3-phenyl-2-thioxo-2,3-dihydro-1H-pyrimido[5,4-b]indol-4(5H)-one | 107127-28-6

• 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: 3-phenyl-2-thioxo-2,3-dihydro-1H-pyrimido[5,4-b]indol-4(5H)-one
• 英文别名: 3-phenyl-2-sulfanylidene-1,5-dihydropyrimido[5,4-b]indol-4-one
• CAS: 107127-28-6
• 化学式: C₁₆H₁₁N₃OS
• 分子量: 293.349
• InChiKey: JTNSSRSQEPMIJO-UHFFFAOYSA-N

物化性质

• 熔点：
  300-302 °C(Solv: N,N-dimethylformamide (68-12-2); water (7732-18-5))
• 沸点：
  533.7±42.0 °C(Predicted)
• 密度：
  1.51±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  21
• 可旋转键数：
  1
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  80.2
• 氢给体数：
  2
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  3-phenyl-2-thioxo-2,3-dihydro-1H-pyrimido[5,4-b]indol-4(5H)-one 在 三乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 、 potassium hydroxide 作用下， 以 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 6.33h， 生成 N-cyclohexyl-2-((4-oxo-3-phenyl-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 乙酰氯 作用下， 以 乙醇 为溶剂， 反应 18.0h， 生成 3-phenyl-2-thioxo-2,3-dihydro-1H-pyrimido[5,4-b]indol-4(5H)-one
  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

• Structure–Activity Relationship Studies of Pyrimido[5,4-<i>b</i>]indoles as Selective Toll-Like Receptor 4 Ligands
  作者：Michael Chan、Yuhei Kakitsubata、Tomoko Hayashi、Alast Ahmadi、Shiyin Yao、Nikunj M. Shukla、Shin-ya Oyama、Akihito Baba、Brandon Nguyen、Maripat Corr、Yasuo Suda、Dennis A. Carson、Howard B. Cottam、Masahiro Wakao

  DOI：10.1021/acs.jmedchem.7b00797

  日期：2017.11.22

  further optimization studies. In this report, compounds belonging to three areas of structural modification were evaluated for biological activity using murine and human TLR4 reporter cells, primary murine bone marrow derived dendritic cells, and human peripheral blood mononuclear cells. The compounds bearing certain aryl groups at the C8 position, such as phenyl (36) and β-naphthyl (39), had potencies

  先前的高通量筛选研究导致发现了两种新型的非脂质样化学型，作为Toll样受体4（TLR4）激动剂。探索了这些化学型之一，嘧啶并[5,4- b ]吲哚相对于TLR4依赖性细胞因子/趋化因子的产生的结构-活性关系趋势，从而产生了半优化的铅（化合物1），为进一步研究提供了起点优化研究。在该报告中，使用鼠类和人类TLR4报告基因细胞，原代小鼠骨髓来源的树突状细胞和人外周血单核细胞对属于三个结构修饰区域的化合物的生物活性进行了评估。在C8位置带有某些芳基的化合物，例如苯基（36）和β-萘基（39）的效力显着大于化合物1。化合物36在亚微摩尔浓度下显示人TLR4激动剂活性。计算分析表明，这些C8-芳基衍生物的效力提高可能是由于TLR4 /髓样分化蛋白2（MD-2）复合物界面上其他结合相互作用的结果。
• 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。
• MONGE, A.;PALOP, J. A.;RECALDE, I.;MARTINEZ-CRESPO, F.;FERNANDEZ-ALVAREZ,+, AN. QUIM. PUBL. REAL SOC. ESP. QUIM., 1985, 81, N 3, 267-270
  作者：MONGE, A.、PALOP, J. A.、RECALDE, I.、MARTINEZ-CRESPO, F.、FERNANDEZ-ALVAREZ,+

  DOI：——

  日期：——
• US9505768B2
  申请人：——

  公开号：US9505768B2

  公开（公告）日：2016-11-29
• METHODS AND COMPOSITIONS FOR TREATING CANCER WITH CANCER-BINDING ADJUVANTS
  申请人：[en]THE UNIVERSITY OF CHICAGO

  公开号：WO2024040169A2

  公开（公告）日：2024-02-22

  Disclosed herein are compositions comprising immune-activating agents that bind the tumor cell surface in the absence of a tumor-targeting protein component. Described herein are methods and compositions for targeting a TLR or STING agonist to tumor cells and/or cells in the tumor microenvironment. It is hypothesized that the metabolic stress of tumor growth also produces an excess of unpaired cysteines on cell surface proteins relative to the rest of the body. Therefore, this chemistry can be used with compounds that would preferentially target unpaired cysteines on cell surface proteins.