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.

Cyclisations and Strategies for Stereoselective Synthesis of Piperidine Iminosugars

“…workers reported α-geminal dihydroxymethyl substituted piperidines. [112] Fustero, Aceña and co-workers used a carbon trifluoride rearrangement to an iminium ion in a quaternary center forming step and applied the methodology in iminosugar synthesis.…”

Editorial: Medicinal Chemistry Research in India

“…In their study, these compounds showed potent inhibitory activity against various glycosidase enzymes having K i and IC 50 values in the micromolar/nanomolar concentration range. 17 Sampath Kumar and co-workers screened a focused library of benzyloxyalkyl-substituted 1,2,3-triazolyl α-GalCer analogues for immunomodulatory activity. 18 Bharate and co-workers discovered 7-(prolinol-N-yl)-2-phenylamino-thiazolo [5,4-d]pyrimidines as a novel chemotype of non-nucleoside partial agonists of the A2A adenosine receptor.…”

A Route to 1‐Deoxynojirimycin and 1‐Deoxymannojirimycin Derivatives with Quaternary Centers Adjacent to the Ring Nitrogen from Methyl α‐d‐Mannopyranoside

“…One recent example by Py and co‐workers, involved synthesis of aziridinyl imino sugars via nitrone‐alkyne cycloaddition and subsequent Baldwin rearrangement . Earlier, Dhavale and co‐workers reported α‐geminal dihydroxymethyl‐substituted piperidines by a route which included a variant of the Corey–Link reaction via suitably oxidized furanoses . Fustero, Aceña and co‐workers prepared chiral lactones using a carbon trifluoride rearrangement to an iminium ion in the quaternary center forming step and applied the methodology in imino sugar synthesis …”