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Targeting copper(II)-induced oxidative stress and the acetylcholinesterase system in Alzheimer's disease using multifunctional tacrine-coumarin hybrid molecules

Identifikátory výsledku

  • Kód výsledku v IS VaVaI

    <a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F60162694%3AG44__%2F16%3A43875612" target="_blank" >RIV/60162694:G44__/16:43875612 - isvavai.cz</a>

  • Nalezeny alternativní kódy

    RIV/62690094:18450/16:50005080 RIV/00179906:_____/16:10324781

  • Výsledek na webu

    <a href="http://www.sciencedirect.com/science/article/pii/S0162013416301258" target="_blank" >http://www.sciencedirect.com/science/article/pii/S0162013416301258</a>

  • DOI - Digital Object Identifier

    <a href="http://dx.doi.org/10.1016/j.jinorgbio.2016.05.001" target="_blank" >10.1016/j.jinorgbio.2016.05.001</a>

Alternativní jazyky

  • Jazyk výsledku

    angličtina

  • Název v původním jazyce

    Targeting copper(II)-induced oxidative stress and the acetylcholinesterase system in Alzheimer's disease using multifunctional tacrine-coumarin hybrid molecules

  • Popis výsledku v původním jazyce

    Alzheimer's disease is a multifactorial disease that is characterized mainly by Amyloid-beta (A-beta) 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 = 38 nM) and compound 5b was the most potent inhibitor of butyrylcholinesterase (hBuChE, IC50 = 63 nM). Compound 5c was the strongest inhibitor of A-beta(1-40) 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.

  • Název v anglickém jazyce

    Targeting copper(II)-induced oxidative stress and the acetylcholinesterase system in Alzheimer's disease using multifunctional tacrine-coumarin hybrid molecules

  • Popis výsledku anglicky

    Alzheimer's disease is a multifactorial disease that is characterized mainly by Amyloid-beta (A-beta) 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 = 38 nM) and compound 5b was the most potent inhibitor of butyrylcholinesterase (hBuChE, IC50 = 63 nM). Compound 5c was the strongest inhibitor of A-beta(1-40) 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.

Klasifikace

  • Druh

    J<sub>x</sub> - Nezařazeno - Článek v odborném periodiku (Jimp, Jsc a Jost)

  • CEP obor

    CE - Biochemie

  • OECD FORD obor

Návaznosti výsledku

  • Projekt

    <a href="/cs/project/NV15-30954A" target="_blank" >NV15-30954A: Vývoj multifunkčního léčiva na Alzheimerovu nemoc: kombinace inhibitoru AChE a derivátu melatoninu</a><br>

  • Návaznosti

    I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Ostatní

  • Rok uplatnění

    2016

  • Kód důvěrnosti údajů

    S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Údaje specifické pro druh výsledku

  • Název periodika

    Journal of Inorganic Biochemistry

  • ISSN

    0162-0134

  • e-ISSN

  • Svazek periodika

    161

  • Číslo periodika v rámci svazku

    August

  • Stát vydavatele periodika

    US - Spojené státy americké

  • Počet stran výsledku

    11

  • Strana od-do

    52-62

  • Kód UT WoS článku

    000378977700007

  • EID výsledku v databázi Scopus