5-(3-methyl-1,4-naphthoquinone-2-yl)pentanoic acid | 64183-64-8

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 英文名称: 5-(3-methyl-1,4-naphthoquinone-2-yl)pentanoic acid
• 英文别名: 5-(3-Methyl-1,4-dioxonaphthalen-2-yl)pentanoic acid
• CAS: 64183-64-8
• 化学式: C₁₆H₁₆O₄
• 分子量: 272.301
• InChiKey: JXMRBOOZUWPZPG-UHFFFAOYSA-N

物化性质

• 熔点：
  108-110 °C(Solv: methanol (67-56-1))
• 沸点：
  475.5±45.0 °C(Predicted)
• 密度：
  1.236±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  20
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  71.4
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  5-(3-methyl-1,4-naphthoquinone-2-yl)pentanoic acid 在 对甲苯磺酸 、 硫脲 作用下， 以 丙酮 、 苯 为溶剂， 反应 78.5h， 生成 5-(3-Methyl-1,4-dioxo-1,4-dihydro-naphthalen-2-yl)-pentanoic acid 2-mercapto-ethyl ester
  参考文献：
  名称：

  含ω-巯基烷基链烷酸酯基团的2-甲基-1,4-萘醌衍生物的合成及金的自组装性能

  摘要：

  报道了一系列2-甲基-1,4-萘醌（2-MeNQ）衍生物的合成，这些衍生物在侧链上具有5-12个原子的表面活性ω-巯基烷基链烷酸酯基团。这些化合物在金上形成稳定的自组装单分子层（SAMs）。通过原位傅里叶变换表面增强拉曼光谱（FT-SERS）证实了SAM中末端2-MeNQ基团的完全还原。通过循环伏安法（CV）测定单层的基本电化学性质。

  DOI：

  10.1016/j.tetlet.2004.03.059
• 作为产物：
  描述：

  5-(1,4-Dihydroxy-3-methyl-naphthalen-2-yl)-pentanoic acid ethyl ester 在 氢氧化钾 、 sodium dithionite 、 三氯化铁 作用下， 生成 5-(3-methyl-1,4-naphthoquinone-2-yl)pentanoic acid
  参考文献：
  名称：

  Synthesis of quinones having carboxy- and hydroxy-alkyl side chains, and their effects on rat-liver lysosomal membrane.

  摘要：

  为了研究辅酶Q、α-生育酚和叶绿醌（Ia, b, c, IIa, b, c）的代谢产物结构活性关系，将3-羧基-2-丁烯基（IIIa, b, c）、6-羟基-3-甲基-2-己烯基（IVa, b, c）、4-羟基-3-甲基丁基（Va, b）、4-羟基-3-甲基-2-丁烯基（VIb, c）、ω-羧基烷基（VIIa, b, c）和ω-羟基烷基（VIIIa, b）侧链引入到2, 3-二甲氧基-5-甲基-1, 4-苯醌和2, 3, 5-三甲基-1, 4-苯醌的6-位以及2-甲基-1, 4-萘醌的3-位。研究了这些醌类化合物对大鼠肝脏溶酶体膜稳定性和牛心磷酸二酯酶活性的影响。苯醌衍生物（VIIa, b）的这些活性之间观察到了良好的相关性。

  DOI：

  10.1248/cpb.30.2797

文献信息

• 2- and 3-Substituted 1,4-Naphthoquinone Derivatives as Subversive Substrates of Trypanothione Reductase and Lipoamide Dehydrogenase from <i>Trypanosoma</i> <i>c</i><i>ruzi</i>:  Synthesis and Correlation between Redox Cycling Activities and in Vitro Cytotoxicity
  作者：Laurence Salmon-Chemin、Eric Buisine、Vanessa Yardley、Sven Kohler、Marie-Ange Debreu、Valérie Landry、Christian Sergheraert、Simon L. Croft、R. Luise Krauth-Siegel、Elisabeth Davioud-Charvet

  DOI：10.1021/jm001079l

  日期：2001.2.1

  Trypanothione reductase (TR) is both a valid and an attractive target for the design of new trypanocidal drugs. Starting from menadione, plumbagin, and juglone, three distinct series of 1,4-naphthoquinones (NQ) were synthesized as potential inhibitors of TR from Trypanosoma cruzi (TcTR). The three parent molecules were functionalized at carbons 2 and/or 3 by various polyamine chains. Optimization of

  Trypanothione还原酶（TR）是设计新的锥虫病药物的既有效又有吸引力的靶标。从甲萘醌，羽扇豆蛋白和胡桃木酮开始，合成了三个不同系列的1,4-萘醌（NQ）作为克氏锥虫（TcTR）潜在的TR抑制剂。三个母体分子通过各种多胺链在碳2和/或3上官能化。利用3,3'-[聚氨基双（羰基烷基）]双（1,4-NQ）系列19-20实现了相对于人类二硫键还原酶的TcTR抑制和TcTR特异性的优化，其中确定了抑制TcTR的最佳链长。锥虫二硫化物还原。还研究了在培养物中针对锥虫的活性最高的衍生物作为TcTR和脂酰胺脱氢酶（TcLipDH）的颠覆性底物。通过随后的NAD（P）H氧化以及将反应与细胞色素c的还原反应耦合来测量活性，从而可以检测单电子转移。对于TcTR，20（4-c）被证明是有效的颠覆性底物，并且是与锥硫磷二硫化物和NADPH相比有效的非竞争性抑制剂。进行了基于TcTR和hGR的已知X射线结构
• Amide linked redox-active naphthoquinones for the treatment of mitochondrial dysfunction
  作者：Krystel L. Woolley、Monila Nadikudi、Mitra N. Koupaei、Monika Corban、Paul McCartney、Alex C. Bissember、Trevor W. Lewis、Nuri Gueven、Jason A. Smith

  DOI：10.1039/c8md00582f

  日期：——

  established. Our results clearly demonstrate that it is the group on the alkyl side chain and not solely the redox characteristics of the naphthoquinone unit or lipophilicity that determines the extent of cytoprotection by individual compounds. From this, we developed a number of amide containing naphthoquinones with superior activity in ATP rescue and cell viability models compared to the clinically used

  萘醌已被研究作为神经退行性疾病的潜在治疗分子，这主要是基于它们的抗氧化潜力。然而，萘醌衍生物的多效保护作用的理论框架在很大程度上缺失。我们合成了一个新型短链 2,3-二取代萘醌衍生物库，并测量了它们的氧化还原特性，以确定与它们的生物活性的潜在联系。使用具有不同还原潜力的两种细胞系，测试了这些化合物的固有毒性、ATP 水平的急性拯救和细胞保护活性。首次建立了萘醌的构效关系。我们的结果清楚地表明，决定单个化合物的细胞保护程度的是烷基侧链上的基团，而不仅仅是萘醌单元的氧化还原特性或亲脂性。由此，我们开发了许多含有酰胺的萘醌，与临床使用的苯醌艾地苯醌相比，它们在 ATP 拯救和细胞活力模型中具有更高的活性。
• 5-Substituted Tetrazoles as Bioisosteres of Carboxylic Acids. Bioisosterism and Mechanistic Studies on Glutathione Reductase Inhibitors as Antimalarials
  作者：Christophe Biot、Holger Bauer、R. Heiner Schirmer、Elisabeth Davioud-Charvet

  DOI：10.1021/jm0497545

  日期：2004.11.1

  on the glutathione reductases of the malarial parasite Plasmodium falciparum and the host erythrocyte. The development of menadione chemistry has led to the selection of the carboxylic acid 6-[2'-(3'-methyl)-1',4'-naphthoquinolyl] hexanoic acid M(5) as an inhibitor of the parasitic enzyme. As reported here, revisiting the mechanism of M(5) action revealed an uncompetitive inhibition type with respect

  在红细胞内生活期间，疟原虫疟原虫暴露于活性氧通量的升高。最重要的抗氧化系统是基于疟原虫恶性疟原虫和宿主红细胞的谷胱甘肽还原酶。甲萘醌化学的发展已导致选择羧酸6- [2'-（3'-甲基）-1'，4'-萘喹啉基]己酸M（5）作为寄生酶的抑制剂。如此处报道，重新探讨M（5）作用的机制揭示了对NADPH和谷胱甘肽二硫键的非竞争性抑制类型。通过酯或酰胺键掩盖M（5）的酸性功能的极性改善了抗血浆活性。用四唑对羧酸官能团进行生物等位取代以增加生物利用度并保持可比的酸度也导致改善的抗疟特性，但仅用氰乙基保护的四唑。使用计算的从头算量子方法，详细的电子图谱和分子特性分析证明了M（5）和生物异构四唑T（4）的相似性。鉴于恶性疟原虫酶的最近解析的晶体结构，讨论了这些分子的潜在结合位点。
• Therapeutic compounds and methods
  申请人：UNIVERSITY OF TASMANIA

  公开号：US10934253B2

  公开（公告）日：2021-03-02

  The invention relates to compounds of Formula (I) and methods for their preparation. Also described are pharmaceutical compositions comprising a compound of Formula (I) and their use in the treatment or prevention of conditions associated with mitochondrial dysfunction. Formula (I)

  本发明涉及式（I）化合物及其制备方法。还描述了包含式（I）化合物的药物组合物及其在治疗或预防线粒体功能障碍相关疾病中的用途。式 (I)
• A Prodrug Form of a <i>Plasmodium falciparum </i>Glutathione Reductase Inhibitor Conjugated with a 4-Anilinoquinoline
  作者：Elisabeth Davioud-Charvet、Sandrine Delarue、Christophe Biot、Babett Schwöbel、Catharina C. Boehme、Andreas Müssigbrodt、Louis Maes、Christian Sergheraert、Philippe Grellier、R. Heiner Schirmer、Katja Becker

  DOI：10.1021/jm010268g

  日期：2001.11.1

  Glutathione (GSH), which is known to guard Plasmodium falciparum from oxidative damage, may have an additional protective role by promoting heme catabolism. An elevation of GSH content in parasites leads to increased resistance to chloroquine (CQ), while GSH depletion in resistant P. falciparum strains is expected to restore the sensitivity to CQ. High intracellular GSH levels depend inter alia on the efficient reduction of GSSG by glutathione reductase (GR). On the basis of this hypothesis, we have developed a new strategy for overcoming glutathione-dependent 4-aminoquinoline resistance. To direct both a 4-aminoquinoline and a GR inhibitor to the parasite, double-drugs were designed and synthesized. Quinoline-based alcohols (with known antimalarial activity) were combined with a GR inhibitor via a metabolically labile ester bond to give double-headed prodrugs. The biochemically most active double-drug 7 of this series was then evaluated as a growth inhibitor against six Plasmodium falciparum strains that differed in their degree of resistance to CQ; the ED50 values for CQ ranged from 14 to 183 nM. While the inhibitory activity of the original 4-aminoquinoline-based alcohol followed that of CQ in these tests, the double-drug exhibited similar efficiency against all strains, the ED50 being as low as 28 nM. For the ester 7, a dose-dependent decrease in glutathione content and GR activity and an increase in glutathione-S-transferase activity were determined in treated parasites. The drug was subsequently tested for its antimalarial action in vivo using murine malaria models infected with P. berghei. A 178% excess mean survival time was determined for the animals treated with 40 mg/kg 7 for 4 days. No cytotoxicity due to this compound was observed. Work is in progress to extend and validate the strategy outlined here.