|Gelastatins and their hydroxamates as dual functional inhibitors for TNF-alpha converting enzyme and matrix metalloproteinases: synthesis, biological evaluation, and mechanism studies.|
|PMID: 16438938 Owner: NLM Status: MEDLINE|
|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.|
|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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|Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2006-01-17|
|Title: Biochemical and biophysical research communications Volume: 341 ISSN: 0006-291X ISO Abbreviation: Biochem. Biophys. Res. Commun. Publication Date: 2006 Mar|
|Created Date: 2006-01-31 Completed Date: 2006-04-18 Revised Date: 2009-11-19|
Medline Journal Info:
|Nlm Unique ID: 0372516 Medline TA: Biochem Biophys Res Commun Country: United States|
|Languages: eng Pagination: 627-34 Citation Subset: IM|
|Korea Research Institute of Bioscience and Biotechnology, 52 Eoeun-dong, Yuseong-gu, Daejeon 305-333, Republic of Korea.|
|APA/MLA Format Download EndNote Download BibTex|
Amyloid Precursor Protein Secretases
Aspartic Acid Endopeptidases
Disease Models, Animal
Dose-Response Relationship, Drug
Endopeptidases / metabolism
Enzyme Inhibitors / pharmacology
Hydroxamic Acids / chemistry*
Inhibitory Concentration 50
Matrix Metalloproteinase 2 / metabolism
Matrix Metalloproteinase 9 / metabolism
Matrix Metalloproteinases / metabolism*
Nitric Oxide Synthase Type II / metabolism
Propionates / chemistry*, metabolism
Pyrones / chemistry*, metabolism
RNA, Messenger / metabolism
Reverse Transcriptase Polymerase Chain Reaction
Tumor Necrosis Factor-alpha / metabolism
|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 126.96.36.199/Nitric Oxide Synthase Type II; EC 3.4.-/Amyloid Precursor Protein Secretases; EC 3.4.-/Endopeptidases; EC 3.4.23.-/Aspartic Acid Endopeptidases; EC 188.8.131.52/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 184.108.40.206/Matrix Metalloproteinase 2; EC 220.127.116.11/Matrix Metalloproteinase 9|
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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