3-[4-[4-[[2-(3,5-Dihydroxyphenyl)-4-oxoquinazolin-3-yl]methyl]triazol-1-yl]butyl]-2-(3-hydroxyphenyl)quinazolin-4-one | 1427579-43-8

• 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: 3-[4-[4-[[2-(3,5-Dihydroxyphenyl)-4-oxoquinazolin-3-yl]methyl]triazol-1-yl]butyl]-2-(3-hydroxyphenyl)quinazolin-4-one
• 英文别名: 3-[4-[4-[[2-(3,5-dihydroxyphenyl)-4-oxoquinazolin-3-yl]methyl]triazol-1-yl]butyl]-2-(3-hydroxyphenyl)quinazolin-4-one
• CAS: 1427579-43-8
• 化学式: C₃₅H₂₉N₇O₅
• 分子量: 627.659
• InChiKey: VSJHPHJIYMKTIF-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  47
• 可旋转键数：
  9
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.14
• 拓扑面积：
  157
• 氢给体数：
  3
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  3-[4-[4-[[2-(3,5-Dihydroxyphenyl)-4-oxoquinazolin-3-yl]methyl]triazol-1-yl]butyl]-2-(3-hydroxyphenyl)quinazolin-4-one 在 三甲基铵三氧化硫共聚物 、 三乙胺 作用下， 以 乙腈 为溶剂， 反应 0.5h， 生成
  参考文献：
  名称：

  Discovery of Allosteric Modulators of Factor XIa by Targeting Hydrophobic Domains Adjacent to Its Heparin-Binding Site

  摘要：

  To discover promising sulfated allosteric modulators (SAMs) of glycosaminoglycan-binding proteins (GBPs), such as human factor XIa (FXIa), we screened a library of 26 synthetic, sulfated quinazolin-4(3H)-ones (QAOs) resulting in the identification of six molecules that reduced the V-max of substrate hydrolysis without influencing the K-M. Mutagenesis of residues of the heparin-binding site (HBS) of FXIa introduced a nearly 5-fold loss in inhibition potency supporting recognition of an allosteric site. Fluorescence studies showed a sigmoidal binding profile indicating highly cooperative binding. Competition with a positively charged, heparin-binding polymer did not fully nullify inhibition suggesting importance of hydrophobic forces to binding. This discovery suggests the operation of a dual-element recognition process, which relies on an initial Coulombic attraction of anionic SAMs to the cationic HBS of FXIa that forms a locked complex through tight interaction with an adjacent hydrophobic patch. The dual-element strategy may be widely applicable for discovering SAMs of other GBPs.

  DOI：

  10.1021/jm301757v
• 作为产物：
  描述：

  3,5-二羟基苯甲醛 在 吡啶 、 sodium hydrogen sulfate 、 copper(ll) sulfate pentahydrate 、 lithium hydroxide monohydrate 、 potassium carbonate 、 sodium ascorbate 作用下， 以 四氢呋喃 、 二氯甲烷 、 N,N-二甲基乙酰胺 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 29.0h， 生成 3-[4-[4-[[2-(3,5-Dihydroxyphenyl)-4-oxoquinazolin-3-yl]methyl]triazol-1-yl]butyl]-2-(3-hydroxyphenyl)quinazolin-4-one
  参考文献：
  名称：

  Discovery of Allosteric Modulators of Factor XIa by Targeting Hydrophobic Domains Adjacent to Its Heparin-Binding Site

  摘要：

  To discover promising sulfated allosteric modulators (SAMs) of glycosaminoglycan-binding proteins (GBPs), such as human factor XIa (FXIa), we screened a library of 26 synthetic, sulfated quinazolin-4(3H)-ones (QAOs) resulting in the identification of six molecules that reduced the V-max of substrate hydrolysis without influencing the K-M. Mutagenesis of residues of the heparin-binding site (HBS) of FXIa introduced a nearly 5-fold loss in inhibition potency supporting recognition of an allosteric site. Fluorescence studies showed a sigmoidal binding profile indicating highly cooperative binding. Competition with a positively charged, heparin-binding polymer did not fully nullify inhibition suggesting importance of hydrophobic forces to binding. This discovery suggests the operation of a dual-element recognition process, which relies on an initial Coulombic attraction of anionic SAMs to the cationic HBS of FXIa that forms a locked complex through tight interaction with an adjacent hydrophobic patch. The dual-element strategy may be widely applicable for discovering SAMs of other GBPs.

  DOI：

  10.1021/jm301757v

文献信息

• Discovery of Allosteric Modulators of Factor XIa by Targeting Hydrophobic Domains Adjacent to Its Heparin-Binding Site
  作者：Rajesh Karuturi、Rami A. Al-Horani、Shrenik C. Mehta、David Gailani、Umesh R. Desai

  DOI：10.1021/jm301757v

  日期：2013.3.28

  To discover promising sulfated allosteric modulators (SAMs) of glycosaminoglycan-binding proteins (GBPs), such as human factor XIa (FXIa), we screened a library of 26 synthetic, sulfated quinazolin-4(3H)-ones (QAOs) resulting in the identification of six molecules that reduced the V-max of substrate hydrolysis without influencing the K-M. Mutagenesis of residues of the heparin-binding site (HBS) of FXIa introduced a nearly 5-fold loss in inhibition potency supporting recognition of an allosteric site. Fluorescence studies showed a sigmoidal binding profile indicating highly cooperative binding. Competition with a positively charged, heparin-binding polymer did not fully nullify inhibition suggesting importance of hydrophobic forces to binding. This discovery suggests the operation of a dual-element recognition process, which relies on an initial Coulombic attraction of anionic SAMs to the cationic HBS of FXIa that forms a locked complex through tight interaction with an adjacent hydrophobic patch. The dual-element strategy may be widely applicable for discovering SAMs of other GBPs.