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Persulfate-driven free radical depolymerization of fucosylated chondroitin sulfate and intrinsic Xase inhibition of the resulting oligosaccharides.

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Title: Persulfate-driven free radical depolymerization of fucosylated chondroitin sulfate and intrinsic Xase inhibition of the resulting oligosaccharides.
Authors: Sun J; School of Pharmaceutical Sciences, South-Central Minzu University, Wuhan, 430074, China., Sha L; School of Pharmaceutical Sciences, South-Central Minzu University, Wuhan, 430074, China., Zhu G; College of Life Sciences, South-Central Minzu University, Wuhan, 430074, China., Li L; School of Pharmaceutical Sciences, South-Central Minzu University, Wuhan, 430074, China., Li P; School of Pharmaceutical Sciences, South-Central Minzu University, Wuhan, 430074, China., Chen M; School of Pharmaceutical Sciences, South-Central Minzu University, Wuhan, 430074, China., Wang J; School of Pharmaceutical Sciences, South-Central Minzu University, Wuhan, 430074, China., Jiao X; School of Pharmaceutical Sciences, South-Central Minzu University, Wuhan, 430074, China., Gao N; School of Pharmaceutical Sciences, South-Central Minzu University, Wuhan, 430074, China. Electronic address: gn2008.happy@163.com., Zhao J; School of Pharmaceutical Sciences, South-Central Minzu University, Wuhan, 430074, China. Electronic address: zhaojhscu@163.com.
Source: Carbohydrate research [Carbohydr Res] 2026 May; Vol. 563, pp. 109844. Date of Electronic Publication: 2026 Jan 29.
Publication Type: Journal Article
Language: English
Journal Info: Publisher: Elsevier Country of Publication: Netherlands NLM ID: 0043535 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1873-426X (Electronic) Linking ISSN: 00086215 NLM ISO Abbreviation: Carbohydr Res Subsets: MEDLINE
Imprint Name(s): Publication: Amsterdam : Elsevier
Original Publication: Amsterdam.
MeSH Terms: Chondroitin Sulfates*/chemistry , Chondroitin Sulfates*/pharmacology , Oligosaccharides*/chemistry , Oligosaccharides*/pharmacology , Sulfates*/chemistry , Potassium Compounds*/chemistry , Enzyme Inhibitors*/chemistry , Enzyme Inhibitors*/pharmacology, Free Radicals/chemistry ; Polymerization ; Animals
Abstract: Free radical depolymerization has been widely employed for polysaccharide structural and functional studies. However, H2O2-induced depolymerization of the unique sea cucumber derived fucosylated chondroitin sulfate (FCS) generated diverse fragments with oxidation at their reducing ends, thus limiting preparation of well-defined oligosaccharides. Here, a thermal dissociation initiator, potassium persulfate (KPS), was utilized to induce radical depolymerization of FCS, leading to depolymerized products that maintained their basic structural units and sulfate substituents. Structural analysis of the resulting oligosaccharides revealed that the reducing ends were uniformly GalNAc4S6S acid, distinct from those generated by H2O2-induced FCS depolymerization. The major components, tetrasaccharide (FIIIa), heptasaccharide (FVa) and decasaccharide (FVIa) possessed GalNAc4S6S residues at their non-reducing ends, demonstrating that the D-GlcA-β1,3-D-GalNAc4S6S linkage was preferentially cleaved. A free radical depolymerization mechanism of FCS by KPS was proposed. The regular aldonic acid terminal formation was attributed to the strong oxidative capacity of the sulfate radical for extensive oxidation of the newly formed GlcA residue after β1,3 glycosidic linkage cleavage, and further oxidation of C-1 of GalNAc. KPS was thermally dissociated to generate sulfate radicals, which subsequently attacked FCS chains and led to their fragmentation. Moreover, biological activity assay showed that heptasaccharide FVa and decasaccharide FVIa demonstrated strong anticoagulant activity, primarily via iXase inhibition mediated by high-affinity interaction with FIXa. Intriguingly, the unique oxidized reducing end exhibited enhanced iXase inhibitory activity. Hence, our findings expanded the free radical depolymerization of FCS and enriched structure-activity relationship information for iXase inhibition.
(Copyright © 2026. Published by Elsevier Ltd.)
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Contributed Indexing: Keywords: FIXa; Free radical; Fucosylated chondroitin sulfate; Oligosaccharides; Persulfate; iXase
Substance Nomenclature: 9007-28-7 (Chondroitin Sulfates)
0 (Oligosaccharides)
0 (Free Radicals)
0 (fucosylated chondroitin sulfate)
0 (Sulfates)
0 (Potassium Compounds)
6B86K0MCZC (potassium persulfate)
0 (Enzyme Inhibitors)
Entry Date(s): Date Created: 20260204 Date Completed: 20260706 Latest Revision: 20260706
Update Code: 20260707
DOI: 10.1016/j.carres.2026.109844
PMID: 41637796
Database: MEDLINE
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  Data: Persulfate-driven free radical depolymerization of fucosylated chondroitin sulfate and intrinsic Xase inhibition of the resulting oligosaccharides.
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  Data: <searchLink fieldCode="AU" term="%22Sun+J%22">Sun J</searchLink>; School of Pharmaceutical Sciences, South-Central Minzu University, Wuhan, 430074, China.<br /><searchLink fieldCode="AU" term="%22Sha+L%22">Sha L</searchLink>; School of Pharmaceutical Sciences, South-Central Minzu University, Wuhan, 430074, China.<br /><searchLink fieldCode="AU" term="%22Zhu+G%22">Zhu G</searchLink>; College of Life Sciences, South-Central Minzu University, Wuhan, 430074, China.<br /><searchLink fieldCode="AU" term="%22Li+L%22">Li L</searchLink>; School of Pharmaceutical Sciences, South-Central Minzu University, Wuhan, 430074, China.<br /><searchLink fieldCode="AU" term="%22Li+P%22">Li P</searchLink>; School of Pharmaceutical Sciences, South-Central Minzu University, Wuhan, 430074, China.<br /><searchLink fieldCode="AU" term="%22Chen+M%22">Chen M</searchLink>; School of Pharmaceutical Sciences, South-Central Minzu University, Wuhan, 430074, China.<br /><searchLink fieldCode="AU" term="%22Wang+J%22">Wang J</searchLink>; School of Pharmaceutical Sciences, South-Central Minzu University, Wuhan, 430074, China.<br /><searchLink fieldCode="AU" term="%22Jiao+X%22">Jiao X</searchLink>; School of Pharmaceutical Sciences, South-Central Minzu University, Wuhan, 430074, China.<br /><searchLink fieldCode="AU" term="%22Gao+N%22">Gao N</searchLink>; School of Pharmaceutical Sciences, South-Central Minzu University, Wuhan, 430074, China. Electronic address: gn2008.happy@163.com.<br /><searchLink fieldCode="AU" term="%22Zhao+J%22">Zhao J</searchLink>; School of Pharmaceutical Sciences, South-Central Minzu University, Wuhan, 430074, China. Electronic address: zhaojhscu@163.com.
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  Data: <searchLink fieldCode="JN" term="%220043535%22">Carbohydrate research</searchLink> [Carbohydr Res] 2026 May; Vol. 563, pp. 109844. <i>Date of Electronic Publication: </i>2026 Jan 29.
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  Data: <i>Publisher: </i><searchLink fieldCode="PB" term="%22Elsevier%22">Elsevier </searchLink><i>Country of Publication: </i>Netherlands <i>NLM ID: </i>0043535 <i>Publication Model: </i>Print-Electronic <i>Cited Medium: </i>Internet <i>ISSN: </i>1873-426X (Electronic) <i>Linking ISSN: </i><searchLink fieldCode="IS" term="%2200086215%22">00086215 </searchLink><i>NLM ISO Abbreviation: </i>Carbohydr Res <i>Subsets: </i>MEDLINE
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  Data: <i>Publication</i>: Amsterdam : Elsevier<br /><i>Original Publication</i>: Amsterdam.
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  Data: <searchLink fieldCode="MM" term="%22Chondroitin+Sulfates%22">Chondroitin Sulfates*</searchLink>/<searchLink fieldCode="MM" term="%22Chondroitin+Sulfates+chemistry%22">chemistry</searchLink> <br /><searchLink fieldCode="MM" term="%22Chondroitin+Sulfates%22">Chondroitin Sulfates*</searchLink>/<searchLink fieldCode="MM" term="%22Chondroitin+Sulfates+pharmacology%22">pharmacology</searchLink> <br /><searchLink fieldCode="MM" term="%22Oligosaccharides%22">Oligosaccharides*</searchLink>/<searchLink fieldCode="MM" term="%22Oligosaccharides+chemistry%22">chemistry</searchLink> <br /><searchLink fieldCode="MM" term="%22Oligosaccharides%22">Oligosaccharides*</searchLink>/<searchLink fieldCode="MM" term="%22Oligosaccharides+pharmacology%22">pharmacology</searchLink> <br /><searchLink fieldCode="MM" term="%22Sulfates%22">Sulfates*</searchLink>/<searchLink fieldCode="MM" term="%22Sulfates+chemistry%22">chemistry</searchLink> <br /><searchLink fieldCode="MM" term="%22Potassium+Compounds%22">Potassium Compounds*</searchLink>/<searchLink fieldCode="MM" term="%22Potassium+Compounds+chemistry%22">chemistry</searchLink> <br /><searchLink fieldCode="MM" term="%22Enzyme+Inhibitors%22">Enzyme Inhibitors*</searchLink>/<searchLink fieldCode="MM" term="%22Enzyme+Inhibitors+chemistry%22">chemistry</searchLink> <br /><searchLink fieldCode="MM" term="%22Enzyme+Inhibitors%22">Enzyme Inhibitors*</searchLink>/<searchLink fieldCode="MM" term="%22Enzyme+Inhibitors+pharmacology%22">pharmacology</searchLink><br /><searchLink fieldCode="MH" term="%22Free+Radicals%22">Free Radicals</searchLink>/<searchLink fieldCode="MH" term="%22Free+Radicals+chemistry%22">chemistry</searchLink> ; <searchLink fieldCode="MH" term="%22Polymerization%22">Polymerization</searchLink> ; <searchLink fieldCode="MH" term="%22Animals%22">Animals</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: Free radical depolymerization has been widely employed for polysaccharide structural and functional studies. However, H<subscript>2</subscript>O<subscript>2</subscript>-induced depolymerization of the unique sea cucumber derived fucosylated chondroitin sulfate (FCS) generated diverse fragments with oxidation at their reducing ends, thus limiting preparation of well-defined oligosaccharides. Here, a thermal dissociation initiator, potassium persulfate (KPS), was utilized to induce radical depolymerization of FCS, leading to depolymerized products that maintained their basic structural units and sulfate substituents. Structural analysis of the resulting oligosaccharides revealed that the reducing ends were uniformly GalNAc<subscript>4S6S</subscript> acid, distinct from those generated by H<subscript>2</subscript>O<subscript>2</subscript>-induced FCS depolymerization. The major components, tetrasaccharide (FIIIa), heptasaccharide (FVa) and decasaccharide (FVIa) possessed GalNAc<subscript>4S6S</subscript> residues at their non-reducing ends, demonstrating that the D-GlcA-β1,3-D-GalNAc<subscript>4S6S</subscript> linkage was preferentially cleaved. A free radical depolymerization mechanism of FCS by KPS was proposed. The regular aldonic acid terminal formation was attributed to the strong oxidative capacity of the sulfate radical for extensive oxidation of the newly formed GlcA residue after β1,3 glycosidic linkage cleavage, and further oxidation of C-1 of GalNAc. KPS was thermally dissociated to generate sulfate radicals, which subsequently attacked FCS chains and led to their fragmentation. Moreover, biological activity assay showed that heptasaccharide FVa and decasaccharide FVIa demonstrated strong anticoagulant activity, primarily via iXase inhibition mediated by high-affinity interaction with FIXa. Intriguingly, the unique oxidized reducing end exhibited enhanced iXase inhibitory activity. Hence, our findings expanded the free radical depolymerization of FCS and enriched structure-activity relationship information for iXase inhibition.<br /> (Copyright © 2026. Published by Elsevier Ltd.)
– Name: Abstract
  Label: Competing Interests
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  Data: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
– Name: SubjectMinor
  Label: Contributed Indexing
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  Data: <i>Keywords: </i>FIXa; Free radical; Fucosylated chondroitin sulfate; Oligosaccharides; Persulfate; iXase
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  Label: Substance Nomenclature
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  Data: 9007-28-7 (Chondroitin Sulfates)<br />0 (Oligosaccharides)<br />0 (Free Radicals)<br />0 (fucosylated chondroitin sulfate)<br />0 (Sulfates)<br />0 (Potassium Compounds)<br />6B86K0MCZC (potassium persulfate)<br />0 (Enzyme Inhibitors)
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  Data: <i>Date Created: </i>20260204 <i>Date Completed: </i>20260706 <i>Latest Revision: </i>20260706
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  Data: 10.1016/j.carres.2026.109844
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PLink https://search.ebscohost.com/login.aspx?direct=true&site=eds-live&db=cmedm&AN=41637796
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        Value: 10.1016/j.carres.2026.109844
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      – Code: eng
        Text: English
    PhysicalDescription:
      Pagination:
        StartPage: 109844
    Subjects:
      – SubjectFull: Free Radicals chemistry
        Type: general
      – SubjectFull: Polymerization
        Type: general
      – SubjectFull: Animals
        Type: general
      – SubjectFull: Chondroitin Sulfates chemistry
        Type: general
      – SubjectFull: Chondroitin Sulfates pharmacology
        Type: general
      – SubjectFull: Oligosaccharides chemistry
        Type: general
      – SubjectFull: Oligosaccharides pharmacology
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      – SubjectFull: Sulfates chemistry
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      – SubjectFull: Enzyme Inhibitors chemistry
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      – SubjectFull: Enzyme Inhibitors pharmacology
        Type: general
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      – TitleFull: Persulfate-driven free radical depolymerization of fucosylated chondroitin sulfate and intrinsic Xase inhibition of the resulting oligosaccharides.
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              Text: 2026 May
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