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Synthesis and biological evaluation of geldanamycin–ferulic acid conjugate as a potent Hsp90 inhibitor

A novel geldanamycin–ferulic acid conjugate LZY228 was prepared and evaluated for anti-proliferation activity on human cancer cell line MDA-MB-231. Compound LZY228 exhibited potent cytotoxicity with IC(50) value of 0.27 μM, which was more potent than 17-AAG. Hepatotoxicity test in mice demonstrated...

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Detalles Bibliográficos
Autores principales: Li, Zhenyu, Jia, Lejiao, Tang, Hui, Shen, Yuemao, Shen, Chengwu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Royal Society of Chemistry 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9076653/
https://www.ncbi.nlm.nih.gov/pubmed/35542888
http://dx.doi.org/10.1039/c9ra08665j
Descripción
Sumario:A novel geldanamycin–ferulic acid conjugate LZY228 was prepared and evaluated for anti-proliferation activity on human cancer cell line MDA-MB-231. Compound LZY228 exhibited potent cytotoxicity with IC(50) value of 0.27 μM, which was more potent than 17-AAG. Hepatotoxicity test in mice demonstrated that the levels of both AST and ALT of LZY228-treated group were lower than that of GA-treated group, indicating that LZY228 was a promising antitumor candidate. In addition, excellent in vivo antitumor potency of LZY228 was observed in MDA-MB-231 xenograft model, which was superior to reference drug 17-AAG. Docking and MD refinement of the Hsp90-LZY228 complex give us an explanation of theoretical binding model of 17-ferulamido-17-demethoxygeldanamycins at molecular level.