Fluorinated piperidine iminosugars and their N-alkylated derivatives: Synthesis, conformational analysis, immunosuppressive and glycosidase inhibitory activity studies

• Published in: Tetrahedron 2018-02, Vol.74 (8), p.852-858
• Main Authors: Bhuma, Naresh, Burade, Sachin S., Louat, Thierry, Herman, Jean, Kawade, Sonali, Doshi, Pooja J., Dhavale, Dilip D.
• Format: Article
• Language: English
• Subjects: Conformational analysis; Glycosidase inhibitory activity; Iminosugars; Immunosuppressive activity
• ISSN: 0040-4020; 1464-5416
• DOI: 10.1016/j.tet.2017.12.059

The fluorinated piperidine iminosugars 2a-4a and their N-octyl and N-decyl derivatives 2b,c-4b,c were synthesized from d-mannose/d-xylose using nucleophilic fluorination as the key step. The conformation of iminosugars 2/3, either 2C5 or 5C2, was assigned based on the 1H NMR studies at different pH. Immunomodulatory activity of 2a,c-4a,c was examined using Mixed Lymphocyte Reaction (MLR) and B-cell assay. The N-alkylated fluorinated d-manno-iminosugars 3b/4b were found to be better immunosuppressive agents (IC50 = 5–6 μM) on T-cells. The fluorinated iminosugar 3a/4a act as potent and selective inhibitors of β-glucosidase (IC50 = 4–8 μM). The N-alkyl-iminosugars 4b-c were found to be moderate inhibitors of α-glucosidase (yeast) and α-galactosidase (coffee beans), respectively. [Display omitted] •Synthesis of mono- and gem-difluorinated piperidine iminosugars and their N-octyl and N-decyl derivatives in a less number of steps.•Introduction of mono- and gem di-fluorine achieved by using DAST (nucleophilic fluorinataing agent) in high yields.•Conformation of iminosugars, either 2C5 or 5C2, was assigned based on the 1H NMR studies at different pH.•Immunosupressive activity evaluated in vitro by MLR assay and B-cell assay.•Glycosidase inhibitory activity study of mono- and gem-difluorinated piperidine-iminosugars is described.