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, -, -, and -, were designed and synthesized, and their Hsp90-Cdc37 disruption activities and antiproliferative activities against cancer cells were evaluated. Among these compounds, , with the highest tumor cell selectivity (15.4-fold), potent Hsp90-Cdc37 disruption activity (IC = 1.9 μM), and antiproliferative activity against MDA-MB-231 cells (IC = 0.2 μM), was selected as the lead compound. Further studies demonstrated has strong antitumor activities both in vitro and in vivo through disrupting the Hsp90-Cdc37 interaction and inhibiting angiogenesis. In addition, exhibited less toxicity than celastrol and showed a good pharmacokinetics profile in vivo. These findings suggest that may be a promising candidate for development of new cancer therapies.
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