2,2-dimethyl-5,6-dioxo-3,4,5,6-tetrahydro-2H-benzo[h]chromen-3-yl 3-((tert-butoxycarbonyl)amino)propanoate | 195156-49-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 萘并吡喃类
• 英文名称: 2,2-dimethyl-5,6-dioxo-3,4,5,6-tetrahydro-2H-benzo[h]chromen-3-yl 3-((tert-butoxycarbonyl)amino)propanoate
• 英文别名: (2,2-Dimethyl-5,6-dioxo-3,4-dihydrobenzo[h]chromen-3-yl) 3-[(2-methylpropan-2-yl)oxycarbonylamino]propanoate；(2,2-dimethyl-5,6-dioxo-3,4-dihydrobenzo[h]chromen-3-yl) 3-[(2-methylpropan-2-yl)oxycarbonylamino]propanoate
• CAS: 195156-49-1
• 化学式: C₂₃H₂₇NO₇
• 分子量: 429.47
• InChiKey: INSRFHKODKNEBN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  31
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  108
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  2,2-dimethyl-5,6-dioxo-3,4,5,6-tetrahydro-2H-benzo[h]chromen-3-yl 3-((tert-butoxycarbonyl)amino)propanoate 在 4-二甲氨基吡啶 、 N-羟基-7-氮杂苯并三氮唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 、 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 12.5h， 生成 2,2-dimethyl-5,6-dioxo-3,4,5,6-tetrahydro-2H-benzo[h]chromen-3-yl 3-((S)-2-((S)-2-((S)-1-((2S,5S,E)-2-benzyl-5-((tert-butoxycarbonyl)amino)-7-methyloct-3-enoyl)pyrrolidine-2-carboxamido)-3-methylbutanamido)-5-(((benzyloxy)carbonyl)amino)pentanamido) propanoate
  参考文献：
  名称：

  Mitochondrial targeted β-lapachone induces mitochondrial dysfunction and catastrophic vacuolization in cancer cells

  摘要：

  Mitochondria play important roles in tumor cell physiology and survival by providing energy and metabolites for proliferation and metastasis. As part of their oncogenic status, cancer cells frequently produce increased levels of mitochondrial-generated reactive oxygen species (ROS). However, extensive stimulation of ROS generation in mitochondria has been shown to be able to induce cancer cell death, and is one of the major mechanisms of action of many anticancer agents. We hypothesized that enhancing mitochondrial ROS generation through direct targeting of a ROS generator into mitochondria will exhibit tumor cell selectivity, as well as high efficacy in inducing cancer cell death. We thus synthesized a mitochondrial targeted version of beta-lapachone (XJB-Lapachone) based on our XJB mitochondrial targeting platform. We found that the mitochondrial targeted b-lapachone is more efficient in inducing apoptosis compared to unconjugated b-lapachone, and the tumor cell selectivity is maintained. XJB-Lapachone also induced extensive cellular vacuolization and autophagy at a concentration not observed with unconjugated b-lapachone. Through characterization of mitochondrial function we revealed that XJB-Lapachone is indeed more capable of stimulating ROS generation in mitochondria, which led to a dramatic mitochondrial uncoupling and autophagic degradation of mitochondria. Taken together, we have demonstrated that targeting b-lapachone accomplishes higher efficacy through inducing ROS generation directly in mitochondria, resulting in extensive mitochondrial and cellular damage. XJB-Lapachone will thus help to establish a novel platform for the design of next generation mitochondrial targeted ROS generators for cancer therapy. (C) 2015 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2015.06.073
• 作为产物：
  描述：

  黄钟花醌 在 三氟化硼乙醚 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 、 间氯过氧苯甲酸 、 N,N'-羰基二咪唑 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 43.0h， 生成 2,2-dimethyl-5,6-dioxo-3,4,5,6-tetrahydro-2H-benzo[h]chromen-3-yl 3-((tert-butoxycarbonyl)amino)propanoate
  参考文献：
  名称：

  拉帕胆及其相关萘醌的制备合成

  摘要：

  通过将氢化锂加到醌在二甲基亚砜中的冷冻溶液中，原位制备2-羟基-1，4-萘醌的锂盐。当溶液解冻时，锂醌缓慢形成，然后用3，3-二甲基烯丙基溴化物烷基化。因此以40％的产率获得了拉帕胆。用间氯过氧苯甲酸处理后，将其转化为环氧化物，用三氟化硼醚化物将其环化为3-羟基-β-拉帕酮，总收率为67％。后者的酯通过使用1，1'-羰基二咪唑和DBU作为缩合剂与羧酸衍生物缩合而制备。

  DOI：

  10.1016/s0040-4039(98)01880-2

文献信息

• [EN] MITOCHONDRIA-TARGETED LAPACHONE COMPOUNDS AND USES THEREFOR<br/>[FR] COMPOSÉS LAPACHONE CIBLANT LES MITOCHONDRIES ET LEURS UTILISATIONS
  申请人：UNIV OF PITTSBURGH-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION

  公开号：WO2016200934A1

  公开（公告）日：2016-12-15

  Compounds, compositions and methods useful for treating cancer and neiirodegeneration are provided. The compounds comprise a mitochondria-targeting moiety linked to β-lapachone or a β-lapachone derivative.

  提供了用于治疗癌症和神经退行性疾病的化合物、组合物和方法。这些化合物包括一个以线粒体为靶向的基团，与β-拉帕酮或β-拉帕酮衍生物相连。
• Substituted β-lapachones for treating cancer
  申请人：University of Pittsburgh—Of the Commonwealth System of Higher Education

  公开号：US10450289B2

  公开（公告）日：2019-10-22

  Provided herein are compounds having the general formula compositions, and methods useful for treating cancer and neurodegeneration. The compounds comprise a mitochondria-targeting moiety linked to β-lapachone or a β-lapachone derivative.

  本文提供的化合物通式如下 以及用于治疗癌症和神经变性的组合物和方法。这些化合物包括与β-拉帕醌或β-拉帕醌衍生物相连的线粒体靶向分子。
• Mitochondria-Targeted Lapachone Compounds and Uses Therefor
  申请人：University of Pittsburgh-Of the Commonwealth System of Higher Education

  公开号：US20180170895A1

  公开（公告）日：2018-06-21

  Compounds, compositions and methods useful for treating cancer and neiirodegeneration are provided. The compounds comprise a mitochondria-targeting moiety linked to β-lapachone or a β-lapachone derivative.
• Substituted Beta-Lapachones and Uses Therefor
  申请人：University of Pittsburgh - Of the Commonwealth System of Higher Education

  公开号：US20200095220A1

  公开（公告）日：2020-03-26

  Compounds, compositions and methods useful for treating cancer and neurodegeneration are provided. The compounds comprise a mitochondria-targeting moiety linked to β-lapachone or a β-lapachone derivative.
• Mitochondrial targeted β-lapachone induces mitochondrial dysfunction and catastrophic vacuolization in cancer cells
  作者：Jing Ma、Chaemin Lim、Joshua R. Sacher、Bennett Van Houten、Wei Qian、Peter Wipf

  DOI：10.1016/j.bmcl.2015.06.073

  日期：2015.11

  Mitochondria play important roles in tumor cell physiology and survival by providing energy and metabolites for proliferation and metastasis. As part of their oncogenic status, cancer cells frequently produce increased levels of mitochondrial-generated reactive oxygen species (ROS). However, extensive stimulation of ROS generation in mitochondria has been shown to be able to induce cancer cell death, and is one of the major mechanisms of action of many anticancer agents. We hypothesized that enhancing mitochondrial ROS generation through direct targeting of a ROS generator into mitochondria will exhibit tumor cell selectivity, as well as high efficacy in inducing cancer cell death. We thus synthesized a mitochondrial targeted version of beta-lapachone (XJB-Lapachone) based on our XJB mitochondrial targeting platform. We found that the mitochondrial targeted b-lapachone is more efficient in inducing apoptosis compared to unconjugated b-lapachone, and the tumor cell selectivity is maintained. XJB-Lapachone also induced extensive cellular vacuolization and autophagy at a concentration not observed with unconjugated b-lapachone. Through characterization of mitochondrial function we revealed that XJB-Lapachone is indeed more capable of stimulating ROS generation in mitochondria, which led to a dramatic mitochondrial uncoupling and autophagic degradation of mitochondria. Taken together, we have demonstrated that targeting b-lapachone accomplishes higher efficacy through inducing ROS generation directly in mitochondria, resulting in extensive mitochondrial and cellular damage. XJB-Lapachone will thus help to establish a novel platform for the design of next generation mitochondrial targeted ROS generators for cancer therapy. (C) 2015 Elsevier Ltd. All rights reserved.