6-(3,5-dimethylisoxazol-4-yl)-3-methyl-3,4-dihydroquinazolin-2(1H)-one | 1125452-67-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: 6-(3,5-dimethylisoxazol-4-yl)-3-methyl-3,4-dihydroquinazolin-2(1H)-one
• 英文别名: 6-(3,5-Dimethyl-1,2-oxazol-4-yl)-3-methyl-1,4-dihydroquinazolin-2-one
• CAS: 1125452-67-6
• 化学式: C₁₄H₁₅N₃O₂
• 分子量: 257.292
• InChiKey: DRKGLYHLBGWKHL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  19
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  58.4
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  3,4-二氢-3-甲基-2(1H)-喹唑啉酮 在 N-溴代丁二酰亚胺(NBS) 、 palladium diacetate 、 sodium carbonate 、 2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯 作用下， 以 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 5.0h， 生成 6-(3,5-dimethylisoxazol-4-yl)-3-methyl-3,4-dihydroquinazolin-2(1H)-one
  参考文献：
  名称：

  3,5-Dimethylisoxazoles Act As Acetyl-lysine-mimetic Bromodomain Ligands

  摘要：

  Histone-lysine acetylation is a vital chromatin post-translational modification involved in the epigenetic regulation of gene transcription. Bromodomains bind acetylated lysines, acting as readers of the histone-acetylation code. Competitive inhibitors of this interaction have antiproliferative and anti-inflammatory properties. With 57 distinct bromodomains known, the discovery of subtype-selective inhibitors of the histone bromodomain interaction is of great importance. We have identified the 3,5-dimethylisoxazole moiety as a novel acetyl-lysine bioisostere, which displaces acetylated histone-mimicking peptides from bromodomains. Using X-ray crystallographic analysis, we have determined the interactions responsible for the activity and selectivity of 4-substituted 3,5-dimethylisoxazoles against a selection of phylogenetically diverse bromodomains. By exploiting these interactions, we have developed compound 4d, which has IC50 values of < 5 mu M for the bromodomain-containing proteins BRD2(1) and BRD4(1). These compounds are promising leads for the further development of selective probes for the bromodomain and extra C-terminal domain (BET) family and CREBBP bromodomains.

  DOI：

  10.1021/jm200640v

文献信息

• 3,5-Dimethylisoxazoles Act As Acetyl-lysine-mimetic Bromodomain Ligands
  作者：David S. Hewings、Minghua Wang、Martin Philpott、Oleg Fedorov、Sagar Uttarkar、Panagis Filippakopoulos、Sarah Picaud、Chaitanya Vuppusetty、Brian Marsden、Stefan Knapp、Stuart J. Conway、Tom D. Heightman

  DOI：10.1021/jm200640v

  日期：2011.10.13

  Histone-lysine acetylation is a vital chromatin post-translational modification involved in the epigenetic regulation of gene transcription. Bromodomains bind acetylated lysines, acting as readers of the histone-acetylation code. Competitive inhibitors of this interaction have antiproliferative and anti-inflammatory properties. With 57 distinct bromodomains known, the discovery of subtype-selective inhibitors of the histone bromodomain interaction is of great importance. We have identified the 3,5-dimethylisoxazole moiety as a novel acetyl-lysine bioisostere, which displaces acetylated histone-mimicking peptides from bromodomains. Using X-ray crystallographic analysis, we have determined the interactions responsible for the activity and selectivity of 4-substituted 3,5-dimethylisoxazoles against a selection of phylogenetically diverse bromodomains. By exploiting these interactions, we have developed compound 4d, which has IC50 values of < 5 mu M for the bromodomain-containing proteins BRD2(1) and BRD4(1). These compounds are promising leads for the further development of selective probes for the bromodomain and extra C-terminal domain (BET) family and CREBBP bromodomains.