So324 | 173070-83-2

• 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: So324
• 英文别名: methyl (2S)-2-[[[(2S,5R)-5-(5-methyl-2,4-dioxopyrimidin-1-yl)-2,5-dihydrofuran-2-yl]methoxy-phenoxyphosphoryl]amino]propanoate
• CAS: 173070-83-2
• 化学式: C₂₀H₂₄N₃O₈P
• 分子量: 465.4
• InChiKey: KSYQFBRGFAUSLN-VRWHETOPSA-N

物化性质

• 密度：
  1.356±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1
• 重原子数：
  32
• 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：

  So324 在 三乙胺 作用下， 反应 3.0h， 以0.051 g的产率得到alaninyl-d4T-monophosphate
  参考文献：
  名称：

  Aryl Phosphoramidate Derivatives of d4T Have Improved Anti-HIV Efficacy in Tissue Culture and May Act by the Generation of a Novel Intracellular Metabolite

  摘要：

  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.

  DOI：

  10.1021/jm950605j
• 作为产物：
  描述：

  司他夫定 在 N-氯代丁二酰亚胺 、 三乙胺 、 叔丁醇 作用下， 以 二氯甲烷 为溶剂， 反应 2.5h， 生成 So324
  参考文献：
  名称：

  作为抗 HIV 前药的 AZT/d4T 芳基磷酰胺衍生物的一锅法合成

  摘要：

  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。

  DOI：

  10.1055/s-2005-917085

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。
• Stereochemical influence on lipase-mediated hydrolysis and biological activity of stampidine and other stavudine phosphoramidates
  作者：T.K. Venkatachalam、P. Samuel、F.M. Uckun

  DOI：10.1016/j.bmc.2004.12.024

  日期：2005.3.1

  by lipase-mediated hydrolysis. The target site for the lipase appears to be the methyl ester group of the L-alanine side chain. Accordingly, the D-amino acid substituted isomers Rp or Sp}are resistant to lipase-mediated hydrolysis and exhibit substantially less anti-HIV activity. Molecular modeling results indicate that the L-amino acid configured isomers Rp or Sp} are preferred in the lipase binding

  马丹定和其他卤素取代的司他夫定氨基磷酸酯可通过脂肪酶介导的水解作用活化。脂肪酶的靶位点似乎是L-丙氨酸侧链的甲酯基。因此，D-氨基酸取代的异构体Rp或Sp}对脂肪酶介导的水解具有抗性并且表现出显着较少的抗HIV活性。分子模型结果表明，在脂肪酶结合口袋中，L-氨基酸构型的异构体Rp或Sp}是优选的。
• A mild and concise synthesis of aryloxy phosphoramidate prodrug of alcohols <i>via</i> transesterification reaction
  作者：Hanglu Ying、Jie Yao、Fan Wu、Yufen Zhao、Feng Ni

  DOI：10.1039/d2ra01995g

  日期：——

  A synthesis of aryloxy phosphoramidate prodrug of alcohols enabled by a transesterification strategy is described here. This reaction operates under mild conditions and thus has excellent functional group tolerance. This method provides an efficient and practical solution to the rapid construction of the aryloxy phosphoramidate prodrugs library for potential SAR studies.

  本文描述了通过酯交换策略实现醇的芳氧基氨基磷酸酯前药的合成。该反应在温和的条件下进行，因此具有优异的官能团耐受性。该方法为快速构建用于潜在S​​AR研究的芳氧基氨基磷酸酯前药库提供了有效且实用的解决方案。
• Potential Multifunctional Inhibitors of HIV-1 Reverse Transcriptase. Novel [AZT]-[TSAO-T] and [d4T]-[TSAO-T] Heterodimers Modified in the Linker and in the Dideoxynucleoside Region
  作者：Sonsoles Velázquez、Victoria Tuñón、María Luisa Jimeno、Cristina Chamorro、Erik De Clercq、Jan Balzarini、María José Camarasa

  DOI：10.1021/jm991092+

  日期：1999.12.1

  In an attempt to combine the anti-HIV-inhibitory capacity of nucleoside reverse transcriptase (RT) inhibitors (NRTI) and non-nucleoside RT inhibitors (NNRTI), several heterodimer analogues of the previously reported [AZT]-(CH(2))(3)-[TSAO-T] prototype have been prepared. In these novel series, other NRTIs, an expanded range of linkers with different conformational freedom and other attachment sites for these linkers on the base part of the NRTI analogue have been explored. Moreover, in order to circumvent the dependence of the NRTI moiety of the heterodimer an activation by cellular nucleoside kinases, novel heterodimers in which the NRTI is bearing a masked monophosphate group at the 5'-position are described. Among the novel heterodimers, several derivatives show a potent anti-HIV-1 activity, which proved comparable, or even superior, to that of the AZT heterodimer prototype. The nature of the NRTI was important far the eventual anti-HIV-1 activity. In particular, the d4T heterodimer derivative containing a propyl linker between the N-3 positions of the base of TSAO-T and d4T was similar to 5- to 10-fold more inhibitory to HIV-1 than the corresponding AZT heterodimer prototype.
• Synthesis and metabolism of naphthyl substituted phosphoramidate derivatives of stavudine
  作者：T.K. Venkatachalam、S. Qazi、F.M. Uckun

  DOI：10.1016/j.bmc.2006.04.006

  日期：2006.8

  The synthesis of naphthylphosphoramidate derivatives of stavudine was achieved using a four-step procedure. The derivatives were subjected to several different enzymes including lipase, esterase, Subtilisin Carlsberg, and Carica papaya, and their hydrolysis rates were determined. Based on the rates of hydrolysis, we were able to differentiate between the chiralities at the phosphorus center of the phosphoramidate compounds. In addition, lipase was found to distinguish between both alpha and beta forms of the compounds. The superior chiral selectivity shown by lipase toward the naphthyl substituted phosphoramidate derivatives is attributed to the restrictive binding pocket of the lipase. (c) 2006 Elsevier Ltd. All rights reserved.