Zhang Xiao, Yao Wang, Xu Xiaojiang, Sun Huifang, Zhao Jinhua, Meng Xiangbao, Wu Mingyi, Li Zhongjun
State Key Laboratory of Natural and Biomimetic Drugs, Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, P.R. China.
State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, P.R. China.
Chemistry. 2018 Feb 1;24(7):1694-1700. doi: 10.1002/chem.201705177. Epub 2017 Dec 28.
Fucosylated chondroitin sulfate (FuCS) is a structurally distinct glycosaminoglycan with excellent anticoagulant activity. Studies show that FuCS and its depolymerized fragments exhibit a different anticoagulant mechanism from that of heparin derivatives, with decreased risks of adverse effects and bleeding. However, further exploitation has been hindered by the scarcity of structurally defined oligosaccharides. Herein, facile method is reported for the synthesis of the repeating trisaccharide unit of FuCS based on the degradation of chondroitin sulfate polymers. A series of simplified FuCS glycomimetics that have highly tunable structures, controllable branches, and defined sulfation motifs were generated by copper-catalyzed alkyne-azide cycloaddition. Remarkable improvement in activated partial thromboplastin time (APTT) assay activities was observed as the branches increased, but no significant influences were observed for prothrombin time (PT) and thrombin time (TT) assay activities. Further FXase inhibition tests suggested that glycoclusters 33 b-40 b selectively inhibited intrinsic anticoagulant activities, but had little effect on the extrinsic and common coagulation pathways. Notably, glycoclusters with the 2,4-di-O-sulfated fucosyl residue displayed the most potency, which was in consistent with that of natural polysaccharides. These FuCS clusters demonstrated potency to mimic linear glycosaminoglycans and offer a new framework for the development of novel anticoagulant agents.
岩藻糖基化硫酸软骨素（FuCS）是一种结构独特的糖胺聚糖，具有出色的抗凝血活性。研究表明，FuCS及其解聚片段表现出与肝素衍生物不同的抗凝血机制，副作用和出血风险降低。然而，由于结构明确的寡糖稀缺，进一步的开发受到了阻碍。本文报道了一种基于硫酸软骨素聚合物降解合成FuCS重复三糖单元的简便方法。通过铜催化的炔基-叠氮环加成反应，生成了一系列结构高度可调、分支可控且硫酸化基序明确的简化FuCS糖模拟物。随着分支增加，活化部分凝血活酶时间（APTT）测定活性有显著提高，但对凝血酶原时间（PT）和凝血酶时间（TT）测定活性没有显著影响。进一步的FXa抑制试验表明，糖簇33b - 40b选择性抑制内源性抗凝血活性，但对外源性和共同凝血途径影响很小。值得注意的是，具有2,4 - 二 - O - 硫酸化岩藻糖基残基的糖簇表现出最强的活性，这与天然多糖一致。这些FuCS簇展示了模拟线性糖胺聚糖的能力，并为新型抗凝血剂的开发提供了新的框架。
