6-[[4-(Benzenesulfonyl)-5-oxido-1,2,5-oxadiazol-5-ium-3-yl]oxy]hexyl 2-[4-[4-[[5-chloro-4-[3-(prop-2-enoylamino)phenoxy]pyrimidin-2-yl]amino]-3-methoxyphenyl]piperazin-1-yl]acetate | 1436851-41-0

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: 6-[[4-(Benzenesulfonyl)-5-oxido-1,2,5-oxadiazol-5-ium-3-yl]oxy]hexyl 2-[4-[4-[[5-chloro-4-[3-(prop-2-enoylamino)phenoxy]pyrimidin-2-yl]amino]-3-methoxyphenyl]piperazin-1-yl]acetate
• 英文别名: 6-[[4-(benzenesulfonyl)-5-oxido-1,2,5-oxadiazol-5-ium-3-yl]oxy]hexyl 2-[4-[4-[[5-chloro-4-[3-(prop-2-enoylamino)phenoxy]pyrimidin-2-yl]amino]-3-methoxyphenyl]piperazin-1-yl]acetate
• CAS: 1436851-41-0
• 化学式: C₄₀H₄₃ClN₈O₁₀S
• 分子量: 863.348
• InChiKey: BVFJPTPBIZMCEM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.8
• 重原子数：
  60
• 可旋转键数：
  21
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  221
• 氢给体数：
  2
• 氢受体数：
  16

反应信息

• 作为产物：
  描述：

  N-(3-((2,5-dichloropyrimidin-4-yl)oxy)phenyl)acrylamide 在 盐酸 、 4-二甲氨基吡啶 、 N,N'-二环己基碳二亚胺 、 三氟乙酸 、 lithium hydroxide 作用下， 以 四氢呋喃 、 二氯甲烷 、 水 、 仲丁醇 为溶剂， 反应 16.0h， 生成 6-[[4-(Benzenesulfonyl)-5-oxido-1,2,5-oxadiazol-5-ium-3-yl]oxy]hexyl 2-[4-[4-[[5-chloro-4-[3-(prop-2-enoylamino)phenoxy]pyrimidin-2-yl]amino]-3-methoxyphenyl]piperazin-1-yl]acetate
  参考文献：
  名称：

  Novel Hybrids of (Phenylsulfonyl)furoxan and Anilinopyrimidine as Potent and Selective Epidermal Growth Factor Receptor Inhibitors for Intervention of Non-Small-Cell Lung Cancer

  摘要：

  A series of hybrids (12a-k) from (phenylsulfonyl)furoxan and anilinopyrimidine were synthesized and biologically evaluated as epidermal growth factor receptor (EGFR) inhibitors for intervention of non-small-cell lung cancer (NSCLC). Compound 12k exhibited strong and selective EGFR L858R/T790M inhibitory activity (IC50 = 0.047 mu M) and displayed antiproliferative effects on EGFR mutation NSCLC cell lines HCC827 (del E746_A750) and H1975 (L858R/T790M) with IC50 values of 0.007 and 0.029 mu M, respectively. Additionally, 12k released high levels of NO in H1975 cells but not in normal human cells, and its activity was diminished by pretreatment with a NO scavenger. Furthermore, 12k induced apoptosis of H1975 and HCC827 cells more strongly than WZ4002 (1), inhibited EGFR downstream signaling in H1975 cells, and suppressed the nuclear factor-kappa B activation in H1975 cells, while 1 had no significant effects under the same conditions. Finally, 12k substantially inhibited tumor growth in an H1975 xenograft mouse model. Overall, 12k might be a promising candidate for the treatment of NSCLC.

  DOI：

  10.1021/jm400463q

文献信息

• Novel Hybrids of (Phenylsulfonyl)furoxan and Anilinopyrimidine as Potent and Selective Epidermal Growth Factor Receptor Inhibitors for Intervention of Non-Small-Cell Lung Cancer
  作者：Chun Han、Zhangjian Huang、Chao Zheng、Ledong Wan、Lianwen Zhang、Sixun Peng、Ke Ding、Hongbin Ji、Jide Tian、Yihua Zhang

  DOI：10.1021/jm400463q

  日期：2013.6.13

  A series of hybrids (12a-k) from (phenylsulfonyl)furoxan and anilinopyrimidine were synthesized and biologically evaluated as epidermal growth factor receptor (EGFR) inhibitors for intervention of non-small-cell lung cancer (NSCLC). Compound 12k exhibited strong and selective EGFR L858R/T790M inhibitory activity (IC50 = 0.047 mu M) and displayed antiproliferative effects on EGFR mutation NSCLC cell lines HCC827 (del E746_A750) and H1975 (L858R/T790M) with IC50 values of 0.007 and 0.029 mu M, respectively. Additionally, 12k released high levels of NO in H1975 cells but not in normal human cells, and its activity was diminished by pretreatment with a NO scavenger. Furthermore, 12k induced apoptosis of H1975 and HCC827 cells more strongly than WZ4002 (1), inhibited EGFR downstream signaling in H1975 cells, and suppressed the nuclear factor-kappa B activation in H1975 cells, while 1 had no significant effects under the same conditions. Finally, 12k substantially inhibited tumor growth in an H1975 xenograft mouse model. Overall, 12k might be a promising candidate for the treatment of NSCLC.