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

[Display omitted] •Compound 6 showed a higher ability to disrupt heat shock protein 90–cell division cycle 37 (Hsp90-Cdc37) interaction.•There was a enhanced covalent binding between compound 6 and thiols (cysteine).•Compound 6 arrested MDA-MB-231 cells in the G0/G1 phase, and induced apoptosis sign...

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Veröffentlicht in:Bioorganic chemistry 2021-06, Vol.111, p.104867-104867, Article 104867
Hauptverfasser: Li, Na, Chen, Cheng, zhu, Huiting, Shi, Zhixian, Sun, Jianbo, Chen, Li
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Sprache:eng
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Zusammenfassung:[Display omitted] •Compound 6 showed a higher ability to disrupt heat shock protein 90–cell division cycle 37 (Hsp90-Cdc37) interaction.•There was a enhanced covalent binding between compound 6 and thiols (cysteine).•Compound 6 arrested MDA-MB-231 cells in the G0/G1 phase, and induced apoptosis significantly. 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.
ISSN:0045-2068
1090-2120
DOI:10.1016/j.bioorg.2021.104867