5-(3-(1H-imidazol-1-yl)propyl)-4-(4-bromophenyl)-1-(2-fluorobenzyl)-3-phenyl-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one | 1542066-72-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 5-(3-(1H-imidazol-1-yl)propyl)-4-(4-bromophenyl)-1-(2-fluorobenzyl)-3-phenyl-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one
• 英文别名: 5-(3-(1H-imidazole)propyl)-4-(4-bromophenyl)-1-o-fluorobenzyl-3-phenyl-4,5-dihydropyrrolo[3,4-c]pyrazole-6(1H)-one；4-(4-bromophenyl)-1-[(2-fluorophenyl)methyl]-5-(3-imidazol-1-ylpropyl)-3-phenyl-4H-pyrrolo[3,4-c]pyrazol-6-one
• CAS: 1542066-72-7
• 化学式: C₃₀H₂₅BrFN₅O
• 分子量: 570.464
• InChiKey: XTCMBTOLDGCYOS-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.4
• 重原子数：
  38
• 可旋转键数：
  8
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  56
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  METHYL (2Z)-2-HYDROXY-4-OXO-4-PHENYLBUT-2-ENOATE 在 potassium carbonate 、 一水合肼 、 溶剂黄146 作用下， 以 1,4-二氧六环 、 乙醇 为溶剂， 反应 26.5h， 生成 5-(3-(1H-imidazol-1-yl)propyl)-4-(4-bromophenyl)-1-(2-fluorobenzyl)-3-phenyl-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one
  参考文献：
  名称：

  Double-Edged Swords as Cancer Therapeutics: Novel, Orally Active, Small Molecules Simultaneously Inhibit p53–MDM2 Interaction and the NF-κB Pathway

  摘要：

  Simultaneous inactivation of p53 and hyperactivation of nuclear factor-kappa B (NF-kappa B) is a common occurrence in human cancer. Currently, antitumor agents are being designed to selectively activate p53 or inhibit NF-kappa B. However, there is no concerted effort yet to deliberately design inhibitors that can simultaneously do both. This paper provided a proof-of-concept study that p53-MDM2 interaction and NF-kappa B pathway can be simultaneously targeted by a small-molecule inhibitor. A series of pyrrolo[3,4-c]pyrazole derivatives were rationally designed and synthesized as the first-in-class inhibitors of p53-MDM2 interaction and NF-kappa B pathway. Most of the compounds were identified to possess nanomolar p53-MDM2 inhibitory activity. Compounds 5q and 5s suppressed NF-kappa B activation through inhibition of I kappa B alpha phosphorylation and elevation of the cytoplasmic levels of p65 and phosphorylated IKK alpha/beta. Biochemical assay for the kinases also supported the fact that pyrrolo[3,4-c]pyrazole compounds directly targeted the NF-kappa B pathway. In addition, four compounds (5j, 5q, 5s, and 5u) effectively inhibited tumor growth in the A549 xenograft model. Further pharmacokinetic study revealed that compound 5q exhibited excellent oral bioavailability (72.9%).

  DOI：

  10.1021/jm401800k