2-bromoethyl N,N,N',N'-tetrakis(2-chloroethyl)phosphorodiamidate | 158382-43-5

• 分子结构分类: 有机化合物 - 有机氮化合物
• 英文名称: 2-bromoethyl N,N,N',N'-tetrakis(2-chloroethyl)phosphorodiamidate
• 英文别名: N-[bis(2-chloroethyl)amino-(2-bromoethoxy)phosphoryl]-2-chloro-N-(2-chloroethyl)ethanamine
• CAS: 158382-43-5
• 化学式: C₁₀H₂₀BrCl₄N₂O₂P
• 分子量: 452.971
• InChiKey: KXLXFVMMTNRJBC-UHFFFAOYSA-N

物化性质

• 沸点：
  468.3±55.0 °C(Predicted)
• 密度：
  1.523±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  20
• 可旋转键数：
  13
• 环数：
  0.0
• sp3杂化的碳原子比例：
  1.0
• 拓扑面积：
  32.8
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  2-bromoethyl N,N,N',N'-tetrakis(2-chloroethyl)phosphorodiamidate 在 过氧乙酸 、 sodium hydroxide 、 双氧水 、 溶剂黄146 作用下， 以 乙醇 、 水 、 乙腈 为溶剂， 反应 2.0h， 生成 γ-glutamyl-α-amino-β-<<<2-<phosphoryl>oxy>ethyl>sulfonyl>propionyl>-(R)-(-)-phenylglycine
  参考文献：
  名称：

  Glutathione-S-transferase Activates Novel Alkylating Agents

  摘要：

  Alkylating agents which are activated by glutathione-S-transferases (GSTs) have been designed and synthesized. The model compound gamma-glutamyl-alpha-amino-beta-[(2-ethyl N,N,N',N'-tetraethylphosphorodiamidate)sulfonyl]propionylglycine (1) and the nitrogen mustards gamma-glutamyl-alpha-amino-beta- [[2-ethyl N,N,N',N'-tetrakis(2-chloroethyl)phosphorodiamidate]sulfonyl]propionylglycine (2) and gamma-glutamyl-alpha-amino-beta-[[2-ethyl-N,N,N',N'-tetrakis(2-chloroethyl)phosphorodiamidate]sulfonyl]propionyl-(R)-(-)-phenylglycine (3) were prepared via multistep chemical synthesis. The compounds were tested with recombinant human A1-1, M1a-1a and P1-1 GSTs. HPLC studies showed that the compounds were differentially and catalytically cleaved by biologically relevant concentrations of the GSTs. Mass spectral studies of the cleavage mixture of 2 showed that M1a-1a GST liberated the cytotoxic phosphate moiety needed for efficacy as an alkylating agent. Cell culture studies with MCF-7 breast cancer cells showed that 1 was not toxic at 200 mu M, while 2 and 3 showed IC(50)s of 40.6 and 37.5 mu M, respectively, for the same cell line. MCF-7 cells transfected to overexpress P1-1 GST showed enhanced sensitivity with 2 and 3, with IC(50)s of 20.9 and 9.5 mu M, respectively. This result correlates well with the rates of cleavage of 2 and 3 by P1-1 GST observed in vitro and demonstrates that higher levels of cellular P1-1 GST will give increased sensitivity to these drugs.

  DOI：

  10.1021/jm00036a016
• 作为产物：
  描述：

  二(2-氯乙基)胺盐酸盐 、 2-溴乙醇 在 三乙胺 、 三氯氧磷 作用下， 生成 2-bromoethyl N,N,N',N'-tetrakis(2-chloroethyl)phosphorodiamidate
  参考文献：
  名称：

  Glutathione-S-transferase Activates Novel Alkylating Agents

  摘要：

  Alkylating agents which are activated by glutathione-S-transferases (GSTs) have been designed and synthesized. The model compound gamma-glutamyl-alpha-amino-beta-[(2-ethyl N,N,N',N'-tetraethylphosphorodiamidate)sulfonyl]propionylglycine (1) and the nitrogen mustards gamma-glutamyl-alpha-amino-beta- [[2-ethyl N,N,N',N'-tetrakis(2-chloroethyl)phosphorodiamidate]sulfonyl]propionylglycine (2) and gamma-glutamyl-alpha-amino-beta-[[2-ethyl-N,N,N',N'-tetrakis(2-chloroethyl)phosphorodiamidate]sulfonyl]propionyl-(R)-(-)-phenylglycine (3) were prepared via multistep chemical synthesis. The compounds were tested with recombinant human A1-1, M1a-1a and P1-1 GSTs. HPLC studies showed that the compounds were differentially and catalytically cleaved by biologically relevant concentrations of the GSTs. Mass spectral studies of the cleavage mixture of 2 showed that M1a-1a GST liberated the cytotoxic phosphate moiety needed for efficacy as an alkylating agent. Cell culture studies with MCF-7 breast cancer cells showed that 1 was not toxic at 200 mu M, while 2 and 3 showed IC(50)s of 40.6 and 37.5 mu M, respectively, for the same cell line. MCF-7 cells transfected to overexpress P1-1 GST showed enhanced sensitivity with 2 and 3, with IC(50)s of 20.9 and 9.5 mu M, respectively. This result correlates well with the rates of cleavage of 2 and 3 by P1-1 GST observed in vitro and demonstrates that higher levels of cellular P1-1 GST will give increased sensitivity to these drugs.

  DOI：

  10.1021/jm00036a016

文献信息

• Process for and intermediates in the preparation of canfosfamide and its salts
  申请人：Boulanger A. William

  公开号：US20060135409A1

  公开（公告）日：2006-06-22

  A process for and intermediates in the preparation of canfosfamide and its salts. Some of the intermediates have anticancer activity.

  一种制备坎福膦酰胺及其盐的过程和中间体。其中一些中间体具有抗癌活性。
• PROCESS FOR AND INTERMEDIATES IN THE PREPARATION OF CANFOSFAMIDE AND ITS SALTS
  申请人：Boulanger William A.

  公开号：US20120238772A1

  公开（公告）日：2012-09-20

  A process for and intermediates in the preparation of canfosfamide and its salts. Some of the intermediates have anticancer activity.

  一种制备坎福磷酰胺及其盐的方法和中间体。其中一些中间体具有抗癌活性。
• PROCESS FOR AND INTERMEDIATES IN THE PREPARATION OF CANFOSFAMIDE AND ITS SALTS, PHARMACEUTICAL COMPOSITIONS CONTAINING SOME INTERMEDIATES, AND THEIR USE AS ANTICANCER AGENTS
  申请人：Telik, Inc.

  公开号：EP1827605B1

  公开（公告）日：2014-03-26
• US8198247B2
  申请人：——

  公开号：US8198247B2

  公开（公告）日：2012-06-12
• US8334266B2
  申请人：——

  公开号：US8334266B2

  公开（公告）日：2012-12-18