sodium 1-(N,N-dimethylamino)diazen-1-ium-1,2-diolate

• 分子结构分类: 有机化合物 - 有机盐 - 有机金属盐
• 英文名称: sodium 1-(N,N-dimethylamino)diazen-1-ium-1,2-diolate
• 英文别名: O2-sodium 1-(N,N-dimethylamino)diazen-1-ium-1,2-diolate；sodium;(Z)-dimethylamino-oxido-oxidoiminoazanium
• 化学式: C₂H₆N₃O₂*Na
• 分子量: 127.078
• InChiKey: GKTKYKCUXVFENU-FBZPGIPVSA-M

计算性质

• 辛醇/水分配系数(LogP)：
  -3.07
• 重原子数：
  8
• 可旋转键数：
  1
• 环数：
  0.0
• sp3杂化的碳原子比例：
  1.0
• 拓扑面积：
  67.4
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  氯甲基甲硫醚 、 sodium 1-(N,N-dimethylamino)diazen-1-ium-1,2-diolate 以 六甲基磷酰三胺 为溶剂， 反应 72.0h， 以21%的产率得到O²-(methylthiomethyl)-1-(N,N-dimethylamino)diazen-1-ium-1,2-diolate
  参考文献：
  名称：

  Novel Nonsteroidal Antiinflammatory Drugs Possessing a Nitric Oxide Donor Diazen-1-ium-1,2-diolate Moiety:  Design, Synthesis, Biological Evaluation, and Nitric Oxide Release Studies

  摘要：

  A novel group of hybrid nitric oxide-releasing nonsteroidal antiinflammatory drugs ((NO)-N-center dot-NSAIDs) possessing a 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (11, 13, 15) or 1-(N,N-dimethylamino)diazen-1-ium-1,2-diolate (12,14,16) moiety attached via a one-carbon methylene spacer to the carboxylic acid group of the traditional NSAIDs aspirin, ibuprofen, and indomethacin were synthesized. Although none of these ester prodrugs (11-16) exhibited in vitro cyclooxygenase (COX) inhibitory activity against the COX-1 and COX-2 isozymes (IC50 > 100 mu M), all of the compounds (11-16) significantly decreased carrageenan-induced rat paw edema. In this regard, the ester prodrugs 11-16 showed equipotent antiinflammatory activities in vivo to that of the parent drugs aspirin, ibuprofen, and indomethacin. All of the compounds released nitric oxide upon incubation with either phosphate buffer solution at pH 7.4 (14-16% range) or porcine liver esterase (16-19% range), but the percentage of (NO)-N-center dot released was up to sixfold higher (93%) when these ester prodrugs were incubated with guinea pig serum. These incubation studies suggest that both (NO)-N-center dot and the parent NSAID would be released upon in vivo cleavage by nonspecific serum esterases. The simultaneous release of aspirin and nitric oxide from the (NO)-N-center dot-aspirin prodrugs constitutes a potentially beneficial property for the prophylactic prevention of thrombus formation and adverse cardiovascular events such as stroke and myocardial infarction. The data acquired in an in vivo ulcer index (UI) assay showed that for this group of ester prodrugs, particularly the (NO)-N-center dot-aspirins (11, 12) and (NO)-N-center dot-ibuprofens (13, 14), no lesions were observed (UI 0) when compared to the parent drugs aspirin (UI 57, 250 mg/kg po dose), ibuprofen (UI 45, 250 mg/kg po dose), or indomethacin (UI = 34, 30 mg/kg po dose) at equivalent doses. Accordingly, these hybrid (NO)-N-center dot-NSAID prodrugs possessing a diazen-1-ium-1,2-diolate moiety, represent a new approach for the rational design of antiinflammatory drugs with reduced gastric ulcerogenicity.

  DOI：

  10.1021/jm050211k
• 作为产物：
  描述：

  二甲胺 在 sodium hydroxide 、 nitric oxide 作用下， 以 水 、 1,4-二氧六环 为溶剂， 反应 48.0h， 以25 g的产率得到sodium 1-(N,N-dimethylamino)diazen-1-ium-1,2-diolate
  参考文献：
  名称：

  仲胺/一氧化氮络离子R（2）N [N（O）NO]（-）作为亲核试剂和S9N）Ar反应中的离去基团。

  摘要：

  结构R（2）N [N（O）NO]（-）及其烷基化产物的离子已越来越多地用作生物医学研究应用中的一氧化氮（NO）生成剂。在这里我们表明，这样的重氮二氮杂阴离子可以很容易地从各种亲电氮杂或硝基芳族底物中取代卤化物，形成结构R（2）NN（O）= N-OAr的O（2）芳基化衍生物。通过X射线晶体学确认了氧的芳基化位点和顺式排列。各种亲核试剂的置换显示R（2）N [N（O）NO]（-）是一个较好的离去基团，其氢氧化物，甲醇盐和异丙胺的置换速率常数介于氯化物和氟化物中。我们调查了S（N）Ar反应。迈森海默中间体可以通过光谱观察到。

  DOI：

  10.1021/jo0016529

文献信息

• The Secondary Amine/Nitric Oxide Complex Ion R₂N[N(O)NO]^- as Nucleophile and Leaving Group in S_NAr Reactions
  作者：Joseph E. Saavedra、Aloka Srinivasan、Challice L. Bonifant、Jingxi Chu、Anna P. Shanklin、Judith L. Flippen-Anderson、William G. Rice、Jim A. Turpin、Keith M. Davies、Larry K. Keefer

  DOI：10.1021/jo0016529

  日期：2001.5.1

  the cis arrangement of the oxygens were confirmed by X-ray crystallography. Displacement by various nucleophiles showed R(2)N[N(O)NO](-) to be a reasonably good leaving group, with rate constants for displacement by hydroxide, methoxide, and isopropylamine that were between those of chloride and fluoride in the S(N)Ar reactions we surveyed. The Meisenheimer intermediate could be spectrally observed. These

  结构R（2）N [N（O）NO]（-）及其烷基化产物的离子已越来越多地用作生物医学研究应用中的一氧化氮（NO）生成剂。在这里我们表明，这样的重氮二氮杂阴离子可以很容易地从各种亲电氮杂或硝基芳族底物中取代卤化物，形成结构R（2）NN（O）= N-OAr的O（2）芳基化衍生物。通过X射线晶体学确认了氧的芳基化位点和顺式排列。各种亲核试剂的置换显示R（2）N [N（O）NO]（-）是一个较好的离去基团，其氢氧化物，甲醇盐和异丙胺的置换速率常数介于氯化物和氟化物中。我们调查了S（N）Ar反应。迈森海默中间体可以通过光谱观察到。
• PABA/NO as an Anticancer Lead:  Analogue Synthesis, Structure Revision, Solution Chemistry, Reactivity toward Glutathione, and in Vitro Activity
  作者：Joseph E. Saavedra、Aloka Srinivasan、Gregory S. Buzard、Keith M. Davies、David J. Waterhouse、Keiko Inami、Thomas C. Wilde、Michael L. Citro、Matthew Cuellar、Jeffrey R. Deschamps、Damon Parrish、Paul J. Shami、Victoria J. Findlay、Danyelle M. Townsend、Kenneth D. Tew、Shivendra Singh、Lee Jia、Xinhua Ji、Larry K. Keefer

  DOI：10.1021/jm050700k

  日期：2006.2.1

  4-dinitrophenyl ring whose 5-substituent is N-methyl-p-aminobenzoic acid). It has shown activity against human ovarian cancer xenografts in mice rivaling that of cisplatin, but it is poorly soluble and relatively unstable in water. Here we report structure-based optimization efforts resulting in three analogues with improved solubility and stability in aqueous solution. We sought to explain PABA/NO's

  PABA / NO是结构Me（2）NN（O）= NOAr的二醇二氮烯鎓盐（其中Ar是5个取代基为N-甲基-对氨基苯甲酸的5个取代的2,4-二硝基苯环）。它已显示出与顺铂竞争的小鼠抗人卵巢癌异种移植物的活性，但它在水中的溶解性差且相对不稳定。在这里，我们报告了基于结构的优化工作，从而得到了三种在水溶液中具有改善的溶解度和稳定性的类似物。我们试图解释这四种化合物中PABA / NO的物理化学唯一性，其氨基苯甲酸前体仅在存在或不存在N-甲基和/或羧基部分（间位或对位）的情况下在结构上有所不同。研究表明，PABA / NO' N-甲基-对氨基苯甲酸取代基通过其羧基氧与二硝基苯环结合，而其他三个通过苯胺氮连接。这构成了先前发布的PABA / NO结构的修订版。四个类似物均与GSH反应生成具有生物活性的一氧化氮（NO），但PABA / NO的反应性最高。与PABA / NO对小鼠A2780人卵巢癌异种
• WO2006/125016
  申请人：——

  公开号：——

  公开（公告）日：——
• Synthesis, nitric oxide release, and anti-leukemic activity of glutathione-activated nitric oxide prodrugs: Structural analogues of PABA/NO, an anti-cancer lead compound
  作者：Harinath Chakrapani、Thomas C. Wilde、Michael L. Citro、Michael M. Goodblatt、Larry K. Keefer、Joseph E. Saavedra

  DOI：10.1016/j.bmc.2007.11.035

  日期：2008.3

  Diazeniumdiolate anions and their prodrug forms are reliable sources of nitric oxide (NO) that have generated interest as promising therapeutic agents. A number of structural analogues of O-2-(2,4-dinitro-5-(4-(N-methylamino)benzoyloxy)phenyl)-1-(N,N-dimetliylamino)diazen-1-ium-1,2-diolate (PABA/NO), an anti-cancer lead compound that is designed to release NO upon activation by glutathione, were prepared. The nitric oxide release patterns of these O-2-(2,4-dinitrophenyl) diazeniumdiolates in the presence of glutathione were tested and it was found that in the absence of competing pathways, these compounds release nearly quantitative amounts of NO. The ability of PABA/NO and its structural analogues to inhibit human leukemia cell proliferation was determined and it was found that compounds releasing elevated amounts of NO displayed superior cytotoxic effects. (C) 2007 Elsevier Ltd. All rights reserved.
• Novel Nonsteroidal Antiinflammatory Drugs Possessing a Nitric Oxide Donor Diazen-1-ium-1,2-diolate Moiety:  Design, Synthesis, Biological Evaluation, and Nitric Oxide Release Studies
  作者：Carlos Velázquez、P. N. Praveen Rao、Edward E. Knaus

  DOI：10.1021/jm050211k

  日期：2005.6.1

  A novel group of hybrid nitric oxide-releasing nonsteroidal antiinflammatory drugs ((NO)-N-center dot-NSAIDs) possessing a 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (11, 13, 15) or 1-(N,N-dimethylamino)diazen-1-ium-1,2-diolate (12,14,16) moiety attached via a one-carbon methylene spacer to the carboxylic acid group of the traditional NSAIDs aspirin, ibuprofen, and indomethacin were synthesized. Although none of these ester prodrugs (11-16) exhibited in vitro cyclooxygenase (COX) inhibitory activity against the COX-1 and COX-2 isozymes (IC50 > 100 mu M), all of the compounds (11-16) significantly decreased carrageenan-induced rat paw edema. In this regard, the ester prodrugs 11-16 showed equipotent antiinflammatory activities in vivo to that of the parent drugs aspirin, ibuprofen, and indomethacin. All of the compounds released nitric oxide upon incubation with either phosphate buffer solution at pH 7.4 (14-16% range) or porcine liver esterase (16-19% range), but the percentage of (NO)-N-center dot released was up to sixfold higher (93%) when these ester prodrugs were incubated with guinea pig serum. These incubation studies suggest that both (NO)-N-center dot and the parent NSAID would be released upon in vivo cleavage by nonspecific serum esterases. The simultaneous release of aspirin and nitric oxide from the (NO)-N-center dot-aspirin prodrugs constitutes a potentially beneficial property for the prophylactic prevention of thrombus formation and adverse cardiovascular events such as stroke and myocardial infarction. The data acquired in an in vivo ulcer index (UI) assay showed that for this group of ester prodrugs, particularly the (NO)-N-center dot-aspirins (11, 12) and (NO)-N-center dot-ibuprofens (13, 14), no lesions were observed (UI 0) when compared to the parent drugs aspirin (UI 57, 250 mg/kg po dose), ibuprofen (UI 45, 250 mg/kg po dose), or indomethacin (UI = 34, 30 mg/kg po dose) at equivalent doses. Accordingly, these hybrid (NO)-N-center dot-NSAID prodrugs possessing a diazen-1-ium-1,2-diolate moiety, represent a new approach for the rational design of antiinflammatory drugs with reduced gastric ulcerogenicity.