5-amino-1-(5-O-tert-butyldimethylsilyl-2,3-O-isopropylidene-β-D-ribofuranosyl)imidazole-4-carbonitrile

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 咪唑核糖核苷和核糖核苷酸
• 英文名称: 5-amino-1-(5-O-tert-butyldimethylsilyl-2,3-O-isopropylidene-β-D-ribofuranosyl)imidazole-4-carbonitrile
• 英文别名: 5-amino-1-[5'-O-(tert-butyldimethylsilyl)-2,3-O-(isopropylidene)-β-D-ribofuranosyl]imidazole-4-nitrile；5-amino-1-[5'-O-(tert-butyldimethylsilyl)-2',3-Oisopropylidene-β-D-ribofuranosyl]-1H-imidazole-4-carbonitrile；1-[(3aR,4R,6R,6aR)-6-[[tert-butyl(dimethyl)silyl]oxymethyl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-5-aminoimidazole-4-carbonitrile
• 化学式: C₁₈H₃₀N₄O₄Si
• 分子量: 394.546
• InChiKey: ACRUNLNRHFSPKX-IXYNUQLISA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.78
• 重原子数：
  27
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.78
• 拓扑面积：
  105
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  5-amino-1-(5-O-tert-butyldimethylsilyl-2,3-O-isopropylidene-β-D-ribofuranosyl)imidazole-4-carbonitrile 在 盐酸羟胺 、 三乙胺 作用下， 以 乙醇 为溶剂， 反应 1.5h， 以70%的产率得到5-amino-1-(5-O-tert-butyldimethylsilyl-2,3-O-isopropylidene-β-D-ribofuranosyl)imidazole-4-carboxamidoxime
  参考文献：
  名称：

  通过 NN 键形成策略合成 3-氨基咪唑并 [4,5-c] 吡唑核苷作为腺苷的 [5:5] 融合类似物

  摘要：

  3-氨基-6-(β-D-呋喃核糖基)咪唑并[4,5-c]吡唑(2)是通过单核杂环重排(MHR)的NN键形成策略合成的。一系列 5-amino-1-(5-O-tert-butyldimethylsilyl-2,3-O-isopropylidene-β-D-ribofuranosyl-4-(1,2,4-oxadiazol-3-yl)imidaz-oles (6a-d)，在 1,2,4-恶二唑的 5-位具有不同的取代基，由 5-氨基-1-(β-D-呋喃核糖基)咪唑-4-甲酰胺 (AICA Ribose, 3 ). 发现5-氨基-1-(5-O-叔丁基二甲基甲硅烷基-2,3-O-异亚丙基-β-D-呋喃核糖基)-4-(5-甲基-1,2,4-恶二唑-3-基）咪唑（6a）与氢化钠在 DMF 或 DMSO 中进行 MHR，以良好的产率得到相应的 3-乙酰氨基咪唑并[4,5-c]吡唑核苷（7b 和/或 7a）。从

  DOI：

  10.1080/15257770500269531
• 作为产物：
  描述：

  5-amino-1-β-D-ribofuranosylimidazole-4-carbonitrile 在 咪唑 、 对甲苯磺酸 作用下， 以 N,N-二甲基甲酰胺 、 丙酮 为溶剂， 反应 21.5h， 生成 5-amino-1-(5-O-tert-butyldimethylsilyl-2,3-O-isopropylidene-β-D-ribofuranosyl)imidazole-4-carbonitrile
  参考文献：
  名称：

  Bisubstrate Inhibitors of Biotin Protein Ligase in Mycobacterium tuberculosis Resistant to Cyclonucleoside Formation

  摘要：

  Mycobacterium tuberculosis (Mtb), the etiological agent of tuberculosis, is the leading cause of bacterial infectious disease mortality. Biotin protein ligase (BirA) globally regulates lipid metabolism in Mtb through the posttranslational biotinylation of acyl coenzyme A carboxylases (ACCs) involved in lipid biosynthesis and is essential for Mtb survival. We previously developed a rationally designed bisubstrate inhibitor of BirA that displays potent enzyme inhibition and whole cell activity against multidrug resistant and extensively drug resistant Mtb strains. Here we present the design, synthesis, and evaluation of a focused series of inhibitors, which are resistant to cyclonucleoside formation, a key decomposition pathway of our initial analogue. Improved chemical stability is realized through replacement of the adenosyl N-3 nitrogen and C-5' oxygen atom with carbon as well as incorporation of a bulky group on the nucleobase to prevent the required synconformation necessary for proper alignment of N-3 with C-5'.

  DOI：

  10.1021/ml400328a

文献信息

• Concise synthesis of novel acyclic analogues of cADPR with an ether chain as the northern moiety
  作者：Huimin Wu、Zhenjun Yang、Liangren Zhang、Lihe Zhang

  DOI：10.1039/b9nj00595a

  日期：——

  To study the properties of hydrolysates of cyclic adenosine diphosphate ribose (cADPR), a series of novel acyclic analogues of cADPR with an ether chain as the northern moiety and 8-substituted adenine or hypoxanthine as the base moiety were synthesized via an N1 substitution construction, followed by bisphosphorylation, phosphoramidition or pyrophosphorylation. These compounds also provide various precursors for synthesizing cADPR analogues.

  为了研究环腺苷二磷酸核糖（cADPR）水解产物的性质，合成了一系列以醚链作为北基团，8取代腺嘌呤或次黄嘌呤作为碱基团的新型无环类cADPR类似物，合成过程包括N1取代反应，随后进行双磷酸化、磷酰胺化或焦磷酸化。这些化合物还提供了合成cADPR类似物的多种前体。
• SYNTHESIS AND BIOLOGICAL ACTIVITIES OF CYCLIC ADP-CARBOCYCLIC-RIBOSE AND ITS ANALOGS
  作者：Masayoshi Fukuoka、Satoshi Shuto、Noriaki Minakawa、Yoshihito Ueno、Akira Matsuda

  DOI：10.1081/ncn-100002554

  日期：2001.3.31

  An efficient synthesis of cyclic ADP-carbocyclic-ribose (2), as a stable mimic for cyclic ADP-ribose, was achieved. Treatment of N 1-carbocyclic-ribosyla-denosine bisphosphate derivative 10 with AgNO3 in the presence of molecular sieves 3A in pyridine gave the desired cyclic product in 93% yield, which was deprotected to give the target cyclic ADP-carbocyclic-ribose (2).

  作为环状ADP-核糖的稳定模拟物，实现了环状ADP-碳环-核糖（2）的有效合成。在吡啶中存在分子筛3A的情况下，用AgNO3处理N 1-碳环-核糖基-腺苷二磷酸双磷酸酯衍生物10得到93％的收率，得到所需的环状产物，将其脱保护，得到目标环状ADP-碳环-核糖（2） 。
• Total Synthesis of Cyclic ADP-carbocyclic-ribose, a Stable Mimic of Ca²⁺-Mobilizing Second Messenger Cyclic ADP-Ribose¹
  作者：Satoshi Shuto、Masayoshi Fukuoka、Andrzej Manikowsky、Yoshihito Ueno、Takashi Nakano、Ritsu Kuroda、Hideyo Kuroda、Akira Matsuda

  DOI：10.1021/ja010756d

  日期：2001.9.1

  The synthesis of cyclic ADP-carbocyclic-ribose (cADPcR, 4) designed as a stable mimic of cyclic ADP-ribose (cADPR, 1), a Ca2+-mobilizing second messenger, was achieved using as the key step a condensation reaction with the phenylthiophosphate-type substrate 14 to form an intramolecular pyrophosphate linkage. The N-1-carbocyclic-ribosyladenosine derivative 16 was prepared via the condensation between

  环状 ADP-碳环核糖 (cADPcR, 4) 的合成设计为环状 ADP-核糖 (cADPR, 1) 的稳定模拟物，Ca2+ 动员第二信使，其关键步骤是与苯硫代磷酸酯的缩合反应型底物14形成分子内焦磷酸键。N-1-碳环-核糖基腺苷衍生物16是通过咪唑核苷衍生物17（由AICA-核苷（19）制备）和容易获得的旋光碳环胺18之间的缩合而制备的。然后将化合物16转化为相应的5 '-磷酰基-5'-苯基硫代磷酸酯衍生物14。在分子筛(3A)的存在下，在吡啶中在室温下用AgNO 3 处理14得到所需的环化产物32，产率为93%，随后的酸处理提供了目标 cADPcR (4)。这代表了合成这种类型的生物学上重要的环核苷酸的通用方法。cADPcR 的 1 H NMR 分析表明其在水性介质中的构象与 cADPR 相似。与 cADPR 不同，cADPcR 在中性和酸性条件下稳定，在碱性条件下，它形成 Dimroth
• Convergent Synthesis and Unexpected Ca²⁺-Mobilizing Activity of 8-Substituted Analogues of Cyclic ADP-Carbocyclic-Ribose, a Stable Mimic of the Ca²⁺-Mobilizing Second Messenger Cyclic ADP-Ribose
  作者：Satoshi Shuto、Masayoshi Fukuoka、Takashi Kudoh、Clive Garnham、Antony Galione、Barry V. L. Potter、Akira Matsuda

  DOI：10.1021/jm030227f

  日期：2003.10.1

  Cyclic ADP-carbocyclic-ribose (cADPcR, 2) is a biologically and chemically stable equivalent of cyclic ADP-ribose (cADPR, 1), a Ca(2+)-mobilizing second messenger. In this study, a series of 8-substituted analogues of cADPcR, namely the 8-chloro analogue 6 (8-Cl-cADPcR), the 8-azido analogue 7 (8-N(3)-cADPcR), the 8-amino analogue 8 (8-NH(2)-cADPcR), and the 8-phenylthio analogue 9 (8-SPh-cADPcR),

  环状ADP-碳环核糖（cADPcR，2）是生物和化学稳定的环状ADP-核糖（cADPR，1），Ca（2+）动员的第二信使。在这项研究中，一系列的cADPcR的8-取代类似物，即8-氯类似物6（8-Cl-cADPcR），8-叠氮基类似物7（8-N（3）-cADPcR），8-氨基类似物8（8-NH（2）-cADPcR）和8-苯硫基类似物9（8-SPh-cADPcR）被设计为有效的药理工具，用于研究cADPR调节的Ca（2+）信号通路。通过8-Cl-cADPcR双丙酮化物（14）的收敛途径，通过收敛路线合成这些目标化合物，其中一种方法是通过用AgNO（3）活化苯硫代磷酸酯型底物15形成分子内的焦磷酸酯键，生成14被用作关键步骤。测试了碳环类似物在海胆卵匀浆系统中的活性。评估化合物的钙动员作用以及它们对正常最大浓度的cADPR诱导的钙释放交叉脱敏的能力，以及对cADPR引起的钙释放的cADPR拮抗
• Bisubstrate Inhibitors of Biotin Protein Ligase in <i>Mycobacterium tuberculosis</i> Resistant to Cyclonucleoside Formation
  作者：Ce Shi、Divya Tiwari、Daniel J. Wilson、Christopher L. Seiler、Dirk Schnappinger、Courtney C. Aldrich

  DOI：10.1021/ml400328a

  日期：2013.12.12

  Mycobacterium tuberculosis (Mtb), the etiological agent of tuberculosis, is the leading cause of bacterial infectious disease mortality. Biotin protein ligase (BirA) globally regulates lipid metabolism in Mtb through the posttranslational biotinylation of acyl coenzyme A carboxylases (ACCs) involved in lipid biosynthesis and is essential for Mtb survival. We previously developed a rationally designed bisubstrate inhibitor of BirA that displays potent enzyme inhibition and whole cell activity against multidrug resistant and extensively drug resistant Mtb strains. Here we present the design, synthesis, and evaluation of a focused series of inhibitors, which are resistant to cyclonucleoside formation, a key decomposition pathway of our initial analogue. Improved chemical stability is realized through replacement of the adenosyl N-3 nitrogen and C-5' oxygen atom with carbon as well as incorporation of a bulky group on the nucleobase to prevent the required synconformation necessary for proper alignment of N-3 with C-5'.