2'-deoxyzebularine 5'-[phenyl(benzoxy-L-alaninyl)]phosphate | 1092106-32-5

• 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: 2'-deoxyzebularine 5'-[phenyl(benzoxy-L-alaninyl)]phosphate
• 英文别名: benzyl (2S)-2-[[[(2R,3S,5R)-3-hydroxy-5-(2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-phenoxyphosphoryl]amino]propanoate
• CAS: 1092106-32-5
• 化学式: C₂₅H₂₈N₃O₈P
• 分子量: 529.486
• InChiKey: PYZMMVJUIASJSA-FXNXOIJDSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  37
• 可旋转键数：
  12
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  136
• 氢给体数：
  2
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  1-(2'-脱氧核糖基)-2-嘧啶酮 、 phenyl(benzyloxy-L-alaninyl)phosphorochloridate 在 N-甲基咪唑 作用下， 以 四氢呋喃 为溶剂， 以14.1%的产率得到2'-deoxyzebularine 5'-[phenyl(benzoxy-L-alaninyl)]phosphate
  参考文献：
  名称：

  Activation of p16 Gene Silenced by DNA Methylation in Cancer Cells by Phosphoramidate Derivatives of 2′-Deoxyzebularine

  摘要：

  We report herein the application of the phosphoramidate ProTide technology to improve the metabolism of the DNA methytransferase inhibitor, zebularine (Z). Zebularine is a riboside that must undergo a complex metabolic transformation before reaching the critical 2'-deoxyzebularine 5'-triphosphate (dZTP). Because 2'-deoxyzebularine (dZ) is not phosphorylated and therefore inactive, the ProTide strategy was employed to bypass the lack of phosphorylation of dZ and the inefficient reduction of zebularine 5'-diphosphate by ribonucleotide-diphosphate reductase required for zebularine. Several compounds were identified as more potent inhibitors of DNA methylation and stronger inducers of p16 tumor suppressor gene than zebularine. However, their activity was dependent on the administration of thymidine to overcome the potent inhibition of thymidylate synthase (TS) and deoxycytidine monophosphate (dCMP) deaminase by dZMP, which deprives cells of essential levels of thymidine. Intriguingly, the activity of the ProTides was cell line-dependent, and activation of p16 was manifest only in Cf-Pac-1 pancreatic ductal adenocarcinoma. cells.

  DOI：

  10.1021/jm8005965

文献信息

• Activation of <i>p16</i> Gene Silenced by DNA Methylation in Cancer Cells by Phosphoramidate Derivatives of 2′-Deoxyzebularine
  作者：Christine B. Yoo、Rocco Valente、Costantino Congiatu、Federica Gavazza、Annette Angel、Maqbool A. Siddiqui、Peter A. Jones、Christopher McGuigan、Victor E. Marquez

  DOI：10.1021/jm8005965

  日期：2008.12.11

  We report herein the application of the phosphoramidate ProTide technology to improve the metabolism of the DNA methytransferase inhibitor, zebularine (Z). Zebularine is a riboside that must undergo a complex metabolic transformation before reaching the critical 2'-deoxyzebularine 5'-triphosphate (dZTP). Because 2'-deoxyzebularine (dZ) is not phosphorylated and therefore inactive, the ProTide strategy was employed to bypass the lack of phosphorylation of dZ and the inefficient reduction of zebularine 5'-diphosphate by ribonucleotide-diphosphate reductase required for zebularine. Several compounds were identified as more potent inhibitors of DNA methylation and stronger inducers of p16 tumor suppressor gene than zebularine. However, their activity was dependent on the administration of thymidine to overcome the potent inhibition of thymidylate synthase (TS) and deoxycytidine monophosphate (dCMP) deaminase by dZMP, which deprives cells of essential levels of thymidine. Intriguingly, the activity of the ProTides was cell line-dependent, and activation of p16 was manifest only in Cf-Pac-1 pancreatic ductal adenocarcinoma. cells.