RESUMEN
Serine/threonine protein kinases Aurora A, B, and C play essential roles in cell mitosis and cytokinesis, and a number of Aurora kinase inhibitors have been evaluated in the clinic. Herein we report the synthesis and their antiproliferation of 3,5-disubstituted-2-aminopyrazines as kinases inhibitors. Amongst, 4-((3-amino-6- (3,5-dimethylisoxazol-4-yl)pyrazin-2-yl)oxy)-N-(3-chlorophenyl) benzamide (12Aj) exhibited the strongest antiproliferative activities against U38, HeLa, HepG2 and LoVo cells with IC50 values were 11.5 ± 3.2, 1.34 ± 0.23, 7.30 ± 1.56 and 1.64 ± 0.48 µM, as well as inhibited Aurora A and B with the IC50 values were 90 and 152 nM, respectively. Molecular docking studies indicated that 12Aj appeared to form stable hydrogen bonds with either Aurora A or Aurora B. Furthermore, 12Aj arrested HeLa cell cycle in G2/M phase by regulating protein levels of cyclinB1 and cdc2. In addition, the bioinformatics prediction further revealed that 12Aj possessed good drug likeness using SwissADME. These results suggested that 12Aj was worthy of future development of potent anticancer agents as pan-Aurora kinases.
Asunto(s)
Antineoplásicos/farmacología , Aurora Quinasa A/antagonistas & inhibidores , Aurora Quinasa B/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Pirazinas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Aurora Quinasa A/metabolismo , Aurora Quinasa B/metabolismo , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Pirazinas/síntesis química , Pirazinas/química , Relación Estructura-ActividadRESUMEN
A series of novel conjugates of podophyllotoxin and norcantharidin was designed using association strategy, and synthesized by coupling 4'-demethylepipodophyllotoxin with N-amino acid norcantharimides, and their cytotoxicitiy was evaluated against four human tumor cell lines (A-549, HepG2, HeLa and HCT-8) and normal human diploid fibroblast line WI-38. These compounds exhibited potent cytotoxic effects on tumor cell lines, whereas it was less toxic to WI-38 cells than anticancer drug VP-16 or its parent compound norcantharidin. Furthermore, conjugates 7a, 7c, 7f, 7j, 7k and 7l displayed excellent PP2A inhibition activity with IC50 values of 0.49-9.52 µM. The most potent compound 7l also exhibited topoisomeraseâ ¡inhibition activity. In addition, compound 7l induced cell-cycle arrest in the G2/M phase in HepG2 by regulating levels of cyclinB1 and cdc2.