Synthesis of Fucosylated Chondroitin Sulfate Glycoclusters: A Robust Route to New Anticoagulant Agents

Fucosylated chondroitin sulfate (FuCS) is a structurally distinct glycosaminoglycan with excellent anticoagulant activity. Studies show that FuCS and its depolymerized fragments exhibit different anticoagulant mechanism from heparin derivatives, with decreased risks of adverse effects and bleeding. However, further exploitation has been hindered by the scarcity of structurally defined oligosaccharides. Herein we report a facile method to synthesize 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 CuAAC. Remarkable improvement in APTT assay activities was observed as the branches increased, while no significant influences were observed for PT and TT assay activities. Further FXase inhibition tests suggested glycoclusters 33b~40b selectively inhibited intrinsic anticoagulant activities while showed little effect on the extrinsic and common coagulation pathways. Notably, glycoclusters bearing 2,4-di-O-sulfated Fuc residue displayed the most potency, which was in consistent with natural polysaccharides. These FuCS clusters demonstrated potency to mimic linear glycosaminoglycans and offer a new framework for the development of novel anticoagulant agents.