(R)-N-(2-(10-(chloromethyl)-5-methyl-4-oxo-5,8,9,10-tetrahydro-4H-pyrrolo[3',2':5,6]naphtho[1,8-de][1,2]oxazine-8-carbonyl)-1H-indol-5-yl)-1H-indole-2-carboxamide | 1433974-86-7

• 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: (R)-N-(2-(10-(chloromethyl)-5-methyl-4-oxo-5,8,9,10-tetrahydro-4H-pyrrolo[3',2':5,6]naphtho[1,8-de][1,2]oxazine-8-carbonyl)-1H-indol-5-yl)-1H-indole-2-carboxamide
• 英文别名: N-[2-[(11R)-11-(chloromethyl)-3-methyl-4-oxo-2-oxa-3,13-diazatetracyclo[7.6.1.05,16.010,14]hexadeca-1(16),5,7,9,14-pentaene-13-carbonyl]-1H-indol-5-yl]-1H-indole-2-carboxamide
• CAS: 1433974-86-7
• 化学式: C₃₃H₂₄ClN₅O₄
• 分子量: 590.038
• InChiKey: REIXRVGJWHKOOM-IBGZPJMESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.8
• 重原子数：
  43
• 可旋转键数：
  4
• 环数：
  8.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  111
• 氢给体数：
  3
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  tert-butyl 1,2-dihydro-5-(benzyloxy)-1-(chloromethyl)-6-(carboxylic acid)benzo[e]indole-3-carboxylate 在 盐酸 、 草酰氯 、 palladium 10% on activated carbon 、 N-甲基羟胺盐酸盐 、 氢气 、 二甲基亚砜 、 三乙胺 、 N,N-二甲基甲酰胺 作用下， 以 四氢呋喃 、 甲醇 、 正己烷 、 二氯甲烷 、 水 、 乙酸乙酯 、 异丙醇 为溶剂， 反应 25.25h， 生成 (R)-N-(2-(10-(chloromethyl)-5-methyl-4-oxo-5,8,9,10-tetrahydro-4H-pyrrolo[3',2':5,6]naphtho[1,8-de][1,2]oxazine-8-carbonyl)-1H-indol-5-yl)-1H-indole-2-carboxamide
  参考文献：
  名称：

  Efficacious Cyclic N-Acyl O-Amino Phenol Duocarmycin Prodrugs

  摘要：

  Two novel cyclic N-acyl O-amino phenol prodrugs are reported as new members of a unique class of reductively cleaved prodrugs of the duocarmycin family of natural products. These prodrugs were explored with the expectation that they may be cleaved selectively within hypoxic tumor environments that have intrinsically higher concentrations of reducing nucleophiles and were designed to liberate the free drug without the release of an extraneous group. In vivo evaluation of the prodrug 6 showed that it exhibits extraordinary efficacy (T/C > 1500, L1210; 6110 one year survivors), substantially exceeding that of the free drug, that its therapeutic window of activity is much larger, permitting a dosing >= 40-fold higher than the free drug, and yet that it displays a potency in vivo that approaches the free drug (within 3-fold). Clearly, the prodrug 6 benefits from either its controlled slow release of the free drug or its preferential intracellular reductive cleavage.

  DOI：

  10.1021/jm400413r

文献信息

• Efficacious Cyclic <i>N</i>-Acyl <i>O</i>-Amino Phenol Duocarmycin Prodrugs
  作者：Amanda L. Wolfe、Katharine K. Duncan、Nikhil K. Parelkar、Douglas Brown、George A. Vielhauer、Dale L. Boger

  DOI：10.1021/jm400413r

  日期：2013.5.23

  Two novel cyclic N-acyl O-amino phenol prodrugs are reported as new members of a unique class of reductively cleaved prodrugs of the duocarmycin family of natural products. These prodrugs were explored with the expectation that they may be cleaved selectively within hypoxic tumor environments that have intrinsically higher concentrations of reducing nucleophiles and were designed to liberate the free drug without the release of an extraneous group. In vivo evaluation of the prodrug 6 showed that it exhibits extraordinary efficacy (T/C > 1500, L1210; 6110 one year survivors), substantially exceeding that of the free drug, that its therapeutic window of activity is much larger, permitting a dosing >= 40-fold higher than the free drug, and yet that it displays a potency in vivo that approaches the free drug (within 3-fold). Clearly, the prodrug 6 benefits from either its controlled slow release of the free drug or its preferential intracellular reductive cleavage.