Liu Hai-Qian, Song Cheng-Cheng, Niu You-Hong, Li Tao, Li Qin, 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.
Org Biomol Chem. 2017 Jul 19;15(28):5912-5919. doi: 10.1039/c7ob01110e.
Since the immunosuppressive agents currently used in clinics have significant side effects, it is very important to search for new effective and safe immunosuppressants. Iminosugars as a new class of immunosuppressants are less explored. In this report, 24 new N-arylated iminosugar derivatives, including d-talo and d-galacto epimers, were designed and synthesized, and their immunosuppressive effects were evaluated by MTT assay. The experimental data demonstrated that compound 20 showed the strongest inhibition effect (IC = 6.94 μM). Further studies revealed that the inhibitory effects on splenocyte proliferation may come from the suppression of both IFN-γ and IL-4 cytokines. The preliminary structure-activity relationship (SAR) analysis suggested that N-arylated d-galacto-type iminosugars showed better inhibitory activities than d-talo-type analogues. The SAR analysis also showed that the inhibition effect of iminosugars can be improved by decreasing the polarity or increasing the hydrophobicity. These results may be beneficial to the discovery of new iminosugar derivatives as immunosuppressive agents.
由于目前临床上使用的免疫抑制剂有显著的副作用，寻找新的有效且安全的免疫抑制剂非常重要。氨基糖作为一类新型免疫抑制剂，其研究较少。在本报告中，设计并合成了24种新的N-芳基化氨基糖衍生物，包括d-塔罗糖和d-半乳糖差向异构体，并通过MTT法评估了它们的免疫抑制作用。实验数据表明化合物20表现出最强的抑制作用（IC = 6.94 μM）。进一步研究表明，对脾细胞增殖的抑制作用可能来自对IFN-γ和IL-4细胞因子的抑制。初步的构效关系（SAR）分析表明，N-芳基化d-半乳糖型氨基糖比d-塔罗糖型类似物表现出更好的抑制活性。SAR分析还表明，通过降低极性或增加疏水性可以提高氨基糖的抑制作用。这些结果可能有助于发现新的作为免疫抑制剂的氨基糖衍生物。
