tert-butyl ethyl((3-(2-hydroxy-2-methylpropyl)-3H-imidazo[4,5-c]quinolin-2-yl)methyl)carbamate N-oxide | 1159840-71-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: tert-butyl ethyl((3-(2-hydroxy-2-methylpropyl)-3H-imidazo[4,5-c]quinolin-2-yl)methyl)carbamate N-oxide
• 英文别名: tert-butyl N-ethyl-N-[[3-(2-hydroxy-2-methylpropyl)-5-oxidoimidazo[4,5-c]quinolin-5-ium-2-yl]methyl]carbamate
• CAS: 1159840-71-7
• 化学式: C₂₂H₃₀N₄O₄
• 分子量: 414.505
• InChiKey: RTULUYJKFBCSOT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  30
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  93
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  tert-butyl ethyl((3-(2-hydroxy-2-methylpropyl)-3H-imidazo[4,5-c]quinolin-2-yl)methyl)carbamate N-oxide 以 二氯甲烷 为溶剂， 反应 1.0h， 生成 N-(2-((ethylamino)methyl)-3-(2-hydroxy-2-methylpropyl)-3H-imidazo[4,5-c]quinolin-4-yl)benzamide ditrifluoroacetate
  参考文献：
  名称：

  Preliminary evaluation of a 3H imidazoquinoline library as dual TLR7/TLR8 antagonists

  摘要：

  Toll-like receptors (TLR) -7 and -8 are thought to play an important role in immune activation processes underlying the pathophysiology of HIV and several clinically important autoimmune diseases. Based on our earlier findings of TLR7-antagonistic activity in a 3H imidazoquinoline, we sought to examine a pilot library of 3H imidazoquinolines for dual TLR7/8 antagonists, since they remain a poorly explored chemotype. 2D-NOE experiments were employed to unequivocally characterize the compounds. A quinolinium compound 12, bearing p-methoxybenzyl substituents on N3 and N5 positions was identified as a lead. Compound 12 was found to inhibit both TLR7 and TLR8 at low micromolar concentrations. Our preliminary results suggest that alkylation with electron-rich substituents on the quinoline N5, or conversely, elimination of the fixed charge of the resultant quaternary amine on the quinolinium may yield more active compounds. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2011.04.052
• 作为产物：
  描述：

  3,4-二氨基喹啉 在 1,8-二氮杂双环[5.4.0]十一碳-7-烯 、 间氯过氧苯甲酸 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 作用下， 以 甲醇 、 二氯甲烷 、 氯仿 、 N,N-二甲基甲酰胺 为溶剂， 反应 0.5h， 生成 tert-butyl ethyl((3-(2-hydroxy-2-methylpropyl)-3H-imidazo[4,5-c]quinolin-2-yl)methyl)carbamate N-oxide
  参考文献：
  名称：

  Preliminary evaluation of a 3H imidazoquinoline library as dual TLR7/TLR8 antagonists

  摘要：

  Toll-like receptors (TLR) -7 and -8 are thought to play an important role in immune activation processes underlying the pathophysiology of HIV and several clinically important autoimmune diseases. Based on our earlier findings of TLR7-antagonistic activity in a 3H imidazoquinoline, we sought to examine a pilot library of 3H imidazoquinolines for dual TLR7/8 antagonists, since they remain a poorly explored chemotype. 2D-NOE experiments were employed to unequivocally characterize the compounds. A quinolinium compound 12, bearing p-methoxybenzyl substituents on N3 and N5 positions was identified as a lead. Compound 12 was found to inhibit both TLR7 and TLR8 at low micromolar concentrations. Our preliminary results suggest that alkylation with electron-rich substituents on the quinoline N5, or conversely, elimination of the fixed charge of the resultant quaternary amine on the quinolinium may yield more active compounds. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2011.04.052

文献信息

• Regioisomerism-dependent TLR7 agonism and antagonism in an imidazoquinoline
  作者：Nikunj M. Shukla、Matthew R. Kimbrell、Subbalakshmi S. Malladi、Sunil A. David

  DOI：10.1016/j.bmcl.2009.02.100

  日期：2009.4

  Chronic immune activation is a hallmark of progressive HIV infection. Recent reports point to the engagement of toll-like receptor 7 (TLR7) and -9 by viral RNA as contributing to the activation of innate immune responses, which drive viral replication leading to immune exhaustion. The only known class of TLR7 antagonists is single-stranded phosphorothioate oligonucleotides, which has been demonstrated to inhibit immune activation in human and Rhesus macaque in vitro models. The availability of a selective and potent small-molecule TLR7 antagonist should allow the evaluation of potential benefits of suppression of TLR7-mediated immune activation in HIV/AIDS. Gardiquimod is a known N-1-substituted 1H-imidazoquinoline TLR7 agonist, the synthesis of which has not been published. We show that the 3H regioisomer is completely inactive as a TLR7 agonist and is weakly antagonistic. A des-amino precursor of the 3H regioisomer is more potent as a TLR7 antagonist, with an IC50 value of 7.5 mu M. This class of compound may serve as a starting point for the development of small-molecule inhibitors of TLR7. (c) 2009 Elsevier Ltd. All rights reserved.