RESUMO
Seven new monoterpene alkaloids (1 - 7), along with 16 known analogues, were isolated from an aqueous decoction of the hook-bearing stems of Uncaria rhynchophylla (Gou-teng). Their structures were determined by spectroscopic data analysis, single crystal X-ray diffraction, and electronic circular dichroism (ECD) calculations. Compounds 1 and 2 are stereoisomers belonging to a novel type of pseudoindoxyl monoterpene alkaloids, 3 is the first monoterpene furoindole alkaloid from nature, and 4 - 7 are derivatives of the known monoterpene alkaloids featuring different structures.
Assuntos
Alcaloides , Uncaria , Alcaloides Indólicos/química , Uncaria/química , MonoterpenosRESUMO
Neolignans and lignans with diverse new chemical structures, including eleven pairs of separated chiral enantiomers [(+)-/(-)-1-(+)-/(-)-5, (+)-/(-)-8, (+)-/(-)-10, and (+)-/(-)-12-(+)-/(-)-15], two achiral compounds (6 and 9), and an unseparated racemate [(±)-11], together with a new natural product (7) and 21 known derivatives, were isolated from an aqueous extract of the Angelica sinensis root head (guitou). Among the chiral isolates, (+)-/(-)-13 and (+)-/(-)-15 were scalemic pairs with enantiomeric ratios of around 3:1 and 1.5:1, respectively, while others were enantiomeric equivalent pairs. This indicates that the diverse neolignans in A. sinensis are biosynthesized via different pathways with varying degrees of stereo-controlled manners.
Assuntos
Angelica sinensis , Medicamentos de Ervas Chinesas , Lignanas , Lignanas/química , EstereoisomerismoRESUMO
Four new lignans (1-4) and one new neolignan (5), along with two known lignan derivatives (6 and 7), were isolated from an aqueous extract of the Isatis indigotica root (ban lan gen). Their structures were determined by spectroscopic data analysis, chemical method, and theoretical calculation, for which 1 was proved by single-crystal X-ray diffraction. Compound 2 exhibited antiviral activity against influenza virus A/Hanfang/359/95 (H3N2) with an IC50 value of 11.1 µM and a selective index (SI) > 9, while 1 and 5 are the first examples of sulfonated lignan and neolignan from nature.
RESUMO
Seven new minor monoterpene derivatives (1-7), together with six known analogues, were isolated from an aqueous decoction of the hook-bearing stems of Uncaria rhynchophylla (Gou-teng). Their structures were determined by spectroscopic data analysis and electronic circular dichroism (ECD) calculations, of which 1 was confirmed by single crystal X-ray diffraction.
Assuntos
Uncaria , Estrutura Molecular , Monoterpenos , Uncaria/química , ÁguaRESUMO
Eleven new sulfonated alkaloids (1 - 11) having diverse structures were isolated from an aqueous extract of the Isatis indigotica root (ban lan gen). Their structures were determined by spectroscopic data analysis, chemical method, and theoretical calculation, of which (-)-4 was proved by single crystal X-ray diffraction.
Assuntos
Alcaloides , Isatis , Alcaloides/química , Isatis/química , Estrutura Molecular , Extratos Vegetais/química , Raízes de Plantas/química , Água/análiseRESUMO
Five new denudatine-type diterpenoid alkaloids (1-5), along with the known analogue aconicarmine (6), were isolated from an aqueous decoction of the lateral roots of Aconitum carmichaelii (fu-zi). Their structures were determined by spectroscopic data analysis and electronic circular dichroism (ECD) calculations. Compound 5 is the first denudatine-type diterpenoid alcohol iminium alkaloid, which could be partially transformed into the aza acetal form in pyridine-d5. Compound 5 inhibited mice writhing in an acetic acid-induced writhing assay.
Assuntos
Aconitum , Alcaloides , Diterpenos , Animais , Camundongos , Estrutura Molecular , Raízes de PlantasRESUMO
BACKGROUND: Chronic neuropathic pain is a frequent sequel to peripheral nerve injury and maladaptive nervous system function. Divanillyl sulfone (DS), a novel structural derivative of 4,4'-dihydroxydibenzyl sulfoxide from a traditional Chinese medicine Gastrodia elata with anti-nociceptive effects, significantly alleviated neuropathic pain following intrathecal injection. Here, we aimed to investigate the underlying mechanisms of DS against neuropathic pain. METHODS: A chronic constrictive injury (CCI) mouse model of neuropathic pain induced by sciatic nerve ligation was performed to evaluate the effect of DS by measuring the limb withdrawal using Von Frey filament test. Immunofluorescence staining was used to assess the cell localizations and expressions of Iba-1, ASC, NLRP3, and ROS, the formation of autolysosome. The levels of NLRP3-related proteins (caspase-1, NLRP3, and IL-1ß), mitophagy-related proteins (LC3, Beclin-1, and p62), and apoptosis-related proteins (Bcl-XL and Bax) were detected by Western blotting. The apoptosis of BV-2 cell and caspase activity were evaluated by flow cytometry. RESULTS: DS significantly alleviated the neuropathic pain by increasing the mechanical withdrawal threshold and inhibiting the activation of NLRP3 in CCI-induced model mice. Our findings indicated that DS promoted the mitophagy by increasing the LC3II and Beclin 1 and decreasing the levels of p62 protein in BV-2 cell. This is accompanied by the inhibition of NLRP3 activation, which was shown as inhibited the expression of NLRP3 in lysates as well as the secretion of mature caspase-1 p10 and IL-1ß p17 in supernatants in cultured BV-2 microglia. In addition, DS could promote mitophagy-induced improvement of dysfunctional mitochondria by clearing intracellular ROS and restoring mitochondrial membrane potential. CONCLUSION: Together, our findings demonstrated that DS ameliorate chronic neuropathic pain in mice by suppressing NLRP3 inflammasome activation induced by mitophagy in microglia. DS may be a promising therapeutic agent for chronic neuropathic pain.
Assuntos
Inflamassomos/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitofagia/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Neuralgia/tratamento farmacológico , Sulfonas/farmacologia , Sulfonas/uso terapêutico , Animais , Apoptose , Caspase 1/metabolismo , Linhagem Celular , Modelos Animais de Doenças , Inflamassomos/metabolismo , Masculino , Medicina Tradicional Chinesa , Camundongos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , Mitocôndrias/patologia , Neuralgia/metabolismo , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/metabolismo , Nervo Isquiático/patologiaRESUMO
Seven new monoterpene alkaloids (1-7), along with 18 known analogues, were isolated from an aqueous decoction of the hook-bearing stems of Uncaria rhynchophylla (Gou-teng). Their structures were determined by spectroscopic data analysis and electronic circular dichroism (ECD) calculations. Compound 1 is the first monoterpene 22-norindoloquinolizidine alkaloid with a ketene unit, while 2 and 3 are unusual indoloquinolizidine alkaloids having an oxazinane ring.[Formula: see text].
Assuntos
Alcaloides , Uncaria , Alcaloides Indólicos , Estrutura Molecular , MonoterpenosRESUMO
Six new triterpenes, uncarinic acids KP (1-6), along with 24 known analogues, were isolated as minor constituents of an aqueous decoction of the hook-bearing stems of Uncaria rhynchophylla (Gou-teng). By comprehensive spectroscopic data analysis, their structures were elucidated as derivatives of olean-12-en-28-oic acid and urs-12-en-28-oic acid with different oxidized forms at C-3, C-6, and/or C-23, respectively. Cell-based preliminary bioassay showed that the (E)-/(Z)-coumaroyloxy and (E)-/(Z)-feruloyloxy units at C-27 of olean-12-en-28-oic acid and urs-12-en-28-oic acid played roles in their bioactivities.[Formula: see text].
Assuntos
Triterpenos , Uncaria , Estrutura Molecular , Extratos VegetaisRESUMO
Parkinson's disease (PD) is a neurodegenerative disease with complicated pathogenesis. A novel bibenzyl compound 2-[4-hydroxy-3-(4-hydroxyphenyl)benzyl]-4-(4-hydroxyphenyl)phenol (20C) has been shown to have some neuroprotective effects, and its mechanism still needs further research. In this study, we used a 6-hydroxydopamine (6-OHDA)-induced PD rat model to evaluate the protective effect of 20C. Our study found that 20C could improve behavioral defects in 6-OHDA-lesion rats, decrease neuroinflammation and protect their DA neurons. It could inhibit the activity of inducible nitric oxide synthase (iNOS) induced by 6-OHDA, and lead to a decrease in the expression of nitrated-α-synuclein. When exposed to AMT-an inhibitor of iNOS, the nitrated-α-synuclein in PC12 decreased, and 20C demonstrated the same function on nitrated-α-synuclein as AMT. Besides, we also found that nitrated-α-synuclein was displayed in microglia. And 20C could decrease the expression of antigen-presenting molecule major histocompatibility complex I (MHC I) in dopamine (DA) neurons and MHC II in microglia induced by 6-OHDA. So, these imply that nitrated-α-synuclein might act as an endogenous antigen activating adaptive immunity, and the neuroprotection of 20C might be associated with inhibiting the activity of iNOS, decreasing the expression of the antigen molecule nitrated-α-synuclein and the antigen presenting molecule MHC. Our results indicated that inhibiting iNOS might be an effective strategy to protect neurons from oxidative stress.
Assuntos
Bibenzilas/farmacologia , Encéfalo/efeitos dos fármacos , Neurônios Dopaminérgicos/efeitos dos fármacos , Microglia/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Transtornos Parkinsonianos/tratamento farmacológico , Animais , Antioxidantes/farmacologia , Encéfalo/imunologia , Encéfalo/metabolismo , Encéfalo/patologia , Citocinas/metabolismo , Modelos Animais de Doenças , Neurônios Dopaminérgicos/imunologia , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Endocitose/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Mediadores da Inflamação/metabolismo , Masculino , Microglia/imunologia , Microglia/metabolismo , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Óxido Nítrico Sintase Tipo II/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Oxidopamina , Células PC12 , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/imunologia , Transtornos Parkinsonianos/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , alfa-Sinucleína/metabolismoRESUMO
Two new folate-derived analogues, named uncarophyllofolic acids A (1) and B (2), respectively, were isolated from the Uncaria rhynchophylla hook bearing stem (Gouteng in Chinese). The distinct stereochemical structures of 1 and 2 were determined by spectroscopic data analysis in combination with acidic hydrolysis and Marfey's derivatization, along with comparison of their specific rotation and Cotton effect (CE) data with those of the biogenetically related known derivatives as well as theoretical calculations of electronic circular dichroism (ECD) spectra. A plausible biosynthetic pathway of 1 and 2, associating to folate metabolism and the previously reported orychophragines A-C from Orychophragmus violaceus, is discussed.
Assuntos
Ácido Fólico/química , Extratos Vegetais/química , Uncaria/química , China , Cromatografia Líquida de Alta Pressão , Ácido Fólico/análogos & derivados , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Caules de Planta/químicaRESUMO
Nine new gastrodin derivatives, including seven p-hydroxybenzyl-modified gastrodin ethers (1-7), 6'-O-acetylgastrodin (8), and 4-[α-D-glucopyranosyl-(1 â6)-ß-D-glucopyranosyloxy]benzyl alcohol (9), together with seven known derivatives, were isolated from an aqueous extract of Gastrodia elata ("tian ma") rhizomes. Their structures were determined by spectroscopic and chemical methods as well as single crystal X-ray diffraction. Compounds 1-4, 7, 10, and 11 were also isolated from a reaction mixture by refluxing gastrodin and p-hydroxybenzyl alcohol in H2O. As both gastrodin and p-hydroxybenzyl alcohol exist in the plant, the reaction results provide evidence for the production and increase/decrease of potential effective/toxic components when "tian ma" is decocted solely or together with ingredients in Chinese traditional medicine formulations, though the isolates were inactive in the preliminarily cell-based assays at concentrations of 10 µM. Moreover, using ultra-performance liquid chromatography high-resolution electrospray ionization mass spectrometry (UPLC-HRESIMS), 4, 7, 10, and 11, as well as component variations, were detectable in the freshly prepared extracts of different types of samples, including the freeze-dried fresh G. elata rhizomes.
RESUMO
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are essential components of highly active antiretroviral therapy (HAART) for human immunodeficiency virus type 1 (HIV-1) infection. In this study, we identified (+)-(7'S,8S,8'S)-3',4,4',5,5'-pentamethoxy-2,7'-cyclolignan (SG-1), a cyclolignan semi-synthesized from Machilus robusta and M. wangchiana extracts, as a potent NNRTI. SG-1 displayed anti-HIV-1 activity with an IC50 of 0.77 µmol/L by inhibiting reverse transcriptase (RT) RNA-dependent DNA polymerase activity through a direct binding. It had synergistic effects when combined with tenofovir/lamivudine or zidovudine/lamivudine. The pharmacodynamics properties of SG-1 render it a valuable lead for the development of novel NNRTIs.
Assuntos
Fármacos Anti-HIV/farmacologia , Transcriptase Reversa do HIV/antagonistas & inibidores , Lignanas/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Fármacos Anti-HIV/síntese química , Descoberta de Drogas , Lignanas/síntese química , Inibidores da Transcriptase Reversa/síntese químicaRESUMO
20C, a novel bibenzyl compound, is isolated from Gastrodia elata. In our previous study, 20C showed protective effects on tunicamycin-induced endoplasmic reticulum stress, rotenone-induced apoptosis and rotenone-induced oxidative damage. However, the anti-neuroinflammatory effect of 20C is still with limited acquaintance. The objective of this study was to confirm the anti-neuroinflammatory effect of 20C on Lipopolysaccharide (LPS)-activated BV-2 cells and further elucidated the underlying molecular mechanisms. In this study, 20C significantly attenuated the protein levels of nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and interleukin (IL)-1ß, and secretion of nitric oxide (NO) and tumor necrosis factor (TNF)-α induced by Lipopolysaccharide (LPS) in BV-2 cells. Moreover, 20C up-regulated the levels of autophagy-related proteins in LPS-activated BV-2 cells. The requirement of mitogen-activated protein kinases (MAPKs) has been well documented for regulating the process of autophagy. Both 20C and rapamycin enhanced autophagy by suppressing the phosphorylation of MAPKs signaling pathway. Furthermore, 20C treatment significantly inhibited the levels of toll like receptor 4 (TLR4), phosphorylated-protein kinase B (Akt) and phosphorylated-mechanistic target of rapamycin (mTOR), indicating blocking TLR4/Akt/mTOR might be an underlying basis for the anti-inflammatory effect of 20C. These findings suggest that 20C has therapeutic potential for treating neurodegenerative diseases in the future.
Assuntos
Anti-Inflamatórios/farmacologia , Autofagia/efeitos dos fármacos , Compostos Benzidrílicos/farmacologia , Gastrodia/química , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fenóis/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Receptor 4 Toll-Like/metabolismo , Animais , Proteínas Relacionadas à Autofagia/metabolismo , Linhagem Celular , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Lipopolissacarídeos/farmacologia , Camundongos , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacosRESUMO
Six new indole alkaloid diglycosides named isatigotindolediosides A-F (1-6), along with three known analogs (7-9), were isolated from an aqueous extract of the Isatis indigotica roots (ban lan gen). Their structures including the absolute configurations were determined by comprehensive spectroscopic data analysis, combined with enzyme or acid hydrolysis, and comparison of experimental circular dichroism (CD) and calculated electronic circular dichroism (ECD) spectra. In the preliminary assays, compounds 3, 5, and 8 showed antiviral activity against Coxsackie virus B3.
Assuntos
Glicosídeos/isolamento & purificação , Alcaloides Indólicos/isolamento & purificação , Isatis/química , Raízes de Plantas/química , Antivirais/química , Antivirais/isolamento & purificação , Antivirais/farmacologia , Dicroísmo Circular , Enterovirus Humano B/efeitos dos fármacos , Glicosídeos/química , Glicosídeos/farmacologia , Alcaloides Indólicos/química , Alcaloides Indólicos/farmacologia , Estrutura Molecular , ÁguaRESUMO
Oxidative stress is thought to be involved in the development of Parkinson's disease (PD). We previously reported that 20C, a bibenzyl compound isolated from Gastrodia elata, possesses antioxidative properties, but its in-depth molecular mechanisms against rotenone-induced neurotoxicity remains unknown. Recent studies indicate that without intact DJ-1, nuclear factor erythroid 2-related factor (Nrf2) protein becomes unstable, and the activity of Nrf2-mediated downstream antioxidant enzymes are thereby suppressed. In this study, we showed that 20C clearly protected PC12 and SH-SY5Y cells against rotenone-induced oxidative injury. Furthermore, 20C markedly up-regulated the levels of DJ-1, which in turn activated phosphoinositide-3-kinase (PI3K)/Akt signaling and inhibited glycogen synthase kinase 3ß (GSK3ß) activation, eventually promoted the nuclear translocation of Nrf2 and induced the expression of hemeoxygenase-1 (HO-1). The antioxidant effects of 20C could be partially blocked by ShRNA-mediated knockdown of DJ-1 and inhibition of the PI3K/Akt pathways with Akt1/2 kinase inhibitor, respectively. Conclusively, our findings confirm that DJ-1 is necessary for 20C-mediated protection against rotenone-induced oxidative damage, at least in part, by activating PI3K/Akt signaling, and subsequently enhancing the nuclear accumulation of Nrf2. The findings from our investigation suggest that 20C should be developed as a novel candidate for alleviating the consequences of PD in the future.
Assuntos
Antioxidantes/farmacologia , Bibenzilas/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Oxidantes/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Fosfatidilinositol 3-Quinase/metabolismo , Proteína Desglicase DJ-1/metabolismo , Rotenona/toxicidade , Animais , Compostos Benzidrílicos/farmacologia , Glicogênio Sintase Quinase 3 beta/metabolismo , Heme Oxigenase (Desciclizante)/metabolismo , Heme Oxigenase-1/metabolismo , Humanos , Neurônios/enzimologia , Neurônios/patologia , Células PC12 , Fenóis/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase , Proteína Desglicase DJ-1/genética , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Interferência de RNA , Ratos , Transdução de Sinais/efeitos dos fármacos , TransfecçãoRESUMO
Five previously undescribed hemiterpene glycosides, cibotiumbarosides E-I, and two known hemiterpene glucosides, were isolated from the rhizome of Cibotium barometz (L.) J. Sm. The structures of cibotiumbarosides E-I were established by 1D and 2D NMR spectroscopic analyses and HRMS. The absolute configuration of the aglycone of cibotiumbaroside E was assigned by calculated ECD with the TDDFT method. Cibotiumbarosides F and I both exhibited remarkable hepatoprotective activity against APAP-induced acute liver damage in vitro, which were more effective than the positive control, bicyclol. On the other hand, seven hemiterpene glycosides were all inactive in assays of cytotoxicity, neuroprotection, antidiabetes and anti-inflammation.