3,7,8-trimethylnaphtho[1,2-b]furan-4,5-dione

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 萘并呋喃类
• 英文名称: 3,7,8-trimethylnaphtho[1,2-b]furan-4,5-dione
• 英文别名: 3,7,8-Trimethylbenzo[g][1]benzofuran-4,5-dione；3,7,8-trimethylbenzo[g][1]benzofuran-4,5-dione
• 化学式: C₁₅H₁₂O₃
• 分子量: 240.258
• InChiKey: VCBCAXHKNPCVCB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  18
• 可旋转键数：
  0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  47.3
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  3,7,8-trimethylnaphtho[1,2-b]furan-4,5-dione 在 盐酸 、 potassium carbonate 、 zinc(II) chloride 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 5.0h， 生成 3,7,8-trimethyl-2-((4-methylpiperazin-1-yl)methyl)naphtho[1,2-b]furan-4,5-dione
  参考文献：
  名称：

  阳离子-π相互作用在酶-底物结合中的应用：NQO1新型亲水底物的设计、合成、生物学评价和分子动力学见解

  摘要：

  阳离子-π相互作用是π-电子系统与带正电的离子或部分之间形成的一种非共价相互作用。在这项研究中，我们通过引入脂肪族含氮侧链，通过形成阳离子-π 相互作用与 NQO1 的 L 形口袋相配合，设计了一系列新型 NQO1 底物。分子动力学 (MD) 模拟表明，NQO1 底物侧链中的碱性 N 原子在生理条件下易于质子化，可以与 NQO1 酶的 Phe232 和 Phe236 残基形成阳离子-π 相互作用。具有甲基哌嗪基取代基的化合物4被鉴定为最有效的 NQO1 底物，还原速率和催化效率为 1263 ± 61 μmol NADPH/min/μmol NQO1 和 2.8 ± 0.3 × 10 6 M -1 s -1分别。值得注意的是，与 β-lap (43 μg/mL) 相比，化合物4表现出增加的水溶性 (110 μg/mL)，尤其是在酸性条件下（pH = 3，溶解度 > 1000 μg/mL）。化合物4

  DOI：

  10.1016/j.ejmech.2021.113515
• 作为产物：
  描述：

  对苯醌 在 盐酸 、 2,3-二氯-5,6-二氰基-1,4-苯醌 、 2-碘酰基苯甲酸 作用下， 以 二氯甲烷 、 水 、 甲苯 、 乙腈 为溶剂， 反应 23.67h， 生成 3,7,8-trimethylnaphtho[1,2-b]furan-4,5-dione
  参考文献：
  名称：

  阳离子-π相互作用在酶-底物结合中的应用：NQO1新型亲水底物的设计、合成、生物学评价和分子动力学见解

  摘要：

  阳离子-π相互作用是π-电子系统与带正电的离子或部分之间形成的一种非共价相互作用。在这项研究中，我们通过引入脂肪族含氮侧链，通过形成阳离子-π 相互作用与 NQO1 的 L 形口袋相配合，设计了一系列新型 NQO1 底物。分子动力学 (MD) 模拟表明，NQO1 底物侧链中的碱性 N 原子在生理条件下易于质子化，可以与 NQO1 酶的 Phe232 和 Phe236 残基形成阳离子-π 相互作用。具有甲基哌嗪基取代基的化合物4被鉴定为最有效的 NQO1 底物，还原速率和催化效率为 1263 ± 61 μmol NADPH/min/μmol NQO1 和 2.8 ± 0.3 × 10 6 M -1 s -1分别。值得注意的是，与 β-lap (43 μg/mL) 相比，化合物4表现出增加的水溶性 (110 μg/mL)，尤其是在酸性条件下（pH = 3，溶解度 > 1000 μg/mL）。化合物4

  DOI：

  10.1016/j.ejmech.2021.113515

文献信息

• Discovery of quinone-directed antitumor agents selectively bioactivated by NQO1 over CPR with improved safety profile
  作者：Jinlei Bian、Xiang Li、Nan Wang、Xingsen Wu、Qidong You、Xiaojin Zhang

  DOI：10.1016/j.ejmech.2017.02.004

  日期：2017.3

  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 beta-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... pi interactions with Trp105 and Phe178 residues compared to the control beta-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. (C) 2017 Elsevier Masson SAS. All rights reserved.
• 2-Substituted 3,7,8-trimethylnaphtho[1,2- b ]furan-4,5-diones as specific L-shaped NQO1-mediated redox modulators for the treatment of non-small cell lung cancer
  作者：Xiaojin Zhang、Jinlei Bian、Xiang Li、Xingsen Wu、Yanan Dong、Qidong You

  DOI：10.1016/j.ejmech.2017.06.028

  日期：2017.9

  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.
• Discovery of Small Molecules Simultaneously Targeting NAD(P)H:Quinone Oxidoreductase 1 and Nicotinamide Phosphoribosyltransferase: Treatment of Drug-Resistant Non-small-Cell Lung Cancer
  作者：Kuojun Zhang、Kaizhen Wang、Xiangyu Zhang、Zhenlong Qian、Wenbo Zhang、Xiao Zheng、Jiaying Wang、Yin Jiang、Wanheng Zhang、Zhiyu Lu、Haiping Hao、Sheng Jiang

  DOI：10.1021/acs.jmedchem.2c00077

  日期：2022.6.9
• Application of cation-π interactions in enzyme-substrate binding: Design, synthesis, biological evaluation, and molecular dynamics insights of novel hydrophilic substrates for NQO1
  作者：Qijie Gong、Quanwei Yu、Nan Wang、Jiabao Hu、Pengfei Wang、Fulai Yang、Tian Li、Qidong You、Xiang Li、Xiaojin Zhang

  DOI：10.1016/j.ejmech.2021.113515

  日期：2021.10

  Cation-π interaction is a type of noncovalent interaction formed between the π-electron system and the positively charged ion or moieties. In this study, we designed a series of novel NQO1 substrates by introducing aliphatic nitrogen-containing side chains to fit with the L-shaped pocket of NQO1 by the formation of cation-π interactions. Molecular dynamics (MD) simulation indicated that the basic N

  阳离子-π相互作用是π-电子系统与带正电的离子或部分之间形成的一种非共价相互作用。在这项研究中，我们通过引入脂肪族含氮侧链，通过形成阳离子-π 相互作用与 NQO1 的 L 形口袋相配合，设计了一系列新型 NQO1 底物。分子动力学 (MD) 模拟表明，NQO1 底物侧链中的碱性 N 原子在生理条件下易于质子化，可以与 NQO1 酶的 Phe232 和 Phe236 残基形成阳离子-π 相互作用。具有甲基哌嗪基取代基的化合物4被鉴定为最有效的 NQO1 底物，还原速率和催化效率为 1263 ± 61 μmol NADPH/min/μmol NQO1 和 2.8 ± 0.3 × 10 6 M -1 s -1分别。值得注意的是，与 β-lap (43 μg/mL) 相比，化合物4表现出增加的水溶性 (110 μg/mL)，尤其是在酸性条件下（pH = 3，溶解度 > 1000 μg/mL）。化合物4