title: Discovery of novel 17-phenylethylaminegeldanamycin derivatives as potent Hsp90 inhibitors.
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 2 y) showed excellent in vitro antitumor activities. Among them, compound 2 y 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 2 y was more active than its precursor geldanamycin against LNCap cells. Liver injury test in mice demonstrated that 2 y group showed no significant difference for serum alanine aminotransferase (ALT) activity versus vehicle control, indicating that 2 y 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.
authors.affiliation: Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, No. 44 West Wenhua Road, Jinan, Shandong, 250012, China.
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Li
authors.forename: Lejiao
authors.initials: L
authors.lastname: Jia
authors.forename: Jifeng
authors.initials: J
authors.lastname: Wang
authors.forename: Xingkang
authors.initials: X
authors.lastname: Wu
authors.forename: Guowei
authors.initials: G
authors.lastname: Shi
authors.forename: Chunhua
authors.initials: C
authors.lastname: Lu
authors.forename: Yuemao
authors.initials: Y
authors.lastname: Shen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D016227:Benzoquinones / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D047029:Lactams, Macrocyclic / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D008297:Male; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C001277:geldanamycin
keywords: Hsp90; antitumor activities; geldanamycin; hepatotoxicity; synthesis