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 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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ADAM Proteins / metabolism*
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ADAM17 Protein
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Amyloid Precursor Protein Secretases
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Animals
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Aspartic Acid Endopeptidases
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Blotting, Western
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Catalytic Domain
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Cell Line
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Disease Models, Animal
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Dose-Response Relationship, Drug
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Endopeptidases / metabolism
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Enzyme Inhibitors / pharmacology
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Hydroxamic Acids / chemistry*
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Immunoassay
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Inhibitory Concentration 50
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Matrix Metalloproteinase 2 / metabolism
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Matrix Metalloproteinase 9 / metabolism
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Matrix Metalloproteinases / metabolism*
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Mice
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Models, Chemical
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Models, Molecular
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Nitric Oxide Synthase Type II / metabolism
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Propionates / chemistry*
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Propionates / metabolism
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Pyrones / chemistry*
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Pyrones / metabolism
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RNA, Messenger / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Sepsis
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Time Factors
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Tumor Necrosis Factor-alpha / metabolism
Substances
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Enzyme Inhibitors
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Hydroxamic Acids
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Propionates
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Pyrones
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RNA, Messenger
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Tumor Necrosis Factor-alpha
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gelastatin A
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gelastatin B
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Nitric Oxide Synthase Type II
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Amyloid Precursor Protein Secretases
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Endopeptidases
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Aspartic Acid Endopeptidases
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Bace1 protein, mouse
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ADAM Proteins
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Matrix Metalloproteinases
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Matrix Metalloproteinase 2
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Matrix Metalloproteinase 9
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ADAM17 Protein
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Adam17 protein, mouse