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

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The hydroxamic acid analogues (2) of the natural product gelastatins (1) were prepared by I step conversion reaction. The synthetic analogues (2) showed potent enzymatic inhibitory activities against MMP-2, MMP-9, and TACE IC50's of 6, 23, and 28 nM, respectively. In addition, 2 were able to inhibit TNF-alpha 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-alpha inhibition was examined by RT-PCR and Western blot analyses. The relation of TACE and alpha-secretase was examined Using cellular alpha-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. (c) 2006 Elsevier Inc. All rights reserved.
Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
Issue Date
2006-03
Language
English
Article Type
Article
Keywords

NECROSIS-FACTOR-ALPHA; RHEUMATOID-ARTHRITIS; TACE INHIBITORS; CATALYTIC DOMAIN; DISCOVERY; DESIGN; P1' DISINTEGRIN; STRATEGIES; PRECURSOR

Citation

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, v.341, no.2, pp.627 - 634

ISSN
0006-291X
DOI
10.1016/j.bbrc.2005.12.219
URI
http://hdl.handle.net/10203/87134
Appears in Collection
CH-Journal Papers(저널논문)
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