锥虫胱甘肽 | 96304-42-6

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 中文名称: 锥虫胱甘肽
• 英文名称: trypanothione disulfide
• 英文别名: Trypanothione；oxidized trypanothione；(2S)-2-amino-5-[[(4R,23R)-4-[[(4S)-4-amino-4-carboxybutanoyl]amino]-5,8,19,22-tetraoxo-1,2-dithia-6,9,13,18,21-pentazacyclotetracos-23-yl]amino]-5-oxopentanoic acid
• CAS: 96304-42-6
• 化学式: C₂₇H₄₇N₉O₁₀S₂
• 分子量: 721.856
• InChiKey: LZMSXDHGHZKXJD-VJANTYMQSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -9.2
• 重原子数：
  48
• 可旋转键数：
  10
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.7
• 拓扑面积：
  364
• 氢给体数：
  11
• 氢受体数：
  15

制备方法与用途

锥硫酮是一种双谷胱甘肽衍生物，在锥虫体内存在。它能够提供对抗氧化应激的保护作用，相关研究显示了其有效性。[1][2][3]

反应信息

• 作为反应物：
  描述：

  锥虫胱甘肽 在 Trypanosoma crusi trypanothione reductase EC 1.6.4.8 乙二胺四乙酸 、 还原型辅酶II(NADPH)四钠盐 、 4-羟乙基哌嗪乙磺酸 作用下， 以 水 为溶剂， 生成 trypanothione
  参考文献：
  名称：

  苯并呋喃基3,5-双-多胺衍生物作为锥虫硫醚还原酶的时间依赖性抑制剂。

  摘要：

  报道了作为原生动物氧化还原酶锥虫硫酮还原酶的时间依赖性抑制剂的3，5-二取代苯并呋喃衍生物的合成和评价。这些分子被设计为天然存在的亚精胺桥联的大环生物碱lunarine 1的简化模拟物，后者是一种已知的时间依赖性的锥虫硫醚还原酶抑制剂。在这一系列化合物中，双-聚氨基丙烯酰胺衍生物2-4均被证明是竞争性抑制剂，但只有双4-甲基-哌嗪-1-基-丙基丙烯酰胺衍生物4表现出时间依赖性。已经确定了1和4的时间依赖性锥虫硫醚还原酶失活的动力学，并在本文中进行了比较和讨论。

  DOI：

  10.1016/s0968-0896(03)00344-4
• 作为产物：
  描述：

  亚精胺 在 氧气 、 三乙胺 作用下， 以 乙醇 为溶剂， 反应 80.0h， 生成 锥虫胱甘肽
  参考文献：
  名称：

  Solid phase applications of Dde and the analogue Nde: Synthesis of trypanothione disulphide

  摘要：

  Bis - Dde and Nde spermidine derivatives selectively protected on the primary amines were readily prepared and attached via the secondary amine group to a p-nitrophenyl-1-chloroformate pre-activated HMPA resin. Deprotection for Nde was monitored by colour change and UV absorption at 290 nm following which the trypanothione backbone was assembled by standard Fmoc procedures. Release from the resin with TFA and subsequent oxidation gave the trypanothione disulphide in > 80% overall yield. (C) 1997 Elsevier Science Ltd.

  DOI：

  10.1016/s0040-4039(97)01010-1
• 作为试剂：
  描述：

  L-胱氨酸 在 乙二胺四乙酸 、 Trypanosoma cruzi glutaredoxin 、 锥虫胱甘肽 、 还原型辅酶II(NADPH)四钠盐 作用下， 以 aq. buffer 为溶剂， 生成 L-半胱氨酸
  参考文献：
  名称：

  Redox metabolism in Trypanosoma cruzi. Biochemical characterization of dithiol glutaredoxin dependent cellular pathways

  摘要：

  In Trypanosoma cruzi, the modification of thiols by glutathionylation-deglutathionylation and its potential relation to protective, regulatory or signaling functions have been scarcely explored. Herein we characterize a dithiolic glutaredoxin (TcrGrx), a redox protein with deglutathionylating activity, having potential functionality to control intracellular homeostasis of protein and non-protein thiols. The catalytic mechanism followed by TcrGrx was found dependent on thiol concentration. Results suggest that TcrGrx operates as a dithiolic or a monothiolic Grx, depending on GSH concentration. TcrGrx functionality to mediate reduction of protein and non-protein disulfides was studied. TcrGrx showed a preference for glutathionylated substrates respect to protein disulfides. From in vivo assays involving TcrGrx overexpressing parasites, we observed the contribution of the protein to increase the general resistance against oxidative damage and intracellular replication of the amastigote stage. Also, studies performed with epimastigotes overexpressing TcrGrx strongly suggest the involvement of the protein in a cellular pathway connecting an apoptotic stimulus and apoptotic-like cell death. Novel information is presented about the participation of this glutaredoxin not only in redox metabolism but also in redox signaling pathways in T cruzi. The influence of TcrGrx in several parasite physiological processes suggests novel insights about the protein involvement in redox signaling. (C) 2014 Elsevier B.V. and Societe francaise de biochimie et biologie Moleculaire (SFBBM). All rights reserved.

  DOI：

  10.1016/j.biochi.2014.07.027

文献信息

• 5-Substituted 3-chlorokenpaullone derivatives are potent inhibitors of Trypanosoma brucei bloodstream forms
  作者：Oliver C.F. Orban、Ricarda S. Korn、Diego Benítez、Andrea Medeiros、Lutz Preu、Nadège Loaëc、Laurent Meijer、Oliver Koch、Marcelo A. Comini、Conrad Kunick

  DOI：10.1016/j.bmc.2016.06.023

  日期：2016.8

  animals. Inspired by the observation that N(5)-substituted paullones inhibit the trypanothione synthetase from the related parasite Leishmania infantum, we designed and synthesized a series of new derivatives. Although none of the new compounds displayed strong inhibition of Trypanosoma brucei trypanothione synthetase, several of them caused a remarkable growth inhibition of cultivated Trypanosoma brucei

  锥虫硫醇合成酶是动素体寄生虫的必不可少的酶，它会在人类和动物中导致高度致残和致命的疾病。受到N（5）取代的paullones抑制来自相关寄生虫婴儿利什曼原虫的锥虫硫醇合成酶的观察的启发，我们设计并合成了一系列新的衍生物。尽管这些新化合物均未显示出对布鲁氏锥虫Trypanothione合成酶的强抑制作用，但其中有几种化合物对培养的布鲁氏锥虫血流形式产生了显着的生长抑制作用。最强大的同类产品3a 在鼠类巨噬细胞中显示出两位数纳摩尔浓度的抗锥虫活性和三个数量级的选择性指数。
• Synthesis of the trypanosomatid metabolites trypanothione, and N 1-mono- and N 8-mono-glutathionylspermidine
  作者：Graeme B. Henderson、Peter Ulrich、Alan H. Fairlamb、Anthony Cerami

  DOI：10.1039/c39860000593

  日期：——

  The trypanosomatid metabolite trypanothione [N1,N8-bis(glutathionyl)spermidine] and its biosynthetic co-metabolites the isomeric N1- and N8-mono-glutathionylspermidines have been synthesised by a mild route which involves coupling of glycinyl-spermidine derivatives to a functionally protected γ-glutamylcysteine dipeptide.

  锥虫的代谢产物锥虫[ N 1，N 8-双（谷胱甘肽）亚精胺]及其生物合成代谢物，N 1-和N 8-单-谷胱甘肽亚精胺异构体是通过温和的途径合成的，该方法涉及偶联甘氨酰基-亚精胺衍生物功能保护的γ-谷氨酰半胱氨酸二肽。
• Inhibition of<i>Leishmania infantum</i>Trypanothione Reductase by Azole-Based Compounds: a Comparative Analysis with Its Physiological Substrate by X-ray Crystallography
  作者：Paola Baiocco、Giovanna Poce、Salvatore Alfonso、Martina Cocozza、Giulio Cesare Porretta、Gianni Colotti、Mariangela Biava、Francesca Moraca、Maurizio Botta、Vanessa Yardley、Annarita Fiorillo、Antonella Lantella、Francesco Malatesta、Andrea Ilari

  DOI：10.1002/cmdc.201300176

  日期：2013.7

  Herein we report a study aimed at discovering a new class of compounds that are able to inhibit Leishmania donovani cell growth. Evaluation of an in‐house library of compounds in a whole‐cell screening assay highlighted 4‐((1‐(4‐ethylphenyl)‐2‐methyl‐5‐(4‐(methylthio)phenyl)‐1H‐pyrrol‐3‐yl)methyl)thiomorpholine (compound 1) as the most active. Enzymatic assays on Leishmania infantum trypanothione reductase

  本文中，我们报告了一项旨在发现能够抑制利什曼原虫多诺万尼细胞生长的新型化合物的研究。在全细胞筛选分析中评估内部化合物库的过程着重指出了4-（（1-（4-乙基苯基）-2-甲基-5-（4-（甲硫基）苯基）-1）H-吡咯-3 ‐yl）甲基）硫代吗啉（化合物1）最具活性。上的酶测定婴儿利什曼原虫trypanothione还原酶（栗TR，属于杜氏利什曼原虫复合物）上都与交互，和抑制由，化合物的性质阐明1。基于对接研究和结合自由能的估计的分子建模方法有助于我们合理化生物学数据。此外，通过X射线晶体结构测定Li TR与化合物1的配合物，证实了我们所有的结果：化合物1与T（SH）2结合位点结合，并排布有疏水性残基，例如Trp21和Met113，以及残基Glu18和Mlu。 110。与锥虫硫磷配合的Li TR的结构分析表明，根据竞争抑制机制，Glu18和Tyr110也参与底物结合。
• Use of nitrogen-containing compounds as antiparasitics, and compositions containing them
  申请人：DRUG & VACCINE DEVELOPMENT CORPORATION

  公开号：EP0355279A2

  公开（公告）日：1990-02-28

  The present invention relates to the treatment of diseases caused by invading organisms in a host by first identifying an enzymatic difference between the host and the invading organism and then administering to the host a pharmaceutically effective amount of a subversive substrate for the differing enzyme of the invading organism, whereby the action of the differing enzyme causes a result counter to the intended result and function of the enzyme that results in its debilitation or death. In particular, treatment of parasitic diseases caused by kinetoplastids including trypanosomes and leishmanias, e.g., African sleeping sickness, Chagas' disease, oriental sore and kala-azar is accomplished by administration of a pharmaceutically effective antiparasitic amount of a competitive toxigenic substrate for trypanothione reductase. Methods of treatment and compositions therefor lcontain a competitive toxigenic substrate for trypanothione reductase. Numerous compounds and corresponding compositions are disclosed.

  本发明涉及对宿主体内入侵生物引起的疾病的治疗，方法是首先确定宿主与入侵生物之间的酶差异，然后向宿主施用药学上有效量的入侵生物差异酶的颠覆性底物，由此差异酶的作用引起与酶的预期结果和功能相反的结果，导致其衰弱或死亡。特别是，对由包括锥虫和利什曼病在内的动植体引起的寄生虫病，如非洲昏睡病、恰加斯病、东方疮和卡拉-扎尔病的治疗，是通过施用药理上有效的抗寄生虫量的锥硫还原酶竞争性毒性底物来实现的。治疗方法及其组合物含有胰硫蛋白还原酶的竞争性毒性底物。公开了许多化合物和相应的组合物。
• Glutathionylspermidine synthetase and processes for recovery and use thereof
  申请人：Leopold Flohe

  公开号：US20020155562A1

  公开（公告）日：2002-10-24

  The present invention describes an enzyme showing glutathionylspermidine synthetase-activity and being distinct from known enzymes with similar activities in several physicochemical parameters, a novel process to isolate said enzyme from Crithidia fasciculata, tools for the production thereof in genetically transformed organisms, and its use as a molecular target for the discovery of trypanocidal drugs.

  本发明描述了一种具有谷胱甘肽合成酶活性的酶，该酶在几个理化参数上有别于具有类似活性的已知酶。 纤毛虫、 在基因转化生物体中生产这种酶的工具，以及将其用作发现杀锥虫药物的分子靶标。