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Title 

Gelastatins and their hydroxamates as dual functional inhibitors for TNF-α converting enzyme and matrix metalloproteinases: Synthesis, biological evaluation, and mechanism studies

Authors 

Song Kyu ParkSang Bae HanKiho LeeHo Jae LeeYung Hee KhoHyo Kon ChunYongseok ChoiJae Young YangYeo Dae YoonChang Woo LeeHwan Mook KimH M ChoiH S TaeH Y LeeK Y NamG Han

Publisher 

Elsevier

Issue Date 

2006

Citation 

Biochemical and Biophysical Research Communications, vol. 341, no. 2, pp. 627-634

Keywords 

α-SecretaseinhibitorsTNFα converting enzymetumor necrosis factor alphatumor necrosis factor alpha converting enzymetumor necrosis factor alpha converting enzyme inhibitorcontrolled studydrug mechanismdrug synthesisenzyme inhibitors

Abstract 

The hydroxamic acid analogues (2) of the natural product gelastatins (1) were prepared by 1 step conversion reaction. The synthetic analogues (2) showed potent enzymatic inhibitory activities against MMP-2, MMP-9, and TACE IC 50's of 6, 23, and 28 nM, respectively. In addition, 2 were able to inhibit TNF-α production effectively in mice as well as in a macrophage cell line, RAW 264.7. The protective effect of 2 also was examined on LPS-induced acute septic shock model. The mechanism of TNF-α inhibition was examined by RT-PCR and Western blot analyses. The relation of TACE and α-secretase was examined using cellular α-secretase assays on IMR-32 and SH-SY5Y cell lines. The docking mode of 2 with the catalytic domain of TACE was illustrated to analyze the binding mode for the further analogue design.

ISSN 

0006-291X

Link 

http://dx.doi.org/10.1016/j.bbrc.2005.12.219

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2017-04-19


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