2-chloro-2′,3′-O-methoxymethylideneadenosine | 478702-41-9

• 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-chloro-2′,3′-O-methoxymethylideneadenosine
• 英文别名: 2-chloro-(2',3'-O-methoxymethylidene)adenosine；2-chloro-2',3'-O-methoxymethylideneadenosine；[(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]methanol
• CAS: 478702-41-9
• 化学式: C₁₂H₁₄ClN₅O₅
• 分子量: 343.727
• InChiKey: PZOYTKVEFHFNIN-BFINSNOLSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.5
• 重原子数：
  23
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.58
• 拓扑面积：
  127
• 氢给体数：
  2
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  2-chloro-2′,3′-O-methoxymethylideneadenosine 在 磷酸三甲酯 、 三正丁胺 、 1,8-双二甲氨基萘 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 1.83h， 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 、 原甲酸三甲酯 在 对甲苯磺酸 作用下， 生成 2-chloro-2′,3′-O-methoxymethylideneadenosine
  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

• Antidiabetic 2-substituted-5' -O- (1-Boranotriphosphate) adenosine derivatives
  申请人：Fischer Bilha

  公开号：US20050065108A1

  公开（公告）日：2005-03-24

  2-Substituted-5′-O-(1-boranotriphosphate)adenosine derivatives having at position 2 a radical R1 selected from the group consisting of H; halogen; O-hydrocarbyl; S-hydrocarbyl; NR3R4; and hydrocarbyl optionally substituted by halogen, CN, SCN, NO2, OR3, SR3 or NR3R4; wherein R3 and R4 are each independently H or hydrocarbyl or R3 and R4 together with the nitrogen atom to which they are attached form a saturated or unsaturated heterocyclic ring optionally containing 1-2 further heteroatoms selected from oxygen, nitrogen and sulfur, and pharmaceutically acceptable salts or diastereoisomers thereof or a mixture of diastereoisomers, are useful for treatment of type 2 diabetes.

  2-取代的-5′-O-(1-三磷酸硼烷)腺苷衍生物，其第 2 位上的基团 R1 选自以下组成的组 H；卤素；O-烃基；S-烃基；NR3R4；以及任选被卤素、CN、SCN、NO2、OR3、SR3 或 NR3R4 取代的烃基；其中 R3 和 R4 各自独立地为 H 或烃基，或 R3 和 R4 与它们所连接的氮原子一起形成饱和或不饱和杂环，可选地再含有 1-2 个选自氧、氮和硫的杂原子，以及它们的药学上可接受的盐或非对映异构体或非对映异构体的混合物，可用于治疗 2 型糖尿病。
• Adenosine 5‘-<i>O</i>-(1-Boranotriphosphate) Derivatives as Novel P2Y₁ Receptor Agonists
  作者：Victoria Nahum、Gregor Zündorf、Sébastien A. Lévesque、Adrien R. Beaudoin、Georg Reiser、Bilha Fischer

  DOI：10.1021/jm020251d

  日期：2002.11.1

  P2-receptors (P2-Rs) represent important targets for novel drug development. Most ATP analogues proposed as potential drug candidates have shortcomings such as limited receptor-selectivity and limited stability that justify the search for new P2-R agonists. Therefore, a novel series of nucleotides based on the adenosine 5'-O-(1-boranotriphosphate) (ATP-alpha-B) scaffold was developed and tested as P2Y(1)-R agonists. An efficient four-step one-pot synthesis of several ATP-alpha-B analogues from the corresponding nucleosides was developed, as well as a facile method for the separation of the diastereoisomers (A and B isomers) of the chiral products. The potency of the new analogues as P2Y(1)-R agonists was evaluated by the agonist-induced Ca2+ release of HEK 293 cells stably transfected with rat-brain P2Y(1)-R. ATP-alpha-B A isomer was equipotent with ATP (EC50 = 2 x 10(-7) M). However, 2-MeS- and 2-Cl- substitutions on ATP-alpha-B (A isomer) increased the potency of the agonist up to 100-fold, with EC50 values of 4.5 x 10(-9) and 3.6 x 10(-9) M, compared to that of the ATP-alpha-B (A isomer). Diastereoisomers A of all ATP-alpha-B analogues were more potent in inducing Ca2+ release than the corresponding B counterparts, with a 20-fold difference for 2-MeS-ATP-alpha-B analogues. The chemical stability of the new P2Y(1)-R agonists was evaluated by P-31 NMR under physiological and gastric-juice pH values at 37 degreesC, with rates of hydrolysis of 2-MeS-ATP-alpha-B of 1.38 x 10(-7) s(-1) (t(1/2) of 1395 h) and 3.24 x 10(-5) s(-1) (t(1/2) = 5.9 h), respectively. The enzymatic stability of the new analogues toward spleen NTPDase was evaluated. Most of the new analogues were poor substrates for the NTPDase, with ATP-alpha-B (A isomer) hydrolysis being 5% of the hydrolysis rate of ATP. Diastereoisomers A and B exhibited different stability, with A isomers being significantly more stable, up to 9-fold. Furthermore, A isomers that are potent P2Y(1)-R agonists barely interact with NTPDase, thus exhibiting protein selectivity. Therefore, on the basis of our findings, the new, highly water-soluble, P2Y(1)-R agonists may be considered as potentially promising drug candidates.
• US7319093B2
  申请人：——

  公开号：US7319093B2

  公开（公告）日：2008-01-15
• 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.