[(2R,3R,4S,5R)-4-(2,2-dimethylpropanoyloxy)-3-hydroxy-5-(6-methoxypurin-9-yl)oxolan-2-yl]methyl 2,2-dimethylpropanoate | 137057-71-7

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 嘌呤核苷
• 英文名称: [(2R,3R,4S,5R)-4-(2,2-dimethylpropanoyloxy)-3-hydroxy-5-(6-methoxypurin-9-yl)oxolan-2-yl]methyl 2,2-dimethylpropanoate
• CAS: 137057-71-7
• 化学式: C₂₁H₃₀N₄O₇
• 分子量: 450.492
• InChiKey: ORYGEISWBGGLNE-MBMVNNNZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  32
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  135
• 氢给体数：
  1
• 氢受体数：
  10

反应信息

• 作为产物：
  描述：

  9-<3-O-(tert-butyldimethylsilyl)-β-D-arabinofuranosyl>-6-methoxy-9H-purine 在 吡啶 、 4-二甲氨基吡啶 、 四丁基氟化铵 作用下， 以 四氢呋喃 、 乙腈 为溶剂， 反应 1.0h， 生成 [(2R,3R,4S,5R)-4-(2,2-dimethylpropanoyloxy)-3-hydroxy-5-(6-methoxypurin-9-yl)oxolan-2-yl]methyl 2,2-dimethylpropanoate
  参考文献：
  名称：

  Di- and triester prodrugs of the varicella-zoster antiviral agent 6-methoxypurine arabinoside

  摘要：

  6-Methoxypurine arabinoside (9-beta-D-arabinofuranosyl-6-methoxy-9H-purine, 1) has potent and selective activity against varicella-zoster virus in vitro. An unfavorable metabolic profile observed with oral dosing in the rat led to the preparation of a variety of 2',3',5'-triesters (2a-n) and several 2',3'-, 2',5'-, and 3',5-diester, of this arabinoside (3a-n, 4a-f, and 5a-j, respectively). The compounds were evaluated as prodrugs by measuring the urinary levels of 1 in rat urine after oral dosing. With the exception of triacetate 2a, the triesters failed to significantly enhance bioavailability. Administration of compound 2a resulted in a 3-fold increase in systemic availability of 1, possibly because of its increased water solubility (1.6 times more soluble than 1) and only slightly increased relative log P value (1.93 vs 0.50 for 1). The longer chain aliphatic triesters and aromatic triesters had lower water solubilities and increased lipophilic partitioning. These factors might account for the lower systemic bioavailability of these compounds. In contrast, the diesters, especially the aliphatic diesters, showed significantly improved systemic availability. This might be a consequence of the higher aqueous solubilities and enhanced partition coefficients seen with these compounds. 2',3-Diacetate 3a showed the best combination of high systemic availability and water solubility of all the prodrugs of 1.

  DOI：

  10.1021/jm00079a006

文献信息

• Di- and triester prodrugs of the varicella-zoster antiviral agent 6-methoxypurine arabinoside
  作者：Lynda A. Jones、Allan R. Moorman、Stanley D. Chamberlain、Paulo De Miranda、David J. Reynolds、Charlene L. Burns、Thomas A. Krenitsky

  DOI：10.1021/jm00079a006

  日期：1992.1

  6-Methoxypurine arabinoside (9-beta-D-arabinofuranosyl-6-methoxy-9H-purine, 1) has potent and selective activity against varicella-zoster virus in vitro. An unfavorable metabolic profile observed with oral dosing in the rat led to the preparation of a variety of 2',3',5'-triesters (2a-n) and several 2',3'-, 2',5'-, and 3',5-diester, of this arabinoside (3a-n, 4a-f, and 5a-j, respectively). The compounds were evaluated as prodrugs by measuring the urinary levels of 1 in rat urine after oral dosing. With the exception of triacetate 2a, the triesters failed to significantly enhance bioavailability. Administration of compound 2a resulted in a 3-fold increase in systemic availability of 1, possibly because of its increased water solubility (1.6 times more soluble than 1) and only slightly increased relative log P value (1.93 vs 0.50 for 1). The longer chain aliphatic triesters and aromatic triesters had lower water solubilities and increased lipophilic partitioning. These factors might account for the lower systemic bioavailability of these compounds. In contrast, the diesters, especially the aliphatic diesters, showed significantly improved systemic availability. This might be a consequence of the higher aqueous solubilities and enhanced partition coefficients seen with these compounds. 2',3-Diacetate 3a showed the best combination of high systemic availability and water solubility of all the prodrugs of 1.