RESUMEN

A phenotypic screening of thienodiazepines derived from a hit compound found through a binding assay targeting co-stimulatory molecules on T cells and antigen presenting cells successfully led to the discovery of a thienotriazolodiazepine compound (7f) possessing potent immunosuppressive activity. A chemical biology approach has succeeded in revealing that 7f is a first inhibitor of epigenetic bromodomain-containing proteins. 7f is expected to become an anti-cancer agent as well as an immunosuppressive agent.

Asunto(s)

Antineoplásicos/farmacología , Azepinas/farmacología , Antígenos CD28/metabolismo , Descubrimiento de Drogas , Inmunosupresores/farmacología , Linfocitos T/citología , Linfocitos T/efectos de los fármacos , Antineoplásicos/síntesis química , Antineoplásicos/química , Azepinas/síntesis química , Azepinas/química , Antígenos CD28/inmunología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Histona Acetiltransferasas , Chaperonas de Histonas , Humanos , Inmunosupresores/síntesis química , Inmunosupresores/química , Estructura Molecular , Proteínas Nucleares/antagonistas & inhibidores , Proteínas Nucleares/metabolismo , Fenotipo , Relación Estructura-Actividad , Linfocitos T/inmunología , Linfocitos T/metabolismo

RESUMEN

The next higher homologue of hexamethylenetetramine was synthesized as the proton cryptate H+ @1⋅Br- (shown schematically), and its X-ray structure determined. The proton trapped by the lone pairs accumulated at the center of the T-symmetric tetraaza cage could not be exchanged or removed, even after heating for three days in 3 M NaOD.