RESUMEN
The synthesis and optimization of a series of orally bioavailable 1-(1H-indol-4-yl)-3,5-disubstituted benzene analogues as antimitotic agents are described. A functionalized dibromobenzene intermediate was used as a key scaffold, which when modified by sequential Suzuki coupling and Buchwald-Hartwig amination provided a flexible entry to 1,3,5-trisubstituted phenyl compounds. A 1H-indol-4-yl moiety at the 1-position was determined to be a critical feature for optimal potency. The compounds have been shown to induce cell cycle arrest at the G2/M phase and demonstrate efficacy in both cell viability and cell proliferation assays. The primary site of action for these agents is revealed by their colchicine competitive inhibition of tubulin polymerization, and a computational model has been developed for the association of these compounds to tubulin. An optimized lead LP-261 significantly inhibits growth of a human non-small-cell lung tumor (NCI-H522) in a mouse xenograft model.
Asunto(s)
Indoles/síntesis química , Ácidos Isonicotínicos/síntesis química , Sulfonamidas/síntesis química , Moduladores de Tubulina/síntesis química , Animales , Disponibilidad Biológica , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Colchicina/química , Ensayos de Selección de Medicamentos Antitumorales , Fase G2 , Humanos , Indoles/química , Indoles/farmacología , Ácidos Isonicotínicos/química , Ácidos Isonicotínicos/farmacología , Ratones , Ratones Desnudos , Modelos Moleculares , Trasplante de Neoplasias , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Sulfonamidas/química , Sulfonamidas/farmacología , Trasplante Heterólogo , Tubulina (Proteína)/química , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacologíaRESUMEN
Two new classes of diphenylether inhibitors of p38alpha MAP kinase are described. Both chemical classes are based on a common diphenylether core that is identified by simulated fragment annealing as one of the most favored chemotypes within a prominent hydrophobic pocket of the p38alpha ATP-binding site. In the fully elaborated molecules, the diphenylether moiety acts as an anchor occupying the deep pocket, while polar extensions make specific interactions with either the adenine binding site or the phosphate binding site of ATP. The synthesis, crystallographic analysis, and biological activity of these p38alpha inhibitors are discussed.