Synthesis and structure-activity relationships of novel warfarin derivatives
Synthesis and structure-activity relationships of novel warfarin derivatives
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DOI：
10.1016/j.bmc.2007.01.014
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发表时间：
2007-03-15
影响因子：
3.5
通讯作者：
Gebauer, Markus
中科院分区：
文献类型：
--
作者：
Gebauer, Markus
20 多年来，华法林 I 等 4-羟基香豆素类药物一直是口服抗凝治疗的中流砥柱。然而，关于 4-羟基香豆素与维生素 K 环氧化物还原酶 (VKER) 之间分子相互作用的细节知之甚少，抑制该酶会导致维生素 K 缺乏，从而导致参与血栓形成的维生素 K 依赖性蛋白质缺乏。使用分子探针，例如 4-巯基华法林 7 和 4-氯华法林 10，体外显示华法林对 VKER 的抑制依赖于 4-羟基香豆素部分的去质子化。此外，4-羟基香豆素的碳3上的取代基的性质调节抑制作用。更具体地说，与华法林中存在的环状取代基相比，线性异戊二烯基侧链增加了对 VKER 的抑制。具有异戊二烯基侧链的 4-羟基香豆素的一个例子是源自阿魏的天然产物阿魏醇 19。在此体外测定中，阿魏醇 19 的抑制作用比华法林强 22 倍，比灭鼠剂 brodifacoum 强 1.5 倍。基于这些数据，假设 4-羟基香豆素与 VKER 的活性位点结合，从而模拟从底物 2-羟基维生素 K 中消除水的过渡状态。(c) 2007 Elsevier Ltd. 保留所有权利。
4-Hydroxycoumarins such as warfarin I have been the mainstay of oral anticoagulation therapy for over 20 years. Yet little detail is known about the molecular interactions between 4-hydroxycoumarins with vitamin K epoxide reductase (VKER), inhibition of which produces a deficiency of vitamin K and consequently a deficiency of vitamin K-dependent proteins involved in thrombus formation. Using molecular probes, such as 4-sulfhydrylwarfarin 7 and 4-chlorowarfarin 10 it is shown in vitro that inhibition of VKER by warfarin is dependent on deprotonation of the 4-hydroxycoumarin moiety. In addition, the nature of the substituent on carbon 3 of the 4-hydroxycoumarin modulated inhibition. More specifically, a linear isoprenyl side chain increased inhibition of VKER when compared to cyclical substituents as present in warfarin. An example of a 4-hydroxycoumarin with an isoprenyl side chain is the natural product ferulenol 19 derived from Ferula communis. Ferulenol 19 confers similar to 22 times more potent inhibition than warfarin and is similar to 1.5 more potent than the rodenticide brodifacoum in this in vitro assay. Based on these data it is hypothesized that 4-hydroxycoumarins bind to the active site of VKER thereby mimicking the transition state of the elimination of water from substrate 2-hydroxyvitamin K. (c) 2007 Elsevier Ltd. All rights reserved.