2-[[(3aR,4R,6R,6aR)-4-(6-amino-2-chloropurin-9-yl)-2-methoxy-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methoxy]-1,3,2-benzodioxaphosphinin-4-one | 1442659-67-7

• 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-[[(3aR,4R,6R,6aR)-4-(6-amino-2-chloropurin-9-yl)-2-methoxy-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methoxy]-1,3,2-benzodioxaphosphinin-4-one
• CAS: 1442659-67-7
• 化学式: C₁₉H₁₇ClN₅O₈P
• 分子量: 509.799
• InChiKey: NLZZOELFEDBJDZ-YKLLULCRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  34
• 可旋转键数：
  5
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.37
• 拓扑面积：
  151
• 氢给体数：
  1
• 氢受体数：
  12

反应信息

• 作为反应物：
  描述：

  2-[[(3aR,4R,6R,6aR)-4-(6-amino-2-chloropurin-9-yl)-2-methoxy-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methoxy]-1,3,2-benzodioxaphosphinin-4-one 在 三正丁胺 、 dimethyl sulfide borane 、 乙二胺 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 3.33h， 生成
  参考文献：
  名称：

  Highly Efficient Biocompatible Neuroprotectants with Dual Activity as Antioxidants and P2Y Receptor Agonists

  摘要：

  Currently, there is a need for novel, biocompatible, and effective neuroprotectants for the treatment of neurodegenerative diseases and brain injury associated with oxidative damage. Here, we developed nucleotide-based neuroprotectants acting dually as antioxidants and P2Y-R agonists. To improve the potency, selectivity, and metabolic stability of ATP/ADP, we substituted adenine C2-position by Cl and P-alpha/P-beta position by borano group, 6-9. Nucleotides 6-9 inhibited oxidation in cell-free systems (Fe(II)-H2O2), as detected by ESR (IC50 up to 175 mu M), and ABTS assay (IC50 up to 40 mu M). They also inhibited FeSO4-induced oxidative stress in PC12 cells (IC50 of 80-200 nM). 2-Cl-ADP(alpha-BH3), 7a, was found to be the most potent P2Y(1)-R agonist currently known (EC50 7 nM) and protected primary cortical neurons from FeSO4 insult (EC50 170 nM). In addition, it proved to be metabolically stable in human blood serum (t(1/2) 7 vs 1.5 h for ADP). Hence, we propose 7a as a highly promising neuroprotectant.

  DOI：

  10.1021/jm400197m
• 作为产物：
  描述：

  2-氯腺嘌呤核苷 在 吡啶 、 对甲苯磺酸 作用下， 以 1,4-二氧六环 、 N,N-二甲基甲酰胺 为溶剂， 反应 0.17h， 生成 2-[[(3aR,4R,6R,6aR)-4-(6-amino-2-chloropurin-9-yl)-2-methoxy-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methoxy]-1,3,2-benzodioxaphosphinin-4-one
  参考文献：
  名称：

  Identification of Highly Promising Antioxidants/Neuroprotectants Based on Nucleoside 5′-Phosphorothioate Scaffold. Synthesis, Activity, and Mechanisms of Action

  摘要：

  With a view to identify novel and biocompatible neuroprotectants, we designed nucleoside 5'-thiophosphate analogues, 6-11. We identified 2-SMe-ADP(alpha-S), 7A, as a most promising neuroprotectant. 7A reduced ROS production in PC12 cells under oxidizing conditions, IC50 of 0.08 vs 21 mu M for ADP. Furthermore, 7A rescued primary neurons subjected to oxidation, EC50 of 0.04 vs 19 mu M for ADP. 7A is a most potent P2Y(1)-R agonist, EC50 of 0.0026 mu M. Activity of 7A in cells involved P2Y(1/12)-R as indicated by blocking P2Y(12)-R or P2Y(1)-R Compound 7A inhibited Fenton reaction better than EDTA, IC50 of 37 vs 54 mu M, due to radical scavenging, IC50 of 12.5 vs 30 mu M for ADP, and Fe(II)-chelation, IC50 of 80 vs >200 mu M for ADP (ferrozine assay). In addition, 7A was stable in human blood serum, 412 of 15 vs 1.5 h for ADP, and resisted hydrolysis by NPP1/3, 2-fold vs ADP. Hence, we propose 7A as a highly promising neuroprotectant.

  DOI：

  10.1021/acs.jmedchem.5b00575

文献信息

• Identification of Highly Promising Antioxidants/Neuroprotectants Based on Nucleoside 5′-Phosphorothioate Scaffold. Synthesis, Activity, and Mechanisms of Action
  作者：Sagit Azran、Ortal Danino、Daniel Förster、Sarah Kenigsberg、Georg Reiser、Mudit Dixit、Vijay Singh、Dan T. Major、Bilha Fischer

  DOI：10.1021/acs.jmedchem.5b00575

  日期：2015.11.12

  With a view to identify novel and biocompatible neuroprotectants, we designed nucleoside 5'-thiophosphate analogues, 6-11. We identified 2-SMe-ADP(alpha-S), 7A, as a most promising neuroprotectant. 7A reduced ROS production in PC12 cells under oxidizing conditions, IC50 of 0.08 vs 21 mu M for ADP. Furthermore, 7A rescued primary neurons subjected to oxidation, EC50 of 0.04 vs 19 mu M for ADP. 7A is a most potent P2Y(1)-R agonist, EC50 of 0.0026 mu M. Activity of 7A in cells involved P2Y(1/12)-R as indicated by blocking P2Y(12)-R or P2Y(1)-R Compound 7A inhibited Fenton reaction better than EDTA, IC50 of 37 vs 54 mu M, due to radical scavenging, IC50 of 12.5 vs 30 mu M for ADP, and Fe(II)-chelation, IC50 of 80 vs >200 mu M for ADP (ferrozine assay). In addition, 7A was stable in human blood serum, 412 of 15 vs 1.5 h for ADP, and resisted hydrolysis by NPP1/3, 2-fold vs ADP. Hence, we propose 7A as a highly promising neuroprotectant.
• Highly Efficient Biocompatible Neuroprotectants with Dual Activity as Antioxidants and P2Y Receptor Agonists
  作者：Sagit Azran、Daniel Förster、Ortal Danino、Yael Nadel、Georg Reiser、Bilha Fischer

  DOI：10.1021/jm400197m

  日期：2013.6.27

  Currently, there is a need for novel, biocompatible, and effective neuroprotectants for the treatment of neurodegenerative diseases and brain injury associated with oxidative damage. Here, we developed nucleotide-based neuroprotectants acting dually as antioxidants and P2Y-R agonists. To improve the potency, selectivity, and metabolic stability of ATP/ADP, we substituted adenine C2-position by Cl and P-alpha/P-beta position by borano group, 6-9. Nucleotides 6-9 inhibited oxidation in cell-free systems (Fe(II)-H2O2), as detected by ESR (IC50 up to 175 mu M), and ABTS assay (IC50 up to 40 mu M). They also inhibited FeSO4-induced oxidative stress in PC12 cells (IC50 of 80-200 nM). 2-Cl-ADP(alpha-BH3), 7a, was found to be the most potent P2Y(1)-R agonist currently known (EC50 7 nM) and protected primary cortical neurons from FeSO4 insult (EC50 170 nM). In addition, it proved to be metabolically stable in human blood serum (t(1/2) 7 vs 1.5 h for ADP). Hence, we propose 7a as a highly promising neuroprotectant.