title: Targeting copper(II)-induced oxidative stress and the acetylcholinesterase system in Alzheimer's disease using multifunctional tacrine-coumarin hybrid molecules.
abstract: Alzheimer's disease is a multifactorial disease that is characterized mainly by Amyloid-β (A-β) deposits, cholinergic deficit and extensive metal (copper, iron)-induced oxidative stress. In this work we present details of the synthesis, antioxidant and copper-chelating properties, DNA protection study, cholinergic activity and amyloid-antiaggregation properties of new multifunctional tacrine-7-hydroxycoumarin hybrids. The mode of interaction between copper(II) and hybrids and interestingly, the reduction of Cu(II) to Cu(I) species (for complexes Cu-5e-g) were confirmed by EPR measurements. EPR spin trapping on the model Fenton reaction, using 5,5-dimethyl-1-pyrroline N-oxide (DMPO) as a spin trap, demonstrated a significantly suppressed formation of hydroxyl radicals for the Cu-5e complex in comparison with free copper(II). This suggests that compound 5e upon coordination to free copper ion prevents the Cu(II)-catalyzed decomposition of hydrogen peroxide, which in turn may alleviate oxidative stress-induced damage. Protective activity of hybrids 5c and 5e against DNA damage in a Fenton system (copper catalyzed) was found to be in excellent agreement with the EPR spin trapping study. Compound 5g was the most effective in the inhibition of acetylcholinesterase (hAChE, IC50=38nM) and compound 5b was the most potent inhibitor of butyrylcholinesterase (hBuChE, IC50=63nM). Compound 5c was the strongest inhibitor of A-β1-40 aggregation, although a significant inhibition (>50%) was detected for compounds 5b, 5d, 5e and 5g. Collectively, these results suggest that the design and investigation of multifunctional agents containing along with the acetylcholinesterase inhibitory segment also an antioxidant moiety capable of alleviating metal (copper)-induced oxidative stress, may be of importance in the treatment of Alzheimer's disease.
authors.affiliation: Institute of Chemistry, Faculty of Science, P. J. Safarik University, SK-041 67 Kosice, Slovakia.
authors.forename: Slavka
authors.initials: S
authors.lastname: Hamulakova
authors.affiliation: Department of Physical Chemistry, Faculty of Chemical and Food Technology, Slovak University of Technology in Bratislava, SK-812 37 Bratislava, Slovakia.
authors.forename: Patrik
authors.initials: P
authors.lastname: Poprac
authors.affiliation: Department of Chemistry, Faculty of Natural Sciences, Constantine the Philosopher University, SK-949 74 Nitra, Slovakia.
authors.forename: Klaudia
authors.initials: K
authors.lastname: Jomova
authors.affiliation: Department of Physical Chemistry, Faculty of Chemical and Food Technology, Slovak University of Technology in Bratislava, SK-812 37 Bratislava, Slovakia.
authors.forename: Vlasta
authors.initials: V
authors.lastname: Brezova
authors.affiliation: Department of Chemistry, Faculty of Natural Sciences, Constantine the Philosopher University, SK-949 74 Nitra, Slovakia.
authors.forename: Peter
authors.initials: P
authors.lastname: Lauro
authors.affiliation: Department of Chemistry, Faculty of Natural Sciences, Constantine the Philosopher University, SK-949 74 Nitra, Slovakia.
authors.forename: Lenka
authors.initials: L
authors.lastname: Drostinova
authors.affiliation: Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence, CZ-500 01 Hradec Kralove, Czech Republic.
authors.forename: Daniel
authors.initials: D
authors.lastname: Jun
authors.affiliation: Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence, CZ-500 01 Hradec Kralove, Czech Republic.
authors.forename: Vendula
authors.initials: V
authors.lastname: Sepsova
authors.affiliation: Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence, CZ-500 01 Hradec Kralove, Czech Republic.
authors.forename: Martina
authors.initials: M
authors.lastname: Hrabinova
authors.affiliation: Biomedical Research Centre, University Hospital Hradec Kralove, CZ-500 05 Hradec Kralove, Czech Republic.
authors.forename: Ondrej
authors.initials: O
authors.lastname: Soukup
authors.affiliation: Institute of Chemistry, Faculty of Science, P. J. Safarik University, SK-041 67 Kosice, Slovakia.
authors.forename: Pavol
authors.initials: P
authors.lastname: Kristian
authors.affiliation: Department of Biophysics, Institute of Experimental Physics, Slovak Academy of Sciences, SK-041 67 Kosice, Slovakia; Department of Medical and Clinical Biochemistry, Faculty of Medicine, P. J. Safarik University, SK-040 11 Kosice, Slovakia.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Gazova
authors.affiliation: Institute of Chemistry, Faculty of Science, P. J. Safarik University, SK-041 67 Kosice, Slovakia; Department of Biophysics, Institute of Experimental Physics, Slovak Academy of Sciences, SK-041 67 Kosice, Slovakia.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Bednarikova
authors.affiliation: Biomedical Research Centre, University Hospital Hradec Kralove, CZ-500 05 Hradec Kralove, Czech Republic; The Center for Basic and Applied Research, University Hradec Kralove, Hradec Kralove, CZ-500 01, Czech Republic.
authors.forename: Kamil
authors.initials: K
authors.lastname: Kuca
authors.affiliation: Department of Physical Chemistry, Faculty of Chemical and Food Technology, Slovak University of Technology in Bratislava, SK-812 37 Bratislava, Slovakia; The Center for Basic and Applied Research, University Hradec Kralove, Hradec Kralove, CZ-500 01, Czech Republic. Electronic address: marian.valko@stuba.sk.
authors.forename: Marian
authors.initials: M
authors.lastname: Valko
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry*; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D002091:Butyrylcholinesterase / Q000737:chemistry; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry; D003300:Copper / Q000737:chemistry*; D003374:Coumarins / Q000138:chemical synthesis / Q000737:chemistry; D058851:GPI-Linked Proteins / Q000737:chemistry; D006801:Humans; D018384:Oxidative Stress; D010446:Peptide Fragments / Q000737:chemistry*; D013619:Tacrine / Q000138:chemical synthesis / Q000737:chemistry
chemical_list: D016229:Amyloid beta-Peptides; D002800:Cholinesterase Inhibitors; D003374:Coumarins; D058851:GPI-Linked Proteins; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D013619:Tacrine; D003300:Copper; C548244:ACHE protein, human; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase
keywords: Alzheimer's disease; DNA damage; Free copper; Oxidative stress; Tacrine-coumarin hybrids