Gelastatins and their hydroxamates as dual functional inhibitors for TNF-alpha converting enzyme and matrix metalloproteinases: synthesis, biological evaluation, and mechanism studies

Biochem Biophys Res Commun. 2006 Mar 10;341(2):627-34. doi: 10.1016/j.bbrc.2005.12.219. Epub 2006 Jan 17.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM Proteins / metabolism*
  • ADAM17 Protein
  • 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*
  • Propionates / metabolism
  • Pyrones / chemistry*
  • Pyrones / metabolism
  • RNA, Messenger / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sepsis
  • Time Factors
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Enzyme Inhibitors
  • Hydroxamic Acids
  • Propionates
  • Pyrones
  • RNA, Messenger
  • Tumor Necrosis Factor-alpha
  • gelastatin A
  • gelastatin B
  • Nitric Oxide Synthase Type II
  • Amyloid Precursor Protein Secretases
  • Endopeptidases
  • Aspartic Acid Endopeptidases
  • Bace1 protein, mouse
  • ADAM Proteins
  • Matrix Metalloproteinases
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 9
  • ADAM17 Protein
  • Adam17 protein, mouse