RESUMEN
A novel class of imidazopyridine derivatives was designed as PLK1 inhibitors. Extensive SAR studies supported by molecular modeling afforded a highly potent and selective compound 36. Compound 36 demonstrated good antitumor efficacy in xenograft nude rat model.
Asunto(s)
Antineoplásicos/química , Proteínas de Ciclo Celular/antagonistas & inhibidores , Imidazoles/química , Inhibidores de Proteínas Quinasas/química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Piridinas/química , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Simulación por Computador , Células HeLa , Humanos , Imidazoles/síntesis química , Imidazoles/farmacología , Modelos Químicos , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Piridinas/síntesis química , Piridinas/farmacología , Ratas , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de Xenoinjerto , Quinasa Tipo Polo 1RESUMEN
Methods for synthesis of a ring system characteristic of isoindolobenzazepine alkaloids were studied. Synthesis of lennoxamine and a formal synthesis of chelenine were accomplished in a short route via radical or Pd(0)-catalyzed cyclization as the key step. An altenative approach based on a radical migration of a cyano group or Pd(0)-catalyzed carbonylation was also developed for both alkaloids.
Asunto(s)
Alcaloides/síntesis química , Benzazepinas/síntesis química , Paladio/química , Alcaloides/química , Benzazepinas/química , Catálisis , Ciclización , Radicales Libres/síntesis química , Radicales Libres/química , Estructura Molecular , EstereoisomerismoRESUMEN
For the synthesis of protopine alkaloids, we studied a reaction sequence based on a ring enlargement of indeno[2,1-a][3]benzazepines by a singlet oxygen oxygenation, followed by conversion of an amide carbonyl group of the resultant 10-membered keto-lactam to a methylene group, which is the last step for completion of the synthesis. The key substances, indeno[2,1-a][3]benzazepines, were prepared by Bischler-Napieralski cyclization of alkoxy-substituted 1-(2-bromobenzyl)-3-benzazepin-2-ones. Steric effects of the substituents in this synthesis were examined.