di-tert-butyl ((2S,2'S)-(((((pentane-1,5-diylbis(oxy))bis(4,1-phenylene))bis(aminomethaneylylidene))bis(azaneylylidene))bis(oxy))bis(3-methyl-1-oxobutane-1,2-diyl))dicarbamate | 1296194-54-1

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: di-tert-butyl ((2S,2'S)-(((((pentane-1,5-diylbis(oxy))bis(4,1-phenylene))bis(aminomethaneylylidene))bis(azaneylylidene))bis(oxy))bis(3-methyl-1-oxobutane-1,2-diyl))dicarbamate
• CAS: 1296194-54-1
• 化学式: C₃₉H₅₈N₆O₁₀
• 分子量: 770.924
• InChiKey: ZTLKLJUDRKWHNE-CONSDPRKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.74
• 重原子数：
  55.0
• 可旋转键数：
  18.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.54
• 拓扑面积：
  224.48
• 氢给体数：
  4.0
• 氢受体数：
  12.0

反应信息

• 作为反应物：
  描述：

  di-tert-butyl ((2S,2'S)-(((((pentane-1,5-diylbis(oxy))bis(4,1-phenylene))bis(aminomethaneylylidene))bis(azaneylylidene))bis(oxy))bis(3-methyl-1-oxobutane-1,2-diyl))dicarbamate 在 盐酸 作用下， 以 乙醚 为溶剂， 以59%的产率得到
  参考文献：
  名称：

  Synthesis and biological evaluation of l-valine-amidoximeesters as double prodrugs of amidines

  摘要：

  In general, drugs containing amidines suffer from poor oral bioavailability and are often converted into amidoxime prodrugs to overcome low uptake from the gastrointestinal tract. The esterification of amidoximes with amino acids represents a newly developed double prodrug principle creating derivatives of amidines with both improved oral availability and water solubility. N-valoxybenzamidine (1) is a model compound for this principle, which has been transferred to the antiprotozoic drug pentamidine (8). Prodrug activation depends on esterases and mARC and is thus independent from activation by P450 enzymes. Therefore, drug-drug interactions or side effects will be minimized. The synthesis of these two compounds was established, and their biotransformation was studied in vitro and in vivo. Bioactivation of N-valoxybenzamidine (1) and N,N'-bis(valoxy)pentamidine (7) via hydrolysis and reduction has been demonstrated in vitro with porcine and human subcellular enzyme preparations and the mitochondrial Amidoxime Reducing Component (mARC). Moreover, activation of N-valoxybenzamidine (1) by porcine hepatocytes was studied. In vivo, the bioavailability in rats after oral application of N-valoxybenzamidine (1) was about 88%. Similarly, N,N'-bis(valoxy)pentamidine (7) showed oral bioavailability. Analysis of tissue samples revealed high concentrations of pentamidine (8) in liver and kidney. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2011.01.066
• 作为产物：
  描述：

  N-Boc-L-缬氨酸 、 4,4'-pentamethylenedioxydibenzamideoxime 在 4-二甲氨基吡啶 、 N,N'-二环己基碳二亚胺 作用下， 以 丙酮 为溶剂， 反应 24.0h， 以35%的产率得到di-tert-butyl ((2S,2'S)-(((((pentane-1,5-diylbis(oxy))bis(4,1-phenylene))bis(aminomethaneylylidene))bis(azaneylylidene))bis(oxy))bis(3-methyl-1-oxobutane-1,2-diyl))dicarbamate
  参考文献：
  名称：

  Synthesis and biological evaluation of l-valine-amidoximeesters as double prodrugs of amidines

  摘要：

  In general, drugs containing amidines suffer from poor oral bioavailability and are often converted into amidoxime prodrugs to overcome low uptake from the gastrointestinal tract. The esterification of amidoximes with amino acids represents a newly developed double prodrug principle creating derivatives of amidines with both improved oral availability and water solubility. N-valoxybenzamidine (1) is a model compound for this principle, which has been transferred to the antiprotozoic drug pentamidine (8). Prodrug activation depends on esterases and mARC and is thus independent from activation by P450 enzymes. Therefore, drug-drug interactions or side effects will be minimized. The synthesis of these two compounds was established, and their biotransformation was studied in vitro and in vivo. Bioactivation of N-valoxybenzamidine (1) and N,N'-bis(valoxy)pentamidine (7) via hydrolysis and reduction has been demonstrated in vitro with porcine and human subcellular enzyme preparations and the mitochondrial Amidoxime Reducing Component (mARC). Moreover, activation of N-valoxybenzamidine (1) by porcine hepatocytes was studied. In vivo, the bioavailability in rats after oral application of N-valoxybenzamidine (1) was about 88%. Similarly, N,N'-bis(valoxy)pentamidine (7) showed oral bioavailability. Analysis of tissue samples revealed high concentrations of pentamidine (8) in liver and kidney. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2011.01.066