3-Acetoxymethyl-1-methyl-5-methoxyindole-4,7-dione

• 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-Acetoxymethyl-1-methyl-5-methoxyindole-4,7-dione
• 英文别名: (5-methoxy-1-methyl-4,7-dioxoindol-3-yl)methyl acetate
• 化学式: C₁₃H₁₃NO₅
• 分子量: 263.25
• InChiKey: BJYZQIACLHYFPT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.4
• 重原子数：
  19
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  74.6
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  3-Acetoxymethyl-1-methyl-5-methoxyindole-4,7-dione 、 sodium dimethyldithiocarbamate 在 sodium dithionite 、 air 作用下， 以 四氢呋喃 为溶剂， 反应 1.25h， 生成 3-(5-methoxy-1-methyl-4,7-indolequinonyl)methyl dimethyldithiocarbamate
  参考文献：
  名称：

  Studies on the Mechanisms of Activation of Indolequinone Phosphoramidate Prodrugs

  摘要：

  Previously a series of 2- and 3-substituted indolequinone phosphoramidate prodrugs was synthesized, and the compounds were shown to be nanomolar inbibitors of cell proliferation. The activation of these compounds following both one- and two-electron reduction has been investigated. P-31 NMR experiments demonstrated that both series of compounds undergo rapid activation following two-electron reduction. Additionally, the 3-series of compounds undergo rapid activation following one-electron reduction, while activation of the 2-series of compounds via this mechanism is very slow. The activation of these prodrugs by direct displacement using sulfur nucleophiles such as glutathione has been examined. Activation via this route is rapid for the 3-regioisomers, but is considerably slower for the 2-substituted analogues under similar conditions. Together these findings suggest that drug delivery via two-electron reduction from the 2-position is the more selective prodrug strategy.

  DOI：

  10.1021/jm0203229
• 作为产物：
  描述：

  乙酰氯 、 3-(hydroxymethyl)-5-methoxy-1-methylindole-4,7-dione 在 三乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 3.0h， 以79%的产率得到3-Acetoxymethyl-1-methyl-5-methoxyindole-4,7-dione
  参考文献：
  名称：

  Design, Synthesis, and Biological Evaluation of Indolequinone Phosphoramidate Prodrugs Targeted to DT-diaphorase

  摘要：

  A series of 2- and 3-substituted indolequinone phosphoramidate prodrugs targeted to DT-diaphorase (DTD) have been synthesized and evaluated. These compounds are designed to undergo activation via quinone reduction by DTD followed by expulsion of the phosphoramide mustard substituent from the hydroquinone. Chemical reduction of the phosphoramidate prodrugs led to rapid expulsion of the corresponding phosphoramidate anions in both series of compounds. Compounds substituted at the 2-position are excellent substrates for human DTD (k(cat)/K-M = (2-5) x 10(6) M-1 s(-1)); however, compounds substituted at the 3-position are potent inhibitors of the target enzyme. Both series of compounds are toxic in HT-29 and BE human colon cancer cell lines in a clonogenic assay. There was a correlation found between cytotoxicity and DTD activity for the 2-series of phosphoramidates; however, there was no correlation between cytotoxicity and DTD activity in the 3-series of compounds. This finding suggests the presence of an alternative mechanism for the activation of these compounds.

  DOI：

  10.1021/jm020191b

文献信息

• Design, Synthesis, and Biological Evaluation of Indolequinone Phosphoramidate Prodrugs Targeted to DT-diaphorase
  作者：Marcy Hernick、Carolee Flader、Richard F. Borch

  DOI：10.1021/jm020191b

  日期：2002.8.1

  A series of 2- and 3-substituted indolequinone phosphoramidate prodrugs targeted to DT-diaphorase (DTD) have been synthesized and evaluated. These compounds are designed to undergo activation via quinone reduction by DTD followed by expulsion of the phosphoramide mustard substituent from the hydroquinone. Chemical reduction of the phosphoramidate prodrugs led to rapid expulsion of the corresponding phosphoramidate anions in both series of compounds. Compounds substituted at the 2-position are excellent substrates for human DTD (k(cat)/K-M = (2-5) x 10(6) M-1 s(-1)); however, compounds substituted at the 3-position are potent inhibitors of the target enzyme. Both series of compounds are toxic in HT-29 and BE human colon cancer cell lines in a clonogenic assay. There was a correlation found between cytotoxicity and DTD activity for the 2-series of phosphoramidates; however, there was no correlation between cytotoxicity and DTD activity in the 3-series of compounds. This finding suggests the presence of an alternative mechanism for the activation of these compounds.
• Studies on the Mechanisms of Activation of Indolequinone Phosphoramidate Prodrugs
  作者：Marcy Hernick、Richard F. Borch

  DOI：10.1021/jm0203229

  日期：2003.1.1

  Previously a series of 2- and 3-substituted indolequinone phosphoramidate prodrugs was synthesized, and the compounds were shown to be nanomolar inbibitors of cell proliferation. The activation of these compounds following both one- and two-electron reduction has been investigated. P-31 NMR experiments demonstrated that both series of compounds undergo rapid activation following two-electron reduction. Additionally, the 3-series of compounds undergo rapid activation following one-electron reduction, while activation of the 2-series of compounds via this mechanism is very slow. The activation of these prodrugs by direct displacement using sulfur nucleophiles such as glutathione has been examined. Activation via this route is rapid for the 3-regioisomers, but is considerably slower for the 2-substituted analogues under similar conditions. Together these findings suggest that drug delivery via two-electron reduction from the 2-position is the more selective prodrug strategy.