Discovery of Novel 17-Phenylethylaminegeldanamycin Derivatives as Potent Hsp90 Inhibitors |
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| Authors: | Zhenyu Li Lejiao Jia Jifeng Wang Xingkang Wu Guowei Shi Chunhua Lu Yuemao Shen |
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| Affiliation: | 1. Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, No. 44 West Wenhua Road, Jinan, Shandong, 250012 China;2. Department of Pharmacy, Shandong University Qilu Hospital, No. 107 West Wenhua Road, Jinan, Shandong, 250012 China;3. Department of Urology, the Fifth People's Hospital of Shanghai, Fudan University, No. 801 Heqing Road, Shanghai, 200240 China Urology Research Center, Fudan University, No. 801 Heqing Road, Shanghai, 200240 China |
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| Abstract: | Twenty-six 17-phenylethylamine-modified geldanamycin derivatives were synthesized and evaluated for antiproliferation activity in human cancer cell lines, LNCaP 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 IC50 values of 0.27 ± 0.11 and 0.86 ± 0.23 μm for LNCaP and MDA-MB-231, respectively. In particular, compound 2y was more active than its precursor geldanamycin against LNCap 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. |
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| Keywords: | antitumor activities geldanamycin hepatotoxicity Hsp90 synthesis |
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