RESUMEN
Herein we report the synthesis and activity of a novel class of HDAC inhibitors based on 2, 3-diphenyl acrylic acid derivatives. The compounds in this series have shown to be potent HDAC inhibitors possessing significant antiproliferative activity. Further compounds in this series were subjected to metabolic stability in human liver microsomes (HLM), mouse liver microsomes (MLM), and exhibits promising stability in both. These efforts culminated with the identification of a developmental candidate (5a), which displayed desirable PK/PD relationships, significant efficacy in the xenograft models and attractive ADME profiles.
Asunto(s)
Antineoplásicos/administración & dosificación , Antineoplásicos/farmacología , Cinamatos/farmacología , Inhibidores de Histona Desacetilasas/administración & dosificación , Inhibidores de Histona Desacetilasas/farmacología , Estilbenos/administración & dosificación , Estilbenos/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto , Administración Oral , Animales , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cinamatos/administración & dosificación , Cinamatos/química , Relación Dosis-Respuesta a Droga , Inhibidores de Histona Desacetilasas/química , Histona Desacetilasas/metabolismo , Humanos , Ratones , Microsomas Hepáticos/química , Microsomas Hepáticos/metabolismo , Estructura Molecular , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/patología , Estilbenos/química , Relación Estructura-ActividadRESUMEN
Herein, we describe a one-pot protocol for the synthesis of a novel series of polycyclic triazole derivatives. Transition metal-catalyzed decarboxylative CuAAC and dehydrogenative cross coupling reactions are combined in a single flask and achieved good yields of the respective triazoles (up to 97% yield). This methodology is more convenient to produce the complex polycyclic molecules in a simple way.
RESUMEN
Herein, we report the development of highly potent HDAC inhibitors for the treatment of cancer. A series of adamantane and nor-adamantane based HDAC inhibitors were designed, synthesized and screened for the inhibitory activity of HDAC. A number of compounds exhibited GI50 of 10-100 nM in human HCT116, NCI-H460 and U251 cancer cells, in vitro. Compound 32 displays efficacy in human tumour animal xenograft model.