4,5-dihydro-8H-6-(N-dodecyl)amino-1-(β-D-ribofuranosyl)imidazo[4,5-e][1,3]diazepine-4,8-dione | 620608-96-0

• 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-dodecyl)amino-1-(β-D-ribofuranosyl)imidazo[4,5-e][1,3]diazepine-4,8-dione
• 英文别名: 1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-(dodecylamino)-7H-imidazo[4,5-e][1,3]diazepine-4,8-dione
• CAS: 620608-96-0
• 化学式: C₂₃H₃₇N₅O₆
• 分子量: 479.577
• InChiKey: SLWXMEVCUZLTFA-CIVUBGFFSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  34
• 可旋转键数：
  14
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.74
• 拓扑面积：
  158
• 氢给体数：
  5
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  4,5-dihydro-8H-6-(N-dodecyl)amino-1-(β-D-ribofuranosyl)imidazo[4,5-e][1,3]diazepine-4,8-dione 在 吡啶 、 4-二甲氨基吡啶 作用下， 以 乙腈 为溶剂， 反应 19.5h， 生成 4,5-dihydro-8H-6-(N-dodecylamino)-1-[(2'-O-phenoxythiocarbonyl-3',5'-O-(1,1,3,3-tetraisopropyldisiloxan-1,3-diyl))-β-D-ribofuranosyl]imidazo[4,5-e][1,3]diazepine-4,8-dione
  参考文献：
  名称：

  Potent Inhibition of NTPase/Helicase of the West Nile Virus by Ring-Expanded (“Fat”) Nucleoside Analogues

  摘要：

  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.

  DOI：

  10.1021/jm030277k
• 作为产物：
  描述：

  十二胍 、 methyl 1-(2',3',5'-tri-O-benzoyl-β-D-ribofuranosyl)imidazole-4,5-dicarboxylate 在 甲醇 、 sodium methylate 作用下， 以89%的产率得到4,5-dihydro-8H-6-(N-dodecyl)amino-1-(β-D-ribofuranosyl)imidazo[4,5-e][1,3]diazepine-4,8-dione
  参考文献：
  名称：

  Potent Inhibition of NTPase/Helicase of the West Nile Virus by Ring-Expanded (“Fat”) Nucleoside Analogues

  摘要：

  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.

  DOI：

  10.1021/jm030277k

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.