N‐Arylated‐Lactam‐Type Iminosugars as New Immunosuppressive Agents: Discovery, Optimization, and Biological Evaluation

Abstract 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.