Synthesis and Biological Evaluation of Celastrol Derivatives with Improved Cytotoxic Selectivity and Antitumor Activities

Cdc37 associates kinase clients to Hsp90 and promotes the development of cancers. Celastrol, a natural friedelane triterpenoid, can disrupt the Hsp90–Cdc37 interaction to provide antitumor effects. In this study, 31 new celastrol derivatives, 2a–2d, 3a–3g, and 4a–4t, were designed and synthesized, and their Hsp90–Cdc37 disruption activities and antiproliferative activities against cancer cells were evaluated. Among these compounds, 4f, with the highest tumor cell selectivity (15.4-fold), potent Hsp90–Cdc37 disruption activity (IC50 = 1.9 μM), and antiproliferative activity against MDA-MB-231 cells (IC50 = 0.2 μM), was selected as the lead compound. Further studies demonstrated 4f has strong antitumor activities both in vitro and in vivo through disrupting the Hsp90–Cdc37 interaction and inhibiting angiogenesis. In addition, 4f exhibited less toxicity than celastrol and showed a good pharmacokinetics profile in vivo. These findings suggest that 4f may be a promising candidate for development of new cancer therapies.