Design, synthesis and biological evaluation of C(6)-indole celastrol derivatives as potential antitumor agents

Celastrol is a natural triterpenoid which possesses diverse pharmacological activities including potent antitumor activity. Previously, we reported a C(6)-modified celastrol derivative NST001A which possesses cytotoxic activity against Colon 205 cells with a 60 nM IC₅₀ value. To further explore the structure activity relationships, a new class of C(6)-indole substituted celastrol derivatives were designed and synthesized. Biological evaluation of these compounds includes their cytotoxic activity against human hepatocellular carcinoma Bel7402 and human glioblastoma cell line H4. Among all these semisynthetic analogues, compound 4f and 4h displayed excellent in vitro antiproliferative activities against Bel7402 cancer cells (IC₅₀ = 0.02 μM and 0.01 μM, respectively).