(4-ethoxycarbonylpiperazin-1-yl)-(5-fluoro-2,4-dinitrophenoxy)imino-oxidoazanium | 903568-90-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: (4-ethoxycarbonylpiperazin-1-yl)-(5-fluoro-2,4-dinitrophenoxy)imino-oxidoazanium
• CAS: 903568-90-1
• 化学式: C₁₃H₁₅FN₆O₈
• 分子量: 402.296
• InChiKey: UGDNIZMKTPCSOS-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.59
• 重原子数：
  28.0
• 可旋转键数：
  6.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  166.72
• 氢给体数：
  0.0
• 氢受体数：
  9.0

反应信息

• 作为反应物：
  描述：

  甲醇 、 (4-ethoxycarbonylpiperazin-1-yl)-(5-fluoro-2,4-dinitrophenoxy)imino-oxidoazanium 在 sodium methylate 作用下， 以 二氯甲烷 为溶剂， 以51%的产率得到O2-(2,4-dinitrophenyl-5-methoxy) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate
  参考文献：
  名称：

  Diazeniumdiolated compounds, pharmaceutical compositions, and method of treating cancer

  摘要：

  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。

  公开号：

  US09205091B2
• 作为产物：
  描述：

  N-哌嗪甲酸乙酯 在 titanium(IV) oxide 、 氧化亚氮 、 sodium methylate 、 碳酸氢钠 作用下， 以 甲醇 、 乙醚 、 丙酮 为溶剂， 25.0 ℃ 、101.33 kPa 条件下， 反应 48.0h， 生成 (4-ethoxycarbonylpiperazin-1-yl)-(5-fluoro-2,4-dinitrophenoxy)imino-oxidoazanium
  参考文献：
  名称：

  O 2-（2,4-二硝基苯基）二氮杂二烯二醇盐和齐墩果酸的杂化分子：谷胱甘肽S-转移酶π-活化的一氧化氮前药，具有选择性的抗人肝细胞癌活性和更高的稳定性

  摘要：

  设计，合成并合成了O 2-（2,4-二硝基苯基）二氮杂二烯二醇盐和齐墩果酸（OA）的一系列杂种，并将其作为可被谷胱甘肽S-转移酶π激活的新型释放一氧化氮（NO）的前药进行了生物学评估。（GSTπ）在许多癌细胞中过表达。发现活性最高的化合物21在HCC细胞中选择性释放高水平的NO，而在正常细胞中则不释放，并且在体外表现出有效的抗增殖活性以及体内显着的肿瘤延缓作用。与报道的GSTπ活化的前药JS-K和PABA / NO相比，在不存在GSTπ的情况下21显示出显着改善的稳定性。重要的是，分解21在谷胱甘肽S-转移酶存在下发生，比谷胱甘肽S-转移酶α有效得多。此外，21通过诱导细胞周期停滞在G2 / M期，激活线粒体介导的途径和MAPK途径，并增强ROS的细胞内产生，从而诱导HepG2细胞凋亡。

  DOI：

  10.1021/jm400393u

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。
• Aryl Bis(diazeniumdiolates): Potent Inducers of <i>S</i>-Glutathionylation of Cellular Proteins and Their in Vitro Antiproliferative Activities
  作者：Daniela Andrei、Anna E. Maciag、Harinath Chakrapani、Michael L. Citro、Larry K. Keefer、Joseph E. Saavedra

  DOI：10.1021/jm800831y

  日期：2008.12.25

  A number of bis(diazeniumdiolates) that we designed to release up to 4 mol of nitric oxide (NO) and that are structural analogues of the NO prodrug and anticancer lead compound O-2-2,4-dinitro-5-[4-(N-methylamino)benzoyloxy]phenyl} 1-(N,N-dimethylamino)diazen-1-ium-1,2-diolate (PABA/NO) were synthesized and studied. A majority of these compounds yielded higher levels of NO, were better inhibitors of proliferation of a number of cancer cell lines, and more rapidly induced substantially increased levels of S-glutathionylation of cellular proteins in comparison with PABA/NO. In most cases, the antiproliferative activity and extents of S-glutathionylation correlated well with levels of intracellular NO release. We report bis(diazeniumdiolates) to be a class of S-glutathionylating agents with potent antiproliferative and S-glutathionylating activity.
• Hybrid Molecule from <i>O</i>²-(2,4-Dinitrophenyl)diazeniumdiolate and Oleanolic Acid: A Glutathione <i>S</i>-Transferase π-Activated Nitric Oxide Prodrug with Selective Anti-Human Hepatocellular Carcinoma Activity and Improved Stability
  作者：Junjie Fu、Ling Liu、Zhangjian Huang、Yisheng Lai、Hui Ji、Sixun Peng、Jide Tian、Yihua Zhang

  DOI：10.1021/jm400393u

  日期：2013.6.13

  A series of hybrids from O2-(2,4-dinitrophenyl)diazeniumdiolate and oleanolic acid (OA) were designed, synthesized, and biologically evaluated as novel nitric oxide (NO)-releasing prodrugs that could be activated by glutathione S-transferase π (GSTπ) overexpressed in a number of cancer cells. It was discovered that the most active compound, 21, released high levels of NO selectively in HCC cells but

  设计，合成并合成了O 2-（2,4-二硝基苯基）二氮杂二烯二醇盐和齐墩果酸（OA）的一系列杂种，并将其作为可被谷胱甘肽S-转移酶π激活的新型释放一氧化氮（NO）的前药进行了生物学评估。（GSTπ）在许多癌细胞中过表达。发现活性最高的化合物21在HCC细胞中选择性释放高水平的NO，而在正常细胞中则不释放，并且在体外表现出有效的抗增殖活性以及体内显着的肿瘤延缓作用。与报道的GSTπ活化的前药JS-K和PABA / NO相比，在不存在GSTπ的情况下21显示出显着改善的稳定性。重要的是，分解21在谷胱甘肽S-转移酶存在下发生，比谷胱甘肽S-转移酶α有效得多。此外，21通过诱导细胞周期停滞在G2 / M期，激活线粒体介导的途径和MAPK途径，并增强ROS的细胞内产生，从而诱导HepG2细胞凋亡。
• 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.