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

• Published in: Chemistry, an Asian journal an Asian journal, 2014-08, Vol.9 (8), p.2260-2271
• Main Authors: Wu, Xiaowei, Zhang, Fu-Yu, Zhu, Jingjing, Song, Chengcheng, Xiong, De-Cai, Zhou, Yifa, Cui, Yuxin, Ye, Xin-Shan
• Format: Article
• Language: English
• Subjects: Animals; arylation; Cell Proliferation - drug effects; Chemistry; cross-coupling; Drug Discovery; Drug Evaluation, Preclinical; Imino Sugars - chemistry; Imino Sugars - pharmacology; iminosugars; immunology; Immunosuppressive Agents - chemistry; Immunosuppressive Agents - pharmacology; lactams; Lactams - chemistry; Lactams - pharmacology; Mass Spectrometry; Mice; Proton Magnetic Resonance Spectroscopy; Spleen - cytology; Spleen - drug effects; Structure-Activity Relationship
• ISSN: 1861-4728; 1861-471X
• DOI: 10.1002/asia.201400023

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. Sugar daddy: A diverse library of N‐arylated iminosugars were synthesized through a Buchwald–Hartwig coupling reaction on iminosugars. Several potent and selective T‐cell‐proliferation inhibitors were identified through systematic SAR studies.