N-arylated-lactam-type iminosugars as new immunosuppressive agents: discovery, optimization, and biological evaluation.

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 21h, 21k, 21n, 21 t, and 21 x with improved activities (IC50=12-30 mm) and low Jurkat cytotoxicities (IC50>100 mm). These new compounds also inhibited the secretion of IFN-gamma 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.