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1.
Biomarkers ; 29(4): 211-221, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38629165

RESUMEN

BACKGROUND: Increased lactate levels and metastasis in tumours are strongly associated with dismal outcomes. But prognostic value of lactate metabolism and transport-related lncRNAs in gastric adenocarcinoma (GA) patients remains unaddressed. METHODS: Gene expression data of GA were provided by The Cancer Genome Atlas. Lactate metabolism and transport-related gene data were accessed from GSEA. LncRNAs related to lactate metabolism and transport were identified by correlation analysis. A prognostic model was built by regression analysis. Validity of prognostic model was confirmed through survival analysis and receiver operating characteristic (ROC) curve. Immunity of each risk group was evaluated by immune correlation analysis .LncRNA-mRNA network was built by correlation analysis using Cytoscape software. RESULTS: A 12-gene prognostic model based on lactate metabolism and transport-related lncRNAs was built in GA. Median riskscore was utilized to classify GA samples into high- and low-risk groups. Survival analysis and ROC curves demonstrated validity of prognostic model. Most immune checkpoint molecules and TIDE scores were lower in the low-risk group. LINC01303 and LINC01545 may be the key prognostic factors in patients with GA. CONCLUSION: This study successfully built a prognostic model of lactate metabolism and transport-related lncRNAs in GA. The findings guide prognostic management of GA patients.


Asunto(s)
Adenocarcinoma , Ácido Láctico , ARN Largo no Codificante , Neoplasias Gástricas , Humanos , ARN Largo no Codificante/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/patología , Pronóstico , Adenocarcinoma/genética , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Ácido Láctico/metabolismo , Regulación Neoplásica de la Expresión Génica , Curva ROC , Biomarcadores de Tumor/genética , Masculino , Femenino , Análisis de Supervivencia
2.
Bioorg Chem ; 146: 107306, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38531150

RESUMEN

The structural modification of curcumin has always been a hotspot in drug development. In this paper, a class of cinnamylaldehyde-derived mono-carbonyl curcumin analogs (MCAs) with 7-carbon-links were designed and synthesized and their anticancer properties were evaluated. Through screening anti-gastric cancer activity of these compounds, H1 exhibited the strongest cytotoxic activity by inhibiting cell viability and colony formation, inducing cell cycle G2/M phase arrest in vitro (SGC-7901 and AGS gastric cancer cells). Moreover, the SGC-7901 subcutaneous tumor-bearing mice studies revealed that H1 significantly inhibited the tumor growth of gastric cancer. We explored the possible potential targets of H1 through network pharmacology. Mechanistically, our results demonstrated that H1 showed potential anti-gastric cancer activity through suppression of the STAT3 and AKT signaling pathway in vitro and in vivo, which was validated by molecular docking. Overall, our results indicate the potential of H1 as a potent chemotherapeutic drug against gastric cancer.


Asunto(s)
Antineoplásicos , Curcumina , Neoplasias Gástricas , Animales , Ratones , Curcumina/química , Proteínas Proto-Oncogénicas c-akt , Neoplasias Gástricas/patología , Simulación del Acoplamiento Molecular , Línea Celular Tumoral , Proliferación Celular , Apoptosis , Antineoplásicos/química
3.
Bioorg Chem ; 142: 106930, 2024 01.
Artículo en Inglés | MEDLINE | ID: mdl-37890212

RESUMEN

Pyroptosis induction is anticipated to be a new approach to developing anti-tumor medications. A novel class of spirocyclic compounds was designed by hybridization of 1H-Benzo[e]indole-2(3H)-one with 1,4-dihydroquinoline and synthesized through a new green "one-pot" synthesis method using 10 wt% SDS/H2O as a solvent to screen novel tumor cell pyroptosis inducers. The anti-tumor activity of all compounds in vitro was determined by the MTT method, and a fraction of the compounds showed good cell growth inhibitory activity. The quantitative structure-activity relationship models of the compounds were established by artificial intelligence random forest algorithm (R2 = 0.9656 and 0.9747). The ideal compound A9 could, in a concentration-dependent manner, prevent ovarian cancer cells from forming colonies, migrating, and invading. Furthermore, A9 could significantly induce pyroptosis and upregulate the expression of pyroptosis-related proteins GSDME-N, in addition to inducing apoptosis and mediating the expression of apoptosis-related proteins in ovarian cancer cells. A9 (5 mg/kg) significantly reduced tumor volume and weight of ovarian cancer in vivo, decreased caspase-3 expression in tumor tissue, and induced the production of GSDME-N. This study provides a green and efficient atom-economic synthesis method for 1H-Benzo[e]indole-2(3H)-one spirocyclic derivatives and a promising pyroptosis inducer with anti-tumor activity.


Asunto(s)
Antineoplásicos , Neoplasias Ováricas , Humanos , Femenino , Piroptosis , Antineoplásicos/farmacología , Inteligencia Artificial , Línea Celular Tumoral , Neoplasias Ováricas/tratamiento farmacológico , Indoles/farmacología , Caspasa 3/metabolismo
4.
Mol Divers ; 2024 Jul 02.
Artículo en Inglés | MEDLINE | ID: mdl-38954072

RESUMEN

Proviral Integrations of Moloney-2 (PIM-2) kinase is a promising target for various cancers and other diseases, and its inhibitors hold potential for treating related diseases. However, there is currently no clinically available PIM-2 inhibitor. In this study, we constructed a generative model for de novo PIM-2 inhibitor design based on artificial intelligence, performed molecular docking and molecular dynamics (MD) simulations to develop an efficient PIM-2 inhibitor generative model and discover potential PIM-2 inhibitors. First, we designed a generative model based on a Bi-directional Long Short-Term Memory (BiLSTM) framework combined with a transfer learning strategy and generated a new PIM-2 small molecule library using existing active drug databases. The generated compound library was then virtually screened by molecular docking and scaffold similarity comparison, identifying 10 initial hit compounds with better performance. Next, using the inhibitor in the crystal structure as a positive control, we performed two rounds of MD simulations, with lengths of 100 ns and 500 ns, respectively, to study the dynamic stability of the protein-ligand systems of the 10 compounds with PIM-2. Analyzed the interactions with key hinge region residues, binding free energies, and changes in the ATP pocket size. The generative model demonstrates good molecular generation capability and can generate efficient novel molecules with similar physicochemical properties as active PIM-2 drugs. Among the 10 initially selected hit compounds, 5 compounds C3 (- 29.69 kcal/mol), C4 (- 33.31 kcal/mol), C5 (- 28.59 kcal/mol), C8 (- 34.68 kcal/mol), and C9 (- 25.88 kcal/mol) have higher binding energies with PIM-2 than the positive drug 3YR (- 26.18 kcal/mol). The MD simulation results are consistent with the docking analysis, these compounds have lower and more stable RMSD values for the complex systems with the reported positive drug 3YR and PIM-2 complex system. They can form long-term stable interactions with active site and the hinge region of PIM-2, which suggests these compounds are likely to have potent inhibitory effects on PIM-2. This study provides an efficient generative model for PIM-2 inhibitor research and discovers 5 potential novel PIM-2 inhibitors.

5.
J Enzyme Inhib Med Chem ; 39(1): 2314233, 2024 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-38385332

RESUMEN

The structure-activity relationship (SAR) between toxicity and the types of linking ketones of C7 bridged monocarbonyl curcumin analogs (MCAs) was not clear yet. In the pursuit of effective and less cytotoxic chemotherapeutics, we conducted a SAR analysis using various diketene skeletons of C7-bridged MCAs, synthesized cyclic C7-bridged MCAs containing the identified low-toxicity cyclopentanone scaffold and an o-methoxy phenyl group, and assessed their anti-gastric cancer activity and safety profile. Most compounds exhibited potent cytotoxic activities against gastric cancer cells. We developed a quantitative structure-activity relationship model (R2 > 0.82) by random Forest method, providing important information for optimizing structure. An optimized compound 2 exhibited in vitro and in vivo anti-gastric cancer activity partly through inhibiting the AKT and STAT3 pathways, and displayed a favorable in vivo safety profile. In summary, this paper provided a promising class of MCAs and a potential compound for the development of chemotherapeutic drugs.


Asunto(s)
Antineoplásicos , Curcumina , Neoplasias Gástricas , Humanos , Curcumina/farmacología , Curcumina/química , Neoplasias Gástricas/tratamiento farmacológico , Antineoplásicos/química , Relación Estructura-Actividad , Relación Estructura-Actividad Cuantitativa , Línea Celular Tumoral
6.
Neurochem Res ; 48(2): 579-590, 2023 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-36243818

RESUMEN

Antioxidants represent a potential therapy for cerebral ischemia-reperfusion injury (CIRI). Compounds which exhibit both direct and indirect antioxidative activity may potentially exert improved effects. Hence, we aimed to assess whether the dual antioxidant DH-217, a derivative of DHAP clinically used to treat coronary heart disease, can reduce oxidative stress damage and elucidate the underlying mechanism. Hydrogen peroxide (H2O2)-induced and Middle Cerebral Artery Occlusion (MCAO)-induced damages were used to imitate oxidative stress. The antioxidation of DH-217 was determined by MTT, ROS, colony and DPPH assay. Besides, immunofluorescence, Real-Time PCR Analyses, western blotting and si-RNA/Plasmid-induced protein expression were used for mechanism validation. DPPH scavenging assay evidenced DH-217 was a well free radical scavenger. Cell survival assay also showed that DH-217 had a significant cytoprotection through direct and indirect clearance mechanisms. Further, it clearly inhibited oxidative stress-induced IkappaB kinase beta (IKKß) phosphorylation and increased heme oxygenase-1 (HO-1) expression. Significantly, these antioxidant beneficial effects were reversed by HO-1 inhibitor, si-nuclear erythroid 2-related factor 2 (Nrf2) and IKKß plasmid. Meanwhile, DH-217 had a good neuroprotective effect on CIRI rats. The dual antioxidant DH-217 has potential reference value for drug development of CIRI. Furthermore, inhibition of IKKß phosphorylation and activation of Nrf2/HO-1 could be a promising antioxidant pathway. Dual antioxidant DH-217 not only has the ability of directly scavenging ROS, but also can clear it by targeting IKKß/Nrf2/HO-1 signal axis. Inhibition of IKKß phosphorylation and activation of Nrf2/HO-1 may be a promising antioxidant pathway for CIRI.


Asunto(s)
Isquemia Encefálica , Daño por Reperfusión , Ratas , Animales , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Antioxidantes/metabolismo , Quinasa I-kappa B/metabolismo , Quinasa I-kappa B/farmacología , Quinasa I-kappa B/uso terapéutico , Factor 2 Relacionado con NF-E2/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Ratas Sprague-Dawley , Peróxido de Hidrógeno/farmacología , Isquemia Encefálica/metabolismo , Estrés Oxidativo , Hemo-Oxigenasa 1/metabolismo , Daño por Reperfusión/metabolismo
7.
J Comput Aided Mol Des ; 37(7): 325-338, 2023 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-37269435

RESUMEN

FGFR3 kinase mutations are associated with a variety of malignancies, but FGFR3 mutant inhibitors have rarely been studied. Furthermore, the mechanism of pan-FGFR inhibitors resistance caused by kinase domain mutations is still unclear. In this study, we try to explain the mechanism of drug resistance to FGFR3 mutation through global analysis and local analysis based on molecular dynamics simulation, binding free energy analysis, umbrella sampling and community network analysis. The results showed that FGFR3 mutations caused a decrease in the affinity between drugs and FGFR3 kinase, which was consistent with the reported experimental results. Possible mechanisms are that mutations affect drug-protein affinity by altering the environment of residues near the hinge region where the protein binds to the drug, or by affecting the A-loop and interfering with the allosteric communication networks. In conclusion, we systematically elucidated the underlying mechanism of pan-FGFR inhibitor resistance caused by FGFR3 mutation based on molecular dynamics simulation strategy, which provided theoretical guidance for the development of FGFR3 mutant kinase inhibitors.


Asunto(s)
Resistencia a Antineoplásicos , Neoplasias , Mutación Puntual , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos , Humanos , Redes Comunitarias , Simulación de Dinámica Molecular , Mutación , Inhibidores de Proteínas Quinasas/farmacología , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/genética , Resistencia a Antineoplásicos/genética
8.
Bioorg Chem ; 136: 106543, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-37119784

RESUMEN

Curcumin is identified that it has the potential to treat Parkinson's disease (PD), but its instability limits its further application in clinic. The mono-carbonyl analogs of curcumin (MACs) with diketene structure can effectively improve its stability, but it is highly toxic. In the present study, a less cytotoxic and more stable monoketene MACs skeleton S2 was obtained, and a series of monoketene MACs were synthesized by combining 4-hydroxy-3­methoxy groups of curcumin. In the 6-OHDA-induced PD's model in-vitro, some compounds exhibited significant neurotherapeutic effect. The quantitative structure-activity relationship (QSAR) model established by the random forest algorithm (RF) for the cell viability rate of above compounds showed that the statistical results are good (R2 = 0.883507), with strong reliability. Among all compounds, the most active compound A4 played an important role in neuroprotection in the PD models both in vitro and in vivo by activating AKT pathway, and then inhibiting the apoptosis of cells caused by endoplasmic reticulum (ER) stress. In the PD model in-vivo, compound A4 significantly improved survival of dopaminergic neurons and the contents of neurotransmitters. It also enhanced the retention of nigrostriatal function which was better than the effect in the mice treated by Madopar, a classical clinical drug for PD. In summary, we screened out the compound A4 with high stability, less cytotoxic monoketene compounds. And these founding provide evidence that the compound A4 can protect dopaminergic neurons via activating AKT and subsequently suppressing ER stress in PD.


Asunto(s)
Curcumina , Fármacos Neuroprotectores , Enfermedad de Parkinson , Animales , Ratones , Apoptosis , Curcumina/farmacología , Curcumina/uso terapéutico , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Reproducibilidad de los Resultados
9.
Br J Cancer ; 127(6): 1014-1025, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-35715638

RESUMEN

BACKGROUND: Fibroblast growth factor receptor (FGFR) signaling influenced tumour occurrence and development. Overexpression of FGFR had been observed in many types of cancers, including colon cancer. FGFR inhibitor is considered to be effective in treating colon cancer patients. METHODS: First, the kinase inhibition rate was determined. MTT, western blotting, colony formation, EdU and comet assays were performed to evaluate the anti-tumour effects of F1-7 in vitro. RNA-seq and bioinformatics analysis were used for further verification. Additionally, a xenograft model was generated to investigate the anti-tumour effect of F1-7. RESULTS: F1-7 can inhibit the proliferation of colon cancer cells in vitro. It could significantly inhibit FGFR phosphorylation and its downstream signaling pathway. Whole-genome RNA-seq analysis found that the changed genes were not only functionally focused on MAPK signaling pathway but also related to cell apoptosis and ferroptosis. Experimental evidence demonstrated that F1-7 can directly increase the level of cellular DNA damage. The occurrence of DNA damage led to cell cycle arrest and inhibition of cell metastasis and cell apoptosis. Mouse model experiments also confirmed that F1-7 could inhibit tumour growth by inhibiting the FGFR pathway. CONCLUSIONS: F1-7 exhibits anti-tumour activity by inhibiting the FGFR pathway. It could be a novel therapeutic agent for targeting colon cancer cells.


Asunto(s)
Neoplasias del Colon , Inhibidores de Proteínas Quinasas , Animales , Muerte Celular , Línea Celular Tumoral , Proliferación Celular , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/genética , Daño del ADN , Humanos , Ratones , Inhibidores de Proteínas Quinasas/farmacología , Receptores de Factores de Crecimiento de Fibroblastos/genética
10.
J Enzyme Inhib Med Chem ; 37(1): 2357-2369, 2022 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-36039017

RESUMEN

Curcumin is a natural medicine with a wide range of anti-tumour activities. However, due to ß-diketone moiety, curcumin exhibits poor stability and pharmacokinetics which significantly limits its clinical applications. In this article, two types of dicarbonyl curcumin analogues with improved stability were designed through the calculation of molecular stability by density functional theory. Twenty compounds were synthesised, and their anti-tumour activity was screened. A plurality of analogues had significantly stronger activity than curcumin. In particular, compound B2 ((2E,2'E)-3,3'-(1,4-phenylene)bis(1-(2-chlorophenyl)prop-2-en-1-one)) exhibited excellent anti-lung cancer activity in vivo and in vitro. In addition, B2 could upregulate the level of reactive oxygen species in lung cancer cells, which in turn activated the endoplasmic reticulum stress and led to cell apoptosis and pyroptosis. Taken together, curcumin analogue B2 is expected to be a novel candidate for lung cancer treatment with improved chemical and biological characteristics.


Asunto(s)
Antineoplásicos , Curcumina , Neoplasias Pulmonares , Antineoplásicos/química , Apoptosis , Línea Celular Tumoral , Proliferación Celular , Diarilheptanoides/farmacología , Humanos , Neoplasias Pulmonares/patología , Piroptosis , Especies Reactivas de Oxígeno/metabolismo
11.
J Periodontal Res ; 56(4): 656-666, 2021 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-33604902

RESUMEN

BACKGROUND AND OBJECTIVE: The application of curcumin is limited by its instability. Mono-carbonyl analogues of curcumin (MCACs) are structurally stable, yet the intermediate bridging ketones in their skeletons account for increased toxicity. This study aimed to synthesize and screen MCACs that exhibit low cytotoxicity and high antioxidant ability, and the effects of MCACs on experimental periodontitis were also investigated. MATERIALS AND METHODS: The cytotoxicity of MCACs on MC3 T3-E1 was determined by MTT assay. The antioxidant capacity was investigated by the cell viability against H2 O2 -induced damage and the level of reactive oxygen species (ROS) and malondialdehyde (MDA). The localization and protein expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) was detected by immunofluorescence and western blot, respectively. In addition, MCAC was intragastrically administrated in rats with ligature-induced experimental periodontitis. The effects were assessed by bone resorption, as well as the immunohistology staining of inflammatory and oxidative stress markers. RESULTS: MCACs with cyclopentanone and containing pyrone showed lower toxicity than natural curcumin were synthesized (1A-10A, 1H-10H), among which, 1A exhibited the most potent cytoprotective effect against H2 O2 -induced damage. Such effects could be explained by the reduced MDA and ROS level, possibly through the nucleus translocation of Nrf2 and the induction of HO-1. Micro-CT results further indicated that 1A significantly reduced bone loss, along with an increased level of Nrf2 and HO-1, and decreased TNF-α and IL-1ß. CONCLUSION: The present study has synthesized a novel antioxidant MCAC 1A with good biosafety and stability. MCAC 1A could serve as a host response modulator with preventive and protective effects on periodontitis.


Asunto(s)
Curcumina , Periodontitis , Animales , Antioxidantes/farmacología , Curcumina/farmacología , Hemo-Oxigenasa 1/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo , Periodontitis/tratamiento farmacológico , Periodontitis/prevención & control , Ratas , Especies Reactivas de Oxígeno
12.
J Nat Prod ; 84(4): 1306-1315, 2021 04 23.
Artículo en Inglés | MEDLINE | ID: mdl-33724827

RESUMEN

Five new diterpenes, including four new hydroazulenes, (8R,11R)-8,11-diacetoxypachydictyol A (1), (8R*,11R*)-6-O-acetyl-8-acetoxy-11-hydroxypachydictyol A (2), (8R*,11S*)-8-acetoxy-11-hydroxypachydictyol A (3), and (8R*,11S*)-6-O-acetyl-8,11-dihydroxypachydictyol A (4), and a secohydroazulene derivative, named 7Z-7,8-seco-7,11-didehydro-8- acetoxypachydictyol A (5), were isolated from a South China Sea collection of a Dictyota sp. nov. brown alga, together with five known analogues (6-10). Structure elucidation was achieved by extensive spectroscopic analysis and comparison with reported data. All compounds showed potent antioxidant effects against H2O2-induced oxidative damage in neuron-like PC12 cells at a low concentration of 2 µM. The antioxidant property of dictyol C (9) was associated with activation of the Nrf2/ARE signaling pathway; it also showed neuroprotective effects against cerebral ischemia-reperfusion injury (CIRI) in a rat model of transient middle cerebral artery occlusion. As such, hydroazulene diterpenes could serve as lead structures for the development of novel neuroprotective agents against CIRI.


Asunto(s)
Antioxidantes/farmacología , Diterpenos/farmacología , Fármacos Neuroprotectores/farmacología , Phaeophyceae/química , Daño por Reperfusión/tratamiento farmacológico , Animales , China , Masculino , Estructura Molecular , Estrés Oxidativo/efectos de los fármacos , Células PC12 , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos
13.
Bioorg Chem ; 114: 105080, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34225164

RESUMEN

Antioxidants with high efficacy and low toxicity have the potential to treat cerebral ischemia reperfusion injury (CIRI). Dienone monocarbonyl curcumin analogs (DMCA) capable of overcoming the instability and pharmacokinetic defects of curcumin possess notable antioxidant activity but are found to be significantly toxic. In this study, a novel skeleton of the monoenone monocarbonyl curcumin analogue sAc possessing reduced toxicity and improved stability was designed on the basis of the DMCA skeleton. Moreover, 32 sAc analogs were obtained by applying a green, simple, and economical synthetic method. Multiple sAc analogs with an antioxidant protective effect in PC12 cells were screened using an H2O2-induced oxidative stress damage model, and quantitative evaluation of structure-activity relationship (QSAR) model with regression coefficient of R2 = 0.918921 was built through random forest algorithm (RF). Among these compounds, the optimally active compound sAc15 elicited a potent protective effect on cell growth of PC12 cells by effectively eliminating ROS generation in response to oxidative stress injury by activating the Nrf2/HO-1 antioxidant signaling pathway. In addition, sAc15 exhibited good protection against CIRI in the mice middle cerebral artery occlusion (MCAO) model. In this paper, we provide a novel class of antioxidants and a potential compound for stroke treatment.


Asunto(s)
Antioxidantes/farmacología , Curcumina/farmacología , Tecnología Química Verde , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Sustancias Protectoras/farmacología , Daño por Reperfusión/tratamiento farmacológico , Animales , Antioxidantes/síntesis química , Antioxidantes/química , Células Cultivadas , Curcumina/análogos & derivados , Curcumina/química , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Infarto de la Arteria Cerebral Media/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Estructura Molecular , Estrés Oxidativo/efectos de los fármacos , Células PC12 , Sustancias Protectoras/síntesis química , Sustancias Protectoras/química , Ratas , Daño por Reperfusión/patología , Relación Estructura-Actividad
14.
Apoptosis ; 24(1-2): 74-82, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-30519834

RESUMEN

Pyroptosis is a novel manner of cell death that can be mediated by chemotherapy drugs. The awareness of pyroptosis is significantly increasing in the fields of anti-tumor research and chemotherapy drugs. Invoking the occurrence of pyroptosis is an attractive prospect for the treatment of lung cancer. Here, the compound L61H10 was obtained as a thiopyran derivative to compare its activity with curcumin. It was indicated that L61H10 exhibited good anti-tumor activity both in vitro and in vivo via the switch of apoptosis-to-pyroptosis, which was associated with the NF-κB signaling pathway. In addition, L61H10 had no obvious side effects both in vitro and in vivo. In brief, L61H10 is shown to be a potential anti-lung cancer agent and research on its anti-tumor mechanism provides new information for chemotherapy drug research.


Asunto(s)
Apoptosis/efectos de los fármacos , Neoplasias Pulmonares/tratamiento farmacológico , Piranos/uso terapéutico , Piroptosis/efectos de los fármacos , Compuestos de Sulfhidrilo/química , Células A549 , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Apoptosis/fisiología , Línea Celular Tumoral , Femenino , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Ratones , Ratones Endogámicos BALB C , FN-kappa B/metabolismo , Piranos/química , Piranos/farmacología , Piroptosis/fisiología , Células RAW 264.7 , Transducción de Señal/efectos de los fármacos , Compuestos de Sulfhidrilo/farmacología , Compuestos de Sulfhidrilo/uso terapéutico , Pruebas de Toxicidad , Ensayos Antitumor por Modelo de Xenoinjerto
15.
J Nat Prod ; 82(6): 1714-1718, 2019 06 28.
Artículo en Inglés | MEDLINE | ID: mdl-31095383

RESUMEN

Five new diterpenes, including an unprecedented 5,5,6,6,5-pentacyclic diterpene, sponalactone (1), two new spongian diterpenes, 17- O-acetylepispongiatriol (2) and 17- O-acetylspongiatriol (3), and two new spongian diterpene artifacts, 15α,16α-dimethoxy-15,16-dihydroepispongiatriol (4) and 15α-ethoxyepispongiatriol-16(15 H)-one (5), were isolated from a South China Sea collection of the marine sponge Spongia officinalis, together with three known analogues (6-8). The structures of the new diterpenes were elucidated by extensive spectroscopic analysis. The absolute configurations were established on the basis of ECD data. Compounds 1-5 and 7 exhibited moderate inhibition against LPS-induced NO production in RAW264.7 macrophages with IC50 values of 12-32 µM.


Asunto(s)
Diterpenos/farmacología , Macrófagos/efectos de los fármacos , Poríferos/química , Animales , China , Diterpenos/química , Diterpenos/aislamiento & purificación , Espectroscopía de Resonancia Magnética , Estructura Molecular
16.
Molecules ; 24(13)2019 Jul 06.
Artículo en Inglés | MEDLINE | ID: mdl-31284561

RESUMEN

Melanoma is the leading cause of skin-cancer related deaths in North America. Metastatic melanoma is difficult to treat and chemotherapies have limited success. Furthermore, chemotherapies lead to toxic side effects due to nonselective targeting of normal cells. Curcumin is a natural product of Curcuma longa (turmeric) and has been shown to possess anti-cancer activity. However, due to its poor bioavailability and stability, natural curcumin is not an effective cancer treatment. We tested synthetic analogs of curcumin that are more stable. One of these derivatives, Compound A, has shown significant anti-cancer efficacy in colon, leukemia, and triple-negative inflammatory breast cancer cells. However, the effects of Compound A against melanoma cells have not been studied before. In this study, for the first time, we demonstrated the efficacy of Compound A for the selective induction of apoptosis in melanoma cells and its interaction with tamoxifen, taxol, and cisplatin. We found that Compound A induced apoptosis selectively in human melanoma cells by increasing oxidative stress. The anti-cancer activity of Compound A was enhanced when combined with tamoxifen and the combination treatment did not result in significant toxicity to noncancerous cells. Additionally, Compound A did not interact negatively with the anti-cancer activity of taxol and cisplatin. These results indicate that Compound A could be developed as a selective and effective melanoma treatment either alone or in combination with other non-toxic agents like tamoxifen.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Curcumina/farmacología , Interacciones Farmacológicas , Antineoplásicos Fitogénicos/síntesis química , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Cisplatino/farmacología , Curcumina/análogos & derivados , Curcumina/síntesis química , Relación Dosis-Respuesta a Droga , Humanos , Melanoma/tratamiento farmacológico , Melanoma/metabolismo , Melanoma/patología , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Estructura Molecular , Estrés Oxidativo/efectos de los fármacos , Paclitaxel/farmacología , Tamoxifeno/farmacología
18.
J Nat Prod ; 81(11): 2567-2575, 2018 11 26.
Artículo en Inglés | MEDLINE | ID: mdl-30407007

RESUMEN

Four new steroids, named 7-dehydroerectasteroid F (1), 11α-acetoxyarmatinol A (2), 22,23-didehydroarmatinol A (3), and 3-O-acetylhyrtiosterol (4), together with 11 previously described analogues, were isolated from a South China Sea collection of the soft coral Dendronephthya gigantea. The structures of the new steroids were elucidated by comprehensive spectroscopic analysis and by comparison with previously reported data. Compound 1 showed potent protection against H2O2-induced oxidative damage in neuron-like PC12 cells by promoting nuclear translocation of Nrf2 and enhancing the expression of HO-1. 1 represents the first steroid-type antioxidant from marine organisms.


Asunto(s)
Antozoos/metabolismo , Antioxidantes/metabolismo , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Transducción de Señal , Esteroides/metabolismo , Animales
19.
Apoptosis ; 22(6): 852-864, 2017 06.
Artículo en Inglés | MEDLINE | ID: mdl-28315172

RESUMEN

Fibroblast growth factor receptor 1 (FGFR1), belonging to receptor tyrosine kinases (RTKs), possesses various biological functions. Over-expression of FGFR1 has been observed in multiple human malignancies. Hence, targeting FGFR1 is an attractive prospect for the advancement of cancer treatment options. Here, we present a novel small molecular FGFR1 inhibitor L16H50, which can inhibit FGFR1 kinase in an ATP-independent manner. It potently inhibits FGFR1-mediated signaling in a gastric cancer cell line, resulting in inhibition of cell growth, survival and migration. It also displays an outstanding anti-tumor activity in a gastric cancer xenograft tumor model by targeting FGFR1 signaling. These results show that L16H50 is a potent non-ATP-competitive FGFR1 inhibitor and may provide strong rationale for its evaluation in gastric cancer patients.


Asunto(s)
Adenosina Trifosfato/metabolismo , Hidrocarburos Clorados/uso terapéutico , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/antagonistas & inhibidores , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/patología , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Fase G2/efectos de los fármacos , Células HEK293 , Humanos , Hidrocarburos Clorados/química , Hidrocarburos Clorados/farmacología , Ratones , Mitosis/efectos de los fármacos , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/metabolismo , Transducción de Señal/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
20.
Bioorg Med Chem Lett ; 27(7): 1616-1619, 2017 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-28238613

RESUMEN

Novel structure compounds (WS) containing 3,4,5-trimethoxyphenyl and acyl pyrazole were designed and synthesized based combination principles. Among them, WS13 was screened out to possess desirable anti-oxidative activity in vitro. Cell survival assay and apoptosis experiment in H2O2 induced PC12 cells injury model all showed that its cytoprotection exhibited a concentration-effect manner. WS13 at 10µM could remove ROS with equal effiency to edaravone. Further, it clearly activated Nrf2 nuclear translocation and upregulated GCLC mRNA transcription and protein expression in dose-dependent manner, and its cytoprotection was reversed by GCLC protein inhibitor. In total, WS13 with further promotion can serve as Nrf2-GCLC activator in anti-oxidative therapy.


Asunto(s)
Antioxidantes/farmacología , Factor 2 Relacionado con NF-E2/metabolismo , Sustancias Protectoras/farmacología , Animales , Antioxidantes/síntesis química , Antipirina/análogos & derivados , Antipirina/farmacología , Apoptosis/efectos de los fármacos , Butionina Sulfoximina/farmacología , Edaravona , Glutamato-Cisteína Ligasa/antagonistas & inhibidores , Glutamato-Cisteína Ligasa/genética , Glutamato-Cisteína Ligasa/metabolismo , Peróxido de Hidrógeno/farmacología , Estrés Oxidativo/efectos de los fármacos , Células PC12 , Sustancias Protectoras/síntesis química , Transporte de Proteínas , ARN Mensajero/metabolismo , Ratas , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal , Regulación hacia Arriba
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