(+)-1-[2,3-dideoxy-2,3-didehydro-3-fluoro-4-thio-β-L-ribofuranosyl]uracil

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: (+)-1-[2,3-dideoxy-2,3-didehydro-3-fluoro-4-thio-β-L-ribofuranosyl]uracil
• 英文别名: 1-[(2S,5S)-4-fluoro-5-(hydroxymethyl)-2,5-dihydrothiophen-2-yl]-4-hydroxy-pyrimidin-2-one；1-[(2S,5S)-4-fluoro-5-(hydroxymethyl)-2,5-dihydrothiophen-2-yl]pyrimidine-2,4-dione
• 化学式: C₉H₉FN₂O₃S
• 分子量: 244.246
• InChiKey: BNLOHWOMHHQKFS-XPUUQOCRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.6
• 重原子数：
  16
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  94.9
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  1-[2,3-dideoxy-3,3-difluoro-4-thio-5-O-toluoyl-α/β-L-ribofuranosyl]uracil 在 potassium tert-butylate 、 氨 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 反应 20.0h， 生成 (+)-1-[2,3-dideoxy-2,3-didehydro-3-fluoro-4-thio-β-L-ribofuranosyl]uracil
  参考文献：
  名称：

  Synthesis, Structure−Activity Relationships, and Mechanism of Drug Resistance of d- and l-β-3‘-Fluoro-2‘,3‘-unsaturated-4‘-thionucleosides as Anti-HIV Agents

  摘要：

  Various D- and L-2',3'-unsaturated 3'-fluoro-4'-thionucleosides (D- and L-3'F-4'Sd4Ns) were synthesized for the studies of structure-activity relationships. The synthesized D-2',3'-unsaturated 3'-fluoro-4'-thionucleosides did not show any significant antiviral activity against HIV-1, while unnatural L-nucleosides such as cytosine 34 (EC50 = 0.13 muM; EC90 = 1.7 muM) and 5-fluorocytosine 35 (EC50 = 0.031 muM; EC90 = 0.35 muM) derivatives exhibited potent antiHIV activity without significant toxicity. Molecular modeling study shows that the X-fluorine atom of the D-2',3'-unsaturated cytidine triphosphate (D-3'F-4'Sd4CTP) experiences unfavorable electrostatic interaction with its own triphosphate moiety, resulting in the decreased binding affinity to wild-type HIV-1 reverse transcriptase (RT), which may be one of the reasons for the insensitivity of HIV-1 RT to these compounds. On the other hand, L-3'F-4'Sd4CTP binds to the active site of wild-type HIV-1 RT without steric hindrance and there is a possible hydrogen bonding between the X-fluorine atom and Asp185, which correlates with its potent anti-HIV activity. However, L-3'F-4'Sd4C 34 and L-3'F-4'Sd4FC 35 showed high cross-resistance to 3TC-resistant mutant (M184V) RT. Like other unnatural L-nucleosides, the unfavorable steric hindrance of the sugar moiety Of L-3'F-4'Sd4CTP with the side chain of Val184 explains its significant cross-resistance to the M184V mutant.

  DOI：

  10.1021/jm0303148

文献信息

• Synthesis, Structure−Activity Relationships, and Mechanism of Drug Resistance of <scp>d</scp>- and <scp>l</scp>-β-3‘-Fluoro-2‘,3‘-unsaturated-4‘-thionucleosides as Anti-HIV Agents
  作者：Wei Zhu、Youhoon Chong、Hyunah Choo、Judy Mathews、Raymond F. Schinazi、Chung K. Chu

  DOI：10.1021/jm0303148

  日期：2004.3.1

  Various D- and L-2',3'-unsaturated 3'-fluoro-4'-thionucleosides (D- and L-3'F-4'Sd4Ns) were synthesized for the studies of structure-activity relationships. The synthesized D-2',3'-unsaturated 3'-fluoro-4'-thionucleosides did not show any significant antiviral activity against HIV-1, while unnatural L-nucleosides such as cytosine 34 (EC50 = 0.13 muM; EC90 = 1.7 muM) and 5-fluorocytosine 35 (EC50 = 0.031 muM; EC90 = 0.35 muM) derivatives exhibited potent antiHIV activity without significant toxicity. Molecular modeling study shows that the X-fluorine atom of the D-2',3'-unsaturated cytidine triphosphate (D-3'F-4'Sd4CTP) experiences unfavorable electrostatic interaction with its own triphosphate moiety, resulting in the decreased binding affinity to wild-type HIV-1 reverse transcriptase (RT), which may be one of the reasons for the insensitivity of HIV-1 RT to these compounds. On the other hand, L-3'F-4'Sd4CTP binds to the active site of wild-type HIV-1 RT without steric hindrance and there is a possible hydrogen bonding between the X-fluorine atom and Asp185, which correlates with its potent anti-HIV activity. However, L-3'F-4'Sd4C 34 and L-3'F-4'Sd4FC 35 showed high cross-resistance to 3TC-resistant mutant (M184V) RT. Like other unnatural L-nucleosides, the unfavorable steric hindrance of the sugar moiety Of L-3'F-4'Sd4CTP with the side chain of Val184 explains its significant cross-resistance to the M184V mutant.