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

摘要

New quaternary indolizidine iminosugars, with hydroxymethyl group at the ring junction, namely, C-8ahydroxymethyl-1-deoxycastanospermine congeners la, 2a, 3a and their 3-oxo analogs lb, 2h, and 3b were synthesized by using intramolecular reductive aminocyclization/lactamization of D-mannose/D-glucose derived CS-y-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 (C-5(8) or C-5(5)) of 1-3 were assigned on the basis of the H-1-1 NMR studies. All compounds were found to be potent inhibitors of various glycosidase enzymes with Ki and IC50 values in the micromolaranomolar 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-gamma was evaluated. All compounds were found to be T-H1 bias increasing the T-HI/T-H2 c-ytoldnes 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.