title: γ-Hydroxyethyl piperidine iminosugar and N-alkylated derivatives: a study of their activity as glycosidase inhibitors and as immunosuppressive agents.
abstract: An efficient and practical strategy for the synthesis of (3R,4s,5S)-4-(2-hydroxyethyl) piperidine-3,4,5-triol and its N-alkyl derivatives 8a-f, starting from the D-glucose, is reported. The chiral pool methodology involves preparation of the C-3-allyl-α-D-ribofuranodialdose 10, which was converted to the C-5-amino derivative 11 by reductive amination. The presence of C-3-allyl group gives an easy access to the requisite hydroxyethyl substituted compound 13. Intramolecular reductive aminocyclization of C-5 amino group with C-1 aldehyde provided the γ-hydroxyethyl substituted piperidine iminosugar 8a that was N-alkylated to get N-alkyl derivatives 8b-f. Iminosugars 8a-f were screened against glycosidase enzymes. Amongst synthetic N-alkylated iminosugars, 8b and 8c were found to be α-galactosidase inhibitors while 8d and 8e were selective and moderate α-mannosidase inhibitors. In addition, immunomodulatory activity of compounds 8a-f was examined. These results were substantiated by molecular docking studies using AUTODOCK 4.2 programme.
authors.affiliation: Department of Chemistry, Garware Research Centre, University of Pune, Pune 411007, India.
authors.forename: Pramod R
authors.initials: PR
authors.lastname: Markad
authors.affiliation: Department of Chemistry, Garware Research Centre, University of Pune, Pune 411007, India.
authors.forename: Dhiraj P
authors.initials: DP
authors.lastname: Sonawane
authors.affiliation: Institute of Bioinformatics and Biotechnology, University of Pune, Pune 411007, India.
authors.forename: Sougata
authors.initials: S
authors.lastname: Ghosh
authors.affiliation: Institute of Bioinformatics and Biotechnology, University of Pune, Pune 411007, India.
authors.forename: Balu A
authors.initials: BA
authors.lastname: Chopade
authors.affiliation: Institute of Bioinformatics and Biotechnology, University of Pune, Pune 411007, India.
authors.forename: Navnath
authors.initials: N
authors.lastname: Kumbhar
authors.affiliation: KU Leuven, Interface Valorisation Platform (IVAP), Kapucijnenvoer 33, 3000 Leuven, Belgium.
authors.forename: Thierry
authors.initials: T
authors.lastname: Louat
authors.affiliation: KU Leuven, Interface Valorisation Platform (IVAP), Kapucijnenvoer 33, 3000 Leuven, Belgium.
authors.forename: Jean
authors.initials: J
authors.lastname: Herman
authors.affiliation: KU Leuven, Interface Valorisation Platform (IVAP), Kapucijnenvoer 33, 3000 Leuven, Belgium.
authors.forename: Mark
authors.initials: M
authors.lastname: Waer
authors.affiliation: KU Leuven, Interface Valorisation Platform (IVAP), Kapucijnenvoer 33, 3000 Leuven, Belgium.
authors.forename: Piet
authors.initials: P
authors.lastname: Herdewijn
authors.affiliation: Department of Chemistry, Garware Research Centre, University of Pune, Pune 411007, India. Electronic address: ddd@chem.unipune.ac.in.
authors.forename: Dilip D
authors.initials: DD
authors.lastname: Dhavale
mesh_terms: D000478:Alkylation; D001665:Binding Sites; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D050111:Imino Sugars / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D019169:Jurkat Cells; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D062105:Molecular Docking Simulation; D010880:Piperidines / Q000737:chemistry*; D017434:Protein Structure, Tertiary; D000519:alpha-Galactosidase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D050111:Imino Sugars; D007166:Immunosuppressive Agents; D010880:Piperidines; C032727:piperidine; D000519:alpha-Galactosidase
keywords: Chiron approach; Glycosidase inhibitors; Iminosugars; Immunosuppressive activity; Reductive amination