methyl (2S)-2-[[chloro-[3-(trifluoromethyl)phenoxy]phosphoryl]amino]propanoate | 247574-59-0

• 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: methyl (2S)-2-[[chloro-[3-(trifluoromethyl)phenoxy]phosphoryl]amino]propanoate
• CAS: 247574-59-0
• 化学式: C₁₁H₁₂ClF₃NO₄P
• 分子量: 345.643
• InChiKey: IRXNLUOANDGXHQ-KUSNVBIKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  21
• 可旋转键数：
  6
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  64.6
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  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
• 作为产物：
  描述：

  间三氟甲基苯酚 在 三乙胺 、 三氯氧磷 作用下， 以 四氢呋喃 、 乙醚 、 二氯甲烷 为溶剂， 生成 methyl (2S)-2-[[chloro-[3-(trifluoromethyl)phenoxy]phosphoryl]amino]propanoate
  参考文献：
  名称：

  氨基磷酸酯ProTide技术的应用显着提高了碳环腺苷衍生物的抗病毒效力。

  摘要：

  我们报告了氨基磷酸酯原核苷酸（ProTide）技术在抗病毒剂碳环L-d4A（L-Cd4A）中的应用。L-Cd4A的苯基甲基丙氨酸基母体ProTide是通过格利雅（Grignard）介导的磷酰氯反应制备的，得到的化合物具有显着改善的抗HIV（2600倍）和HBV活性。我们描述了ProTide的芳基，酯和氨基酸区域的修饰，以及这些变化如何影响抗病毒活性和代谢稳定性。注意到针对HIV和HBV的SAR分别且不同。另外，由D-核苷D-Cd4A和双脱氧类似物L-CddA和D-CddA制备ProTide。与母体药物相比，这些化合物显示出更适度的效能改善。综上所述，当将ProTide方法应用于L-Cd4A时，在体外的效价提高了9000倍，非常成功，抗HIV的能力提高了。为了临床前候选人的选择，我们使用食蟹猴肝脏和肠道S9馏分进行了代谢稳定性研究。

  DOI：

  10.1021/jm060776w

文献信息

• Application of Phosphoramidate ProTide Technology Significantly Improves Antiviral Potency of Carbocyclic Adenosine Derivatives
  作者：Christopher McGuigan、Alshaimaa Hassan-Abdallah、Sheila Srinivasan、Yikang Wang、Adam Siddiqui、Susan M. Daluge、Kristjan S. Gudmundsson、Huiqiang Zhou、Ed W. McLean、Jennifer P. Peckham、Thimysta C. Burnette、Harry Marr、Richard Hazen、Lynn D. Condreay、Lance Johnson、Jan Balzarini

  DOI：10.1021/jm060776w

  日期：2006.11.30

  phosphoramidate pronucleotide (ProTide) technology to the antiviral agent carbocyclic L-d4A (L-Cd4A). The phenyl methyl alaninyl parent ProTide of L-Cd4A was prepared by Grignard-mediated phosphorochloridate reaction and resulted in a compound with significantly improved anti-HIV (2600-fold) and HBV activity. We describe modifications of the aryl, ester, and amino acid regions of the ProTide and how these changes

  我们报告了氨基磷酸酯原核苷酸（ProTide）技术在抗病毒剂碳环L-d4A（L-Cd4A）中的应用。L-Cd4A的苯基甲基丙氨酸基母体ProTide是通过格利雅（Grignard）介导的磷酰氯反应制备的，得到的化合物具有显着改善的抗HIV（2600倍）和HBV活性。我们描述了ProTide的芳基，酯和氨基酸区域的修饰，以及这些变化如何影响抗病毒活性和代谢稳定性。注意到针对HIV和HBV的SAR分别且不同。另外，由D-核苷D-Cd4A和双脱氧类似物L-CddA和D-CddA制备ProTide。与母体药物相比，这些化合物显示出更适度的效能改善。综上所述，当将ProTide方法应用于L-Cd4A时，在体外的效价提高了9000倍，非常成功，抗HIV的能力提高了。为了临床前候选人的选择，我们使用食蟹猴肝脏和肠道S9馏分进行了代谢稳定性研究。
• 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.
• Polyfluoroaromatic stavudine (d4T) ProTides exhibit enhanced anti-HIV activity
  作者：Sahar Kandil、Christophe Pannecouque、Fiona M. Chapman、Andrew D. Westwell、Christopher McGuigan

  DOI：10.1016/j.bmcl.2019.126721

  日期：2019.12

  Human Immunodeficiency Virus (HIV) damages the immune system and leads to the life-threatening acquired immunodeficiency syndrome (AIDS). Despite the advances in the field of antiretroviral treatment, HIV remains a major public health challenge.Nucleosides represent a prominent chemotherapeutic class for treating viruses, however their cellular uptake, kinase-mediated activation and catabolism are limiting factors. Herein, we report the synthesis and in vitro evaluation of stavudine (d4T) ProTides containing polyfluorinated aryl groups against two strains; HIV-1 (IIIB) and HIV-2 (ROD). ProTide 5d containing a meta-substituted pentafluorosulfanyl (3-SF5) aryl group showed superior antiviral activity over the parent d4T and the nonfluorinated analogue 5a. ProTide 5d has low nano-molar antiviral activity; (IC50=30 nM, HIV-1) and (IC50=36 nM, HIV-2) which is over tenfold more potent than d4T. Interestingly, ProTide 5d showed a significantly high selectivity indices with SI=1753 (HIV-1) and 1461 (HIV-2) which is more than twice that of the d4T. All ProTides were screened in wild type as well as thymidine kinase deficient (TK-) cells. Enzymatic activation of ProTide 5d using carboxypeptidase Y enzyme and monitored using both P-31 and F-19 NMR is presented.
• 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.