RESUMEN
Naturally occurring pterostilbene (PTER) and isothiocyanate (ITC) attract great attention due to their wide range of biological properties, including anti-cancer, anti-leukemic, anti-bacterial and anti-inflammatory activities. A novel class of hybrid compound synthesized by introducing an ITC moiety on PTER backbone was evaluated for its anti-cancer efficacy in hormone-dependent breast cancer cell line (MCF-7) in vitro and Ehrlich ascitic tumor bearing mice model in vivo. The novel hybrid molecule showed significant in vitro anti-cancer activity (IC50=25 ± 0.38) when compared to reference compound PTER (IC50=65 ± 0.42). The conjugate molecule induced both S and G2/M phase cell cycle arrest as indicated by flow cytometry analysis. In addition, the conjugate induced cell death was characterized by changes in cell morphology, DNA fragmentation, activation of caspase-9, release of cytochrome-c into cytosol and increased Bax: Bcl-2 ratio. The conjugate also suppressed the phosphorylation of Akt and ERK. The conjugate induced cell death was significantly increased in presence of A6730 (a potent Akt1/2 kinase inhibitor) and PD98059 (a specific ERK inhibitor). Moreover, the conjugated PTER inhibited tumor growth in Ehrlich ascitic cell induced tumor bearing mice as observed by reduction in tumor volume compared to untreated animals. Collectively, the pro-apoptotic effect of conjugate is mediated through the activation of caspases, and is correlated with the blockade of the Akt and ERK signaling pathways in MCF-7 cells.
Asunto(s)
Carcinoma de Ehrlich/patología , Proliferación Celular/efectos de los fármacos , Isotiocianatos/farmacología , Estilbenos/farmacología , Animales , Regulación hacia Abajo/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Femenino , Células Hep G2 , Humanos , Isotiocianatos/química , Células MCF-7 , Masculino , Ratones , Estilbenos/química , Carga Tumoral/efectos de los fármacos , Células Tumorales CultivadasRESUMEN
A simple and efficient method for the synthesis of p-quinone monoimide ketals and p-benzoquinone monoketals by using a hypervalent iodine reagent, diacetoxyiodobenzene, has been developed. These two types of ketals are achieved from a single starting material by varying the reaction conditions.
Asunto(s)
Benzoquinonas/química , Carbamatos/síntesis química , Iminas/química , Yodo/química , Cetonas/química , Estructura Molecular , Oxidación-ReducciónRESUMEN
This study shows the effect of pterostilbene on intracellular neutral lipid accumulation in MCF-7 breast cancer cells leading to growth arrest and autophagy. On exposing the breast cancer cells with 30 µM pterostilbene for 72 h there was almost 2-folds increase in neutral lipids and triglycerides. Also the phytochemical caused a 4-folds increase in the expression of adipogenic differentiation marker c/EBPα. Further, pterostilbene inhibited 3ß-hydroxylsterol-Δ(7)-reductase, the enzyme which catalyzes the last step conversion of 7-dehydrocholesterol to cholesterol, and thereby causes the intracellular accumulation of the former sterol. These results were associated with over-expression of oxysterol binding protein homologue and liver X receptor (LXR) by ~7-folds. Pterostilbene also caused a simultaneous increase in the expression autophagic marker proteins Beclin 1 and LC3 II (microtubule-associated protein 1 light chain 3) by approximately 6-folds, which leads to an alternative pathway of autophagy. These effects were observed in association with the loss of mitotic and metastatic potential of MCF-7 cells which was abolished in the presence of catalase (ROS scavenger) or 3MA (autophagic inhibitor). Thus the present data shows that the long term exposure to pterostilbene causes growth arrest in MCF-7 cells which may be due to differentiation of the mammary carcinoma cells into normal epithelial cell like morphology and activation of autophagy.
Asunto(s)
Autofagia/efectos de los fármacos , Neoplasias de la Mama/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Estilbenos/farmacología , Proteínas Reguladoras de la Apoptosis/agonistas , Proteínas Reguladoras de la Apoptosis/genética , Beclina-1 , Biomarcadores/metabolismo , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Proteínas Potenciadoras de Unión a CCAAT/agonistas , Proteínas Potenciadoras de Unión a CCAAT/genética , Diferenciación Celular/efectos de los fármacos , Línea Celular Tumoral , Deshidrocolesteroles/antagonistas & inhibidores , Deshidrocolesteroles/metabolismo , Femenino , Humanos , Receptores X del Hígado , Proteínas de la Membrana/agonistas , Proteínas de la Membrana/genética , Proteínas Asociadas a Microtúbulos/agonistas , Proteínas Asociadas a Microtúbulos/genética , Receptores Nucleares Huérfanos/agonistas , Receptores Nucleares Huérfanos/genética , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/antagonistas & inhibidores , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/genética , Especies Reactivas de Oxígeno/metabolismo , Receptores de Esteroides/agonistas , Receptores de Esteroides/genética , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Triglicéridos/biosíntesisRESUMEN
Highly reactive o-benzoquinone monoimines were chemically generated and successfully trapped with electron-rich olefins that led to the synthesis of hitherto unknown 1,4-benzoxazine derivatives. This unprecedented transformation was achieved by the oxidation of o-aminophenols bearing appropriate functionality on the arene residue with less expensive hypervalent iodine reagent in the presence of vinylic ethers or thioethers.
