2',3'-didehydro-2',3'-dideoxythymidine 5'-(4-chlorophenyl (methoxyalaninyl)phosphate) | 222021-16-1

• 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'-(4-chlorophenyl (methoxyalaninyl)phosphate)
• 英文别名: CF 1523；Cf1523；methyl (2S)-2-[[(4-chlorophenoxy)-[[(2S,5R)-5-(5-methyl-2,4-dioxo-pyrimidin-1-yl)-2,5-dihydrofuran-2-yl]methoxy]phosphoryl]amino]propanoate；methyl (2S)-2-[[(4-chlorophenoxy)-[[(2S,5R)-5-(5-methyl-2,4-dioxopyrimidin-1-yl)-2,5-dihydrofuran-2-yl]methoxy]phosphoryl]amino]propanoate
• CAS: 222021-16-1
• 化学式: C₂₀H₂₃ClN₃O₈P
• 分子量: 499.845
• InChiKey: QMHCERIZINJQIK-MIOXLMGNSA-N

物化性质

• 熔点：
  42-44 °C
• 密度：
  1.407±0.06 g/cm3(Predicted)

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'-(4-chlorophenyl (methoxyalaninyl)phosphate) 以 phosphate buffer 、 二甲基亚砜 为溶剂， 反应 20.0h， 生成 [(2S,5R)-5-(5-methyl-2,4-dioxopyrimidin-1-yl)-2,5-dihydrofuran-2-yl]methyl phosphate
  参考文献：
  名称：

  Stereospecific chemical and enzymatic stability of phosphoramidate triester prodrugs of d4T in vitro

  摘要：

  The phosphoramidate triester prodrug approach is widely used to deliver nucleotide forms of nucleoside analogues into target cells. We investigated the stereoselective stability of a series of prodrugs of the anti-HIV agent 2',3'-didehydro-2',3'-dideoxythymidine (d4T). Chemical stability was evaluated in phosphate buffer at pH values of biological relevance (i.e. pH 2.0, 4.6, 7.4). Enzymatic stability was tested in human plasma, in Caco-2 cell homogenates and monolayers and in rat liver. The compounds were relatively stable to chemical hydrolysis. Between 50 and 70% of unchanged prodrug was recovered after 16 h incubation in human plasma, with no stereoselective preference for phosphate diastereoisomers. The p-OMe phenyl derivative, however, was an exception and only 5% of one diastereoisomer was recovered. In Caco-2 cells the stability and stereoselectivity largely depended on the experimental conditions: high enzymatic activity and stereoselectivity was observed in cell homogenates, but not in monolayers. In rat liver S9 fractions the stability profile was similar to that in Caco-2 cells and carboxyl ester cleavage appeared to be the sole mechanism of degradation in both media. The large and unpredictable differences in stereoselective metabolic rate of the pronucleotide series here presented suggest that in vivo circulating levels of intact prodrug could exert profoundly different activity or toxicity due to preferential body distribution of one diastereoisomeric form. (C) 2004 Elsevier B.V. All rights reserved.

  DOI：

  10.1016/j.ejps.2004.02.006
• 作为产物：
  描述：

  司他夫定 、 (((1S)-(4-chlorophenoxy)-(1-methyl)oxycarbonylethyl)amino)phosphinyl chloride 在 N-甲基咪唑 作用下， 以 四氢呋喃 为溶剂， 反应 16.0h， 以72%的产率得到2',3'-didehydro-2',3'-dideoxythymidine 5'-(4-chlorophenyl (methoxyalaninyl)phosphate)
  参考文献：
  名称：

  d4T的芳基氨基磷酸酯衍生物的芳基部分上存在取代基，可以增强细胞培养中的抗HIV功效：结构-活性关系。

  摘要：

  合成了抗HIV药物d4T的新的取代芳基氨基磷酸酯衍生物，作为膜溶性细胞内前药，用于游离的生物活性磷酸盐，从而建立化合物结构与体外抗病毒活性之间的关系。相对于亲本核苷，大多数化合物表现出体外效力的提高，并且与d4T不同，它们在胸苷激酶缺陷型细胞中均保留了全部活性。带有对氯芳基（8e）的化合物在体外表达纳摩尔活性，相对于未取代的氨基磷酸酯而言，活性提高了14倍（与d4T相比，提高了100倍）。使用猪肝酯酶的测定用于建立化合物对酶促降解的稳定性。虽然在体外活性和酶促降解的半衰期之间没有明显的相关性，但由辛醇/水分配系数确定的化合物亲脂性与体外效能之间却有着密切的相关性。我们建议对d4T的氨基磷酸氨基磷酸酯的芳基部分进行取代，从而导致亲脂性增强，这可能通过被动扩散增加前药的细胞摄取，从而导致前药浓度降低时抗病毒效力的表达。

  DOI：

  10.1021/jm9803931

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。
• Effect of change in nucleoside structure on the activation and antiviral activity of phosphoramidate derivatives
  作者：T.K. Venkatachalam、P. Samuel、S. Qazi、F.M. Uckun

  DOI：10.1016/j.bmc.2005.04.083

  日期：2005.9

  Changing the nucleoside group of a series of phosphoramidate derivatives affects the enzyme mediated hydrolysis rate of the compounds. d4T and AZT-substituted analogs were activated by enzymes such as lipases, esterases, and proteases. On the other hand, 3dT-substituted derivatives were comparatively less prone to hydrolysis under similar experimental conditions. From the experimental results, we propose that-the most preferable nucleoside group for enzyme activation is d4T rather than AZT or 3dT. Additionally, we also observed that depending on the enzymes used the chiral selectivity of the enzymes for the phosphorus center of these phosphoramidate derivatives differed, demonstrating the importance of the nucleoside structure for this class of compounds. (c) 2005 Elsevier Ltd. All rights reserved.