Fluorinated Iminosugar Glycomimetics: Synthesis and Activity as GCase Ligands

The incorporation of fluorine into bioactive molecules is a widely employed strategy for tuning molecular recognition and pharmacological properties. The enzyme β‐glucocerebrosidase (GCase), whose deficiency causes Gaucher disease and represents a major genetic risk factor for Parkinson disease, is emerging as a key therapeutic target for both pathologies. We report the synthesis and biological evaluation toward GCase of a small collection of fluorinated iminosugars, together with some non‐fluorinated novel control compounds. Diethylaminosulfur trifluoride (DAST)‐mediated deoxyfluorination of suitably protected piperidine intermediates afforded the corresponding fluorinated derivatives. Fluorination proceeded with retention of configuration and, if an alkyl chain at C‐2 is present, induced unexpected stereoselective ring contraction to fluorinated pyrrolidines. Biological evaluation, including enzyme inhibition assays and ex vivo studies in Gaucher disease fibroblasts, revealed distinct behaviors. Fluorination generally enhanced GCase inhibitory potency provided that an alkyl chain was present, whereas restoration of GCase activity in mutant cells depended more subtly on the overall piperidine substitution pattern and was favored by the presence of a trifluoromethyl group in the N ‐alkyl chain. Overall, this study identified new high‐affinity GCase ligands, including a potent fluorinated piperidine, a fluorinated pyrrolidine generated through the ring‐contraction process, and a trifluoromethyl analog retaining the ability to restore GCase activity in Gaucher disease fibroblasts.