2',3'-O-methoxymethylidene-5'-O-tosyl-2-MeS-adenosine | 1215007-88-7

• 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: 2',3'-O-methoxymethylidene-5'-O-tosyl-2-MeS-adenosine
• 英文别名: [(3aR,4R,6R,6aR)-4-(6-amino-2-methylsulfanylpurin-9-yl)-2-methoxy-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methyl 4-methylbenzenesulfonate
• CAS: 1215007-88-7
• 化学式: C₂₀H₂₃N₅O₇S₂
• 分子量: 509.564
• InChiKey: CKUAYEJOCPSWPJ-WXNRVYFKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.4
• 重原子数：
  34
• 可旋转键数：
  7
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  184
• 氢给体数：
  1
• 氢受体数：
  12

反应信息

• 作为反应物：
  描述：

  bis(tetra-n-butylammonium)dihydrogen methylenepyrophosphate 、 2',3'-O-methoxymethylidene-5'-O-tosyl-2-MeS-adenosine 以 N,N-二甲基甲酰胺 为溶剂， 反应 48.0h， 生成
  参考文献：
  名称：

  A Novel Insulin Secretagogue Based on a Dinucleoside Polyphosphate Scaffold

  摘要：

  Dinucleoside polyphosphates exert their physiological effects via P2 receptors (P2Rs). They are attractive drug candidates, as they offer better stability and specificity compared to nucleotides, the most common P2 receptor ligands. The activation of pancreatic P2Y receptors by nucleotides increases insulin secretion. Therefore, in the current study, dinucleoside polyphosphate analogues (di-(2-MeS)-adenosine-5',5 ''-P-1,P-4,alpha,beta-methylene-tetraphosphate), 8, (di-(2-MeS)-adenosine-5',5 ''-P-1,P-4,beta,gamma-methylenetetraphosphate), 9, and di-(2-MeS)-adenosine-5',5 ''-P-1,P-3,alpha,beta-methylene triphosphate, 10, were developed as potential insulin secretagogues. Analogues 8 and 9 were found to be agonists of the P2Y(1)R with EC50 values of 0.42 and 0.46 mu M, respectively, whereas analogue 10 had no activity. Analogues 8-10 were found to be completely resistant to hydrolysis by alkaline phosphatase over 3 h at 37 degrees C. Analogue 8 also was found to be 2.5-fold more stable in human blood serum than ATP, with a half-life of 12.1 h. Analogue 8 administration in rats caused a decrease in a blood glucose load from 155 mg/dL to ca. 100 mg/dL and increased blood insulin levels 4-fold as compared to basal levels. In addition, analogue 8 reduced a blood glucose load to normal values (80-110 mg/dL), unlike the commonly prescribed glibenclamide, which reduced glucose levels below normal values (60 mg/dL). These findings suggest that analogue 8 may prove to be an effective and safe treatment for type 2 diabetes.

  DOI：

  10.1021/jm901621h
• 作为产物：
  描述：

  对甲苯磺酰氯 、 2-methylthio-(2',3'-O-methoxymethylidene)adenosine 在 4-二甲氨基吡啶 作用下， 以 二氯甲烷 为溶剂， 反应 2.0h， 以85%的产率得到2',3'-O-methoxymethylidene-5'-O-tosyl-2-MeS-adenosine
  参考文献：
  名称：

  A Novel Insulin Secretagogue Based on a Dinucleoside Polyphosphate Scaffold

  摘要：

  Dinucleoside polyphosphates exert their physiological effects via P2 receptors (P2Rs). They are attractive drug candidates, as they offer better stability and specificity compared to nucleotides, the most common P2 receptor ligands. The activation of pancreatic P2Y receptors by nucleotides increases insulin secretion. Therefore, in the current study, dinucleoside polyphosphate analogues (di-(2-MeS)-adenosine-5',5 ''-P-1,P-4,alpha,beta-methylene-tetraphosphate), 8, (di-(2-MeS)-adenosine-5',5 ''-P-1,P-4,beta,gamma-methylenetetraphosphate), 9, and di-(2-MeS)-adenosine-5',5 ''-P-1,P-3,alpha,beta-methylene triphosphate, 10, were developed as potential insulin secretagogues. Analogues 8 and 9 were found to be agonists of the P2Y(1)R with EC50 values of 0.42 and 0.46 mu M, respectively, whereas analogue 10 had no activity. Analogues 8-10 were found to be completely resistant to hydrolysis by alkaline phosphatase over 3 h at 37 degrees C. Analogue 8 also was found to be 2.5-fold more stable in human blood serum than ATP, with a half-life of 12.1 h. Analogue 8 administration in rats caused a decrease in a blood glucose load from 155 mg/dL to ca. 100 mg/dL and increased blood insulin levels 4-fold as compared to basal levels. In addition, analogue 8 reduced a blood glucose load to normal values (80-110 mg/dL), unlike the commonly prescribed glibenclamide, which reduced glucose levels below normal values (60 mg/dL). These findings suggest that analogue 8 may prove to be an effective and safe treatment for type 2 diabetes.

  DOI：

  10.1021/jm901621h

文献信息

• 2-MeS-β,γ-CCl₂-ATP is a Potent Agent for Reducing Intraocular Pressure
  作者：Shay Eliahu、Alba Martín-Gil、María Jesús Perez de Lara、Jesús Pintor、Jean Camden、Gary A. Weisman、Joanna Lecka、Jean Sévigny、Bilha Fischer

  DOI：10.1021/jm100030u

  日期：2010.4.22

  Extracellular nucleotides can modify the production or drainage of the aqueous humor via activation of P2 receptors and therefore affect the intraocular pressure (IOP). We have synthesized slowly hydrolyzable nucleoside di- and triphosphate analogues, 1, and 8-14. Analogues 8-14 were completely resistant to hydrolysis by alkaline phosphatase over 30 min at 37 degrees C. In human blood serum, analogues 8-14 exhibited high stability, e.g., analogues 9 and 10-14 were only 15% and 0% degraded after 24 h, respectively. Moreover, analogues 8-14 were highly stable at pH 1.4 (t(1/2) 1 h-30 days). Analogues 8-14 were agonists of the P2Y(1) receptor (EC50 0.57-9.54 mu M). Ocular administration of most analogues into rabbits reduced IOP, e.g., analogue 9 reduced IOP by 32% (EC50 95.5 nM). Analogue 9 was more effective at reducing IOP than several common glaucoma drugs and represents a promising alternative to timolol maleate, which cannot be used for the treatment of patients suffering from asthma or cardiac problems.
• A Novel Insulin Secretagogue Based on a Dinucleoside Polyphosphate Scaffold
  作者：Shay Eliahu、Haim M. Barr、Jean Camden、Gary A. Weisman、Bilha Fischer

  DOI：10.1021/jm901621h

  日期：2010.3.25

  Dinucleoside polyphosphates exert their physiological effects via P2 receptors (P2Rs). They are attractive drug candidates, as they offer better stability and specificity compared to nucleotides, the most common P2 receptor ligands. The activation of pancreatic P2Y receptors by nucleotides increases insulin secretion. Therefore, in the current study, dinucleoside polyphosphate analogues (di-(2-MeS)-adenosine-5',5 ''-P-1,P-4,alpha,beta-methylene-tetraphosphate), 8, (di-(2-MeS)-adenosine-5',5 ''-P-1,P-4,beta,gamma-methylenetetraphosphate), 9, and di-(2-MeS)-adenosine-5',5 ''-P-1,P-3,alpha,beta-methylene triphosphate, 10, were developed as potential insulin secretagogues. Analogues 8 and 9 were found to be agonists of the P2Y(1)R with EC50 values of 0.42 and 0.46 mu M, respectively, whereas analogue 10 had no activity. Analogues 8-10 were found to be completely resistant to hydrolysis by alkaline phosphatase over 3 h at 37 degrees C. Analogue 8 also was found to be 2.5-fold more stable in human blood serum than ATP, with a half-life of 12.1 h. Analogue 8 administration in rats caused a decrease in a blood glucose load from 155 mg/dL to ca. 100 mg/dL and increased blood insulin levels 4-fold as compared to basal levels. In addition, analogue 8 reduced a blood glucose load to normal values (80-110 mg/dL), unlike the commonly prescribed glibenclamide, which reduced glucose levels below normal values (60 mg/dL). These findings suggest that analogue 8 may prove to be an effective and safe treatment for type 2 diabetes.