Potent metabolic sialylation inhibitors based on C-5 modified fluorinated sialic acids

Research output: Contribution to journalJournal articleResearchpeer-review

Torben Heise, Johan Pijnenborg, Christian Büll, Niek van Hilten, Esther Kers-Rebel, Natasja Balneger, Hidde Elferink, Gosse J Adema, Thomas J Boltje

Sialic acid sugars on mammalian cells regulate numerous biological processes, while aberrant expression of sialic acid is associated with diseases like cancer and pathogenic infection. Inhibition of the sialic acid biosynthesis may therefore hold considerable therapeutic potential. To effectively decrease 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 underlying mechanism, we have identified that carba-mate-modified 3-fluoro sialic acid inhibitors are more efficiently metabolized to their active CMP-analogs, reaching higher effective inhibitor concentrations inside cells.

Original languageEnglish
JournalJournal of Medicinal Chemistry
Volume62
Issue number2
Pages (from-to)1014-1021
ISSN0022-2623
DOIs
Publication statusE-pub ahead of print - 2019
Externally publishedYes

ID: 210003470