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)

• DOI: 10.1016/j.ejmech.2014.05.041
• Publication Date: 2014-05-14T12:17:11Z
• Authors: Jinlei Bian; Bang Deng; Lili Xu; Xiaoli Xu; Nan Wang; Tianhan Hu; Zeyu Yao; Jianyao Du; Li Yang; Yonghua Lei; Xiang Li; Haopeng Sun; Xiaojin Zhang; Qidong You
• Keywords: Dicoumarol; Naphthoquinone; Docking (animal)

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.