RESUMEN
1, 2, 3, 4-Tetrahydro-ß-carboline (THßC) scaffold is widespread in many natural products (NPs) and synthetic compounds which show a variety of pharmacological activities. In this article, we reviewed the design, structures and biological characteristics of reported synthetic THßC compounds, and structure and activity relationship (SAR) of them were also discussed. This work might provide a reference for subsequent drug development based on THßC.
Asunto(s)
Carbolinas/síntesis química , Analgésicos/síntesis química , Analgésicos/química , Analgésicos/farmacología , Antimaláricos/síntesis química , Antimaláricos/química , Antimaláricos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Antiprotozoarios/síntesis química , Antiprotozoarios/química , Antiprotozoarios/farmacología , Antivirales/síntesis química , Antivirales/química , Antivirales/farmacología , Carbolinas/química , Carbolinas/farmacología , Química Farmacéutica , Fungicidas Industriales/síntesis química , Fungicidas Industriales/química , Fungicidas Industriales/farmacología , Humanos , Estructura MolecularRESUMEN
EGFR and VEGFR-2 are involved in pathological disorders and the progression of different kinds of tumors, the combined blockade of EGFR and VEGFR signaling pathways appears to be an attractive approach to cancer therapy. In this work, a series of 4-anilinoquinazoline derivatives containing substituted diaryl urea or glycine methyl ester moiety were designed and identified as EGFR and VEGFR-2 dual inhibitors. Compounds 19i, 19j and 19l exhibited the most potent inhibitory activities against EGFR (IC50 = 1 nM, 78 nM and 51 nM, respectively) and VEGFR-2 (IC50 = 79 nM, 14 nM and 14 nM, respectively), they showed good antiproliferative activities as well. Molecular docking established the interaction of 19i with the DFG-out conformation of VEGFR-2, suggesting that they might be type II kinase inhibitors.
Asunto(s)
Compuestos de Anilina/farmacología , Receptores ErbB/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/síntesis química , Quinazolinas/farmacología , Urea/análogos & derivados , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Compuestos de Anilina/síntesis química , Antineoplásicos/síntesis química , Antineoplásicos/farmacocinética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Simulación del Acoplamiento Molecular , Inhibidores de Proteínas Quinasas/farmacología , Quinazolinas/síntesis química , Urea/farmacologíaRESUMEN
Both EGFR and VEGFR-2 are important targets for cancer therapy, the combined inhibition of both EGFR and VEGFR-2 signaling pathway represents a promising approach to the treatment of cancers with a synergistic effect. In this study, a series of novel 4-anilinoquinazoline-acylamino derivatives designed as EGFR and VEGFR-2 dual inhibitors were synthesized and evaluated for biological activities. Most of them exhibited interesting inhibitory potencies against EGFR and VEGFR-2 as well as good antiproliferative activities. Compounds 15a, 15b and 15e exhibited the most potent inhibitory activity against EGFR (IC50 = 0.13 µM, 0.15 µM and 0.69 µM, respectively) and VEGFR-2 (IC50 = 0.56 µM, 1.81 µM and 0.87 µM, respectively), among them, compound 15b showed the highest antiproliferative activities against three cancer cell lines (HT-29, MCF-7 and H460) with IC50 of 5.27 µM, 4.41 µM and 11.95 µM, respectively. Molecular docking established the interaction of 15a with the DFG-out conformation of VEGFR-2, suggesting that they might be type II kinase inhibitors.