LAUSR

To discover celastrol (CEL) derivatives with enhanced Hsp90-Cdc37 inhibition, C-20-COOH was introduced with various substituted imidazoles, which might affect the Michael addition of CEL by nucleophilic attack. The most potent compound 9, which showed higher antiproliferation, covalent-binding ability, and Hsp90-Cdc37 inhibition than CEL, was selected from 28 new target compounds. Then, the binding sites and the docking mode of 9 to Hsp90 and Cdc37 were studied. Furthermore, the activity of 9 sharply decreased or even disappeared in the Hsp90- and/or Cdc37-overexpressing A549 cells, indicating that the activity was related to its combination with Hsp90 and Cdc37. Moreover, 9 could more effectively induce apoptosis and inhibit tumor growth than CEL in vivo. This study first found that imidazoles linked to C-20 of CEL might affect its Michael addition, which will provide support of CEL or even the other Michael acceptors for the development as antitumor agents.