Synthesis of Fucosylated Chondroitin Sulfate Glycoclusters: A Robust Route to New Anticoagulant Agents
Zhang, Xiao1; Yao, Wang1; Xu, Xiaojiang1; Sun, Huifang2; Zhao, Jinhua2; Meng, Xiangbao1; Wu, Mingyi2; Li, Zhongjun1
2018-02-01
发表期刊CHEMISTRY-A EUROPEAN JOURNAL
ISSN0947-6539
卷号24期号:7页码:1694-1700
摘要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 33b-40b 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.
关键词Anticoagulants Drug Discovery Glycoconjugates Structure-activity Relationships Synthesis Design
语种英语
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文献类型期刊论文
条目标识符http://ir.kib.ac.cn/handle/151853/60577
专题植物化学与西部植物资源持续利用国家重点实验室
作者单位1.Peking Univ, State Key Lab Nat & Biomimet Drugs, Dept Chem Biol, Sch Pharmaceut Sci, Beijing 100191, Peoples R China
2.Chinese Acad Sci, State Key Lab Phytochem & Plant Resources West Ch, Kunming Inst Bot, Kunming 650201, Yunnan, Peoples R China
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Zhang, Xiao,Yao, Wang,Xu, Xiaojiang,et al. Synthesis of Fucosylated Chondroitin Sulfate Glycoclusters: A Robust Route to New Anticoagulant Agents[J]. CHEMISTRY-A EUROPEAN JOURNAL,2018,24(7):1694-1700.
APA Zhang, Xiao.,Yao, Wang.,Xu, Xiaojiang.,Sun, Huifang.,Zhao, Jinhua.,...&Li, Zhongjun.(2018).Synthesis of Fucosylated Chondroitin Sulfate Glycoclusters: A Robust Route to New Anticoagulant Agents.CHEMISTRY-A EUROPEAN JOURNAL,24(7),1694-1700.
MLA Zhang, Xiao,et al."Synthesis of Fucosylated Chondroitin Sulfate Glycoclusters: A Robust Route to New Anticoagulant Agents".CHEMISTRY-A EUROPEAN JOURNAL 24.7(2018):1694-1700.
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