RESUMEN
Natural products (NPs) have played a crucial role in the discovery and development of antitumor drugs. However, the high structural complexity of NPs generally results in unfavorable physicochemical profiles and poor drug-likeness. A powerful strategy to tackle this obstacle is the structural simplification of NPs by truncating nonessential structures. Herein, a series of tetrahydro-ß-carboline derivatives were designed by elimination of the D ring of NP evodiamine. Structure-activity relationship studies led to the discovery of compound 45, which displayed highly potent antitumor activity against all the tested cancer cell lines and excellent in vivo antitumor activity in the HCT116 xenograft model with low toxicity. Further mechanistic research indicated that compound 45 acted by dual Top1/2 inhibition and induced caspase-dependent cell apoptosis coupled with G2/M cell cycle arrest. This proof-of-concept study validated the effectiveness of structural simplification in NP-based drug development, discovered compound 45 as a potent antitumor lead compound and enriched the structure-activity relationships of evodiamine.
Asunto(s)
Antineoplásicos/uso terapéutico , Carbolinas/uso terapéutico , Neoplasias/tratamiento farmacológico , Inhibidores de Topoisomerasa I/uso terapéutico , Inhibidores de Topoisomerasa II/uso terapéutico , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Carbolinas/síntesis química , Carbolinas/farmacología , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Células HCT116 , Humanos , Masculino , Ratones Desnudos , Estructura Molecular , Prueba de Estudio Conceptual , Quinazolinas/química , Relación Estructura-Actividad , Inhibidores de Topoisomerasa I/síntesis química , Inhibidores de Topoisomerasa I/farmacología , Inhibidores de Topoisomerasa II/síntesis química , Inhibidores de Topoisomerasa II/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
In order to improve the antitumor potency of the natural product evodiamine, novel boron-containing evodiamine derivatives were designed by incorporating boronic acid and boronate as trigger units. Boronate derivative 13a could be triggered by reactive oxygen species (ROS) in the HCT116 colon cancer cell line and showed excellent antitumor activity in vitro and in vivo. It induced apoptosis in HCT116 cancer cells in a dose-dependent manner and cell growth arrest at the G2 phase.