RESUMEN
A series of novel 1,3,4-oxadiazole thioether derivatives (compounds 9-44) were designed and synthesized as potential inhibitors of thymidylate synthase (TS) and as anticancer agents. The in vitro anticancer activities of these compounds were evaluated against three cancer cell lines by the MTT method. Among all the designed compounds, compound 18 bearing a nitro substituent exhibited more potent in vitro anticancer activities with IC50 values of 0.7±0.2, 30.0±1.2, 18.3±1.4 µM, respectively, which was superior to the positive control. In the further study, it was identified as the most potent inhibitor against two kinds of TS protein (for human TS and Escherichia coli TS, IC50 values: 0.62 and 0.47 µM, respectively) in the TS inhibition assay in vitro and the most potent antibacterial agents with MIC (minimum inhibitory concentrations) of 1.56-3.13 µg/mL against the tested four bacterial strains. Molecular docking and 3D-QSAR study supported that compound 18 can be selected as dual antitumor/antibacterial candidate in the future study.
Asunto(s)
Antiinfecciosos/química , Antiinfecciosos/farmacología , Antineoplásicos/química , Antineoplásicos/farmacología , Oxadiazoles/química , Oxadiazoles/farmacología , Timidilato Sintasa/antagonistas & inhibidores , Línea Celular Tumoral , Cristalografía por Rayos X , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Escherichia coli/efectos de los fármacos , Escherichia coli/enzimología , Humanos , Cinética , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Relación Estructura-Actividad Cuantitativa , Relación Estructura-Actividad , Termodinámica , Timidilato Sintasa/químicaRESUMEN
OBJECTIVE: To explore the ability and mechanism of insulin-like growth factor 1 (IGF-1) induced bone mesenchymal stem cells (BMSCs) differentiation into cardiomyocyte-like cells (CLCs). METHODS: BMSCs were isolated and purified in vitro. BMSCs were treated with control medium and 15 ng/ml IGF-1 for 3, 7, 14 and 21 d, respectively. The expression of Troponin-T (TNT), Troponin-I (TNI) and pIGF-1R were detected by immunocytochemistry and Western blot. In another experimental setting, BMSCs were treated with control medium and 15 ng/ml IGF-1, IGF-1 antagonist I-OMe AG538 (300 nmol/L) and 300 nmol/L I-OMe AG538 + 15 ng/ml IGF-1 for 3 to 48 h, respectively. Phosphorylation status of ERK1/2 and AKT, the two downstream mediators of mitogen-activated protein kinase (MAPK) kinase and phosphatidylinositol 3-kinase (PI3K) pathways, were detected by immunocytochemistry and Western blot. RESULTS: After 3 to 21 d exposure to IGF-1, the expression of pIGF-1R, TNT and TNI were significantly higher in IGF-1 group than those in control group, pIGF-1R peaked 14 d (all P < 0.05). After 3 and 6 h treatment, the ratio of pAKT/AKT (0.17 ± 0.03) and pERK1/2/ERK1/2 (0.06 ± 0.03) were significantly downregulated in I-OMe AG538 group compared to control group (1.00 ± 0.05) (all P < 0.05). The ratio of pAKT/AKT (1.00 ± 0.07) and pERK1/2/ERK1/2 (1.00 ± 0.09) were significantly upregulated in IGF-1 group compared to control group (0.72 ± 0.05) (all P < 0.05), but the ratio of pAKT/AKT (0.31 ± 0.10) and pERK1/2/ERK1/2 (0.39 ± 0.04) were significantly downregulated in I-OMe AG538 group compared to control group (0.63 ± 0.05) (all P < 0.05), the value of gray scale of TNT (195.06 ± 5.98) and TNI (198.32 ± 3.46) in I-OMe AG538 + IGF-1 group were significantly upregulated than that in IGF-1 group for TNT (188.70 ± 5.35) and TNI (176.10 ± 4.96) (all P < 0.05). CONCLUSIONS: IGF-1 could induce BMSCs differentiation into CLCs in vitro by activating MAPK and PI3K signaling pathways.
Asunto(s)
Células de la Médula Ósea/citología , Factor I del Crecimiento Similar a la Insulina/farmacología , Células Madre Mesenquimatosas/citología , Animales , Células de la Médula Ósea/metabolismo , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Masculino , Células Madre Mesenquimatosas/metabolismo , Miocitos Cardíacos/citología , Ratas , Ratas Sprague-Dawley , Transducción de SeñalRESUMEN
A series of N,1,3-triphenyl-1H-pyrazole-4-carboxamide derivatives have been designed, synthesized and evaluated for their potential antiproliferation activity and Aurora-A kinase inhibitory activity. Among all the compounds, compound 10e possessed the most potent biological activity against HCT116 and MCF-7 cell lines with IC(50) values of 0.39±0.06µM and 0.46±0.04 µM, respectively, which were comparable to the positive control. Compound 10e also exhibited significant Aurora-A kinase inhibitory activity (IC(50)=0.16±0.03 µM). Docking simulation was performed to position compound 10e into the active site of Aurora-A kinase, in order to get the probable binding model for further study. The results of Western-blot assay demonstrated that compound 10e possessed good Aurora-A kinase inhibitory activity against HCT116. Based on the preliminary results, it is deduced that compound 10e with potent Aurora-A kinase inhibitory activity may be a potential anticancer agent.
Asunto(s)
Amidas/química , Antineoplásicos/síntesis química , Pirazoles/química , Pirazoles/síntesis química , Amidas/síntesis química , Amidas/farmacología , Antineoplásicos/química , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Aurora Quinasas , Sitios de Unión , Línea Celular Tumoral , Simulación por Computador , Células HCT116 , Humanos , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/metabolismo , Estructura Terciaria de Proteína , Pirazoles/farmacologíaRESUMEN
It had been reported that some dioxygenated rings fusing with the quinazoline scaffold could lead to new EGFR inhibitors. Based on this, several kinds of oxygenated alkane quinazoline derivatives were synthetized and evaluated as EGFR inhibitors. Their antiproliferative activities were tested against four cancer cell lines: A431, MCF-7, A549, and B16-F10. Most derivatives could counteract EGF-induced EGFR phosphorylation, and their potency was comparable to the reference compound Erlotinib. The size of the fused dioxygenated ring was crucial for the biological activity and the heptatomic ring derivative 19 showed potent in vitro inhibitory activity in the enzymatic assay as well as in the cellular assay.
Asunto(s)
Antineoplásicos/farmacología , Descubrimiento de Drogas , Receptores ErbB/antagonistas & inhibidores , Oxígeno/química , Inhibidores de Proteínas Quinasas/farmacología , Quinazolinas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Receptores ErbB/metabolismo , Humanos , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Quinazolinas/síntesis química , Quinazolinas/química , Relación Estructura-ActividadRESUMEN
A series of sulfur-containing heterocyclic pyrazoline derivatives (C1-C18; D1-D9) have been synthesized and purified (all are new except one) to be screened for FabH inhibitory activity. Compound C14 showed the most potent biological activity against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus and Bacillus subtilis (MIC values: 1.56-3.13 µg/mL), being comparable with the positive control, while D6 performed the best in the thiazolidinone series (MIC values: 3.13-6.25 µg/mL). They also demonstrated strong broad-spectrum antimicrobial activity. Compounds C14 and D6 exhibited the most potent E. coli FabH inhibitory activity with IC(50) of 4.6 and 8.4 µM, respectively, comparable with the positive control DDCP (IC(50)=2.8 µM). Docking simulation was performed to position compound C14 and D6 into the E. coli FabH structure active site to determine the probable binding model. The structurally modification of previous compounds and the attempt in innovative target have brought a positive progress.
Asunto(s)
3-Oxoacil-(Proteína Transportadora de Acil) Sintasa/antagonistas & inhibidores , Inhibidores Enzimáticos/química , Compuestos Heterocíclicos/química , Pirazoles/química , Compuestos de Azufre/química , Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Compuestos Heterocíclicos/farmacología , Enlace de Hidrógeno , Viabilidad Microbiana/efectos de los fármacos , Modelos Moleculares , Estructura Molecular , Pirazoles/farmacología , Relación Estructura-Actividad , Compuestos de Azufre/farmacologíaRESUMEN
A series of dihydro-pyrazolyl-thiazolinone derivatives (5a-5t) have been synthesized and their biological activities were also evaluated as potential cyclooxygenase-2 (COX-2) inhibitors. Among these compounds, compound 2-(3-(3,4-dimethylphenyl)-5-phenyl-4,5-dihydro-1H-pyrazol-1-yl)thiazol-4(5H)-one (5a) displayed the most potent COX-2 inhibitory activity with IC(50) of 0.5µM, but weak to COX-1. Docking simulation was performed to position compound 5a into the COX-2 active site to determine the probable binding model. Based on the preliminary results, compound 5a with potent inhibitory activity and low toxicity would be a potential and selective anti-cyclooxygenase-2 agent.
Asunto(s)
Inhibidores de la Ciclooxigenasa 2/síntesis química , Ciclooxigenasa 2/química , Pirazoles/síntesis química , Tiazoles/química , Animales , Sitios de Unión , Dominio Catalítico , Línea Celular , Supervivencia Celular/efectos de los fármacos , Ciclooxigenasa 2/metabolismo , Inhibidores de la Ciclooxigenasa 2/química , Inhibidores de la Ciclooxigenasa 2/toxicidad , Ratones , Simulación del Acoplamiento Molecular , Pirazoles/química , Pirazoles/toxicidad , Tiazoles/síntesis química , Tiazoles/toxicidadRESUMEN
In present study, a series of novel 1,3,4-oxadiazole derivatives have been designed, synthesized and purified. All of these compounds are reported for the first time, the chemical structures of these compounds were confirmed by means of (1)H NMR, ESI-MS and elemental analyses. Besides, we evaluated their immunosuppressive activity. Most of these synthesized compounds were proved to have potent immunosuppressive activity and low toxicity. Among them, the bioassay results demonstrated that compounds 5c, 5n, 5p, 5o, 6f and 6g exhibited immunosuppressive activities with IC(50) concentration range from 1.25µM to 7.60 µM against the T cells, and the IC(50) of positive control (csa) is 2.12 µM. Moreover, all the title compounds were assayed for PI3K/AKT signaling pathway inhibition using the ELISA assay. We examined the compounds with potent inhibitory activities against IL-1, IL-6 and IL-10 released in ConA-simulated mouse lymph node cells. The results showed compounds 5o and 6f displayed the most potential biological activity against T cells (IC(50)=1.25 µM and 4.75 µM for T cells). The preliminary mechanism of compound 5o inhibition effects was also detected by flow cytometry (FCM). The results of apoptosis and ELISA assay demonstrated that the immunosuppressive activity of compounds 5o and 6f against T cells may be mediated by the inhibition of PI3Kγ/AKT signaling pathway. Molecular docking was performed to position compounds 5o and 6f into PI3Kγ binding site in order to indicate the potential target.
Asunto(s)
Diseño de Fármacos , Inmunosupresores/síntesis química , Simulación de Dinámica Molecular , Oxadiazoles/química , Fenoles/síntesis química , Ácido Vanílico/química , Animales , Apoptosis/efectos de los fármacos , Sitios de Unión , Inmunosupresores/farmacología , Inmunosupresores/toxicidad , Interleucina-1/metabolismo , Interleucina-10/metabolismo , Interleucina-6/metabolismo , Ratones , Oxadiazoles/síntesis química , Oxadiazoles/farmacología , Oxadiazoles/toxicidad , Fenoles/farmacología , Fenoles/toxicidad , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3 , Estructura Terciaria de Proteína , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos , Relación Estructura-Actividad , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunologíaRESUMEN
Nitroimidazoles and their derivatives have drawn continuing interest over the years because of their varied biological activities, recently found application in drug development for antimicrobial chemotherapeutics and antiangiogenic hypoxic cell radiosensitizers. In order to search for novel antibacterial agents, we designed and synthesized a series of secnidazole analogs based on oxadiazole scaffold (4-21). Among these compounds, 4 and 7-21 were reported for the first time. These compounds were tested for antibacterial activities against Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis and Staphylococcus aureus. This new nitroimidazole derivatives class demonstrated strong antibacterial activities. Escherichia coli ß-ketoacyl-acyl carrier protein synthase III (FabH) inhibitory assay and docking simulation indicated that the compounds 2-(2-methoxyphenyl)-5-((2-methyl-5-nitro-1H-imidazol-1-yl)methyl)-1,3,4-oxadiazole (11) with MIC of 1.56-3.13 µg/mL against the tested bacterial strains and 2-((2-methyl-5-nitro-1H-imidazol-1-yl)methyl)-5-(2-methylbenzyl)-1,3,4-oxadiazole (12) with MIC of 1.56-6.25 µg/mL were most potent inhibitors of Escherichia coli FabH.
Asunto(s)
Acetiltransferasas/antagonistas & inhibidores , Antiinfecciosos/síntesis química , Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Proteínas de Escherichia coli/antagonistas & inhibidores , Nitroimidazoles/química , Oxadiazoles/química , 3-Oxoacil-(Proteína Transportadora de Acil) Sintasa , Acetiltransferasas/metabolismo , Antiinfecciosos/química , Antiinfecciosos/farmacología , Sitios de Unión , Simulación por Computador , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Escherichia coli/efectos de los fármacos , Escherichia coli/metabolismo , Proteínas de Escherichia coli/metabolismo , Acido Graso Sintasa Tipo II/antagonistas & inhibidores , Acido Graso Sintasa Tipo II/metabolismo , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Nitroimidazoles/síntesis química , Nitroimidazoles/farmacología , Estructura Terciaria de Proteína , Relación Estructura-ActividadRESUMEN
In present study, a series of 3-(1,3-diphenyl-1H-pyrazol-4-yl)-N-phenylacrylamide derivatives (5a-8d) were designed, synthesized, and evaluated for HDAC inhibition and tumor cell antiproliferation. All of these compounds are reported for the first time, the chemical structures of these compounds were confirmed by means of (1)H NMR, ESI-MS and elemental analyzes. Among the compounds, compound 8c showed the most potent biological activity against HCT116 cancer cell line (IC(50) of 0.42 ± 0.02 µM for HDAC-1 and IC(50)=0.62 ± 0.02 for HCT116). Docking simulation was performed to position compound 8c into the HDAC active site to determine the probable binding model. The results of antiproliferative assay and western-blot demonstrated that compound 8c with potent inhibitory activity in tumor growth inhibition may be a potential anticancer agent against HCT116 cancer cell.
Asunto(s)
Acrilamidas/química , Antineoplásicos/síntesis química , Inhibidores de Histona Desacetilasas/síntesis química , Histona Desacetilasas/química , Pirazoles/química , Acrilamidas/síntesis química , Acrilamidas/toxicidad , Antineoplásicos/química , Antineoplásicos/toxicidad , Sitios de Unión , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Simulación por Computador , Ensayos de Selección de Medicamentos Antitumorales , Células HCT116 , Inhibidores de Histona Desacetilasas/química , Inhibidores de Histona Desacetilasas/toxicidad , Histona Desacetilasas/metabolismo , Humanos , Estructura Terciaria de Proteína , Pirazoles/síntesis química , Pirazoles/toxicidad , Relación Estructura-ActividadRESUMEN
A series of 2,6-dinitro-4-(trifluoromethyl)phenoxysalicylaldoxime derivatives (1h-20h) have been designed and synthesized, and their biological activities were also evaluated as potential antiproliferation and tubulin polymerization inhibitors. Among all the compounds, 2h showed the most potent activity in vitro, which inhibited the growth of MCF-7, Hep-G2 and A549 cell lines with IC(50) values of 0.70 ± 0.05, 0.68 ± 0.02 and 0.86 ± 0.05 µM, respectively. Compound 2h also exhibited significant tubulin polymerization inhibitory activity (IC(50)=3.06 ± 0.05 µM). The result of flow cytometry (FCM) demonstrated that compound 2h induced cell apoptosis. Docking simulation was performed to insert compound 2h into the crystal structure of tubulin at colchicine binding site to determine the probable binding model. Based on the preliminary results, compound 2h with potent inhibitory activity in tumor growth may be a potential anticancer agent.
Asunto(s)
Flúor/química , Oximas , Moduladores de Tubulina , Apoptosis/efectos de los fármacos , Sitios de Unión , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Simulación por Computador , Ensayos de Selección de Medicamentos Antitumorales , Citometría de Flujo , Humanos , Concentración 50 Inhibidora , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Estructura Molecular , Oximas/síntesis química , Oximas/química , Oximas/farmacología , Polimerizacion/efectos de los fármacos , Relación Estructura-Actividad , Moduladores de Tubulina/síntesis química , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacologíaRESUMEN
A series of novel 4,5-dihydropyrazole derivatives containing niacinamide moiety as potential V600E mutant BRAF kinase (BRAF(V600E)) inhibitors were designed and synthesized. Results of the bioassays against BRAF(V600E) and WM266.4 human melanoma cell line showed several compounds to be endowed potent activities with IC(50) and GI(50) value in low micromolar range, among which compound 27e, (5-(4-Chlorophenyl)-3-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl)6-methylpyridin-3-yl methanone (IC(50)=0.20 µM, GI(50)=0.89 µM) was bearing the best bioactivity comparable with the positive control Sorafenib. Docking simulation was performed to determine the probable binding model and 3D-QSAR model was built to provide more pharmacophore understanding that could use to design new agents with more potent BRAF(V600E) inhibitory activity.
Asunto(s)
Niacinamida/farmacología , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Relación Estructura-Actividad Cuantitativa , Animales , Proliferación Celular/efectos de los fármacos , Diseño de Fármacos , Humanos , Ratones , Modelos Moleculares , Niacinamida/química , Inhibidores de Proteínas Quinasas/química , Proteínas Proto-Oncogénicas B-raf/metabolismo , Ratas , Células Tumorales CultivadasRESUMEN
A series of 1,3,4-oxadiazole derivatives derived from 4-methoxysalicylic acid or 4-methylsalicylic acid (6a-6z) have been first synthesized for their potential immunosuppressive activity. Among them, compound 6z displayed the most potent biological activity against lymph node cells (inhibition=38.76% for lymph node cells and IC(50)=0.31 µM for PI3Kγ). The preliminary mechanism of compound 6z inhibition effects was also detected by flow cytometry (FCM) and the compound exerted immunosuppressive activity via inducing the apoptosis of activated lymph node cells in a dose dependent manner. Docking simulation was performed to position compound 6z into the PI3Kγ structure active site to determine the probable binding model.
Asunto(s)
Inmunosupresores , Oxadiazoles , Animales , Apoptosis/efectos de los fármacos , Dominio Catalítico , Proliferación Celular/efectos de los fármacos , Citometría de Flujo , Inmunosupresores/síntesis química , Inmunosupresores/química , Inmunosupresores/farmacología , Concentración 50 Inhibidora , Ratones , Ratones Endogámicos BALB C , Modelos Moleculares , Oxadiazoles/síntesis química , Oxadiazoles/química , Oxadiazoles/farmacología , Linfocitos T/efectos de los fármacosRESUMEN
In present study, a series of new 2-(1,3,4-oxadiazol-2-ylthio)-1-phenylethanone derivatives (6a-6x) as potential focal adhesion kinase (FAK) inhibitors were synthesized. The bioassay assays demonstrated that compound 6i showed the most potent activity, which inhibited the growth of MCF-7 and A431 cell lines with IC(50) values of 140 ± 10 nM and 10 ± 1 nM, respectively. Compound 6i also exhibited significant FAK inhibitory activity (IC(50)=20 ± 1 nM). Docking simulation was performed to position compound 6i into the active site of FAK to determine the probable binding model.
Asunto(s)
Acetofenonas/química , Proteína-Tirosina Quinasas de Adhesión Focal/antagonistas & inhibidores , Modelos Moleculares , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Acetofenonas/farmacología , Animales , Apoptosis/efectos de los fármacos , Dominio Catalítico , Bovinos , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Proteína-Tirosina Quinasas de Adhesión Focal/metabolismo , Humanos , Concentración 50 Inhibidora , Inhibidores de Proteínas Quinasas/síntesis química , Relación Estructura-ActividadRESUMEN
A series of novel chalcone derivatives have been designed and synthesized, and their biological activities were also evaluated as potential inhibitors of tubulin. These compounds were assayed for growth-inhibitory activity against MCF-7 and A549 cell lines in vitro. Compound 3d showed the most potent antiproliferative activity against MCF-7 and A549 cell lines with IC(50) values of 0.03 and 0.95 µg/mL and exhibited the most potent tubulin inhibitory activity with IC(50) of 1.42 µg/mL. Docking simulation was performed to insert compound 3d into the crystal structure of tubulin at colchicines binding site to determine the probable binding model. Based on the preliminary results, compound 3d with potent inhibitory activity in tumor growth may be a potential anticancer agent.
Asunto(s)
Chalcona/síntesis química , Chalcona/farmacología , Diseño de Fármacos , Moduladores de Tubulina/síntesis química , Moduladores de Tubulina/farmacología , Neoplasias de la Mama , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Chalcona/análogos & derivados , Chalcona/química , Femenino , Humanos , Concentración 50 Inhibidora , Modelos Moleculares , Moduladores de Tubulina/químicaRESUMEN
A series of 1,3,4-thiadiazol-2-amide derivatives (5a-5y) have been designed and synthesized, and their biological activities were also evaluated as potential antiproliferation and FAK inhibitors. Among all the compounds, 5h showed the most potent activity in vitro, which inhibited the growth of MCF-7 and B16-F10 cell lines with IC(50) values of 0.45 and 0.31 µM, respectively. Compound 5h also exhibited significant FAK inhibitory activity (IC(50)=5.32 µM). Docking simulation was performed to position compound 5h into the FAK structure active site to determine the probable binding model. The results of antiproliferative and Western-blot assay demonstrated that compound 5h possessed good antiproliferative activity. Therefore, compound 5h with potent FAK inhibitory activity may be a potential anticancer agent.
Asunto(s)
Amidas/química , Antineoplásicos/síntesis química , Inhibidores de Proteínas Quinasas/síntesis química , Tiadiazoles/química , Amidas/síntesis química , Amidas/farmacología , Antineoplásicos/química , Antineoplásicos/farmacología , Sitios de Unión , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Simulación por Computador , Ensayos de Selección de Medicamentos Antitumorales , Quinasa 1 de Adhesión Focal/antagonistas & inhibidores , Quinasa 1 de Adhesión Focal/metabolismo , Humanos , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Estructura Terciaria de Proteína , Relación Estructura-ActividadRESUMEN
A series of novel 4,5-dihydropyrazole derivatives (3a-3t) containing hydroxyphenyl moiety as potential V600E mutant BRAF kinase (BRAF(V600E)) inhibitors were designed and synthesized. Docking simulation was performed to insert compounds 3d (1-(5-(5-chloro-2-hydroxyphenyl)-3-(p-tolyl)-4,5-dihydro-1H-pyrazol-1-yl)ethanone) and 3m (1-(3-(4-chlorophenyl)-5-(3,5-dibromo-2-hydroxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl)ethanone) into the crystal structure of BRAF(V600E) to determine the probable binding model, respectively. Based on the preliminary results, compound 3d and 3m with potent inhibitory activity in tumor growth may be a potential anticancer agent. Results of the bioassays against BRAF(V600E), MCF-7 human breast cancer cell line and WM266.4 human melanoma cell line all showed several compounds had potent activities IC(50) value in low micromolar range, among them, compound 3d and compound 3m showed strong potent anticancer activity, which were proved by that 3d: IC(50) = 1.31 µM for MCF-7 and IC(50) = 0.45 µM for WM266.5, IC(50) = 0.22 µM for BRAF(V600E), 3m: IC(50) = 0.97 µM for MCF-7 and IC(50) = 0.72 µM for WM266.5, IC(50) = 0.46 µM for BRAF(V600E), which were comparable with the positive control Erlotinib.
Asunto(s)
Antineoplásicos/síntesis química , Clorofenoles/síntesis química , Fenoles/síntesis química , Inhibidores de Proteínas Quinasas/síntesis química , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Pirazoles/química , Pirazoles/síntesis química , Sustitución de Aminoácidos , Antineoplásicos/química , Antineoplásicos/toxicidad , Sitios de Unión , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Clorofenoles/química , Clorofenoles/toxicidad , Humanos , Células MCF-7 , Simulación del Acoplamiento Molecular , Fenoles/química , Fenoles/toxicidad , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/toxicidad , Estructura Terciaria de Proteína , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas B-raf/metabolismo , Pirazoles/toxicidad , Relación Estructura-ActividadRESUMEN
The present study is aimed to study the effect of sarcoplasmic reticulum Ca(2+)-ATPase 2a (SERCA2a) gene transfer on the contractile function of isolated cardiomyocytes of canines. The cardiomyocytes were isolated with collagenases. The isolated cardiac cells were divided into untransfected group, empty vector group and SERCA2a-transfected group. Recombinant adenovirus vector carrying enhanced green fluorescent protein gene was used for SERCA2a gene delivery. The expression of SERCA2a protein in cardiomyocytes was determined by Western blot. Contractile function of cardiomyocytes was measured with motion edge-detection system of single cell at 48 h after transfection. The results showed, compared with untransfected group, SERCA2a protein level, percentage of peak contraction amplitude under normal condition, percentages of peak contraction amplitude under Ca(2+) or isoproterenol stimulation, time-to-peak contraction (TTP) and time-to-50% relaxation (R50) in SERCA2a-transfected group all increased significantly. While all the above indices in empty vector group did not show any differences with those in untransfected group. These results suggest that the overexpression of SERCA2a by gene transfer may enhance the contraction function of canine myocardial cells.
Asunto(s)
Contracción Miocárdica/fisiología , Miocitos Cardíacos/metabolismo , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/metabolismo , Transfección , Adenoviridae/genética , Adenoviridae/metabolismo , Animales , Perros , Masculino , Contracción Miocárdica/efectos de los fármacos , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/genéticaRESUMEN
The mononuclear title complex, [Zn(C(22)H(15)O(5))(2)(C(2)H(5)OH)(2)], contains a Zn(II) atom (site symmetry ) surrounded by six O atoms of the keto groups of two substituted 1,3-diketonate ligands and of two ethanol mol-ecules, resulting in a distorted octa-hedral coordination environment. The mol-ecular configuration is stabilized by an intra-molecular hydrogen bond between the phenolic hy-droxy group and the adjacent keto group. The hy-droxy group acts likewise as an acceptor of an inter-molecular O-Hâ¯O hydrogen bond with the hy-droxy group of the ethanol mol-ecule as the donor. The hydrogen-bonding scheme leads to the formation of supra-molecular layers parallel to (010).
RESUMEN
Isoliquiritigenin (2',4',4-trihydroxychalcone, ISL) is one of the most important chalcone compounds which is mainly derived from licorice root and many other plants. It exhibits a remarkable range of potent biological and pharmacological activities such as antioxidative, antitumor, antiaging, anti-inflammatory, anti-diabetic activities, etc. Numerous research teams have demonstrated that ISL posseses the ability to carry out antigrowth and proliferation in various cancer cells in vitro and in vivo. Meanwhile, the underlying mechanisms of ISL that inhibit cancer cell proliferation have not been well explored. However, the poor bioavailability and low water-soluble limit its clinical application. This review aims at providing a comprehensive overview of the pharmacology antitumor activity of ISL and its mechanisms in different malignancy especially in breast cancer cell line and summarize developments of formulation utilized to overcome the barrier between its delivery characteristics and application in clinics over the past 20 years.
Asunto(s)
Antineoplásicos/farmacología , Chalconas/farmacología , Animales , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Chalconas/química , Composición de Medicamentos , Ensayos de Selección de Medicamentos Antitumorales , HumanosRESUMEN
In the title compound, C(17)H(13)ClF(2)O(3), a multifunctional aromatic compound, the dihedral angle between the two benzene rings is 51.8â (3)°.