The antioxidant properties of 4–quinolones compared to structurally related flavonoids
Abstract
Oxidative stress is a common occurrence in neuro-degenerative disorders such as
Alzheimer's and Parkinson's disease and is suggested to take place before the onset of
neuro-degenerative disease, leading to, or exacerbating deterioration. The oxidative status of the cells is regulated by antioxidant enzymes responsible for neutralising free radicals. With increasing age the enzymes are overwhelmed by the amount of free radicals requiring deactivation, leading to decreased protection by the body's antioxidant systems. The mitochondria also produce more reactive oxygen species at the cost of producing less ATP. These natural by-products of cellular respiration in the mitochondria act to injure the mitochondria themselves and cell structures containing lipids, proteins and DNA and serve to
decrease the lifespan of the cell. During oxygen radical damage of the brain, an area
containing high concentrations of oxidisable substrate and oxidative catalysts as well as low concentrations of antioxidant enzymes, apoptosis of the brain cells takes place, contributing to irreversible neuro-degeneration. This deterioration is only diagnosed when damage to the
brain is sufficient to induce disability and it is too late to be restored. The area of interest in this study was therefore to discover compounds useful in decreasing brain damage caused by reactive oxygen species, thereby curbing the progression of neuro-degenerative disease and prolonging the lifespan and quality of life of the patient.
Flavonoids are naturally occurring compounds, abundant in plants with established antioxidant activity. Hydrogen donating substituents on the natural flavonoids are responsible for elevated antioxidant activity and it was therefore hypothesised that synthesising structurally similar compounds containing hydrogen donating functional groups might improve the antioxidant activity observed for the flavonoids. As a result, the flavone moiety
was selected as the lead compound, substituted with hydroxyl groups on different positions and were compared to the correlating hydroxyl substituted
2-phenylquinolin-4(1 H)-ones, which were prepared by the Conrad-Limpach method and characterised by NMR, IR and MS techniques. Biological activity was evaluated using a range of antioxidant assays to evaluate the potential value of the flavones and synthesised 2-phenylquinolin-4( 1 H)-ones. The oxygen radical absorbance capacity (ORAC) assay was performed to establish the ability of the test series to scavenge peroxyl radicals leading to lipid peroxidation. The 2-phenylquinolin-4( 1 H)-ones demonstrated moderate activity, with
7-hydroxy-2-phenylquinolin-4(1 H)-one (9) observed to be the best of the group.
6-Hydroxyflavone (5) however, performed the best of the test series. In the ferric
reduction/antioxidant power (FRAP) assay the chemical ability to reduce ferric iron was
evaluated in order to assess the theoretical inhibition of the Haber-Weis reaction, leading to reduced hydroxyl radical production. In this case the 2-phenylquinolin-4(1 H)-ones showed
the best activity of the compounds, with the performance of 8-hydroxy-2-phenylquinolin-4(1H)-one (10) comparable to that of Trolox, followed by 6-hydroxy-2-phenylquinolin-4(1 H)-one (8). The superoxide anion (NBT) assay demonstrated the ability of the compounds to scavenge superoxide anions, the first oxygen radical produced by the mitochondria, which is responsible for most of further oxygen radical production in the cell. The 2-phenylquinolin-4(1 H)-ones showed moderate activity, 7 -hydroxy-2-phenylquinolin-4( 1 H)-one (9) demonstrating the best activity in the group while 8-hydroxyquinoline (3) was the best superoxide anion scavenger. In the lipid peroxidation (TBARS) assay the ability of the compounds to scavenge the hydroxyl radical was assessed, to ascertain the ability to inhibit the initiation of lipid peroxidation. In this assay 6-hydroxy-2-phenylquinolin-4( 1 H)-one (8) performed the best of the 2-phenylquinolin-4(1 H)-ones, its 1 mM concentration performing better than the 0.01 mM Trolox concentration, while the compound displaying the best hydroxyl radical scavenging activity in the assay was 4-hydroxyquinoline (2). From the above-mentioned evaluations it was possible to establish that 2-phenylquinolin-4( 1 H)-ones acted as chain-breaking antioxidants, with a postulated hydrogen donor mechanism of action. The slightly acidic amine present in the synthesised series of 2-phenylquinolin-4(1 H)-ones did not however prove advantageous compared to the basic amine of the quinolines, except in the FRAP assay. It was however clear that hydroxyl substitution lead to an increase in antioxidant activity, with the 8- and 6-hydroxyl substitution of the 2-phenylquinolin-4(1H)-ones (10 and 8) able to enhance antioxidant activity in the
FRAP and TBARS assays and the ?-substitution (9) in the ORAC and NBT assays. The hydroxyl substituted 2-phenylquinolin-4(1 H)-ones outperformed the flavones in the FRAP, NBT and TBARS assays., indicating that under certain conditions the hydroxyl substituted
synthesised series may inhibit radical mediated damage better than the flavones and thus show promise as possible neuro-protective agents. It however remains to establish the ability of the test compounds to permeate the blood brain barrier, to determine the antioxidant effect
that may be obtained in a living brain.
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