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. Epub 2020 Aug 21.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Cytokines / antagonists & inhibitors
  • Drug Screening Assays, Antitumor
  • Humans
  • Immunosuppressive Agents / chemical synthesis*
  • Immunosuppressive Agents / pharmacology*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Pentacyclic Triterpenes / chemical synthesis*
  • Pentacyclic Triterpenes / pharmacology*
  • Signal Transduction / drug effects
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology
  • ZAP-70 Protein-Tyrosine Kinase / drug effects

Substances

  • Antineoplastic Agents
  • Cytokines
  • Immunosuppressive Agents
  • Pentacyclic Triterpenes
  • ZAP-70 Protein-Tyrosine Kinase
  • Zap70 protein, mouse
  • celastrol