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

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• 作者：Nitin J. Pawar ; Vijay Singh Parihar ; Ayesha Khan ; Rakesh Joshi ; Dilip D. Dhavale
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：October 8, 2015
• 年：2015
• 卷：58
• 期：19
• 页码：7820-7832
• 全文大小：584K
• ISSN：1520-4804

文摘

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-纬-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 (⁵C₈ or ⁸C₅) of 1鈥?b>3 were assigned on the basis of the ¹H NMR studies. All compounds were found to be potent inhibitors of various glycosidase enzymes with K_i and IC₅₀ values in the micromolar/nanomolar concentration range and further substantiated by molecular docking studies. The effect of synthesized iminosugars 1鈥?b>3 on the cytokine secretion of IL-4, IL-6, and IFN-纬 was evaluated. All compounds were found to be T_H1 bias increasing the T_H1/T_H2 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.