2. Academic Validation
  3. 2-Substituted 3-methylnaphtho[1,2-b]furan-4,5-diones as novel L-shaped ortho-quinone substrates for NAD(P)H:quinone oxidoreductase (NQO1)

2-Substituted 3-methylnaphtho[1,2-b]furan-4,5-diones as novel L-shaped ortho-quinone substrates for NAD(P)H:quinone oxidoreductase (NQO1)

  • Eur J Med Chem. 2014 Jul 23:82:56-67. doi: 10.1016/j.ejmech.2014.05.041.
Jinlei Bian 1,  Bang Deng 1,  Lili Xu 1,  Xiaoli Xu 1,  Nan Wang 1,  Tianhan Hu 2,  Zeyu Yao 2,  Jianyao Du 2,  Li Yang 1,  Yonghua Lei 1,  Xiang Li 3,  Haopeng Sun 1,  Xiaojin Zhang 4,  Qidong You 5
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
  • 2 Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
  • 3 Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
  • 4 Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Organic Chemistry, School of Science, China Pharmaceutical University, Nanjing 210009, China. Electronic address: zhangxiaojin@outlook.com.
  • 5 Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China. Electronic address: youqidong@gmail.com.
PMID: 24874653 DOI: 10.1016/j.ejmech.2014.05.041
Abstract

A series of L-shaped ortho-quinone analogs were designed by analyzing the binding mode with NQO1. Metabolic studies demonstrated that compounds 2m, 2n and 2q exhibited higher metabolic rates than β-lapachone. The docking studies, which supported the rationalization of the metabolic studies, constituted a prospective rational basis for the development of optimized ortho-quinone analogs. Besides, good substrates (2m, 2n and 2r) for NQO1 showed higher selective toxicity than β-lapachone toward A549 (NQO1-rich) Cancer cells versus H596 (NQO1-deficient) cells. Determination of superoxide (O2(•-)) production and in vitro cytotoxicity evaluation in the presence of the NQO1 inhibitor dicoumarol confirmed that the ortho-quinones exerted their antitumor activity through NQO1-mediated ROS production by redox cycling. It was suggested that the L-shaped quinone substrates for NQO1 possessed better specificity and safety than β-lapachone.

Keywords

Antitumor; NQO1 substrates; Ortho-quinones; Tanshione IIA; β-Lapachone.

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