(2E)-N-(4-(3,4-dimethoxybenzyl)-5-(4-(diethylamino)benzyl)-1-methyl-1H-imidazol-2-yl)-3-(3,4,5-trimethoxyphenyl)-N-((E)-3-(3,4,5-trimethoxyphenyl)acryloyl)acrylamide | 1620893-82-4

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 肉桂酸及其衍生物
• 英文名称: (2E)-N-(4-(3,4-dimethoxybenzyl)-5-(4-(diethylamino)benzyl)-1-methyl-1H-imidazol-2-yl)-3-(3,4,5-trimethoxyphenyl)-N-((E)-3-(3,4,5-trimethoxyphenyl)acryloyl)acrylamide
• 英文别名: (E)-N-[5-[[4-(diethylamino)phenyl]methyl]-4-[(3,4-dimethoxyphenyl)methyl]-1-methylimidazol-2-yl]-3-(3,4,5-trimethoxyphenyl)-N-[(E)-3-(3,4,5-trimethoxyphenyl)prop-2-enoyl]prop-2-enamide
• CAS: 1620893-82-4
• 化学式: C₄₈H₅₆N₄O₁₀
• 分子量: 848.993
• InChiKey: FVYUIGDNXGJUGZ-SKWBHROBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  8.2
• 重原子数：
  62
• 可旋转键数：
  20
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  132
• 氢给体数：
  0
• 氢受体数：
  12

反应信息

• 作为产物：
  描述：

  N,N-二乙基-4-氨基苯甲醛 在 三乙基硅烷 、 sodium tetrahydroborate 、 正丁基锂 、 palladium 10% on activated carbon 、 三氟化硼乙醚 、 乙基溴化镁 、 氢气 、 溶剂黄146 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 甲醇 、 正己烷 为溶剂， -78.0~60.0 ℃ 、4.05 MPa 条件下， 反应 134.5h， 生成 (2E)-N-(4-(3,4-dimethoxybenzyl)-5-(4-(diethylamino)benzyl)-1-methyl-1H-imidazol-2-yl)-3-(3,4,5-trimethoxyphenyl)-N-((E)-3-(3,4,5-trimethoxyphenyl)acryloyl)acrylamide
  参考文献：
  名称：

  4,5-Di-substituted benzyl-imidazol-2-substituted amines as the structure template for the design and synthesis of reversal agents against P-gp-mediated multidrug resistance breast cancer cells

  摘要：

  Over-expression of P-glycoprotein (P-gp), a primary multidrug transporter which is located in plasma membranes, plays a major role in the multidrug resistance (MDR) of cytotoxic chemotherapy. Naamidines are a class of marine imidazole alkaloids isolated from Leucetta and Clathrina sponges, possessing a Y-shaped scaffold. Based on the results previously obtained from the third-generation MDR modulator ONT-093 and other modulators developed in our group, we designed and synthesized a series of novel 4,5-di-substituted benzyl-1-methyl-1H-imidazol-2-substituted amines using the Naamidine scaffold as the structure template. Subsequently, their reversing activity for Taxol resistance has been evaluated in P-gp-mediated multidrug resistance breast cancer cell line MDA435/LCC6MDR. Compounds 12c with a Y-shaped scaffold, and compound 17c which is 'X-shaped' scaffold and possesses a 4-diethylamino group at aryl ring B, turned out to be the most potent P-gp modulators. It appears that compounds 12c and 17c at 1 μM concentration can sensitize LCC6MDR cells toward Taxol by 26.4 and 24.5 folds, with an EC50 212.5 and 210.5 nM, respectively. These two compounds are about 5-6 folds more potent than verapamil (RF = 4.5). Moreover, compounds 12c and 17c did not exhibit obvious cytotoxicity in either cancer cell lines or normal mouse fibroblast cell lines. This study has demonstrated that the synthetic Naamidine analogues can be potentially employed as effective, safe modulators for the P-gp-mediated drug resistance cancer cells.

  DOI：

  10.1016/j.ejmech.2014.06.016

文献信息

• 4,5-Di-substituted benzyl-imidazol-2-substituted amines as the structure template for the design and synthesis of reversal agents against P-gp-mediated multidrug resistance breast cancer cells
  作者：Nan Zhang、Zhaohui Zhang、Iris L.K. Wong、Shengbiao Wan、Larry M.C. Chow、Tao Jiang

  DOI：10.1016/j.ejmech.2014.06.016

  日期：2014.8

  Over-expression of P-glycoprotein (P-gp), a primary multidrug transporter which is located in plasma membranes, plays a major role in the multidrug resistance (MDR) of cytotoxic chemotherapy. Naamidines are a class of marine imidazole alkaloids isolated from Leucetta and Clathrina sponges, possessing a Y-shaped scaffold. Based on the results previously obtained from the third-generation MDR modulator ONT-093 and other modulators developed in our group, we designed and synthesized a series of novel 4,5-di-substituted benzyl-1-methyl-1H-imidazol-2-substituted amines using the Naamidine scaffold as the structure template. Subsequently, their reversing activity for Taxol resistance has been evaluated in P-gp-mediated multidrug resistance breast cancer cell line MDA435/LCC6MDR. Compounds 12c with a Y-shaped scaffold, and compound 17c which is 'X-shaped' scaffold and possesses a 4-diethylamino group at aryl ring B, turned out to be the most potent P-gp modulators. It appears that compounds 12c and 17c at 1 μM concentration can sensitize LCC6MDR cells toward Taxol by 26.4 and 24.5 folds, with an EC50 212.5 and 210.5 nM, respectively. These two compounds are about 5-6 folds more potent than verapamil (RF = 4.5). Moreover, compounds 12c and 17c did not exhibit obvious cytotoxicity in either cancer cell lines or normal mouse fibroblast cell lines. This study has demonstrated that the synthetic Naamidine analogues can be potentially employed as effective, safe modulators for the P-gp-mediated drug resistance cancer cells.