title: PAC-1 and isatin derivatives are weak matrix metalloproteinase inhibitors.
abstract: BACKGROUND
  Dysregulation of apoptotic cell death is observed in a large number of pathological conditions. As caspases are central enzymes in the regulation of apoptosis, a large number of procaspase-activating compounds (PAC-1 derivatives) and inhibitors (isatin derivatives) have been developed. Matrix metalloproteinases (MMPs) have been shown to have a dual role in apoptosis. Hence compounds that either activate or inhibit caspases should ideally not affect MMPs. As many PAC-1 derivatives contain a zinc chelating ortho-hydroxy N-acyl hydrazone moiety and isatin derivatives has two carbonyl groups on the indole core, it was of interest to determine to which extent these compounds can inhibit MMPs.
  
  
  METHODS
  Eight PAC-1 and five isatin derivatives were docked into MMP-9 and MMP-14. The same compounds were synthesized, characterized, purified and tested as inhibitors of MMP-9 and MMP-14, using fluorescence quenched peptide and biological substrates. Some of the compounds were also tested for fluorescence quenching.
  
  
  RESULTS
  Molecular docking suggested that the different compounds can bind to the MMP active sites. However, kinetic studies showed that neither of these compounds was a strong MMP inhibitor. IC50 values over 100μM were obtained after the enzyme activities were corrected for quenching. These IC50 values are far above the concentrations needed to activate or inhibit the caspases.
  
  
  CONCLUSIONS
  The use of PAC-1 and isatin derivatives against caspases should have little or no effect on the activity of MMPs.
  
  
  CONCLUSIONS
  Activators and inhibitors of caspases are important potential therapeutic agents for several diseases such as cancer, diabetes and neurodegenerative disorders.
authors.affiliation: Department of Medical Biology, Faculty of Health Sciences, UiT-The Arctic University of Norway, 9037 Tromsø, Norway.
authors.forename: Stian
authors.initials: S
authors.lastname: Sjøli
authors.affiliation: Department of Medical Biology, Faculty of Health Sciences, UiT-The Arctic University of Norway, 9037 Tromsø, Norway.
authors.forename: Ann Iren
authors.initials: AI
authors.lastname: Solli
authors.affiliation: School of Pharmacy, Department of Pharmaceutical Chemistry, University of Oslo, PO Box 1068, N-0316 Oslo, Norway.
authors.forename: Oyvind
authors.initials: O
authors.lastname: Akselsen
authors.affiliation: School of Pharmacy, Department of Pharmaceutical Chemistry, University of Oslo, PO Box 1068, N-0316 Oslo, Norway.
authors.forename: Yang
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Department of Medical Biology, Faculty of Health Sciences, UiT-The Arctic University of Norway, 9037 Tromsø, Norway.
authors.forename: Eli
authors.initials: E
authors.lastname: Berg
authors.affiliation: School of Pharmacy, Department of Pharmaceutical Chemistry, University of Oslo, PO Box 1068, N-0316 Oslo, Norway.
authors.forename: Trond Vidar
authors.initials: TV
authors.lastname: Hansen
authors.affiliation: Department of Medical Biology, Faculty of Health Sciences, UiT-The Arctic University of Norway, 9037 Tromsø, Norway.
authors.forename: Ingebrigt
authors.initials: I
authors.lastname: Sylte
authors.affiliation: Department of Medical Biology, Faculty of Health Sciences, UiT-The Arctic University of Norway, 9037 Tromsø, Norway. Electronic address: jan.o.winberg@uit.no.
authors.forename: Jan-Olof
authors.initials: JO
authors.lastname: Winberg
mesh_terms: D020134:Catalytic Domain; D045744:Cell Line, Tumor; D006801:Humans; D006835:Hydrazones / Q000737:chemistry*; D007510:Isatin / Q000737:chemistry*; D053511:Matrix Metalloproteinase 14 / Q000737:chemistry*; D020780:Matrix Metalloproteinase 9 / Q000737:chemistry*; D062105:Molecular Docking Simulation; D010879:Piperazines / Q000737:chemistry*; D011480:Protease Inhibitors / Q000737:chemistry*
chemical_list: C514579:(4-benzylpiperazin-1-yl)acetic acid (3-allyl-2-hydroxybenzylidene)hydrazine; D006835:Hydrazones; D010879:Piperazines; D011480:Protease Inhibitors; D007510:Isatin; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14
keywords: Docking; Inhibition; Isatin derivatives; MMPs; PAC-1