title: Design, synthesis and biological evaluation of 17-arylmethylamine-17-demethoxygeldanamycin derivatives as potent Hsp90 inhibitors.
abstract: Thirty-three 17-arylmethylamine-substituted derivatives of geldanamycin (GA) were designed, synthesized and evaluated for the anti-proliferation activity on human cancer cell lines, LNCaP and MDA-MB-231. Three derivatives (22, 33 and 34) exhibited potent cytotoxicity with IC50 values range from 0.05 to 0.51 μM against both cell lines. Hepatotoxicity test in mice demonstrated that the levels of both AST and ALT of 34-treated group were lower than that of 17-AAG group. Western blot assay indicated that 34 was more potent than 17-AAG in the down-regulation of Hsp90 client proteins CDK4, Her2, EGFR and Raf. Moreover, 34 showed excellent in vivo antitumor activity in the MDA-MB-231 xenograft nude mice, which is superior to 22 and 33, and 17-AAG, indicating that 34 was a promising antitumor candidate. Additionally, preliminary structure-activity relationship (SAR) and molecular dynamics (MD) simulations of this new series of GA derivatives were also investigated, suggesting a theoretical model of 17-arylmethylamine geldanamycins 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, PR China.
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Li
authors.affiliation: Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, No. 44 West Wenhua Road, Jinan, Shandong 250012, PR China.
authors.forename: Lejiao
authors.initials: L
authors.lastname: Jia
authors.affiliation: Department of Urology, The Fifth People's Hospital of Shanghai, Fudan University, No. 801 Heqing Road, Shanghai 200240, PR China; Urology Research Center, Fudan University, No. 801 Heqing Road, Shanghai 200240, PR China.
authors.forename: Jifeng
authors.initials: J
authors.lastname: Wang
authors.affiliation: Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, No. 44 West Wenhua Road, Jinan, Shandong 250012, PR China.
authors.forename: Xingkang
authors.initials: X
authors.lastname: Wu
authors.affiliation: Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, No. 44 West Wenhua Road, Jinan, Shandong 250012, PR China.
authors.forename: Huilin
authors.initials: H
authors.lastname: Hao
authors.affiliation: Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, No. 44 West Wenhua Road, Jinan, Shandong 250012, PR China.
authors.forename: Hongjiao
authors.initials: H
authors.lastname: Xu
authors.affiliation: Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, No. 44 West Wenhua Road, Jinan, Shandong 250012, PR China.
authors.forename: Yunfei
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Urology, The Fifth People's Hospital of Shanghai, Fudan University, No. 801 Heqing Road, Shanghai 200240, PR China; Urology Research Center, Fudan University, No. 801 Heqing Road, Shanghai 200240, PR China.
authors.forename: Guowei
authors.initials: G
authors.lastname: Shi
authors.affiliation: Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, No. 44 West Wenhua Road, Jinan, Shandong 250012, PR China.
authors.forename: Chunhua
authors.initials: C
authors.lastname: Lu
authors.affiliation: Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, No. 44 West Wenhua Road, Jinan, Shandong 250012, PR China. Electronic address: yshen@sdu.edu.cn.
authors.forename: Yuemao
authors.initials: Y
authors.lastname: Shen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D016227:Benzoquinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D047029:Lactams, Macrocyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D008099:Liver / Q000187:drug effects; D008297:Male; D051379:Mice; D008958:Models, Molecular; D011487:Protein Conformation
chemical_list: D000970:Antineoplastic Agents; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C001277:geldanamycin
keywords: Antitumor activities; Geldanamycin; Hepatotoxicity; Hsp90; Molecular dynamics