Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 138, Issue -, Pages 616-629Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2017.06.028
Keywords
NSCLC; NQ01; Anticancer; ROS; beta-lap
Categories
Funding
- National Natural Science Foundation of China [81603025, 81302636]
- Natural Science Foundation of Jiangsu Province [BK20170088]
- National Major Science and Technology Project of China [2015ZX09101032]
- Fundamental Research Funds for the Central Universities [2632017ZD03]
- Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD)
- State Key Laboratory of Natural Medicines, China Pharmaceutical University [SKLNMZZCX201611]
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Based on the scaffold of 3,7,8-trimethylnaphtho[1,2-b]furan-4,5-dione, a series of L-shaped derivatives with substituted side chains at the position of C2 were designed by analyzing the binding mode with NQO1. The drug-like compound 6q (named as DDO-7178) emerged as the most specific substrate of the two-electron oxidoreductase NQO1 and could hardly be reduced by one-electron oxidoreductases CPR (NQO1/CPR = 20.8). In addition, compound 6q showed much improved physicochemical properties such as water solubility than the control beta-lap. The follow-up studies indicated that 6q showed a NQO1-expressing cancer-cell-selective killing property. Preliminary mechanism studies on the anticancer effect indicated that 6q induced ROS production in an NQO1 dependent manner and activated Akt/MAPK pathways in a ROS-dependent fashion, thereby inducing apoptosis. In addition, emphasized compound 6q showed more significant antitumor efficacy than beta-lap without producing obvious toxic effects in vivo, which gave us a new tool for further investigation of NQO1-mediated redox modulators as anticancer drugs for the treatment of NQO1-overexpressed NSCLC. (C) 2017 Published by Elsevier Masson SAS.
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