Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 82, Issue -, Pages 56-67Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2014.05.041
Keywords
NQO1 substrates; Ortho-quinones; Antitumor; beta-Lapachone; Tanshione IIA
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Funding
- National Natural Science Foundation of China [81302636]
- National Natural Science Foundation of Jiangsu Province of China [BK20130656]
- Project Program of State Key Laboratory of Natural Medicines, China Pharmaceutical University [SKLNMZZ201202]
- National Found for Fostering Talents of Basic Science (NFFTBS) of China [J1030830]
- fundamental Research Funds for the Central Universities
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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 beta-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 beta-lapachone toward A549 (NQO1-rich) cancer cells versus H596 (NQO1-deficient) cells. Determination of superoxide (O-2(center dot-)) 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 beta-lapachone. (C) 2014 Elsevier Masson SAS. All rights reserved.
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