RESUMO
Various physiological and pathological changes are related to the occurrence and development of neurodegenerative diseases. Neuroinflammation is a major trigger and exacerbation of neurodegenerative diseases. One of the main symptoms of neuritis is the activation of microglia. Thus, to alleviate the occurrence of neuroinflammatory diseases, an important method is to inhibit the abnormal activation of microglia. This research evaluated the inhibitory effect of trans-ferulic acid (TJZ-1) and methyl ferulate (TJZ-2), isolated from Zanthoxylum armatum, on neuroinflammation, by establishing the human HMC3 microglial cell neuroinflammation model induced by lipopolysaccharide (LPS). The results showed both compounds significantly inhibited the production and expression of nitric oxide (NO), tumor necrosis factor-α (TNF-α), and interleukin-1ß (IL-1ß) contents, and increased the level of anti-inflammatory factor ß-endorphin (ß-EP). Furthermore, TJZ-1 and TJZ-2 can inhibit LPS-induced activation of nuclear factor kappa B (NF-κB). It was found that of two ferulic acid derivatives, both had anti-neuroinflammatory effects by inhibiting the NF-κB signaling pathway and regulating the release of inflammatory mediators, such as NO, TNF-α, IL-1ß, and ß-EP. This is the first report that demonstrates that TJZ-1 and TJZ-2 had inhibitory effects on LPS-induced neuroinflammation in human HMC3 microglial cells, which indicates that two ferulic acid derivates from Z. armatum could be used as potential anti-neuroinflammatory agents.
Assuntos
Microglia , NF-kappa B , Humanos , NF-kappa B/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Doenças Neuroinflamatórias , Lipopolissacarídeos/farmacologia , Transdução de Sinais , Inflamação/metabolismo , Óxido Nítrico/metabolismoRESUMO
Pancreatic cancer has an extremely poor prognosis, and the clinical drugs for the treatment of pancreatic cancer are usually multi-drug combinations. Therefore, it is necessary to search for and find specific new bioactive agents against pancreatic cancer. Carabrone is a carabrane-type sesquiterpenolide extracted from Carpesium cernuum L., and this natural compound has been reported to be a potential anti-tumor agent. However, there are few reports on the function of carabrone related to anti-tumor activity in pancreatic cancer. Herein, cell experiments indicated that carabrone had anti-proliferation inhibition and anti-migration and anti-invasion activity against SW1990 cells. Furthermore, the tandem mass spectrometry and network pharmacology analysis showed that this activity may be related to the ferroptosis and Hippo signaling pathway. Taken together, our results demonstrated that carabrone exhibited prominent anti-pancreatic cancer activity and could be a promising agent against pancreatic cancer.
Assuntos
Asteraceae , Ferroptose , Neoplasias Pancreáticas , Asteraceae/química , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Pâncreas/metabolismo , Neoplasias Pancreáticas/patologia , Neoplasias PancreáticasRESUMO
Natural products (NPs) were a rich source of diverse bioactive molecules. Most anti-tumor agents were built on natural scaffolds. Nardostachys jatamansi DC. was an important plant used to process the traditional Chinese herbal medicines "gansong". Pancreatic cancer was the fourth most common cause of cancer-related death in the world. Hence, there was an urgent need to develop novel agents for the treatment of pancreatic cancer. In this paper, nardoguaianone L (G-6) is isolated from N. jatamansi, which inhibited SW1990 cells colony formation and cell migration, and induced cell apoptosis. Furthermore, we analyzed the differential expression proteins after treatment with G-6 in SW1990 cells by using iTRAQ/TMT-based quantitative proteomics technology, and the results showed that G-6 regulated 143 proteins' differential expression by GO annotation, including biological process, cellular component, and molecular function. Meanwhile, KEGG enrichment found that with Human T-cell leukemia virus, one infection was the most highly enhanced pathway. Furthermore, the MET/PTEN/TGF-ß pathway was identified as a significant pathway that had important biological functions, including cell migration and motility by PPI network analysis in SW1990 cells. Taken together, our study found that G-6 is a potential anti-pancreatic cancer agent with regulation of MET/PTEN/TGF-ß pathway.
Assuntos
Nardostachys , Neoplasias , Humanos , Apoptose , Fator de Crescimento Transformador betaRESUMO
Pancreatic cancer is the seventh leading cause of cancer-related death worldwide and is known as "the king of cancers". Currently, gemcitabine (GEM) as the clinical drug of choice for chemotherapy of advanced pancreatic cancer has poor drug sensitivity and ineffective chemotherapy. Nardoguaianone L (G-6) is a novel guaiane-type sesquiterpenoid isolated from Nardostachys jatamansi DC., and it exhibits anti-tumor activity. Based on the newly discovered G-6 with anti-pancreatic cancer activity in our laboratory, this paper aimed to evaluate the potential value of the combination of G-6 and GEM in SW1990 cells, including cell viability, cell apoptosis, colony assay and tandem mass tags (TMT) marker-based proteomic technology. These results showed that G-6 combined with GEM significantly inhibited cell viability, and the effect was more obvious than that with single drug. In addition, the use of TMT marker-based proteomic technology demonstrated that the AGE-RAGE signaling pathway was activated after medication-combination. Furthermore, reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) assays were used to validate the proteomic results. Finally, apoptosis was detected by flow cytometry. In conclusion, G-6 combined with GEM induced an increase in ROS level and a decrease in MMP in SW1990 cells through the AGE-RAGE signaling pathway, ultimately leading to apoptosis. G-6 improved the effect of GEM chemotherapy and may be used as a potential combination therapy for pancreatic cancer.
Assuntos
Nardostachys , Neoplasias Pancreáticas , Espécies Reativas de Oxigênio/farmacologia , Proteômica , Linhagem Celular Tumoral , Neoplasias Pancreáticas/patologia , Transdução de Sinais , Apoptose , Proliferação de Células , Gencitabina , Neoplasias PancreáticasRESUMO
To find novel effective Aurora kinases inhibitors, a series of structurally interesting nitroxide labeled pyrimidines were synthesized and evaluated their anti-proliferative and Aurora kinases inhibitory activities. Among them, butyl 2-(3-((5-fluoro-2-((4-((1-oxyl-2,2,6,6-tetramethylpiperidin-4-yl)carbamoyl) phenyl) amino)pyrimidin-4-yl)amino)-1H-pyrazol-5-yl)acetate (22) possessed the most potent anti-proliferative effects against four carcinoma cell lines with IC50 values in range of 0.89-11.41⯵M, and kinases inhibition against Aurora A and B with the IC50 values were 9.3 and 2.8â¯nM, respectively. Furthermore, compound 22 blocked the phosphorylation of Aurora A (T288), Aurora B (Thr232) and HisH3, decreased the expression of proteins TPX2, Eg5 and Bora, as well as disrupted the mitotic spindle formation in HeLa cells. Molecular docking studies indicated that compound 22 well interact with both Aurora A and B. The results showed that compound 22 is a potential anticancer agent as promising pan-Aurora kinase inhibitor.
Assuntos
Aurora Quinases/antagonistas & inibidores , Óxidos de Nitrogênio/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Concentração Inibidora 50 , FosforilaçãoRESUMO
The Aurora kinases are a family of serine/threonine kinases that interact with components of the mitotic apparatus and serve as potential therapeutic targets in oncology. Herein, we reported a series of 2,4-bisanilinopyrimidines bearing 2,2,6,6-tetramethylpiperidine-N-oxyl with selective inhibition of Aurora A in either enzymatic assays or cellular phenotypic assays, and displaying more potent anti-proliferation compared with that of VX-680. The most potent compound 10a forms better interaction with Aurora A than Aurora B in molecular docking. Mechanistic studies revealed that 10a disrupt the spindle formation, block the cell cycle progression in the G2/M phase and induce apoptosis in HeLa cell. These results suggested that the produced series of compounds are potential anticancer agents for further development as selective Aurora A inhibitors.
Assuntos
Compostos de Anilina/farmacologia , Óxidos N-Cíclicos/farmacologia , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Compostos de Anilina/síntese química , Compostos de Anilina/química , Apoptose/efeitos dos fármacos , Aurora Quinase A/química , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Óxidos N-Cíclicos/síntese química , Óxidos N-Cíclicos/química , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Simulação de Acoplamento Molecular , Piperidinas/síntese química , Piperidinas/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirimidinas/síntese química , Pirimidinas/química , Fuso Acromático/efeitos dos fármacosRESUMO
A series of 4ß-(thiazol-2-yl)amino-4'-O-demethyl-4-deoxypodophyllotoxins were synthesized, and their cytotoxicities were evaluated against four human cancer cell lines (A549, HepG2, HeLa, and LOVO cells) and normal human diploid fibroblast line WI-38. Some of the compounds exhibited promising antitumor activity and less toxicity than the anticancer drug etoposide. Among them, compounds 15 and 17 were found to be the most potent synthetic derivatives as topo-II inhibitors, and induced DNA double-strand breaks via the p73/ATM pathway as well as the H2AX phosphorylation in A549 cells. These compounds also arrested A549 cells cycle in G2/M phase by regulating cyclinB1/cdc2(p34). Taken together, these results show that a series of compounds are potential anticancer agents.
Assuntos
Antineoplásicos/farmacologia , DNA Topoisomerases Tipo II/metabolismo , Peptídeos/farmacologia , Inibidores da Topoisomerase II/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Fibroblastos/efeitos dos fármacos , Humanos , Estrutura Molecular , Peptídeos/síntese química , Peptídeos/química , Relação Estrutura-Atividade , Inibidores da Topoisomerase II/síntese química , Inibidores da Topoisomerase II/químicaRESUMO
Prolyl hydroxylase domain 2 (PHD2) is an important enzyme in the human body that perceives changes in oxygen concentration and regulates response in hypoxic environments. Evaluation of PHD2 inhibitory activity of natural products is crucial for drug development of hypoxia related diseases. At present, the detection of low concentration of α-ketoglutaric acid (the substrate of PHD2 enzymatic reaction) requires derivatization reactions or sample pretreatment, which undoubtedly increases the workload of PHD2 inhibitory activity evaluation. In this paper, a direct detection approach of α-ketoglutaric acid was established by using the online stacking strategy of capillary electrophoresis to evaluate the PHD2 inhibitory activity of natural products. Under optimized conditions, detection of a single sample can be achieved within 2 min. By calculation, the intraday precision RSD of the apparent electrophoretic mobility and peak areas of α-ketoglutaric acid are 0.92 % and 0.79 %, respectively, and the interday RSD were 1.27 % and 0.96 % respectively. The recoveries of the present approach were 97.9-105.2 %, and the LOQ and LOD were 2.0 µM and 5.0 µM, respectively. Furthermore, this approach was applied for the evaluation of inhibitory activity of PHD2 for 13 natural products, and PHD2 inhibitory activity of salvianolic acid A was firstly reported. The present work not only realizes evaluation of PHD2 inhibitory activity through direct detection of α-ketoglutaric acid, but also provides technical support for the discovery of potential drug molecules in hypoxia related diseases.
Assuntos
Produtos Biológicos , Eletroforese Capilar , Prolina Dioxigenases do Fator Induzível por Hipóxia , Ácidos Cetoglutáricos , Humanos , Produtos Biológicos/farmacologia , Eletroforese Capilar/métodos , Prolina Dioxigenases do Fator Induzível por Hipóxia/antagonistas & inibidores , Ácidos Cetoglutáricos/análiseRESUMO
We found that the deoxypodophyllotoxin derivative, 2,6-dimethoxy-4-(6-oxo-(5R,5aR,6,8,8aR,9-hexahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-5-yl)phenyl ((R)-1-amino-4-(methylthio)-1-oxobutan-2-yl)carbamate (DPMA), exhibited superior cytotoxicity compared with etoposide. In this study, we investigated the mechanism of action of DPMA. DPMA exhibited anti-proliferative activity and induced apoptosis in A549 cells in a dose- and time-dependant manner. DPMA inhibited microtubule formation and induced expression of Bax, cleaved caspase-3, p53 and ROS, and inhibited Bcl-2 expression. DPMA also affected cyclinB1, cdc2 and p-cdc2 expression, inducing cell cycle arrest. DPMA also inhibited tube formation of VEGF-induced human umbilical vein endothelial cells. These studies demonstrate that DPMA inhibits p53/cdc2/Bax signaling, thereby inhibiting cell growth/angiogenesis and inducing apoptosis.
Assuntos
Adenosina/análogos & derivados , Apoptose/efeitos dos fármacos , Neovascularização Fisiológica/efeitos dos fármacos , Podofilotoxina/análogos & derivados , Adenosina/química , Adenosina/farmacologia , Proteína Quinase CDC2/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Medicamentos de Ervas Chinesas , Células Endoteliais da Veia Umbilical Humana , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Podofilotoxina/química , Podofilotoxina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Proteína Supressora de Tumor p53/metabolismo , Fator A de Crescimento do Endotélio Vascular/farmacologia , Proteína X Associada a bcl-2/metabolismoRESUMO
A series of 4ß-amino-4'-O-demethyl-4-deoxypodophyllotoxin derivatives were synthesized, and their cytotoxicities against several human cancer cell lines, including HepG2, A549, HeLa and HCT-8 cells, evaluated. Some of these compounds exhibited higher levels of cytotoxicity than the anticancer drug etoposide. 4ß-N-(4-Nitrophenyl piperazinyl)-4'-O-demethyl-4-deoxypodophyllotoxin (11) was found to be the most potent synthesized compound in the current study, and induced cell cycle arrest in the G2/M phase in HeLa cells, which was accompanied by apoptosis. Furthermore, this compound activated the expression of cdc2, cyclin B1, p53 and caspase-3 in HeLa cells, leading to changes in the conformation of calf thymus DNA from the B-form to a more compact C-form.
Assuntos
Antineoplásicos/síntese química , DNA/metabolismo , Piperazinas/síntese química , Podofilotoxina/análogos & derivados , Animais , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Proteína Quinase CDC2/metabolismo , Caspase 3/metabolismo , Bovinos , Linhagem Celular Tumoral , Ciclina B1/metabolismo , Medicamentos de Ervas Chinesas , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Células HeLa , Células Hep G2 , Humanos , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Microtúbulos/química , Microtúbulos/metabolismo , Piperazinas/metabolismo , Piperazinas/toxicidade , Podofilotoxina/síntese química , Podofilotoxina/química , Podofilotoxina/metabolismo , Podofilotoxina/toxicidade , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/metabolismo , Moduladores de Tubulina/toxicidade , Proteína Supressora de Tumor p53/metabolismoRESUMO
Eight previously unreported sesquiterpene coumarins, namely (+)- and (-)-ferulasinkian A (1), (-)-fukanefuromarin M (2), (±)-ferulasinkian C (3), (±)-ferulasinkian D (4), ferulasinkian E (5), ferulasinkian F (7), and ferulasinkian G (8), together with two known compounds, (+)-fukanefuromarin M (2) and 7-hydroxyferprenin (6), have been isolated from the roots of Ferula sinkiangensis (Umbelliferae). The structures of all compounds were elucidated by spectroscopic analysis, along with ECD calculations and optical rotation calculations. Compounds 1-6 are dimers consisting of a chain sesquiterpene and a coumarin with an oxygen-containing six-membered ring connected from coumarin C-3 and C-4. Currently, there are only seven such structures reported in the genus Ferula, and their absolute configurations have not yet been determined. Compounds 7-8 are sesquiterpene coumarin derivatives with a chain sesquiterpene connected with coumarin C-4. In the present study, the chiral separation of compounds (±)-1 and (±)-2 was successfully carried out, and the absolute configurations of compounds (±)-1, (±)-2, 5, 7 and 8 were determined. The isolates were evaluated for their cytotoxic activity against human pancreatic cancer cell lines including CFPAC-1, PANC-1, CAPAN-2 and SW 1990. Compounds (+)-1, (-)-1 and 7 exhibited potent cytotoxicity against pancreatic cancer cells with IC50 values ranging from 4.57 ± 0.94 to 14.01 ± 1.03 µM. Furthermore, the primary mechanistic study of (-)-1 demonstrated that it could induce apoptosis in CFPAC-1 cells.
RESUMO
Twenty-two isolates, including two previously undescribed compounds identified as benzoyltembamide (1) and P-benzoyphenethyl anisate (21), were isolated and identified from a methanol extract of the roots of Zanthoxylum bungeanum Maxim. (Rutaceae) using diverse chromatographic materials and pre-HPLC. Their structures were elucidated on the basis of spectroscopic and spectrometric data analysis such as HR-ESI-MS, 1D and 2D NMR, IR and UV, as well as single-crystal X-ray diffraction for crystalline compounds. All the compounds (except for compound 16) were isolated from the roots of Z. bungeanum for the first time. Selected compounds were evaluated for their antioxidant activities. Compound 18 attenuated the H2O2-induced cytotoxicity and blocked the accumulation of ROS in SH-SY5Y cells, and exhibited potent neuroprotective activity.
Assuntos
Neuroblastoma , Zanthoxylum , Humanos , Zanthoxylum/química , Peróxido de Hidrogênio , Estrutura Molecular , Cromatografia Líquida de Alta PressãoRESUMO
Three unreported dammarane-type triterpenoids with rare skeletons (1-3), along with one undescribed gypenoside (4), were isolated from the aerial parts of Gynostemma pentaphyllum using diverse chromatographic materials and pre-HPLC. Their structures were elucidated on the basis of spectroscopic and spectrometric data, while the absolute configurations of 1-3 were assessed via electronic circular dichroism (ECD) analyses. Notably, compounds 1-3 possess a 3,19-hemiketal bridge in the A ring. Saponin 4 possesses an unreported 20,25-oxa structural moiety. Their antiproliferative effects against HepG2, MCF-7, and DU145 cell lines were screened. Compounds 1-3 displayed moderate cytotoxicity with IC50 values ranging from 13.7 ± 0.2 to 32.0 ± 1.7 µM.
Assuntos
Antineoplásicos , Saponinas , Triterpenos , Gynostemma , Estrutura Molecular , Saponinas/farmacologia , Esqueleto , Triterpenos/química , Triterpenos/farmacologia , DamaranosRESUMO
Oxygen is a necessary substance for life activities, but reduced oxygen utilization due to high altitude exposure and respiratory dysfunction diseases could lead to pathological changes in the organisms. Herein gypenosides, the active ingredients in the food and medicine resource plant Gynostemma pentaphyllum (Thunb.) Makino were found to alleviate hypoxia-induced injury in PC12 cells. Moreover, hypoxia induced an increase in Ca2+ and reactive oxygen species content, and such patterns were both significantly reduced by gypenosides treatment. At the same time, gypenosides significantly blocked the decrease of both NO content and mitochondrial membrane potential caused by hypoxia. Furthermore, gypenosides gavage treatment significantly prolonged the survival time of C57BL/6 mice in confinement up to 24.3% and enhanced the locomotor ability of mice. Therefore, gypenosides have good neuroprotective effects and hypoxia tolerance activity and have the prospect of being developed as a preventive and therapeutic drug for hypoxia-related diseases. PRACTICAL APPLICATIONS: Gypenosides can enhance tolerance of cells and mice to hypoxia and have the potential to be developed into hypoxia-resistant health food and drugs.
Assuntos
Gynostemma , Hipóxia , Ratos , Camundongos , Animais , Células PC12 , Camundongos Endogâmicos C57BL , Hipóxia/tratamento farmacológico , OxigênioRESUMO
Five previously unreported terpenoids, together with fifteen known analogs, were isolated from a methanol extract of the roots and rhizomes of Nardostachys jatamansi. Their structures, including absolute configurations, were elucidated by spectroscopic data and electronic circular dichroism (ECD) spectra analyses, as well as single-crystal X-ray diffraction for crystalline compounds. Structurally, (4R,5S,6S,7R)-1(10)-aristolane-8,9-diacid is a novel 8,9-dicarboxylic acid derivative of aristolane-type sesquiterpenoid. (4R,6S,7R,10S)-10-Hydroxyguaia-1(5)-6,7-epoxy-2-one is an undescribed analogue of nardoguaianone K, with a rare 6,7-epoxide group. (4R,5R,6R,8R)-1(10)-Isonardosinone-8-ol-9-one-7,11-lactone is an isonardosinane-type sesquiterpene bearing a γ-lactone ring. Dinardokanshone F is a rare example of a sesquiterpene dimer from N. jatamansi connected by an oxo bridge. The isolates were evaluated for their cytotoxic activity against four human pancreatic cancer cell lines (CFPAC-1, PANC-1, CAPAN-2 and SW1990). Compound epoxynardosinone exhibited significant cytotoxicity against CAPAN-2 cell lines with IC50 value of 2.60 ± 1.85 µM. 1-Hydroxylaristolone displayed comparable cytotoxicity on CFPAC-1 cell lines (IC50 1.12 ± 1.19 µM), compared to Taxol (IC50 0.32 ± 0.13 µM). 1-Hydroxylaristolone, 1(10)-aristolane-9ß-ol, 1(10)-aristolen-2-one, alpinenone, valtrate isovaleroyloxyhydrine and nardostachin displayed stronger cytotoxicity against PANC-1 cell lines with IC50 values ranging from 0.01 ± 0.01 to 6.50 ± 1.10 µM. 1(10)-Aristolane-9ß-ol, 10-hydroxyguaia-1(5)-6,7-epoxy-2-one, nardoguaianone K, nardonoxide, epoxynardosinone, 1(10)-isonardosinone-8-ol-9-one-7,11-lactone, valtrate isovaleroyloxyhydrine and nardostachin showed remarkable cytotoxicity against SW1990 cell lines with IC50 values ranging from 0.07 ± 0.05 to 4.82 ± 6.96 µM. Furthermore, the primary mechanistic study of nardostachin demonstrated that it induced cell apoptosis via the mitochondria-dependent pathway, and induced SW1900 cell arrest at G2/M phase.
Assuntos
Antineoplásicos , Nardostachys , Neoplasias Pancreáticas , Sesquiterpenos , Linhagem Celular , Humanos , Lactonas , Estrutura Molecular , Nardostachys/química , Neoplasias Pancreáticas/tratamento farmacológico , Sesquiterpenos/química , Sesquiterpenos/farmacologia , Terpenos/farmacologiaRESUMO
The Aurora kinases are a family of serine/threonine kinases that interact with components of the mitotic apparatus and serve as potential therapeutic targets in oncology. Here we synthesized 15 2,4-diaminopyrimidines and evaluated their biological activities, including antiproliferation, inhibition against Aurora kinases and cell cycle effects. These compounds generally exhibited more potent cytotoxicity against tumor cell lines compared with the VX-680 control, especially compound 11c, which showed the highest cytotoxicities, with IC50 values of 0.5-4.0 µM. Compound 11c had more than 35-fold more selectivity for Aurora A over Aurora B, and molecular docking analysis indicated that compound 11c form better interaction with Aurora A both from the perspective of structure and energy. Furthermore, compound 11c induced G2/M cell cycle arrest in HeLa cells. This series of compounds has the potential for further development as selective Aurora A inhibitors for anticancer activity.
Assuntos
Aurora Quinase A/antagonistas & inibidores , Aurora Quinase B/antagonistas & inibidores , Piperazinas/síntese química , Piperazinas/farmacologia , Piperidinas/síntese química , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/química , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Células HeLa , Humanos , Immunoblotting , Simulação de Acoplamento MolecularRESUMO
A series of carbamate derivatives of 4'-demethylepipodophyllotoxin have been synthesized, and their cytotoxicities against several human cancer cell lines, including HeLa, A549, HCT-8, and HL-60 cells, evaluated. Some of these compounds exhibited higher levels of cytotoxicity than the anticancer drug etoposide. 4ß-4'-Demethylepipodophyllotoxin 1-(4-nitrophenyl) piperazinyl carbamate (19) was found to be the most potent compound of those synthesized in the current study, and induced cell cycle arrest in the G2/M phase in HeLa cells, which was accompanied by apoptosis. Furthermore, this compound activated the expression of Bax, p53 and caspase-3 in HeLa cells, leading to changes in the conformation of calf thymus DNA from the B-form to a more compact C-form.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carbamatos/farmacologia , DNA/química , Animais , Antineoplásicos/síntese química , Carbamatos/síntese química , Carbamatos/química , Bovinos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HL-60 , Células HeLa , Humanos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Carbamate derivatives of 4ß-(1,2,3-triazol-1-yl)podophyllotoxin were synthesized by means of click chemistry, and their cytotoxicities against human cancer cell lines HL-60, A-549, HeLa, and HCT-8 were evaluated. Some compounds were more potent than the anticancer drug etoposide. 4'-O-Demethyl-4ß-[(4-hydroxymethyl)-1,2,3-triazol-1-yl]-4-deoxypodophyllotoxin cyclopentyl carbamate, the most potent compound, induced cell cycle arrest in the G2/M phase accompanied by apoptosis in A-549 cells. Furthermore, this compound inhibited the formation of microtubules in A-549 cells and caused the inhibition of DNA topoisomerase-II.