5-fluoro-2'-deoxy-5'-uridyl 5-nitro-2-furylmethyl bis(2-bromoethyl)phosphoramidate

• 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: 5-fluoro-2'-deoxy-5'-uridyl 5-nitro-2-furylmethyl bis(2-bromoethyl)phosphoramidate
• 英文别名: 1-[(2R,4S,5R)-5-[[[bis(2-bromoethyl)amino]-[(5-nitrofuran-2-yl)methoxy]phosphoryl]oxymethyl]-4-hydroxyoxolan-2-yl]-5-fluoropyrimidine-2,4-dione
• 化学式: C₁₈H₂₂Br₂FN₄O₁₀P
• 分子量: 664.174
• InChiKey: CPASFEPFAMMOIU-GBAYKSTESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.9
• 重原子数：
  36
• 可旋转键数：
  12
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  177
• 氢给体数：
  2
• 氢受体数：
  12

反应信息

• 作为产物：
  描述：

  5-氟-2'-脱氧脲核苷 在 吡啶 、 N-甲基咪唑 、 乙基溴化镁 作用下， 以 四氢呋喃 为溶剂， 反应 13.0h， 生成 5-fluoro-2'-deoxy-5'-uridyl 5-nitro-2-furylmethyl bis(2-bromoethyl)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

• 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.