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 (IC50 =12-30 μM) and low Jurkat cytotoxicities (IC50 >100 μM). 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.

Biological activities of 3,4,5‐trihydroxypiperidines and their N‐ and O‐derivatives

“…N ‐Arylated derivatives of iminosugar 3L, 56 – 58, [36] tested at 50 μ m , showed some inhibitory effect on the ex vivo concanavalin A‐stimulated mouse‐spleenocyte proliferation assay with CsA as positive control (90% inhibitory rate at 1 μ m ), however, slightly decreased inhibitory effect when compared to their lactam counterparts. 56 's corresponding lactam with the biphenyl R‐group was the most potent hit in this focused library with an inhibitory rate of 56%.…”

“…Two studies report on the immunosuppressant activities of 3,4,5‐trihydroxypiperidine N ‐alkylated [35] and N ‐arylated [36] derivatives with alkylation providing more potent agents than the parent 3,4,5‐trihydroxypiperidines.…”

Iminosugars as Immunomodulating Agents: Synthesis and Biological Activities of 1‐Deoxynojirimycin and Related Compounds

“…[35] The SAR studies, guided by a mouse spleen proliferation assay, led to the identifiScheme 8. The preparation of 5F-DNJ.…”

Synthetic Routes to 3,4,5‐Trihydroxypiperidines via Stereoselective and Biocatalysed Protocols, and Strategies to N‐ and O‐Derivatisation

“…Wu and Ye N ‐arylated via a Buchwald‐Hartwig coupling reaction to gain access to a diversity‐oriented library of iminosugars with improved immunosuppressive properties. This library also included derivatives of iminosugars meso ‐1 , 3D and 3L .…”