Design, synthesis, and biological evaluation of 4-substituted-3,4-dihydrobenzo[h]quinoline-2,5,6(1H)-triones as NQO1-directed antitumor agents

摘要

A novel series of 4-substituted-3,4-dihydrobenzo[h]quinoline-2,5,6(1H)-triones as NQO1-directed anti-tumor agents were designed, synthesized, biologically evaluated. Compounds 3n, 3o and 3j proved to be good NQO1 substrates that showed increased metabolic rates relative to that of beta-lapachone. In addition, 3n, 3o and 3j potently inhibited the growth of NQO1-rich breast cancer MCF-7 cell, liver hepatocellular HepG2 cell, and lung cancer A549 cell. In cellular mechanistic studies, the representative compound 3o triggered ROS generation depending on the NQO1 dose, and induce HepG2 cell apoptosis by the generated oxidative stress. In HepG2 xenografts mouse model, at the dose of 20 mg/kg, 3o remarkably suppressed the tumor growth without affecting the animal weights. (C) 2020 Elsevier Masson SAS. All rights reserved.