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J Med Chem. 2015 Oct 8;58(19):7820-32. doi: 10.1021/acs.jmedchem.5b00951. Epub 2015 Sep 25.

Quaternary Indolizidine and Indolizidone Iminosugars as Potential Immunostimulating and Glycosidase Inhibitory Agents: Synthesis, Conformational Analysis, Biological Activity, and Molecular Docking Study.

Author information

1
Department of Chemistry, Garware Research Centre, Savitribai Phule Pune University (formerly University of Pune), Pune 411 007, India.
2
Department of Chemistry, Savitribai Phule Pune University , Pune 411 007, India.
3
Institute of Bioinformatics and Biotechnology, Savitribai Phule Pune University , Pune 411 007, India.

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.

PMID:
26375725
DOI:
10.1021/acs.jmedchem.5b00951
[Indexed for MEDLINE]

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