4,5-dihydro-8H-6-(N-methyl)amino-1-(β-D-ribofuranosyl)imidazo[4,5-e][1,3]diazepine-4,8-dione

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 4,5-dihydro-8H-6-(N-methyl)amino-1-(β-D-ribofuranosyl)imidazo[4,5-e][1,3]diazepine-4,8-dione
• 英文别名: 4,5-dihydro-8H-6-(N-methylamino)-1-(β-D-ribofuranosyl)imidazo[4,5-e][1,3]diazepine-4,8-dione；3-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]-6-(methylamino)-7H-imidazo[4,5-e][1,3]diazepine-4,8-dione；1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-(methylamino)-7H-imidazo[4,5-e][1,3]diazepine-4,8-dione
• 化学式: C₁₂H₁₅N₅O₆
• 分子量: 325.281
• InChiKey: IFAGPALHNOZTOH-TZQXKBMNSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -1.6
• 重原子数：
  23
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  158
• 氢给体数：
  5
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  1H-咪唑-4,5-二甲酸二甲酯 在 三甲基氯硅烷 、 三氟甲磺酸 、 sodium methylate 、 六甲基二硅氮烷 作用下， 以 甲醇 、 乙腈 为溶剂， 反应 1.5h， 生成 4,5-dihydro-8H-6-(N-methyl)amino-1-(β-D-ribofuranosyl)imidazo[4,5-e][1,3]diazepine-4,8-dione
  参考文献：
  名称：

  含有咪唑并[4,5-e]二氮杂pine环系统的新型环扩（“脂肪”）核苷类似物体外抑制麻疹病毒。

  摘要：

  据报道，含有标题杂环系统的一类环膨胀（“脂肪”）核苷类似物（1-4）的合成和体外抗麻疹病毒（anti-MV）活性。通过适当取代的咪唑-1-核糖苷的4，5-二羧酸酯与适当取代的胍衍生物的碱催化缩合来合成目标化合物。以利巴韦林为对照标准，筛选化合物在非洲绿猴肾细胞（CV-1）中的抗MV活性。虽然母体化合物1本身未显示出对MV的任何重要抗病毒活性，其在2位（2）或6位（4）处含有疏水取代基的类似物在亚微摩尔或微摩尔浓度水平下显示出有希望的抗病毒活性，对宿主细胞系无明显毒性。两种化合物均显示出比对照药物利巴韦林更高的抗MV活性。

  DOI：

  10.1016/s0960-894x(02)00762-x

文献信息

• Potent Inhibition of NTPase/Helicase of the West Nile Virus by Ring-Expanded (“Fat”) Nucleoside Analogues
  作者：Ning Zhang、Huan-Ming Chen、Verena Koch、Herbert Schmitz、Michal Minczuk、Piotr Stepien、Ali I. Fattom、Robert B. Naso、Kishna Kalicharran、Peter Borowski、Ramachandra S. Hosmane

  DOI：10.1021/jm030277k

  日期：2003.10.1

  A series of ring-expanded ("fat") nucleoside analogues (RENs) containing the 6-aminoimidazo-[4,5-e] [1,3]diazepine-4,8-dione ring system have been synthesized and screened for inhibition of NTPase/helicase of the West Nile Virus (WNV). To assess the selectivity of RENs against the viral enzymes, a truncated form of human enzyme Suv3((Delta1-159)) was also included in the study. Ring-expanded nucleosides 16, 17, and 19, which possess the long C-12, C-14, and C-18 side-chains, respectively, at position 6, as well as the ring-expanded heterocycle 39, which contains aralkyl substitution at position 1, were all found to have excellent profiles of activity and selectivity toward the viral versus human enzymes against the West Nile Virus (IC50 ranging 1-10 muM). Compound 30, while being an equally potent inhibitor of WNV, was found to be somewhat less selective, whereas compound 36, which is an alpha-anomeric counterpart of 30, exhibited potent and selective inhibition of WN-V (IC50 1-3 muM). The same compounds that showed potent inhibition of viral helicase activity completely failed to show any activity against the viral NTPase reaction even up to 500 muM. However, at concentrations >500 muM of RENs and the ATP concentrations >10 times the K-m value of the enzyme, a significant activation of NTPase activity was observed. This activating effect underwent further dramatic enhancement (>1000%) by further increases in ATP concentration in the reaction mixture, suggesting that the viral helicase and NTPase reactions are not coupled. A tentative mechanistic model has been proposed to explain the observed results.