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: Slavka Hamulakova, Patrik Poprac, Klaudia Jomova, Vlasta Brezova, Peter Lauro, Lenka Drostinova, Daniel Jun, Vendula Sepsova, Martina Hrabinova, Ondrej Soukup, Pavol Kristian, Zuzana Gazova, Zuzana Bednarikova, Kamil Kuca, Marian Valko
• Journal: Journal of inorganic biochemistry (J Inorg Biochem) Vol. 161 Pg. 52-62 (08 2016) ISSN: 1873-3344 [Electronic] United States
• PMID: 27230386 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 Elsevier Inc. All rights reserved.

Chemical References

• Amyloid beta-Peptides
• Cholinesterase Inhibitors
• Coumarins
• GPI-Linked Proteins
• Peptide Fragments
• amyloid beta-protein (1-42)
• Tacrine
• Copper
• ACHE protein, human
• Acetylcholinesterase
• Butyrylcholinesterase

Topics

• Acetylcholinesterase (chemistry)
• Alzheimer Disease (drug therapy, metabolism)
• Amyloid beta-Peptides (chemistry)
• Butyrylcholinesterase (chemistry)
• Cholinesterase Inhibitors (chemical synthesis, chemistry)
• Copper (chemistry)
• Coumarins (chemical synthesis, chemistry)
• GPI-Linked Proteins (chemistry)
• Humans
• Oxidative Stress
• Peptide Fragments (chemistry)
• Tacrine (chemical synthesis, chemistry)