methyl (2S)-3-methyl-2-[[[(2S,5R)-5-(5-methyl-2,4-dioxo-pyrimidin-1-yl)-2,5-dihydrofuran-2-yl]methoxy-phenoxy-phosphoryl]amino]butanoate

• 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: methyl (2S)-3-methyl-2-[[[(2S,5R)-5-(5-methyl-2,4-dioxo-pyrimidin-1-yl)-2,5-dihydrofuran-2-yl]methoxy-phenoxy-phosphoryl]amino]butanoate
• 英文别名: methyl (2S)-3-methyl-2-[[[(2S,5R)-5-(5-methyl-2,4-dioxopyrimidin-1-yl)-2,5-dihydrofuran-2-yl]methoxy-phenoxyphosphoryl]amino]butanoate
• 化学式: C₂₂H₂₈N₃O₈P
• 分子量: 493.453
• InChiKey: MWYOTFYZEYNJJL-NRDQIAGSSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  34
• 可旋转键数：
  11
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  133
• 氢给体数：
  2
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  司他夫定 在 六氯乙烷 、 三乙胺 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 20.0h， 生成 methyl (2S)-3-methyl-2-[[[(2S,5R)-5-(5-methyl-2,4-dioxo-pyrimidin-1-yl)-2,5-dihydrofuran-2-yl]methoxy-phenoxy-phosphoryl]amino]butanoate
  参考文献：
  名称：

  New and Efficient Approach to Aryl Phosphoramidate Derivatives of AZT/d4T as Anti-HIV Prodrugs

  摘要：

  二芳基磷酸酯与AZT或d4T的酯交换反应产生了芳基AZT/d4T H-磷酸酯，随后在六氯乙烷和三乙胺的存在下与氨基酸酯反应，得到膜可溶的抗HIV前药芳基磷酰胺衍生物AZT和d4T，产率良好。

  DOI：

  10.1055/s-2004-834800

文献信息

• One-Pot Synthesis of Aryl Phosphoramidate Derivatives of AZT/d4T as Anti-HIV Prodrugs
  作者：Hua Fu、Peng Jiang、Xin Guo、Yuyang Jiang、Yufen Zhao

  DOI：10.1055/s-2005-917085

  日期：——

  Arbuzov reaction of aryl phosphorodichloridite with mixture of one equivalent of AZT or d4T and one equivalent of tert-butyl alcohol led to the corresponding AZT/d4T aryl H-phosphonate diesters, and the following reactionof the H-phosphonate diesters with amino acid methyl esters in the presence of N-chloro-succinimide (NCS) produced membrane-soluble anti-HIV prodrugs AZT/d4T aryl phosphoramidate derivatives

  芳基二氯化磷与一当量 AZT 或 d4T 和一当量叔丁醇的混合物的 Arbuzov 反应产生相应的 AZT/d4T 芳基 H-膦酸二酯，H-膦酸二酯与氨基酸甲酯的以下反应N-氯-琥珀酰亚胺 (NCS) 的存在以良好的产率产生了膜溶性抗 HIV 前药 AZT/d4T 芳基氨基磷酸酯衍生物。
• Aryl Phosphoramidate Derivatives of d4T Have Improved Anti-HIV Efficacy in Tissue Culture and May Act by the Generation of a Novel Intracellular Metabolite
  作者：Christopher McGuigan、Dominique Cahard、Hendrika M. Sheeka、Erik De Clercq、Jan Balzarini

  DOI：10.1021/jm950605j

  日期：1996.1.1

  New phosphate derivatives of the anti-HIV nucleoside analogue d4T were prepared as potential membrane-soluble prodrugs of the bioactive free nucleotide. The enhanced antiviral potency and/or reduced cytotoxicity of the derivatives leads to an increase in selectivity relative to the parent nucleoside analogue. Moreover, the derivatives appear to bypass the dependence of the nucleoside on thymidine kinase-mediated activation, retaining full activity in thymidine kinase-deficient cells. This strongly suggests the successful intracellular delivery of free nucleotides by the masked phosphate triester prodrugs. This is further confirmed by studies using radiolabeled compound which clearly demonstrate the generation of d4T mono-, di- and triphosphates from the prodrug, even in thymidine kinase-deficient cells. Moreover, we herein report the generation of a new metabolite, a partially hydrolyzed phosphate diester, alaninyl d4T monophosphate. We suggest that at least part of the antiviral action of the prodrugs derives from the intracellular generation of such novel diesters which may add considerable weight to the suggested further preclinical development of the phosphate prodrugs.