5-(3-(4-氟苯基)-1-苯基-1H-吡唑-4-基)咪唑啉-2,4-二酮 | 484049-04-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 中文名称: 5-(3-(4-氟苯基)-1-苯基-1H-吡唑-4-基)咪唑啉-2,4-二酮
• 中文别名: 5-(3-(4-氟苯基)-1-苯基-1H-吡唑-4-基)咪唑烷-2,4-二酮
• 英文名称: DPH
• 英文别名: 5-[3-(4-fluorophenyl)-1-phenyl-1H-pyrazol-4-yl]-2,4-imidazolidinedione；5-(1,3-diaryl-1H-pyrazol-4-yl)hydantoin；5-(3-(4-fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)imidazolidine-2,4-dione；5-[3-(4-fluorophenyl)-1-phenylpyrazol-4-yl]imidazolidine-2,4-dione
• CAS: 484049-04-9
• 化学式: C₁₈H₁₃FN₄O₂
• 分子量: 336.325
• InChiKey: MPQWYPLPWGUMJE-UHFFFAOYSA-N

物化性质

• 密度：
  1.45
• 溶解度：
  二甲基亚砜：≥10mg/mL

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  25
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.06
• 拓扑面积：
  76
• 氢给体数：
  2
• 氢受体数：
  4

制备方法与用途

生物活性

DPH 是一种有效的细胞渗透性 c-Abl 激活剂，在酶和细胞活动中，能够有效刺激 c-Abl 的活化。

体外研究

DPH 与棕榈酰化结合位点结合，并通过立体阻碍防止 αI 螺旋形成弯曲构象，其作用机制不同于之前已知的另一种非竞争性 c-Abl 抑制剂 GNF-2，后者也结合在棕榈酰化结合位点。DPH 是首个可用于细胞渗透的小分子工具化合物，用于激活 c-Abl。

反应信息

• 作为产物：
  描述：

  potassium cyanide 、 3-(4-氟-苯基)-1-苯基-1H-吡唑-4-甲醛 在 碳酸氢铵 、 盐酸 作用下， 以 乙醇 、 水 为溶剂， 反应 3.5h， 以87%的产率得到5-(3-(4-氟苯基)-1-苯基-1H-吡唑-4-基)咪唑啉-2,4-二酮
  参考文献：
  名称：

  Discovery and Characterization of a Cell-Permeable, Small-Molecule c-Abl Kinase Activator that Binds to the Myristoyl Binding Site

  摘要：

  c-Abl kinase activity is regulated by a unique mechanism involving the formation of an autoinhibited conformation in which the N-terminal myristoyl group binds intramolecularly to the myristoyl binding site on the kinase domain and induces the bending of the alpha l helix that creates a docking surface for the SH2 domain. Here, we report a small-molecule c-Abl activator, DPH, that displays potent enzymatic and cellular activity in stimulating c-Abl activation. Structural analyses indicate that DPH binds to the myristoyl binding site and prevents the formation of the bent conformation of the al helix through steric hindrance, a mode of action distinct from the previously identified allosteric c-Abl inhibitor, GNF-2, that also binds to the myristoyl binding site. DPH represents the first cell-permeable, small-molecule tool compound for c-Abl activation.

  DOI：

  10.1016/j.chembiol.2010.12.013
• 作为试剂：
  描述：

  在 bis{rhodium[3,3'-(1,3-phenylene)bis(2,2-dimethylpropanoic acid)]} 、 5-(3-(4-氟苯基)-1-苯基-1H-吡唑-4-基)咪唑啉-2,4-二酮 、 2,4-二硝基苯基羟胺 作用下， 以 甲苯 为溶剂， 生成
  参考文献：
  名称：

  氯菌素的功能化：Dehalogenil 作为有前景的体内应用先导化合物

  摘要：

  通过后期功能化和新颖反应对天然产物百草枯进行修饰。修改新位置后，显示出针对多重耐药革兰氏阳性菌和恶性疟原虫的活性和选择性。这种新物质 dehalogenil 缺乏对毒性至关重要的氯基团，经过体内测试，在不同的金黄色葡萄球菌感染小鼠模型中显示出显着改善的药代动力学和功效。

  DOI：

  10.1002/anie.202319765

文献信息

• CHAPERONE INTERACTION ASSAYS AND USES THEREOF
  申请人：Whitehead Institute For Biomedical Research

  公开号：EP2707714B1

  公开（公告）日：2019-10-09
• US9746470B2
  申请人：——

  公开号：US9746470B2

  公开（公告）日：2017-08-29
• [EN] CHAPERONE INTERACTION ASSAYS AND USES THEREOF<br/>[FR] ESSAIS D'INTERACTION AVEC LES CHAPERONNES ET LEURS UTILISATIONS
  申请人：WHITEHEAD BIOMEDICAL INST

  公开号：WO2012154858A1

  公开（公告）日：2012-11-15

  In some aspects, the invention provides methods of identifying, detecting, and/or measuring protein-protein interactions. In some aspects, the invention provides methods of identifying and/or characterizing modulators of protein-protein interactions. In some aspects, the invention provides methods of identifying and/or characterizing modulators of protein activity, wherein the methods are based at least in part on measuring interaction between a chaperone and client protein. In some aspects, the invention provides methods for identifying and/or characterizing compounds and/or for assessing compound specificity, wherein the methods are based at least in part on measuring interaction between a chaperone and client protein. In some embodiments, a client protein is a kinase. In some embodiments, a compound is a kinase inhibitor. In some aspects, the invention provides methods of profiling kinase inhibitor specificity. In some aspects, the invention provides assay systems and/or reagents useful for performing one or more of the inventive methods. In some aspects, the invention provides newly identified targets of a variety of kinase inhibitors. In some aspect, the invention provides methods of inhibiting kinases identified herein as targets of certain kinase inhibitors. In some aspects, the invention provides methods of treating a disease, e.g., cancer, by inhibiting one or more kinase(s) newly identified as targets of certain kinase inhibitors.
• Discovery and Characterization of a Cell-Permeable, Small-Molecule c-Abl Kinase Activator that Binds to the Myristoyl Binding Site
  作者：Jingsong Yang、Nino Campobasso、Mangatt P. Biju、Kelly Fisher、Xiao-Qing Pan、Josh Cottom、Sarah Galbraith、Thau Ho、Hong Zhang、Xuan Hong、Paris Ward、Glenn Hofmann、Brett Siegfried、Francesca Zappacosta、Yoshiaki Washio、Ping Cao、Junya Qu、Sophie Bertrand、Da-Yuan Wang、Martha S. Head、Hu Li、Sheri Moores、Zhihong Lai、Kyung Johanson、George Burton、Connie Erickson-Miller、Graham Simpson、Peter Tummino、Robert A. Copeland、Allen Oliff

  DOI：10.1016/j.chembiol.2010.12.013

  日期：2011.2

  c-Abl kinase activity is regulated by a unique mechanism involving the formation of an autoinhibited conformation in which the N-terminal myristoyl group binds intramolecularly to the myristoyl binding site on the kinase domain and induces the bending of the alpha l helix that creates a docking surface for the SH2 domain. Here, we report a small-molecule c-Abl activator, DPH, that displays potent enzymatic and cellular activity in stimulating c-Abl activation. Structural analyses indicate that DPH binds to the myristoyl binding site and prevents the formation of the bent conformation of the al helix through steric hindrance, a mode of action distinct from the previously identified allosteric c-Abl inhibitor, GNF-2, that also binds to the myristoyl binding site. DPH represents the first cell-permeable, small-molecule tool compound for c-Abl activation.