Synthesis and Biological Evaluation of Celastrol Derivatives as Potential Immunosuppressive Agents
Qi-Wei He, Jiahao Feng, Xiaolong Hu, Huan Long, Xuefeng Huang, Zhenzhou Jiang, Xiao‐Qi Zhang, Wen‐Cai Ye, Hao Wang
Abstract
Celastrol, a friedelane-type triterpenoid isolated from the genus Triperygium, possesses antitumor, anti-inflammatory, and immunosuppressive activities. A total of 42 celastrol derivatives (1a–1t, 2a–2l, and 3a–3j) were synthesized and evaluated for their immunosuppressive activities. Compounds 2a–2e showed immunosuppressive effects, with IC50 values ranging from 25 to 83 nM, and weak cytotoxicity (CC50 > 1 μM). Compound 2a, with a selectivity index value 31 times higher than that of celastrol, was selected as a lead compound. Further research showed that 2a exerted its immunosuppressive effects by inducing apoptosis and inhibiting cytokine secretion via Lck- and ZAP-70-mediated signaling pathways.