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- Title
N-Arylated-Lactam-Type Iminosugars as New Immunosuppressive Agents: Discovery, Optimization, and Biological Evaluation.
- Authors
Wu, Xiaowei; Zhang, Fu ‐ Yu; Zhu, Jingjing; Song, Chengcheng; Xiong, De ‐ Cai; Zhou, Yifa; Cui, Yuxin; Ye, Xin ‐ Shan
- 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 μ M) and low Jurkat cytotoxicities (IC50>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.
- Subjects
IMINOSUGARS; CYTOKINES; CHEMICAL synthesis; IMMUNOSUPPRESSIVE agents; IMINO compounds
- Publication
Chemistry - An Asian Journal, 2014, Vol 9, Issue 8, p2260
- ISSN
1861-4728
- Publication type
Article
- DOI
10.1002/asia.201400023