Comprehensive synthesis and anticoagulant evaluation of a diverse fucoidan library
Si‐Cong Chen, Xianjin Qin, Nanyu Xiong, Lisha Lin, Yanfen Wu, Qin Li, Dongyue Sun, De‐Cai Xiong, Cassandra E. Callmann, Mingyi Wu, Xin‐Shan Ye
Abstract
Fucoidan, a sulfated glycan derived from brown algae, has garnered significant attention for its anticoagulant properties. However, the structural complexity and heterogeneity of naturally extracted fucoidan have hindered a comprehensive understanding of its structure-activity relationship, limiting the development of fucoidan-based anticoagulant drugs. To address this challenge, we synthesize a diverse library of 58 distinct fucoidans with multiple contiguous 1,2-cis glycosidic bonds, ranging from disaccharides to dodecasaccharides, using a highly efficient preactivation-based one-pot glycosylation strategy. This library includes compounds with various sulfation patterns (2,3-O-di-, 3,4-O-di-, and 2,3,4-O-tri-sulfation) encompassing nearly all possible fucoidan structures. In vitro anticoagulant assays demonstrate that both molecular size and degree of sulfation play crucial roles in anticoagulant potency. Notably, compounds 29, 30, 37, and 58 significantly prolong human plasma activated partial thromboplastin time (APTT), comparable to the effect of enoxaparin, without affecting prothrombin time (PT) or thrombin time (TT). This selective inhibition of the intrinsic coagulation pathway suggests a reduced risk of bleeding, highlighting the therapeutic potential of these fucoidans as safer anticoagulant agents. Fucoidan is a sulfated glycan with anticoagulant properties, but its structural complexity and heterogeneity hinders understanding of its structure-activity relationship. Here, the authors synthesize a diverse library of 58 distinct fucoidans with multiple contiguous 1,2-cis glycosidic bonds and various sulfation patterns, and investigate their anticoagulant activity.