N,N'-bis(4-ethoxybenzensulfonyl)naphthalenediimine

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 英文名称: N,N'-bis(4-ethoxybenzensulfonyl)naphthalenediimine
• 英文别名: 4-ethoxy-N-[4-(4-ethoxyphenyl)sulfonyliminonaphthalen-1-ylidene]benzenesulfonamide
• 化学式: C₂₆H₂₄N₂O₆S₂
• 分子量: 524.618
• InChiKey: RVBGGNNODKMXQJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.9
• 重原子数：
  36
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.15
• 拓扑面积：
  128
• 氢给体数：
  0
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  N,N'-bis(4-ethoxybenzensulfonyl)naphthalenediimine 在 盐酸羟胺 、 三乙胺 作用下， 以 水 、 溶剂黄146 、 甲苯 为溶剂， 生成 1-(4-ethoxyphenyl)sulfonyl-5-[(4-ethoxyphenyl)sulfonylamino]-N-hydroxy-2-methylbenzo[g]indole-3-carboxamide
  参考文献：
  名称：

  Discovery of benzo[g]indoles as a novel class of non-covalent Keap1-Nrf2 protein-protein interaction inhibitor

  摘要：

  The Keap1-Nrf2 system is an attractive target for drug discovery regarding various unmet medical needs. Only covalent inhibitors for protein-protein interaction (PPI) between Keap1 and Nrf2 to activate Nrf2 have been approved or are under clinical trials, but such electrophilic compounds lack selectivity. Therefore, specific non-covalent Keap1-Nrf2 PPI inhibitors are expected to be safer Nrf2 activators. We found a novel class of non-covalent Keap1-Nrf2 PPI inhibitor that has a benzo[g]indole skeleton and an indole-3-hydroxamic acid moiety and that exhibits significant PPI inhibitory activity. Additionally, the benzo[g]indole-3-carbohydrazide derivatives were newly prepared. The benzo[g]indole derivatives showed a stronger Keap1-Nrf2 PPI inhibitory activity than Cpd16, a previously reported non-covalent PPI inhibitor. Moreover, most of the PPI inhibitors showed a high metabolic stability in a human microsome system with a low cytotoxicity against HepG2 cell lines, which suggests that novel benzo[g]indole-type Keap1-Nrf2 PPI inhibitors are expected to be biological tools or lead compounds for Nrf2 activators. (C) 2017 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2017.10.008
• 作为产物：
  描述：

  1-氨基-4-硝基萘 在 吡啶 、 ammonium cerium (IV) nitrate 、 palladium on activated charcoal 、 氢气 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 反应 26.5h， 生成 N,N'-bis(4-ethoxybenzensulfonyl)naphthalenediimine
  参考文献：
  名称：

  磷酸化 p62 和 Keap1 之间蛋白质-蛋白质相互作用的抑制剂减弱人肝细胞癌细胞系的化学抗性

  摘要：

  摘要 对抗癌药物的耐药性一直是开发治疗方法和降低医疗成本的障碍。虽然索拉非尼用于治疗人类肝细胞癌 (HCC)，但耐药性限制了其疗效。p62 是一种多功能蛋白，在几种 HCC 细胞系（例如 Huh-1 细胞）中过表达。磷酸化的 p62 ( p -p62) 抑制 Keap1 和 Nrf2 之间的蛋白质-蛋白质相互作用 (PPI)，导致 Nrf2 过度激活，从而导致耐药性。我们发现了一种独特的 Nrf2 灭活剂，名为 K67，它抑制了 Keap1 和p之间的 PPI-p62 并减弱 Huh-1 细胞中的索拉非尼耐药性。在此，我们通过修饰 K67 的两个苯磺酰基的 4 位取代基，设计并合成了新型 K67 衍生物。尽管这些新衍生物抑制 Keap1- p- p62 PPI 的水平与 K67 相当或更弱，但异丙氧基衍生物比 K67 更大程度地增强了 Huh-1 细胞对索拉非尼的敏感性，而对细胞活力没有任何影响。

  DOI：

  10.1080/10715762.2020.1732955

文献信息

• Synthesis of Keap1-phosphorylated p62 and Keap1-Nrf2 protein-protein interaction inhibitors and their inhibitory activity
  作者：Daisuke Yasuda、Mao Nakajima、Akihiro Yuasa、Rika Obata、Kyoko Takahashi、Tomoyuki Ohe、Yoshinobu Ichimura、Masaaki Komatsu、Masayuki Yamamoto、Riyo Imamura、Hirotatsu Kojima、Takayoshi Okabe、Tetsuo Nagano、Tadahiko Mashino

  DOI：10.1016/j.bmcl.2016.10.083

  日期：2016.12

  cancers, competes with Nrf2 for Keap1 binding, leading to activation of Nrf2-mediated gene expression and survival of cancer cells. We had previously identified an inhibitor for the Keap1-phosphorylated-p62 (p-p62) protein-protein interaction (PPI), the acetonyl naphthalene derivative K67. In this study, we established facile synthetic routes for K67 and derivatives with various side chains on the C-2

  Keap1-Nrf2系统不仅参与生物防御，而且还参与恶性进展和化学抗药性。在多种癌症中高度表达的泛素结合蛋白p62 / Sqstm1（p62）与Nrf2竞争Keap1结合，从而激活Nrf2介导的基因表达和癌细胞的存活。我们先前已经确定了Keap1-磷酸化p62（p-p62）蛋白质-蛋白质相互作用（PPI）的抑制剂，即丙酮基萘衍生物K67。在这项研究中，我们为萘环的C-2位置上的各种侧链的K67及其衍生物建立了简便的合成路线。K67在抑制Keap1-p-p62方面具有很高的选择性。其他衍生物显示出有效的Keap1-Nrf2和Keap1-p-p62 PPI抑制活性，
• Inhibitors of the protein–protein interaction between phosphorylated p62 and Keap1 attenuate chemoresistance in a human hepatocellular carcinoma cell line
  作者：Daisuke Yasuda、Tomoyuki Ohe、Kyoko Takahashi、Riyo Imamura、Hirotatsu Kojima、Takayoshi Okabe、Yoshinobu Ichimura、Masaaki Komatsu、Masayuki Yamamoto、Tetsuo Nagano、Tadahiko Mashino

  DOI：10.1080/10715762.2020.1732955

  日期：2020.12.1

  overexpressed in several HCC cell lines, such as Huh-1 cells. Phosphorylated p62 (p-p62) inhibits the protein–protein interaction (PPI) between Keap1 and Nrf2, resulting in the Nrf2 overactivation that causes drug resistance. We have found a unique Nrf2 inactivator, named K67, that inhibited the PPI between Keap1 and p-p62 and attenuated sorafenib resistance in Huh-1 cells. Herein, we designed and synthesised

  摘要 对抗癌药物的耐药性一直是开发治疗方法和降低医疗成本的障碍。虽然索拉非尼用于治疗人类肝细胞癌 (HCC)，但耐药性限制了其疗效。p62 是一种多功能蛋白，在几种 HCC 细胞系（例如 Huh-1 细胞）中过表达。磷酸化的 p62 ( p -p62) 抑制 Keap1 和 Nrf2 之间的蛋白质-蛋白质相互作用 (PPI)，导致 Nrf2 过度激活，从而导致耐药性。我们发现了一种独特的 Nrf2 灭活剂，名为 K67，它抑制了 Keap1 和p之间的 PPI-p62 并减弱 Huh-1 细胞中的索拉非尼耐药性。在此，我们通过修饰 K67 的两个苯磺酰基的 4 位取代基，设计并合成了新型 K67 衍生物。尽管这些新衍生物抑制 Keap1- p- p62 PPI 的水平与 K67 相当或更弱，但异丙氧基衍生物比 K67 更大程度地增强了 Huh-1 细胞对索拉非尼的敏感性，而对细胞活力没有任何影响。
• Discovery of benzo[g]indoles as a novel class of non-covalent Keap1-Nrf2 protein-protein interaction inhibitor
  作者：Daisuke Yasuda、Akihiro Yuasa、Rika Obata、Mao Nakajima、Kyoko Takahashi、Tomoyuki Ohe、Yoshinobu Ichimura、Masaaki Komatsu、Masayuki Yamamoto、Riyo Imamura、Hirotatsu Kojima、Takayoshi Okabe、Tetsuo Nagano、Tadahiko Mashino

  DOI：10.1016/j.bmcl.2017.10.008

  日期：2017.11

  The Keap1-Nrf2 system is an attractive target for drug discovery regarding various unmet medical needs. Only covalent inhibitors for protein-protein interaction (PPI) between Keap1 and Nrf2 to activate Nrf2 have been approved or are under clinical trials, but such electrophilic compounds lack selectivity. Therefore, specific non-covalent Keap1-Nrf2 PPI inhibitors are expected to be safer Nrf2 activators. We found a novel class of non-covalent Keap1-Nrf2 PPI inhibitor that has a benzo[g]indole skeleton and an indole-3-hydroxamic acid moiety and that exhibits significant PPI inhibitory activity. Additionally, the benzo[g]indole-3-carbohydrazide derivatives were newly prepared. The benzo[g]indole derivatives showed a stronger Keap1-Nrf2 PPI inhibitory activity than Cpd16, a previously reported non-covalent PPI inhibitor. Moreover, most of the PPI inhibitors showed a high metabolic stability in a human microsome system with a low cytotoxicity against HepG2 cell lines, which suggests that novel benzo[g]indole-type Keap1-Nrf2 PPI inhibitors are expected to be biological tools or lead compounds for Nrf2 activators. (C) 2017 Elsevier Ltd. All rights reserved.