RESUMO
Zhigancao decoction is a traditional prescription for treating irregular pulse and palpitations in China. As the monarch drug of Zhigancao decoction, the bioactive molecules of licorice against heart diseases remain elusive. We established the HRESIMS-guided method leading to the isolation of three novel bicyclic peptides, glycnsisitins A-C (1-3), with distinctive C-C and C-O-C side-chain-to-side-chain linkages from the roots of Glycyrrhiza uralensis (Licorice). Glycnsisitin A demonstrated stronger cardioprotective activity than glycnsisitins B and C in an in vitro model of doxorubicin (DOX)-induced cardiomyocyte injury. Glycnsisitin A treatment not only reduced the mortality of heart failure (HF) mice in a dose-dependent manner but also significantly attenuated DOX-induced cardiac dysfunction and myocardial fibrosis. Gene set enrichment analysis (GSEA) of the differentially expressed genes indicated that the cardioprotective effect of glycnsisitin A was mainly attributed to its ability to maintain iron homeostasis in the myocardium. Mechanistically, glycnsisitin A interacted with transferrin and facilitated its binding to the transferrin receptor (TFRC), which caused increased uptake of iron in cardiomyocytes. These findings highlight the key role of bicyclic peptides as bioactive molecules of Zhigancao decoction for the treatment of HF, and glycnsisitin A constitutes a promising therapeutic agent for the treatment of HF.
RESUMO
IDO/TDO/Kyn/AhR signaling plays a crucial role in regulating innate and adaptive immunity, and targeting Ah receptor (AhR) inhibition can potentially redirect immune cells toward an antitumoral phenotype. Therefore, AhR is an attractive drug target for novel small molecule cancer immunotherapies. In this study, natural products tanshinolic A-D (1-4), the first adducts composed of ortho-naphthoquinone-type tanshinone and phenolic acid featuring a unique 1,4-benzodioxan hemiacetal structure, were isolated and characterized from the roots of Salvia miltiorrhiza Bunge. Luciferase reporter gene assay revealed that these adducts exhibited significant AhR inhibitory activity. A linear strategy was developed to construct a cis-3,4-disubstituted 1,4-benzodioxan hemiacetal structure. Encouragingly, in both in vitro and in vivo experiments, (±)-13e demonstrated the ability to inhibit tumor cell proliferation, promote INF-γ secretion in CD8+ T cells, and inhibit PD-1/PD-L1 signal transduction, which could exert tumor inhibition properties by inhibiting AhR activity, positioning it as a promising candidate for tumor immunotherapy.
Assuntos
Neoplasias , Salvia miltiorrhiza , Humanos , Linfócitos T CD8-Positivos , Imunoterapia , Receptores de Hidrocarboneto Arílico , Salvia miltiorrhiza/química , Piperoxano/química , Piperoxano/farmacologiaRESUMO
Six new iridoid glycosides were isolated from the ethyl acetate fraction of the whole plants of Hedyotis diffusa Willd. They were identified as E-6-O-p-methoxycinnamoyl-10-O-acetyl scandoside acid methyl ester (1), Z-6-O-p-methoxycinnamoyl-10-O-acetyl scandoside acid methyl ester (2), E-6-O-caffeoyl scandoside methyl ester (3), E-6-O-p-coumaroyl-6'-O-acetyl scandoside methyl ester (4), Z-6-O-p-coumaroyl-6'-O-acetyl scandoside methyl ester (5), and E-6-O-p-coumaroyl-4'-O-acetyl scandoside methyl ester (6). The structures of them were elucidated based on unambiguous spectroscopic data (UV, IR, HRESIMS, and NMR). They were screened for anti-inflammatory effect, antioxidant effect, antitumor effect, and neuroprotective effect and did not show potent activities.
Assuntos
Ácidos Cumáricos , Hedyotis , Glicosídeos Iridoides , Glicosídeos Iridoides/farmacologia , Hedyotis/química , Antioxidantes , Espectroscopia de Ressonância Magnética , Ésteres , Glicosídeos/farmacologiaRESUMO
Five new dimeric phloroglucinol derivatives, agrimones A - E (1-5), were isolated from the whole plant of Agrimonia pilosa. Their structures including absolute configurations were determined by a series of spectroscopic data (UV, IR, HR-ESI-MS, 1D and 2D NMR), complemented with the comparison of the experimental and calculated ECD spectra, and gauge-independent atomic orbital (GIAO) NMR calculations. Notably, compounds 1 and 2 represent a highly oxidized 6/6/6 tricyclic ring skeleton based on the cis-fused paraquinone and chroman. Compounds 1a, 4, and 5 exhibited moderate hepatoprotective activities against APAP-induced HepG2 cell injury at 10 µM.
Assuntos
Agrimonia/química , Floroglucinol/farmacologia , Substâncias Protetoras/farmacologia , Acetaminofen , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células Hep G2 , Humanos , Estrutura Molecular , Floroglucinol/química , Floroglucinol/isolamento & purificação , Substâncias Protetoras/química , Substâncias Protetoras/isolamento & purificação , Relação Estrutura-AtividadeRESUMO
Thirteen undescribed diterpenoid quinones were isolated from the dried roots of Salvia miltiorrhiza. Their structures were determined by extensive analysis, including NMR, HRESIMS, and IR. Their absolute configurations were determined by X-ray diffraction, calculated and experimental circular dichroism spectroscopy, and optical rotation. In the evaluation of bioactivities, salviadionether obviously inhibited the proliferation of HCT-116 cells. R-(+)-salmiltiorin E and R-(+)-grandifolia D both showed inhibitory activities on a variety of tumor cells. Salvianone ester A showed strong cytotoxicity to tumor-repopulating cells (TRCs) with an IC50 value of 2.19 µM.
Assuntos
Diterpenos , Salvia miltiorrhiza , Salvia , Diterpenos/farmacologia , Estrutura Molecular , Raízes de Plantas , Quinonas/farmacologia , RizomaRESUMO
Neuroinflammation is emerging as a crucial reason of major neurodegenerative diseases in recent years. Increasingly evidences have supported that bioactive natural products from traditional Chinese medicines have efficiency for neuroinflammation. Forsythia suspensa, a typical medicinal herb, showed potential neuroprotective and anti-inflammatory properties in previous pharmacological studies. In our research to obtain neuroprotective and anti-inflammatory natural products, three unprecedented C6-C7'/C6-C16' linked phenylethanoidglycoside dimers (1-3), three new phenylethanoidglycosides (4-6), and six known compounds (7-12) were isolated from the fruits of Forsythia suspensa. Their structures were determined by comprehensive spectroscopic data and comparison to the literature data. All isolated compounds were evaluated their neuroprotective and anti-inflammatory activities. Compounds 1 and 10 exhibited significant neuroprotective activities with the cell viability values of 75.24 ± 8.05% and 93.65 ± 10.17%, respectively, for the serum-deprivation and rotenone induced pheochromocytoma (PC12) cell injury. Meanwhile, compound 1 exhibited excellent anti-inflammatory activity against tumor necrosis factor (TNF)-α expression in LPS induced RAW264.7 cells with the IC50 value of 1.30 µM. This study revealed that the bioactive phenylethanoidglycosides may attenuate neuroinflammation through their neuroprotective and anti-inflammatory activities.
Assuntos
Anti-Inflamatórios/química , Forsythia/química , Glicosídeos/química , Fármacos Neuroprotetores/química , Animais , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Forsythia/metabolismo , Frutas/química , Frutas/metabolismo , Glicosídeos/isolamento & purificação , Glicosídeos/farmacologia , Lipopolissacarídeos/farmacologia , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Conformação Molecular , Fármacos Neuroprotetores/isolamento & purificação , Fármacos Neuroprotetores/farmacologia , Células PC12 , Extratos Vegetais/química , Células RAW 264.7 , Ratos , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Aiming to discover potent anti-proliferative agents from the roots of Sophora flavescens, seven new prenylated flavanones were isolated, along with 16 known compounds. Their structures were elucidated by interpretation of their spectroscopic data (1D and 2D NMR, UV, IR, CD, and HRESIMS) and comparison to literature data. In the in vitro assay, 21 showed anti-proliferative activity against human hepatoma cells (HepG2). Studies of its mechanism revealed that 21 could significantly activate autophagic flux and trigger ROS release in HepG2 cells. Western blot experiments demonstrated that 21 could activate the key signaling protein of autophagy and ROS, while it does not affect the main protein of the apoptosis signaling pathway. These results suggested that 21 mediates its anti-proliferative effects through autophagic cell death, which is apoptosis-independent.
Assuntos
Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Flavanonas/química , Raízes de Plantas/química , Sophora/química , Animais , Autofagia/efeitos dos fármacos , Células CHO , Cricetinae , Cricetulus , Células Hep G2 , Humanos , Estrutura MolecularRESUMO
Eight new geranylquinol derivatives (1-8) were purified from the roots of Arnebia euchroma. Compounds 1-6 possess an unprecedented dearomatic benzocogeijerene skeleton with a rare trans-fused hydronaphthalene moiety. Their structures and absolute configurations were elucidated by HRESIMS, NMR, ECD, and X-ray diffraction. A convenient strategy for rapid determination of the relative configuration of H-1/H-7/Me-16 and the absolute configuration at C-1 for 1-6 was summarized. Compound 2 exhibited cytotoxicity against all the tested cell lines, namely PC9, BGC823, HCT116, HepG2, HeLa, and U87-MG, with IC50 values ranging from 13.7 to 29.3 µM.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Boraginaceae/química , Raízes de Plantas/química , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Conformação Molecular , Relação Estrutura-AtividadeRESUMO
Ligusticum chuanxiong Hort is a famous health promoting plant cultivated in China, and widely consumed due to its various curative effects. To study the potential bioactive constituents from the rhizome of L. chuanxiong, a chemical investigation was thus performed. In present study, we report the isolation and identification of ten new compounds, including two coumarins (1-2), four lignans (3-6), and four phenols (7-10), along with five known compounds (11-15) from the rhizome of L. chuanxiong. The structures of these compounds were unambiguously established by HR-ESI-MS, UV, IR, CD, NMR spectral data and comparison to reported data. Meanwhile, the anti-inflammation and hepatoprotective activities of all these compounds were evaluated. The results show that compounds 5, 6 and 7 showed excellent inhibition of NO production in LPS-induced RAW 264.7 cells stronger than curcumin, and compounds 5, 7 and 9 exhibited greater hepatoprotective effect than that of bicyclol.
Assuntos
Anti-Inflamatórios/farmacologia , Ligusticum/química , Fígado/efeitos dos fármacos , Animais , Anti-Inflamatórios/química , Células Hep G2 , Humanos , Lipopolissacarídeos/farmacologia , Camundongos , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Células RAW 264.7 , Análise Espectral/métodosRESUMO
Four new compounds including two new phenylpropanoid esters of sucrose, polygonusucroside A (1) and B (2); two new anthraquinones, 8-O-ß-d-(6'-galloyl)-glucopyranoside (3) and polyanthraquinoside A (4), together with six known compounds were isolated from Polygonum cuspidatum. Their structures were established using UV, IR, HRESIMS, and NMR data. All compounds were evaluated for their α-glucosidase inhibitory activities and neuroprotective effects. Compounds 5, 7 and 9 showed significant α-glucosidase inhibitory activities with IC50 values of 27.30, 5.51, and 1.09 µmol/L, respectively (acarbose as positive control, IC50 = 6.17 µmol/L). In addition, the assessment of neuroprotective effect showed that compound 3 exhibited remarkable effect against PC12 cells injured by serum-deprivation and compounds 2, 7, and 9 exhibited moderate effects against PC12 cells injured by rotenone.
Assuntos
Antraquinonas/farmacologia , Ésteres/farmacologia , Fallopia japonica/química , Fármacos Neuroprotetores/farmacologia , Animais , Antraquinonas/isolamento & purificação , China , Ésteres/isolamento & purificação , Inibidores de Glicosídeo Hidrolases/isolamento & purificação , Inibidores de Glicosídeo Hidrolases/farmacologia , Estrutura Molecular , Fármacos Neuroprotetores/isolamento & purificação , Células PC12 , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Ratos , Rotenona , Sacarose , alfa-GlucosidasesRESUMO
Two new isobenzofuranone derivatives, polyphthaliside A (1) and polyphthaliside B (2), and a new isocoumarin derivative, polyisocoumarin (3), were isolated from Polygonum cuspidatum. Their structures were elucidated by detailed spectroscopic analysis and chemical methods. The cytotoxicity activity and PTP1B inhibitory activity of compounds 1-3 were estimated and none of them exhibited activities at a concentration of 10 µM.
Assuntos
Fallopia japonica , Polygonum , Glicosídeos , Isocumarinas , Estrutura Molecular , FenóisRESUMO
One new tanshinone derivative, which possesses an unusual 6/6/5/6 fused-ring skeleton system (1), together with four new five-membered lactone benzohexa-membered ring compounds (2, 3, 4A and 4B), and three new carboxyl substituted 5,5-spiroketal compounds (5-7), were isolated from the dried rhizomes of Salvia miltiorrhiza. The structures of these compounds were determined by multiple spectral analyses (UV, IR, NMR, and HR-ESI-MS). In addition, the absolute configurations were established by X-ray diffraction experiments, calculated and experimental circular dichroism spectra. Evaluation of antitumor activity showed that 1 had strong cytotoxicity to tumor-repopulating cells (TRCs) with an IC50 value of 2.83 µM. In the evaluation of neuroprotective activity, 4A and 6 showed a strong improvement in the survival rates of SK-N-SH cell injury induced by oxygen glucose deprivation (OGD).
RESUMO
Five new phenylpropanoid glycosides, susaroysides A-E (1-5) were isolated from the fruits of Forsythia suspensa. Their structures were elucidated by comprehensive spectroscopic data analysis. The absolute configurations of their sugars were determined by GC analysis. Notably, susaroysides A-D possessed a sugar with an unsubstituted anomeric carbon, which is relatively rare in natural sources. Compound 1 exhibited significant anti-inflammatory activity against the lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-α expression in macrophage cells with the IC50 value of 1.053⯵M.
Assuntos
Anti-Inflamatórios/farmacologia , Forsythia/química , Frutas/química , Glicosídeos/farmacologia , Macrófagos/efeitos dos fármacos , Extratos Vegetais/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Humanos , Lipopolissacarídeos/farmacologia , Macrófagos/citologia , Macrófagos/imunologia , Macrófagos/metabolismo , Fenóis/química , Propanóis/químicaRESUMO
Seven new butylphthalide derivatives, ligusticumolide A-G (1-7), together with two known butylphthalide derivatives (8-9) were isolated from an ethanol extract of Ligusticum chuanxiong Hort. The structures of these derivatives were elucidated from analysis of 1D/2D NMR, UV, IR and HRESIMS data. The absolute configurations of these derivatives were determined by electronic circular dichroism (ECD) calculations and Mosher's method. Ligusticumolide A (1) and ligusticumolide B (2) are enantiomers that were obtained by chiral separation. Ligusticumolide C (3) and ligusticumolide D (4) are diastereomers. All of the compounds were evaluated for their hepatoprotective activity against N-acetyl-p-aminophenol-induced HepG2 cell injury. Compounds 4, 5, and 7-9 showed more significant hepatoprotective activity than that of the positive control drug (bicyclol) at a concentration of 10⯵M (pâ¯<â¯0.01).
Assuntos
Benzofuranos/química , Ligusticum/química , Substâncias Protetoras/química , Benzofuranos/isolamento & purificação , Benzofuranos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Dicroísmo Circular , Humanos , Ligusticum/metabolismo , Espectroscopia de Ressonância Magnética , Conformação Molecular , Raízes de Plantas/química , Raízes de Plantas/metabolismo , Substâncias Protetoras/isolamento & purificação , Substâncias Protetoras/farmacologia , EstereoisomerismoRESUMO
Eight new triterpenoid saponins (1-8), were isolated from the roots of Glycyrrhiza uralensis Fisch., together with 10 known triterpenoid saponins (9-18). Their structures were determined by analysis of their spectroscopic data and comparison with the reference. All of the compounds were evaluated for their antioxidant effects in the in vitro assay. Compounds 2 and 8 showed significant antioxidant activities against Fe2+/cysteine-induced liver microsomal lipid peroxidation at 0.1 µM.
Assuntos
Antioxidantes/farmacologia , Glycyrrhiza uralensis/química , Saponinas/farmacologia , Triterpenos/farmacologia , Antioxidantes/isolamento & purificação , China , Peroxidação de Lipídeos , Microssomos Hepáticos/efeitos dos fármacos , Estrutura Molecular , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Raízes de Plantas/química , Saponinas/isolamento & purificação , Triterpenos/isolamento & purificaçãoRESUMO
Flower of Chrysanthemum morifolium is widely used in China and Japan as a folk medicine in treatment of many diseases. However, its active compounds remain largely unknown. In the present work, we have isolated, purified and characterized six new compounds (1-6), including two new arylnaphthalene lignans and four new phenolic glycosides, together with eight known compounds (7-14), from the flower of C. morifolium. Their structures and absolute configurations were elucidated in detail using 1D and 2D NMR, UV, IR, ORD, HRESIMS and ECD spectrometric data. In addition, compounds 1-3 possessed the significant neuroprotective activity against hydrogen peroxide-induced neurotoxicity in human neuroblastoma SH-SY5Y cells.
Assuntos
Catecóis/farmacologia , Chrysanthemum/química , Flores/química , Glucosídeos/farmacologia , Lignanas/farmacologia , Fármacos Neuroprotetores/farmacologia , Animais , Catecóis/química , Catecóis/isolamento & purificação , Linhagem Celular Tumoral , Glucosídeos/química , Glucosídeos/isolamento & purificação , Humanos , Peróxido de Hidrogênio/efeitos adversos , Lignanas/química , Lignanas/isolamento & purificação , Camundongos , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/isolamento & purificação , Estresse Oxidativo/efeitos dos fármacos , Células RAW 264.7RESUMO
The first synthesis of polyflavanostilbeneâ B (1), which has seven contiguous stereocenters including two quaternary carbon centers, from abundant polymeric (-)-epicatechin gallate on a gram scale in three steps without the use of protecting groups is reported. The key transformations of this strategy include a regioselective and stereoselective substitution of resveratrol to give the 4-derivative of (-)-epicatechin 3-gallate and an iron-catalyzed cyclization reaction. The possible radical cyclization mechanism in the formation of the hexahydrocyclopenta[c]furan core is also discussed.
RESUMO
In our ongoing investigation of the bioactive compounds from the extract of the roots of Sophora flavescens, two novel prenylated flavanones, named sophoflavanones A (1) and B (2), each with an unusual pyran ring were isolated. Their structures, as well as their absolute configurations, were elucidated based on spectroscopic data including a comparison of their experimental and calculated electronic circular dichroism (ECD) spectra. Additionally, compounds 1 and 2 showed moderate antioxidant activities against Fe2+/cysteine-induced toxicity at a concentration of 0.1⯵M (inhibition values of 71.65% and 72.49%, respectively, using vitamin C as a positive control (87.83%)).
Assuntos
Antioxidantes/farmacologia , Flavanonas/farmacologia , Raízes de Plantas/química , Sophora/química , Antioxidantes/química , Antioxidantes/isolamento & purificação , Linhagem Celular Tumoral , Flavanonas/química , Flavanonas/isolamento & purificação , Humanos , Microssomos Hepáticos/metabolismo , EstereoisomerismoRESUMO
Four new ferulic acid derivatives ligusticumacid A-C (1-3) and ligusticumaldehyde A (4), one new dimer ligusticumacid D (5), and two novel 8-8' lignans ligusticumacid E-F (6-7) were isolated from the rhizome of Ligusticum chuanxiong Hort. In particular, compounds 1-2, 5 were rarely phenylpropanoid phenolic acid dimers through different polymerization action in natural products. Their structures were established using UV, IR, HRESIMS, NMR data. The absolute configurations of 3 was determined by quantum ECD calculation and 4, 6-7 were determined by the ECD exciton chirality method. In addition, all compounds were evaluated for their neuroprotective effects on human neuroblastoma SH-SY5Y cell injury induced by H2O2. Compound 2 had a moderate neuroprotective activity and 7 had a weak neuroprotective activity on human neuroblastoma SH-SY5Y cell injury induced by H2O2 respectively.
Assuntos
Ácidos Cumáricos/química , Ligusticum/química , Fármacos Neuroprotetores/química , Linhagem Celular Tumoral , China , Ácidos Cumáricos/isolamento & purificação , Humanos , Estrutura Molecular , Fármacos Neuroprotetores/isolamento & purificação , Rizoma/químicaRESUMO
A novel iridoid glycoside trimer named forsydoitriside A (1) and five new iridoid glycosides (2-6) were isolated from the fruits of Forsythia suspensa together with two known compounds (7, 8). These new structures were elucidated by comprehensive spectroscopic data and the comparison of experimental and calculated electronic circular dichroism spectra. Compounds 1-8 were all assayed on acetaminophen-induced HepG2 cell damage. The results exhibited that compounds 2, 3, 5 and 6 possessed strong hepatoprotective activities against the damage in HepG2 cell.