[2,2-dimethylpropanoyloxymethoxy-[(3R)-3-hydroxy-4-[[3-[2-[2-[2-(1H-indol-3-yl)ethylamino]-2-oxoethyl]sulfanylethylamino]-3-oxopropyl]amino]-2,2-dimethyl-4-oxobutoxy]phosphoryl]oxymethyl 2,2-dimethylpropanoate | 700865-64-1

• 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: [2,2-dimethylpropanoyloxymethoxy-[(3R)-3-hydroxy-4-[[3-[2-[2-[2-(1H-indol-3-yl)ethylamino]-2-oxoethyl]sulfanylethylamino]-3-oxopropyl]amino]-2,2-dimethyl-4-oxobutoxy]phosphoryl]oxymethyl 2,2-dimethylpropanoate
• CAS: 700865-64-1
• 化学式: C₃₅H₅₅N₄O₁₂PS
• 分子量: 786.881
• InChiKey: FCIRQAKMEXKRKD-LJAQVGFWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  53
• 可旋转键数：
  26
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.63
• 拓扑面积：
  246
• 氢给体数：
  5
• 氢受体数：
  13

反应信息

• 作为反应物：
  描述：

  [2,2-dimethylpropanoyloxymethoxy-[(3R)-3-hydroxy-4-[[3-[2-[2-[2-(1H-indol-3-yl)ethylamino]-2-oxoethyl]sulfanylethylamino]-3-oxopropyl]amino]-2,2-dimethyl-4-oxobutoxy]phosphoryl]oxymethyl 2,2-dimethylpropanoate 在 porcine liver esterase 、 NaH₂PO₄ buffer 作用下， 以 二氯甲烷 为溶剂， 反应 1.0h， 生成
  参考文献：
  名称：

  Enzymatic and cellular study of a serotonin N-acetyltransferase phosphopantetheine-based prodrug

  摘要：

  Serotonin N-acetyltransferase (arylalkylamine N-acetyltransferase, AANAT) regulates the daily rhythm in the production of melatonin and is therefore an attractive target for pharmacologic modulation of the synthesis of this hormone. Previously prepared bisubstrate analogs show potent inhibition of AANAT but have unfavorable pharmacokinetic properties due to the presence of phosphate groups which prevents transfer across the plasma membrane. Here, we examine a bis-pivaloyloxymethylene (POM)-tryptamine-phosphopantetheine prodrug (2) and its biotransformations in vitro by homogenates and pineal cells. Compound 2 is an efficient porcine liver esterase substrate for POM cleavage in vitro although cyclization of the phosphate moiety is a potential side product. Tryptamine phosphopantetheine (3) is converted to tryptamine-coenzyme A (CoA) bisubstrate analog (1) by human phosphoribosyl pyrophosphate amidotransferase (PPAT) and dephosphocoenzyme A kinase (DPCK) in vitro. Compound 2 was found to inhibit melatonin production in rat pineal cell culture. It was also found that the POM groups are readily removed to generate 3; however, further processing to tryptamine-CoA (1) is much slower in pineal extracts or cell culture. Implications for CoA prodrug development based on the strategy used here are discussed. (c) 2006 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2006.12.016
• 作为产物：
  描述：

  ((hydroxyphosphoryl)bis(oxy))bis(methylene) bis(2,2-dimethylpropanoate) 在 草酰氯 、 三乙胺 、 N,N-二甲基甲酰胺 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 2.0h， 生成 [2,2-dimethylpropanoyloxymethoxy-[(3R)-3-hydroxy-4-[[3-[2-[2-[2-(1H-indol-3-yl)ethylamino]-2-oxoethyl]sulfanylethylamino]-3-oxopropyl]amino]-2,2-dimethyl-4-oxobutoxy]phosphoryl]oxymethyl 2,2-dimethylpropanoate
  参考文献：
  名称：

  Efficient Synthesis of Phosphorylated Prodrugs with Bis(POM)-phosphoryl Chloride

  摘要：

  An efficient method for the synthesis of phosphorylated prodrugs is described. The preparation of various bis-pivaloyloxymethyl (POM) phosphate triesters was accomplished in moderate to good yields with the use of bis(POM) phosphoryl chloride under mild conditions.

  DOI：

  10.1021/ol049714v

文献信息

• Efficient Synthesis of Phosphorylated Prodrugs with Bis(POM)-phosphoryl Chloride
  作者：Yousang Hwang、Philip A. Cole

  DOI：10.1021/ol049714v

  日期：2004.5.1

  An efficient method for the synthesis of phosphorylated prodrugs is described. The preparation of various bis-pivaloyloxymethyl (POM) phosphate triesters was accomplished in moderate to good yields with the use of bis(POM) phosphoryl chloride under mild conditions.
• Enzymatic and cellular study of a serotonin N-acetyltransferase phosphopantetheine-based prodrug
  作者：Yousang Hwang、Surajit Ganguly、Anthony K. Ho、David C. Klein、Philip A. Cole

  DOI：10.1016/j.bmc.2006.12.016

  日期：2007.3

  Serotonin N-acetyltransferase (arylalkylamine N-acetyltransferase, AANAT) regulates the daily rhythm in the production of melatonin and is therefore an attractive target for pharmacologic modulation of the synthesis of this hormone. Previously prepared bisubstrate analogs show potent inhibition of AANAT but have unfavorable pharmacokinetic properties due to the presence of phosphate groups which prevents transfer across the plasma membrane. Here, we examine a bis-pivaloyloxymethylene (POM)-tryptamine-phosphopantetheine prodrug (2) and its biotransformations in vitro by homogenates and pineal cells. Compound 2 is an efficient porcine liver esterase substrate for POM cleavage in vitro although cyclization of the phosphate moiety is a potential side product. Tryptamine phosphopantetheine (3) is converted to tryptamine-coenzyme A (CoA) bisubstrate analog (1) by human phosphoribosyl pyrophosphate amidotransferase (PPAT) and dephosphocoenzyme A kinase (DPCK) in vitro. Compound 2 was found to inhibit melatonin production in rat pineal cell culture. It was also found that the POM groups are readily removed to generate 3; however, further processing to tryptamine-CoA (1) is much slower in pineal extracts or cell culture. Implications for CoA prodrug development based on the strategy used here are discussed. (c) 2006 Elsevier Ltd. All rights reserved.