Potent Metabolic Sialylation Inhibitors Based on C‑5-Modified Fluorinated Sialic Acids

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.