RESUMO
Lysidrhodosides A-I (1-9), nine acylphloroglucinol glucoside derivatives along with three known analogues (10-12) were isolated from the leaves of Lysidice rhodostegia. Their structures and absolute configuration were elucidated by spectroscopic data analysis (NMR, UV, IR, HR-ESI-MS), single-crystal X-ray diffraction, and acid hydrolysis with HPLC analysis. Notably, compounds 7-9 represent the first examples of 3-methylbutyryl phloroglucinol glucoside dimers isolated from this plant. Additionally, compounds 1-12 were assessed for their inhibitory effects on nitric oxide (NO) in the LPS-induced BV-2 cells. The results showed that compounds 6 and 12 significantly inhibited the production of the inflammatory mediator NO, with an inhibitory rate of 95.96 and 91.13% at a concentration of 50 µM, respectively.
Assuntos
Fabaceae , Glucosídeos , Glucosídeos/farmacologia , Estrutura Molecular , Floroglucinol/química , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Espectroscopia de Ressonância Magnética , Fabaceae/química , Óxido NítricoRESUMO
Three novel diterpenoid alkaloids, comprising two C19 -diterpenoid alkaloids (1 and 2) and one C20 -diterpenoid alkaloid (3), were isolated from Delphinium ajacis, alongside the six known compoundsâ (4-9). Their structures were elucidated by spectroscopic methods (MS, UV, IR, 1D and 2D NMR) and chemical properties. Simultaneously, the anti-inflammatory properties of all compoundsâ (1-9) was conducted, focusing on nitric oxide (NO) production in LPS-induced BV-2 cells. The results indicated compoundsâ 1-3, 7, and 8 have potential anti-inflammatory activity.
Assuntos
Alcaloides , Delphinium , Diterpenos , Delphinium/química , Espectroscopia de Ressonância Magnética , Alcaloides/farmacologia , Alcaloides/química , Diterpenos/farmacologia , Diterpenos/química , Anti-Inflamatórios/farmacologia , Estrutura MolecularRESUMO
IMPORTANCE: Respiratory syncytial virus (RSV) is the leading etiological agent of lower respiratory tract illness. However, efficacious vaccines or antiviral drugs for treating RSV infections are currently not available. Indeed, RSV depends on host cells to provide energy needed to produce progeny virions. Glycolysis is a series of oxidative reactions used to metabolize glucose and provide energy to host cells. Therefore, glycolysis may be helpful for RSV infection. In this study, we show that RSV increases glycolysis by inducing the stabilization, transcription, translation, and activation of hypoxia-inducible factor (HIF)-1α in infected cells, which is important for the production of progeny RSV virions. This study contributes to understanding the molecular mechanism by which HIF-1α-mediated glycolysis controls RSV infection and reveals an effective target for the development of highly efficient anti-RSV drugs.
Assuntos
Doenças Transmissíveis , Infecções por Vírus Respiratório Sincicial , Vírus Sincicial Respiratório Humano , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Vírus Sincicial Respiratório Humano/genética , GlicóliseRESUMO
Five new sesquiterpenoids (1-5), elephantmollides A-E, along with four known compounds (6-9), were isolated from the whole plants of E. mollis. Their planar structures were elucidated using the spectroscopic methods, including HRESIMS, IR, UV, and NMR (1H, 13C, DEPT, HSQC, HMBC, 1H-1H COSY). The relative configurations of them were partially deduced by the NOESY experiment, and the absolute configurations were assigned by comparing the calculated electronic circular dichroism (ECD) results with the experimental data. In addition, cytotoxic activities of 1-9 against HepG2 cells ware tested, and compounds 1-9 exhibited cytotoxic activities with IC50 values ranging from 6.7 to 25.8 µM.
RESUMO
Fifteen undescribed lindenane-type sesquiterpenoid dimers, designated chloranholides F-T (1-15), together with twenty-five known analogs (16-40), were isolated from the whole plants of Chloranthus holostegius. The isolate structures were elucidated by analysis of spectroscopic data and chemical methods, and their absolute configurations were determined by X-ray crystallography and electronic circular dichroism spectra. In anti-neuroinflammatory assays, all isolates were evaluated by examination of their inhibitory effect on nitric oxide (NO) in LPS-stimulated BV-2 cells, and the results showed that 21-24, 26, 30, 32 and 36 significantly inhibited the production of the inflammatory mediator NO, with IC50 values ranging from 3.18 to 11.46 µM, which was better than that of quercetin. Structure-activity relationship analysis revealed that two essential functional groups played an indispensable role in the anti-inflammatory effects. Moreover, 22 and 24 inhibited the LPS-induced upregulation of iNOS and COX-2 enzymes in BV-2 microglia at the protein level.
Assuntos
Magnoliopsida , Sesquiterpenos , Microglia/metabolismo , Lipopolissacarídeos/farmacologia , Magnoliopsida/química , Relação Estrutura-Atividade , Sesquiterpenos/química , Óxido Nítrico , Estrutura MolecularRESUMO
One new fawcettimine-type alkaloid (1), one new miscellaneous-type alkaloid (2), four new lycodine-type alkaloids (3-6), and eight known ones (7-14) were isolated from the whole plants of Huperzia serrata. Their structures and absolute configurations were elucidated based on spectroscopic data, X-ray diffraction, ECD calculation and Mosher's method. Compound 1 was a rare C18 N2 -type Lycopodium alkaloid, possessing serratinine skeleton with an amide side chain in C-5. The absolute configuration of the 18-OH of compounds 4-6 were first determined by Mosher's method. Moreover, compounds 1-14 were assayed anti-acetylcholinesterase effect inâ vitro, and compound 7 showed significant anti-acetylcholinesterase activity with an IC50 value of 16.18±1.64â µM.
Assuntos
Alcaloides , Huperzia , Lycopodium , Acetilcolinesterase , Alcaloides/farmacologia , Alcaloides/química , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/química , Huperzia/química , Lycopodium/química , Estrutura MolecularRESUMO
Nine undescribed phloroglucinol derivatives (dryatraols A-I) with five different backbones and three known dimeric acylphloroglucinols were isolated from the rhizome of Dryopteris atrata (Wall. Ex Kunze) Ching (Dryopteridaceae). Dryatraol A contains an unprecedented carbon skeleton-a butyrylphloroglucinol and a rulepidanol-type sesquiterpene are linked via a furan ring to form a 6/5/6/6 ring system. Dryatraols B and C are the first examples of monomeric phloroglucinols coupled with the aristolane-type sesquiterpene through the C-C bond. Dryatraol D features a rare spiro [benzofuran-2',5â³-furan] backbone. Dryatraols E-I are five undescribed adducts with a butyrylphloroglucinol or filicinic acid incorporated into the germacrene-type sesquiterpene via a pyran ring. These undescribed structures were determined by comprehensively analysing the spectroscopic data, X-ray diffraction results, and electronic circular dichroism calculations. The result of in vitro antiviral activity evaluation indicated that dryatraol C displayed the strongest antiviral effect against both respiratory syncytial virus and influenza A virus (H1N1), with IC50 values of 11.9 µM and 5.5 µM, respectively. Dryatraols F-H exhibited considerable inhibitory activity against herpes simplex virus type 1 (HSV-1), with IC50 values ranging from 2.6 to 6.3 µM. Analysis of the inhibitory mechanism using a time-of-addition assay revealed that dryatraol G may inhibit the replication of HSV-1 by interfering with the late stage of the viral life cycle.
Assuntos
Dryopteris , Herpesvirus Humano 1 , Vírus da Influenza A Subtipo H1N1 , Dryopteris/química , Floroglucinol , Antivirais/química , Furanos/farmacologia , Estrutura MolecularRESUMO
One new alkaloid, 6, 7-dimethoxyisoquinoline-N-oxide (1), one new benzofuran derivative, 3,7-dimethyl-6-acetyl-8-benzofuranol (2) and one new lignan, salsolains A (3), along with seven known compounds (4-10), were isolated from the whole plant of Salsola collina Pall. Their structures were elucidated by extensive analysis of spectroscopic data (IR, UV, HR-ESI-MS, 1 D and 2 D NMR), and their absolute configurations were determined by the X-ray crystallography and ECD calculation. The activities of compounds 1-10 against inflammatory cytokines IL-6 and TNF-α levels on LPS-induced RAW 264.7 macrophages were assessed, especially, compound 5 (50 µM) exhibited the most significant anti-inflammatory activity with the secretion levels of IL-6 and TNF-α at 3.87% and 4.03%, respectively.
Assuntos
Alcaloides , Salsola , Animais , Camundongos , Salsola/química , Fator de Necrose Tumoral alfa , Interleucina-6 , Macrófagos , Células RAW 264.7 , Estrutura MolecularRESUMO
Phosphoinositide-3 kinase (PI3K) signaling regulates many cellular processes, including cell survival, differentiation, proliferation, cytoskeleton reorganization, and apoptosis. The actin cytoskeleton regulated by PI3K signaling plays an important role in plasma membrane rearrangement. Currently, it is known that respiratory syncytial virus (RSV) infection requires PI3K signaling. However, the regulatory pattern or corresponding molecular mechanism of PI3K signaling on cell-to-cell fusion during syncytium formation remains unclear. This study synthesized a novel PI3K inhibitor PIK-24 designed with PI3K as a target and used it as a molecular probe to investigate the involvement of PI3K signaling in syncytium formation during RSV infection. The results of the antiviral mechanism revealed that syncytium formation required PI3K signaling to activate RHO family GTPases Cdc42, to upregulate the inactive form of cofilin, and to increase the amount of F-actin in cells, thereby causing actin cytoskeleton reorganization and membrane fusion between adjacent cells. PIK-24 treatment significantly abolished the generation of these events by blocking the activation of PI3K signaling. Moreover, PIK-24 had an obvious binding activity with the p85α regulatory subunit of PI3K. The anti-RSV effect similar to PIK-24 was obtained after knockdown of p85α in vitro or knockout of p85α in vivo, suggesting that PIK-24 inhibited RSV infection by targeting PI3K p85α. Most importantly, PIK-24 exerted a potent anti-RSV activity, and its antiviral effect was stronger than that of the classic PI3K inhibitor LY294002, PI-103, and broad-spectrum antiviral drug ribavirin. Thus, PIK-24 has the potential to be developed into a novel anti-RSV agent targeting cellular PI3K signaling. IMPORTANCE PI3K protein has many functions and regulates various cellular processes. As an important regulatory subunit of PI3K, p85α can regulate the activity of PI3K signaling. Therefore, it serves as the key target for virus infection. Indeed, p85α-regulated PI3K signaling facilitates various intracellular plasma membrane rearrangement events by modulating the actin cytoskeleton, which may be critical for RSV-induced syncytium formation. In this study, we show that a novel PI3K inhibitor inhibits RSV-induced PI3K signaling activation and actin cytoskeleton reorganization by targeting the p85α protein, thereby inhibiting syncytium formation and exerting a potent antiviral effect. Respiratory syncytial virus (RSV) is one of the most common respiratory pathogens, causing enormous morbidity, mortality, and economic burden. Currently, no effective antiviral drugs or vaccines exist for RSV infection. This study contributes to understanding the molecular mechanism by which PI3K signaling regulates syncytium formation and provides a leading compound for anti-RSV infection drug development.
Assuntos
Classe Ia de Fosfatidilinositol 3-Quinase , Células Gigantes , Inibidores de Fosfoinositídeo-3 Quinase , Infecções por Vírus Respiratório Sincicial , Vírus Sincicial Respiratório Humano , Humanos , Actinas/metabolismo , Antivirais/farmacologia , Células Gigantes/virologia , Vírus Sincicial Respiratório Humano/fisiologia , Proteínas rho de Ligação ao GTP/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/farmacologiaRESUMO
Eighteen stilbenes (1-18), including six previously undescribed ones (1-6), with diverse modification patterns were isolated from the leaves of edible and medicinal plant Cajanus cajan. Among the new isolates, compounds 1-3 were initially obtained as three racemic mixtures, which were further resolved into three pairs of optically pure enantiomers, respectively, by chiral HPLC. Besides, compounds 8, 10, 11, and 18 were obtained from C. cajan for the first time. The chemical structures and absolute configurations of the new stilbenes were elucidated unambiguously on the basis of extensive spectroscopic analyses, single crystal X-ray crystallographic study, and quantum chemical electronic circular dichroism (ECD) calculations. In addition, the in vitro anti-inflammatory activities of all isolated stilbenes were evaluated. Compounds 2, 9, 10, 11, and 14 exerted moderate suppression of nitric oxide (NO) secretion in lipopolysaccharide (LPS)-induced RAW264.7 cells without exhibiting substantial cytotoxicity.
Assuntos
Cajanus , Estilbenos , Anti-Inflamatórios/farmacologia , Cajanus/química , Estrutura Molecular , Folhas de Planta/química , Estilbenos/química , Estilbenos/farmacologiaRESUMO
Inspired by a previously reported biomimetic synthesis study, four new naturally occurring phloroglucinol trimers 1-4 with unusual 6/5/5/6/6/6-fused hexacyclic ring systems, along with two known analogues (5 and 6) and two known biogenetically related dimers (10 and 11), were isolated from Rhodomyrtus tomentosa. Their structures and absolute configurations were unambiguously elucidated by spectroscopic analysis, X-ray diffraction, and electronic circular dichroism calculation. By mimicking two potentially alternative biosynthetic pathways, the first asymmetric syntheses of 1-4 and the racemic syntheses of 5 and 6 were achieved in only five to six steps without the need for protecting groups. Furthermore, phloroglucinol dimers 10 and 11 exhibited significant in vitro antiviral activity against the respiratory syncytial virus.
Assuntos
Myrtaceae , Floroglucinol , Biomimética , Dicroísmo Circular , Estrutura Molecular , Myrtaceae/química , Floroglucinol/químicaRESUMO
Three new sesquiterpene lactones, named scabertopinolides H - J (1 - 3), along with four known ones, desacylisodeoxyelephantopin 2-methylbutyrate (4), iso-17,19-dihydrodeoxyelephantopin (5), scabertopinolide D (6) and (2R,6R,7R,8S)-8-tigloyloxy-1(10),4(5),11(13)-germacratrien-2,15,6,12-diolide (7) were isolated from the whole plants of Elephantopus scaber. Their structures were elucidated by extensive analysis of spectroscopic data (including IR, UV, HRESIMS, 1 D and 2 D NMR) and single-crystal X-ray. These isolated compounds showed effective anti-inflammatory effects on LPS-stimulated RAW 264.7 cells with IC50 values of 6.27 ± 0.18 to 18.31 ± 1.38 µM.
Assuntos
Asteraceae , Sesquiterpenos , Animais , Asteraceae/química , Lactonas/química , Lactonas/farmacologia , Camundongos , Estrutura Molecular , Compostos Fitoquímicos , Células RAW 264.7 , Sesquiterpenos/química , Sesquiterpenos/farmacologiaRESUMO
A phytochemical investigation on the alkaloids from water-soluble part of Sophora alopecuroides led to obtain forty matrine-type alkaloids (1-40) including eighteen new ones (1-18), which covers almost all positions of the oxygen substitution in matrine-type structure. Notably, eight compounds (1-8) belong to rare bis-amide matrine-type alkaloid. The new structures were determined based on extensive spectroscopic data, electronic circular dichroism (ECD) calculations, and six instances, verified by X-ray crystallography. Most of isolates showed anti-neuroinflammatory activities based on the expression of tumor necrosis factor (TNF)-α and interleukin (IL)-6 in BV2 microglia cells. Especially, compound 39 can suppress those two mediator secretions in a dose-dependent manner with IC50 values of 21.6 ± 0.5 and 16.7 ± 0.8 µM, respectively. Further mechanistic study revealed that 39 suppressed the phosphorylation of IκBα and p65 subunit to regulate the NF-κB signaling pathway.
Assuntos
Alcaloides/farmacologia , Anti-Inflamatórios/farmacologia , Quinolizinas/farmacologia , Sophora/química , Alcaloides/química , Alcaloides/isolamento & purificação , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Linhagem Celular , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Interleucina-6/antagonistas & inibidores , Interleucina-6/metabolismo , Camundongos , Modelos Moleculares , Estrutura Molecular , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Quinolizinas/química , Quinolizinas/isolamento & purificação , Sementes/química , Transdução de Sinais/efeitos dos fármacos , Solubilidade , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/metabolismo , Água/química , MatrinasRESUMO
Eight new stilbene dimer xylosides (1-8) and one new flavanol (9), along with seven known ones (10-16) were isolated from the roots of Lysidice rhodostegia. Their structures were elucidated by extensive analysis of spectroscopic data (IR, UV, HR-ESI-MS, 1D and 2D NMR), ECD calculations and acid hydrolysis. Compounds 1-16 were evaluated for their antioxidant activities using DPPH radical-scavenging assay. Especially, compounds 9 and 10 exhibited stronger antioxidant effects than the positive control (vitamin E), with IC50 values of 9.57 ± 1.30 and 13.60 ± 1.47 µM, respectively.
Assuntos
Antioxidantes/farmacologia , Fabaceae/química , Glicosídeos/farmacologia , Polifenóis/farmacologia , Estilbenos/farmacologia , Antioxidantes/isolamento & purificação , China , Glicosídeos/isolamento & purificação , Estrutura Molecular , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Raízes de Plantas/química , Polifenóis/isolamento & purificação , Estilbenos/isolamento & purificaçãoRESUMO
Rhodomentosones A and B (1 and 2), two pairs of novel enantiomeric phloroglucinol trimers featuring a unique 6/5/5/6/5/5/6-fused ring system were isolated from Rhodomyrtus tomentosa. Their structures with absolute configurations were elucidated by NMR spectroscopy, X-ray crystallography, and ECD calculation. The bioinspired syntheses of 1 and 2 were achieved in six steps featuring an organocatalytic asymmetric dehydroxylation/Michael addition/Kornblum-DeLaMare rearrangement/ketalization cascade reaction. Compounds 1 and 2 exhibited promising antiviral activities against respiratory syncytial virus (RSV).
Assuntos
Antivirais/química , Myrtaceae/química , Floroglucinol/química , Vírus Sinciciais Respiratórios/química , Biomimética , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Extratos Vegetais/química , Terpenos/químicaRESUMO
Five matrine-type alkaloids (1â5) including two new compounds (1 and 3) and a new natural product (2) were isolated from the roots of Sophora tonkinesis. Their structures were identified by extensive spectroscopic analysis (UV, IR, HRESIMS and NMR). The absolute configurations of 2 and 3 were determined by X-ray diffraction. Compounds 1â5 were evaluated their activity against inflammatory cytokines TNF-α and IL-6 levels on LPS-induced RAW 264.7 macrophages, and compound 1 showed the most significant activity, potent than that of matrine, the representative ingredient from Sophora plants.
Assuntos
Alcaloides/farmacologia , Anti-Inflamatórios/química , Quinolizinas/farmacologia , Sophora/química , Alcaloides/química , Animais , China , Espectroscopia de Ressonância Magnética , Camundongos , Estrutura Molecular , Raízes de Plantas/química , Células RAW 264.7 , MatrinasRESUMO
Two new isoquinoline alkaloids, 6 R,6aS-N-nantenine Nß-oxide (1), 6S,6aS-N-nantenine Nα-oxide (2), along with nine known alkaloids, nantenine (3), oxonantenine (4), protopine (5), nornantenine (6), N-methyl-laurotetanine (7), isocorydine (8), O-methyflavinantine (9), N-methyl-2,3,6-trimethoxymorphinan-dien-7-one Nß-oxide (10) and (+)-10-O-methylhernovine Nß-oxide (11) were isolated from the seeds of Nandina domestica. Their structures were elucidated by extensive analyses of spectroscopic data (IR, UV, HRESIMS, 1 D and 2 D NMR), ECD calculation and comparison with the related literatures. In addition, the cytotoxicity against A549 cells of these alkaloids was determined by the MTT assay.
Assuntos
Alcaloides , Berberidaceae , Isoquinolinas/farmacologia , Células A549 , Alcaloides/isolamento & purificação , Alcaloides/farmacologia , Berberidaceae/química , Humanos , Isoquinolinas/isolamento & purificação , Estrutura Molecular , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Extratos Vegetais , Sementes/químicaRESUMO
A new sesquiterpene pyridine alkaloid (1), along with four known compounds (2-5), were isolated from the stems and leaves of Euonymus fortunei. The new structure was determined by extensive spectroscopic analyses (IR, UV, NMR, HRESIMS and ECD). In addition, compound 3 showed a stronger anti-respiratory syncytial virus (RSV) activity with an IC50 value of 1.20 ± 0.10 µM than the positive control ribavirin with an IC50 value of 5.62 ± 0.49 µM.[Formula: see text].
Assuntos
Alcaloides , Euonymus , Sesquiterpenos , Estrutura Molecular , Folhas de Planta , PiridinasRESUMO
Pegaharines A-G (1-6), six novel ß-carboline alkaloids representing three types of skeleton, were isolated from the seeds of Peganum harmala. Compound 1 is a peculiar ß-carboline alkaloid characterized by the unprecedented carbon skeleton of an azepine-indole system. Compounds 3-6 represent the first examples of heterodimers constructed from rare tetracyclic ß-carboline and classic tricyclic ß-carboline alkaloids. Compounds 1 and 2 were characterized by X-ray crystallography. Compound 4 exhibited strong antiviral activity against HSV-2, with an IC50 value of 2.12 ± 0.14 µM.
Assuntos
Alcaloides/química , Antivirais/farmacologia , Carbolinas/química , Herpesvirus Humano 2/efeitos dos fármacos , Peganum/química , Extratos Vegetais/química , Antivirais/química , Herpesvirus Humano 2/química , Estrutura Molecular , Sementes/químicaRESUMO
Phosphoinositide-3 kinase signaling modulates many cellular processes, including cell survival, proliferation, differentiation, and apoptosis. Currently, it is known that the establishment of respiratory syncytial virus infection requires phosphoinositide-3 kinase signaling. However, the regulatory pattern of phosphoinositide-3 kinase signaling or its corresponding molecular mechanism during respiratory syncytial virus entry remains unclear. Here, the involvement of phosphoinositide-3 kinase signaling in respiratory syncytial virus entry was studied. PIK-24, a novel compound designed with phosphoinositide-3 kinase as a target, had potent anti-respiratory syncytial virus activity both in vitro and in vivo PIK-24 significantly reduced viral entry into the host cell through blocking the late stage of the fusion process. In a mouse model, PIK-24 effectively reduced the viral load and alleviated inflammation in lung tissue. Subsequent studies on the antiviral mechanism of PIK-24 revealed that viral entry was accompanied by phosphoinositide-3 kinase signaling activation, downstream RhoA and cofilin upregulation, and actin cytoskeleton rearrangement. PIK-24 treatment significantly reversed all these effects. The disruption of actin cytoskeleton dynamics or the modulation of phosphoinositide-3 kinase activity by knockdown also affected viral entry efficacy. Altogether, it is reasonable to conclude that the antiviral activity of PIK-24 depends on the phosphoinositide-3 kinase signaling and that the use of phosphoinositide-3 kinase signaling to regulate actin cytoskeleton rearrangement plays a key role in respiratory syncytial virus entry.