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, Hyokon Chun, Yongseok Choi, Jae Young Yang, Yeo Dae Yoon, Chang Woo Lee, Hwan Mook Kim, Hyun Moo Choi, Hyun Seop Tae, Hee Yoon Lee, Ky Youb Nam, Gyoonhee Han

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11 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)627-634
Number of pages8
JournalBiochemical and Biophysical Research Communications
Volume341
Issue number2
DOIs
Publication statusPublished - 2006 Mar 10
Externally publishedYes

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Keywords

  • α-Secretase
  • Inhibitors
  • TNFα converting enzyme
  • Tumor necrosis factor alpha

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

Cite this

Park, S. K., Han, S. B., Lee, K., Lee, H. J., Kho, Y. H., Chun, H., Choi, Y., Yang, J. Y., Yoon, Y. D., Lee, C. W., Kim, H. M., Choi, H. M., Tae, H. S., Lee, H. Y., Nam, K. Y., & Han, G. (2006). Gelastatins and their hydroxamates as dual functional inhibitors for TNF-α converting enzyme and matrix metalloproteinases: Synthesis, biological evaluation, and mechanism studies. Biochemical and Biophysical Research Communications, 341(2), 627-634. https://doi.org/10.1016/j.bbrc.2005.12.219