2. Academic Validation
  3. Discovery of diamine-linked 17-aroylamido-17-demethoxygeldanamycins as potent Hsp90 inhibitors

Discovery of diamine-linked 17-aroylamido-17-demethoxygeldanamycins as potent Hsp90 inhibitors

  • Eur J Med Chem. 2014 Nov 24:87:346-63. doi: 10.1016/j.ejmech.2014.09.078.
Zhenyu Li 1,  Lejiao Jia 2,  Jifeng Wang 3,  Xingkang Wu 1,  Huilin Hao 1,  Yunfei Wu 1,  Hongjiao Xu 1,  Zhen Wang 1,  Guowei Shi 3,  Chunhua Lu 1,  Yuemao Shen 4
Affiliations

Affiliations

  • 1 Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, No. 44 West Wenhua Road, Jinan 250012, Shandong, PR China.
  • 2 Department of Pharmacy, Shandong University Qilu Hospital, No. 107 West Wenhua Road, Jinan 250012, Shandong, PR China.
  • 3 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.
  • 4 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.
PMID: 25277067 DOI: 10.1016/j.ejmech.2014.09.078
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.

Keywords

Antitumor activities; Geldanamycin; Hepatotoxicity; Hsp90; Molecular dynamics; Synthesis.

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