2',3'-didehydro-3'-deoxythymidine-5'-α-P-thio-β,γ-(difluoromethylene)triphosphate

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 核苷和核苷酸类似物
• 英文名称: 2',3'-didehydro-3'-deoxythymidine-5'-α-P-thio-β,γ-(difluoromethylene)triphosphate
• 英文别名: [difluoro-[hydroxy-[hydroxy-[[(2S,5R)-5-(5-methyl-2,4-dioxopyrimidin-1-yl)-2,5-dihydrofuran-2-yl]methoxy]phosphinothioyl]oxyphosphoryl]methyl]phosphonic acid
• 化学式: C₁₁H₁₅F₂N₂O₁₁P₃S
• 分子量: 514.231
• InChiKey: VUAJBLFSKDVJMW-UZBWQZEFSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -1.7
• 重原子数：
  30
• 可旋转键数：
  8
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  224
• 氢给体数：
  5
• 氢受体数：
  14

反应信息

• 作为产物：
  描述：

  司他夫定 在 吡啶 、 三正丁胺 、 水 、 sulfur 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 3.5h， 生成 2',3'-didehydro-3'-deoxythymidine-5'-α-P-thio-β,γ-(difluoromethylene)triphosphate
  参考文献：
  名称：

  2′,3′-Dideoxynucleoside 5′-β,γ-(Difluoromethylene) Triphosphates With α-P-Thio or α-P-Seleno Modifications: Synthesis and Their Inhibition of HIV-1 Reverse Transcriptase

  摘要：

  Nucleoside reverse transcriptase inhibitors (NRTIs) are prodrugs which require three intracellular phosphorylation steps to yield their corresponding, biologically active, nucleoside triphosphate. In order to circumvent this often inefficient phosphorylation cascade, a plausible approach is to provide the active species directly in the form of a stabilized nucleoside triphosphate mimic. We have previously shown that such a mimic, namely 5'-alpha-R-p-borano-beta,gamma-(difluoromethylene) triphosphate (5'-alpha BCF2TP) is a generic triphosphate mimic that is biologically stable and can render antiviral ddNs with potent inhibitory activity against HIV-1 RT.([1,2]) Herein we report the synthesis and activity against HIV-1 RT of several ddN 5'-alpha-modified-beta,gamma-(difluoromethylene) triphosphate mimics with either a non-bridging alpha-P-thio (5'-alpha SCF2TP) or alpha-P-seleno (5'-alpha SeCF2TP) modification. One compound, namely, AZT-5'-alpha-P-seleno-beta,gamma-(difluoromethylene) triphosphate (diastereomer I), was identified as a potent inhibitor of HIV-1 RT (K-i = 64 nM) and represents the first report of HIV-1 RT inhibition data for a nucleotide bearing an alpha-P-seleno modification. These triphosphate mimics may be useful in the investigation of enzyme mechanism and may have interesting properties with respect to drug resistance and polymerase selectivity.

  DOI：

  10.1080/15257770500267055

文献信息

• Nucleotide mimics and their prodrugs
  申请人：Cook D. Phillip

  公开号：US20070259832A1

  公开（公告）日：2007-11-08

  The present invention relates to nucleoside diphosphate mimics and nucleoside triphosphate mimics, which contain diphosphate or triphosphate moiety mimics and optionally sugar-modifications and/or base-modifications. The nucleotide mimics of the present invention, in a form of a pharmaceutically acceptable salt, a pharmaceutically acceptable prodrug, or a pharmaceutical formulation, are useful as antiviral, antimicrobial, and anticancer agents. The present invention provides a method for the treatment of viral infections, microbial infections, and proliferative disorders. The present invention also relates to pharmaceutical compositions comprising the compounds of the present invention optionally in combination with other pharmaceutically active agents.

  本发明涉及核苷酸二磷酸类似物和核苷酸三磷酸类似物，其包含二磷酸或三磷酸基类似物，以及可选的糖修饰和/或碱基修饰。本发明的核苷酸类似物以药学上可接受的盐、药学上可接受的前药或制剂形式，可用作抗病毒、抗微生物和抗癌药物。本发明提供了一种治疗病毒感染、微生物感染和增殖性疾病的方法。本发明还涉及包含本发明化合物的制药组合物，可选地与其他药学活性剂组合使用。
• 2′,3′-Dideoxynucleoside 5′-β,γ-(Difluoromethylene) Triphosphates With α-<i>P</i>-Thio or α-<i>P</i>-Seleno Modifications: Synthesis and Their Inhibition of HIV-1 Reverse Transcriptase
  作者：Nicholas A. Boyle、Patrick Fagan、Jennifer L. Brooks、Marija Prhavc、John Lambert、P. Dan Cook

  DOI：10.1080/15257770500267055

  日期：2005.9.1

  Nucleoside reverse transcriptase inhibitors (NRTIs) are prodrugs which require three intracellular phosphorylation steps to yield their corresponding, biologically active, nucleoside triphosphate. In order to circumvent this often inefficient phosphorylation cascade, a plausible approach is to provide the active species directly in the form of a stabilized nucleoside triphosphate mimic. We have previously shown that such a mimic, namely 5'-alpha-R-p-borano-beta,gamma-(difluoromethylene) triphosphate (5'-alpha BCF2TP) is a generic triphosphate mimic that is biologically stable and can render antiviral ddNs with potent inhibitory activity against HIV-1 RT.([1,2]) Herein we report the synthesis and activity against HIV-1 RT of several ddN 5'-alpha-modified-beta,gamma-(difluoromethylene) triphosphate mimics with either a non-bridging alpha-P-thio (5'-alpha SCF2TP) or alpha-P-seleno (5'-alpha SeCF2TP) modification. One compound, namely, AZT-5'-alpha-P-seleno-beta,gamma-(difluoromethylene) triphosphate (diastereomer I), was identified as a potent inhibitor of HIV-1 RT (K-i = 64 nM) and represents the first report of HIV-1 RT inhibition data for a nucleotide bearing an alpha-P-seleno modification. These triphosphate mimics may be useful in the investigation of enzyme mechanism and may have interesting properties with respect to drug resistance and polymerase selectivity.