[(2S,4S,5R)-4-fluoro-5-purin-9-yloxolan-2-yl]methyl benzoate | 1027658-35-0

• 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: [(2S,4S,5R)-4-fluoro-5-purin-9-yloxolan-2-yl]methyl benzoate
• CAS: 1027658-35-0
• 化学式: C₁₇H₁₅FN₄O₃
• 分子量: 342.33
• InChiKey: NOBMGGNUCZRGDN-HEHGZKQESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  25
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  79.1
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  [(2S,4S,5R)-4-fluoro-5-purin-9-yloxolan-2-yl]methyl benzoate 在 氨 作用下， 生成 [(2S,4S,5R)-4-氟-5-嘌呤-9-基四氢呋喃-2-基]甲醇
  参考文献：
  名称：

  Enhanced Brain Delivery of an Anti-HIV Nucleoside 2'-F-ara-ddI by Xanthine Oxidase Mediated Biotransformation

  摘要：

  In order to enhance the brain delivery of 2'-F-ara-ddI, 2'-F-ara-ddP 6 was synthesized and its in vitro and in vivo bioconversion reaction studied. For the study, a new efficient synthetic method for 2'-F-ara-ddP 6 was developed from 5-benzoyl-1,2-0-isopropylidene-3-deoxyribose 1. For in vitro study 2'-F-ara-ddP was incubated in pH 2, mouse liver homogenate, and mouse serum at 37-degrees-C. No degradation was observed in pH 2 and serum, while in liver homogenate 2'-F-ara-ddP was almost completely converted to 2'-F-ara-ddI within 20 min (t1/2 = 3.54 min). In order to determine the role of xanthine oxidase in the conversion of 2'-F-ara-ddP to 2'-F-ara-ddI, in vitro studies were conducted in phosphate buffer (pH 7.4) in the presence or absence of allopurinol, in which the half-lives of 2'-F-ara-ddP were 7.4 and 3.4 h, respectively, indicating the conversions were catalyzed by the xanthine oxidase. A similar experiment with aldehyde oxidase isolated from the human liver did not affect the biotransformation. The biotransformation was also detected in the brain homogenate, although the rate of conversion was low and incomplete. In order to assess the bioconversion in vivo, pharmacokinetic studies of 2'-F-ara-ddP and 2'-F-ara-ddI were conducted in mice. The maximum serum concentrations of 2'-F-ara-ddI administered itself and as 2'-F-ara-ddP reached 48.1 +/- 10.00 and 89.3 +/- 26.0 muM and were observed in 1 and 0.25 h, respectively. The data indicate that 2'-F-ara-ddI is absorbed at a slower rate than that of 2'-F-ara-ddP. The bioavailability of the prodrug after oral administration was 60.7 %. The concentration of 2'-F-ara-ddI following oral administration of 2'-ara-ddI was close to the detection limits while 2'-F-ara-ddI was detected at significantly higher concentrations in the brain after oral administration of 2'-F-ara-ddP. From this study, we have administered the enhanced brain delivery of anti-HIV nucleoside utilizing an in vivo biotransformation system.

  DOI：

  10.1021/jm00032a017
• 作为产物：
  描述：

  [(3aR,5S,6aR)-2,2-dimethyltetrhydrofuro[2,3-d][1,3]dioxol-5-yl]methyl benzoate 在 palladium on activated charcoal ammonium hydroxide 、 二乙胺基三氟化硫 、 硫酸 、 氢溴酸 、 氢气 、 sodium hydride 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 二氯甲烷 、 水 为溶剂， 80.0 ℃ 、344.73 kPa 条件下， 反应 12.5h， 生成 [(2S,4S,5R)-4-fluoro-5-purin-9-yloxolan-2-yl]methyl benzoate
  参考文献：
  名称：

  Enhanced Brain Delivery of an Anti-HIV Nucleoside 2'-F-ara-ddI by Xanthine Oxidase Mediated Biotransformation

  摘要：

  In order to enhance the brain delivery of 2'-F-ara-ddI, 2'-F-ara-ddP 6 was synthesized and its in vitro and in vivo bioconversion reaction studied. For the study, a new efficient synthetic method for 2'-F-ara-ddP 6 was developed from 5-benzoyl-1,2-0-isopropylidene-3-deoxyribose 1. For in vitro study 2'-F-ara-ddP was incubated in pH 2, mouse liver homogenate, and mouse serum at 37-degrees-C. No degradation was observed in pH 2 and serum, while in liver homogenate 2'-F-ara-ddP was almost completely converted to 2'-F-ara-ddI within 20 min (t1/2 = 3.54 min). In order to determine the role of xanthine oxidase in the conversion of 2'-F-ara-ddP to 2'-F-ara-ddI, in vitro studies were conducted in phosphate buffer (pH 7.4) in the presence or absence of allopurinol, in which the half-lives of 2'-F-ara-ddP were 7.4 and 3.4 h, respectively, indicating the conversions were catalyzed by the xanthine oxidase. A similar experiment with aldehyde oxidase isolated from the human liver did not affect the biotransformation. The biotransformation was also detected in the brain homogenate, although the rate of conversion was low and incomplete. In order to assess the bioconversion in vivo, pharmacokinetic studies of 2'-F-ara-ddP and 2'-F-ara-ddI were conducted in mice. The maximum serum concentrations of 2'-F-ara-ddI administered itself and as 2'-F-ara-ddP reached 48.1 +/- 10.00 and 89.3 +/- 26.0 muM and were observed in 1 and 0.25 h, respectively. The data indicate that 2'-F-ara-ddI is absorbed at a slower rate than that of 2'-F-ara-ddP. The bioavailability of the prodrug after oral administration was 60.7 %. The concentration of 2'-F-ara-ddI following oral administration of 2'-ara-ddI was close to the detection limits while 2'-F-ara-ddI was detected at significantly higher concentrations in the brain after oral administration of 2'-F-ara-ddP. From this study, we have administered the enhanced brain delivery of anti-HIV nucleoside utilizing an in vivo biotransformation system.

  DOI：

  10.1021/jm00032a017

文献信息

• Enhanced Brain Delivery of an Anti-HIV Nucleoside 2'-F-ara-ddI by Xanthine Oxidase Mediated Biotransformation
  作者：Kirupa Shanmuganathan、Tatiana Koudriakova、Satyanarayana Nampalli、Jinfa Du、James M. Gallo、Raymond F. Schinazi、Chung K. Chu

  DOI：10.1021/jm00032a017

  日期：1994.3

  In order to enhance the brain delivery of 2'-F-ara-ddI, 2'-F-ara-ddP 6 was synthesized and its in vitro and in vivo bioconversion reaction studied. For the study, a new efficient synthetic method for 2'-F-ara-ddP 6 was developed from 5-benzoyl-1,2-0-isopropylidene-3-deoxyribose 1. For in vitro study 2'-F-ara-ddP was incubated in pH 2, mouse liver homogenate, and mouse serum at 37-degrees-C. No degradation was observed in pH 2 and serum, while in liver homogenate 2'-F-ara-ddP was almost completely converted to 2'-F-ara-ddI within 20 min (t1/2 = 3.54 min). In order to determine the role of xanthine oxidase in the conversion of 2'-F-ara-ddP to 2'-F-ara-ddI, in vitro studies were conducted in phosphate buffer (pH 7.4) in the presence or absence of allopurinol, in which the half-lives of 2'-F-ara-ddP were 7.4 and 3.4 h, respectively, indicating the conversions were catalyzed by the xanthine oxidase. A similar experiment with aldehyde oxidase isolated from the human liver did not affect the biotransformation. The biotransformation was also detected in the brain homogenate, although the rate of conversion was low and incomplete. In order to assess the bioconversion in vivo, pharmacokinetic studies of 2'-F-ara-ddP and 2'-F-ara-ddI were conducted in mice. The maximum serum concentrations of 2'-F-ara-ddI administered itself and as 2'-F-ara-ddP reached 48.1 +/- 10.00 and 89.3 +/- 26.0 muM and were observed in 1 and 0.25 h, respectively. The data indicate that 2'-F-ara-ddI is absorbed at a slower rate than that of 2'-F-ara-ddP. The bioavailability of the prodrug after oral administration was 60.7 %. The concentration of 2'-F-ara-ddI following oral administration of 2'-ara-ddI was close to the detection limits while 2'-F-ara-ddI was detected at significantly higher concentrations in the brain after oral administration of 2'-F-ara-ddP. From this study, we have administered the enhanced brain delivery of anti-HIV nucleoside utilizing an in vivo biotransformation system.