Discovery of novel celastrol-triazole derivatives with Hsp90-Cdc37 disruption to induce tumor cell apoptosis.

To enhance the disruption of Hsp90-Cdc37, we designed and synthesized a series (27) of CEL-triazole derivatives. Most of the target compounds showed enhanced anti-proliferative activity on four cancer cell lines (MDA-MB-231, MCF-7, HepG2 and A459). Among them, compound 6 showed the best anti-proliferation (IC50 = 0.34 ± 0.01 μM) on MDA-MB-231. Pharmacological studies had found that compound 6 showed a higher ability to disrupt Hsp90-Cdc37 interaction in cells and inhibited the expression of the key Hsp90-Cdc37 clients in a concentration-dependent manner. Further studies indicated that an enhanced covalent binding between compound 6 and thiols (cysteine) might be one of the reasons for the increased activity. Furthermore, compound 6 arrested cells in the G0/G1 phase and induced tumor cell apoptosis significantly. Overall, for cancer treatment, compound 6 was worth further exploring.