4-[2-(5-chloro-2-oxo-2,3-dihydro-1,3-benzothiazol-3-yl)-acetamido]benzoic acid

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 4-[2-(5-chloro-2-oxo-2,3-dihydro-1,3-benzothiazol-3-yl)-acetamido]benzoic acid
• 英文别名: 4-[[2-(5-Chloro-2-oxo-1,3-benzothiazol-3-yl)acetyl]amino]benzoic acid；4-[[2-(5-chloro-2-oxo-1,3-benzothiazol-3-yl)acetyl]amino]benzoic acid
• 化学式: C₁₆H₁₁ClN₂O₄S
• 分子量: 362.793
• InChiKey: RHHHPTFTBKCDFL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  24
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.06
• 拓扑面积：
  112
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  4-[2-(5-chloro-2-oxo-2,3-dihydro-1,3-benzothiazol-3-yl)-acetamido]benzoic acid 、 3-chloro-4-methoxybenzene-1-sulfonamide 在 N,N-二异丙基乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 二氯甲烷 为溶剂， 以28%的产率得到4-(2-(5-chloro-2-oxo-2,3-dihydro-1,3-benzothiazol-3-yl)-acetamido)-N-[(3-chloro-4-methoxyphenyl)sulfonyl]benzamide
  参考文献：
  名称：

  Structure-Based Development of a Protein–Protein Interaction Inhibitor Targeting Tumor Necrosis Factor Receptor-Associated Factor 6

  摘要：

  The interactions between tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) and TNF superfamily receptors (TNFRSFs) are promising targets for rheumatoid arthritis (RA) treatment. However, due to the challenging nature of protein-protein interactions (PPIs), a potent inhibitor that surpasses the affinity of the TRAF6-TNFRSF interactions has not been developed. We developed a small-molecule PPI inhibitor of TRAF6-TNFRSF interactions using NMR and in silico techniques. The most potent compound, TRI4, exhibited an affinity higher than those of TNFRSFs and competitively inhibited a TRAF6-TNFRSF interaction. Structural characterization of the TRAF6-TRI4 complex revealed that TRI4 supplants key interactions in the TRAF6-TNFRSF interfaces. In addition, some TRAF6-TRI4 interactions extend beyond the TRAF6-TNFRSF interfaces and increase the binding affinity. Our successful development of TRI4 provides a new Opportunity for RA treatment and implications fur structure-guided development of PPI inhibitors.

  DOI：

  10.1021/acs.jmedchem.5b00778
• 作为产物：
  描述：

  (5-氯-2-氧代-1,3-苯并噻唑-3(2H)-基)乙酸 在 N,N-二异丙基乙胺 、 三氟乙酸 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 二氯甲烷 为溶剂， 反应 2.0h， 生成 4-[2-(5-chloro-2-oxo-2,3-dihydro-1,3-benzothiazol-3-yl)-acetamido]benzoic acid
  参考文献：
  名称：

  Structure-Based Development of a Protein–Protein Interaction Inhibitor Targeting Tumor Necrosis Factor Receptor-Associated Factor 6

  摘要：

  The interactions between tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) and TNF superfamily receptors (TNFRSFs) are promising targets for rheumatoid arthritis (RA) treatment. However, due to the challenging nature of protein-protein interactions (PPIs), a potent inhibitor that surpasses the affinity of the TRAF6-TNFRSF interactions has not been developed. We developed a small-molecule PPI inhibitor of TRAF6-TNFRSF interactions using NMR and in silico techniques. The most potent compound, TRI4, exhibited an affinity higher than those of TNFRSFs and competitively inhibited a TRAF6-TNFRSF interaction. Structural characterization of the TRAF6-TRI4 complex revealed that TRI4 supplants key interactions in the TRAF6-TNFRSF interfaces. In addition, some TRAF6-TRI4 interactions extend beyond the TRAF6-TNFRSF interfaces and increase the binding affinity. Our successful development of TRI4 provides a new Opportunity for RA treatment and implications fur structure-guided development of PPI inhibitors.

  DOI：

  10.1021/acs.jmedchem.5b00778

文献信息

• Structure-Based Development of a Protein–Protein Interaction Inhibitor Targeting Tumor Necrosis Factor Receptor-Associated Factor 6
  作者：Jun Moriya、Koh Takeuchi、Kenji Tai、Kenzo Arai、Naoki Kobayashi、Naoki Yoneda、Yoshifumi Fukunishi、Atsushi Inoue、Miho Kihara、Takumi Murakami、Kenichi Chiba、Ichio Shimada

  DOI：10.1021/acs.jmedchem.5b00778

  日期：2015.7.23

  The interactions between tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) and TNF superfamily receptors (TNFRSFs) are promising targets for rheumatoid arthritis (RA) treatment. However, due to the challenging nature of protein-protein interactions (PPIs), a potent inhibitor that surpasses the affinity of the TRAF6-TNFRSF interactions has not been developed. We developed a small-molecule PPI inhibitor of TRAF6-TNFRSF interactions using NMR and in silico techniques. The most potent compound, TRI4, exhibited an affinity higher than those of TNFRSFs and competitively inhibited a TRAF6-TNFRSF interaction. Structural characterization of the TRAF6-TRI4 complex revealed that TRI4 supplants key interactions in the TRAF6-TNFRSF interfaces. In addition, some TRAF6-TRI4 interactions extend beyond the TRAF6-TNFRSF interfaces and increase the binding affinity. Our successful development of TRI4 provides a new Opportunity for RA treatment and implications fur structure-guided development of PPI inhibitors.