RESUMEN
Oxadiazole derivatives were synthesized and evaluated for their ability to inhibit tubulin polymerization and to cause mitotic arrest in tumor cells. The most potent compounds inhibited tubulin polymerization at concentrations below 1 microM. Lead analogs caused mitotic arrest of A431 human epidermoid cells and cells derived from multi-drug resistant tumors (10, EC(50)=7.8 nM). Competition for the colchicine binding site and pharmacokinetic properties of selected potent compounds were also investigated and are reported herein, along with structure-activity relationships for this novel series of antimitotic agents.
Asunto(s)
Antimitóticos/síntesis química , Antimitóticos/farmacología , Oxadiazoles/química , Oxadiazoles/farmacología , Tubulina (Proteína)/química , Tubulina (Proteína)/metabolismo , Animales , Antimitóticos/química , Antimitóticos/clasificación , Biopolímeros/química , Biopolímeros/metabolismo , Línea Celular Tumoral , Humanos , Concentración 50 Inhibidora , Ratones , Estructura Molecular , Oxadiazoles/síntesis química , Oxadiazoles/clasificación , Conformación Proteica/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
A novel class of pyrimido[4,5-b]-1,4-benzoxazepines is described as inhibitors of epidermal growth factor receptor (EGFR) tyrosine kinase. Two compounds display potent EGFR inhibitory activity of less than 1 microM in cellular phosphorylation assays (IC(50) 0.47-0.69 microM) and are highly selective against a small kinase panel. Such compounds demonstrate anti-EGFR activity within a class that is different from any known EGFR inhibitor scaffolds. They also provide a basis for the design of kinase inhibitors with the desired selectivity profile.
Asunto(s)
Azepinas/síntesis química , Azepinas/farmacología , Receptores ErbB/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Adenosina Trifosfato/metabolismo , Azepinas/química , Sitios de Unión , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Humanos , Estructura Molecular , Fosforilación/efectos de los fármacos , Inhibidores de Proteínas Quinasas/química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Receptor ErbB-2/antagonistas & inhibidores , Relación Estructura-Actividad , Especificidad por SustratoRESUMEN
Novel tricyclic derivatives containing an oxazepine, thiazepine, or diazepine ring were studied for their EGFR tyrosine kinase inhibitory activity. While the oxazepines were in general more potent than thiazepines, the diazepines displayed somewhat different structure-activity relationships. Moreover, the diazepines, in contrast to the oxazepines, showed appreciable inhibitory activity against the KDR tyrosine kinase. Furthermore, both oxazepines and diazepines demonstrated significant ability to inhibit autophosphorylation of EGFR in DiFi cells (generally, IC(50) values in the single-digit micromolar to submicromolar range).