2-hydroxymethyl-5-methoxy-1-methylindole-4,7-dione | 206647-13-4

• 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: 2-hydroxymethyl-5-methoxy-1-methylindole-4,7-dione
• 英文别名: 2-(Hydroxymethyl)-5-methoxy-1-methyl-1H-indole-4,7-dione；2-(hydroxymethyl)-5-methoxy-1-methylindole-4,7-dione
• CAS: 206647-13-4
• 化学式: C₁₁H₁₁NO₄
• 分子量: 221.213
• InChiKey: YGBLXUIENDKTBJ-UHFFFAOYSA-N

物化性质

• 熔点：
  203-204 °C
• 沸点：
  481.3±45.0 °C(Predicted)
• 密度：
  1.38±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -0.1
• 重原子数：
  16
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.27
• 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：

  2-hydroxymethyl-5-methoxy-1-methylindole-4,7-dione 在 氨 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 为溶剂， 反应 1.79h， 生成 2-[[Amino(morpholin-4-yl)phosphoryl]oxymethyl]-5-methoxy-1-methylindole-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
• 作为产物：
  描述：

  4-(benzyloxy)-5-methoxy-1-methylindole-2-methanol 在 palladium on activated charcoal potassium nitrososulfonate 、 氢气 作用下， 以 甲醇 、 phosphate buffer 、 丙酮 为溶剂， 反应 13.0h， 生成 2-hydroxymethyl-5-methoxy-1-methylindole-4,7-dione
  参考文献：
  名称：

  Indolequinone antitumour agents: correlation between quinone structure and rate of metabolism by recombinant human NAD(P)H:quinone oxidoreductase

  摘要：

  一系列在（吲哚-2-基）亚甲基位置带有不同取代基的吲哚醌已被合成。这些吲哚醌作为重组人NAD(P)H：醌氧化还原酶（NQO1）底物的能力，以及它们对一对同基因肿瘤细胞系的毒性（该细胞系分为NQO1表达细胞（BE-NQ）或NQO1缺陷细胞（BE-WT））已被测定。总体来说，2-取代的吲哚醌是NQO1相对较差的底物。C-2位置上的羟甲基导致了更高的还原速率，这一发现与先前观察到的3-羟甲基化吲哚醌的情况一致。可以预见的是，最佳底物在吲哚-2-位置有一个吸电子的酯基团。除了在吲哚-5-位置带有甲基氮丙啶基团的醌类化合物外，这些吲哚醌对两种细胞系普遍无毒。这些化合物在通过还原活化后能够形成DNA交联，并且对BE-NQ细胞的毒性是BE-WT细胞的3倍之多。

  DOI：

  10.1039/b703370b

文献信息

• [EN] PYRROLOBENZODIAZEPINE PRODRUGS AND ANTIBODY CONJUGATES THEREOF<br/>[FR] PROMÉDICAMENTS DE PYRROLOBENZODIAZÉPINE ET CONJUGUÉS D'ANTICORPS DE CEUX-CI
  申请人：GENENTECH INC

  公开号：WO2018031662A1

  公开（公告）日：2018-02-15

  The invention relates generally to pyrrolobenzodiazepine monomer and dimer prodrugs having a glutathione-activated disulfide prodrug moiety, a DT-diaphorase-activated quinone prodrug moiety or a reactive oxygen species-activated aryl boronic acid or aryl boronic ester prodrug moiety. The invention further relates to pyrrolobenzodiazepine prodrug dimer-antibody conjugates.

  这项发明涉及具有谷胱甘肽活化二硫键前药基团、DT-二氢呋喃酮酶活化醌前药基团或活化氧化物种的芳基硼酸或芳基硼酯前药基团的吡咯苯并二氮杂环烷单体和二聚体前药。该发明还涉及吡咯苯并二氮杂环烷前药二聚体-抗体共轭物。
• Phosphoramide compounds
  申请人：——

  公开号：US20030008850A1

  公开（公告）日：2003-01-09

  The invention provides a compound of formula I: 1 wherein R 1 , R a , R b , R c , and R d have any of the values defined in the specification, as well as pharmaceutical compositions comprising such compounds or salts. The compounds are useful for treating cancer in animals.

  本发明提供了一种I式化合物：1，其中R1、Ra、Rb、Rc和Rd的任何值均定义在规范中，以及包含这种化合物或盐的药物组合物。这些化合物对于治疗动物的癌症具有用处。
• Prodrugs for targeting hypoxic tissues: Regiospecific elimination of aspirin from reduced indolequinones
  作者：M Jaffar、S.A Everett、M.A Naylor、S.G Moore、S Ulhaq、K.B Patel、M.R.L Stratford、J Nolan、P Wardman、I.J Stratford

  DOI：10.1016/s0960-894x(98)00695-7

  日期：1999.1

  A series of regioisomeric derivatives of a 1-methylindole-4,7-dione were synthesised, substituted with a 2-acetoxybenzoate leaving group linked through the (indol-2-yl)methyl or (indol-3-yl)methyl (or propenyl) positions. Reductive elimination of the leaving group occurred from the (indol-3-yl)methyl derivatives but not the 2-substituted regioisomers, indicating that only the C-3 position may be utilised in bioreductively-activated drug delivery, which was demonstrated with an aspirin prodrug. (C) 1998 Elsevier Science Ltd. All rights reserved.
• PYRROLOBENZODIAZEPINE PRODRUGS AND ANTIBODY CONJUGATES THEREOF
  申请人：GENENTECH, INC.

  公开号：US20190175749A1

  公开（公告）日：2019-06-13

  The invention relates generally to pyrrolobenzodiazepine monomer and dimer prodrugs having a glutathione-activated disulfide prodrug moiety, a DT-diaphorase-activated quinone prodrug moiety or a reactive oxygen species-activated aryl boronic acid or aryl boronic ester prodrug moiety. The invention further relates to pyrrolobenzodiazepine prodrug dimer-antibody conjugates.
• US6656926B2
  申请人：——

  公开号：US6656926B2

  公开（公告）日：2003-12-02