(5-nitro-2-furyl)methyl N^ε-(O-allyllysyl)-N,N-bis(2-chloroethyl)phosphorodiamidate | 324770-54-9

• 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: (5-nitro-2-furyl)methyl N^ε-(O-allyllysyl)-N,N-bis(2-chloroethyl)phosphorodiamidate
• 英文别名: prop-2-enyl (2S)-2-amino-6-[[bis(2-chloroethyl)amino-[(5-nitrofuran-2-yl)methoxy]phosphoryl]amino]hexanoate
• CAS: 324770-54-9
• 化学式: C₁₈H₂₉Cl₂N₄O₇P
• 分子量: 515.331
• InChiKey: KFPKZCCRBRZGPO-KXJSNILUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  32
• 可旋转键数：
  18
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.61
• 拓扑面积：
  153
• 氢给体数：
  2
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  (5-nitro-2-furyl)methyl N^ε-(O-allyllysyl)-N,N-bis(2-chloroethyl)phosphorodiamidate 在 四(三苯基膦)钯 、 对甲苯亚磺酸 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 2.5h， 生成 (5-nitro-2-furyl)methyl Nε-(N10-(trifluoroacetyl)pteroyllysyl)-N,N-bis(2-chloroethyl)phosphorodiamidate
  参考文献：
  名称：

  Synthesis and Evaluation of Pteroic Acid-Conjugated Nitroheterocyclic Phosphoramidates as Folate Receptor-Targeted Alkylating Agents

  摘要：

  A novel nitroheterocyclic bis(haloethyl)phosphoramidate prodrug linked through lysine to a pteroic acid has been prepared and evaluated as a potential alkylating agent, to target tumor cells that overexpress the folate receptor. The prodrug exhibited IC50 values in the micromolar range and was 10-400-fold less cytotoxic in vitro than the phosphoramidate that lacks the lysine-pteroyl moiety. The data does not support a contribution of the folate receptor to cytotoxicity. In an attempt to determine the basis for the decreased cytotoxicity in the pteroyl-lysyl analogue, compounds were prepared in which the lysine-pteroyl moiety was replaced with lysine alone or with an n-propyl group. The n-propyl and the lysyl analogues were on average 3.8- and 21-fold less potent than the unsubstituted bis(haloethyl)phosphoramidate, respectively. Chemical reduction of the prodrugs followed by P-31 NMR kinetics demonstrated that all of the phosphoramidate anions cyclized to the aziridinium ion at similar rates and gave comparable product distributions, suggesting that changes in chemical activation did not account for the differences in cytotoxicity. It, is likely that folate receptor-mediated transport is not sufficient to deliver adequate intracellular concentrations of the cytotoxic phosphoramide mustard.

  DOI：

  10.1021/jm000306g
• 作为产物：
  描述：

  2-chloro-N-(2-chloroethyl)-N-[chloro-[(5-nitrofuran-2-yl)methoxy]phosphoryl]ethanamine 、 allyl lysinate bistrifluoroacetate 在 N,N-二异丙基乙胺 作用下， 以 乙腈 为溶剂， 反应 2.5h， 以90%的产率得到(5-nitro-2-furyl)methyl N^ε-(O-allyllysyl)-N,N-bis(2-chloroethyl)phosphorodiamidate
  参考文献：
  名称：

  Synthesis and Evaluation of Pteroic Acid-Conjugated Nitroheterocyclic Phosphoramidates as Folate Receptor-Targeted Alkylating Agents

  摘要：

  A novel nitroheterocyclic bis(haloethyl)phosphoramidate prodrug linked through lysine to a pteroic acid has been prepared and evaluated as a potential alkylating agent, to target tumor cells that overexpress the folate receptor. The prodrug exhibited IC50 values in the micromolar range and was 10-400-fold less cytotoxic in vitro than the phosphoramidate that lacks the lysine-pteroyl moiety. The data does not support a contribution of the folate receptor to cytotoxicity. In an attempt to determine the basis for the decreased cytotoxicity in the pteroyl-lysyl analogue, compounds were prepared in which the lysine-pteroyl moiety was replaced with lysine alone or with an n-propyl group. The n-propyl and the lysyl analogues were on average 3.8- and 21-fold less potent than the unsubstituted bis(haloethyl)phosphoramidate, respectively. Chemical reduction of the prodrugs followed by P-31 NMR kinetics demonstrated that all of the phosphoramidate anions cyclized to the aziridinium ion at similar rates and gave comparable product distributions, suggesting that changes in chemical activation did not account for the differences in cytotoxicity. It, is likely that folate receptor-mediated transport is not sufficient to deliver adequate intracellular concentrations of the cytotoxic phosphoramide mustard.

  DOI：

  10.1021/jm000306g

文献信息

• Synthesis and Evaluation of Pteroic Acid-Conjugated Nitroheterocyclic Phosphoramidates as Folate Receptor-Targeted Alkylating Agents
  作者：Gali Steinberg、Richard F. Borch

  DOI：10.1021/jm000306g

  日期：2001.1.1

  A novel nitroheterocyclic bis(haloethyl)phosphoramidate prodrug linked through lysine to a pteroic acid has been prepared and evaluated as a potential alkylating agent, to target tumor cells that overexpress the folate receptor. The prodrug exhibited IC50 values in the micromolar range and was 10-400-fold less cytotoxic in vitro than the phosphoramidate that lacks the lysine-pteroyl moiety. The data does not support a contribution of the folate receptor to cytotoxicity. In an attempt to determine the basis for the decreased cytotoxicity in the pteroyl-lysyl analogue, compounds were prepared in which the lysine-pteroyl moiety was replaced with lysine alone or with an n-propyl group. The n-propyl and the lysyl analogues were on average 3.8- and 21-fold less potent than the unsubstituted bis(haloethyl)phosphoramidate, respectively. Chemical reduction of the prodrugs followed by P-31 NMR kinetics demonstrated that all of the phosphoramidate anions cyclized to the aziridinium ion at similar rates and gave comparable product distributions, suggesting that changes in chemical activation did not account for the differences in cytotoxicity. It, is likely that folate receptor-mediated transport is not sufficient to deliver adequate intracellular concentrations of the cytotoxic phosphoramide mustard.