Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
1395716 | European Journal of Medicinal Chemistry | 2014 | 12 Pages |
•Novel L-shaped ortho-quinone substrates for NQO1 were designed, synthesized and evaluated.•The obtained results were rationalized by means of docking experiments.•YK-01 (2n) possessed better specificity and safety than β-lapachone.•YK-01 exerted its antitumor activity through NQO1-mediated ROS production via redox cycling.
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.
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