6-(6-amino-1,3-dioxobenzo[de]isoquinolin-2-yl)-N-[4-(1,3,2-dithiarsinan-2-yl)phenyl]hexanamide | 1613402-21-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异喹啉及其衍生物
• 英文名称: 6-(6-amino-1,3-dioxobenzo[de]isoquinolin-2-yl)-N-[4-(1,3,2-dithiarsinan-2-yl)phenyl]hexanamide
• CAS: 1613402-21-3
• 化学式: C₂₇H₂₈AsN₃O₃S₂
• 分子量: 581.591
• InChiKey: KBGNRKKYTNLEDD-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.78
• 重原子数：
  36
• 可旋转键数：
  8
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  143
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  对氨基苯砷酸 在 盐酸 、 二氧化硫 、 氯甲酸乙酯 、 三乙胺 、 potassium iodide 作用下， 以 甲醇 、 乙醇 、 水 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 22.67h， 生成 6-(6-amino-1,3-dioxobenzo[de]isoquinolin-2-yl)-N-[4-(1,3,2-dithiarsinan-2-yl)phenyl]hexanamide
  参考文献：
  名称：

  Dithiaarsanes Induce Oxidative Stress-Mediated Apoptosis in HL-60 Cells by Selectively Targeting Thioredoxin Reductase

  摘要：

  The selenoprotein thioredoxin reductase (TrxR) plays a pivotal role in regulating cellular redox homeostasis and has attracted increasing attention as a promising anticancer drug target. We report here that 2-(4-aminophenyl)-1,3,2-dithiarsinane (PAO-PDT, 4), a potent and highly selective small molecule inhibitor of TrxR, stoichiometrically binds to the C-terminal selenocysteine/cysteine pair in the enzyme in vitro and induces oxidative stress-mediated apoptosis in HL-60 cells. The molecular action of 4 in cells involves inhibition of TrxR, elevation of reactive oxygen species, depletion of cellular thiols, and activation of caspase-3. Knockdown of TrxR sensitizes the cells to 4 treatment, whereas overexpression of the functional enzyme alleviates the cytotoxicity, providing physiological relevance for targeting TrxR by 4 in cells. The simplicity of the structure and the presence of an easily manipulated amine group will facilitate the further development of 4 as a potential cancer chemotherapeutic agent.

  DOI：

  10.1021/jm500221p

文献信息

• Dithiaarsanes Induce Oxidative Stress-Mediated Apoptosis in HL-60 Cells by Selectively Targeting Thioredoxin Reductase
  作者：Yaping Liu、Dongzhu Duan、Juan Yao、Baoxin Zhang、Shoujiao Peng、HuiLong Ma、Yanlin Song、Jianguo Fang

  DOI：10.1021/jm500221p

  日期：2014.6.26

  The selenoprotein thioredoxin reductase (TrxR) plays a pivotal role in regulating cellular redox homeostasis and has attracted increasing attention as a promising anticancer drug target. We report here that 2-(4-aminophenyl)-1,3,2-dithiarsinane (PAO-PDT, 4), a potent and highly selective small molecule inhibitor of TrxR, stoichiometrically binds to the C-terminal selenocysteine/cysteine pair in the enzyme in vitro and induces oxidative stress-mediated apoptosis in HL-60 cells. The molecular action of 4 in cells involves inhibition of TrxR, elevation of reactive oxygen species, depletion of cellular thiols, and activation of caspase-3. Knockdown of TrxR sensitizes the cells to 4 treatment, whereas overexpression of the functional enzyme alleviates the cytotoxicity, providing physiological relevance for targeting TrxR by 4 in cells. The simplicity of the structure and the presence of an easily manipulated amine group will facilitate the further development of 4 as a potential cancer chemotherapeutic agent.