Henry Brian L, Thakkar Jay N, Martin Erika J, Brophy Donald F, Desai Umesh R
Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, Virginia, USA.
Blood Coagul Fibrinolysis. 2009 Jan;20(1):27-34. doi: 10.1097/MBC.0b013e328304e077.
Recently, we designed sulfated dehydropolymers (DHPs) of 4-hydroxycinnamic acids that displayed interesting anticoagulant properties. Structurally and mechanistically, sulfated DHPs are radically different from all the anticoagulants studied to date. To assess whether their unique mechanism and structure is worth exploiting for further rational design of homogeneous DHP-based molecules, we investigated their anticoagulant potential in human plasma and blood using a range of clotting assays. Sulfated DHPs prolong plasma clotting times, prothrombin and activated partial thromboplastin times at concentrations comparable to the clinically used low-molecular-weight heparin, enoxaparin. Fibrin formation studies on human plasma show that there is a structural dependence of anticoagulant action. Human whole blood studies using thromboelastography and hemostasis analysis system indicate that they are 17-140-fold less potent than enoxaparin. These results demonstrate that sulfated DHPs possess good in-vitro and ex-vivo activity, which will likely be improved through a rational design.
最近，我们设计了4-羟基肉桂酸的硫酸化脱聚合物（DHP），其表现出有趣的抗凝血特性。在结构和作用机制上，硫酸化DHP与迄今为止研究的所有抗凝血剂截然不同。为了评估其独特的机制和结构是否值得用于基于DHP的均相分子的进一步合理设计，我们使用一系列凝血试验研究了它们在人血浆和血液中的抗凝血潜力。硫酸化DHP在与临床使用的低分子量肝素依诺肝素相当的浓度下延长血浆凝血时间、凝血酶原时间和活化部分凝血活酶时间。对人血浆的纤维蛋白形成研究表明，抗凝血作用存在结构依赖性。使用血栓弹力图和止血分析系统对人全血进行的研究表明，它们的效力比依诺肝素低17至140倍。这些结果表明，硫酸化DHP具有良好的体外和体内活性，通过合理设计可能会得到改善。
