4-((1-(4-chlorophenyl)-1-((1-(hydroxymethyl)cyclopropyl)methoxy)-3-oxoisoindolin-2-yl)methyl)pyridine 1-oxide | 1268692-18-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异吲哚及其衍生物
• 英文名称: 4-((1-(4-chlorophenyl)-1-((1-(hydroxymethyl)cyclopropyl)methoxy)-3-oxoisoindolin-2-yl)methyl)pyridine 1-oxide
• 英文别名: 3-(4-Chlorophenyl)-3-[[1-(hydroxymethyl)cyclopropyl]methoxy]-2-[(1-oxidopyridin-1-ium-4-yl)methyl]isoindol-1-one
• CAS: 1268692-18-7
• 化学式: C₂₅H₂₃ClN₂O₄
• 分子量: 450.922
• InChiKey: HXZDDUDYNIAFTO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  32
• 可旋转键数：
  7
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.28
• 拓扑面积：
  75.2
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  3-(4-chlorophenyl)-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-2-(pyridin-4-ylmethyl)isoindolin-1-one 在 间氯过氧苯甲酸 作用下， 以 二氯甲烷 为溶剂， 反应 4.0h， 以52%的产率得到4-((1-(4-chlorophenyl)-1-((1-(hydroxymethyl)cyclopropyl)methoxy)-3-oxoisoindolin-2-yl)methyl)pyridine 1-oxide
  参考文献：
  名称：

  Isoindolinone Inhibitors of the Murine Double Minute 2 (MDM2)-p53 Protein−Protein Interaction: Structure−Activity Studies Leading to Improved Potency

  摘要：

  Inhibition of the MDM2-p53 interaction has been shown to produce an antitumor effect, especially in MDM2 amplified tumors.. The isoindolinone scaffold has proved to be versatile for the discovery of MDM2-p53 antagonists. Optimization of previously reported inhibitors, for example, NU8231 (7) and NU8165 (49), was guided by MDM2 NMR titrations, which indicated key areas of the binding interaction to be explored. Variation of the 2-N-benzyl and 3-alkoxy substituents resulted in the identification of 3-(4-nitrobenzyl)-3-((1-(hydroxymethyl)cyclopropyl)methoxy)-2-(4-nitrobenzyl)isoindolin-1-one (74) as a potent MDM2-p53 inhibitor (IC(50) = 0.23 +/- 0.01 mu M). Resolution of the enantiomers of 74 showed that potent MDM2-p53 activity primarily resided with the (+)R-enantiomer (74a; IC(50) = 0.17 +/- 0.02 mu M). The cellular activity of key compounds has been examined in cell lines with defined p53 and MDM2 status. Compound 74a activates p53, MDM2, and p21 transcription in MDM2 amplified cells and shows moderate selectivity for wild-type p53 cell lines in growth inhibition assays.

  DOI：

  10.1021/jm1011929