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

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

  • Eur J Med Chem. 2020 Jul 15;198:112396. doi: 10.1016/j.ejmech.2020.112396.
Li-Qiang Wu 1,  Xin Ma 2,  Chong Zhang 2,  Zhao-Peng Liu 3
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, PR China; School of Pharmacy, Xinxiang Medical University, Xinxiang, 453003, PR China.
  • 2 School of Pharmacy, Xinxiang Medical University, Xinxiang, 453003, PR China.
  • 3 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, PR China. Electronic address: liuzhaop@sdu.edu.cn.
PMID: 32464425 DOI: 10.1016/j.ejmech.2020.112396
Abstract

A novel series of 4-substituted-3,4-dihydrobenzo[h]quinoline-2,5,6(1H)-triones as NQO1-directed antitumor 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 β-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.

Keywords

Antitumor; NQO1-Directed antitumor agents; β-Lapachone; δ-lactam.

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