2',3'-didehydro-2',3'-dideoxythymidine-5'-(3-(trifluoromethyl)phenylmethoxyalaninylphosphate)

• 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'-(3-(trifluoromethyl)phenylmethoxyalaninylphosphate)
• 英文别名: methyl (2S)-2-[[[(2S,5R)-5-(5-methyl-2,4-dioxo-pyrimidin-1-yl)-2,5-dihydrofuran-2-yl]methoxy-[3-(trifluoromethyl)phenoxy]phosphoryl]amino]propanoate；methyl (2S)-2-[[[(2S,5R)-5-(5-methyl-2,4-dioxopyrimidin-1-yl)-2,5-dihydrofuran-2-yl]methoxy-[3-(trifluoromethyl)phenoxy]phosphoryl]amino]propanoate
• 化学式: C₂₁H₂₃F₃N₃O₈P
• 分子量: 533.398
• InChiKey: ZVZJCSUGWFZOLS-MTTXXRTRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  36
• 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：
  12

反应信息

• 作为产物：
  描述：

  司他夫定 、 methyl (2S)-2-[[chloro-[3-(trifluoromethyl)phenoxy]phosphoryl]amino]propanoate 在 N-甲基咪唑 作用下， 以 四氢呋喃 为溶剂， 反应 4.0h， 以80%的产率得到2',3'-didehydro-2',3'-dideoxythymidine-5'-(3-(trifluoromethyl)phenylmethoxyalaninylphosphate)
  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

文献信息

• 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.
• 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.