(2R,3R,4S)-1-(benzyloxycarbonyl)-2-<(phosphooxy)methyl>pyrrolidine-3,4-diol | 148252-71-5

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: (2R,3R,4S)-1-(benzyloxycarbonyl)-2-<(phosphooxy)methyl>pyrrolidine-3,4-diol
• 英文别名: (2R,3R,4S)-1-(benzyloxycarbonyl)-2-[(phosphooxy)methyl]pyrrolidine-3,4-diol；benzyl (2R,3R,4S)-3,4-dihydroxy-2-(phosphonooxymethyl)pyrrolidine-1-carboxylate
• CAS: 148252-71-5
• 化学式: C₁₃H₁₈NO₈P
• 分子量: 347.262
• InChiKey: ZDPVAUONHXPQLD-GRYCIOLGSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -1.6
• 重原子数：
  23
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  137
• 氢给体数：
  4
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  (2R,3R,4S)-1-(benzyloxycarbonyl)-2-<(phosphooxy)methyl>pyrrolidine-3,4-diol 在 palladium on activated charcoal 氢气 作用下， 生成 [[(2R,3R,4S)-3,4-dihydroxypyrrolidin-2-yl]methoxy-hydroxyphosphoryl] [(2R,3S,4R,5R)-5-[6-(hexylamino)purin-9-yl]-3,4-dihydroxyoxolan-2-yl]methyl hydrogen phosphate
  参考文献：
  名称：

  SAR Analysis of Adenosine Diphosphate (Hydroxymethyl)pyrrolidinediol Inhibition of Poly(ADP-ribose) Glycohydrolase

  摘要：

  Polyadenosine diphosphoribose glycohydrolase (PARG) catalyzes the intracellular hydrolysis of adenosine diphosphoribose polymers. Because structure-activity data are lacking for PARG, the specific inhibitor adenosine diphosphate (hydroxymethyl)pyrrolidinediol (ADP-HPD) was utilized to determine the effects of structure on inhibitor potency using PARG isolated from bovine thymus (bPARG) and recombinant bovine PARG catalytic fragment (rPARG-CF). Both enzymes were strongly inhibited by submicromolar levels of ADP-HPD, but ADP and the phosphorylated pyrrolidine displayed no activity. Utilizing ADP-HPD analogues containing 2-, N-6, or 8-adenosyl substituents or guanine instead of adenine, the importance of adenine ring recognition as well as a correlation between loss of PARG inhibition and the length and bulkiness of 8-adenosyl substituents was shown. Utilization of ADP-HPD analogues lacking one or both pyrrolidine cis-hydroxyls demonstrated their importance for inhibitor binding. Last, the similarity between naturally occurring bPARG and heterologously expressed rPARG-CF was demonstrated. Therefore, readily available rPARG-CF is suitable for use in future studies to determine the structural aspects of PARG.

  DOI：

  10.1021/jm020541u
• 作为产物：
  描述：

  (2R,3R,4S)-1-(benzyloxycarbonyl)-2-(hydroxymethyl)pyrrolidine-3,4-diol 3,4-O-isopropylidene acetal 在 盐酸 、 三乙胺 、 三氯氧磷 作用下， 生成 (2R,3R,4S)-1-(benzyloxycarbonyl)-2-<(phosphooxy)methyl>pyrrolidine-3,4-diol
  参考文献：
  名称：

  Specific Inhibition of Poly(ADP-ribose) Glycohydrolase by Adenosine Diphosphate (Hydroxymethyl)pyrrolidinediol

  摘要：

  Adenosine diphosphate (hydroxymethyl)pyrrolidinediol (ADP-HPD), an NH analog of ADP-ribose, was chemically synthesized and shown to be a potent and specific inhibitor of poly(ADP-ribose) glycohydrolase. The synthetic starting material was the protected pyrroidine, (2R,3R,4S)-1-(benzyloxycarbonyl)-2-(hydroxymethyl)pyrrolidine-3,4-diol 3,4-O-isopropylidene acetal. This starting pyrrolidine was phosphorylated, coupled to adenosine 5'-monophosphate, and deprotected, yielding the title inhibitor ADP-HPD. ADP-HDP was shown to inhibit the activity of poly(ADP-ribose) glycohydrolase by 50% (IC50) at 0.12 mu M, a value 1000-times lower than the IC50 of the product, ADP-ribose. The NAD glycohydrolase from Bungarus fasciatus venom was less sensitive to inhibition by ADP-HPD,exhibiting an IC50 of 260 mu M. ADP-HPD did not inhibit either poly(ADP-ribose) polymerase or NAD:arginine mono(ADP-ribosyl)-transferase A at inhibitor concentrations up to 1 mM. At low ADP-HPD concentration, inhibition was therefore shown to be highly specific for poly(ADP-ribose) glycohydrolase,the hydrolytic enzyme in the metabolism of ADP-ribose polymers.

  DOI：

  10.1021/jm00002a021

文献信息

• Specific Inhibition of Poly(ADP-ribose) Glycohydrolase by Adenosine Diphosphate (Hydroxymethyl)pyrrolidinediol
  作者：James T. Slama、Nasreen Aboul-Ela、Deepa M. Goli、Bruce V. Cheesman、Anne M. Simmons、Myron K. Jacobson

  DOI：10.1021/jm00002a021

  日期：1995.1

  Adenosine diphosphate (hydroxymethyl)pyrrolidinediol (ADP-HPD), an NH analog of ADP-ribose, was chemically synthesized and shown to be a potent and specific inhibitor of poly(ADP-ribose) glycohydrolase. The synthetic starting material was the protected pyrroidine, (2R,3R,4S)-1-(benzyloxycarbonyl)-2-(hydroxymethyl)pyrrolidine-3,4-diol 3,4-O-isopropylidene acetal. This starting pyrrolidine was phosphorylated, coupled to adenosine 5'-monophosphate, and deprotected, yielding the title inhibitor ADP-HPD. ADP-HDP was shown to inhibit the activity of poly(ADP-ribose) glycohydrolase by 50% (IC50) at 0.12 mu M, a value 1000-times lower than the IC50 of the product, ADP-ribose. The NAD glycohydrolase from Bungarus fasciatus venom was less sensitive to inhibition by ADP-HPD,exhibiting an IC50 of 260 mu M. ADP-HPD did not inhibit either poly(ADP-ribose) polymerase or NAD:arginine mono(ADP-ribosyl)-transferase A at inhibitor concentrations up to 1 mM. At low ADP-HPD concentration, inhibition was therefore shown to be highly specific for poly(ADP-ribose) glycohydrolase,the hydrolytic enzyme in the metabolism of ADP-ribose polymers.
• SAR Analysis of Adenosine Diphosphate (Hydroxymethyl)pyrrolidinediol Inhibition of Poly(ADP-ribose) Glycohydrolase
  作者：David W. Koh、Donna L. Coyle、Nimish Mehta、Sushma Ramsinghani、Hyuntae Kim、James T. Slama、Myron K. Jacobson

  DOI：10.1021/jm020541u

  日期：2003.9.1

  Polyadenosine diphosphoribose glycohydrolase (PARG) catalyzes the intracellular hydrolysis of adenosine diphosphoribose polymers. Because structure-activity data are lacking for PARG, the specific inhibitor adenosine diphosphate (hydroxymethyl)pyrrolidinediol (ADP-HPD) was utilized to determine the effects of structure on inhibitor potency using PARG isolated from bovine thymus (bPARG) and recombinant bovine PARG catalytic fragment (rPARG-CF). Both enzymes were strongly inhibited by submicromolar levels of ADP-HPD, but ADP and the phosphorylated pyrrolidine displayed no activity. Utilizing ADP-HPD analogues containing 2-, N-6, or 8-adenosyl substituents or guanine instead of adenine, the importance of adenine ring recognition as well as a correlation between loss of PARG inhibition and the length and bulkiness of 8-adenosyl substituents was shown. Utilization of ADP-HPD analogues lacking one or both pyrrolidine cis-hydroxyls demonstrated their importance for inhibitor binding. Last, the similarity between naturally occurring bPARG and heterologously expressed rPARG-CF was demonstrated. Therefore, readily available rPARG-CF is suitable for use in future studies to determine the structural aspects of PARG.