N-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethyl)-2-(3-(hydroxymethyl)-5-methoxy-2-methyl-4,7-dioxo-4,7-dihydro-1H-indol-1-yl)acetamide | 1219705-82-4

• 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: N-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethyl)-2-(3-(hydroxymethyl)-5-methoxy-2-methyl-4,7-dioxo-4,7-dihydro-1H-indol-1-yl)acetamide
• CAS: 1219705-82-4
• 化学式: C₂₁H₂₉N₅O₈
• 分子量: 479.49
• InChiKey: LTYJFSKSQYVBPS-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.67
• 重原子数：
  34.0
• 可旋转键数：
  16.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  174.08
• 氢给体数：
  2.0
• 氢受体数：
  10.0

反应信息

• 作为反应物：
  描述：

  N-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethyl)-2-(3-(hydroxymethyl)-5-methoxy-2-methyl-4,7-dioxo-4,7-dihydro-1H-indol-1-yl)acetamide 在 吡啶 、 对硝基苯基氯甲酸酯 作用下， 以 二氯甲烷 为溶剂， 以91%的产率得到(1-(14-azido-2-oxo-6,9,12-trioxa-3-azatetradecyl)-5-methoxy-2-methyl-4,7-dioxo-4,7-dihydro-1H-indol-3-yl)methyl (4-nitrophenyl) carbonate
  参考文献：
  名称：

  The Synthesis of a c(RGDyK) Targeted SN38 Prodrug with an Indolequinone Structure for Bioreductive Drug Release

  摘要：

  Preparation of a novel c(RGDyK) targeted SN38 prodrug Incorporating an indolequinone structure for bioreductively triggered drug release is described. This design yields a prodrug that targets surface molecules on tumor cells (alpha(v)beta(3) integrins) and releases drug under bioreductive conditions. There are three moieties in the prodrug design, namely a therapeutic drug SN38, an indolequinone structure serving as a drug releasing trigger, and an alpha(v)beta(3) integrin targeting peptide c(RGDyK). Preliminary studies showed that SN38 is released In the presence of a bioreductive enzyme (DT-diaphorase).

  DOI：

  10.1021/ol1002626
• 作为产物：
  描述：

  5-甲氧基-2-甲基-1H-吲哚-3-甲醛 在 sodium tetrahydroborate 、 potassium nitrososulfonate 、 硝酸 、 sodium hydride 、 溶剂黄146 、 三乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 、 lithium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 aq. phosphate buffer 、 水 、 N,N-二甲基甲酰胺 、 丙酮 、 mineral oil 为溶剂， 反应 28.13h， 生成 N-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethyl)-2-(3-(hydroxymethyl)-5-methoxy-2-methyl-4,7-dioxo-4,7-dihydro-1H-indol-1-yl)acetamide
  参考文献：
  名称：

  吲哚醌连接吴茱萸碱与厄洛替尼组合物的设计、合成及生物活性评价

  摘要：

  与单靶向治疗相比，杂合分子的设计和合成仍然是抗肿瘤药物发现的重大挑战。醌氧化还原酶-1 (NQO1) 因其在许多癌细胞中过度表达及其独特的生物氧化还原特性而成为选择性癌症治疗的潜在靶点。基于组合药物设计原理，我们成功合成了具有吲哚醌结构的新型杂化分子13。我们发现合成的化合物对测试的癌细胞表现出比游离药物更高的细胞毒性。进一步的机制研究证实，化合物13诱导细胞凋亡是通过调节p53依赖性线粒体途径和细胞周期停滞在G0/G1期来实现的。

  DOI：

  10.1016/j.bmcl.2024.129619

文献信息

• 一种含有吲哚醌单元的羟基吴茱萸碱与厄洛替尼拼合药物及其制备方法与应用
  申请人：陕西中医药大学

  公开号：CN115894490A

  公开（公告）日：2023-04-04

  本发明涉及一种含有吲哚醌单元的羟基吴茱萸碱与厄洛替尼拼合药物及其制备方法与应用。本发明合成了具有吲哚醌单元的羟基吴茱萸碱与厄洛替尼拼合药物。本发明通过体外实验评估了具有吲哚醌单元的羟基吴茱萸碱与厄洛替尼拼合药物生物活性，发现对非小细胞肺癌(non‑small cell lung cancer,NSCLC)细胞具有较强的抗增殖活性，且表现出时间剂量依赖性。并且，羟基吴茱萸碱、厄洛替尼、羟基吴茱萸碱+厄洛替尼联合给药的效果，都不如具有吲哚醌单元的羟基吴茱萸碱与厄洛替尼拼合药物。进一步的，具有吲哚醌单元的羟基吴茱萸碱与厄洛替尼拼合药物处理正常LO2细胞，毒性明显低于羟基吴茱萸碱、厄洛替尼，且远小于现有公开的含有吲哚醌单元的吴茱萸碱前药。
• Human plasma-mediated hypoxic activation of indolequinone-based naloxone pro-drugs
  作者：Baohua Huang、Shengzhuang Tang、Ankur Desai、Xue-min Cheng、Alina Kotlyar、Abraham Van Der Spek、Thommey P. Thomas、James R. Baker

  DOI：10.1016/j.bmcl.2009.07.061

  日期：2009.9

  Hypoxia is known to occur in tissues in response to narcotic analgesic therapy using as a result of respiratory depression. The aim of this study was to synthesize a narcotic antagonist pro-drug that can be activated by tissue hypoxia to prevent the damage associated with respiratory depression. We synthesized three different pro-drugs of the narcotic antagonist naloxone utilizing indolequinone as the hypoxia-sensitive moiety. The indolequinone structure in the pro-drugs was designed to have an open reactive point at the N-1 position offering the possibility of further conjugation with macromolecules to modify the bio-availability of these pro-drugs in vivo. A pro-drug (labeled 1) where naloxone and the indolequinone moiety were linked through a carbonate bond was rapidly hydrolyzed in phosphate buffered saline. However, two additional pro-drugs (labeled 2 and 3) having carbamate linkers were stable in phosphate buffered saline for 24 h. The reductive release of naloxone from the pro-drugs was achieved in the presence of the bio-reductive enzyme DT-Diaphorase, with about 80% release occurring from the two pro-drugs in 24 h. More than 99% of naloxone was released from pro-drug 2 in 30% human plasma, however the release only occurred under hypoxic conditions. This system provides a potential means for feedback control to counter critical respiratory depression induced by narcotic analgesics. (C) 2009 Elsevier Ltd. All rights reserved.