sodium 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯烷类
• 英文名称: sodium 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate
• 英文别名: sodium;(Z)-oxido-oxidoimino-pyrrolidin-1-ylazanium
• 化学式: C₄H₈N₃O₂*Na
• 分子量: 153.116
• InChiKey: YCYMDCAPZUCBNB-YJOCEBFMSA-M

计算性质

• 辛醇/水分配系数(LogP)：
  -2.54
• 重原子数：
  10
• 可旋转键数：
  1
• 环数：
  1.0
• 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：

  溴甲基乙酸酯 、 sodium 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate 在 silver(I) acetate 、 sodium carbonate 作用下， 以 二甲基亚砜 为溶剂， 反应 72.0h， 生成 O²-(acetoxymethyl) 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate
  参考文献：
  名称：

  Esterase-Sensitive Nitric Oxide Donors of the Diazeniumdiolate Family:  In Vitro Antileukemic Activity

  摘要：

  We have designed a novel prodrug class that is stable in neutral aqueous media but releases bioactive nitric oxide (NO) on metabolism by esterase. Diazeniumdiolates of structure R2N-N(O)=N-OR', in which R' = Na, were reacted with BrCH2OAc to convert the spontaneously NO-releasing salts 1a (R2N = diethylamino) and 1b (R2N = pyrrolidino) to prodrugs 2a (AcOM-DEA/NO) and 2b (AcOM-PYRRO/NO), respectively, where R' = CH2OAc. In contrast to anions la and Ib (half-lives in pH 7.4 phosphate at 37 degrees C of 2 min and 3 s, respectively), 2a and 2b showed only minimal decomposition after 16 h under these conditions. Very rapid hydrolysis occurred in the presence of porcine liver esterase, however, with free anion 1a being observed as an intermediate in the esterase-induced generation of NO from 2a. The potential utility of this prodrug class is illustrated with a comparison of 1 and 2 as antiproliferative agents in NO-sensitive human leukemia cell lines HL-60 and U937. While the 72-h IC50's for 1a and 1b (which generate NO throughout the medium) in HL-60 cell cultures were >600 mu M, those of 2a and 2b were 8.3 and 6.4 mu M, respectively. This result is consistent with our hypothesis that 2 is selectively hydrolyzed to 1 and thence to NO intracellularly. For U937 cells, the 72-h IC50 for both 2a and 2b was 53 mu M. By contrast, relatively high antiproliferative IC50's (>100 mu M in U937 cells) were observed for analogues in which R' = CH2CH2SC(O)Me, from which acetyl and 2-mercaptoethyl groups must be successively cleaved to free the NO-releasing diazeniumdiolate function. Within 24 h at initial concentrations of 50 mu M, 2a and 2b induced apoptosis in 50% and 57% of the HL-60 cells, respectively (35% and 40% of the U937 cells, respectively). The data reveal significant in vitro antileukemic activity on the part of these novel compounds. Moreover, their substantial ease-of-handling advantages over the anionic diazeniumdiolates from which they are derived suggest their use as convenient agents for probing the biological roles of NO.

  DOI：

  10.1021/jm9903850
• 作为产物：
  描述：

  四氢吡咯 在 氧化亚氮 、 sodium methylate 作用下， 以 甲醇 、 乙醚 为溶剂， 20.0 ℃ 、275.8 kPa 条件下， 反应 24.0h， 生成 sodium 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate
  参考文献：
  名称：

  来自diazen-1-ium-1,2-glycate一氧化氮供体和ROS诱导剂plumbagin的新型抗癌杂种：设计，合成和生物学评估。

  摘要：

  高水平的一氧化氮（NO）和活性氧（ROS）可能在癌细胞中充当促凋亡信号。在这项研究中，我们将一类重要的NO供体diazeniumdiolates（NONOates）与天然的铅蛋白（PL）结合在一起，而后者主要是出色的ROS诱导剂。本文中，总共合成了12种新颖的lumbagin / NONOate杂种，并评估了它们对一组人类癌细胞系（MDA-MB-231，A549，HepG2和HCT-116细胞）和两个正常人类细胞（ HK-2和WRL-68电池）。其中，与上述母体化合物相比，化合物10a和10b显示出比其母体化合物优越的效力（IC 50值为3.48-6.68μM），但是对正常细胞的抑制作用较弱。根据其选择性的细胞毒性，10a和10b在癌细胞中释放的NO水平高于正常细胞。此外，与母体化合物plumbagin相比，有效的化合物10a以浓度依赖的方式诱导A549细胞凋亡，并导致更多的ROS产生。

  DOI：

  10.1016/j.ejmech.2018.04.047

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。
• Synthesis of Diazen-1-ium-1,2-diolates Monitored by the “NOtizer” Apparatus: Relationship between Formation Rates, Molecular Structure and the Release of Nitric Oxide
  作者：Joerg Konter、Gamal El-Din A. A. Abuo-Rahma、Ali El-Emam、Jochen Lehmann

  DOI：10.1002/ejoc.200600662

  日期：2007.2

  generally prepared from secondary amines and nitric oxide and are compounds of first choice for the direct release of nitric oxide (NO). First, we report on the relationships between the structures of the amines and the formation rates of the corresponding NONOates, second on the structures of the NONOates and the rate of NO release and finally between the rates of NONOate formation and NO release from these

  氮结合的diazen-1-ium-1,2-diolates（diazeniumdiolates，“NONOates”，“solid NO”）通常由仲胺和一氧化氮制备，是直接释放一氧化氮（NO ）。首先，我们报告了胺的结构与相应 NONOates 形成速率之间的关系，其次报告了 NONOates 的结构和 NO 释放速率之间的关系，最后是 NONOate 形成速率与这些物种的 NO 释放速率之间的关系。通过使用 NOtizer 监测 NO 压力的降低，使用一系列不同大小和取代的环状和脂肪族胺来量化胺对 NO 的反应性，NOtizer 是为这项研究开发的一种装置。NO 的释放是用 NO 敏感电极通过电流测量法测量的，新型二氮烯二醇的半衰期由紫外光谱法确定。发现胺侧链中的空间位阻和杂原子取代基降低了 NONOates 钠盐的形成速率，也减缓了 NO 从它们中的释放。在哌啶-2-羧酸衍生物中发现了
• Novel β-galactosidase-specific O²-glycosylated diazeniumdiolate probes
  作者：Barry J. Bedell、D. Scott Bohle、Zhijie Chua、Alexander Czerniewski、Alan C. Evans、Shadreck Mzengeza

  DOI：10.1139/v10-087

  日期：2010.9

  Three β-galactosidase-specific nitric-oxide-releasing diazeniumdiolate conjugated probes were prepared as a prelude to studies of new potential molecular MRI imaging agents. A glycosylated derivative, 2e, designed to be trafficked across cell membranes, was also prepared. We report, in detail, the synthesis and characterization of these probes. In addition, the release of diazeniumdiolate from the probes by β-galactosidase-catalyzed hydrolysis was used to estimate their efficacy as serum-stable, specific NO donors.

  我们制备了三种β-半乳糖苷酶特异性一氧化氮释放二氮杂环戊酸酯共轭探针，作为研究新的潜在分子磁共振成像剂的前奏。我们还制备了一种糖基化衍生物 2e，其设计目的是能在细胞膜上传播。我们详细报告了这些探针的合成和特性。此外，我们还利用β-半乳糖苷酶催化的水解作用从探针中释放出二氮杂环戊酸来评估它们作为血清稳定的特异性 NO 供体的功效。
• Nanometre-sized titanium dioxide-catalyzed reactions of nitric oxide with aliphatic cyclic and aromatic amines
  作者：Zhangjian Huang、Yihua Zhang、Lei Fang、Zhiguo Zhang、Yisheng Lai、Ye Ding、Fengqi Cao、Ji Zhang、Sixun Peng

  DOI：10.1039/b820535c

  日期：——

  Activated on the surface of nanometre-sized TiO2, NO gas can easily react with aliphatic cyclic amines and aryl free radicals at RT under atmospheric pressure to offer NONOates and cupferron sodiums, respectively.

  NO气体在纳米级TiO2的表面上被激活，可以在室温和大气压下轻松地与脂肪族环胺和芳基自由基反应，分别提供NONOate和铜铁酸钠。
• Synthesis and Biological Evaluation of NO-Donor-Tacrine Hybrids as Hepatoprotective Anti-Alzheimer Drug Candidates
  作者：Lei Fang、Dorothea Appenroth、Michael Decker、Michael Kiehntopf、Carolin Roegler、Thomas Deufel、Christian Fleck、Sixun Peng、Yihua Zhang、Jochen Lehmann

  DOI：10.1021/jm701491k

  日期：2008.2.1

  In search of safer anti-Alzheimer drugs, 14 NO-donor-tacrine hybrids (1-14) were synthesized and evaluated for their ability to inhibit cholinesterases and for vasorelaxation effects. Compounds 1-13 showed good cholinesterases inhibitory activities in vitro, while 14, particularly, was highly selective, preferring butyrylcholinesterase rather than acetylcholinesterase. Four selected compounds (1, 9, 11, and 14) moderately relaxed the porcine pulmonary arteries in organ bath. In the hepatotoxicity study, significant hepatotoxicity was caused by tacrine but not by 9.