RESUMEN
A series of novel indazole-based diarylurea derivatives targeting c-kit were designed by structure-based drug design. The derivatives were prepared, and their antiproliferative activities were evaluated against human colon cancer HCT-116 cell line and hepatocellular carcinoma PLC/PRF/5 cell line. The antiproliferative activities demonstrated that six of nine compounds exhibited comparable activities with sorafenib against HCT-116. The structure-activity relationship (SAR) analysis indicated that the indazole ring part tolerated different kinds of substituents, and the N position of the central pyridine ring played key roles in antiproliferative activity. The SAR and interaction mechanisms were further explored using molecular docking method. Compound 1i with N-(2-(pyrrolidin-1-yl)ethyl)-carboxamide possessed improved solubility, 596.1 ng/ml and best activities, IC50 at 1.0 µm against HCT-116, and 3.48 µm against PLC/PRF/5. It is a promising anticancer agent for further development.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Indazoles/química , Indazoles/farmacología , Urea/análogos & derivados , Urea/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Diseño Asistido por Computadora , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Células HCT116 , Humanos , Simulación del Acoplamiento Molecular , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Niacinamida/análogos & derivados , Niacinamida/farmacología , Compuestos de Fenilurea/farmacología , Proteínas Proto-Oncogénicas c-kit/metabolismo , Sorafenib , Relación Estructura-ActividadRESUMEN
New series of indazole based diarylureas were synthesized and their anticancer activity against cancer cells H460, A549, OS-RC-2, HT-29, Lovo, HepG2, Bel-7402, SGC-7901 and MDA-MB-231 were examined. These derivatives of diarylureas, except azaindazole based diarylureas 5f, 5l and 5m, showed superior or similar activity against most of these selected cancer cell lines to the reference compound sorafenib. The effect of substituents on the indazole ring was also investigated. Derivatives with trifluoromenthy or halogen substituent on the indazole ring showed higher activity against the selected cancer cell lines than sorafenib. The acute toxicity assay showed that compounds 5a, 5b and 5i possessed lower toxicity than sorafenib. Compound 5i with 4-(trifluoromenthy)-1H-indazole and 4-(trifluoromenthy) benzene moieties exhibited the most potent anticancer activity.