title: Anticoagulant and antithrombotic evaluation of native fucosylated chondroitin sulfates and their derivatives as selective inhibitors of intrinsic factor Xase.
abstract: Fucosylated chondroitin sulfate (FCS), a structurally unusual glycosaminoglycan, has distinct anticoagulant properties, and is an especially strong inhibitor of the intrinsic factor Xase (anti-Xase). To obtain a highly selective inhibitor of human Xase, we purified six native FCSs with various sulfation patterns, prepared a series of FCS derivatives, and then elucidated the relationship between the structures and the anticoagulant activities of FCSs. FCSs 1-3 containing higher Fuc2S4S exhibit stronger AT-dependent anti-IIa activities, whereas 4-6 containing more Fuc3S4S produce potent HCII-dependent anti-IIa activities. Saccharides containing a minimum of 6-8 trisaccharide units, free carboxyl groups, and full fucosylation of GlcA may be required for potent anti-Xase activity, and approximately six trisaccharide units and partial fucosylation of GlcA may contribute to potent HCII-dependent activity. Decreasing of the molecular weights markedly reduces their AT-dependent anti-IIa activities, and even eliminates human platelet and factor XII activation. Furthermore, in vitro and in vivo studies suggested that fractions of 6-12 kDa may be very promising compounds as putative selective intrinsic Xase inhibitors with antithrombotic action, but without the consequences of major bleeding and factor XII activation.
authors.affiliation: State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China.
authors.forename: Mingyi
authors.initials: M
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China; School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Dandan
authors.initials: D
authors.lastname: Wen
authors.affiliation: State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China.
authors.forename: Na
authors.initials: N
authors.lastname: Gao
authors.affiliation: State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China; College of Life Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Chuang
authors.initials: C
authors.lastname: Xiao
authors.affiliation: State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China.
authors.forename: Lian
authors.initials: L
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China.
authors.forename: Li
authors.initials: L
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China; College of Life Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Wu
authors.initials: W
authors.lastname: Lian
authors.affiliation: College of Life Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Wenlie
authors.initials: W
authors.lastname: Peng
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China. Electronic address: lssjjm@mail.sysu.edu.cn.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Jiang
authors.affiliation: State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China. Electronic address: zhao.jinhua@yahoo.com.
authors.forename: Jinhua
authors.initials: J
authors.lastname: Zhao
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001777:Blood Coagulation / Q000187:drug effects; D002809:Chondroitin Sulfates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005174:Factor XII / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005343:Fibrinolytic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008815:Mice, Inbred Strains; D008968:Molecular Conformation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013927:Thrombosis / Q000188:drug therapy
chemical_list: D000925:Anticoagulants; D004791:Enzyme Inhibitors; D005343:Fibrinolytic Agents; D005174:Factor XII; D002809:Chondroitin Sulfates; D003546:Cysteine Endopeptidases
keywords: Anticoagulant; Antithrombotic; Factor Xase inhibitor; Fucosylated chondroitin sulfate; Structure–activity relationship