title: Discovery of quinone-directed antitumor agents selectively bioactivated by NQO1 over CPR with improved safety profile.
abstract: In this work, we mainly focused on discovering compounds with good selectivity for NQO1 over CPR. The NQO1-mediated two-electron reduction of compounds would kill cancer cells selectively, while CPR-mediated one-electron reduction would induce potential hepatotoxicity. Several novel quinone-directed antitumor agents were discovered as specific NQO1 substrates through structure-activity relationship studies. Among them, compound 3,7,8-trimethylnaphtho[1,2-b]furan-4,5-dione (12b) emerged as the most specific substrate of the two-electron oxidoreductase NQO1 and could hardly be reduced by CPR. It afforded the highest selectivity between NQO1/CPR (selectivity ratio = 6.37), much higher than the control β-lapachone (selectivity ratio = 1.36), indicated 12b may possess superior safety profile. The electrochemical studies provided a reasonable explanation to the good selectivity toward NQO1. Molecular docking studies supported that 12b was capable of forming additional C-H … π interactions with Trp105 and Phe178 residues compared to the control β-lap. In addition, compound 12b was shown to kill cancer cells efficiently both in vitro and in vivo model. This work gave us a promising and novel scaffold for further investigation.
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Jinlei
authors.initials: J
authors.lastname: Bian
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Li
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Natural Medicines, 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.
authors.forename: Xingsen
authors.initials: X
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China. Electronic address: youqd@163.com.
authors.forename: Qidong
authors.initials: Q
authors.lastname: You
authors.affiliation: State Key Laboratory of Natural Medicines, 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: zxj@cpu.edu.cn.
authors.forename: Xiaojin
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D016227:Benzoquinones / Q000737:chemistry; D001665:Binding Sites; D016923:Cell Death / Q000187:drug effects; D055808:Drug Discovery; D006801:Humans; D062105:Molecular Docking Simulation; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism*; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism*; D061214:Patient Safety; D017382:Reactive Oxygen Species / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D016227:Benzoquinones; D017382:Reactive Oxygen Species; C004532:quinone; D009251:NADPH-Ferrihemoprotein Reductase; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human
keywords: Cancer cells; NQO1 substrates; Ortho-quinones; ROS; β-Lapachone