N-(4-methoxyphenyl)-N-(ethyl)-α-benzyl-4-methoxyphenylacetamide | 293743-76-7

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 二苯乙烯类
• 英文名称: N-(4-methoxyphenyl)-N-(ethyl)-α-benzyl-4-methoxyphenylacetamide
• CAS: 293743-76-7
• 化学式: C₂₅H₂₇NO₃
• 分子量: 389.494
• InChiKey: PDMDLSMZHKLJEN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.08
• 重原子数：
  29.0
• 可旋转键数：
  8.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  38.77
• 氢给体数：
  0.0
• 氢受体数：
  3.0

反应信息

• 作为反应物：
  描述：

  N-(4-methoxyphenyl)-N-(ethyl)-α-benzyl-4-methoxyphenylacetamide 在 劳森试剂 、 三溴化硼 作用下， 以 二氯甲烷 为溶剂， 生成 N-ethyl-N,2-bis(4-hydroxyphenyl)-3-phenylpropanethioamide
  参考文献：
  名称：

  Acyclic amides as estrogen receptor ligands: Synthesis, binding, activity and receptor interaction

  摘要：

  We have prepared a series of bisphenolic amides that mimic bibenzyl and homobibenzyl motifs commonly found as substructures in ligands for the estrogen receptor (ER). Representative members were prepared from three classes: N-phenyl benzamides, N-phenyl acetamides, and N-benzyl benzamides; in some cases the corresponding thiocarboxamides and sulfonamides were also prepared. Of these three classes, the N-phenyl benzamides had the highest affinity for ER, the N-phenyl acetamides had lower, and the N-benzyl benzamides were prone to fragmentation via a quinone methide intermediate. In the N-phenyl benzamide series, the highest affinity analogues had bulky N-substituents; a CF3 group, in particular, conferred high affinity. The thiocarboxamides bound better than the corresponding carboxamides and these bound better than the corresponding sulfonamides. Binding affinity comparisons suggest that the p-hydroxy group on the benzoate ring, which contributes most to the binding, is playing the role of the phenolic hydroxyl of estradiol. Computational studies and NMR and X-ray crystallographic analysis indicate that the two anilide systems studied have a strong preference for the s-cis or exo amide conformation, which places the two aromatic rings in a syn orientation. We used this structural template. together with the X-ray structure of the ER ligand binding domain, to elaborate an additional hydrogen bonding site on a benzamide system that elevated receptor binding further. When assayed on the individual ER subtypes, ER alpha and ER beta, these compounds show modest binding affinity preference for ER alpha. In a reporter gene transfection assay of transcriptional activity, the amides generally have full to nearly full agonist character on ERa, but have moderate to full antagonist character on ER beta. One high affinity carboxamide is 500-fold more potent as an agonist on ER alpha than on ER beta. This work illustrates that ER ligands having simple amide core structures can be readily prepared, but that high affinity binding requires an appropriate distribution of bulk, polarity, and functionality. The strong conformational preference of the core anilide function in all of these ligands defines a rather rigid geometry for further structural and functional expansion of these series. (C) 2000 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(00)00075-4
• 作为产物：
  描述：

  4-甲氧基苯乙酰氯 在 吡啶 、 氢氧化钾 、 正丁基锂 、 四丁基溴化铵 、 二异丙胺 作用下， 以 四氢呋喃 、 正己烷 、 二氯甲烷 、 苯 为溶剂， 反应 4.33h， 生成 N-(4-methoxyphenyl)-N-(ethyl)-α-benzyl-4-methoxyphenylacetamide
  参考文献：
  名称：

  Acyclic amides as estrogen receptor ligands: Synthesis, binding, activity and receptor interaction

  摘要：

  We have prepared a series of bisphenolic amides that mimic bibenzyl and homobibenzyl motifs commonly found as substructures in ligands for the estrogen receptor (ER). Representative members were prepared from three classes: N-phenyl benzamides, N-phenyl acetamides, and N-benzyl benzamides; in some cases the corresponding thiocarboxamides and sulfonamides were also prepared. Of these three classes, the N-phenyl benzamides had the highest affinity for ER, the N-phenyl acetamides had lower, and the N-benzyl benzamides were prone to fragmentation via a quinone methide intermediate. In the N-phenyl benzamide series, the highest affinity analogues had bulky N-substituents; a CF3 group, in particular, conferred high affinity. The thiocarboxamides bound better than the corresponding carboxamides and these bound better than the corresponding sulfonamides. Binding affinity comparisons suggest that the p-hydroxy group on the benzoate ring, which contributes most to the binding, is playing the role of the phenolic hydroxyl of estradiol. Computational studies and NMR and X-ray crystallographic analysis indicate that the two anilide systems studied have a strong preference for the s-cis or exo amide conformation, which places the two aromatic rings in a syn orientation. We used this structural template. together with the X-ray structure of the ER ligand binding domain, to elaborate an additional hydrogen bonding site on a benzamide system that elevated receptor binding further. When assayed on the individual ER subtypes, ER alpha and ER beta, these compounds show modest binding affinity preference for ER alpha. In a reporter gene transfection assay of transcriptional activity, the amides generally have full to nearly full agonist character on ERa, but have moderate to full antagonist character on ER beta. One high affinity carboxamide is 500-fold more potent as an agonist on ER alpha than on ER beta. This work illustrates that ER ligands having simple amide core structures can be readily prepared, but that high affinity binding requires an appropriate distribution of bulk, polarity, and functionality. The strong conformational preference of the core anilide function in all of these ligands defines a rather rigid geometry for further structural and functional expansion of these series. (C) 2000 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(00)00075-4