N-(3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-N-(2-methoxyethyl)acetamide | 354824-10-5

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 英文名称: N-(3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-N-(2-methoxyethyl)acetamide
• 英文别名: N-(3-chloro-1,4-dioxonaphthalen-2-yl)-N-(2-methoxyethyl)acetamide
• CAS: 354824-10-5
• 化学式: C₁₅H₁₄ClNO₄
• 分子量: 307.733
• InChiKey: QZUINWYTHMCTQK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  21
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  63.7
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  N-(3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-N-(2-methoxyethyl)acetamide 在 氢溴酸 作用下， 以 乙醇 、 水 、 乙酸乙酯 、 甲苯 为溶剂， 反应 4.0h， 生成 3-(2-methoxyethyl)-2-methyl-4,9-dioxo-1-(thiophen-2-ylmethyl)-4,9-dihydro-3H-naphtho[2,3-d]imidazol-1-ium bromide
  参考文献：
  名称：

  Dioxonaphthoimidazolium 是具有 SOX2 抑制特性的强效和选择性流氓干细胞清除剂

  摘要：

  多能干细胞在再生医学方面具有独特的定位，但只有将其致瘤倾向与其多能特性脱钩，才能实现其临床潜力。使用小分子去除残留的未分化多能细胞，否则这些细胞会转化为畸胎瘤和畸胎瘤，与非药物方法相比具有几个优势。Dioxonapthoimidazolium YM155 是一种存活素抑制剂，可诱导未分化干细胞的选择性和强效细胞死亡。在此，对干细胞毒性的结构要求进行了研究，发现其与恶性细胞中细胞毒性所必需的结构要求密切相关。对醌和咪唑鎓部分的依赖性很大，但对环取代基的依赖性较小，主要用于微调活动。鉴定出几种有效的类似物，如 YM155，抑制干细胞中的 survivin 并降低 SOX2。SOX2 的减少会导致多能因子的不平衡，这可能会促使细胞分化，从而降低异常畸胎瘤形成的风险。由于 NF-κB p50 亚基的磷酸化也被抑制，磷酸化-p50、SOX2 和 survivin 之间的串扰可能暗示 NF-κB 信号

  DOI：

  10.1002/cmdc.201600262
• 作为产物：
  描述：

  2,3-二氯-1,4-萘醌 在 硫酸 作用下， 以 乙醇 为溶剂， 反应 19.5h， 生成 N-(3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-N-(2-methoxyethyl)acetamide
  参考文献：
  名称：

  Dioxonaphthoimidazolium 是具有 SOX2 抑制特性的强效和选择性流氓干细胞清除剂

  摘要：

  多能干细胞在再生医学方面具有独特的定位，但只有将其致瘤倾向与其多能特性脱钩，才能实现其临床潜力。使用小分子去除残留的未分化多能细胞，否则这些细胞会转化为畸胎瘤和畸胎瘤，与非药物方法相比具有几个优势。Dioxonapthoimidazolium YM155 是一种存活素抑制剂，可诱导未分化干细胞的选择性和强效细胞死亡。在此，对干细胞毒性的结构要求进行了研究，发现其与恶性细胞中细胞毒性所必需的结构要求密切相关。对醌和咪唑鎓部分的依赖性很大，但对环取代基的依赖性较小，主要用于微调活动。鉴定出几种有效的类似物，如 YM155，抑制干细胞中的 survivin 并降低 SOX2。SOX2 的减少会导致多能因子的不平衡，这可能会促使细胞分化，从而降低异常畸胎瘤形成的风险。由于 NF-κB p50 亚基的磷酸化也被抑制，磷酸化-p50、SOX2 和 survivin 之间的串扰可能暗示 NF-κB 信号

  DOI：

  10.1002/cmdc.201600262

文献信息

• Synthesis and biological evaluation of novel 2-arylvinyl-substituted naphtho[2,3- d ]imidazolium halide derivatives as potent antitumor agents
  作者：Qingyun Wei、Ju Li、Feng Tang、Yin Yin、Yong Zhao、Qizheng Yao

  DOI：10.1016/j.ejmech.2017.12.008

  日期：2018.1

  Two series of novel 2-arylvinyl-naphtho[2,3-d]imidazol-3-ium iodide derivatives and 2-arylvinyl-naphtho[2,3-d]imidazol-3-ium bromide derivatives were designed and synthesized by the structural combination of YM155 with stilbenoids. All compounds were tested for anti-proliferative activity against PC-3, A375 and HeLa human cancer cell lines. Two of the compounds were selected for further investigation:

  设计并合成了两个系列的新型2-芳基乙烯基萘[2,3- d ]咪唑-3-溴化碘衍生物和2-芳基乙烯基萘[2,3 - d ]咪唑-3-溴化碘衍生物。YM155与类胡萝卜素的组合。测试所有化合物对PC-3，A375和HeLa人癌细胞系的抗增殖活性。选择了两种化合物进行进一步研究：12b，对三种测试的细胞系均表现出强大的细胞毒性，IC 50值在0.06-0.21μM范围内，而7l对具有IC的PC-3细胞显示出优异的选择性仅22 nM中的50。蛋白质印迹分析结果表明，两种12b7l和7l抑制Bcl-2和Survivin蛋白的表达，有助于诱导细胞凋亡。如膜联蛋白V-FITC阳性凋亡细胞的百分比所确定，在PC-3细胞中浓度为100 nM时，12b不仅比7l更有效，而且还以剂量依赖性方式诱导细胞凋亡，效力高于7l。在A375细胞中浓度为1000 nM。因此，选择化合物12b用于进一步深入研究以研究细胞凋亡
• Fused imidazolium derivatives
  申请人：——

  公开号：US20030114508A1

  公开（公告）日：2003-06-19

  This invention relates to medicaments, particularly novel fused imidazolium derivatives useful for the treatment of cancers and novel synthetic intermediate compounds thereof. The novel imidazolium derivatives fused with an aryl or heteroaryl ring, characterized in that the 1- and/or 3-position is substituted by an alkyl group etc. having a substituent selected from the group consisting of —OR a , —SRa and the like, have excellent anti-tumor activity and low toxicity and are useful as anticancer agents having wide margins of safety. 1

  这项发明涉及药物，特别是用于治疗癌症的新型融合咪唑基衍生物，以及其新型合成中间化合物。这些新型咪唑基衍生物与芳基或杂环芳基环融合，其特征在于1-和/或3-位置被取代为具有从羟基、烷基等取代基中选择的取代基，具有出色的抗肿瘤活性和低毒性，并且作为具有广泛安全边界的抗癌剂而有用。
• A Cell Type Selective YM155 Prodrug Targets Receptor-Interacting Protein Kinase 2 to Induce Brain Cancer Cell Death
  作者：Thomas J. West、Junfeng Bi、Francisco Martínez-Peña、Ellis J. Curtis、Nathalia R. Gazaniga、Paul S. Mischel、Luke L. Lairson

  DOI：10.1021/jacs.2c11715

  日期：——

  cell-type selectivity results from relative rates of prodrug activation in transformed versus non-transformed cell types. The prodrug strategy also facilitates transport into the brain (brain-to-plasma ratio, aYM155 = 0.56; YM155 = BLQ). In addition, we determine that the survivin-suppressing and apoptosis-inducing activities of YM155 involve its interaction with receptor-interacting protein kinase 2 (RIPK2)

  胶质母细胞瘤（GBM）是最常见和最具侵袭性的原发性中枢神经系统（CNS）恶性肿瘤。 YM155是一种高效广谱抗癌药物，源自生存素表达功能抑制剂的表型筛选，但相关生物分子靶点仍不清楚。大概由于缺乏细胞类型选择性，YM155 在临床上遇到了耐受性问题。基于其与 GBM 选择性前药 RIGBM 的结构相似性，我们在此报告了 YM155 前药形式（称为 aYM155）的设计、合成和表征。 aYM155 对多种患者来源的 GBM 癌症干细胞样细胞 (IC 50 = 0.7–10 nM) 以及 EGFR 扩增和表达 EGFR 变异 III (EGFRvIII) 细胞系 (IC 50)显示出有效的细胞杀伤活性= 3.8–36 nM），并以细胞类型依赖性方式被激活。基于质谱的分析表明，细胞类型选择性的增强是由于转化细胞类型与非转化细胞类型中前药激活的相对速率所致。前药策略还有助于转运到大脑中（大脑与血浆比率，aYM155
• FUSED IMIDAZOLIUM DERIVATIVES
  申请人：YAMANOUCHI PHARMACEUTICAL CO. LTD.

  公开号：EP1256576A1

  公开（公告）日：2002-11-13

  This invention relates to medicaments, particularly novel fused imidazolium derivatives useful for the treatment of cancers and novel synthetic intermediate compounds thereof. The novel imidazolium derivatives fused with an aryl or heteroaryl ring, characterized in that the 1- and/or 3-position is substituted by an alkyl group etc. having a substituent selected from the group consisting of -ORa, -SRa and the like, have excellent anti-tumor activity and low toxicity and are useful as anticancer agents having wide margins of safety.

  本发明涉及药物，特别是用于治疗癌症的新型融合咪唑鎓衍生物及其新型合成中间体化合物。 与芳基或杂芳基环融合的新型咪唑鎓衍生物，其特征在于1位和/或3位被烷基等取代，该烷基的取代基选自-ORa、-SRa等组成的组，具有优异的抗肿瘤活性和低毒性，可用作抗癌剂，具有较宽的安全范围。
• Antiproliferative, DNA intercalation and redox cycling activities of dioxonaphtho[2,3-d]imidazolium analogs of YM155: A structure–activity relationship study
  作者：Si-Han Sherman Ho、Mei-Yi Sim、Wei-Loong Sherman Yee、Tianming Yang、Shyi-Peng John Yuen、Mei-Lin Go

  DOI：10.1016/j.ejmech.2015.09.026

  日期：2015.11

  The anticancer agent YM155 is widely investigated as a specific survivin suppressant. More recently, YM155 was found to induce DNA damage and this has raised doubts as to whether survivin is its primary target. In an effort to assess the contribution of DNA damage to the anticancer activity of YM155, several analogs were prepared and evaluated for antiproliferative activity on malignant cells, participation in DNA intercalation and free radical generation by redox cycling. The intact positively charged scaffold was found to be essential for antiproliferative activity and intercalation but was less critical for redox cycling where the minimal requirement was a pared down bicyclic quinone. Side chain requirements at the N-1 and N-3 positions of the scaffold were more alike for redox cycling and intercalation than antiproliferative activity, underscoring yet again, the limited structural overlaps for these activities. Furthermore, antiproliferative activities were poorly correlated to DNA intercalation and redox cycling. Potent antiproliferative activity (IC50 9-23 nM), exceeding that of YM155, was found for a minimally substituted methyl analog AB7. Like YM155 and other dioxonaphthoimidazoliums, AB7 was a modest DNA intercalator but with weak redox cycling activity. Thus, the capacity of this scaffold to inflict direct DNA damage leading to cell death may not be significant and YM155 should not be routinely classified as a DNA damaging agent. (C) 2015 Elsevier Masson SAS. All rights reserved.