tert-butyl 1,2-dihydro-5-(benzyloxy)-1-(chloromethyl)-6-(carboxylic acid)benzo[e]indole-3-carboxylate | 1433974-78-7

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 英文名称: tert-butyl 1,2-dihydro-5-(benzyloxy)-1-(chloromethyl)-6-(carboxylic acid)benzo[e]indole-3-carboxylate
• 英文别名: tert-butyl 1,2-dihydro-5-(benzyloxy)-1-(chloromethyl)-6-(carboxylicacid)benzo[e]indole-3-carboxylate；1-(Chloromethyl)-3-[(2-methylpropan-2-yl)oxycarbonyl]-5-phenylmethoxy-1,2-dihydrobenzo[e]indole-6-carboxylic acid；1-(chloromethyl)-3-[(2-methylpropan-2-yl)oxycarbonyl]-5-phenylmethoxy-1,2-dihydrobenzo[e]indole-6-carboxylic acid
• CAS: 1433974-78-7
• 化学式: C₂₆H₂₆ClNO₅
• 分子量: 467.949
• InChiKey: LERHCGAWAVUFDR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.3
• 重原子数：
  33
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  76.1
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  tert-butyl 1,2-dihydro-5-(benzyloxy)-1-(chloromethyl)-6-(carboxylic acid)benzo[e]indole-3-carboxylate 在 N-甲基吗啉 、 2-氯-4,6-二甲氧基-1,3,5-三嗪 、 盐酸羟胺 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 8.0h， 以93%的产率得到
  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
• 作为产物：
  描述：

  二氧化碳 、 tert-butyl 1,2-dihydro-5-(benzyloxy)-6-bromo-1-(chloromethyl)-1H-benzo[e]indole-3(2H)-carboxylate 在 苯基锂 、 盐酸 作用下， 以 四氢呋喃 、 水 为溶剂， 反应 0.75h， 以94%的产率得到tert-butyl 1,2-dihydro-5-(benzyloxy)-1-(chloromethyl)-6-(carboxylic acid)benzo[e]indole-3-carboxylate
  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

• [EN] CYCLIC N-ACYL O-AMINO PHENOL CBI DERIVATIVE<br/>[FR] DÉRIVÉ DE N-ACYL O-AMINO PHÉNOL CBI CYCLIQUE
  申请人：SCRIPPS RESEARCH INST

  公开号：WO2014160586A8

  公开（公告）日：2014-11-06
• 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.