sodium;[4-(4-oxo-3H-quinazolin-2-yl)phenyl] sulfate | 1427578-74-2

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 有机硫酸及其衍生物
• 英文名称: sodium;[4-(4-oxo-3H-quinazolin-2-yl)phenyl] sulfate
• CAS: 1427578-74-2
• 化学式: C₁₄H₉N₂O₅S*Na
• 分子量: 340.292
• InChiKey: SKECNAFRYHASNA-UHFFFAOYSA-M

计算性质

• 辛醇/水分配系数(LogP)：
  -1.57
• 重原子数：
  23
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  116
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  对羟基苯甲醛 在 sodium hydrogen sulfate 、 三甲基铵三氧化硫共聚物 、 三乙胺 作用下， 以 N,N-二甲基乙酰胺 、 乙腈 为溶剂， 反应 12.5h， 生成 sodium;[4-(4-oxo-3H-quinazolin-2-yl)phenyl] sulfate
  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

• Studies on fragment-based design of allosteric inhibitors of human factor XIa
  作者：Rio S. Boothello、Nehru Viji Sankaranarayanan、Daniel K. Afosah、Rajesh Karuturi、Rami A. Al-Horani、Umesh R. Desai

  DOI：10.1016/j.bmc.2020.115762

  日期：2020.12

  Human factor XIa (hFXIa) has emerged as an attractive target for development of new anticoagulants that promise higher level of safety. Different strategies have been adopted so far for the design of anti-hFXIa molecules including competitive and non-competitive inhibition. Of these, allosteric dysfunction of hFXIa's active site is especially promising because of the possibility of controlled reduction in activity that may offer a route to safer anticoagulants. In this work, we assess fragment-based design approach to realize a group of novel allosteric hFXIa inhibitors. Starting with our earlier discovery that sulfated quinazolinone (QAO) bind in the heparin-binding site of hFXIa, we developed a group of two dozen dimeric sulfated QAOs with intervening linkers that displayed a progressive variation in inhibition potency. In direct opposition to the traditional wisdom, increasing linker flexibility led to higher potency, which could be explained by computational studies. Sulfated QAO 19S was identified as the most potent and selective inhibitor of hFXIa. Enzyme inhibition studies revealed that 19S utilizes a non-competitive mechanism of action, which was supported by fluorescence studies showing a classic sigmoidal binding profile. Studies with selected mutants of hFXIa indicated that sulfated QAOs bind in heparin-binding site of the catalytic domain of hFXIa. Overall, the approach of fragment-based design offers considerable promise for designing heparin-binding site-directed allosteric inhibitors of hFXIa.