(1'S,2'R,3'S,4'R,5'S)-4-(6-methylamino-9H-purin-9-yl)-1-[hydroxymethyl]bicyclo[3.1.0]hexane-2,3-(O-isopropylidene) | 436847-25-5

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 核苷和核苷酸类似物
• 英文名称: (1'S,2'R,3'S,4'R,5'S)-4-(6-methylamino-9H-purin-9-yl)-1-[hydroxymethyl]bicyclo[3.1.0]hexane-2,3-(O-isopropylidene)
• 英文别名: [(1R,2R,4S,5R,6S)-8,8-dimethyl-5-[6-(methylamino)purin-9-yl]-7,9-dioxatricyclo[4.3.0.02,4]nonan-2-yl]methanol
• CAS: 436847-25-5
• 化学式: C₁₆H₂₁N₅O₃
• 分子量: 331.374
• InChiKey: SMLSJJAJMWQDJN-MHDWVLHZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.3
• 重原子数：
  24
• 可旋转键数：
  3
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.69
• 拓扑面积：
  94.3
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  (1'S,2'R,3'S,4'R,5'S)-4-(6-methylamino-9H-purin-9-yl)-1-[hydroxymethyl]bicyclo[3.1.0]hexane-2,3-(O-isopropylidene) 在 四氮唑 、 Dowex 50X₈-200 、 三乙胺 、 间氯过氧苯甲酸 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 8.33h， 生成 [(1R,2R,3S,4R,5S)-2,3-dihydroxy-4-[6-(methylamino)purin-9-yl]-1-bicyclo[3.1.0]hexanyl]methoxy-imidazol-1-ylphosphinic acid
  参考文献：
  名称：

  Adenine Nucleotide Analogues Locked in a Northern Methanocarba Conformation:  Enhanced Stability and Potency as P2Y₁ Receptor Agonists

  摘要：

  Preference for the Northern (N) ring conformation of the ribose moiety of nucleotide 5'-triphosphate agonists at P2Y(1), P2Y(2), P2Y(4), and P2Y(11) receptors, but not P2Y(6) receptors, was established using a ring-constrained methanocarba (a 3.1.0-bicyclohexane) ring as a ribose substitute (Kim et al. J. Med. Chem. 2002, 45, 208-218.). We have now combined the ring-constrained (N)-methanocarba modification of adenine nucleotides with other functionalities known to enhance potency at P2 receptors. The potency of the newly synthesized analogues was determined in the stimulation of phospholipase C through activation of turkey erythrocyte P2Y, or human P2Y, and P2Y2 receptors stably expressed in astrocytoma cells. An (N)methanocarba-2-methylthio-ADP analogue displayed an EC50 at the hP2Y(1) receptor of 0.40 nM and was 55-fold more potent than the corresponding triphosphate and 16-fold more potent than the riboside 5'-diphosphate. 2-Cl-(N)-methanocarba-ATP and its N-6-Me analogue were also highly selective, full agonists at P2Y, receptors. The (N)-methanocarba-2-methylthio and 2-chloromonophosphate analogues were full agonists exhibiting micromolar potency at P2Y(1) receptors, while the corresponding ribosides were inactive. Although beta,y-methylene-ATP was inactive at P2Y receptors beta,y-methylene-(N)-methanocarba-ATP was a potent hP2Y1 receptor agonist with an EC50 of 160 nM and was selective versus hP2Y(2) and hP2Y(4) receptors. The rates of hydrolysis of Northern (N) and Southern (S) methanocarba analogues of AMP by rat 5'-ectonucleotidase were negligible. The rates of hydrolysis of the corresponding triphosphates by recombinant rat NTPDase 1 and 2 were studied. Both isomers were hydrolyzed by NTPDase 1 at about half the rate of ATP hydrolysis. The (N) isomer was hardly hydrolyzed by NTPDase 2, while the (S) isomer was hydrolyzed at one-third of the rate of ATP hydrolysis. This suggests that new, more stable and selective nucleotide agonists may be designed on the basis of the (N)-conformation, which greatly enhanced potency at P2Y, receptors.

  DOI：

  10.1021/jm010538v
• 作为产物：
  描述：

  (1'R,2'R,3'S,4'R,5'S)-4-(chloropurin-9-yl)-1-[(phenylmethoxy)methyl]-bicyclo[3.1.0]hexane-2,3-(O-isopropylidene) 在 钯 甲酸 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 反应 15.0h， 生成 (1'S,2'R,3'S,4'R,5'S)-4-(6-methylamino-9H-purin-9-yl)-1-[hydroxymethyl]bicyclo[3.1.0]hexane-2,3-(O-isopropylidene)
  参考文献：
  名称：

  Adenine Nucleotide Analogues Locked in a Northern Methanocarba Conformation:  Enhanced Stability and Potency as P2Y₁ Receptor Agonists

  摘要：

  Preference for the Northern (N) ring conformation of the ribose moiety of nucleotide 5'-triphosphate agonists at P2Y(1), P2Y(2), P2Y(4), and P2Y(11) receptors, but not P2Y(6) receptors, was established using a ring-constrained methanocarba (a 3.1.0-bicyclohexane) ring as a ribose substitute (Kim et al. J. Med. Chem. 2002, 45, 208-218.). We have now combined the ring-constrained (N)-methanocarba modification of adenine nucleotides with other functionalities known to enhance potency at P2 receptors. The potency of the newly synthesized analogues was determined in the stimulation of phospholipase C through activation of turkey erythrocyte P2Y, or human P2Y, and P2Y2 receptors stably expressed in astrocytoma cells. An (N)methanocarba-2-methylthio-ADP analogue displayed an EC50 at the hP2Y(1) receptor of 0.40 nM and was 55-fold more potent than the corresponding triphosphate and 16-fold more potent than the riboside 5'-diphosphate. 2-Cl-(N)-methanocarba-ATP and its N-6-Me analogue were also highly selective, full agonists at P2Y, receptors. The (N)-methanocarba-2-methylthio and 2-chloromonophosphate analogues were full agonists exhibiting micromolar potency at P2Y(1) receptors, while the corresponding ribosides were inactive. Although beta,y-methylene-ATP was inactive at P2Y receptors beta,y-methylene-(N)-methanocarba-ATP was a potent hP2Y1 receptor agonist with an EC50 of 160 nM and was selective versus hP2Y(2) and hP2Y(4) receptors. The rates of hydrolysis of Northern (N) and Southern (S) methanocarba analogues of AMP by rat 5'-ectonucleotidase were negligible. The rates of hydrolysis of the corresponding triphosphates by recombinant rat NTPDase 1 and 2 were studied. Both isomers were hydrolyzed by NTPDase 1 at about half the rate of ATP hydrolysis. The (N) isomer was hardly hydrolyzed by NTPDase 2, while the (S) isomer was hydrolyzed at one-third of the rate of ATP hydrolysis. This suggests that new, more stable and selective nucleotide agonists may be designed on the basis of the (N)-conformation, which greatly enhanced potency at P2Y, receptors.

  DOI：

  10.1021/jm010538v

文献信息

• Adenine Nucleotide Analogues Locked in a Northern Methanocarba Conformation:  Enhanced Stability and Potency as P2Y₁ Receptor Agonists
  作者：R. Gnana Ravi、Hak Sung Kim、Jörg Servos、Herbert Zimmermann、Kyeong Lee、Savitri Maddileti、José L. Boyer、T. Kendall Harden、Kenneth A. Jacobson

  DOI：10.1021/jm010538v

  日期：2002.5.1

  Preference for the Northern (N) ring conformation of the ribose moiety of nucleotide 5'-triphosphate agonists at P2Y(1), P2Y(2), P2Y(4), and P2Y(11) receptors, but not P2Y(6) receptors, was established using a ring-constrained methanocarba (a 3.1.0-bicyclohexane) ring as a ribose substitute (Kim et al. J. Med. Chem. 2002, 45, 208-218.). We have now combined the ring-constrained (N)-methanocarba modification of adenine nucleotides with other functionalities known to enhance potency at P2 receptors. The potency of the newly synthesized analogues was determined in the stimulation of phospholipase C through activation of turkey erythrocyte P2Y, or human P2Y, and P2Y2 receptors stably expressed in astrocytoma cells. An (N)methanocarba-2-methylthio-ADP analogue displayed an EC50 at the hP2Y(1) receptor of 0.40 nM and was 55-fold more potent than the corresponding triphosphate and 16-fold more potent than the riboside 5'-diphosphate. 2-Cl-(N)-methanocarba-ATP and its N-6-Me analogue were also highly selective, full agonists at P2Y, receptors. The (N)-methanocarba-2-methylthio and 2-chloromonophosphate analogues were full agonists exhibiting micromolar potency at P2Y(1) receptors, while the corresponding ribosides were inactive. Although beta,y-methylene-ATP was inactive at P2Y receptors beta,y-methylene-(N)-methanocarba-ATP was a potent hP2Y1 receptor agonist with an EC50 of 160 nM and was selective versus hP2Y(2) and hP2Y(4) receptors. The rates of hydrolysis of Northern (N) and Southern (S) methanocarba analogues of AMP by rat 5'-ectonucleotidase were negligible. The rates of hydrolysis of the corresponding triphosphates by recombinant rat NTPDase 1 and 2 were studied. Both isomers were hydrolyzed by NTPDase 1 at about half the rate of ATP hydrolysis. The (N) isomer was hardly hydrolyzed by NTPDase 2, while the (S) isomer was hydrolyzed at one-third of the rate of ATP hydrolysis. This suggests that new, more stable and selective nucleotide agonists may be designed on the basis of the (N)-conformation, which greatly enhanced potency at P2Y, receptors.