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.
|Number of pages||8|
|Journal||Biochemical and Biophysical Research Communications|
|Publication status||Published - 2006 Mar 10|
- TNFα converting enzyme
- Tumor necrosis factor alpha
ASJC Scopus subject areas
- Molecular Biology