(3-(3,5-dimethylisoxazol-4-yl)-5-hydroxyphenyl)(phenyl)methanone | 1429129-72-5

• 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: (3-(3,5-dimethylisoxazol-4-yl)-5-hydroxyphenyl)(phenyl)methanone
• 英文别名: [3-(3,5-Dimethyl-1,2-oxazol-4-yl)-5-hydroxyphenyl]-phenylmethanone；[3-(3,5-dimethyl-1,2-oxazol-4-yl)-5-hydroxyphenyl]-phenylmethanone
• CAS: 1429129-72-5
• 化学式: C₁₈H₁₅NO₃
• 分子量: 293.322
• InChiKey: LLCUDNVKDVHKCZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  22
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.11
• 拓扑面积：
  63.3
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (3-(3,5-dimethylisoxazol-4-yl)-5-hydroxyphenyl)(phenyl)methanone 在 盐酸羟胺 、 四丁基碘化铵 、 potassium carbonate 、 potassium hydroxide 作用下， 以 甲醇 、 丙酮 为溶剂， 反应 4.0h， 生成 6-(3-benzoyl-5-(3,5-dimethylisoxazol-4-yl)phenoxy)-N-hydroxyhexanamide
  参考文献：
  名称：

  针对表观遗传阅读器和橡皮擦：作为BRD4 / HDAC双重抑制剂的二甲基异恶唑衍生物的合理设计，合成和体外评估

  摘要：

  溴结构域蛋白模块和组蛋白脱乙酰基酶（HDAC）分别识别和去除乙酰化的赖氨酸，已成为癌症治疗中重要的表观遗传学治疗靶标。在这里，我们提出了一种通过在一个分子中结合溴结构域和HDAC抑制活性来开发癌症药物开发的新颖设计方法。合成了所设计的化合物，其显示出对溴结构域4和HDAC1的抑制活性。代表性的双溴结构域/ HDAC抑制剂化合物11和12在细胞测定中显示出对人白血病细胞株K562和MV4-11的有效抗增殖活性。这项工作可能为开发双溴结构域/ HDAC抑制剂作为潜在的抗癌治疗剂奠定基础。

  DOI：

  10.1016/j.bmcl.2016.04.034
• 作为产物：
  描述：

  3-溴-5-羟基苯甲醛 在 manganese(IV) oxide 、 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 四氢呋喃 、 1,4-二氧六环 、 乙醇 为溶剂， 反应 56.0h， 生成 (3-(3,5-dimethylisoxazol-4-yl)-5-hydroxyphenyl)(phenyl)methanone
  参考文献：
  名称：

  Optimization of 3,5-Dimethylisoxazole Derivatives as Potent Bromodomain Ligands

  摘要：

  The bromodomain protein module, which binds to acetylated lysine, is emerging as an important epigenetic therapeutic target. We report the structure-guided optimization of 3,5-dimethylisoxazole derivatives to develop potent inhibitors of the BET (bromodomain and extra terminal domain) bromodomain family with good ligand efficiency. X-ray crystal structures of the most potent compounds reveal key interactions required for high affinity at BRD4(1). Cellular studies demonstrate that the phenol and acetate derivatives of the lead compounds showed strong antiproliferative effects on MV4;11 acute myeloid leukemia cells, as shown for other BET bromodomain inhibitors and genetic BRD4 knockdown, whereas the reported compounds showed no general cytotoxicity in other cancer cell lines tested.

  DOI：

  10.1021/jm301588r

文献信息

• Targeting epigenetic reader and eraser: Rational design, synthesis and in vitro evaluation of dimethylisoxazoles derivatives as BRD4/HDAC dual inhibitors
  作者：Zhimin Zhang、Shaohua Hou、Hongli Chen、Ting Ran、Fei Jiang、Yuanyuan Bian、Dewei Zhang、Yanle Zhi、Lu Wang、Li Zhang、Hongmei Li、Yanmin Zhang、Weifang Tang、Tao Lu、Yadong Chen

  DOI：10.1016/j.bmcl.2016.04.034

  日期：2016.6

  (HDAC), which recognize and remove acetylated lysine, respectively, have emerged as important epigenetic therapeutic targets in cancer treatments. Herein we presented a novel design approach for cancer drug development by combination of bromodomain and HDAC inhibitory activity in one molecule. The designed compounds were synthesized which showed inhibitory activity against bromodomain 4 and HDAC1. The

  溴结构域蛋白模块和组蛋白脱乙酰基酶（HDAC）分别识别和去除乙酰化的赖氨酸，已成为癌症治疗中重要的表观遗传学治疗靶标。在这里，我们提出了一种通过在一个分子中结合溴结构域和HDAC抑制活性来开发癌症药物开发的新颖设计方法。合成了所设计的化合物，其显示出对溴结构域4和HDAC1的抑制活性。代表性的双溴结构域/ HDAC抑制剂化合物11和12在细胞测定中显示出对人白血病细胞株K562和MV4-11的有效抗增殖活性。这项工作可能为开发双溴结构域/ HDAC抑制剂作为潜在的抗癌治疗剂奠定基础。
• Optimization of 3,5-Dimethylisoxazole Derivatives as Potent Bromodomain Ligands
  作者：David S. Hewings、Oleg Fedorov、Panagis Filippakopoulos、Sarah Martin、Sarah Picaud、Anthony Tumber、Christopher Wells、Monica M. Olcina、Katherine Freeman、Andrew Gill、Alison J. Ritchie、David W. Sheppard、Angela J. Russell、Ester M. Hammond、Stefan Knapp、Paul E. Brennan、Stuart J. Conway

  DOI：10.1021/jm301588r

  日期：2013.4.25

  The bromodomain protein module, which binds to acetylated lysine, is emerging as an important epigenetic therapeutic target. We report the structure-guided optimization of 3,5-dimethylisoxazole derivatives to develop potent inhibitors of the BET (bromodomain and extra terminal domain) bromodomain family with good ligand efficiency. X-ray crystal structures of the most potent compounds reveal key interactions required for high affinity at BRD4(1). Cellular studies demonstrate that the phenol and acetate derivatives of the lead compounds showed strong antiproliferative effects on MV4;11 acute myeloid leukemia cells, as shown for other BET bromodomain inhibitors and genetic BRD4 knockdown, whereas the reported compounds showed no general cytotoxicity in other cancer cell lines tested.