RESUMEN
Two series of novel tricyclic oxazine and oxazepine fused quinazolines have been designed, synthesized and evaluated for their inhibitory activity against EGFR and HER2. Structure-activity relationship (SAR) of these compounds was discussed. From the SAR studies, we found that intramolecular cyclization which possessed a functional Michael acceptor group can enhance the antitumor activities. Compounds 1e and 1h were identified as lead compounds which displayed almost 3-4 times more potent inhibition of EGFR and HER2 than the approved drug lapatinib. The satisfactory physicochemical properties of these compounds were also supported by ACD labs. The results presented here will promote the development of newer dual inhibitors of EGFR and HER2.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Quinazolinas/química , Quinazolinas/farmacología , Receptor ErbB-2/antagonistas & inhibidores , Línea Celular Tumoral , Diseño de Fármacos , Receptores ErbB/antagonistas & inhibidores , Humanos , Concentración 50 Inhibidora , Relación Estructura-ActividadRESUMEN
Two series of novel tricyclic oxazine and oxazepine fused quinazolines have been designed and synthesized. The in vitro antitumor effect of the title compounds was screened on N87, A431, H1975, BT474 and Calu-3 cell lines. Compared to gefitinib and erlotinib, compounds 1a-1h were found to demonstrate more potent antitumor activities. Several derivatives could counteract EGF-induced phosphorylation of EGFR in cells, and their potency was comparable to the reference compounds. Compounds 1a-1f, 1h were chosen for further evaluation of EGFR and HER2 in vitro kinase inhibitory activity. Compounds 1c-1f, 1h effectively inhibited the in vitro kinase activity of EGFR and HER2 with similar efficacy as gefitinib and erlotinib.
Asunto(s)
Quinazolinas/química , Quinazolinas/farmacología , Línea Celular , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/metabolismo , Gefitinib , Humanos , FosforilaciónRESUMEN
Two series of novel tricyclic oxazine and oxazepine fused quinazolines have been designed and synthesized. The in vitro antitumor effect of the title compounds was screened on N87, A431, H1975, BT474 and Calu-3 cell lines. Compared to erlotinib and gefitinib, compounds 1a-1h were found to demonstrate more potent antitumor activities. Several derivatives could counteract EGF-induced phosphorylation of EGFR in cells, and their potency was comparable to the reference compounds. Compounds 1a-1h were chosen for further evaluation of EGFR and HER2 in vitro kinase inhibitory activity. Compounds 1b-1f, 1h effectively inhibited the in vitro kinase activity of EGFR and HER2 with similar efficacy as erlotinib and gefitinib.