O2-(2,4-dinitrophenyl-5-methoxy) 1-[(4-ethoxycarbonyl)homopiperazin-1-yl]diazen-1-ium-1,2-diolate | 1307309-25-6

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: O2-(2,4-dinitrophenyl-5-methoxy) 1-[(4-ethoxycarbonyl)homopiperazin-1-yl]diazen-1-ium-1,2-diolate
• 英文别名: RN-2-50；O2-(2,4-dinitro-5-methoxyphenyl)-1-[(4-ethoxycarbonyl)homopiperazin-1-yl]diazen-1-ium-1,2-diolate；(4-ethoxycarbonyl-1,4-diazepan-1-yl)-(5-methoxy-2,4-dinitrophenoxy)imino-oxidoazanium
• CAS: 1307309-25-6
• 化学式: C₁₅H₂₀N₆O₉
• 分子量: 428.359
• InChiKey: IDRSMIYARZZPPX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.85
• 重原子数：
  30.0
• 可旋转键数：
  7.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  175.95
• 氢给体数：
  0.0
• 氢受体数：
  10.0

反应信息

• 作为产物：
  描述：

  sodium 1-[4-(ethoxycarbonyl)-1,4-diazacycloheptan-1-yl]diazen-1-ium-1,2-diolate 、 1-fluoro-5-methoxy-2,4-dinitrobenzene 在 碳酸氢钠 作用下， 以 四氢呋喃 、 叔丁醇 为溶剂， 反应 12.0h， 以63%的产率得到O2-(2,4-dinitrophenyl-5-methoxy) 1-[(4-ethoxycarbonyl)homopiperazin-1-yl]diazen-1-ium-1,2-diolate
  参考文献：
  名称：

  Activation of the c-Jun N-terminal Kinase/Activating Transcription Factor 3 (ATF3) Pathway Characterizes Effective Arylated Diazeniumdiolate-Based Nitric Oxide-Releasing Anticancer Prodrugs

  摘要：

  Improved therapies are needed for nonsmall cell lung cancer. Diazeniumdiolate-based nitric oxide (NO)-releasing prodrugs are a growing class of promising NO-based therapeutics. Recently, we have shown that O-2-(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate (JS-K, 1) is effective against nonsmall cell lung cancer (NSCLC) cells in culture and in vivo. Here we report mechanistic studies with compound 1 and its homopiperazine analogue and structural modification of these into more stable prodrugs. Compound 1 and its., homopiperazine analogue were potent cytotoxic agents against NSCLC cells in vitro and in vivo, concomitant with activation of the SAPK/JNK stress pathway and upregulation of its downstream effector ATF3. Apoptosis followed these events. An aryl-substituted analogue, despite extended half-life in the presence of glutathione, did not activate JNK or have antitumor activity. The data suggest that rate of reactivity with glutathione and activation of JNK/ATF3 are determinants of cancer cell killing by these prodrugs.

  DOI：

  10.1021/jm2004128

文献信息

• Diazeniumdiolated compounds, pharmaceutical compositions, and method of treating cancer
  申请人：Maciag Anna E.

  公开号：US09205091B2

  公开（公告）日：2015-12-08

  Disclosed is a method of treating cancer in a patient comprising administering to the patient an effective amount of a diazeniumdiolated (N2O2-containing) compound or a pharmaceutically acceptable salt thereof, wherein the cancer cell has an elevated level of reactive oxygen species (ROS) and/or a decreased level of one or more of PRX1, PRX6, and OGG1, compared to a normal cell of the same tissue or tissue type. An example of a diazeniumdiolated compound is Formula (I), wherein X and Q are defined herein. Also disclosed are diazeniumdiolated compounds, pharmaceutical compositions, and methods of use including enhancing the chemotherapeutic treatment of chemotherapeutic agents and high energy radiation.

  本发明公开了一种治疗癌症的方法，包括向患者施用有效量的重氮二氧化物化合物或其药用盐，其中癌细胞的反应性氧化物种（ROS）水平升高和/或与同一组织或组织类型的正常细胞相比，PRX1、PRX6和OGG1中的一个或多个水平降低。重氮二氧化物化合物的一个例子是式（I），其中X和Q在此定义。本发明还公开了重氮二氧化物化合物、药物组成物和使用方法，包括增强化疗药物和高能辐射的化疗治疗。
• Activation of the c-Jun N-terminal Kinase/Activating Transcription Factor 3 (ATF3) Pathway Characterizes Effective Arylated Diazeniumdiolate-Based Nitric Oxide-Releasing Anticancer Prodrugs
  作者：Anna E. Maciag、Rahul S. Nandurdikar、Sam Y. Hong、Harinath Chakrapani、Bhalchandra Diwan、Nicole L. Morris、Paul J. Shami、Yih-Horng Shiao、Lucy M. Anderson、Larry K. Keefer、Joseph E. Saavedra

  DOI：10.1021/jm2004128

  日期：2011.11.24

  Improved therapies are needed for nonsmall cell lung cancer. Diazeniumdiolate-based nitric oxide (NO)-releasing prodrugs are a growing class of promising NO-based therapeutics. Recently, we have shown that O-2-(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate (JS-K, 1) is effective against nonsmall cell lung cancer (NSCLC) cells in culture and in vivo. Here we report mechanistic studies with compound 1 and its homopiperazine analogue and structural modification of these into more stable prodrugs. Compound 1 and its., homopiperazine analogue were potent cytotoxic agents against NSCLC cells in vitro and in vivo, concomitant with activation of the SAPK/JNK stress pathway and upregulation of its downstream effector ATF3. Apoptosis followed these events. An aryl-substituted analogue, despite extended half-life in the presence of glutathione, did not activate JNK or have antitumor activity. The data suggest that rate of reactivity with glutathione and activation of JNK/ATF3 are determinants of cancer cell killing by these prodrugs.