4-nitrobenzyl N,N-bis(2-chloroethyl)phosphorodiamidate | 630392-71-1

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 4-nitrobenzyl N,N-bis(2-chloroethyl)phosphorodiamidate
• 英文别名: LH7；4-nitrobenzyl N,N-bis(2-chloroethyl)phosphordiamidate；4-Nitrobenzylphosphoramide Mustard；N-[amino-[(4-nitrophenyl)methoxy]phosphoryl]-2-chloro-N-(2-chloroethyl)ethanamine
• CAS: 630392-71-1
• 化学式: C₁₁H₁₆Cl₂N₃O₄P
• 分子量: 356.145
• InChiKey: KHWBOTPHMVANOX-UHFFFAOYSA-N

物化性质

• 熔点：
  86-88 °C
• 沸点：
  507.7±60.0 °C(Predicted)
• 密度：
  1.437±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.4
• 重原子数：
  21
• 可旋转键数：
  8
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  101
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  4-nitrobenzyl N,N-bis(2-chloroethyl)phosphorodiamidate 在 1,4-dihydronicotinamide adenine dinucleotide 、 Escherichia coli K₁₂ nitroreductase 作用下， 以 various solvents 为溶剂， 反应 0.06h， 生成 4-methylenecyclohexa-2,5-dien-1-one oxime 、 磷酰胺氮芥
  参考文献：
  名称：

  Improving Nature's Enzyme Active Site with Genetically Encoded Unnatural Amino Acids

  摘要：

  The ability to site-specifically incorporate a diverse set of unnatural amino acids (> 30) into proteins and quickly add new structures of interest has recently changed our approach to protein use and study. One important question yet unaddressed with unnatural amino acids ( UAAs) is whether they can improve the activity of an enzyme beyond that available from the natural 20 amino acids. Herein, we report the > 30- fold improvement of prodrug activator nitroreductase activity with an UAA over that of the native active site and a > 2.3- fold improvement over the best possible natural amino acid. Because immense structural and electrostatic diversity at a single location can be sampled very quickly, UAAs can be implemented to improve enzyme active sites and tune a site to multiple substrates.

  DOI：

  10.1021/ja061099y
• 作为产物：
  描述：

  双(2-氯乙基)氨基磷酰二氯 、 对硝基苯甲醇 在 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 为溶剂， 反应 1.08h， 以62%的产率得到4-nitrobenzyl N,N-bis(2-chloroethyl)phosphorodiamidate
  参考文献：
  名称：

  设计，合成和评估用于软骨肉瘤化疗的靶向低氧激活前药。

  摘要：

  软骨肉瘤（CHS）中的肿瘤微环境是一种化学耐药和放射耐药性癌症，为开发软骨肉瘤靶向药物递送系统提供了独特的标志。使用季铵盐功能（QA）作为聚集蛋白聚糖的配体，CHS细胞外基质的主要高负电荷蛋白聚糖和2-硝基咪唑作为触发剂，可实现低氧反应性药物释放，从而实现肿瘤靶向。在以前的工作中，ICF05016被鉴定为小鼠骨骼肌黏液样软骨肉瘤模型中靶向蛋白聚糖的低氧激活前药，并且对QA功能与烷基接头长度的结构-活性关系进行了首次研究。在这里，我们报告研究的第二部分，即硝基芳香族触发物的修饰和蛋白聚糖靶向配体在芳环上的位置以及烷基化芥菜的性质。已经建立了合成方法来用末端叔烷基胺官能化N-1和C-4位的2-硝基咪唑环，并进行磷酸化步骤，即通过使用胺硼烷络合物，从而生成磷酰胺和异磷酰胺芥末以及带有四个2-氯乙基链的磷酰胺芥末。在使用还原性化学活化的初步研究中，除4-硝基苄基外，QA共轭物被证明可有效裂解并释放相应的芥末。但是N，N

  DOI：

  10.1016/j.bioorg.2020.103747

文献信息

• Nitroaryl phosphoramide compositions and methods for targeting and inhibiting undesirable cell growth or proliferation
  申请人：——

  公开号：US20040214798A1

  公开（公告）日：2004-10-28

  The present invention relates to nitroaryl-substituted phosphoramide prodrug compounds and methods of producing the same for use in targeting and inhibiting undesirable cell growth or proliferation.

  本发明涉及硝基芳基取代的磷酰胺前药化合物及其制备方法，用于靶向和抑制不良细胞生长或增殖。
• Nitroaryl Phosphoramides as Novel Prodrugs for <i>E. coli</i> Nitroreductase Activation in Enzyme Prodrug Therapy
  作者：Longqin Hu、Chengzhi Yu、Yongying Jiang、Jiye Han、Zhuorong Li、Patrick Browne、Paul R. Race、Richard J. Knox、Peter F. Searle、Eva I. Hyde

  DOI：10.1021/jm034133h

  日期：2003.11.1

  Cyclic and acyclic nitroaryl phosphoramide mustard analogues were activated by E. coli nitroreductase, an enzyme explored in GDEPT. The more active acyclic 4-nitrobenzyl phosphoramide mustard (7) showed 167 500x selective cytotoxicity toward nitroreductase-expressing V79 cells with an IC50 as low as 0.4 nM. This is about 100 x more active and 27x more selective than CB1954 (1). The superior activity was attributed to its better substrate activity (k(cat)/K-m 19x better than 1) and/or excellent cytotoxicity of phosphoramide mustard released.
• Design, synthesis and evaluation of targeted hypoxia-activated prodrugs applied to chondrosarcoma chemotherapy
  作者：Yvain Gerard、Aurélien Voissière、Caroline Peyrode、Marie-Josephe Galmier、Elise Maubert、Donia Ghedira、Sebastien Tarrit、Vincent Gaumet、Damien Canitrot、Elisabeth Miot-Noirault、Jean-Michel Chezal、Valérie Weber

  DOI：10.1016/j.bioorg.2020.103747

  日期：2020.5

  The tumor microenvironment in chondrosarcoma (CHS), a chemo- and radio-resistant cancer provides unique hallmarks for developing a chondrosarcoma targeted drug-delivery system. Tumor targeting could be achieved using a quaternary ammonium function (QA) as a ligand for aggrecan, the main high negative charged proteoglycan of the extracellular matrix of CHS, and a 2-nitroimidazole as trigger that enables

  软骨肉瘤（CHS）中的肿瘤微环境是一种化学耐药和放射耐药性癌症，为开发软骨肉瘤靶向药物递送系统提供了独特的标志。使用季铵盐功能（QA）作为聚集蛋白聚糖的配体，CHS细胞外基质的主要高负电荷蛋白聚糖和2-硝基咪唑作为触发剂，可实现低氧反应性药物释放，从而实现肿瘤靶向。在以前的工作中，ICF05016被鉴定为小鼠骨骼肌黏液样软骨肉瘤模型中靶向蛋白聚糖的低氧激活前药，并且对QA功能与烷基接头长度的结构-活性关系进行了首次研究。在这里，我们报告研究的第二部分，即硝基芳香族触发物的修饰和蛋白聚糖靶向配体在芳环上的位置以及烷基化芥菜的性质。已经建立了合成方法来用末端叔烷基胺官能化N-1和C-4位的2-硝基咪唑环，并进行磷酸化步骤，即通过使用胺硼烷络合物，从而生成磷酰胺和异磷酰胺芥末以及带有四个2-氯乙基链的磷酰胺芥末。在使用还原性化学活化的初步研究中，除4-硝基苄基外，QA共轭物被证明可有效裂解并释放相应的芥末。但是N，N
• Improving Nature's Enzyme Active Site with Genetically Encoded Unnatural Amino Acids
  作者：Jennifer C. Jackson、Sean P. Duffy、Kenneth R. Hess、Ryan A. Mehl

  DOI：10.1021/ja061099y

  日期：2006.8.1

  The ability to site-specifically incorporate a diverse set of unnatural amino acids (> 30) into proteins and quickly add new structures of interest has recently changed our approach to protein use and study. One important question yet unaddressed with unnatural amino acids ( UAAs) is whether they can improve the activity of an enzyme beyond that available from the natural 20 amino acids. Herein, we report the > 30- fold improvement of prodrug activator nitroreductase activity with an UAA over that of the native active site and a > 2.3- fold improvement over the best possible natural amino acid. Because immense structural and electrostatic diversity at a single location can be sampled very quickly, UAAs can be implemented to improve enzyme active sites and tune a site to multiple substrates.