Synthesis of Fucosylated Chondroitin Sulfate Glycoclusters: A Robust Route to New Anticoagulant Agents
Synthesis of Fucosylated Chondroitin Sulfate Glycoclusters: A Robust Route to New Anticoagulant Agents
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岩藻糖基化硫酸软骨素糖簇的合成：新型抗凝剂的稳健途径
DOI：
10.1002/chem.201705177
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Zhongjun Li
中科院分区：
文献类型：
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作者：
Xiao Zhang;Zhongjun Li
岩藻糖基化硫酸软骨素（FuCS）是一种结构独特的糖胺聚糖，具有良好的抗凝活性。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机制，降低了不良反应和出血的风险。然而，由于缺乏结构明确的寡糖，阻碍了进一步的开发。本文报道了一种基于硫酸软骨素聚合物降解的合成FuCS重复三糖单元的简便方法。通过铜催化的炔-叠氮化物环加成反应产生了一系列简化的FuCS糖模拟物，其具有高度可调的结构、可控的分支和确定的硫酸化基序。随着分支的增加，观察到活化部分凝血活酶时间（APTT）测定活性的显著改善，但未观察到凝血酶原时间（PT）和凝血酶时间（TT）测定活性的显著影响。进一步的FXase抑制试验表明，糖簇33 B-40 b选择性抑制内源性抗凝活性，但对外源性和常见的凝血途径几乎没有影响。值得注意的是，具有2，4-二-O-硫酸化岩藻糖基残基的糖簇显示出最大的效力，这与天然多糖的效力一致。这些FuCS簇表现出模仿线性糖胺聚糖的效力，并为开发新型抗凝剂提供了新的框架。
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 glycoclusters33 b–40 bselectively 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.