Ethyl 2-(bromomethyl)-5-[tert-butyl(dimethyl)silyl]oxy-6-methoxy-1-benzofuran-3-carboxylate | 1318263-93-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并呋喃
• 英文名称: Ethyl 2-(bromomethyl)-5-[tert-butyl(dimethyl)silyl]oxy-6-methoxy-1-benzofuran-3-carboxylate
• CAS: 1318263-93-2
• 化学式: C₁₉H₂₇BrO₅Si
• 分子量: 443.41
• InChiKey: KCTVRZAXWGTRDN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.9
• 重原子数：
  26
• 可旋转键数：
  8
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  57.9
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  Ethyl 2-(bromomethyl)-5-[tert-butyl(dimethyl)silyl]oxy-6-methoxy-1-benzofuran-3-carboxylate 在 potassium fluoride 、 caesium carbonate 、 溶剂黄146 、 N,N-二甲基甲酰胺 作用下， 以 乙酸乙酯 、 N,N-二甲基甲酰胺 为溶剂， 反应 35.0h， 生成 allyl 5-((5-((5-((tert-butyldimethylsilyl)oxy)-3-(ethoxycarbonyl)-6-methoxybenzofuran-2-yl)methoxy)-3-(ethoxycarbonyl)-6-methoxybenzofuran-2-yl)methoxy)-6-methoxy-2-methylbenzofuran-3-carboxylate
  参考文献：
  名称：

  Designing Allosteric Regulators of Thrombin. Exosite 2 Features Multiple Subsites That Can Be Targeted by Sulfated Small Molecules for Inducing Inhibition

  摘要：

  We recently designed a group of novel exosite-2-directed sulfated, small, allosteric inhibitors of thrombin. To develop more potent inhibitors, monosulfated benzofuran tri- and tetrameric homologues of the parent designed dimers were synthesized in seven to eight steps and found to exhibit a wide range of potencies. Among these, trimer 9a was found to be nearly 10-fold more potent than the first generation molecules. Michaelis-Menten studies indicated an allosteric mechanism of inhibition. Competitive studies using a hirudin peptide (exosite 1 ligand) and unfractionated heparin, heparin octasaccharide, and gamma'-fibrinogen peptide (exosite 2 ligands) demonstrated exosite 2 recognition in a manner different from that of the parent dimers. Alanine scanning mutagenesis of 12 Arg/Lys residues of exosite 2 revealed a defect in 9a potency for Arg233Ala thrombin only confirming the major difference in site of recognition between the two structurally related sulfated benzofurans. The results suggest that multiple avenues are available within exosite 2 for inducing thrombin inhibition.

  DOI：

  10.1021/jm400369q
• 作为产物：
  描述：

  5-hydroxy-6-methoxy-2-methyl-benzofuran-3-carboxylic acid ethyl ester 在 咪唑 、 N-溴代丁二酰亚胺(NBS) 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 17.0h， 生成 Ethyl 2-(bromomethyl)-5-[tert-butyl(dimethyl)silyl]oxy-6-methoxy-1-benzofuran-3-carboxylate
  参考文献：
  名称：

  Rational Design of Potent, Small, Synthetic Allosteric Inhibitors of Thrombin

  摘要：

  Thrombin is a key enzyme targeted by the majority of current anticoagulants that are direct inhibitors. Allosteric inhibition of thrombin may. offer a major advantage of finely tuned regulation. We present here sulfated benzofurans as the first examples of potent, small allosteric inhibitors of thrombin. A sulfated benzofuran library of 15 sulfated monomers and 13 sulfated dimers with different charged, polar, and hydrophobic substituents was studied in this work. Synthesis of the sulfated benzofurans was achieved through a multiple step, highly branched strategy, which culminated with microwave-assisted chemical sulfation. Of the 28 potential inhibitors, 11 exhibited reasonable inhibition of human a.-thrombin at pH 7.4. Structure-activity relationship analysis indicated that sulfation at the 5-position of the benzofuran scaffold was essential for targeting thrombin. A tert-butyl 5-sulfated benzofuran derivative was found to be the most potent thrombin inhibitor with an IC50 of 7.3 mu M under physiologically relevant conditions. Michaelis-Menten studies showed an allosteric inhibition phenomenon. Plasma clotting assays indicate that the sulfated benzofurans prolong both the activated partial thromboplastin time and prothrombin time. Overall, this work puts forward sulfated benzofurans as the first small, synthetic molecules as powerful lead compounds for the design of a new class of allosteric inhibitors of thrombin.

  DOI：

  10.1021/jm2005767

文献信息

• Rational Design of Potent, Small, Synthetic Allosteric Inhibitors of Thrombin
  作者：Preetpal Singh Sidhu、Aiye Liang、Akul Y. Mehta、May H. Abdel Aziz、Qibing Zhou、Umesh R. Desai

  DOI：10.1021/jm2005767

  日期：2011.8.11

  Thrombin is a key enzyme targeted by the majority of current anticoagulants that are direct inhibitors. Allosteric inhibition of thrombin may. offer a major advantage of finely tuned regulation. We present here sulfated benzofurans as the first examples of potent, small allosteric inhibitors of thrombin. A sulfated benzofuran library of 15 sulfated monomers and 13 sulfated dimers with different charged, polar, and hydrophobic substituents was studied in this work. Synthesis of the sulfated benzofurans was achieved through a multiple step, highly branched strategy, which culminated with microwave-assisted chemical sulfation. Of the 28 potential inhibitors, 11 exhibited reasonable inhibition of human a.-thrombin at pH 7.4. Structure-activity relationship analysis indicated that sulfation at the 5-position of the benzofuran scaffold was essential for targeting thrombin. A tert-butyl 5-sulfated benzofuran derivative was found to be the most potent thrombin inhibitor with an IC50 of 7.3 mu M under physiologically relevant conditions. Michaelis-Menten studies showed an allosteric inhibition phenomenon. Plasma clotting assays indicate that the sulfated benzofurans prolong both the activated partial thromboplastin time and prothrombin time. Overall, this work puts forward sulfated benzofurans as the first small, synthetic molecules as powerful lead compounds for the design of a new class of allosteric inhibitors of thrombin.
• A small group of sulfated benzofurans induces steady-state submaximal inhibition of thrombin
  作者：Daniel K. Afosah、Stephen Verespy、Rami A. Al-Horani、Rio S. Boothello、Rajesh Karuturi、Umesh R. Desai

  DOI：10.1016/j.bmcl.2018.01.069

  日期：2018.4

  Despite the development of promising direct oral anticoagulants, which are all orthosteric inhibitors, a sizable number of patients suffer from bleeding complications. We have hypothesized that allosterism based on the heparin-binding exosites presents a major opportunity to induce sub-maximal inhibition of coagulation proteases, thereby avoiding/reducing bleeding risk. We present the design of a group of sulfated benzofuran dimers that display heparin-binding site-dependent partial allosteric inhibition of thrombin against fibrinogen (Delta Y = 55-75%), the first time that a small molecule (MW < 800) has been found to thwart macromolecular cleavage by a monomeric protease in a controlled manner. The work leads to the promising concept that it should be possible to develop allosteric inhibitors that reduce clotting, but do not completely eliminate it, thereby avoiding major bleeding complications that beset anti-coagulants today. (C) 2018 Elsevier Ltd. All rights reserved.
• Designing Allosteric Regulators of Thrombin. Exosite 2 Features Multiple Subsites That Can Be Targeted by Sulfated Small Molecules for Inducing Inhibition
  作者：Preetpal Singh Sidhu、May H. Abdel Aziz、Aurijit Sarkar、Akul Y. Mehta、Qibing Zhou、Umesh R. Desai

  DOI：10.1021/jm400369q

  日期：2013.6.27

  We recently designed a group of novel exosite-2-directed sulfated, small, allosteric inhibitors of thrombin. To develop more potent inhibitors, monosulfated benzofuran tri- and tetrameric homologues of the parent designed dimers were synthesized in seven to eight steps and found to exhibit a wide range of potencies. Among these, trimer 9a was found to be nearly 10-fold more potent than the first generation molecules. Michaelis-Menten studies indicated an allosteric mechanism of inhibition. Competitive studies using a hirudin peptide (exosite 1 ligand) and unfractionated heparin, heparin octasaccharide, and gamma'-fibrinogen peptide (exosite 2 ligands) demonstrated exosite 2 recognition in a manner different from that of the parent dimers. Alanine scanning mutagenesis of 12 Arg/Lys residues of exosite 2 revealed a defect in 9a potency for Arg233Ala thrombin only confirming the major difference in site of recognition between the two structurally related sulfated benzofurans. The results suggest that multiple avenues are available within exosite 2 for inducing thrombin inhibition.