RESUMEN
Oxidative stress is one of the causes of cardiomyopathy. In the present study, NecroXs, novel class of mitochondrial ROS/RNS scavengers, were evaluated for cardioprotection in in vitro and in vivo model, and the putative mechanism of the cardioprotection of NecroX-7 was investigated by global gene expression profiling and subsequent biochemical analysis. NecroX-7 prevented tert-butyl hydroperoxide (tBHP)-induced death of H9C2 rat cardiomyocytes at EC(50)=0.057 µM. In doxorubicin (DOX)-induced cardiomyopathy in rats, NecroX-7 significantly reduced the plasma levels of creatine kinase (CK-MB) and lactate dehydrogenase (LDH) which were increased by DOX treatment (p<0.05). Microarray analysis revealed that 21 genes differentially expressed in tBHP-treated H9C2 cells were involved in 'Production of reactive oxygen species' (p=0.022), and they were resolved by concurrent NecroX-7 treatment. Gene-to-gene networking also identified that NecroX-7 relieved cell death through Ncf1/p47phox and Rac2 modulation. In subsequent biochemical analysis, NecroX-7 inhibited NADPH oxidase (NOX) activity by 53.3% (p<0.001). These findings demonstrate that NecroX-7, in part, provides substantial protection of cardiomyopathy induced by tBHP or DOX via NOX-mediated cell death.
Asunto(s)
Cardiomiopatías/prevención & control , Depuradores de Radicales Libres/farmacología , NADPH Oxidasas/antagonistas & inhibidores , Compuestos Orgánicos/farmacología , Estrés Oxidativo/efectos de los fármacos , Animales , Cardiomiopatías/inducido químicamente , Cardiomiopatías/enzimología , Cardiotónicos/farmacología , Línea Celular , Creatina Quinasa/sangre , Doxorrubicina/farmacología , L-Lactato Deshidrogenasa/sangre , Masculino , Análisis por Micromatrices , Miocitos Cardíacos/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Reacción en Cadena en Tiempo Real de la Polimerasa , terc-Butilhidroperóxido/antagonistas & inhibidoresRESUMEN
We describe synthesis and evaluation of a series of cyclic urea derivatives with hydroxylethylamine isostere. Modification of P3, P1, and P2' and combination of SAR display a >100-fold increase in potency with good cellular activity (IC(50)=0.15microM) relative to the previously reported compound 3.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Etilaminas/farmacología , Inhibidores de Proteasas/farmacología , Urea/farmacología , Línea Celular , Cristalografía por Rayos X , Ciclización , Etilaminas/síntesis química , Humanos , Hidroxilación , Concentración 50 Inhibidora , Inhibidores de Proteasas/síntesis química , Relación Estructura-Actividad , Urea/análogos & derivados , Urea/síntesis químicaRESUMEN
Chiral secondary alcohols may be prepared from primary alcohols via asymmetric C-H insertion reactions of alpha'-alkoxy-alpha-diazoketones catalyzed by rhodium(II)(2R,3R)-3-phenylcholestane-2-carboxylate.
RESUMEN
Mitochondrial reactive oxygen species and reactive nitrogen species are proven to be major sources of oxidative stress in the cell; they play a prominent role in a wide range of human disorders resulting from nonapoptotic cell death. The aim of this study is to examine the cytoprotective effect of the NecroX series against harmful stresses, including pro-oxidant (tertiarybutylhydroperoxide), doxorubicin, CCl4, and hypoxic injury. In this study, these novel chemical molecules inhibited caspase-independent cell death with necrotic morphology, which is distinctly different from apoptosis, autophagy, and necroptosis. In addition, they displayed strong mitochondrial reactive oxygen species and ONOOâ» scavenging activity. Further, oral administration of these molecules in C57BL/6 mice attenuated streptozotocin-induced pancreatic islet ß-cell destruction as well as CCl4-induced hepatotoxicity in vivo. Taken together, these results demonstrate that the NecroX series are involved in the blockade of nonapoptotic cell death against mitochondrial oxidative stresses. Thus, these chemical molecules are potential therapeutic agents in mitochondria-related human diseases involving necrotic tissue injury.
Asunto(s)
Antioxidantes/farmacología , Depuradores de Radicales Libres/farmacología , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Especies de Nitrógeno Reactivo/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Animales , Apoptosis/efectos de los fármacos , Caspasas/metabolismo , Citoprotección , Humanos , Células LLC-PK1 , Masculino , Ratones , Ratones Endogámicos ICR , Necrosis , Estrés Oxidativo , Ratas , Ratas Sprague-Dawley , PorcinosRESUMEN
Homolasonolide A and 10-desmethyllasonolide A are biologically less active than lasonolide A. The ethyl ester analogue of lasonolide A exhibited higher activity than the parent compound in some biological test.
Asunto(s)
Macrólidos/síntesis química , Macrólidos/farmacología , División Celular/efectos de los fármacos , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Macrólidos/química , EstereoisomerismoRESUMEN
The proposed structure of lasonolide A was synthesized employing radical cyclization reactions of beta-alkoxyacrylates for preparation of the tetrahydropyranyl units A and B, but the spectroscopic data did not match those of the natural product. Both enantiomers of a revised structure featuring 17E,25Z double bonds were synthesized, and the (-)-isomer was found to be the biologically active enantiomer.