4-[hydroxy-(4-methoxyphenyl)]methyl-5-(4-methoxy-benzyl)-1-methyl-1H-imidazole | 1206617-48-2

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 英文名称: 4-[hydroxy-(4-methoxyphenyl)]methyl-5-(4-methoxy-benzyl)-1-methyl-1H-imidazole
• 英文别名: (4-Methoxyphenyl)-[5-[(4-methoxyphenyl)methyl]-1-methylimidazol-4-yl]methanol
• CAS: 1206617-48-2
• 化学式: C₂₀H₂₂N₂O₃
• 分子量: 338.406
• InChiKey: USBMDXNJBGIUEG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  25
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  56.5
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  4-[hydroxy-(4-methoxyphenyl)]methyl-5-(4-methoxy-benzyl)-1-methyl-1H-imidazole 在 sodium tetrahydroborate 、 正丁基锂 、 palladium 10% on activated carbon 、 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， -78.0~50.0 ℃ 、4.05 MPa 条件下， 反应 61.5h， 生成 N-(4,5-bis(4-methoxybenzyl)-1-methyl-1H-imidazol-2-yl)-N-benzoylbenzamide
  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
• 作为产物：
  描述：

  (4-iodo-1-methyl-1H-imidazol-5-yl)(4-methoxyphenyl)methanol 在 三乙基硅烷 、 乙基溴化镁 、 magnesium 、 三氟乙酸 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 62.0h， 生成 4-[hydroxy-(4-methoxyphenyl)]methyl-5-(4-methoxy-benzyl)-1-methyl-1H-imidazole
  参考文献：
  名称：

  Leucetta生物碱的总合成和细胞毒性

  摘要：

  描述了从含有多取代的2-氨基咪唑的Leucetta和Clathrina海绵分离的许多代表性天然产物的全合成。这些合成利用了4,5-二碘咪唑的位点特定的金属化反应，从而合成了三类不同的Leucetta衍生的天然产物。通过MTT生长测定法确定了这些天然产物以及MCF7细胞中的几种前体的细胞毒性。为了比较起见，包括一系列含萘咪唑的家族成员。

  DOI：

  10.1016/j.bmc.2017.01.024

文献信息

• Total syntheses of naamidine G and 14-methoxynaamidine G
  作者：Panduka B. Koswatta、Carl J. Lovely

  DOI：10.1016/j.tetlet.2009.10.117

  日期：2010.1

  Simple total syntheses of two Leucetta-derived marine alkaloids have been developed using position-specific halogen-metal exchange of polyhaloimidazoles to introduce the benzyl substituted sidechains. Introduction of the C2 amine group by lithiation and trapping with tosyl azide provides amines on catalytic hydrogenation, which can be converted to naamidine G and 14-methoxynaamidine G using a procedure

  两种Leucetta衍生的海洋生物碱的简单全合成已经使用多卤咪唑的位置特异性卤素金属交换来引入苄基取代的侧链。通过锂化作用引入 C2 胺基团并用甲苯磺酰叠氮化物捕获，在催化氢化作用下提供胺，可使用文献中描述的程序将其转化为萘脒 G 和 14-甲氧基萘脒 G。
• Total synthesis and cytotoxicity of Leucetta alkaloids
  作者：Panduka B. Koswatta、Sabha Kasiri、Jayanta K. Das、Arunoday Bhan、Heather M. Lima、Beatriz Garcia-Barboza、Nicole N. Khatibi、Muhammed Yousufuddin、Subhrangsu S. Mandal、Carl J. Lovely

  DOI：10.1016/j.bmc.2017.01.024

  日期：2017.3

  The total synthesis of a number of representative natural products isolated from Leucetta and Clathrina sponges containing a polysubstituted 2-aminoimidazole are described. These syntheses take advantage of the site specific metallation reactions of 4,5-diiodoimidazoles resulting in the syntheses of three different classes of Leucetta derived natural products. The cytotoxicities of these natural products

  描述了从含有多取代的2-氨基咪唑的Leucetta和Clathrina海绵分离的许多代表性天然产物的全合成。这些合成利用了4,5-二碘咪唑的位点特定的金属化反应，从而合成了三类不同的Leucetta衍生的天然产物。通过MTT生长测定法确定了这些天然产物以及MCF7细胞中的几种前体的细胞毒性。为了比较起见，包括一系列含萘咪唑的家族成员。
• 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.