molecular , Componentes Aéreos da Planta/química , Extratos Vegetais/isolamento & purificação
9.
J Nat Prod ; 80(8): 2204-2214, 2017 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-28753309

RESUMO

Frutescones H-R (1-11), new sesqui- or monoterpene-based meroterpenoids, were isolated from the aerial parts of Baeckea frutescens. Their structures and absolute configurations were established by means of spectroscopic analyses (HRESIMS, 1D and 2D NMR, and ECD), as well as single-crystal X-ray crystallography of 1, (-)-7, and 9. The anti-inflammatory activities of all isolates were evaluated by measuring their inhibitory effects on NO production in LPS-stimulated RAW 264.7 macrophages, and the structure-activity relationships of 1-11 are also discussed. Compound 8 exhibited anti-inflammatory activity with an IC50 value of 0.36 µM, which might be related to the regulation of the NF-κB signaling pathway via the suppression of p65 nuclear translocation and the consequent decrease of IL-6 and TNF-α.


Assuntos
Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/farmacologia , Interleucina-6/metabolismo , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Myrtaceae/química , NF-kappa B/antagonistas & inibidores , Componentes Aéreos da Planta/química , Transdução de Sinais/efeitos dos fármacos , Terpenos/isolamento & purificação , Terpenos/farmacologia , Fator de Necrose Tumoral alfa/farmacologia , Animais , Anti-Inflamatórios/química , Cristalografia por Raios X , Interleucina-6/química , Lipopolissacarídeos/química , Macrófagos/química , Estrutura Molecular , NF-kappa B/química , Relação Estrutura-Atividade , Terpenos/química , Fator de Necrose Tumoral alfa/química
10.
Chin J Nat Med ; 15(6): 463-466, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28629537

RESUMO

The present study was designed to investigate the chemical constituents of the roots of Cyathula officinalis. Compounds were isolated by silica gel, Sephadex LH-20, ODS column chromatography, and preparative HPLC. Their structures were determined on the basis of 1D and 2D NMR techniques, mass spectrometry, and chemical methods. One new oleanane-type triterpenoid saponin, 28-O-[α-L-rhamnopyranosyl-(1→3)-ß-D-glucuronopyranosyl-(1→3)-ß-D-glucopyranosyl] hederagenin (1), was isolated from the roots of Cyathula officinalis. The anti-inflammatory activities of the isolates were evaluated for their inhibitory effects against LPS-induced nitric oxide (NO) production in RAW 264.7 macrophages cells. Compounds 2, 4, and 6 exhibited moderate anti-inflammatory activities.


Assuntos
Amaranthaceae/química , Anti-Inflamatórios/isolamento & purificação , Óxido Nítrico/antagonistas & inibidores , Saponinas/isolamento & purificação , Triterpenos/isolamento & purificação , Animais , Células Cultivadas , Espectroscopia de Ressonância Magnética , Camundongos , Óxido Nítrico/biossíntese , Raízes de Plantas/química , Saponinas/química , Saponinas/farmacologia , Triterpenos/química , Triterpenos/farmacologia
11.
J Org Chem ; 82(3): 1448-1457, 2017 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-28029250

RESUMO

Frutescone A-G [(1-6), (+)-7, (-)-7], a new group of naturally occurring tasmanone-based meroterpenoids, were isolated from the aerial parts of Baeckea frutescens L. Compounds 1 and 4 featured a rare carbon skeleton with an unprecedented oxa-spiro[5.8] tetradecadiene ring system, existing as two favored equilibrating conformers in CDCl3 solution, identified by variable-temperature NMR. The regioselective syntheses of 4-7 were achieved in a concise manner by a biomimetically inspired key hetero-Diels-Alder reaction "on water". Compounds 1, 4, and 5 exhibited moderate cytotoxicities in vitro.


Assuntos
Myrtaceae/química , Componentes Aéreos da Planta/química , Terpenos/isolamento & purificação , Estrutura Molecular , Estereoisomerismo , Terpenos/química
12.
Artigo em Chinês | WPRIM (Pacífico Ocidental) | ID: wpr-290199

RESUMO

<p><b>OBJECTIVE</b>To study the changes of serum interleukin-2 (IL-2), interleukin-8 (IL-8) and immunoglobulin (IgG, IgA, IgM) in patients with esophageal cancer, and to probe the relationship between the levels of IL-2, IL-8, IgG, IgA and IgM and the progress of cancer.</p><p><b>METHODS</b>The serum levels of IL-2 and IL-8 were detected by enzyme-linked immunosorbent assay for 72 case of primary esophageal cancer, 68 advanced esophageal cancer and 120 healthy controls, and the level of immunoglobulin (IgG, IgA, IgM) in patients with esophageal cancer was dynamically observed.</p><p><b>RESULTS</b>The IL-2 level in patients with early esophageal cancer [(1.69 +/- 0.53) ng/ml] or late esophageal cancer [(1.11 +/- 0.60) ng/ml] was lower than the control group [(2.78 +/- 0.51) ng/ml] (P < 0.01), the late esophageal cancer group was lower than early esophageal cancer group (P < 0.05). The level of IL-8 in patients with early esophageal cancer [(85.48 +/- 6.14) ng/L] or late esophageal cancer [(121.41 +/- 6.22) ng/L] was much higher than the control group [(54.48 +/- 12.20) ng/L] (P < 0.01), the late esophageal cancer group was much higher than early esophageal cancer group (P < 0.01); There was correlation between the levels of IL-2 and IL-8 and the worsen-extent of the tumour in patients with early esophageal cancer or late esophageal cancer. But the level of IgG [(12.23 +/- 2.50) g/L], IgM [(1.60 +/- 0.80) g/L] in the patients with esophageal cancer compared with the level of IgG [(11.65 +/- 3.70) g/L], IgM [(1.46 +/- 0.71) g/L] in the health control group have no significant difference (P > 0.05), the level of IgA [(3.50 +/- 1.10) g/L] in patients with esophageal cancer Compared with the control group [(1.88 +/- 1.08) g/L] has significant difference (P < 0.01), and along with the worsen-extent of the tumor in patients the level of IgA has the increased tendency.</p><p><b>CONCLUSION</b>The IL-8 might accelerate the pathogenesis of esophageal cancer, and the IL-2 might restrain. The positive correlation between the level of IgA and the patients with esophageal cancer is observed in this study; the immune maladjustment of IL-2, IL-8 and IgA might be correlative to esophageal cancer, and the IL-2, IL-8 and IgA levels might be an available index for the severity of esophageal cancer, Which may be of some help for clinic practitioners to judge the progress, curative effect and prognosis of the cancer.</p>


Assuntos
Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos de Casos e Controles , Neoplasias Esofágicas , Sangue , Patologia , Imunoglobulina A , Sangue , Imunoglobulina G , Sangue , Imunoglobulina M , Sangue , Interleucina-2 , Sangue , Interleucina-8 , Sangue , Estadiamento de Neoplasias
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