5'-deoxy-5',5'-difluoro-2',3'-O-isopropylideneadenosine | 134868-31-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 咪唑并嘧啶类
• 英文名称: 5'-deoxy-5',5'-difluoro-2',3'-O-isopropylideneadenosine
• 英文别名: 5',5'-difluoro-5'-deoxy-2',3'-O-isopropylideneadenosine；5'-Deoxy-5',5'-difluoro-2',3'-0-isopropylidene adenosine；9-[(3aR,4R,6S,6aS)-6-(difluoromethyl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]purin-6-amine
• CAS: 134868-31-8
• 化学式: C₁₃H₁₅F₂N₅O₃
• 分子量: 327.291
• InChiKey: SGPJTFMASUVEER-BSFVXNEUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.6
• 重原子数：
  23
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  97.3
• 氢给体数：
  1
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  5'-deoxy-5',5'-difluoro-2',3'-O-isopropylideneadenosine 在 三氟乙酸 作用下， 以 水 为溶剂， 反应 1.0h， 以68%的产率得到(2R,3R,4S,5S)-2-(6-氨基嘌呤-9-基)-5-(二氟甲基)四氢呋喃-3,4-二醇
  参考文献：
  名称：

  4'，5'-不饱和5'-卤代核苷。基于机制的竞争性S-腺苷-L-高半胱氨酸水解酶抑制剂。

  摘要：

  （E）-和（Z）-5'-氟-4'，5'-二氢-5'-脱氧腺苷（分别为6和13）的设计和合成，这是一类新的基于机理的S-抑制剂描述了腺苷-L-高半胱氨酸（SAH）水解酶。为了确定抑制该酶所必需的结构-活性关系，合成了许多6和13的类似物。用氯代替6（即44）中的氟，在5'-乙烯基位置（即51和52）添加额外的氯，将2'-羟基修饰为脱氧（34和35）和阿拉伯糖（ 36和37）核苷提供了SAH水解酶的竞争性抑制剂。核苷6和13以及5'-脱氧-5'，5'-二氟腺苷（14）被证明是SAH水解酶的时间依赖性抑制剂。假定所有这三种化合物都通过强力亲电试剂来抑制，该亲电试剂是由6或13的3'-羟基氧化成酮（即3和/或E-异构体）而形成的。与提出的通过6、13和14灭活SAH水解酶的机理一致的观察结果是，纯化的大鼠肝脏SAH水解酶与6孵育会释放1当量的氟离子（通过19F NMR），与14孵育会导致释放2当量

  DOI：

  10.1021/jm00106a028
• 作为产物：
  描述：

  N⁶,N⁶-di-benzoyl-2',3'-O-isopropylideneadenosine 在 二氯乙酸 、 氨 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 [双(2-甲氧基乙基)胺]三氟化硫 作用下， 以 四氢呋喃 、 甲醇 、 二甲基亚砜 为溶剂， 反应 19.0h， 生成 5'-deoxy-5',5'-difluoro-2',3'-O-isopropylideneadenosine
  参考文献：
  名称：

  Exploration of a potential difluoromethyl-nucleoside substrate with the fluorinase enzyme

  摘要：

  The investigation of a difluoromethyl-bearing nucleoside with the fluorinase enzyme is described. 5',5'-Difluoro-5'-deoxyadenosine 7 (F(2)DA) was synthesised from adenosine, and found to bind to the fluorinase enzyme by isothermal titration calorimetry with similar affinity compared to 5'-fluoro-5'deoxyadenosine 2 (FDA), the natural product of the enzymatic reaction. F(2)DA 7 was found, however, not to undergo the enzyme catalysed reaction with L-selenomethionine, unlike FDA 2, which undergoes reaction with L-selenomethionine to generate Se-adenosylselenomethionine. A co-crystal structure of the fluorinase and F(2)DA 7 and tartrate was solved to 1.8 angstrom, and revealed that the difluoromethyl group bridges interactions known to be essential for activation of the single fluorine in FDA 2. An unusual hydrogen bonding interaction between the hydrogen of the difluoromethyl group and one of the hydroxyl oxygens of the tartrate ligand was also observed. The bridging interactions, coupled with the inherently stronger C-F bond in the difluoromethyl group, offers an explanation for why no reaction is observed. (C) 2015 Elsevier Inc. All rights reserved.

  DOI：

  10.1016/j.bioorg.2015.11.003

文献信息

• 4'-5'-Unsaturated 5'-halogenated nucleosides. Mechanism-based and competitive inhibitors of S-adenosyl-L-homocysteine hydrolase
  作者：Esa T. Jarvi、James R. McCarthy、Shujaath Mehdi、Donald P. Matthews、Michael L. Edwards、Nellikunja J. Prakash、Terry L. Bowlin、Prasad S. Sunkara、Philippe Bey

  DOI：10.1021/jm00106a028

  日期：1991.2

  an extra chlorine to the 5'-vinyl position (i.e. 51 and 52), modification of the 2'-hydroxyl group to the deoxy (34 and 35) and arabino (36 and 37) nucleosides provided competitive inhibitors of SAH hydrolase. Nucleosides 6 and 13, as well as 5'-deoxy-5',5'-difluoroadenosine (14) proved to be time-dependent inhibitors of SAH hydrolase. All three compounds are postulated to inhibit through the potent

  （E）-和（Z）-5'-氟-4'，5'-二氢-5'-脱氧腺苷（分别为6和13）的设计和合成，这是一类新的基于机理的S-抑制剂描述了腺苷-L-高半胱氨酸（SAH）水解酶。为了确定抑制该酶所必需的结构-活性关系，合成了许多6和13的类似物。用氯代替6（即44）中的氟，在5'-乙烯基位置（即51和52）添加额外的氯，将2'-羟基修饰为脱氧（34和35）和阿拉伯糖（ 36和37）核苷提供了SAH水解酶的竞争性抑制剂。核苷6和13以及5'-脱氧-5'，5'-二氟腺苷（14）被证明是SAH水解酶的时间依赖性抑制剂。假定所有这三种化合物都通过强力亲电试剂来抑制，该亲电试剂是由6或13的3'-羟基氧化成酮（即3和/或E-异构体）而形成的。与提出的通过6、13和14灭活SAH水解酶的机理一致的观察结果是，纯化的大鼠肝脏SAH水解酶与6孵育会释放1当量的氟离子（通过19F NMR），与14孵育会导致释放2当量
• US4997925A
  申请人：——

  公开号：US4997925A

  公开（公告）日：1991-03-05
• Exploration of a potential difluoromethyl-nucleoside substrate with the fluorinase enzyme
  作者：Stephen Thompson、Stephen A. McMahon、James H. Naismith、David O’Hagan

  DOI：10.1016/j.bioorg.2015.11.003

  日期：2016.2

  The investigation of a difluoromethyl-bearing nucleoside with the fluorinase enzyme is described. 5',5'-Difluoro-5'-deoxyadenosine 7 (F(2)DA) was synthesised from adenosine, and found to bind to the fluorinase enzyme by isothermal titration calorimetry with similar affinity compared to 5'-fluoro-5'deoxyadenosine 2 (FDA), the natural product of the enzymatic reaction. F(2)DA 7 was found, however, not to undergo the enzyme catalysed reaction with L-selenomethionine, unlike FDA 2, which undergoes reaction with L-selenomethionine to generate Se-adenosylselenomethionine. A co-crystal structure of the fluorinase and F(2)DA 7 and tartrate was solved to 1.8 angstrom, and revealed that the difluoromethyl group bridges interactions known to be essential for activation of the single fluorine in FDA 2. An unusual hydrogen bonding interaction between the hydrogen of the difluoromethyl group and one of the hydroxyl oxygens of the tartrate ligand was also observed. The bridging interactions, coupled with the inherently stronger C-F bond in the difluoromethyl group, offers an explanation for why no reaction is observed. (C) 2015 Elsevier Inc. All rights reserved.