1. Potent Metabolic Sialylation Inhibitors Based on C-5-Modified Fluorinated Sialic Acids
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Johan F. A. Pijnenborg, Niek van Hilten, Thomas J. Boltje, Natasja Balneger, Torben Heise, Hidde Elferink, Christian Büll, Esther D. Kers-Rebel, and Gosse J. Adema
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Cytidine monophosphate ,Halogenation ,Sialyltransferase ,Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2] ,Synthetic Organic Chemistry ,Inhibitory postsynaptic potential ,01 natural sciences ,Article ,Cell Line ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,All institutes and research themes of the Radboud University Medical Center ,Biosynthesis ,Drug Discovery ,Cytidine Monophosphate ,medicine ,Animals ,Humans ,030304 developmental biology ,0303 health sciences ,biology ,Cancer ,Human cell ,medicine.disease ,Amides ,Carbon ,Sialyltransferases ,3. Good health ,0104 chemical sciences ,Sialic acid ,carbohydrates (lipids) ,010404 medicinal & biomolecular chemistry ,chemistry ,Biochemistry ,Cell culture ,Sialic Acids ,biology.protein ,Molecular Medicine ,Carbamates - Abstract
Sialic acid sugars on mammalian cells regulate numerous biological processes, while aberrant expression of sialic acid is associated with diseases such as cancer and pathogenic infection. Inhibition of the sialic acid biosynthesis may therefore hold considerable therapeutic potential. To effectively decrease the sialic acid expression, we synthesized C-5-modified 3-fluoro sialic acid sialyltransferase inhibitors. We found that C-5 carbamates significantly enhanced and prolonged the inhibitory activity in multiple mouse and human cell lines. As an underlying mechanism, we have identified that carbamate-modified 3-fluoro sialic acid inhibitors are more efficiently metabolized to their active cytidine monophosphate analogues, reaching higher effective inhibitor concentrations inside cells.
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