3-(1-hydroxyethyl)-5-methoxy-1,2-dimethylindole-4,7-dione | 360053-70-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: 3-(1-hydroxyethyl)-5-methoxy-1,2-dimethylindole-4,7-dione
• 英文别名: 3-(1'-hydroxyethyl)-5-methoxy-1,2-dimethyl-1H-indole-4,7-dione；3-(1-hydroxyethyl)-5-methoxy-1,2-dimethyl-1H-indole-4,7-dione
• CAS: 360053-70-9
• 化学式: C₁₃H₁₅NO₄
• 分子量: 249.266
• InChiKey: DEKPSPCIEBKNSC-UHFFFAOYSA-N

物化性质

• 沸点：
  501.0±50.0 °C(Predicted)
• 密度：
  1.30±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.6
• 重原子数：
  18
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  68.5
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  3-(1-hydroxyethyl)-5-methoxy-1,2-dimethylindole-4,7-dione 在 三苯基膦 、 偶氮二甲酸二乙酯 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 24.0h， 生成 1,2-dimethyl-5-(4-methylpiperazin-1-yl)-3-[1-(4-nitrophenoxy)ethyl]indole-4,7-dione
  参考文献：
  名称：

  Controlling the rates of reductively-activated elimination from the (indol-3-yl)methyl position of indolequinones

  摘要：

  合成了一系列取代的3-(4-硝基苯氧基)甲基吲哚-4,7-二酮（Q）。研究了取代模式对吲哚核心在4-硝基苯酚释放速率上的影响，作为药物释放的模型，药物释放是通过酚醚连接链的断裂发生的。在还原为自由基阴离子（Q˙−）或氢醌（QH2）后，4-硝基苯酚从（吲哚-3-基）甲基位置释放。Q˙−自由基在[O2] ≈ 5 µmol dm−3（典型的肿瘤缺氧环境）下的半衰期为t½ ≈ 0.3–1.8毫秒，较高的半衰期值与较高的还原电位相关。在相同的氧浓度下，QH2的自氧化半衰期明显更长（t½ ≈ 8–102分钟），在存在4 µmol dm−3超氧化物歧化酶的情况下更长（t½ ≈ 8–19小时）。尽管吲哚醌能够以高效率释放4-硝基苯酚，但仅有3-羧基取代的Q˙−自由基具有足够短的半衰期（t½ ≈ 41–2毫秒）以与氧的电子转移竞争，因此具有将离去基团靶向缺氧组织的潜力。即使在正常组织中预期的氧浓度下，氢醌的氧敏感性不足以阻止4-硝基苯酚的释放（t½ ≈ 1.5–3.5秒）。通过在吲哚基甲基位置引入富电子取代基，可以控制还原性碎裂的速率。这可能成为设计基于吲哚醌的生物还原药物递送系统的重要因素。

  DOI：

  10.1039/b009652k
• 作为产物：
  描述：

  3-acetyl-5-methoxy-1,2-dimethylindole-4,7-dione 在 sodium tetrahydroborate 作用下， 以 甲醇 为溶剂， 反应 0.17h， 以56%的产率得到3-(1-hydroxyethyl)-5-methoxy-1,2-dimethylindole-4,7-dione
  参考文献：
  名称：

  Controlling the rates of reductively-activated elimination from the (indol-3-yl)methyl position of indolequinones

  摘要：

  合成了一系列取代的3-(4-硝基苯氧基)甲基吲哚-4,7-二酮（Q）。研究了取代模式对吲哚核心在4-硝基苯酚释放速率上的影响，作为药物释放的模型，药物释放是通过酚醚连接链的断裂发生的。在还原为自由基阴离子（Q˙−）或氢醌（QH2）后，4-硝基苯酚从（吲哚-3-基）甲基位置释放。Q˙−自由基在[O2] ≈ 5 µmol dm−3（典型的肿瘤缺氧环境）下的半衰期为t½ ≈ 0.3–1.8毫秒，较高的半衰期值与较高的还原电位相关。在相同的氧浓度下，QH2的自氧化半衰期明显更长（t½ ≈ 8–102分钟），在存在4 µmol dm−3超氧化物歧化酶的情况下更长（t½ ≈ 8–19小时）。尽管吲哚醌能够以高效率释放4-硝基苯酚，但仅有3-羧基取代的Q˙−自由基具有足够短的半衰期（t½ ≈ 41–2毫秒）以与氧的电子转移竞争，因此具有将离去基团靶向缺氧组织的潜力。即使在正常组织中预期的氧浓度下，氢醌的氧敏感性不足以阻止4-硝基苯酚的释放（t½ ≈ 1.5–3.5秒）。通过在吲哚基甲基位置引入富电子取代基，可以控制还原性碎裂的速率。这可能成为设计基于吲哚醌的生物还原药物递送系统的重要因素。

  DOI：

  10.1039/b009652k

文献信息

• Rates of reductive elimination of substituted nitrophenols from the (indol-3-yl)methyl position of indolequinones
  作者：Elizabeth Swann、Christopher J. Moody、Michael R. L. Stratford、Kantilal B. Patel、Matthew A. Naylor、Borivoj Vojnovic、Peter Wardman、Steven A. Everett

  DOI：10.1039/b101842f

  日期：——

  A series of indolequinones bearing substituted nitrophenols on the (indol-3-yl)methyl position was synthesised. The nitrophenol leaving groups were appropriately substituted to give a wide range (4 units) in phenolic pKa value. The rate of reductive elimination of phenoxide anions from the (indol-3-yl)methyl position of semiquinone radicals was dependent upon this pKa, with a decrease in 3.8 pK units shortening the half-life from 28 to 1.5 ms. Only 2,4-dinitrophenol (pKa = 3.9) was eliminated from an unsubstituted (indol-3-yl)methyl position at a rate that would compete with reoxidation of the radical by oxygen. A nitrothiophenol leaving group was eliminated comparatively slowly and only from the hydroquinone. These studies demonstrate the dependence upon leaving group pKa of the rate of reductive elimination from the (indol-3-yl)methyl position of indolequinones.

  一系列带有取代硝基苯酚的吲哚醌类化合物在（吲哚-3-基）甲基位置被合成。硝基苯酚离去基团被适当取代，使得酚pKa值范围广泛（4个单位）。从半醌自由基的（吲哚-3-基）甲基位置上，羟基阴离子的还原消除速率依赖于这个pKa值，pKa值每降低3.8个单位，半衰期从28毫秒缩短到1.5毫秒。只有2,4-二硝基苯酚（pKa = 3.9）能够以与自由基被氧再氧化竞争的速率从无取代（吲哚-3-基）甲基位置上消除。硝硫苯酚离去基团消除相对缓慢，并且仅从对苯二酚中消除。这些研究表明，从吲哚醌类的（吲哚-3-基）甲基位置上还原消除的速率依赖于离去基团的pKa值。
• Modifying rates of reductive elimination of leaving groups from indolequinone prodrugs: a key factor in controlling hypoxia-selective drug release
  作者：Steven A. Everett、Elizabeth Swann、Matthew A. Naylor、Michael R.L. Stratford、Kantilal B. Patel、Natasha Tian、Robert G. Newman、Borivoj Vojnovic、Christopher J. Moody、Peter Wardman

  DOI：10.1016/s0006-2952(02)00885-7

  日期：2002.5

  Rates of reductive release of the fluorophore from the non-fluorescent parent indolequinones (R=H, Me, thienyl) were similar under anoxia ( approximately 1.7 nmol coumarinmin(-1)mg protein(-1)) reflecting the similarity in one-electron reduction potential. Whereas coumarin release from the indolequinone (R=H) was completely inhibited above 0.5% O2, the enhanced rate of reductive elimination when R=thienyl

  合成3-（4-甲基香豆素-7-酰氧基）甲基吲哚-4,7-二酮作为模型前药，以研究（吲哚基-3-基）甲基位置的还原消除速率与低氧引起的还原代谢之间的相关性肿瘤细胞和NADPH：细胞色素P450。通过使用分光光度法和荧光检测的脉冲辐射分解法测定吲哚醌被单电子还原为半醌自由基（Q *-）后发色团/荧光团（7-羟基-4-甲基香豆素）的消除速率。在（吲哚-3-基）CHR位上掺入噻吩基或甲基取代基（其中R =与酚醚连接键相邻的噻吩基或甲基）显着缩短了还原消除的半衰期，从87毫秒缩短至6毫秒和2毫秒， 分别。因此，消除甲基取代的类似物可以有效地竞争半醌自由基与氧气在肿瘤中通常存在的水平下发生反应（在0.5％的O2下，半衰期约为1.8毫秒）。化学动力学预测已通过在0-2.1％O2之间的乳腺肿瘤MCF-7细胞中的代谢来证实。在缺氧条件下，非荧光母体吲哚醌（R = H，Me，噻吩基）的荧光团还原释放速率相似（约1
• Two Color Imaging of Different Hypoxia Levels in Cancer Cells
  作者：Antoine L. D. Wallabregue、Hannah Bolland、Stephen Faulkner、Ester M. Hammond、Stuart J. Conway

  DOI：10.1021/jacs.2c12493

  日期：2023.2.1

  Hypoxia (low oxygen levels) occurs in a range of biological contexts, including plants, bacterial biofilms, and solid tumors; it elicits responses from these biological systems that impact their survival. For example, conditions of low oxygen make treating tumors more difficult and have a negative impact on patient prognosis. Therefore, chemical probes that enable the study of biological hypoxia are

  缺氧（低氧水平）发生在一系列生物环境中，包括植物、细菌生物膜和实体瘤；它引起这些影响其生存的生物系统的反应。例如，低氧条件使治疗肿瘤更加困难，并对患者预后产生负面影响。因此，能够研究生物缺氧的化学探针是增加对涉及低氧水平的疾病相关病症的理解的宝贵工具，最终导致改进诊断和治疗。虽然存在小分子缺氧传感探针，但这些探针中的大多数只显示非常严重的缺氧（<1% O 2)，因此没有给出异质生物缺氧的全貌。常用的基于抗体的缺氧成像工具不如小分子方便，因为需要涉及免疫染色的二次检测步骤。在这里，我们报告了一系列基于吲哚醌的生物还原荧光探针的合成、电化学性质、光物理分析和生物学验证。我们展示了这些化合物在 2D 和 3D 细胞培养物中对不同程度的缺氧进行成像。基于试卤灵的探针2在 4% O 2或更低的条件下被激活，而基于 Me-Tokyo Green 的探针4仅在严重缺氧─0.5% O 2时被激活和更少。在
• Bexarotene prodrugs: Targeting through cleavage by NQO1 (DT-diaphorase)
  作者：Anja Schäfer、Ethan S. Burstein、Roger Olsson

  DOI：10.1016/j.bmcl.2014.03.003

  日期：2014.4

  Bexarotene, a retinoid X receptor (RXR) agonist, is being tested as a potential disease modifying treatment for neurodegenerative conditions. To limit the peripheral exposure of bexarotene and release it only in the affected areas of the brain, we designed a prodrug strategy based on the enzyme NAD( P) H/quinone oxidoreductase (NQO1) that is elevated in neurodegenerative diseases. A series of indolequinones (known substrates of NQO1) was synthesized and coupled to bexarotene. Bexarotene-3(hydroxymethyl)-5-methoxy-1,2-dimethyl-1H-indole-4,7-dione ester 7a was cleaved best by NQO1. The prodrugs are not cleaved by esterase. (C) 2014 Elsevier Ltd. All rights reserved.
• Indolequinone Antitumor Agents:  Correlation between Quinone Structure and Rate of Metabolism by Recombinant Human NAD(P)H:Quinone Oxidoreductase. Part 2
  作者：Elizabeth Swann、Paola Barraja、Ann M. Oberlander、Walter T. Gardipee、Anna R. Hudnott、Howard D. Beall、Christopher J. Moody

  DOI：10.1021/jm010884c

  日期：2001.9.1

  A series of indolequinones bearing various functional groups has been synthesized, and the effects of substituents on the metabolism of the quinones. by recombinant human NAD(P)H: quinone oxidoreductase (NQO1) were studied. Indolequinones were selected for study on the basis of the X-ray crystal structure of the human enzyme, and were designed to probe the effect of substituents particularly at N-1. Metabolism of the quinones. by NQO1 revealed that, in general, compounds with electron-withdrawing groups at the indole 3-position were among the best substrates, and that groups larger than methyl at N-1 are clearly tolerated. Compounds with a leaving group at the 3-indolyl methyl position generally inactivated the enzyme. The toxicity toward human colon carcinoma cells with either no detectable activity (BE-WT) or high NQO1 activity (BE-NQ) was also studied in representative quinones. The most toxic compounds were those with a leaving group at the C-3 position; these compounds were 1.1-5.3-fold more toxic. to the BE-NQ than the BE-WT cells.