Carbohydr Polym 2026 May 01;385:125402. doi: 10.1016/j.carbpol.2026.125402.

Unveiling and suppressing side reactions in the deacetylation and deaminative depolymerization of fucosylated chondroitin sulfate for enhanced oligosaccharide preparation.

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Deacetylative-deaminative depolymerization represents a critical methodology for selective glycosidic bond cleavage in glycosaminoglycans, essential for structural elucidation and bioactive oligosaccharide preparation. While concurrent side reactions in fucosylated chondroitin sulfate (FCS) during this process remain poorly understood. Using highly regular FCS from Stichopus horrens as a model, side reactions during hydrazinolysis and deamination cleavage were systematically characterized. We report the first discovery that backbone glycosidic bond scission-preferentially at β1,3-linkages-dominates the de-N-acetylation step, with both deacetylation and this side reaction following first-order kinetics. Notably, GlcA residues at newly exposed reducing ends may undergo unique reductive-isomerization under hydrazinolysis condition. Orthogonal design optimization achieved 1.9-fold higher efficiency in generating deacetylated units versus conventional methods. Additionally, nitrite-mediated "peeling-off" was identified as the critical side reaction during deaminative cleavage, wherein residual nitrous acid species "peel" the target oligosaccharides. Scavenger screening demonstrated that immediate introduction of l-ascorbic acid, ammonium salts, or organic amines effectively quenches this side reaction, eliminating by-products and enhancing reproducibility. This study clarifies the key side reactions during the deacetylation-deaminative depolymerization of FCS, laying the methodological foundation for precise structural analysis of FCS and development of FCS-based therapeutics.

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