RESUMO
Meroterpenoid clavilactones feature a unique benzo-fused ten-membered carbocyclic ring unit with an α,ß-epoxy-γ-lactone moiety, forming an intriguing 10/5/3 tricyclic nested skeleton. These compounds are good inhibitors of the tyrosine kinase, attracting a lot of chemical synthesis studies. However, the natural enzymes involved in the formation of the 10/5/3 tricyclic nested skeleton remain unexplored. Here, we identified a gene cluster responsible for the biosynthesis of clavilactone A in the basidiomycetous fungus Clitocybe clavipes. We showed that a key cytochrome P450 monooxygenase ClaR catalyzes the diradical coupling reaction between the intramolecular hydroquinone and allyl moieties to form the benzo-fused ten-membered carbocyclic ring unit, followed by the P450 ClaT that exquisitely and stereoselectively assembles the α,ß-epoxy-γ-lactone moiety in clavilactone biosynthesis. ClaR unprecedentedly acts as a macrocyclase to catalyze the oxidative cyclization of the isopentenyl to the nonterpenoid moieties to form the benzo-fused macrocycle, and a multifunctional P450 ClaT catalyzes a ten-electron oxidation to accomplish the biosynthesis of the 10/5/3 tricyclic nested skeleton in clavilactones. Our findings establish the foundation for the efficient production of clavilactones using synthetic biology approaches and provide the mechanistic insights into the macrocycle formation in the biosynthesis of fungal meroterpenoids.
RESUMO
In this study, a six-month pot experiment was conducted to explore the effects of nanoparticles (NPs), including CeO2, TiO2 and SiO2 NPs at 200 and 800â¯mg/kg, on the growth and quality of model medicinal plant Salvia miltiorrhiza. A control group was implemented without the application of NPs. Results showed that NPs had no significant effect on root biomass. Treatment with 200â¯mg/kg of SiO2 NPs significantly increased the total tanshinone content by 44.07â¯%, while 200â¯mg/kg of CeO2 NPs were conducive to a 22.34â¯% increase in salvianolic acid B content. Exposure to CeO2 NPs induced a substantial rise in the MDA content in leaves (176.25â¯% and 329.15â¯% under low and high concentration exposure, respectively), resulting in pronounced oxidative stress. However, TiO2 and SiO2 NPs did not evoke a robust response from the antioxidant system. Besides, high doses of CeO2 NP-amended soil led to reduced nitrogen, phosphorus and potassium contents. Furthermore, the NP amendment disturbed the carbon and nitrogen metabolism in the plant rhizosphere and reshaped the rhizosphere microbial community structure. The application of CeO2 and TiO2 NPs promoted the accumulation of metabolites with antioxidant functions, such as D-altrose, trehalose, arachidonic acid and ergosterol. NPs displayed a notable suppressive effect on pathogenic fungi (Fusarium and Gibberella) in the rhizosphere, while enriching beneficial taxa with disease resistance, heavy metal antagonism and plant growth promotion ability (Lysobacter, Streptomycetaceae, Bacillaceae and Hannaella). Correlation analysis indicated the involvement of rhizosphere microorganisms in plant adaptation to NP amendments. NPs regulate plant growth and quality by altering soil properties, rhizosphere microbial community structure, and influencing plant and rhizosphere microbe metabolism. These findings were beneficial to deepening the understanding of the mechanism by which NPs affect medicinal plants.
Assuntos
Cério , Nanopartículas , Plantas Medicinais , Salvia miltiorrhiza , Dióxido de Silício , Solo , Titânio , Titânio/toxicidade , Salvia miltiorrhiza/efeitos dos fármacos , Salvia miltiorrhiza/crescimento & desenvolvimento , Plantas Medicinais/efeitos dos fármacos , Plantas Medicinais/crescimento & desenvolvimento , Nanopartículas/toxicidade , Solo/química , Cério/toxicidade , Rizosfera , Poluentes do Solo/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Raízes de Plantas/efeitos dos fármacos , Raízes de Plantas/crescimento & desenvolvimento , Microbiologia do Solo , Antioxidantes/metabolismo , Benzofuranos , Abietanos , DepsídeosRESUMO
This paper aimed to study the chemical constituents from Clitocybe clavipes. Silica gel, ODS, Sephadex LH-20, and semi-p reparative HPLC were employed to separate the ethanol extract of C. clavipes. Six compounds were identified by ~1H-NMR, ~(13)CNMR,and ESI-MS as clavilactone L(1), clavilactone A(2), clavilactone B(3), clavilactone E(4), clavilactone H(5), and clav ilactone I(6). Among them, compound 1 was a new meroterpenoid with a 10-membered carbocycle connected to a hydroquinone. Theantitumor activities of compounds 1-6 were determined by the methyl thiazolyl tetrazolium(MTT) ass ay. The results showed that compounds 1-6 exerted inhibitory effects on the proliferation of human gastric cancer cells(MGC-803),human non-small cell lung cancer cells(A549), and cervical cancer cells(HeLa). Compound 1 exhibited significant inhibitory activity against MGC-803 cells, with the half maximal inhibitory concentration(IC_(50)) of 11. 76 µmol·L~(-1).
Assuntos
Proliferação de Células , Humanos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Estrutura Molecular , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/químicaRESUMO
We have previously reported that Gypenoside LXXV (GP-75), a novel natural PPARγ agonist isolated from Gynostemma pentaphyllum, ameliorated cognitive deficits in db/db mice. In this study, we further investigated the beneficial effects on cognitive impairment in APP/PS1 mice and a mouse model of diabetic AD (APP/PS1xdb/db mice). Interestingly, intragastric administration of GP-75 (40 mg/kg/day) for 3 months significantly attenuated cognitive deficits in APP/PS1 and APP/PS1xdb/db mice. GP-75 treatment markedly reduced the levels of glucose, HbA1c and insulin in serum and improved glucose tolerance and insulin sensitivity in APP/PS1xdb/db mice. Notably, GP-75 treatment decreased the ß-amyloid (Aß) burden, as measured by 11 C-PIB PET imaging. Importantly, GP-75 treatment increased brain glucose uptake as measured by 18 F-FDG PET imaging. Moreover, GP-75 treatment upregulated PPARγ and increased phosphorylation of Akt (Ser473) and GLUT4 expression levels but decreased phosphorylation of IRS-1 (Ser616) in the hippocampi of both APP/PS1 and APP/PS1xdb/db mice. Furthermore, GP-75-induced increases in GLUT4 membrane translocation in primary hippocampal neurons from APP/PS1xdb/db mice was abolished by cotreatment with the selective PPARγ antagonist GW9662 or the PI3K inhibitor LY294002. In summary, GP-75 ameliorated cognitive deficits in APP/PS1 and APP/PS1xdb/db mice by enhancing glucose uptake via activation of the PPARγ/Akt/GLUT4 signaling pathways.
Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Diabetes Mellitus , Camundongos , Animais , Doença de Alzheimer/metabolismo , PPAR gama/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Camundongos Transgênicos , Peptídeos beta-Amiloides/metabolismo , Modelos Animais de Doenças , Disfunção Cognitiva/tratamento farmacológico , Encéfalo , Glucose/metabolismo , Cognição , Precursor de Proteína beta-Amiloide/metabolismoRESUMO
HIV-1 maturation is the final step in the retroviral lifecycle that is regulated by the proteolytic cleavage of the Gag precursor protein. As a first-in-class HIV-1 maturation inhibitor (MI), bevirimat blocks virion maturation by disrupting capsid-spacer peptide 1 (CA-SP1) cleavage, which acts as the target of MIs. Previous alterations of beesioside I (1) produced (20S,24S)-15êµ,16êµ-diacetoxy-18,24; 20,24-diepoxy-9,19-cyclolanostane-3êµ,25-diol 3-O-3',3'-dimethylsuccinate (3, DSC), showing similar anti-HIV potency compared to bevirimat. To ascertain the binding modes of this derivative, further modification of compound 1 was conducted. Three-dimensional quantitative structure−activity relationship (3D-QSAR) analysis combined with docking simulations and molecular dynamics (MD) were conducted. Five new derivatives were synthesized, among which compound 3b showed significant activity against HIV-1NL4-3 with an EC50 value of 0.28 µM. The developed 3D-QSAR model resulted in great predictive ability with training set (r2 = 0.99, q2 = 0.55). Molecular docking studies were complementary to the 3D-QSAR analysis, showing that DSC was differently bound to CA-SP1 with higher affinity than that of bevirimat. MD studies revealed that the complex of the ligand and the protein was stable, with root mean square deviation (RMSD) values <2.5 Å. The above results provided valuable insights into the potential of DSC as a prototype to develop new antiviral agents.
Assuntos
Fármacos Anti-HIV , Replicação Viral , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Relação Quantitativa Estrutura-Atividade , Proteínas do Capsídeo/química , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/químicaRESUMO
Traditional Chinese medicine has been proven to be of great significance in cardioprotective effects. Clinopodium chinense (Lamiaceae) has unique advantages in the treatment and prevention of cardiovascular diseases. Tournefolic acid B (TAB) was proven to be a potent component against myocardial ischemia reperfusion injury (MIRI) from Clinopodium chinense (Lamiaceae). This article will attempt to establish a gram-scale synthesis method of TAB and discuss the structure-activity relationship of its analogs. The total synthesis of TAB was completed in 10 steps with an overall yield of 13%. In addition, analogs were synthesized, and their cardioprotective activity was evaluated on the hypoxia/reoxygenation of H9c2 cells. Amidation of the acid position is helpful to the activity, while methylation of phenolic hydroxyl groups greatly decreased the cardioprotective activity. The easily prepared azxepin analogs also showed cardioprotective activity. Most of the clogP values calculated by Molinspiration ranged from 2.5 to 5, which is in accordance with Lipinski's rule of 5. These findings represent a novel kind of cardioprotective agent that is worthy of further study.
Assuntos
Compostos Heterocíclicos com 3 Anéis , Traumatismo por Reperfusão Miocárdica , Humanos , Compostos Heterocíclicos com 3 Anéis/farmacologia , Cardiotônicos/farmacologia , Relação Estrutura-Atividade , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miócitos Cardíacos , ApoptoseRESUMO
Four new meroterpenoids, Clavilactone M-P, possessing novel aminoglycoside moiety (1-4) and a 10-membered carbocycle fused with an α,ß-epoxy-γ-lactone, were isolated from Clitocybe clavipes, a basidiomycete. Their structures with absolute configurations were determined by extensive analysis of their spectroscopic data, and the ECD method. All the isolated compounds (1-4) were evaluated for their antitumor activity against three human cancer cell lines using the MTT assay. Compound 1 and 2 exhibited a significant suppression of cell viability in the Hela (IC50 = 22.8 and 19.7 µM) cell line.
Assuntos
Antineoplásicos , Basidiomycota , Humanos , Aminoglicosídeos/farmacologia , Estrutura Molecular , Antineoplásicos/farmacologia , Antineoplásicos/química , Basidiomycota/química , Linhagem Celular Tumoral , AntibacterianosRESUMO
We performed a meta-analysis to evaluate the effect of platelet-rich plasma vs standard management for the treatment of diabetic foot ulcer wounds. A systematic literature search up to March 2022 was performed and 1435 subjects with diabetic foot ulcer wounds at the baseline of the studies; 723 of them were treated with platelet-rich plasma, and 712 used control. Odds ratio (OR) with 95% confidence intervals (CIs) was calculated to assess the effect of platelet-rich plasma vs standard management for the treatment of diabetic foot ulcer wounds using the dichotomous method with a random or fixed-effect model. The use of autologous platelet-rich plasma resulted in significantly higher complete-healed diabetic foot ulcer wounds compared with control (OR, 1.95; 95% CI, 1.49-2.56, P < 0.001). The use of allogeneic platelet-rich plasma resulted in significantly higher complete-healed diabetic foot ulcer wounds compared with control (OR, 6.19; 95% CI, 2.32-16.56, P < 0.001). The use of autologous and allogeneic platelet-rich plasma resulted in significantly higher complete-healed diabetic foot ulcer wounds compared with control. Though, the analysis of outcomes should be with caution because of the low number of studies in certain comparisons, for example, allogeneic platelet-rich plasma compared with control.
Assuntos
Diabetes Mellitus , Pé Diabético , Plasma Rico em Plaquetas , Humanos , Pé Diabético/terapia , CicatrizaçãoRESUMO
Cucurbitacin IIb (CuIIb) extracted from Hemsleya penxianensis has been demonstrated anticancer activity in many malignancies, however, its effect against bladder cancer cells and the molecular mechanism remains unclear. Accordingly, in the present study, we evaluated the effect and further the underlying mechanism of CuIIb on bladder cancer cells. Cell viability and clonogenicity were examined to evaluate growth suppressive effect of CuIIb, alongside mechanism exploration was conducted based on RNA sequencing (RNA-seq). The results showed that CuIIb exposure inhibited the growth of T24 and UM-UC-3 bladder cancer cells as indicated by its obvious suppression on cell viability and clonogenicity. Mechanistic studies by RNA-seq and quantifying analysis of RNA-seq data by TMNP indicated cell cycle modulated by cell cycle checkpoints and apoptosis mediated by PI3K/Akt pathway might account for the anticancer activity of CuIIb. Consistently, results of flow cytometry and AO/EB staining demonstrated that the growth-suppressive effect of CuIIb was mediated by cell cycle arrest in G2/M phase and robust induction of cell apoptosis, which was further confirmed by immunoblotting and mitochondrial membrane potential (ΔΨm) analysis. Collectively, the results presented herein indicated that CuIIb exhibited anticancer activity on bladder cancer which may be a potential candidate for improving bladder cancer outcomes.
Assuntos
Transdução de Sinais , Neoplasias da Bexiga Urinária , Fosfatidilinositol 3-Quinases/metabolismo , Fosfatidilinositol 3-Quinases/farmacologia , Linhagem Celular Tumoral , Pontos de Checagem do Ciclo Celular , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/patologia , Apoptose , Proliferação de CélulasRESUMO
This study aimed to investigate the chemical constituents of supercritical extract from Qi-nan Aquilariae Lignum Resinatum by silica gel column chromatography, thin-layer chromatography, and semi-preparative high-performance liquid chromatography. One new elemane-type and one new eudesmane-type sesquiterpene compounds were isolated from the extract, and their structures were identified by MS, UV, IR, NMR, and ECD spectroscopic techniques, and named aquqinanol C(1) and aquqinanol D(2). Both compounds are novel compounds. The neuroprotective effect of the compounds on CORT-induced PC12 cell damage was determined in vitro. The results showed that compounds 1 and 2 exhibited a certain protective effect against CORT-induced damage in PC12 cells.
Assuntos
Qi , Sesquiterpenos , Ratos , Animais , Sesquiterpenos/farmacologia , Estrutura MolecularRESUMO
Eight new cadinane sesquiterpenoids (1-8), along with two known compounds (9 and 10), were isolated from infected stems of the semi-mangrove plant, Hibiscus tiliaceus. The structures of compounds 1-8 were elucidated through the analysis of their 1D and 2D NMR and MS data, and their absolute configurations were determined by comparing their experimental and calculated ECD spectra and by single-crystal X-ray diffraction. The two confused known compounds (9 and 10) were resolved using single-crystal X-ray crystallography. Compounds 1-3 have novel norsesquiterpene carbon skeletons arising from a ring contraction rearrangement. All obtained isolates were evaluated against the HepG2 and Huh7 cell lines, and compounds 1b, 2b, 4, 6, and 8 showed cytotoxic activity toward both cell lines, with IC50 values ranging from 3.5 to 6.8 µM.
Assuntos
Hibiscus/química , Caules de Planta/química , Sesquiterpenos Policíclicos/farmacologia , Linhagem Celular Tumoral , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Sesquiterpenos Policíclicos/química , Sesquiterpenos Policíclicos/isolamento & purificação , Análise Espectral/métodosRESUMO
In the present study, six new cucurbitane type compounds, including three triterpenoids hemsleyacins P-R (6-7, 13) and three cucurbitane-type triterpenoid glycosides hemsleyaosides L-N (15-17), along with seventeen known cucurbitacin analogues were separated from the root tuber of Hemsleya penxianensis and elucidated based on NMR and HRESIMS. Then, 23 analogues of three types, namely, polyhydroxy-type (I) (1-7), monohydroxy-type (II) (8-13), and glycosides-type (III) (14-23), were assessed for their antitumor activity and structure-activity relationship analysis (SAR). We determined temozolomide (TMZ)-resistant GBM cell was the most sensitive to the tested compounds, and found hemsleyaoside N (HDN) displayed the best antineoplastic potency. Furthermore, we confirmed the anti-glioma activity of HDN in patient-derived recurrent GBM strains, GBM organoid (GBO) and orthotopic nude mouse models. Investigations exploring the mechanism made clear that HDN induced synchronous activation of UPR and MAPK signaling, which triggered deadly ER stress and apoptosis. Taken together, the potent antitumor activity of HDN warrants further comprehensive evaluation as a novel anti-glioma agent.
Assuntos
Cucurbitaceae , Glioma , Triterpenos , Animais , Apoptose , Linhagem Celular Tumoral , Cucurbitaceae/química , Resistencia a Medicamentos Antineoplásicos , Glioma/tratamento farmacológico , Glioma/patologia , Glicosídeos/química , Glicosídeos/farmacologia , Camundongos , Triterpenos/química , Triterpenos/farmacologiaRESUMO
Three new cadinane-type sesquiterpenoid dimeric diastereomers (1-3) named hibisceusones A-C were obtained from the infected stems of Hibiscus tiliaceus. The structures were determined by NMR spectroscopy and MS techniques, and the absolute configurations were assigned by ECD and single-crystal X-ray diffraction techniques. Compounds 1-3 are diastereomers, and contain a 1,4-dioxane ring linearly fused to different cadinane-type polycyclic skeletons. This is the first time that such a structure has been identified in natural products. Compounds 1-3 exhibited cytotoxic activities, and 2 showed a significantly high anti-triple-negative breast cancer (TNBC) effect. The anti-cancer effect of compound 2 was 3-4 fold higher than that of 1 and 3. The anti-cancer effect was generated via the induction of the apoptosis of the MDA-MB-231 cells by inhibiting the PI3Kα pathway.
Assuntos
Antineoplásicos , Hibiscus , Sesquiterpenos , Neoplasias de Mama Triplo Negativas , Antineoplásicos/farmacologia , Hibiscus/química , Humanos , Estrutura Molecular , Sesquiterpenos Policíclicos , Sesquiterpenos/química , Sesquiterpenos/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológicoRESUMO
Targeting the PPARγ might be a potential therapeutic strategy for diabetes-associated cognitive decline (DACD). In this study, Gypenoside LXXV (GP-75), a dammarane-type triterpene compound isolated from Gynostemma pentaphyllum, was found to be a novel PPARγ agonist using a dual-luciferase reporter assay system. However, whether GP-75 has protective effects against DACD remains unknown. Interestingly, intragastric administration of GP-75 (40 mg/kg/day) for 12 weeks significantly attenuated the cognitive deficit in db/db mice. GP-75 treatment significantly improved the glucose tolerance and lipid metabolism, and suppressed neuroinflammation. Notably, GP-75 treatment dramatically increased the uptake of glucose by the brain, as detected by 18 F-FDG PET. Incubation of primary cortical neurons with GP-75 significantly increased 2-deoxyglucose uptake. In addition, GP-75 treatment markedly increased the p-Akt (Ser 473)/total Akt levels and the expression levels of PPARγ and GLUT4, while decreasing the levels of p-IRS-1 (Ser 616)/total IRS-1. Importantly, all of these protective effects mediated by GP-75 were abolished by cotreatment with the PPARγ antagonist, GW9662. However, GP-75-mediated PPARγ upregulation was not affected by coincubation with the phosphatidylinositol 3-kinase inhibitor, LY294002. Collectively, GP-75 might be a novel PPARγ agonist that ameliorates cognitive deficit by enhancing brain glucose uptake via the activation of Akt/GLUT4 signaling in db/db mice.
Assuntos
Disfunção Cognitiva , Diabetes Mellitus Tipo 2 , Resistência à Insulina , Animais , Encéfalo/metabolismo , Cognição , Disfunção Cognitiva/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucose/metabolismo , Transportador de Glucose Tipo 4/metabolismo , Gynostemma/metabolismo , Insulina/metabolismo , Camundongos , PPAR gama/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Saponinas , TriterpenosRESUMO
Enhancing glucagon-like peptide 1 (GLP-1) signaling with a dipeptidyl peptidase IV (DPP-4) inhibitor might exert protective effects on Alzheimer's disease (AD). We found that intragastric administration of Gramcyclin A (10, 20 and 40 mg/kg), a novel DPP-4 inhibitor, for 3 months significantly reversed cognitive decline in APP/PS1/tau triple transgenic mice in a dose-dependent manner. Gramcyclin A treatment markedly reduced Aß plaques as well as the insoluble and soluble forms of Aß40 and Aß42 in the hippocampus of APP/PS1/tau mice. Treatment with Gramcyclin A remarkedly decreased the level of microglia and suppressed neuroinflammation in the hippocampus of APP/PS1/tau mice. Moreover, Gramcyclin A treatment could increase brain glucose uptake in APP/PS1/tau mice, as detected by 18-fluoro-2-deoxyglucose (18 F-FDG) micro-positron emission tomography (micro-PET) imaging. Furthermore, Gramcyclin A significantly increased expression of glucagon-like peptide-1 (GLP-1), GLP-1R, proliferator-activated receptor gamma coactivator (PGC)-1α and glucose transporter 4 (GLUT4), and inhibited insulin receptor (IRS)-1 phosphorylation and tau hyperphosphorylation in the hippocampus of APP/PS1/tau mice. Collectively, Gramcyclin A conferred protective effects against AD via enhancing brain GLP-1-dependent glucose uptake. The DPP-4 inhibitor Gramcyclin A might be a potential therapeutic drug for AD.
Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Inibidores da Dipeptidil Peptidase IV , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/farmacologia , Animais , Encéfalo , Cognição , Disfunção Cognitiva/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/farmacologia , Modelos Animais de Doenças , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Peptídeo 1 Semelhante ao Glucagon/uso terapêutico , Glucose/metabolismo , Hipocampo , Camundongos , Camundongos TransgênicosRESUMO
From the dried vines of Aspidopterys obcordata Hemsl, five new polyoxypregnane glycosides, named obcordatas J-N (1-5), were obtained. Their structures were fully elucidated and characterized by HRESIMS and extensive spectroscopic data. In addition, all of the new compounds were screened for their antinephrolithiasis activity in vitro. The results showed that compounds 1-3 have prominent protective effects on calcium oxalate crystal-induced human kidney 2 (HK-2) cells, with EC50 values ranging from 6.72 to 14.00 µM, which is consistent with the application value of A. obcordata in folk medicine for kidney stones.
Assuntos
Medicamentos de Ervas Chinesas , Malpighiaceae , Saponinas , Medicamentos de Ervas Chinesas/química , Glicosídeos/química , Glicosídeos/farmacologia , Humanos , Malpighiaceae/química , Estrutura Molecular , Saponinas/químicaRESUMO
Four new daphnane-type diterpenes named tianchaterpenes C-F (1-4) and six known ones were isolated from Stelleropsis tianschanica. Their structures were elucidated based on chemical and spectral analyses. The comparisons of calculated and experimental electronic circular dichroism (ECD) methods were used to determine the absolute configurations of new compounds. Additionally, compounds 1-10 were evaluated for their cytotoxic activities against HGC-27 cell lines; the results demonstrate that compound 2 had strong cytotoxic activities with IC50 values of 8.8 µM, for which activity was better than that of cisplatin (13.2 ± 0.67 µM).
Assuntos
Antineoplásicos Fitogênicos , Antineoplásicos , Diterpenos , Medicamentos de Ervas Chinesas , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos Fitogênicos/química , Linhagem Celular Tumoral , Diterpenos/química , Diterpenos/farmacologia , Medicamentos de Ervas Chinesas/química , Estrutura MolecularRESUMO
Indole diterpenes are a large class of secondary metabolites produced by fungi, possessing a cyclic diterpenoid backbone and an indole moiety. Novel structures and important biological activity have made indole diterpenes one of the focuses of synthetic chemists. Although the discovery, identification, structural diversity, biological activity and especially structure-activity relationship of indole diterpenes have been reported in some papers in recent years, they are absent of a systematic and comprehensive analysis, and there is no elucidation of enzymes related to this kind of natural product. Therefore, it is necessary to summarize the relevant reports to provide new perspectives for the following research. In this review, for the first time, the function of related synthases and the structure-activity relationship of indole diterpenes are expounded, and the recent research advances of them are emphasized.
Assuntos
Produtos Biológicos , Diterpenos , Diterpenos/química , Fungos/metabolismo , Indóis/química , Produtos Biológicos/farmacologia , Produtos Biológicos/metabolismoRESUMO
Clavipyrrine A (1), a novel polycyclic nitrogenous meroterpenoid with a pyrrolo[1,2-a]imidazole and a 10-membered carbocycle fused with an α,ß-epoxy-γ-lactone, was isolated from Clitocybe clavipes, a basidiomycete. X-ray crystallography and spectroscopic analysis were used to fully elucidate its structure. The biosynthetic origin of the pyrrole unit in this nitrogenous meroterpenoid was identified by incorporating 15N-labeled γ-aminobutyric acid. Compound 1 displayed promising anti-glioma activities and induced glioma cell apoptosis through inhibiting the JAK/STAT3 pathway and reinforcing SOCS1/3.
Assuntos
Agaricales/química , Antineoplásicos/farmacologia , Glioma/tratamento farmacológico , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Glioma/metabolismo , Humanos , Janus Quinases/antagonistas & inibidores , Janus Quinases/metabolismo , Modelos Moleculares , Estrutura Molecular , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/metabolismo , Relação Estrutura-AtividadeRESUMO
Glioblastoma multiforme (GBM) is the most frequent, lethal, and aggressive tumor of the central nervous system in adults. In this study, we found for the first time that moschamindole (MCD), a rare phenolic amide with 8/6/6/5/5 rings, is a major bioactive constituent derived from Phragmites communis Trin (Poaceae) that exhibits a potential cytotoxic effect on both TMZ-resistant GBM cell lines and xenograft models. MCD-induced intrinsic apoptosis signals and mitochondrial dysfunction were confirmed by cell cycle arrest, caspase-3/7 activation, and membrane potential depolarization. Furthermore, investigations exploring the mechanism showed that MCD specifically inhibits Mia40-mediated oxidative folding of mitochondrial intermembrane space (IMS) proteins via PCR assay and immunoblot analysis. MCD relies on its positive charge to associate with mitochondrial oxidative respiration, thus blocking energy metabolism and inducing apoptosis. Overexpression and upregulation of Mia40 were proven to reverse MCD-induced apoptosis and were correlated with the chemoresistance of GBM in vitro and in vivo, respectively. Taken together, our study demonstrates that Mia40 is a potential target of the chemoresistance of glioblastoma and suggests that MCD might be a potential agent for the individualized treatment of chemoresistant GBM based on mitochondrial metabolic characteristics and Mia40 expression.