N-methyl-2-(2-bromoethyl) thymidyl phosphoramidate | 310398-27-7

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 嘧啶核苷
• 英文名称: N-methyl-2-(2-bromoethyl) thymidyl phosphoramidate
• 英文别名: 5'-thymidyl N-methyl-N-(2-bromoethyl)phosphoramidic acid；N-(2-bromoethyl)-[[(2R,3S,5R)-3-hydroxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy]-N-methylphosphonamidic acid
• CAS: 310398-27-7
• 化学式: C₁₃H₂₁BrN₃O₇P
• 分子量: 442.203
• InChiKey: NBHJTKHTYALHMB-HBNTYKKESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -1.3
• 重原子数：
  25
• 可旋转键数：
  7
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.69
• 拓扑面积：
  129
• 氢给体数：
  3
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  β-D-glucose 1-phosphate 、 N-methyl-2-(2-bromoethyl) thymidyl phosphoramidate 在 吡啶 、 四丁基氯化铵 作用下， 生成 Thymidine, 5'-O-(3-methyl-2-oxido-1,3,2-oxazaphospholidin-2-yl)- 、 thymidine 5'-diphospho-β-D-glucose
  参考文献：
  名称：

  一种制备二磷酸核苷的新方法。

  摘要：

  [反应-见正文]糖核苷二磷酸酯是使用有效的磷酸酯偶联反应制备的，该反应采用高反应性的两性离子氨基磷酸酯中间体作为磷酸化物质。

  DOI：

  10.1021/ol0167309
• 作为产物：
  描述：

  5'-thymidyl benzyl N-methyl-N-(2-bromoethyl)phosphoramidate 在 10percent Pd/C 氢气 作用下， 以 四氢呋喃 为溶剂， 反应 0.17h， 生成 N-methyl-2-(2-bromoethyl) thymidyl phosphoramidate
  参考文献：
  名称：

  Synthesis and Biological Activity of Novel 5-Fluoro-2‘-deoxyuridine Phosphoramidate Prodrugs

  摘要：

  A series of novel haloethyl and piperidyl phosphoramidate FdUMP prodrug analogues has been synthesized, and the growth inhibitory activity of these compounds has been evaluated against L1210 mouse leukemia cells. All compounds exhibited potent inhibition of L1210 cell proliferation with IC50 values in the nanomolar range. Growth inhibition was reversed by the addition of 5 muM thymidine, suggesting a mechanism of action involving the intracellular release of FdUMP. P-31 NMR studies carried out on model haloethyl phosphoramidates confirm the release of nucleotide via cyclization of the phosphoramidate anion to the aziridinium ion intermediate followed by hydrolysis of the P-N bond. The data suggests that <50% of the prodrug is converted to FdUMP intracellularly by this pathway. Piperidyl phosphoramidate analogues are also converted to nucleotide intracellularly, presumably by the action of an endogenous phosphoramidase.

  DOI：

  10.1021/jm000301j

文献信息

• Activation Mechanisms of Nucleoside Phosphoramidate Prodrugs
  作者：Caren L. Freel Meyers、Richard F. Borch

  DOI：10.1021/jm000302b

  日期：2000.11.1

  A series of thymidine and tetrahydrofurfuryl phosphoramidates bearing haloethyl or piperidyl sulostituents was synthesized and used to investigate the activation mechanisms of nucleoside phosphoramidate prodrugs. Structure assignments for the tetrahydrofurfuryl reaction products were confirmed by comparison to authentic samples. Structural assignments for thymidine phosphoramidate reaction products were made by analogy to the tetrahydrofurfuryl products. Generation of the phosphoramidate anion leads to cyclization and subsequent nucleophilic attack at carbon and phosphorus of the resulting aziridinium ion intermediate to give the observed products. Nucleophilic attack by water at carbon and phosphorus occurs without selectivity, supporting a mechanism of action of haloethylamine nucleoside prodrugs involving intracellular release of the nucleotide. Activation of the benzotriazolyl piperidyl phosphoramidates is followed by P-N bond hydrolysis; this reaction is subject to specific acid catalysis and to nucleophilic catalysis by 1-hydroxybenzotriazole. These results suggest that the mechanism of action of the piperidyl nucleoside phosphoramidates involves the intracellular release of the active nucleotide following P-N bond cleavage, presumably by the action of an endogenous phosphoramidase.
• A Novel Method for the Preparation of Nucleoside Diphosphates
  作者：Caren L. Freel Meyers、Richard F. Borch

  DOI：10.1021/ol0167309

  日期：2001.11.1

  [reaction--see text] Sugar nucleoside diphosphates have been prepared using an efficient phosphate coupling reaction that employs a highly reactive zwitterionic phosphoramidate intermediate as the phosphorylating species.

  [反应-见正文]糖核苷二磷酸酯是使用有效的磷酸酯偶联反应制备的，该反应采用高反应性的两性离子氨基磷酸酯中间体作为磷酸化物质。
• Synthesis and Biological Activity of Novel 5-Fluoro-2‘-deoxyuridine Phosphoramidate Prodrugs
  作者：Caren L. Freel Meyers、Liping Hong、Carolyn Joswig、Richard F. Borch

  DOI：10.1021/jm000301j

  日期：2000.11.1

  A series of novel haloethyl and piperidyl phosphoramidate FdUMP prodrug analogues has been synthesized, and the growth inhibitory activity of these compounds has been evaluated against L1210 mouse leukemia cells. All compounds exhibited potent inhibition of L1210 cell proliferation with IC50 values in the nanomolar range. Growth inhibition was reversed by the addition of 5 muM thymidine, suggesting a mechanism of action involving the intracellular release of FdUMP. P-31 NMR studies carried out on model haloethyl phosphoramidates confirm the release of nucleotide via cyclization of the phosphoramidate anion to the aziridinium ion intermediate followed by hydrolysis of the P-N bond. The data suggests that <50% of the prodrug is converted to FdUMP intracellularly by this pathway. Piperidyl phosphoramidate analogues are also converted to nucleotide intracellularly, presumably by the action of an endogenous phosphoramidase.