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Metabolic Oligosaccharide Engineering with N-Acyl Functionalized ManNAc Analogues: Cytotoxicity Metabolic Flux and Glycan-display Considerations

机译：与N-酰基官能化甘露糖类似物的代谢寡糖工程：细胞毒性代谢助焊剂和聚糖 - 显示器考虑

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Metabolic oligosaccharide engineering is a maturing technology capable of modifying cell surface sugars in living cells and animals through the biosynthetic installation of non-natural monosaccharides into the glycocalyx. A particularly robust area of investigation involves the incorporation of azide functional groups onto the cell surface, which can then be further derivatized using “click chemistry.” While considerable effort has gone into optimizing the reagents used for the azide ligation reactions, less optimization of the monosaccharide analogues used in the preceding metabolic incorporation steps has been done. This study fills this void by reporting novel butanoylated ManNAc analogues that are used by cells with greater efficiency and less cytotoxicity than the current “gold standard,” which are peracetylated compounds such as Ac4ManNAz. In particular, tributanoylated, N-acetyl, N-azido, and N-levulinoyl ManNAc analogues with the high flux 1,3,4-O-hydroxyl pattern of butanoylation were compared with their counterparts having the pro-apoptotic 3,4,6-O-butanoylation pattern. The results reveal that the ketone-bearing N-levulinoyl analogue 3,4,6-O-Bu3ManNLev is highly apoptotic, and thus is a promising anti-cancer drug candidate. By contrast, the azide-bearing analogue 1,3,4-O-Bu3ManNAz effectively labeled cellular sialoglycans at concentrations ∼3 to 5-fold lower (e.g., at 12.5 to 25 μM) than Ac4ManNAz (50 to 150 μM) and exhibited no indications of apoptosis even at concentrations up to 400 μM. In summary, this work extends emerging structure activity relationships that predict the effects of short chain fatty acid modified monosaccharides on mammalian cells and also provides a tangible advance in efforts to make metabolic oligosaccharide engineering a practical technology for the medical and biotechnology communities.

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