2-(3,5-Dihydroxyphenyl)-3-[4-[4-[[2-(3,5-dihydroxyphenyl)-4-oxoquinazolin-3-yl]methyl]triazol-1-yl]butyl]quinazolin-4-one | 1427579-46-1

• 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: 2-(3,5-Dihydroxyphenyl)-3-[4-[4-[[2-(3,5-dihydroxyphenyl)-4-oxoquinazolin-3-yl]methyl]triazol-1-yl]butyl]quinazolin-4-one
• 英文别名: 2-(3,5-dihydroxyphenyl)-3-[4-[4-[[2-(3,5-dihydroxyphenyl)-4-oxoquinazolin-3-yl]methyl]triazol-1-yl]butyl]quinazolin-4-one
• CAS: 1427579-46-1
• 化学式: C₃₅H₂₉N₇O₆
• 分子量: 643.659
• InChiKey: LSNUFLXCZVDUTQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  48
• 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：
  177
• 氢给体数：
  4
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  2-(3,5-Dihydroxyphenyl)-3-[4-[4-[[2-(3,5-dihydroxyphenyl)-4-oxoquinazolin-3-yl]methyl]triazol-1-yl]butyl]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 2-(3,5-Dihydroxyphenyl)-3-[4-[4-[[2-(3,5-dihydroxyphenyl)-4-oxoquinazolin-3-yl]methyl]triazol-1-yl]butyl]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

• [EN] ALLOSTERIC MODULATORS OF FACTOR XIa AS ANTICOAGULANT AGENTS<br/>[FR] MODULATEURS ALLOSTÉRIQUES DE FACTEUR XIA EN TANT QU'AGENTS ANTICOAGULANTS
  申请人：UNIV VIRGINIA COMMONWEALTH

  公开号：WO2014075045A1

  公开（公告）日：2014-05-15

  Compounds which allosterically modulate and/or inhibit factor XIa activity are provided, as are methods of their use. These compounds include i) sulfated gallolyl glucosides, ii) sulfated quinazolinones, and iii) sulfated inositol analogs. The compounds used as anticoagulant agents.

  提供了能够以别构调节和/或抑制XIa因子活性的化合物，以及它们的使用方法。这些化合物包括i) 硫酸酯化没食子醇葡萄糖苷，ii) 硫酸酯化喹唑啉酮，和iii) 硫酸酯化肌醇类似物。这些化合物被用作抗凝剂。
• ALLOSTERIC MODULATORS OF FACTOR XIa AS ANTICOAGULANT AGENTS
  申请人：VIRGINIA COMMONWEALTH UNIVERSITY

  公开号：US20160311842A1

  公开（公告）日：2016-10-27

  Compounds which allosterically modulate and/or inhibit factor XIa activity are provided, as are methods of their use. These compounds include i) sulfated gallolyl glucosides, ii) sulfated quinazolinones, and iii) sulfated inositol analogs. The compounds used as anticoagulant agents.
• US9758459B2
  申请人：——

  公开号：US9758459B2

  公开（公告）日：2017-09-12
• 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.