Novel celastrol derivatives with improved selectivity and enhanced antitumour activity: Design, synthesis and biological evaluation.

Celastrol is one of the most active antitumour compounds among the natural triterpenoids. It has been reported to be highly active against a wide variety of tumours and to affect multiple cellular pathways. A series of new celastrol derivatives, including compounds bearing a urea group, have been synthesised and analysed for their biological activity against human cancer cell lines. Several compounds presented a stronger growth inhibition effect than celastrol on the cell lines studied. Among them, compound 24 was the most promising derivative, as it exhibited both a remarkable antiproliferative activity and an improved selectivity in tumour versus non-tumour cells. The anticancer molecular mechanism of compound 24 in the human ovary cancer cell line SKOV-3 was further studied and the results showed that compound 24 induced apoptosis through the activation of the extrinsic death receptor pathway. Interestingly, the results revealed that compound 24 might be able to decrease the levels of dysfunctional p53. The assays also suggested that compound 24 is an Hsp90 inhibitor, and that the Akt/mTOR pathway might be involved in the downstream regulation that leads to its antiproliferative activity. Moreover, a synergistic anticancer effect was evidenced when SKOV-3 cells were simultaneously treated with compound 24 and cisplatin. Taken together, these results suggest that compound 24 may be a promising lead for the development of new cancer therapies.