RESUMEN
IKH12 is a novel histone deacetylase 6 selective inhibitor. A rapid and sensitive liquid chromatography tandem mass spectrometry method was developed and validated for the quantification of IKH12 in rat plasma and tissue with kendine 91 as internal standard (IS). The samples were prepared by liquid-liquid extraction with tert-butyl methyl ether. The chromatographic separation was accomplished by using a Zorbax Extend C18 4.6 × 150 mm, 5 µm column, with a mobile phase consisting of methanol and 0.1% formic acid (75:25 v/v). Multiple reaction monitoring, using electrospray ionization in positive ion mode, was employed to quantitatively detect IKH12 and IS. The monitored transitions were set at m/z 418 â 252 and 444 â 169 for IKH12 and kendine 91, respectively. The calibration curve was linear over the concentration range 2-1000 ng mL(-1) . The intra- and inter-assay precision and accuracy of the quality controls and the limit of quantification were satisfactory in all cases (according to European Medicines Agency guidelines). Stability studies showed that plasma samples were stable in the chromatography rack for 24 h and at -80°C for 2 months and also after three freeze-thaw cycles. This method was successfully applied to a pharmacokinetic study of IKH12 in rat.
Asunto(s)
Antineoplásicos/sangre , Inhibidores de Histona Desacetilasas/sangre , Ácidos Hidroxámicos/sangre , Prolina/análogos & derivados , Espectrometría de Masa por Ionización de Electrospray/métodos , Animales , Cromatografía Líquida de Alta Presión/métodos , Límite de Detección , Extracción Líquido-Líquido/métodos , Masculino , Éteres Metílicos/química , Prolina/sangre , Ratas Wistar , Espectrometría de Masas en Tándem/métodosAsunto(s)
Histona Desacetilasa 6/antagonistas & inhibidores , Inhibidores de Histona Desacetilasas/farmacología , Linfoma de Células del Manto/tratamiento farmacológico , Proteínas de Neoplasias/antagonistas & inhibidores , Células A549 , Animales , Células HCT116 , Células Hep G2 , Histona Desacetilasa 6/genética , Histona Desacetilasa 6/metabolismo , Inhibidores de Histona Desacetilasas/síntesis química , Inhibidores de Histona Desacetilasas/química , Humanos , Linfoma de Células del Manto/enzimología , Linfoma de Células del Manto/genética , Linfoma de Células del Manto/metabolismo , Células MCF-7 , Ratones , Ratones SCID , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Células PC-3 , Ensayos Antitumor por Modelo de XenoinjertoAsunto(s)
Antineoplásicos/síntesis química , Integrina alfa4beta1/antagonistas & inhibidores , Neoplasias Hepáticas , Melanoma , Animales , Antineoplásicos/uso terapéutico , Cristalografía por Rayos X , Ciclización , Diseño de Fármacos , Neoplasias Hepáticas/tratamiento farmacológico , Masculino , Melanoma/tratamiento farmacológico , Melanoma/secundario , Ratones , Ratones Endogámicos C57BL , Estructura Molecular , EstereoisomerismoRESUMEN
The scope and regioselectivity of the Bischler (or Bischler-Möhlau) reaction between aromatic amines and alpha-bromoketones has been studied by computational and experimental techniques. It has been found that in many cases the reaction yields are improved under microwave irradiation and working in the absence of solvent. When di- and trisubstituted amines are used as substrates the regioselectivity of the reaction is different to that obtained with the corresponding primary anilines. The reaction between benzene-1,2-diamine and alpha-bromoacetophenones under the same conditions yields 2-substituted quinoxalines instead of indoles. Finally, when pyridin-2-amines and pyrimidine-2-amines are allowed to react with the corresponding alpha-bromoacetophenones, the corresponding imidazo[1,2-a]pyridines and imidazo[1,2-a]pyrimidines are obtained, respectively.
RESUMEN
The reaction between homophthalic anhydride and imines in the presence of TiCl4 and diisopropyl ethyl amine is trans-selective. Under these conditions, the reaction using homochiral imines can be highly diastereoselective, thus allowing the synthesis of enantiopure 1,2,3,4-tetrahydro-1-oxoquinoline-4-carboxylic acids.