2',3'-didehydro-2',3'-dideoxythymidine-5'-(2-chlorophenylmethoxyalaninylphosphate)

• 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: 2',3'-didehydro-2',3'-dideoxythymidine-5'-(2-chlorophenylmethoxyalaninylphosphate)
• 英文别名: methyl (2S)-2-[[(2-chlorophenoxy)-[[(2S,5R)-5-(5-methyl-2,4-dioxo-pyrimidin-1-yl)-2,5-dihydrofuran-2-yl]methoxy]phosphoryl]amino]propanoate；methyl (2S)-2-[[(2-chlorophenoxy)-[[(2S,5R)-5-(5-methyl-2,4-dioxopyrimidin-1-yl)-2,5-dihydrofuran-2-yl]methoxy]phosphoryl]amino]propanoate
• 化学式: C₂₀H₂₃ClN₃O₈P
• 分子量: 499.845
• InChiKey: KTAGXYUYBSTYKU-OXLJJGGYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  33
• 可旋转键数：
  10
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  133
• 氢给体数：
  2
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  2',3'-didehydro-2',3'-dideoxythymidine-5'-(2-chlorophenylmethoxyalaninylphosphate) 在 Subtilisin Carlsberg serine protease 作用下， 以 甲醇 、 水 为溶剂， 生成 邻氯苯酚 、 alaninyl-d4T-monophosphate
  参考文献：
  名称：

  蛋白酶介导的司他夫定磷酸氨基芳基酯衍生物的酶促水解和活化。

  摘要：

  几种蛋白酶能够水解司他夫定的芳基取代的氨基磷酸酯衍生物，从而形成活性代谢产物丙氨酰基d4T单磷酸酯。枯草蛋白酶蛋白酶A，枯草杆菌蛋白酶Griseus，枯草杆菌蛋白酶Carlsberg，木瓜，芽孢杆菌是水解司他夫定衍生物的最有效蛋白酶之一，并且使用几种蛋白酶抑制剂来阻断这些氨基磷酸酯衍生物的水解已证实了其活性的特异性。我们发现这些蛋白酶在司他夫定衍生物的磷中心具有手性选择性。我们的结果表明，细胞蛋白酶可能负责这些氨基磷酸酯衍生物的活化。此外，我们表明，酶促水解发生在这些前药的羧甲基酯侧链上，并且不会发生这些酶对磷中心的直接攻击。最后，我们描述了迄今未知的司他夫定的这些氨基磷酸酯衍生物的活化和病毒抑制特性的新型活化途径。

  DOI：

  10.1016/j.ejmech.2004.11.015
• 作为产物：
  描述：

  司他夫定 、 在 N-甲基咪唑 作用下， 以 四氢呋喃 为溶剂， 反应 16.0h， 以45%的产率得到2',3'-didehydro-2',3'-dideoxythymidine-5'-(2-chlorophenylmethoxyalaninylphosphate)
  参考文献：
  名称：

  Design and Synthesis of Lipophilic Phosphoramidate d4T-MP Prodrugs Expressing High Potency Against HIV in Cell Culture:  Structural Determinants for in Vitro Activity and QSAR

  摘要：

  A series of new substituted-aryl phosphoramidate derivatives of the anti-HIV drug d4T were synthesized as membrane-soluble nucleotide prodrugs, to extend and quantify the SAR observed for an earlier series of related derivatives, All of the compounds were found to be significantly more potent against HIV in cell culture than the nucleoside analogue d4T, and most were also found to be significantly more potent than the parent phosphoramidate. A Hansch type QSAR analysis was applied to-the combined series of 21 compounds. The results of this analysis revealed anti-HIV activity to be principally dependent on lipophilicity in a quadratic manner, with terms representing substituent steric bulk and electronic effects having a minimal significance.

  DOI：

  10.1021/jm9807104

文献信息

• Protease-mediated enzymatic hydrolysis and activation of aryl phosphoramidate derivatives of stavudine
  作者：T.K. Venkatachalam、P. Samuel、S. Qazi、F.M. Uckun

  DOI：10.1016/j.ejmech.2004.11.015

  日期：2005.5

  several protease inhibitors to block the hydrolysis of these phosphoramidate derivatives. We found that these proteases exhibit chiral selectivity at the phosphorus center of stavudine derivatives. Our results indicate that cellular proteases may be responsible for the activation of these phosphoramidate derivatives. In addition, we show that the enzymatic hydrolysis takes place at the carboxymethyl ester

  几种蛋白酶能够水解司他夫定的芳基取代的氨基磷酸酯衍生物，从而形成活性代谢产物丙氨酰基d4T单磷酸酯。枯草蛋白酶蛋白酶A，枯草杆菌蛋白酶Griseus，枯草杆菌蛋白酶Carlsberg，木瓜，芽孢杆菌是水解司他夫定衍生物的最有效蛋白酶之一，并且使用几种蛋白酶抑制剂来阻断这些氨基磷酸酯衍生物的水解已证实了其活性的特异性。我们发现这些蛋白酶在司他夫定衍生物的磷中心具有手性选择性。我们的结果表明，细胞蛋白酶可能负责这些氨基磷酸酯衍生物的活化。此外，我们表明，酶促水解发生在这些前药的羧甲基酯侧链上，并且不会发生这些酶对磷中心的直接攻击。最后，我们描述了迄今未知的司他夫定的这些氨基磷酸酯衍生物的活化和病毒抑制特性的新型活化途径。
• Design and Synthesis of Lipophilic Phosphoramidate d4T-MP Prodrugs Expressing High Potency Against HIV in Cell Culture:  Structural Determinants for in Vitro Activity and QSAR
  作者：Adam Q. Siddiqui、Christopher McGuigan、Carlo Ballatore、Fabio Zuccotto、Ian H. Gilbert、Erik De Clercq、Jan Balzarini

  DOI：10.1021/jm9807104

  日期：1999.10.1

  A series of new substituted-aryl phosphoramidate derivatives of the anti-HIV drug d4T were synthesized as membrane-soluble nucleotide prodrugs, to extend and quantify the SAR observed for an earlier series of related derivatives, All of the compounds were found to be significantly more potent against HIV in cell culture than the nucleoside analogue d4T, and most were also found to be significantly more potent than the parent phosphoramidate. A Hansch type QSAR analysis was applied to-the combined series of 21 compounds. The results of this analysis revealed anti-HIV activity to be principally dependent on lipophilicity in a quadratic manner, with terms representing substituent steric bulk and electronic effects having a minimal significance.