Wu Xiaowei, Zhang Fu-Yu, Zhu Jingjing, Song Chengcheng, Xiong De-Cai, Zhou Yifa, Cui Yuxin, Ye Xin-Shan
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.
Chem Asian J. 2014 Aug;9(8):2260-71. doi: 10.1002/asia.201400023. Epub 2014 Apr 2.
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.
我们之前描述过N-烷基化亚氨基糖的发现，其在体外和体内均表现出免疫抑制活性。在此，我们报告N-芳基内酰胺型亚氨基糖衍生物的合成及生物学评价。合成从简单的单糖开始，其特点是通过布赫瓦尔德-哈特维希偶联反应构建关键的N-芳基连接，从而提供了一个高度多样化的化合物库。在小鼠脾脏增殖试验的指导下进行构效关系研究，鉴定出了“命中”化合物12 f。随后，对化合物12 f进行系统修饰，得到了活性提高（IC50 =12 - 30 μM）且对Jurkat细胞毒性低（IC50 >100 μM）的化合物21 h、21 k、21 n、21 t和21 x。这些新化合物还分别抑制了Th1和Th2细胞标志性细胞因子IFN-γ和IL-4的分泌。这项工作表明，N-芳基化亚氨基糖结构代表了一种具有免疫抑制活性的新骨架。
