N'-(3-allyl-2-hydroxybenzylidene)-2-(4-(4-fluorobenzyl)piperazin-1-yl)acetohydrazide | 1075725-64-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: N'-(3-allyl-2-hydroxybenzylidene)-2-(4-(4-fluorobenzyl)piperazin-1-yl)acetohydrazide
• 英文别名: N′-[[2-hydroxy-3-(2-propenyl)phenyl]methylene]-4-[(4-fluorophenyl)methyl]-1-piperazineacetohydrazide；2-[4-[(4-fluorophenyl)methyl]piperazin-1-yl]-N-[(2-hydroxy-3-prop-2-enylphenyl)methylideneamino]acetamide
• CAS: 1075725-64-2
• 化学式: C₂₃H₂₇FN₄O₂
• 分子量: 410.491
• InChiKey: KERGYASDYSCRBT-UHFFFAOYSA-N

物化性质

• 熔点：
  113.8-114.5 °C
• 密度：
  1.19±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  30
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  68.2
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  水杨醛 在 盐酸 、 potassium carbonate 作用下， 以 乙醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， 生成 N'-(3-allyl-2-hydroxybenzylidene)-2-(4-(4-fluorobenzyl)piperazin-1-yl)acetohydrazide
  参考文献：
  名称：

  Removal of Metabolic Liabilities Enables Development of Derivatives of Procaspase-Activating Compound 1 (PAC-1) with Improved Pharmacokinetics

  摘要：

  Procaspase-activating compound 1 (PAC-1) is an o-hydroxy-N-acylhydrazone that induces apoptosis in cancer cells by chelation of labile inhibitory zinc from procaspase-3. PAC-1 has been assessed in a wide variety of cell culture experiments and in vivo models of cancer, with promising results, and a phase 1 clinical trial in cancer patients has been initiated (NCT02355535). For certain applications, however, the in vivo half-life of PAC-1 could be limiting. Thus, with the goal of developing a compound with enhanced metabolic stability, a series of PAC-1 analogues were designed containing modifications that systematically block sites of metabolic vulnerability. Evaluation of the library of compounds identified four potentially superior candidates with comparable anticancer activity in cell culture, enhanced metabolic stability in liver microsomes, and improved tolerability in mice. In head-to-head experiments with PAC-1, pharmacokinetic evaluation in mice demonstrated extended elimination half-lives and greater area under the curve values for each of the four compounds, suggesting them as promising candidates for further development.

  DOI：

  10.1021/acs.jmedchem.5b00413

文献信息

• WO2008/134474
  申请人：——

  公开号：——

  公开（公告）日：——
• Procaspase-3 Activation as an Anti-Cancer Strategy: Structure−Activity Relationship of Procaspase-Activating Compound 1 (PAC-1) and Its Cellular Co-Localization with Caspase-3
  作者：Quinn P. Peterson、Danny C. Hsu、David R. Goode、Chris J. Novotny、Ryan K. Totten、Paul J. Hergenrother

  DOI：10.1021/jm900722z

  日期：2009.9.24

  A goal of personalized medicine as applied to oncology is to identify compounds that exploit a defined molecular defect in a cancerous cell. A compound called procaspase-activating compound I (PAC-1) was reported that enhances the activity of procaspase-3 in vitro and induces apoptotic death in cancer cells in culture and in mouse xenograft models. Experimental evidence indicates that PAC-1 activates procaspase-3 in vitro through chelation of inhibitory zinc ions. Described herein is the synthesis and biological activity of a family of PAC-1 derivatives where key functional groups have been systematically altered. Analysis of these compounds reveals a strong correlation between the in vitro procaspase-3 activating effect and their ability to induce death in cancer cells in culture. Importantly, we also show that a fluorescently labeled version of PAC-1 co-localizes with sites of caspase-3 activity in cancer cells. The data presented herein further bolster the hypothesis that PAC-1 induces apoptosis in cancer cells through the direct activation of procaspase-3, has implications for the design and discovery of next-generation procaspase-3 activating compounds, and sheds light on the anti-apoptotic role of cellular zinc.