(-)-epicatechin sulfate

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 黄酮类化合物
• 英文名称: (-)-epicatechin sulfate
• 英文别名: [(2R,3R)-2-(3,4-disulfooxyphenyl)-3,5-disulfooxy-3,4-dihydro-2H-chromen-7-yl] hydrogen sulfate
• 化学式: C₁₅H₁₄O₂₁S₅
• 分子量: 690.594
• InChiKey: DUBGYLQUPCECLW-HUUCEWRRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -1.3
• 重原子数：
  41
• 可旋转键数：
  11
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  369
• 氢给体数：
  5
• 氢受体数：
  21

反应信息

• 作为产物：
  描述：

  表儿茶素 在 三氧化硫-三乙胺复合物 作用下， 以 N,N-二甲基乙酰胺 为溶剂， 反应 3.0h， 生成 (-)-epicatechin sulfate
  参考文献：
  名称：

  Exploring new non-sugar sulfated molecules as activators of antithrombin

  摘要：

  New non-sugar, small. sulfated molecules. based on our de novo rationally designed activator (-)-epicatechin sulfate (ECS), were investigated to bind and activate antithrombin, an inhibitor of plasma coagulation enzyme factor Xa, For the activators studied, the equilibrium dissociation constant (K-D) of the interaction,with plasma antithrombin varies nearly 53-fold, with the highest affinity of 1.8 muM observed for morin sulfate, while the acceleration in factor Xa inhibition varies 2.6-fold. The results demonstrate Lit antithrombin binding and activation is a common property of these small sulfated molecules and suggests plausible directions for designing more potent activators. (C) 2003 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0960-894x(02)01055-7

文献信息

• Interaction of Designed Sulfated Flavanoids with Antithrombin:  Lessons on the Design of Organic Activators
  作者：Gunnar T. Gunnarsson、Umesh R. Desai

  DOI：10.1021/jm020132y

  日期：2002.9.1

  Recently, we designed (-)-epicatechin sulfate (ECS), the first small nonsaccharide molecule, as an activator of antithrombin for the accelerated inhibition of factor Xa, a key proteinase of the coagulation cascade (Gunnarsson, G. T.; Desai, U. R. J. Med. Chem. 2002,45, 1233-1243). Although sulfated flavanoid ECS was found to bind antithrombin with an affinity (similar to10.7 muM) comparable to the reference trisaccharide DEF (similar to4.5 muM), it accelerated the inhibition of factor Xa only 10-fold as compared to the similar to300-fold observed with DEF. To determine whether this conformational activation of the inhibitor is dependent on the structure of the organic activator and to probe the basis for the deficiency in activation, we studied the interaction of similar sulfated flavanoids with antithrombin. (+)-Catechin sulfate (CS), a chiral stereoisomer of ECS, bound plasma antithrombin with a 3-fold higher affinity (K-D = 3.5 muM) and a 2-fold higher second-order rate constant for factor Xa inhibition (k(ACT) = 6750 M-1 s(-1)). On the contrary, the K-D and k(ACT) were found to be lower similar to7.4- and similar to2.4-fold, respectively, for its racemic counterpart, (+/-)-catechin sulfate. Dependence of the equilibrium dissociation constant on the ionic strength of the medium at pH 6.0 and 7.4 suggests that nonionic interactions contribute a major proportion (similar to55-73%) of the total binding energy, and only 1-2 ion pairs, in comparison to the expected similar to4 ion pairs for the reference trisaccharide, are formed in the interaction. Competitive binding experiments indicate that activator CS does not compete with a saccharide ligand that binds antithrombin in the pentasaccharide binding site, while it competes with full-length low-affinity heparin. A molecular docking study suggests plausible binding of CS in the extended heparin binding site, which is adjacent to the binding domain for the reference trisaccharide DEF. In combination, the results demonstrate that although conformational activation of antithrombin with small sulfated flavanoids is dependent on the structure of the activator, the designed activators do not bind in the pentasaccharide binding site, in antithrombin resulting in weak activation. The mechanistic investigation highlights plausible directions to take in the rational design of specific high-affinity organic antithrombin activators.
• Designing Small, Nonsugar Activators of Antithrombin Using Hydropathic Interaction Analyses
  作者：Gunnar T. Gunnarsson、Umesh R. Desai

  DOI：10.1021/jm020012q

  日期：2002.3.1

  Conformational activation of antithrombin is a critical mechanism for the inhibition of factor Xa, a proteinase of the blood coagulation cascade, and is typically achieved with heparin, a polyanionic polysaccharide clinically used for anticoagulation. Although numerous efforts have been directed toward the design of better activators, a fundamental tenet of these studies has been the assumed requirement of an oligo- or a polysaccharide backbone. We demonstrate here a concept that small nonsaccharidic nonpolymeric molecules may be rationally designed to interact with and activate antithrombin for enhanced inhibition of factor Xa. The rational design strategy is based on a study of complexes of natural and mutant antithrombins with heparin-based oligosaccharides using hydropathic interaction (HINT) technique, a quantitative computerized tool for analysis of molecular interactions. A linear correlation was observed between the free energy of binding for antithrombin-oligosaccharide complexes and the HINT score over a wide range of similar to13 kcal/mol, indicating strong predictive capability of the HINT technique. Using this approach, a small, nonsugar, aromatic molecule, (-)-epicatechin sulfate (ECS), was designed to mimic the nonreducing end trisaccharide unit DEF of the sequence specific heparin pentasaccharide DEFGH. HINT suggested a comparable antithrombin-binding geometry and interaction profile for ECS and trisaccharide DEF. Biochemical studies indicated that ECS binds antithrombin with equilibrium dissociation constants of 10.5 and 66 muM at pH 6.0,I0.025, and pH 7.4,I0.035, respectively, that compare favorably with 2 and 80 muM observed for the natural activator DEF ECS accelerates the antithrombin inhibition of factor Xa nearly 8-fold demonstrating for the first time that conformational activation of antithrombin is feasible with appropriately designed small nonsugar organic molecules. The results present unique opportunities for de novo activator design based on this first-generation lead.