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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