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.