L-2',3'-dideoxy-3'-thiacytidine-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: L-2',3'-dideoxy-3'-thiacytidine-5'-α-P-thio-β,γ-(difluoromethylene)triphosphate
• 英文别名: [[[[(2S,5R)-5-(4-amino-2-oxopyrimidin-1-yl)-1,3-oxathiolan-2-yl]methoxy-hydroxyphosphinothioyl]oxy-hydroxyphosphoryl]-difluoromethyl]phosphonic acid
• 化学式: C₉H₁₄F₂N₃O₁₀P₃S₂
• 分子量: 519.274
• InChiKey: JZHAZHJSEBANBF-FQKHXDKNSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -1.9
• 重原子数：
  29
• 可旋转键数：
  8
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  259
• 氢给体数：
  5
• 氢受体数：
  14

反应信息

• 作为产物：
  描述：

  ent-拉米夫定 在 三正丁胺 、 水 、 sulfur 、 N,N-二异丙基乙胺 作用下， 以 氯仿 、 N,N-二甲基甲酰胺 为溶剂， 反应 7.5h， 生成 L-2',3'-dideoxy-3'-thiacytidine-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

• 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.