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

• Published in: Journal of inorganic biochemistry Vol. 161; pp. 52 - 62
• Main Authors: Hamulakova, Slavka, Poprac, Patrik, Jomova, Klaudia, Brezova, Vlasta, Lauro, Peter, Drostinova, Lenka, Jun, Daniel, Sepsova, Vendula, Hrabinova, Martina, Soukup, Ondrej, Kristian, Pavol, Gazova, Zuzana, Bednarikova, Zuzana, Kuca, Kamil, Valko, Marian
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2016
• Subjects: Acetylcholinesterase - chemistry; Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Alzheimer's disease; Amyloid beta-Peptides - chemistry; Butyrylcholinesterase - chemistry; Cholinesterase Inhibitors - chemical synthesis; Cholinesterase Inhibitors - chemistry; Copper - chemistry; Coumarins - chemical synthesis; Coumarins - chemistry; DNA damage; Free copper; GPI-Linked Proteins - chemistry; Humans; Oxidative Stress; Peptide Fragments - chemistry; Tacrine - chemical synthesis; Tacrine - chemistry; Tacrine-coumarin hybrids; Oxidative stress; Tacrine-coumarin hybrids; Alzheimer's disease; Free copper; DNA damage
• ISSN: 0162-0134; 1873-3344
• DOI: 10.1016/j.jinorgbio.2016.05.001

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. A series of studies revealed that multifunctional tacrine-7-hydroxycoumarin hybrid molecules upon coordination to free copper ions prevented Cu(II)-catalyzed decomposition of hydrogen peroxide (to form hydroxyl radicals via the Fenton reaction) which in turn, alleviate the effects of oxidative stress that are typical for Alzheimer's disease. [Display omitted] •Tacrine-coumarin hybrids are agents against Cu(II)-induced oxidative stress in Alzheimer's disease.•EPR spectroscopy was used to describe interaction between hybrids and Cu(II) ions.•Coordinated hybrids to Cu(II) ions suppressed formation of HO via Fenton reaction.•DNA damage protection study agrees with the results from EPR spin trapping study.•Compound 5g showed the most potent acetylcholinesterase inhibitory activity.