Synthesis and characterization of poly-amido-saccharides with novel structures and properties
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Polysaccharides are complex biopolymers that play essential roles in the biological systems including energy storage, structural support, lubrication, and signal transduction. Despite their importance, the synthesis of polysaccharides has proven to be very challenging due to the presence of multiple hydroxyl groups and difficulty in controlling the stereochemical outcome of glycosylation reactions. As a conventional chemical method to synthesize polysaccharides, ring-opening polymerization of anhydrosugars enables the synthesis of stereoregular α-(1→6)-linked polysaccharides, but is less effective in preparing polysaccharides with other linkages. Enzymatic polymerizations have also been explored, however, these methods typically require expensive monomers, and suffer from a narrow scope of enzymes and small scale of reactions. The limited approaches to polysaccharides have inspired chemists to synthesize polysaccharide mimetics with achiral linkages that can be constructed efficiently. Poly-amido-saccharides (PASs) are a new type of saccharide polymers in which the O-glycosidic linkages in natural polysaccharides are replaced with (1→2)-amide linkages. With saccharide moieties inter-connected by amide bonds, PASs exhibit characteristics of both polysaccharides and polypeptides, such as possessing pyranose-backbones and lots of hydroxyl groups, and adopting a left-handed helical conformation. However, due to lack of sufficient terminal saccharide residues, previously synthesized glucose and galactose PASs display weak interactions with carbohydrate binding lectins and receptors, limiting their applications in biomedical and pharmaceutical fields. Herein, the design and synthesis of PASs with novel structures and properties is described. By pre-installing the stereochemistry in the monomer, Altrose PASs (Alt-PASs) with β-(1→2)-amide linkages are prepared via ring-opening polymerization of an altrose-based β-lactam followed by debenzylation. Circular dichroism shows that Alt-PASs adopt a right-handed helical conformation in aqueous solution. Via the polymerization of disaccharide-based β-lactams, two PASs with either 4-O-α-D-glucose branches (Mal-PASs) or 6-O-β-D-glucose branches (Gen-PASs) are obtained. Biological studies reveal that Mal-PASs are multivalent ligands to lectin Concanavalin A, while Gen-PASs activate RAW 264.7 macrophage cells by enhancing the secretion of TNF-α and NO. The anionic ring-opening polymerization of sugar-based β-lactams is a useful method to synthesize well-defined polysaccharide mimetics, and this method expands the current repertory of approaches available to complex saccharide polymers with biological activities.