Discovery of Novel 17‐Phenylethylaminegeldanamycin Derivatives as Potent Hsp90 Inhibitors

Twenty‐six 17‐phenylethylamine‐modified geldanamycin derivatives were synthesized and evaluated for antiproliferation activity in human cancer cell lines, LNC aP and MDA ‐ MB ‐231. Five derivatives ( 2j , 2q , 2v , 2x , and 2y ) showed excellent in vitro antitumor activities. Among them, compound 2y was the most potent lead, with IC 50 values of 0.27 ± 0.11 and 0.86 ± 0.23  μ m for LNC aP and MDA ‐ MB ‐231, respectively. In particular, compound 2y was more active than its precursor geldanamycin against LNC ap cells. Liver injury test in mice demonstrated that 2y group showed no significant difference for serum alanine aminotransferase ( ALT ) activity versus vehicle control, indicating that 2y was a promising antitumor candidate. Preliminary structure–activity relationship ( SAR ) and molecular dynamics ( MD ) simulations of this new series of geldanamycin derivatives were also investigated, suggesting a theoretical model of 17‐phenylethylaminegeldanamycins binding to Hsp90.