(Z)-((4-((3-ethynylphenyl)amino)quinazoline-6,7-diyl)bis(oxy))bis(ethane-2,1-diyl) bis(2-((Z)-5-fluoro-2-methyl-1-(4-(methylsulfinyl)benzylidene)-1H-inden-3-yl)acetate)

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: (Z)-((4-((3-ethynylphenyl)amino)quinazoline-6,7-diyl)bis(oxy))bis(ethane-2,1-diyl) bis(2-((Z)-5-fluoro-2-methyl-1-(4-(methylsulfinyl)benzylidene)-1H-inden-3-yl)acetate)
• 英文别名: 2-[4-(3-ethynylanilino)-7-[2-[2-[(3Z)-6-fluoro-2-methyl-3-[(4-methylsulfinylphenyl)methylidene]inden-1-yl]acetyl]oxyethoxy]quinazolin-6-yl]oxyethyl 2-[(3Z)-6-fluoro-2-methyl-3-[(4-methylsulfinylphenyl)methylidene]inden-1-yl]acetate
• 化学式: C₆₀H₄₉F₂N₃O₈S₂
• 分子量: 1042.19
• InChiKey: PALXYTXSYLZDRR-AGTSVBGFSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  8.7
• 重原子数：
  75
• 可旋转键数：
  21
• 环数：
  9.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  181
• 氢给体数：
  1
• 氢受体数：
  15

反应信息

• 作为产物：
  描述：

  Sulindac 在 氯化亚砜 、 potassium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 (Z)-((4-((3-ethynylphenyl)amino)quinazoline-6,7-diyl)bis(oxy))bis(ethane-2,1-diyl) bis(2-((Z)-5-fluoro-2-methyl-1-(4-(methylsulfinyl)benzylidene)-1H-inden-3-yl)acetate)
  参考文献：
  名称：

  Synthesis and Evaluation of Novel Erlotinib–NSAID Conjugates as More Comprehensive Anticancer Agents

  摘要：

  A series of novel anticancer agents were designed and synthesized based on coupling of different nonsteroidal anti-inflammatory drugs (NSAIDs) with the epidermal growth-factor receptor (EGFR) tyrosine kinase inhibitor, erlotinib. Both the antiproliferative and pharmacokinetic activity of the target compounds were evaluated using HCC827 and A431 tumor cell lines. Among the derivatives made, compounds 10a, 10c, and 21g showed superb potency, comparable to that of erlotinib. Furthermore, preliminary SAR analysis showed that when the NSAIDs were conjugated via linkage to C-6 OH versus linkage to C-7 OH of the quinazoline nucleus, superior anticancer activity was achieved. Finally, the in vitro pharmacokinetic profile of several conjugates demonstrated the desired dissociation kinetics as the coupled molecules were effectively hydrolyzed, releasing both erlotinib and the specific NSAID in a time-dependent manner. The conjugation strategy represents a unique and simplified approach toward combination therapy, particularly for the treatment of cancers where both EGFR overexpression and inflammation play a direct role in disease progression.

  DOI：

  10.1021/acsmedchemlett.5b00286

文献信息

• Synthesis and Evaluation of Novel Erlotinib–NSAID Conjugates as More Comprehensive Anticancer Agents
  作者：Yanmei Zhang、Micky D. Tortorella、Jinxi Liao、Xiaochu Qin、Tingting Chen、Jinfeng Luo、Jiantong Guan、John J. Talley、Zhengchao Tu

  DOI：10.1021/acsmedchemlett.5b00286

  日期：2015.10.8

  A series of novel anticancer agents were designed and synthesized based on coupling of different nonsteroidal anti-inflammatory drugs (NSAIDs) with the epidermal growth-factor receptor (EGFR) tyrosine kinase inhibitor, erlotinib. Both the antiproliferative and pharmacokinetic activity of the target compounds were evaluated using HCC827 and A431 tumor cell lines. Among the derivatives made, compounds 10a, 10c, and 21g showed superb potency, comparable to that of erlotinib. Furthermore, preliminary SAR analysis showed that when the NSAIDs were conjugated via linkage to C-6 OH versus linkage to C-7 OH of the quinazoline nucleus, superior anticancer activity was achieved. Finally, the in vitro pharmacokinetic profile of several conjugates demonstrated the desired dissociation kinetics as the coupled molecules were effectively hydrolyzed, releasing both erlotinib and the specific NSAID in a time-dependent manner. The conjugation strategy represents a unique and simplified approach toward combination therapy, particularly for the treatment of cancers where both EGFR overexpression and inflammation play a direct role in disease progression.