Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 87, Issue -, Pages 346-363Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2014.09.078
Keywords
Geldanamycin; Synthesis; Hsp90; Antitumor activities; Hepatotoxicity; Molecular dynamics
Categories
Funding
- 973 Program [2010CB833802]
- NSFC [81273384, 81302214, 91313303]
- Program for Changjiang Scholars and Innovative Research Team in University [IRT13028]
- Distinguished Young Scholars Grant [30325044]
- Independent Innovation Foundation of Shandong University [2010TB016]
- Post-graduate Independent Innovation Foundation of Shandong University [YZC12095]
- Shanghai Nature Science Foundation of Shanghai Science and Technology Committee [13ZR1432700]
Ask authors/readers for more resources
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 mu M) 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. (C) 2014 Elsevier Masson SAS. All rights reserved.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available