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Medicinal Chemistry


ISSN (Print): 1573-4064
ISSN (Online): 1875-6638

In vitro and in vivo Evaluation of 17-phenylpropylamine/phenoxyethylamine- 17-demethoxygeldanamycins as Potent Hsp90 Inhibitors

Author(s): Zhenyu Li, Lejiao Jia, Hongjiao Xu, Chunhua Lu and Yuemao Shena

Volume 11 , Issue 5 , 2015

Page: [482 - 488] Pages: 7

DOI: 10.2174/1573406411666141230104953

Price: $65


A series of 17-phenylpropylamine/phenoxyethylamine-substituted derivatives of geldanamycin (GA) was synthesized and evaluated for the anti-proliferation activity on human cancer cell line MDA-MB-231. All the derivatives exhibited potent cytotoxicity with IC50 values range from 0.35 to 1.03 M. Among them, 17-(2-phenoxyethylamino)-17-demethoxygeldanamycin (3) was identified as the most potent compound. Hepatotoxicity test in mice demonstrated that the levels of both aspartate aminotransferase (AST) and alanine aminotransferase (ALT) of 3-treated group were lower than that of GA-treated group, indicating that compound 3 was a promising antitumor candidate. Additionally, the Hsp90 inhibitory activity of compound 3 was more active than 17-AAG. Docking and molecular dynamics (MD) refinements of this new series of GA derivatives were also investigated, suggesting a theoretical model between 17- phenylpropylamine/phenoxyethyl-amines and Hsp90.

Keywords: GA, Hsp90, antitumor activities, hepatotoxicity.

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