3'-azido-3'-deoxythymidin-5'-yl O-(4-hydroxybutyl) carbonate | 313343-81-6

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 嘧啶核苷
• 英文名称: 3'-azido-3'-deoxythymidin-5'-yl O-(4-hydroxybutyl) carbonate
• 英文别名: [(2S,3S,5R)-3-azido-5-(5-methyl-2,4-dioxo-pyrimidin-1-yl)tetrahydrofuran-2-yl]methyl 4-hydroxybutyl carbonate；[(2S,3S,5R)-3-azido-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methyl 4-hydroxybutyl carbonate
• CAS: 313343-81-6
• 化学式: C₁₅H₂₁N₅O₇
• 分子量: 383.361
• InChiKey: KMLDURAWTUGXSV-QJPTWQEYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.1
• 重原子数：
  27
• 可旋转键数：
  10
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  129
• 氢给体数：
  2
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  3'-azido-3'-deoxythymidin-5'-yl O-(4-hydroxybutyl) carbonate 在 4-二甲氨基吡啶 、 Tempo*HCl 、 三乙胺 、 间氯过氧苯甲酸 作用下， 以 二氯甲烷 、 乙酸乙酯 为溶剂， 反应 20.0h， 生成 3'-azido-3'-deoxythymidin-5'-yl O-[3-(tert-butoxycarbonyl)propyl] carbonate
  参考文献：
  名称：

  New 3‘-Azido-3‘-deoxythymidin-5‘-yl O-(ω-Hydroxyalkyl) Carbonate Prodrugs:  Synthesis and Anti-HIV Evaluation

  摘要：

  Prodrugs of zidovudine (AZT) have been synthesized in an effort to enhance its uptake by HIV-1 infected cells and its anti-HIV activity. The 5'-OH function of AZT was functionalized with various enzymatically labile alkyl groups using specific procedures. The prodrug moieties included 5'-O-carbonate, 5'-O-carbamate, and 5'-O-ester. Analogues of the 3'-azido-3'-deoxy-thymidin-5'-yl O-(omega -hydroxyalkyl) carbonate series were particularly interesting since they were rearranged through an intramolecular cyclic process during their enzymatic hydrolysis. Evidence of this prodrug rearrangement was confirmed by comparison of the serum half-lives of 5'-O-carbonate prodrugs with their corresponding 5'-O-ester- and 5'-O-carbamate-AZT prodrugs. Interestingly, the anti-HIV-1 activities (EC50) of 3'-azido-3'-deoxythymidin-5'-yl O-(4-hydroxybutyl) carbonate 10 in acutely infected MT-4 cells and in peripheral blood mononuclear cells (PBMCs) were 0.5 nM and 0.78 nM, respectively. Compound 10 was 30 to 50 times more potent than its parent drug AZT. Our results suggest that the specific intramolecular rearrangement associated with the 3'-azido-3'-deoxythymidin-5'-yl O-(omega -hydroxyalkyl) carbonate prodrugs could explain the remarkable anti-HIV-1 activity of this series of AZT prodrugs. Prodrug 10 may therefore have better clinical potential than AZT for the treatment of AIDS.

  DOI：

  10.1021/jm001033s
• 作为产物：
  描述：

  1,4-丁二醇 、 齐多夫定 、 N,N'-羰基二咪唑 以 N,N-二甲基甲酰胺 为溶剂， 反应 2.0h， 以85%的产率得到3'-azido-3'-deoxythymidin-5'-yl O-(4-hydroxybutyl) carbonate
  参考文献：
  名称：

  New 3‘-Azido-3‘-deoxythymidin-5‘-yl O-(ω-Hydroxyalkyl) Carbonate Prodrugs:  Synthesis and Anti-HIV Evaluation

  摘要：

  Prodrugs of zidovudine (AZT) have been synthesized in an effort to enhance its uptake by HIV-1 infected cells and its anti-HIV activity. The 5'-OH function of AZT was functionalized with various enzymatically labile alkyl groups using specific procedures. The prodrug moieties included 5'-O-carbonate, 5'-O-carbamate, and 5'-O-ester. Analogues of the 3'-azido-3'-deoxy-thymidin-5'-yl O-(omega -hydroxyalkyl) carbonate series were particularly interesting since they were rearranged through an intramolecular cyclic process during their enzymatic hydrolysis. Evidence of this prodrug rearrangement was confirmed by comparison of the serum half-lives of 5'-O-carbonate prodrugs with their corresponding 5'-O-ester- and 5'-O-carbamate-AZT prodrugs. Interestingly, the anti-HIV-1 activities (EC50) of 3'-azido-3'-deoxythymidin-5'-yl O-(4-hydroxybutyl) carbonate 10 in acutely infected MT-4 cells and in peripheral blood mononuclear cells (PBMCs) were 0.5 nM and 0.78 nM, respectively. Compound 10 was 30 to 50 times more potent than its parent drug AZT. Our results suggest that the specific intramolecular rearrangement associated with the 3'-azido-3'-deoxythymidin-5'-yl O-(omega -hydroxyalkyl) carbonate prodrugs could explain the remarkable anti-HIV-1 activity of this series of AZT prodrugs. Prodrug 10 may therefore have better clinical potential than AZT for the treatment of AIDS.

  DOI：

  10.1021/jm001033s

文献信息

• New 3‘-Azido-3‘-deoxythymidin-5‘-yl <i>O</i>-(4-Hydroxyalkyl or -Alkenyl or -Alkylepoxide) Carbonate Prodrugs:  Synthesis and Anti-HIV Evaluation
  作者：Patrick Vlieghe、Thierry Clerc、Christophe Pannecouque、Myriam Witvrouw、Erik De Clercq、Jean-Pierre Salles、Jean-Louis Kraus

  DOI：10.1021/jm010863i

  日期：2001.8.1

  New 5 ' -O-carbonate prodrugs of zidovudine (AZT) have been synthesized in order to enhance its uptake by HIV-1 infected cells, to improve its anti-HIV potency, and to optimize the intramolecular cyclic rearrangement process related to the 5 ' -O-(4-hydroxybutyl) carbonate moiety. Evidence of this prodrug rearrangement was confirmed by comparison of the serum half-lives of the 3 ' -azido-3 ' -deoxythymidin-5 ' -yl O-(4-hydroxyalkyl or -alkenyl or -alkylepoxide) carbonate prodrugs with our thermodynamic predictions. Interestingly, these 5 ' -O-carbonate prodrug series show increased anti-HIV potencies in conjunction with, or without, reduced cytotoxicity as compared to AZT that lead to a gain in selectivity indexes. The cytotocity of AZT could be reduced with these 5 ' -O-carbonate prodrug series by delaying the 5 ' -O-glucuronidation of AZT, which is one of the major limitations of AZT.
• New 3‘-Azido-3‘-deoxythymidin-5‘-yl <i>O</i>-(<i>ω</i>-Hydroxyalkyl) Carbonate Prodrugs:  Synthesis and Anti-HIV Evaluation
  作者：Patrick Vlieghe、Frédéric Bihel、Thierry Clerc、Christophe Pannecouque、Myriam Witvrouw、Erik De Clercq、Jean-Pierre Salles、Jean-Claude Chermann、Jean-Louis Kraus

  DOI：10.1021/jm001033s

  日期：2001.3.1

  Prodrugs of zidovudine (AZT) have been synthesized in an effort to enhance its uptake by HIV-1 infected cells and its anti-HIV activity. The 5'-OH function of AZT was functionalized with various enzymatically labile alkyl groups using specific procedures. The prodrug moieties included 5'-O-carbonate, 5'-O-carbamate, and 5'-O-ester. Analogues of the 3'-azido-3'-deoxy-thymidin-5'-yl O-(omega -hydroxyalkyl) carbonate series were particularly interesting since they were rearranged through an intramolecular cyclic process during their enzymatic hydrolysis. Evidence of this prodrug rearrangement was confirmed by comparison of the serum half-lives of 5'-O-carbonate prodrugs with their corresponding 5'-O-ester- and 5'-O-carbamate-AZT prodrugs. Interestingly, the anti-HIV-1 activities (EC50) of 3'-azido-3'-deoxythymidin-5'-yl O-(4-hydroxybutyl) carbonate 10 in acutely infected MT-4 cells and in peripheral blood mononuclear cells (PBMCs) were 0.5 nM and 0.78 nM, respectively. Compound 10 was 30 to 50 times more potent than its parent drug AZT. Our results suggest that the specific intramolecular rearrangement associated with the 3'-azido-3'-deoxythymidin-5'-yl O-(omega -hydroxyalkyl) carbonate prodrugs could explain the remarkable anti-HIV-1 activity of this series of AZT prodrugs. Prodrug 10 may therefore have better clinical potential than AZT for the treatment of AIDS.