| 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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MedLine Citation:
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PMID: 16438938 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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 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. |
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Authors:
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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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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2006-01-17 |
Journal Detail:
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Title: Biochemical and biophysical research communications Volume: 341 ISSN: 0006-291X ISO Abbreviation: Biochem. Biophys. Res. Commun. Publication Date: 2006 Mar |
Date Detail:
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Created Date: 2006-01-31 Completed Date: 2006-04-18 Revised Date: 2009-11-19 |
Medline Journal Info:
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Nlm Unique ID: 0372516 Medline TA: Biochem Biophys Res Commun Country: United States |
Other Details:
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Languages: eng Pagination: 627-34 Citation Subset: IM |
Affiliation:
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Korea Research Institute of Bioscience and Biotechnology, 52 Eoeun-dong, Yuseong-gu, Daejeon 305-333, Republic of Korea. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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ADAM Proteins
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metabolism* Amyloid Precursor Protein Secretases Animals Aspartic Acid Endopeptidases Blotting, Western Catalytic Domain Cell Line Disease Models, Animal Dose-Response Relationship, Drug Endopeptidases / metabolism Enzyme Inhibitors / pharmacology Hydroxamic Acids / chemistry* Immunoassay Inhibitory Concentration 50 Matrix Metalloproteinase 2 / metabolism Matrix Metalloproteinase 9 / metabolism Matrix Metalloproteinases / metabolism* Mice Models, Chemical Models, Molecular Nitric Oxide Synthase Type II / metabolism Propionates / chemistry*, metabolism Pyrones / chemistry*, metabolism RNA, Messenger / metabolism Reverse Transcriptase Polymerase Chain Reaction Sepsis Time Factors Tumor Necrosis Factor-alpha / metabolism |
| Chemical | |
Reg. No./Substance:
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0/Enzyme Inhibitors; 0/Hydroxamic Acids; 0/Propionates; 0/Pyrones; 0/RNA, Messenger; 0/Tumor Necrosis Factor-alpha; 0/gelastatin A; 0/gelastatin B; EC 1.14.13.39/Nitric Oxide Synthase Type II; EC 3.4.-/Amyloid Precursor Protein Secretases; EC 3.4.-/Endopeptidases; EC 3.4.23.-/Aspartic Acid Endopeptidases; EC 3.4.23.46/Bace1 protein, mouse; EC 3.4.24.-/ADAM Proteins; EC 3.4.24.-/Matrix Metalloproteinases; EC 3.4.24.-/tumor necrosis factor-alpha convertase; EC 3.4.24.24/Matrix Metalloproteinase 2; EC 3.4.24.35/Matrix Metalloproteinase 9 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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