2-methylthio-(2',3'-O-methoxymethylidene)adenosine | 478702-40-8

• 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-methylthio-(2',3'-O-methoxymethylidene)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]methanol
• CAS: 478702-40-8
• 化学式: C₁₃H₁₇N₅O₅S
• 分子量: 355.374
• InChiKey: HQENDHGLRPOUMU-QHQIBUKQSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.7
• 重原子数：
  24
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  152
• 氢给体数：
  2
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  2-methylthio-(2',3'-O-methoxymethylidene)adenosine 在 1,8-双二甲氨基萘 、 三氯氧磷 作用下， 以 磷酸三甲酯 为溶剂， 反应 2.33h， 生成 9-[(3aR,4R,6R,6aR)-6-(dichlorophosphoryloxymethyl)-2-methoxy-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-2-methylsulfanylpurin-6-amine
  参考文献：
  名称：

  水解稳定和选择性 P2Y1 受体激动剂的鉴定

  摘要：

  P2Y 核苷酸受体 (P2YRs) 是有吸引力的药物靶点。大多数作为药物提出的 P2YR 激动剂由核苷酸支架组成，但由于其化学和酶学不稳定性，它们的使用受到限制。为了鉴定候选药物，我们开发了不可水解的 P2YR 激动剂。我们合成了 ATP-β,γ-CH 2类似物2 – 4，并评估了它们在 P2Y 1,2,4,6受体上的化学和代谢稳定性和活性。类似物2 - 4展出吨1/2的胃液的pH 14.5-65ħ值。它们在 37°C 下对碱性磷酸酶完全耐受 30 分钟，并在人血清中缓慢水解（t 1/212.7–71.9 小时）。与 ATP 相比，类似物2 – 4几乎不被三磷酸核苷二磷酸水解酶 NTPDase1,2,3,8（<8% 水解）和核苷酸焦磷酸酶 NPP1,3（水解≤10%）水解。类似物2和4B是 P2Y 1 R 的选择性激动剂，EC 50 s 分别为 0.08 和 17.2 μM。这些特征使类似物2和4B

  DOI：

  10.1016/j.ejmech.2008.07.015
• 作为产物：
  描述：

  5-amino-1-(β-D-ribofuranosyl)imidazole-4-carboxamidoxime 在 ammonium sulfide 、 sodium dithionite 、 对甲苯磺酸 作用下， 以 甲醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 23.67h， 生成 2-methylthio-(2',3'-O-methoxymethylidene)adenosine
  参考文献：
  名称：

  New highly active antiplatelet agents with dual specificity for platelet P2Y1 and P2Y12 adenosine diphosphate receptors

  摘要：

  Currently approved platelet adenosine diphosphate (ADP) receptor antagonists target only the platelet P2Y(12) receptor. Moreover, especially in patients with acute coronary syndromes, there is a strong need for rapidly acting and reversible antiplatelet agents in order to minimize the risk of thrombotic events and bleeding complications. In this study, a series of new P-1,P-4-di(adenosine-5') tetraphosphate (Ap(4)A) derivatives with modifications in the base and in the tetraphosphate chain were synthesized and evaluated with respect to their effects on platelet aggregation and function of the platelet P2Y(1), P2Y(12), and P2X1 receptors. The resulting structure activity relationships were used to design Ap(4)A analogs which inhibit human platelet aggregation by simultaneously antagonizing both P2Y(1) and P2Y(12) platelet receptors. Unlike Ap(4)A, the analogs do not activate platelet P2X1 receptors. Furthermore, the new compounds exhibit fast onset and offset of action and are significantly more stable than Ap(4)A to degradation in plasma, thus presenting a new promising class of antiplatelet agents. (C) 2015 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2015.10.055

文献信息

• [EN] NON-HYDROLYZABLE NUCLEOSIDE DI- OR TRI-PHOSPHATE DERIVATIVES AND USES THEREOF<br/>[FR] DÉRIVÉS DE NUCLÉOSIDES DI- OU TRI-PHOSPHATES NON HYDROLYSABLES ET LEURS UTILISATIONS
  申请人：UNIV BAR ILAN

  公开号：WO2009066298A1

  公开（公告）日：2009-05-28

  The invention provides non-hydrolyzable nucleoside polyphosphate derivatives, e.g., 2MeS-adenosine- β,γ-CH2-5'-O-(1-boranotriphosphate), 2MeS-adenosine- β,γ-CC12-5'-O-(1-boranotriphosphate), 2-MeS-adenosine-5'-dichloro methylene-diphosphate, 2-MeS-adenosine-5'-difluoromethylene- diphosphate and 2MeS-adenosine-5'-O-(1-boranodiphosphate), as well as pharmaceutical compositions thereof. These compounds are useful for prevention or treatment of diseases or disorders modulated by P2Y-receptors such as type 2 diabetes, and for pain control.

  该发明提供了非水解核苷酸多聚物衍生物，例如2MeS-腺苷-β，γ-CH2-5'-O-(1-硼酸三磷酸盐)、2MeS-腺苷-β，γ-CC12-5'-O-(1-硼酸三磷酸盐)、2-MeS-腺苷-5'-二氯甲基二磷酸盐、2-MeS-腺苷-5'-二氟甲基二磷酸盐和2MeS-腺苷-5'-O-(1-硼二磷酸盐)，以及其制备的药物组合物。这些化合物对于预防或治疗由P2Y受体调节的疾病或紊乱，如2型糖尿病，以及疼痛控制非常有用。
• 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.
• 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.
• 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.