2-(3-chlorophenyl)-1-(4-acetamido-2,6-dimethoxyphenyl)ethanone

• 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: 2-(3-chlorophenyl)-1-(4-acetamido-2,6-dimethoxyphenyl)ethanone
• 英文别名: N-[4-[2-(3-chlorophenyl)acetyl]-3,5-dimethoxyphenyl]acetamide
• 化学式: C₁₈H₁₈ClNO₄
• 分子量: 347.798
• InChiKey: UYLCAHKEMBJOEZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  24
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  64.6
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  N-(3,5-二甲氧基苯基)乙酰胺 、 (3-氯苯基)乙酰氯 在 四氯化锡 作用下， 以 1,2-二氯乙烷 为溶剂， 反应 3.0h， 以65%的产率得到2-(3-chlorophenyl)-1-(6-acetamido-2,4-dimethoxyphenyl)ethanone
  参考文献：
  名称：

  Use of a Pharmacophore Model for the Design of EGFR Tyrosine Kinase Inhibitors:  Isoflavones and 3-Phenyl-4(1H)-quinolones

  摘要：

  Using a pharmacophore model for ATP-competitive inhibitors interacting with the active site of the EGFR protein tyrosine kinase together with published X-ray crystal data of quercetin (2) in complex with the lick tyrosine kinase and of deschloroflavopiridol (3b) in complex with CDK2, a putative binding mode of the isoflavone genistein (1) was proposed. Then, based on literature data suggesting that a salicylic acid function, which is represented by the 5-hydroxy-4-keto motif in I, could serve as a pharmacophore replacement of a pyrimidine ring, superposition of 1 onto the potent EGFR tyrosine kinase inhibitor 4-(3'-chlorophenylamino)-6,7-dimethoxyquinazoline (4) led to 3'-chloro-5,7-clibydroxyisoflavone (fi) as a target structure which in fact was 10 times more potent than 1. The putative binding mode of 6 suggests a sulfur-aromatic interaction of the m-chlorophenyl moiety with Cys 773 in the "sugar pocket" of the EGFR kinase model. Replacement of the oxygen in the chromenone ring of 6 by a nitrogen atom further improved the inhibitory activity against the EGFR kinase. With IC50 values of 38 and 8 nM, respectively, the quinolones 11 and 12 were the most potent compounds of the series. N-Alkylation of II did not further improve enzyme inhibitory activity but; led to derivatives with cellular activity in the lower micromolar range.

  DOI：

  10.1021/jm980551o

文献信息

• Use of a Pharmacophore Model for the Design of EGFR Tyrosine Kinase Inhibitors:  Isoflavones and 3-Phenyl-4(1<i>H</i>)-quinolones
  作者：Peter Traxler、Jennifer Green、Helmut Mett、Urs Séquin、Pascal Furet

  DOI：10.1021/jm980551o

  日期：1999.3.1

  Using a pharmacophore model for ATP-competitive inhibitors interacting with the active site of the EGFR protein tyrosine kinase together with published X-ray crystal data of quercetin (2) in complex with the lick tyrosine kinase and of deschloroflavopiridol (3b) in complex with CDK2, a putative binding mode of the isoflavone genistein (1) was proposed. Then, based on literature data suggesting that a salicylic acid function, which is represented by the 5-hydroxy-4-keto motif in I, could serve as a pharmacophore replacement of a pyrimidine ring, superposition of 1 onto the potent EGFR tyrosine kinase inhibitor 4-(3'-chlorophenylamino)-6,7-dimethoxyquinazoline (4) led to 3'-chloro-5,7-clibydroxyisoflavone (fi) as a target structure which in fact was 10 times more potent than 1. The putative binding mode of 6 suggests a sulfur-aromatic interaction of the m-chlorophenyl moiety with Cys 773 in the "sugar pocket" of the EGFR kinase model. Replacement of the oxygen in the chromenone ring of 6 by a nitrogen atom further improved the inhibitory activity against the EGFR kinase. With IC50 values of 38 and 8 nM, respectively, the quinolones 11 and 12 were the most potent compounds of the series. N-Alkylation of II did not further improve enzyme inhibitory activity but; led to derivatives with cellular activity in the lower micromolar range.