Effect of Hydroxyl Groups Esterification with Fatty Acids on the Cytotoxicity and Antioxidant Activity of Flavones

Abstract

Flavonoids and polyunsaturated fatty acids due to low cytotoxicity in vitro studies are suggested as potential substances in the prevention of diseases associated with oxidative stress. We examined novel 6-hydroxy-flavanone and 7-hydroxy-flavone conjugates with selected fatty acids (FA) of different length and saturation and examined their cytotoxic and antioxidant potential. Our findings indicate that the conjugation with FA affects the biological activity of both the original flavonoids. The conjugation of 6-hydroxy-flavanone increased its cytotoxicity towards prostate cancer PC3 cells. The most noticeable effect was found for oleate conjugate. A similar trend was observed for 7-hydroxy-flavone conjugates with the most evident effect for oleate and stearate. The cytotoxic potential of all tested conjugates was not specific towards PC3 because the viability of human keratinocytes HaCaT cells decreased after exposure to all conjugates. Additionally, we showed that esterification of the two flavonoids decreased their antioxidant activity compared to that of the original compounds. Of all the tested compounds, only 6-sorbic flavanone showed a slight increase in antioxidant potential compared to that of the original compound. Our data show that conjugated flavonoids are better absorbed and enhance cytotoxic effects, but the presence of FA lowered the antioxidant potential.

Rutin bioconjugates as potential nutraceutical prodrugs: An in vitro and in ovo toxicological screening

“…However, other flavonoid/fatty acid derivatives were investigated. As regards the more elevated cytotoxic potential of RUT-O compared to RUT-L, a similar observation has been made by Kubiak-Tomaszewska et al whose study revealed that oleic derivatives of 6-hydroxy-flavanone and 7-hydroxy-flavanone (0-100 µM) had an increased cytotoxic effect both in HaCaT keratinocytes and PC3 prostate cancer cells following a 72 h treatment compared to the linoleic conjugates and to the parent compounds (Kubiak-Tomaszewska et al, 2022). In other study, OA and LA esters of quercetin-3-O-glucoside were shown to possess no cytotoxicity to human primary hepatocytes, while exerting a cytoprotective effect by overcoming the H 2 O 2 -induced damage (Warnakulasuriya and Ziaullah, 2016).…”

“…By comparing the tested REs, the computational predictions indicated a higher lipophilicity (cLogP) and lower solubility for RUT-O than for RUT-L. Correlated to the viability and Hoechst 33342 results, it can be assumed that the increased hydrophobic degree results in enhanced cell membrane crossing and thus a slightly elevated toxicity of the OA-derivative towards healthy H9c2(2-1), HepaRG, and HaCaT cells in comparison to the LA-conjugate, highlighted via reduced cell viability and nuclear dysmorphology. Similar conclusions were expressed by other researchers observing a possible link between the lipophilic properties of flavonoid conjugates, their cellular uptake, and consequent cytotoxicity (Danihelová et al, 2013;Kubiak-Tomaszewska et al, 2022). Viskupicova et al showed that the lipophilic derivatization of rutin using fatty acids (such as OA and LA, among others) effectively increases its hydrophobicity and solubility in fats (Viskupicova, 2010).…”

“…In a recent review, the authors also summarized several studies revealing that lipophilic rutin derivatives possess improved bioavailability and penetration through cell membrane (Viskupicova and Maliar, 2017). RUT, OA, and LA showed higher drug-likeness and drug scores compared to REs, since any slight structural alternation might affect the activity of flavonoids (Kubiak-Tomaszewska et al, 2022), and MW increasing is often correlated with an improved lipophilicity but also with a loss in drug-like properties (Naylor et al, 2018), suggesting the application of REs not as drug candidates, but as drug precursors capable of releasing the original active flavonoid following absorption. All molecules (RUT, OA, LA, RUT-O, and RUT-L) were predicted as being free of mutagenic, tumorigenic, irritant, and reproductive toxicity.…”

By-Product of the Red Ginseng Manufacturing Process as Potential Material for Use as Cosmetics: Chemical Profiling and In Vitro Antioxidant and Whitening Activities

“…The hydroxyl radical scavenging activity was assayed according to references [ 44 , 45 ]. The EAE and CE of RG and SGD were dissolved in 20% DMSO, and the other extracts were dissolved in distilled water.…”

Antioxidant and Antibacterial Activity of Endophytic Fungi Isolated from The Leaves of Sungkai (Peronema canescens)

“…Several studies have shown that hydroxyl groups at specific positions on the aromatic ring can increase antioxidant activity. [76][77][78][79][80] Thus, the position of the hydroxyl group greatly influences the ability of a compound to scavenge free radicals. Research has explained that the removal of hydroxyl groups decreases the ability of compounds to scavenge free radicals.…”