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

Research output: Contribution to journalArticle

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

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Amyloid Precursor Protein Secretases
Matrix Metalloproteinases
Cells
Hydroxamic Acids
Conversion Disorder
Macrophages
Enzymes
Septic Shock
Biological Products
Assays
Catalytic Domain
Western Blotting
Cell Line
Polymerase Chain Reaction
RAW 264.7 Cells
Inhibition (Psychology)

All Science Journal Classification (ASJC) codes

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Park, Song Kyu ; Han, Sang Bae ; Lee, Kiho ; Lee, Ho Jae ; Kho, Yung Hee ; Chun, Hyokon ; Choi, Yongseok ; Yang, Jae Young ; Yoon, Yeo Dae ; Lee, Chang Woo ; Kim, Hwan Mook ; Choi, Hyun Moo ; Tae, Hyun Seop ; Lee, Hee Yoon ; Nam, Ky Youb ; Han, Gyoonhee. / Gelastatins and their hydroxamates as dual functional inhibitors for TNF-α converting enzyme and matrix metalloproteinases : Synthesis, biological evaluation, and mechanism studies. In: Biochemical and Biophysical Research Communications. 2006 ; Vol. 341, No. 2. pp. 627-634.
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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. / Park, Song Kyu; Han, Sang Bae; Lee, Kiho; Lee, Ho Jae; Kho, Yung Hee; Chun, Hyokon; Choi, Yongseok; Yang, Jae Young; Yoon, Yeo Dae; Lee, Chang Woo; Kim, Hwan Mook; Choi, Hyun Moo; Tae, Hyun Seop; Lee, Hee Yoon; Nam, Ky Youb; Han, Gyoonhee.

In: Biochemical and Biophysical Research Communications, Vol. 341, No. 2, 10.03.2006, p. 627-634.

Research output: Contribution to journalArticle

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AU - Park, Song Kyu

AU - Han, Sang Bae

AU - Lee, Kiho

AU - Lee, Ho Jae

AU - Kho, Yung Hee

AU - Chun, Hyokon

AU - Choi, Yongseok

AU - Yang, Jae Young

AU - Yoon, Yeo Dae

AU - Lee, Chang Woo

AU - Kim, Hwan Mook

AU - Choi, Hyun Moo

AU - Tae, Hyun Seop

AU - Lee, Hee Yoon

AU - Nam, Ky Youb

AU - Han, Gyoonhee

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