cyclosaligenyl-5'-O-(2',3'-dideoxy-2'-fluororibosyladenyl)phosphate

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 嘌呤核苷酸
• 英文名称: cyclosaligenyl-5'-O-(2',3'-dideoxy-2'-fluororibosyladenyl)phosphate
• 英文别名: 9-[(2R,3R,5S)-3-fluoro-5-[(2-oxo-4H-1,3,2$l^{5}-benzodioxaphosphinin-2-yl)oxymethyl]tetrahydrofuran-2-yl]purin-6-amine；9-[(2R,3R,5S)-3-fluoro-5-[(2-oxo-4H-1,3,2λ5-benzodioxaphosphinin-2-yl)oxymethyl]oxolan-2-yl]purin-6-amine
• 化学式: C₁₇H₁₇FN₅O₅P
• 分子量: 421.325
• InChiKey: RGTPCJQKGORYNJ-NRMJGAJDSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  29
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  124
• 氢给体数：
  1
• 氢受体数：
  10

反应信息

• 作为产物：
  描述：

  2-chloro-4H-1,3,2-benzodioxaphosphorin 在 叔丁基过氧化氢 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 0.83h， 生成 cyclosaligenyl-5'-O-(2',3'-dideoxy-2'-fluororibosyladenyl)phosphate
  参考文献：
  名称：

  cycloSal-Pronucleotides of 2‘-Fluoro-ara- and 2‘-Fluoro-ribo-2‘,3‘- dideoxyadenosine as a Strategy to Bypass a Metabolic Blockade

  摘要：

  Novel, lipophilic cycloSal triesters 4a-c and 5a-c were synthesized, respectively, from the ara- and ribo-configurated 2'-fluorinated-2',3'-dideoxyadenosines 2 and 3. The cycloSal phosphotriesters were used as tools to study the effects of the two different sugar pucker conformations induced by two opposite configurations of the fluorine substituent at C2' of the dideoxyribose moiety. F-ara-ddA (2) is known to be an active anti-HIV agent, whereas the ribo-analogue 3 is inactive. Hydrolysis studies with the triester precursors 4a-c and 5a-c showed selective formation of the monophosphates of 2 and 3. The lipophilicity of the triester prodrugs was considerably increased by the cycloSal mask with respect to ddA (1), F-ara-ddA (2), and F-ribo-ddA (3). Phosphotriesters 4 and 5 proved to be completely resistant to ADA and AMPDA deamination. In parallel experiments, ribo-nucleoside 3 showed a 50-fold faster deamination rate relative to the ara-analogue 2. Against HIV in CEM cells, the phosphotriesters 4 proved to be 10-fold more potent than the parent nucleoside 2. Furthermore, the prodrugs 4 were active against MSV-induced transformation of C3H/3T3 fibroblasts, while 2 was inactive. More interestingly, the ribo-configurated phosphotriesters 5, prepared from the inactive F-ribo-ddA (3), showed a level of anti-HIV activity that was even higher than that of F-ara-ddA (2). Our findings clearly prove that the application of the cycloSal-pronucleotide concept to F-ribo-ddA (3) overcomes a metabolic blockade in the formation of the corresponding monophosphate.

  DOI：

  10.1021/jm981097r

文献信息

• <i>cyclo</i>Sal-Pronucleotides of 2‘-Fluoro-<i>ara</i>- and 2‘-Fluoro-<i>ribo</i>-2‘,3‘- dideoxyadenosine as a Strategy to Bypass a Metabolic Blockade
  作者：Chris Meier、Tina Knispel、Victor E. Marquez、Maqbool A. Siddiqui、Erik De Clercq、Jan Balzarini

  DOI：10.1021/jm981097r

  日期：1999.5.1

  Novel, lipophilic cycloSal triesters 4a-c and 5a-c were synthesized, respectively, from the ara- and ribo-configurated 2'-fluorinated-2',3'-dideoxyadenosines 2 and 3. The cycloSal phosphotriesters were used as tools to study the effects of the two different sugar pucker conformations induced by two opposite configurations of the fluorine substituent at C2' of the dideoxyribose moiety. F-ara-ddA (2) is known to be an active anti-HIV agent, whereas the ribo-analogue 3 is inactive. Hydrolysis studies with the triester precursors 4a-c and 5a-c showed selective formation of the monophosphates of 2 and 3. The lipophilicity of the triester prodrugs was considerably increased by the cycloSal mask with respect to ddA (1), F-ara-ddA (2), and F-ribo-ddA (3). Phosphotriesters 4 and 5 proved to be completely resistant to ADA and AMPDA deamination. In parallel experiments, ribo-nucleoside 3 showed a 50-fold faster deamination rate relative to the ara-analogue 2. Against HIV in CEM cells, the phosphotriesters 4 proved to be 10-fold more potent than the parent nucleoside 2. Furthermore, the prodrugs 4 were active against MSV-induced transformation of C3H/3T3 fibroblasts, while 2 was inactive. More interestingly, the ribo-configurated phosphotriesters 5, prepared from the inactive F-ribo-ddA (3), showed a level of anti-HIV activity that was even higher than that of F-ara-ddA (2). Our findings clearly prove that the application of the cycloSal-pronucleotide concept to F-ribo-ddA (3) overcomes a metabolic blockade in the formation of the corresponding monophosphate.