title: Quaternary Indolizidine and Indolizidone Iminosugars as Potential Immunostimulating and Glycosidase Inhibitory Agents: Synthesis, Conformational Analysis, Biological Activity, and Molecular Docking Study.
abstract: New quaternary indolizidine iminosugars, with hydroxymethyl group at the ring junction, namely, C-8a-hydroxymethyl-1-deoxycastanospermine congeners 1a, 2a, 3a and their 3-oxo analogs 1b, 2b, and 3b were synthesized by using intramolecular reductive aminocyclization/lactamization of d-mannose/D-glucose derived C5-γ-azido esters as a key step wherein both the rings of the indolizidine skeleton were built up in one pot following the cascade reaction pathway. The conformations ((5)C8 or (8)C5) of 1-3 were assigned on the basis of the (1)H NMR studies. All compounds were found to be potent inhibitors of various glycosidase enzymes with Ki and IC50 values in the micromolar/nanomolar concentration range and further substantiated by molecular docking studies. The effect of synthesized iminosugars 1-3 on the cytokine secretion of IL-4, IL-6, and IFN-γ was evaluated. All compounds were found to be TH1 bias increasing the TH1/TH2 cytokines ratio (IL-6 and IL-4) indicating their potency as immunostimulating agents. Our study suggests that immunomodulatory activity of indolizidine iminosugars can be tuned by minor structural/stereochemical alterations.
authors.affiliation: Department of Chemistry, Garware Research Centre, Savitribai Phule Pune University (formerly University of Pune), Pune 411 007, India.
authors.forename: Nitin J
authors.initials: NJ
authors.lastname: Pawar
authors.affiliation: Department of Chemistry, Garware Research Centre, Savitribai Phule Pune University (formerly University of Pune), Pune 411 007, India.
authors.forename: Vijay Singh
authors.initials: VS
authors.lastname: Parihar
authors.affiliation: Department of Chemistry, Savitribai Phule Pune University , Pune 411 007, India.
authors.forename: Ayesha
authors.initials: A
authors.lastname: Khan
authors.affiliation: Institute of Bioinformatics and Biotechnology, Savitribai Phule Pune University , Pune 411 007, India.
authors.forename: Rakesh
authors.initials: R
authors.lastname: Joshi
authors.affiliation: Department of Chemistry, Garware Research Centre, Savitribai Phule Pune University (formerly University of Pune), Pune 411 007, India.
authors.forename: Dilip D
authors.initials: DD
authors.lastname: Dhavale
mesh_terms: D000276:Adjuvants, Immunologic / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D060326:Chemistry Techniques, Synthetic; D016207:Cytokines / Q000378:metabolism; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006026:Glycoside Hydrolases / Q000037:antagonists & inhibitors*; D050111:Imino Sugars / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D054836:Indolizidines / Q000138:chemical synthesis / Q000737:chemistry; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
chemical_list: D000276:Adjuvants, Immunologic; D016207:Cytokines; D004791:Enzyme Inhibitors; D050111:Imino Sugars; D054836:Indolizidines; D006026:Glycoside Hydrolases