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 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.
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Xue Yuan Road No. 38, Beijing 100191 (China), Fax: (+86) 10-82802724.
Xiaowei
X
Wu
Fu-Yu
FY
Zhang
Jingjing
J
Zhu
Chengcheng
C
Song
De-Cai
DC
Xiong
Yifa
Y
Zhou
Yuxin
Y
Cui
Xin-Shan
XS
Ye
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D050111:Imino Sugars / Q000737:chemistry / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000737:chemistry / Q000494:pharmacology*; D007769:Lactams / Q000737:chemistry / Q000494:pharmacology*; D013058:Mass Spectrometry; D051379:Mice; D066244:Proton Magnetic Resonance Spectroscopy; D013154:Spleen / Q000166:cytology / Q000187:drug effects; D013329:Structure-Activity Relationship
D050111:Imino Sugars; D007166:Immunosuppressive Agents; D007769:Lactams
arylation; cross-coupling; iminosugars; immunology; lactams