RESUMEN
High-throughput screening against the human sirtuin SIRT1 led to the discovery of a series of indoles as potent inhibitors that are selective for SIRT1 over other deacetylases and NAD-processing enzymes. The most potent compounds described herein inhibit SIRT1 with IC50 values of 60-100 nM, representing a 500-fold improvement over previously reported SIRT inhibitors. Preparation of enantiomerically pure indole derivatives allowed for their characterization in vitro and in vivo. Kinetic analyses suggest that these inhibitors bind after the release of nicotinamide from the enzyme and prevent the release of deacetylated peptide and O-acetyl-ADP-ribose, the products of enzyme-catalyzed deacetylation. These SIRT1 inhibitors are low molecular weight, cell-permeable, orally bioavailable, and metabolically stable. These compounds provide chemical tools to study the biology of SIRT1 and to explore therapeutic uses for SIRT1 inhibitors.
Asunto(s)
Carbazoles/síntesis química , Inhibidores de Histona Desacetilasas , Indoles/síntesis química , Sirtuinas/antagonistas & inhibidores , Animales , Disponibilidad Biológica , Células CHO , Carbazoles/química , Carbazoles/farmacología , Permeabilidad de la Membrana Celular , Cricetinae , Cricetulus , Estabilidad de Medicamentos , Fluorometría , Histona Desacetilasas/química , Humanos , Técnicas In Vitro , Indoles/química , Indoles/farmacología , Cinética , Ratones , Ratones Endogámicos C57BL , Microsomas Hepáticos/metabolismo , NAD/química , NAD+ Nucleosidasa/química , Niacinamida/química , Ratas , Proteínas Recombinantes/antagonistas & inhibidores , Proteínas Recombinantes/química , Sirtuina 1 , Sirtuinas/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A series of analogues of the peptide deformylase (PDF) inhibitor BB-3497 where the P3' amide bond was replaced with a ketone functionality is described. The in vitro antibacterial profiling of these compounds revealed that they demonstrate activity against pathogens associated with respiratory tract infections.