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N ‐Arylated‐Lactam‐Type Iminosugars as New Immunosuppressive Agents: Discovery, Optimization, and Biological Evaluation
Author(s) -
Wu Xiaowei,
Zhang FuYu,
Zhu Jingjing,
Song Chengcheng,
Xiong DeCai,
Zhou Yifa,
Cui Yuxin,
Ye XinShan
Publication year - 2014
Publication title -
chemistry – an asian journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.18
H-Index - 106
eISSN - 1861-471X
pISSN - 1861-4728
DOI - 10.1002/asia.201400023
Subject(s) - iminosugar , jurkat cells , chemistry , in vitro , in vivo , aryl , combinatorial chemistry , drug discovery , stereochemistry , biochemistry , biology , enzyme , immunology , t cell , immune system , organic chemistry , alkyl , microbiology and biotechnology
We have previously described the discovery of N ‐alkylated iminosugars that showed immunosuppressive activity both in vitro and in vivo. Herein, we report the synthesis and biological evaluation of N ‐arylated lactam‐type iminosugar derivatives. The synthesis started from simple monosaccharides and featured a Buchwald–Hartwig coupling reaction to construct the key N ‐aryl connection, thereby providing a highly diverse compound library. Structure–activity relationship studies, guided by a mouse‐spleen‐proliferation assay, led to the identification of ′hit′ compound 12 f . Subsequently, the systematic modification of compound 12 f afforded compounds 21 h , 21 k , 21 n , 21 t , and 21 x with improved activities (IC 50 =12–30 μ M ) and low Jurkat cytotoxicities (IC 50 >100 μ M ). These new compounds also inhibited the secretion of IFN‐γ and IL‐4, which are hallmark cytokines of Th1 and Th2 cells, respectively. This work demonstrated that the N ‐arylated iminosugar structure represents a new scaffold with immunosuppressive activity.