title: Novel naphtho[2,1-d]oxazole-4,5-diones as NQO1 substrates with improved aqueous solubility: Design, synthesis, and in vivo antitumor evaluation.
abstract: A new series of ortho-naphthoquinone analogs of β-lapachone were designed, synthesized and evaluated. The biological results indicated that most of our compounds were efficient substrates for NQO1. The new scaffold with water-soluble side chain resulted in greater solubility under acidic condition compared to β-lapachone. Thus avoiding the use of hydroxylpropyl β-cyclodextrin which would finally cause the rapid drug clearance from the blood and dose-limiting toxicity in the form of hemolytic anemia. The most soluble and promising compound in this series was 2-((4-benzylpiperazin-1-yl)methyl)naphtho[2,1-d]oxazole-4,5-dione (3k), which inhibited cancer cell (NQO1-rich A549 cell line) growth at IC50 values of 4.6±1.0μmol·L(-1). Furthermore, compound 3k had in vivo antitumor activity in an A549 tumor xenografts mouse model comparable to the activity obtained with β-lapachone. The results indicated that these ortho-naphthoquinones could serve as promising leads for further optimization as novel substrates for NQO1.
authors.affiliation: Jiangsu Key Laboratory of Drug Design and Optimization, and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; Department of Pharmaceutical Engineering, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Li
authors.affiliation: Jiangsu Key Laboratory of Drug Design and Optimization, and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Jinlei
authors.initials: J
authors.lastname: Bian
authors.affiliation: Jiangsu Key Laboratory of Drug Design and Optimization, and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Wang
authors.affiliation: Jiangsu Key Laboratory of Drug Design and Optimization, and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Qian
authors.affiliation: Jiangsu Key Laboratory of Drug Design and Optimization, and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Gu
authors.affiliation: Jiangsu Key Laboratory of Drug Design and Optimization, and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Tong
authors.initials: T
authors.lastname: Mu
authors.affiliation: Jiangsu Key Laboratory of Drug Design and Optimization, and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Fan
authors.affiliation: Jiangsu Key Laboratory of Drug Design and Optimization, and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Xiuwen
authors.initials: X
authors.lastname: Yang
authors.affiliation: Jiangsu Key Laboratory of Drug Design and Optimization, and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Shangzhen
authors.initials: S
authors.lastname: Li
authors.affiliation: Jiangsu Key Laboratory of Drug Design and Optimization, and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Yang
authors.affiliation: Jiangsu Key Laboratory of Drug Design and Optimization, and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; Department of Organic Chemistry, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Haopeng
authors.initials: H
authors.lastname: Sun
authors.affiliation: Jiangsu Key Laboratory of Drug Design and Optimization, and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China. Electronic address: youqd@163.com.
authors.forename: Qidong
authors.initials: Q
authors.lastname: You
authors.affiliation: Jiangsu Key Laboratory of Drug Design and Optimization, and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; Department of Organic Chemistry, China Pharmaceutical University, Nanjing 210009, China. Electronic address: zxj@cpu.edu.cn.
authors.forename: Xiaojin
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D062105:Molecular Docking Simulation; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism*; D009285:Naphthoquinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use*; D012995:Solubility; D014867:Water / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D009285:Naphthoquinones; D014867:Water; C014638:beta-lapachone; C040756:1,2-naphthoquinone; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human
keywords: Antitumor; In vivo; NQO1 substrates; ortho-Naphthoquinones; β-Lapachone