2-bromoethyl N,N,N',N'-tetraethylphosphorodiamidate | 158382-41-3

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 有机磷酸及其衍生物
• 英文名称: 2-bromoethyl N,N,N',N'-tetraethylphosphorodiamidate
• 英文别名: 2-Bromoethyl-N,N,N,N-tetraethylphosphorodiamidate；N-[2-bromoethoxy(diethylamino)phosphoryl]-N-ethylethanamine
• CAS: 158382-41-3
• 化学式: C₁₀H₂₄BrN₂O₂P
• 分子量: 315.191
• InChiKey: UIQBIPJYXJRMGT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  16
• 可旋转键数：
  9
• 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'-tetraethylphosphorodiamidate 在 过氧乙酸 、 sodium hydroxide 、 双氧水 、 溶剂黄146 作用下， 以 乙醇 为溶剂， 反应 6.5h， 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 、 水 、 丙酮 为溶剂， 反应 33.0h， 生成 2-bromoethyl N,N,N',N'-tetraethylphosphorodiamidate
  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

• [EN] GLUTATHIONE S-TRANSFERASE-ACTIVATED COMPOUNDS<br/>[FR] COMPOSES ACTIVES PAR LA GLUTATHIONE S-TRANSFERASE
  申请人：TERRAPIN TECHNOLOGIES, INC.

  公开号：WO1995009866A1

  公开（公告）日：1995-04-13

  (EN) Compounds of formula (1) or the amides, esters or salts thereof, wherein: L is an electron withdrawing leaving group; Sx is S=O, O=S=O, S=NH, HN=S=O, Se=O, O=Se=O, Se=NH, HN=Se=O, S+R4 wherein R4 is alkyl (1-6C), or O-C=O or HN-C=O; each R of R1, R2 and R3 is independently H or a noninterfering substituent; n is 0, 1 or 2; Y-CO is selected from the group consisting of $g(g)-Glu, $g(b)-Asp, Glu, Asp, $g(g)-GluGly, $g(b)-AspGly, GluGly and AspGly; and AAc is an amino acid linked through a peptide bond to the ramainder of said compound of Formula (1), are disclosed. These compounds are useful prodrugs for selective treatment of target tissues which contain compatible glutathione S-transferase (GST) isoenzymes, and simultaneously elevate the levels of GM progenitor cells in bone marrow.(FR) Composés de la formule (I), ou amides, esters ou sels desdits composés, formule dans laquelle L est un groupe partant retirant des électrons, Sx est S=O, O=S=O, S=NH, HN=S=O, Se=O, O=Se=O, Se=NH, HN=Se=O, S+R4, R4 étant alkyle (1-6C) ou O-C=O ou HN-C=O; chaque R parmi R1, R2 et R3 est indépendamment H ou un substituant non intervenant; n est 0, 1 ou 2; Y-CO est choisi dans le groupe constitué de $g(g)-Glu, $g(b)-Asp, Glu, Asp, $g(g)-GluGly, $g(b)-AspGly, GluGly et AspGly; et AAc est un acide aminé relié par une liaison peptidique au reste dudit composé de formule (I). Ces composés sont des promédicaments utiles pour le traitement sélectif de tissus cibles qui contiennent des isoenzymes glutathione S-transférase (GST) et ils élèvent simultanément les taux de cellules parentes de granulocytes macrophages dans la moelle osseuse.

  化合物的化学式为(1)，或其酰胺、酯或盐，其中：L是一个电子吸引的离去基团；Sx是S=O，O=S=O，S=NH，HN=S=O，Se=O，O=Se=O，Se=NH，HN=Se=O，S+R4，其中R4是烷基(1-6C)，或O-C=O或HN-C=O；R1，R2和R3中的每个R独立地是H或非干扰性取代基；n为0、1或2；Y-CO从$g(g)-Glu、$g(b)-Asp、Glu、Asp、$g(g)-GluGly、$g(b)-AspGly、GluGly和AspGly组中选择；AAc是通过肽键连接到化合物的剩余部分的氨基酸。这些化合物是有用的前药，用于选择性治疗含有兼容谷胱甘肽S转移酶(GST)同工酶的靶组织，并同时提高骨髓中GM祖细胞的水平。
• GLUTATHIONE S-TRANSFERASE-ACTIVATED COMPOUNDS
  申请人：TERRAPIN TECHNOLOGIES, INC.

  公开号：EP0721465A1

  公开（公告）日：1996-07-17
• US5545621A
  申请人：——

  公开号：US5545621A

  公开（公告）日：1996-08-13
• US5556942A
  申请人：——

  公开号：US5556942A

  公开（公告）日：1996-09-17
• 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.