Synthesis and Biological Evaluation of Celastrol Derivatives as Potential Immunosuppressive Agents

J Nat Prod. 2020 Sep 25;83(9):2578-2586. doi: 10.1021/acs.jnatprod.0c00067.

Qi-Wei He ¹, Jia-Hao Feng ¹, Xiao-Long Hu ¹, Huan Long ¹, Xue-Feng Huang ¹, Zhen-Zhou Jiang ², Xiao-Qi Zhang ³, Wen-Cai Ye ³, Hao Wang ¹

Affiliations

1 State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, People's Republic of China.
2 Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, People's Republic of China.
3 Institute of Traditional Chinese Medicine and Natural Products, Jinan University, Guangzhou 510632, People's Republic of China.

PMID: 32822186 DOI: 10.1021/acs.jnatprod.0c00067

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.

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