(E)-4-( (4-hydroxy-3,5-dimethylphenyl)diazenyl)-N-(4-(trifluoromethyl)phenyl)benzenesulfonamide | 1395084-39-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 偶氮苯
• 英文名称: (E)-4-( (4-hydroxy-3,5-dimethylphenyl)diazenyl)-N-(4-(trifluoromethyl)phenyl)benzenesulfonamide
• 英文别名: (E)-4-((4-hydroxy-3,5-dimethylphenyl)diazenyl)-N-(4-(trifluoromethyl)phenyl)benzenesulfonamide
• CAS: 1395084-39-5
• 化学式: C₂₁H₁₈F₃N₃O₃S
• 分子量: 449.453
• InChiKey: TXXXOOBUYYCCJA-OCEACIFDSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.24
• 重原子数：
  31.0
• 可旋转键数：
  5.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.14
• 拓扑面积：
  91.12
• 氢给体数：
  2.0
• 氢受体数：
  5.0

反应信息

• 作为产物：
  描述：

  N-(4-(N-(4-(trifluoromethyl)phenyl)sulfamoyl)phenyl)acetamide 在 盐酸 、 sodium hydroxide 作用下， 以 甲醇 、 乙腈 为溶剂， 反应 0.25h， 生成 (E)-4-( (4-hydroxy-3,5-dimethylphenyl)diazenyl)-N-(4-(trifluoromethyl)phenyl)benzenesulfonamide
  参考文献：
  名称：

  Structure-Guided Design of Potent Diazobenzene Inhibitors for the BET Bromodomains

  摘要：

  BRD4, characterized by two acetyl-lysine binding bromodomains and an extra-terminal (ET) domain, is a key chromatin organizer that directs gene activation in chromatin through transcription factor recruitment, enhancer assembly, and pause release of the RNA polymerase II complex for transcription elongation. BRD4 has been recently validated as a new epigenetic drug target for cancer and inflammation. Our current knowledge of the functional differences of the two bromodomains of BRD4, however, is limited and is hindered by the lack of selective inhibitors. Here, we report our structure-guided development of diazobenzene-based small-molecule inhibitors for the BRD4 bromodomains that have over 90% sequence identity at the acetyl-lysine binding site. Our lead compound, MS436, through a set of water-mediated interactions, exhibits low nanomolar affinity (estimated Ki of 30-50 nM), with preference for the first bromodomain over the second. We demonstrated that MS436 effectively inhibits BRD4 activity in NF-κB-directed production of nitric oxide and proinflammatory cytokine interleukin-6 in murine macrophages. MS436 represents a new class of bromodomain inhibitors and will facilitate further investigation of the biological functions of the two bromodomains of BRD4 in gene expression.

  DOI：

  10.1021/jm401334s

文献信息

• INHIBITORS OF BROMODOMAINS AS MODULATORS OF GENE EXPRESSION
  申请人：Zhou Ming-Ming

  公开号：US20140066410A1

  公开（公告）日：2014-03-06

  This disclosure relates generally to compounds and compositions comprising one or more diphenylethylene, diphenylethylyne, and azobenzene analogs. These compounds are useful for treating diseases associated with NF-kB and p53 activity, such as cancer and inflammatory disease.

  本公开涉及一种化合物和组合物，其中包括一种或多种二苯乙烯，二苯乙炔和偶氮苯类似物。这些化合物可用于治疗与NF-kB和p53活性相关的疾病，如癌症和炎症性疾病。
• Structure-Guided Design of Potent Diazobenzene Inhibitors for the BET Bromodomains
  作者：Guangtao Zhang、Alexander N. Plotnikov、Elena Rusinova、Tong Shen、Keita Morohashi、Jennifer Joshua、Lei Zeng、Shiraz Mujtaba、Michael Ohlmeyer、Ming-Ming Zhou

  DOI：10.1021/jm401334s

  日期：2013.11.27

  BRD4, characterized by two acetyl-lysine binding bromodomains and an extra-terminal (ET) domain, is a key chromatin organizer that directs gene activation in chromatin through transcription factor recruitment, enhancer assembly, and pause release of the RNA polymerase II complex for transcription elongation. BRD4 has been recently validated as a new epigenetic drug target for cancer and inflammation. Our current knowledge of the functional differences of the two bromodomains of BRD4, however, is limited and is hindered by the lack of selective inhibitors. Here, we report our structure-guided development of diazobenzene-based small-molecule inhibitors for the BRD4 bromodomains that have over 90% sequence identity at the acetyl-lysine binding site. Our lead compound, MS436, through a set of water-mediated interactions, exhibits low nanomolar affinity (estimated Ki of 30-50 nM), with preference for the first bromodomain over the second. We demonstrated that MS436 effectively inhibits BRD4 activity in NF-κB-directed production of nitric oxide and proinflammatory cytokine interleukin-6 in murine macrophages. MS436 represents a new class of bromodomain inhibitors and will facilitate further investigation of the biological functions of the two bromodomains of BRD4 in gene expression.