Gelastatins and their hydroxamates as dual functional inhibitors for TNF-α converting enzyme and matrix metalloproteinases: Synthesis, biological evaluation, and mechanism studies
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- Gelastatins and their hydroxamates as dual functional inhibitors for TNF-α converting enzyme and matrix metalloproteinases: Synthesis, biological evaluation, and mechanism studies
- Song Kyu Park; Sang Bae Han; Kiho Lee; Ho Jae Lee; Yung Hee Kho; Hyo Kon Chun; Yongseok Choi; Jae Young Yang; Yeo Dae Yoon; Chang Woo Lee; Hwan Mook Kim; H M Choi; H S Tae; H Y Lee; K Y Nam; G Han
- Bibliographic Citation
- Biochemical and Biophysical Research Communications, vol. 341, no. 2, pp. 627-634
- Publication Year
- 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.
- α-SecretaseInhibitorsTNFα converting enzymeTumor necrosis factor alpha
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- Division of Bio Technology Innovation > SME Support Center > 1. Journal Articles
Ochang Branch Institute > Division of National Bio-Infrastructure > Laboratory Animal Resource & Research Center > 1. Journal Articles
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