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

Result code in 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>

Alternative codes found

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

Result on the web

<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>

Result language

angličtina

Original language name

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

Original language description

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.

Czech name

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Czech description

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Type

J_x - Unclassified - Peer-reviewed scientific article (Jimp, Jsc and Jost)

CEP classification

CE - Biochemistry

OECD FORD branch

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Project

<a href="/en/project/NV15-30954A" target="_blank" >NV15-30954A: Development of multi-target drugs for Alzheimer´s disease: combination of AChE inhibitor and melatonin derivative</a><br>

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2016

Confidentiality

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

Name of the periodical

Journal of Inorganic Biochemistry

ISSN

0162-0134

e-ISSN

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Volume of the periodical

161

Issue of the periodical within the volume

August

Country of publishing house

US - UNITED STATES

Number of pages

11

Pages from-to

52-62

UT code for WoS article

000378977700007

EID of the result in the Scopus database

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