3,3'-((2-butyl-5-chloro-1H-imidazol-4-yl)methylene)bis(4-hydroxy-2H-chromen-2-one)

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 香豆素及其衍生物
• 英文名称: 3,3'-((2-butyl-5-chloro-1H-imidazol-4-yl)methylene)bis(4-hydroxy-2H-chromen-2-one)
• 英文别名: 3,3'-((2-Butyl-4-chloro-1H-imidazol-5-yl)methylene)bis(4-hydroxy-2H-chromen-2-one)；3-[(2-butyl-4-chloro-1H-imidazol-5-yl)-(4-hydroxy-2-oxochromen-3-yl)methyl]-4-hydroxychromen-2-one
• 化学式: C₂₆H₂₁ClN₂O₆
• 分子量: 492.916
• InChiKey: YDLKVAMYKVCOFK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.9
• 重原子数：
  35
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  122
• 氢给体数：
  3
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  4-羟基香豆素 、 咪唑醛 在 盐酸硫胺 作用下， 以 水 为溶剂， 生成 3,3'-((2-butyl-5-chloro-1H-imidazol-4-yl)methylene)bis(4-hydroxy-2H-chromen-2-one)
  参考文献：
  名称：

  Novel Synthetic Biscoumarins Target Tumor Necrosis Factor-α in Hepatocellular Carcinoma in Vitro and in Vivo

  摘要：

  Background: TNF--induced NF-B pathway is associated with the progression of several cancers and abrogation of TNF signaling a potential target for cancer treatment. Results: Novel biscoumarin inhibits TNF signaling in vitro and in vivo in IBD model. Conclusion: The lead compound interrupts the trimeric structure of TNF to achieve this effect. Significance: This study introduces a novel TNF inhibitor with the potential to target pro-inflammatory diseases.TNF is a pleotropic cytokine known to be involved in the progression of several pro-inflammatory disorders. Many therapeutic agents have been designed to counteract the effect of TNF in rheumatoid arthritis as well as a number of cancers. In the present study we have synthesized and evaluated the anti-cancer activity of novel biscoumarins in vitro and in vivo. Among new compounds, BIHC was found to be the most cytotoxic agent against the HepG2 cell line while exhibiting less toxicity toward normal hepatocytes. Furthermore, BIHC inhibited the proliferation of various hepatocellular carcinoma (HCC) cells in a dose- and time-dependent manner. Subsequently, using in silico target prediction, BIHC was predicted as a TNF blocker. Experimental validation was able to confirm this hypothesis, where BIHC could significantly inhibit the recombinant mouse TNF- binding to its antibody with an IC50 of 16.5 m. Furthermore, in silico docking suggested a binding mode of BIHC similar to a ligand known to disrupt the native, trimeric structure of TNF, and also validated with molecular dynamics simulations. Moreover, we have demonstrated the down-regulation of p65 phosphorylation and other NF-B-regulated gene products upon BIHC treatment, and on the phenotypic level the compound shows inhibition of CXCL12-induced invasion of HepG2 cells. Also, we demonstrate that BIHC inhibits infiltration of macrophages to the peritoneal cavity and suppresses the activity of TNF- in vivo in mice primed with thioglycollate broth and lipopolysaccharide. We comprehensively validated the TNF- inhibitory efficacy of BIHC in an inflammatory bowel disease mice model.

  DOI：

  10.1074/jbc.m114.593855