γ-glutamyl-α-amino-β-<(2-ethyl N,N,N',N'-tetraethylphosphorodiamidate)thio>propionylglycine

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: γ-glutamyl-α-amino-β-<(2-ethyl N,N,N',N'-tetraethylphosphorodiamidate)thio>propionylglycine
• 英文别名: γ-glutamyl-α-amino-β-[(2-ethyl N,N,N',N'-tetraethylphosphorodiamidate)thio]propionylglycine；2-Amino-5-[[3-[2-[bis(diethylamino)phosphoryloxy]ethylsulfanyl]-1-(carboxymethylamino)-1-oxopropan-2-yl]amino]-5-oxopentanoic acid
• 化学式: C₂₀H₄₀N₅O₈PS
• 分子量: 541.606
• InChiKey: ZYXNGLDQKDFQQV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -3
• 重原子数：
  35
• 可旋转键数：
  20
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.8
• 拓扑面积：
  217
• 氢给体数：
  5
• 氢受体数：
  12

反应信息

• 作为反应物：
  描述：

  γ-glutamyl-α-amino-β-<(2-ethyl N,N,N',N'-tetraethylphosphorodiamidate)thio>propionylglycine 在 过氧乙酸 、 双氧水 、 溶剂黄146 作用下， 生成 γ-glutamyl-α-amino-β-<(2-ethyl N,N,N',N'-tetraethylphosphordiamidate)sulfonyl>propionylglycine
  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：

  双(二乙基胺基)磷酰氯 在 甲醇 、 sodium hydroxide 、 sodium hydride 、 对甲苯磺酸 、 lithium bromide 作用下， 以 四氢呋喃 、 乙醇 、 水 、 丙酮 为溶剂， 反应 37.0h， 生成 γ-glutamyl-α-amino-β-<(2-ethyl N,N,N',N'-tetraethylphosphorodiamidate)thio>propionylglycine
  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

• Glutathione-S-transferase Activates Novel Alkylating Agents
  作者：Matthew H. Lyttle、Apparao Satyam、Michael D. Hocker、Karin E. Bauer、Colby G. Caldwell、Hon C. Hui、Amy S. Morgan、Alemayehu Mergia、Lawrence M. Kauvar

  DOI：10.1021/jm00036a016

  日期：1994.5

  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.