Synthesis of novel tricyclic chromenone-based inhibitors of IRE-1 RNase activity.
J Med Chem
; 57(10): 4289-301, 2014 May 22.
Article
em En
| MEDLINE
| ID: mdl-24749861
ABSTRACT
Inositol-requiring enzyme 1 (IRE-1) is a kinase/RNase ER stress sensor that is activated in response to excessive accumulation of unfolded proteins, hypoxic conditions, calcium imbalance, and other stress stimuli. Activation of IRE-1 RNase function exerts a cytoprotective effect and has been implicated in the progression of cancer via increased expression of the transcription factor XBP-1s. Here, we describe the synthesis and biological evaluation of novel chromenone-based covalent inhibitors of IRE-1. Preparation of a family of 8-formyltetrahydrochromeno[3,4-c]pyridines was achieved via a Duff formylation that is attended by an unusual cyclization reaction. Biological evaluation in vitro and in whole cells led to the identification of 30 as a potent inhibitor of IRE-1 RNase activity and XBP-1s expression in wild type B cells and human mantle cell lymphoma cell lines.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Cromonas
/
Proteínas Serina-Treonina Quinases
/
Inibidores de Proteínas Quinases
/
Endorribonucleases
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
J Med Chem
Assunto da revista:
QUIMICA
Ano de publicação:
2014
Tipo de documento:
Article
País de afiliação:
Estados Unidos