title: Discovery of diamine-linked 17-aroylamido-17-demethoxygeldanamycins as potent Hsp90 inhibitors.
abstract: Heat shock protein 90 (Hsp90) is an attractive target for the development of antitumor agents. Geldanamycin (GA), the first Hsp90 inhibitor, has potent antitumor activity, but showed significant hepatotoxicity. To get rid of the hepatotoxicity of GA, in this study we incorporated aroyl groups via three types of linkers (4-aminomethylpiperidine, 1,4-butanediamine, and 1,6-hexanediamine) to the 17-position of GA and synthesized fifty-three 17-diamine-linked 17-aroylamido-17-demethoxygeldanamycins. All the derivatives were evaluated by MTT assay for their inhibitory activities against human breast cancer cell line MDA-MB-231. Among these compounds, 17-(6-(3,4,5-trimethoxycinnamamido)hexylamino)-17-demethoxygeldanamycin (7h29) showed the most potent cytotoxicity against MDA-MB-231 (IC50 = 0.19 ± 0.02 μM) with the lowest hepatotoxicity (AST = 181.0 ± 23.6 U/L, ALT = 40.4 ± 11.8 U/L). Compared to tanespimycin (17-AAG), 7h29 exhibited lower hepatotoxicity in mice, higher Hsp90 inhibitory activity in vitro and antitumor activity in human breast carcinoma (MDA-MB-231) xenograft nude mice.
authors.affiliation: Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, No. 44 West Wenhua Road, Jinan 250012, Shandong, PR China.
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Pharmacy, Shandong University Qilu Hospital, No. 107 West Wenhua Road, Jinan 250012, Shandong, PR China.
authors.forename: Lejiao
authors.initials: L
authors.lastname: Jia
authors.affiliation: cDepartment 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 250012, Shandong, 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 250012, Shandong, 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 250012, Shandong, PR China.
authors.forename: Yunfei
authors.initials: Y
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 250012, Shandong, 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 250012, Shandong, PR China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Wang
authors.affiliation: cDepartment 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 250012, Shandong, 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 250012, Shandong, 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* / Q000378:metabolism / Q000494:pharmacology*; D016227:Benzoquinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003959:Diamines / Q000737:chemistry*; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D047029:Lactams, Macrocyclic / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D016227:Benzoquinones; D003959:Diamines; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C001277:geldanamycin
keywords: Antitumor activities; Geldanamycin; Hepatotoxicity; Hsp90; Molecular dynamics; Synthesis