2',3'-didehydro-2',3'-dideoxythymidine 5'-(4-methylphenyl (methoxyalaninyl)phosphate)

• 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-methylphenyl (methoxyalaninyl)phosphate)
• 英文别名: CF 1525；Cf1525；Methyl 2-[({[5-(5-methyl-2,4-dioxo(1,3-dihydropyrimidinyl))(2-2,5-dihydrofuryl)]methoxy}(4-methylphenoxy)carbonyl)amino]propanoate；methyl (2S)-2-[[[(2S,5R)-5-(5-methyl-2,4-dioxopyrimidin-1-yl)-2,5-dihydrofuran-2-yl]methoxy-(4-methylphenoxy)phosphoryl]amino]propanoate
• 化学式: C₂₁H₂₆N₃O₈P
• 分子量: 479.427
• InChiKey: PCVKMWBHMRDXJU-TZDHYOIISA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  33
• 可旋转键数：
  10
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.38
• 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-methylphenyl (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：

  p-methylphenyl methoxyalaninyl phosphorochloridate 、 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65%的产率得到2',3'-didehydro-2',3'-dideoxythymidine 5'-(4-methylphenyl (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