RESUMEN
Focal adhesion kinase (FAK) is an important drug target that plays a fundamental role in mediating signal transduction system. We report herein the discovery of a novel class of 1,3,4-oxadiazole-2(3H)-thione derivatives containing piperazine skeleton with improved potency toward FAK. All of the 17 new synthesized compounds were assayed for the anticancer activities against four cancer cells, HepG2, Hela, SW116 and BGC823. Because of the combination of 1,4-benzodioxan, 1,3,4-oxadiazole and piperazine ring, most of them exhibited remarkable antitumor activities. Notably, compound 5m showed the most potent biological activities (IC50=5.78µM for HepG2, and IC50=47.15µM for SW1116), and its anti-FAK inhibitory activity (IC50=0.78µM) was also the best. Computational docking studies also showed that compound 5m has interaction with FAK key residues in the active site.
Asunto(s)
Dioxanos/farmacología , Quinasa 1 de Adhesión Focal/antagonistas & inhibidores , Oxadiazoles/farmacología , Piperazinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Tionas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Dioxanos/síntesis química , Dioxanos/química , Pruebas de Enzimas , Humanos , Simulación del Acoplamiento Molecular , Oxadiazoles/síntesis química , Oxadiazoles/química , Piperazinas/síntesis química , Piperazinas/química , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Relación Estructura-Actividad , Tionas/síntesis química , Tionas/químicaRESUMEN
Cyclooxygenase-2 is frequently overexpression in malignant tumors and the product PGE2 promotes cancer cell progression and metastasis. We designed novel series of coumarin sulfonamides derivatives to improve biological activities of COX-2 inhibition and anticancer. Among them, compound 7t showed most powerful selective inhibitory and antiproliferative activity (IC50=0.09µM for COX-2, IC50=48.20µM for COX-1, IC50=0.36µM against HeLa cells), comparable to the control positive compound Celecoxib (0.31µM, 43.37µM, 7.79µM). Cancer cell apoptosis assay were performed and results indicated that compound 7t effectively fuels HeLa cells apoptosis in a dose and time-dependent manner. Moreover, 7t could significantly suppress cancer cell adhesion, migration and invasion which were essential process of cancer metastasis. Docking simulations results was further indicated that compound 7t could bind well to the COX-2 active site and guided a reasonable design of selective COX-2 inhibitor with anticancer activities in future.
Asunto(s)
Cumarinas/farmacología , Inhibidores de la Ciclooxigenasa 2/farmacología , Ciclooxigenasa 2/metabolismo , Sulfonamidas/farmacología , Apoptosis/efectos de los fármacos , Adhesión Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cumarinas/síntesis química , Cumarinas/química , Inhibidores de la Ciclooxigenasa 2/síntesis química , Inhibidores de la Ciclooxigenasa 2/química , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/químicaRESUMEN
New series of sulfonamide derivatives containing a dihydropyrazole moieties inhibitors of MMP-2/MMP-9 were discovered using structure-based drug design. Synthesis, antitumor activity, structure-activity relationship and optimization of physicochemical properties were described. In vitro the bioassay results revealed that most target compounds showed potent inhibitory activity in the enzymatic and cellular assays. Among the compounds, compound 3i exhibited the most potent inhibitory activity with IC50 values of 0.21 µM inhibiting MMP-2 and 1.87 µM inhibiting MMP-9, comparable to the control positive compound CMT-1 (1.26 µM, 2.52 µM). Docking simulation was performed to position compound 3i into the MMP-2 active site to determine the probable binding pose. Docking simulation was further performed to position compound 3i into the MMP-2 active site to determine the probable binding model the 3D-QSAR models were built for reasonable design of MMP-2/MMP-9 inhibitors at present and in future.
Asunto(s)
Antineoplásicos/farmacología , Diseño de Fármacos , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Inhibidores de la Metaloproteinasa de la Matriz/farmacología , Pirazoles/farmacología , Relación Estructura-Actividad Cuantitativa , Sulfonamidas/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 , Humanos , Inhibidores de la Metaloproteinasa de la Matriz/síntesis química , Inhibidores de la Metaloproteinasa de la Matriz/química , Simulación del Acoplamiento Molecular , Estructura Molecular , Pirazoles/química , Sulfonamidas/síntesis química , Sulfonamidas/químicaRESUMEN
Novel dihydropyrazole sulfonamide derivatives (30-56) were designed, synthesized, and evaluated for their biological activities as COX-1 and COX-2 inhibitors. In vitro biological evaluation against three human tumor cell lines revealed that most target compounds showed antiproliferative activities. Among the compounds, compound 48 exhibited the most potent and selective COX-2 inhibitor (COX-2 IC50=0.33 µM; COX-1 IC50=68.49 µM) relative to the reference drugs celecoxib (IC50=0.052 µM). Docking simulation was performed to position compound 48 into the COX-2 active site and the result showed that compound 48 could bind well at the COX-2 active site and it indicated that compound 48 could be a potent and selective COX-2 inhibitor.
Asunto(s)
Antineoplásicos/farmacología , Ciclooxigenasa 1/metabolismo , Ciclooxigenasa 2/metabolismo , Inhibidores de la Ciclooxigenasa/química , Inhibidores de la Ciclooxigenasa/farmacología , Diseño de Fármacos , Modelos Moleculares , Pirazoles/farmacología , Sulfonamidas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Inhibidores de la Ciclooxigenasa/síntesis química , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Células HeLa , Humanos , Células MCF-7 , Estructura Molecular , Pirazoles/síntesis química , Pirazoles/química , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/químicaRESUMEN
OBJECTIVE: To study the effects of anti-oncogene WWOX on cell growth of epithelial ovarian cancer,in order to find a new approach of gene therapy for ovarian cancer. METHODS: A eukaryotic expression vector containing WWOX was transfected into ovarian cancer cell line HO8910 in vitro (recombinant plasmid group), and positive cell clones were selected and amplified. Expression of WWOX protein was detected by western blot. Untransfected cell (blank contrast group) and transfected empty plasmid cell (empty plasmid group) were served as control groups. In vitro, the biology effect of WWOX on HO8910 cell was analyzed through the methyl thiazolyl tetrazolium test, transwell chamber cell invasion assay in vitro, agarose clony-formation and flow cytometry. In vivo, the cell of transfection was transplanted intraperitoneally in to BALB/c nude mice. The survival time and growth ability of nude mice were observed. RESULTS: (1) Recombinant plasmid group cell could steadily express WWOX protein, while in empty plasmid group and blank control group the expression of WWOX protein were not detected. (2) The growth rate of recombinant plasmid group cell was inhibited. (3) The agarose clony-formation rate of recombinant plasmid group (19.8%) was significantly lower than that of the empty plasmid group (54.5%) and blank control group (56.0%, P < 0.05). (4) Flow cytometry showed that (72.08 +/- 0. 39)% of cells was arrested at G0/G1 stage in recombinant plasmid group, while in empty plasmid group and blank control group G0/G1 stage cells were at (41.02 +/- 1.08)% and (39.31 +/- 0.67)% (P < 0.05). (5) In vitro invasion assay showed that invasion cell number in recombinant plasmid group (89.7 +/- 3.1) was not significantly different from that of empty plasmid group (91.2 +/- 1.3) and blank control group (91.4 +/- 1.3, P > 0.05). (6) In vivo test in nude mice showed that WWOX gene could inhibit tumor growth of the HO8910 cells. CONCLUSIONS: Tumor suppressor gene WWOX could interfere with the cell cycles of ovarian cancer cell and inhibit cell proliferation. As a new valuable tool, it promises to have application in the gene therapy of ovarian cancer.