tert-butyl 10-(chloromethyl)-5-methyl-4-oxo-9,10-dihydro-4H-pyrrolo[3′,2′:5,6]naphtho[1,8-de][1,2]oxazine-8(5H)-carboxylate | 1433974-81-2

• 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: tert-butyl 10-(chloromethyl)-5-methyl-4-oxo-9,10-dihydro-4H-pyrrolo[3′,2′:5,6]naphtho[1,8-de][1,2]oxazine-8(5H)-carboxylate
• 英文别名: tert-butyl 10-(chloromethyl)-5-methyl-4-oxo-9,10-dihydro-4H-pyrrolo[3',2':5,6]naphtho[1,8-de][1,2]oxazine-8(5H)-carboxylate；Tert-butyl 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-carboxylate；tert-butyl 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-carboxylate
• CAS: 1433974-81-2
• 化学式: C₂₀H₂₁ClN₂O₄
• 分子量: 388.851
• InChiKey: PJFGCGIILHLKJD-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  27
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  59.1
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  tert-butyl 10-(chloromethyl)-5-methyl-4-oxo-9,10-dihydro-4H-pyrrolo[3′,2′:5,6]naphtho[1,8-de][1,2]oxazine-8(5H)-carboxylate 在 盐酸 作用下， 以 正己烷 、 乙酸乙酯 、 异丙醇 为溶剂， 反应 20.25h， 生成 (S)-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
• 作为产物：
  描述：

  tert-butyl 1,2-dihydro-5-(benzyloxy)-1-(chloromethyl)-6-(carboxylic acid)benzo[e]indole-3-carboxylate 在 草酰氯 、 palladium 10% on activated carbon 、 氢气 、 二甲基亚砜 、 N,N-二甲基甲酰胺 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 反应 5.0h， 生成 tert-butyl 10-(chloromethyl)-5-methyl-4-oxo-9,10-dihydro-4H-pyrrolo[3′,2′:5,6]naphtho[1,8-de][1,2]oxazine-8(5H)-carboxylate
  参考文献：
  名称：

  [EN] CYCLIC N-ACYL O-AMINO PHENOL CBI DERIVATIVE
  [FR] DÉRIVÉ DE N-ACYL O-AMINO PHÉNOL CBI CYCLIQUE

  摘要：

  公开号：

  WO2014160586A8

文献信息

• Cyclic N-Acyl O-Amino Phenol CBI Derivative
  申请人：BOGER Dale L.

  公开号：US20160016972A1

  公开（公告）日：2016-01-21

  A group of cyclic N-acyl O-amino phenol CBI derivatives were synthesized and shown to be pro-drugs, subject to reductive activation by cleavage of a N—O bond, effectively releasing the free drug in functional in vitro cellular assays for cytotoxic activity approaching the activity of the free drug, yet remain essentially stable to ex vivo DNA alkylation conditions. Assessment of the in vivo antitumor activity of a representative pro-drug indicates that a contemplated pro-drug approaches the potency and exceeds the efficacy of the free drug itself (CBI-indole 2 ), indicating that the inactive pro-drugs not only effectively release the free drug in vivo, but that they offer additional advantages related to a controlled or targeted release in vivo.

  一组环状N-酰基O-氨基苯酚CBI衍生物被合成并表明是前药，受还原活化的影响，通过断裂N-O键有效地释放自由药物，在体外细胞活性测定中，细胞毒性活性接近自由药物，但基本稳定于体外DNA烷基化条件。对代表性前药的体内抗肿瘤活性评估表明，考虑的前药接近于自由药物的效力，并超过了自由药物本身（CBI-indole2），表明不活性前药不仅在体内有效地释放自由药物，而且它们提供了与体内控制或靶向释放相关的额外优势。
• [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
• US9586974B2
  申请人：——

  公开号：US9586974B2

  公开（公告）日：2017-03-07
• 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.