2-((4-oxo-3-phenethyl-4,5-dihydro-3H-pyrimido[5,4-b]indol-2-yl)thio)acetic acid | 1438280-88-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯并嘧啶类
• 英文名称: 2-((4-oxo-3-phenethyl-4,5-dihydro-3H-pyrimido[5,4-b]indol-2-yl)thio)acetic acid
• 英文别名: 2-((4-Oxo-3-phenethyl-4,5-dihydro-3H-pyrimido[5,4-b]indol-2-yl)thio)acetic acid；2-[[4-oxo-3-(2-phenylethyl)-5H-pyrimido[5,4-b]indol-2-yl]sulfanyl]acetic acid
• CAS: 1438280-88-6
• 化学式: C₂₀H₁₇N₃O₃S
• 分子量: 379.439
• InChiKey: KTXYMDGASDJICA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  27
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.15
• 拓扑面积：
  111
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  2-((4-oxo-3-phenethyl-4,5-dihydro-3H-pyrimido[5,4-b]indol-2-yl)thio)acetic acid 、 环己胺 在 三乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 0.33h， 以60%的产率得到N-cyclohexyl-2-((4-oxo-3-phenethyl-4,5-dihydro-3H-pyrimido[5,4-b]indol-2-yl)thio)acetamide
  参考文献：
  名称：

  Identification of Substituted Pyrimido[5,4-b]indoles as Selective Toll-Like Receptor 4 Ligands

  摘要：

  A cell-based high-throughput screen to identify small molecular weight stimulators of the innate immune system revealed substituted pyrimido[5,4-b]indoles as potent NF kappa beta activators. The most potent hit compound selectively stimulated Toll-like receptor 4 (TLR4) in human and mouse cells. Synthetic modifications of the pyrimido[5,4-b]indole scaffold at the carboxamide, N-3, and N-5 positions revealed differential TLR4 dependent production of NF kappa beta and type I interferon associated cytokines, IL-6 and interferon gamma-induced protein 10 (IP-10) respectively. Specifically, a subset of compounds bearing phenyl and substituted phenyl carboxamides induced lower IL-6 release while maintaining higher IP-10 production, skewing toward the type I interferon pathway. Substitution at N-5 with short alkyl substituents reduced the cytotoxicity of the leading hit compound. Computational studies supported that active compounds appeared to bind primarily to MD-2 in the TLR4/MD-2 complex. These small molecules, which stimulate innate immune cells with minimal toxicity, could potentially be used as adjuvants or immune modulators.

  DOI：

  10.1021/jm301694x
• 作为产物：
  描述：

  3-氨基-2-吲哚羧酸乙酯 在 potassium hydroxide 作用下， 以 乙醇 为溶剂， 反应 15.5h， 生成 2-((4-oxo-3-phenethyl-4,5-dihydro-3H-pyrimido[5,4-b]indol-2-yl)thio)acetic acid
  参考文献：
  名称：

  Identification of Substituted Pyrimido[5,4-b]indoles as Selective Toll-Like Receptor 4 Ligands

  摘要：

  A cell-based high-throughput screen to identify small molecular weight stimulators of the innate immune system revealed substituted pyrimido[5,4-b]indoles as potent NF kappa beta activators. The most potent hit compound selectively stimulated Toll-like receptor 4 (TLR4) in human and mouse cells. Synthetic modifications of the pyrimido[5,4-b]indole scaffold at the carboxamide, N-3, and N-5 positions revealed differential TLR4 dependent production of NF kappa beta and type I interferon associated cytokines, IL-6 and interferon gamma-induced protein 10 (IP-10) respectively. Specifically, a subset of compounds bearing phenyl and substituted phenyl carboxamides induced lower IL-6 release while maintaining higher IP-10 production, skewing toward the type I interferon pathway. Substitution at N-5 with short alkyl substituents reduced the cytotoxicity of the leading hit compound. Computational studies supported that active compounds appeared to bind primarily to MD-2 in the TLR4/MD-2 complex. These small molecules, which stimulate innate immune cells with minimal toxicity, could potentially be used as adjuvants or immune modulators.

  DOI：

  10.1021/jm301694x

文献信息

• COMPOSITIONS AND METHODS FOR MODULATING TLR4
  申请人：THE REGENTS OF THE UNIVERSITY OF CALIFORNIA

  公开号：US20150197527A1

  公开（公告）日：2015-07-16

  Provided herein, inter alia, are methods and compositions for modulating TLR-4.

  本文提供了一些调节TLR-4的方法和组合物。
• US9505768B2
  申请人：——

  公开号：US9505768B2

  公开（公告）日：2016-11-29
• Identification of Substituted Pyrimido[5,4-<i>b</i>]indoles as Selective Toll-Like Receptor 4 Ligands
  作者：Michael Chan、Tomoko Hayashi、Richard D. Mathewson、Afshin Nour、Yuki Hayashi、Shiyin Yao、Rommel I. Tawatao、Brian Crain、Igor F. Tsigelny、Valentina L. Kouznetsova、Karen Messer、Minya Pu、Maripat Corr、Dennis A. Carson、Howard B. Cottam

  DOI：10.1021/jm301694x

  日期：2013.6.13

  A cell-based high-throughput screen to identify small molecular weight stimulators of the innate immune system revealed substituted pyrimido[5,4-b]indoles as potent NF kappa beta activators. The most potent hit compound selectively stimulated Toll-like receptor 4 (TLR4) in human and mouse cells. Synthetic modifications of the pyrimido[5,4-b]indole scaffold at the carboxamide, N-3, and N-5 positions revealed differential TLR4 dependent production of NF kappa beta and type I interferon associated cytokines, IL-6 and interferon gamma-induced protein 10 (IP-10) respectively. Specifically, a subset of compounds bearing phenyl and substituted phenyl carboxamides induced lower IL-6 release while maintaining higher IP-10 production, skewing toward the type I interferon pathway. Substitution at N-5 with short alkyl substituents reduced the cytotoxicity of the leading hit compound. Computational studies supported that active compounds appeared to bind primarily to MD-2 in the TLR4/MD-2 complex. These small molecules, which stimulate innate immune cells with minimal toxicity, could potentially be used as adjuvants or immune modulators.