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
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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
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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
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