State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Xue Yuan Road No. 38, Beijing, 100191, China.
ChemMedChem. 2018 Feb 20;13(4):338-351. doi: 10.1002/cmdc.201700706. Epub 2018 Feb 1.
It is important to find more effective and safer immunosuppressants, because clinically used immunosuppressive agents have significant side effects. A series of N-substituted iminosugar derivatives were designed and synthesized, and their immunosuppressive effects were evaluated by the CCK-8 assay. The results revealed that iminosugars 10 e and 10 i, that is, (3R,4S)-1-(4-heptyloxylphenylethyl)pyrrolidine-3,4-diol and (3R,4S)-1-[2-(2-chloro-4-(p-tolylthio)-phenyl-1-yl)ethyl]pyrrolidine-3,4-diol, respectively, exhibited the strongest inhibitory effects on mouse splenocyte proliferation (IC =2.16 and 2.48 μm, respectively), whereas the iminosugars containing an amide group near the hydrophilic head (compounds 10 j-n) exhibited no inhibitory effects. Further studies revealed that the inhibitory effects on splenocyte proliferation may have come from the suppression of both IFN-γ and IL-4 cytokines. Our results suggest that synthetic iminosugars, especially compounds 10 e and 10 i, hold potential as immunosuppressive agents.
找到更有效和更安全的免疫抑制剂很重要，因为临床上使用的免疫抑制剂有明显的副作用。设计和合成了一系列 N-取代亚氨基糖衍生物，并通过 CCK-8 法评估了它们的免疫抑制作用。结果表明，亚氨基糖 10e 和 10i，即（3R，4S）-1-（4-庚氧基苯乙基）吡咯烷-3,4-二醇和（3R，4S）-1-[2-（2-氯-4-（对甲苯基硫代）-苯基-1-基）乙基]吡咯烷-3,4-二醇，对小鼠脾细胞增殖的抑制作用最强（IC=2.16 和 2.48μm），而亲水头部附近含有酰胺基团的亚氨基糖（化合物 10j-n）则没有抑制作用。进一步的研究表明，对脾细胞增殖的抑制作用可能来自于对 IFN-γ 和 IL-4 细胞因子的抑制。我们的研究结果表明，合成的亚氨基糖，特别是化合物 10e 和 10i，具有作为免疫抑制剂的潜力。
