5-[(3-bromophenyl)amino]-3-[(N,N-bis(2-hydroxyethyl)amino)methyl]pyrrolo[3,2-g]quinazoline

• 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: 5-[(3-bromophenyl)amino]-3-[(N,N-bis(2-hydroxyethyl)amino)methyl]pyrrolo[3,2-g]quinazoline
• 英文别名: Pyrroloquinazoline deriv. 4；2-[[4-(3-bromoanilino)-8H-pyrrolo[3,2-g]quinazolin-6-yl]methyl-(2-hydroxyethyl)amino]ethanol
• 化学式: C₂₁H₂₂BrN₅O₂
• 分子量: 456.342
• InChiKey: OSXILVFPMQVTSK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  29
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  97.3
• 氢给体数：
  4
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  聚合甲醛 、 二乙醇胺 、 N-(3-bromophenyl)-8H-pyrrolo[3,2-g]quinazolin-4-amine 以 水 为溶剂， 反应 3.0h， 以18%的产率得到5-[(3-bromophenyl)amino]-3-[(N,N-bis(2-hydroxyethyl)amino)methyl]pyrrolo[3,2-g]quinazoline
  参考文献：
  名称：

  Tyrosine Kinase Inhibitors. 11. Soluble Analogues of Pyrrolo- and Pyrazoloquinazolines as Epidermal Growth Factor Receptor Inhibitors:  Synthesis, Biological Evaluation, and Modeling of the Mode of Binding

  摘要：

  A new route to N-1-substituted pyrazolo- and pyrroloquinazolines has been developed from the known quinazolones 19 and 23, via conversion to the corresponding thiones, S-methylation to the thioethers, N-1-alkylation, and coupling with 3-bromoaniline. C-S-Substituted pyrroloquinazolines were prepared by Mannich base chemistry. A series of compounds bearing solubilizing side chains at these positions has been prepared and evaluated for inhibition of the tyrosine kinase activity of the isolated epidermal growth factor receptor (EGFR) and of its autophosphorylation in EGF-stimulated A431 cells. Several analogues, particularly C-3-substituted pyrroloquinazolines, retained high potency in both assays. A model for the binding of the general class of 4-anilinoquinazolines to the EGFR was constructed from structural information (particularly for the catalytic subunit of the cAMP-dependent protein kinase) and structure-activity relationships (SAR) in the series. In this model, the pyrrole ring in pyrroloquinazolines (and the 6- and 7-positions of quinazoline and related pyridopyrimidine inhibitors) occupies the entrance of the ATP binding pocket of the enzyme, with the pyrrole nitrogen located at the bottom of the cleft and the pyrrole C-3 position pointing toward a pocket corresponding to the ribose binding site of ATP. This allows considerable bulk tolerance for C-3 substituents and lesser but still significant bulk tolerance for N-1 substituents. The observed high selectivity of these compounds for binding to EGFR over other similar tyrosine kinases is attributed to the 4-anilino ring binding in an adjacent hydrophobic pocket which has an amino acid composition unique to the EGFR. The SAR seen for inhibition of the isolated enzyme by the pyrazolo- and pyrroloquinazolines discussed here is fully consistent with this binding model. For the N-1-substituted compounds, inhibition of autophosphorylation in A431 cells correlates well with inhibition of the isolated enzyme, as seen previously for related pyridopyrimidines. However, the C-S-substituted pyrroloquinazolines show unexpectedly high potencies in the autophosphorylation assay, making them of particular interest.

  DOI：

  10.1021/jm960789h

文献信息

• Tyrosine Kinase Inhibitors. 11. Soluble Analogues of Pyrrolo- and Pyrazoloquinazolines as Epidermal Growth Factor Receptor Inhibitors:  Synthesis, Biological Evaluation, and Modeling of the Mode of Binding
  作者：Brian D. Palmer、Susanne Trumpp-Kallmeyer、David W. Fry、James M. Nelson、H. D. Hollis Showalter、William A. Denny

  DOI：10.1021/jm960789h

  日期：1997.5.1

  A new route to N-1-substituted pyrazolo- and pyrroloquinazolines has been developed from the known quinazolones 19 and 23, via conversion to the corresponding thiones, S-methylation to the thioethers, N-1-alkylation, and coupling with 3-bromoaniline. C-S-Substituted pyrroloquinazolines were prepared by Mannich base chemistry. A series of compounds bearing solubilizing side chains at these positions has been prepared and evaluated for inhibition of the tyrosine kinase activity of the isolated epidermal growth factor receptor (EGFR) and of its autophosphorylation in EGF-stimulated A431 cells. Several analogues, particularly C-3-substituted pyrroloquinazolines, retained high potency in both assays. A model for the binding of the general class of 4-anilinoquinazolines to the EGFR was constructed from structural information (particularly for the catalytic subunit of the cAMP-dependent protein kinase) and structure-activity relationships (SAR) in the series. In this model, the pyrrole ring in pyrroloquinazolines (and the 6- and 7-positions of quinazoline and related pyridopyrimidine inhibitors) occupies the entrance of the ATP binding pocket of the enzyme, with the pyrrole nitrogen located at the bottom of the cleft and the pyrrole C-3 position pointing toward a pocket corresponding to the ribose binding site of ATP. This allows considerable bulk tolerance for C-3 substituents and lesser but still significant bulk tolerance for N-1 substituents. The observed high selectivity of these compounds for binding to EGFR over other similar tyrosine kinases is attributed to the 4-anilino ring binding in an adjacent hydrophobic pocket which has an amino acid composition unique to the EGFR. The SAR seen for inhibition of the isolated enzyme by the pyrazolo- and pyrroloquinazolines discussed here is fully consistent with this binding model. For the N-1-substituted compounds, inhibition of autophosphorylation in A431 cells correlates well with inhibition of the isolated enzyme, as seen previously for related pyridopyrimidines. However, the C-S-substituted pyrroloquinazolines show unexpectedly high potencies in the autophosphorylation assay, making them of particular interest.