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Structure-Activity Relationship of Flavonol O-Methylation Revealed by In Vitro, In Silico and Zebrafish
Kamila Borowiec1,2, Agnieszka Michalak2, Katarzyna Targowska-Duda3
1Department of Biotechnology, Microbiology and Human Nutrition, Faculty of Food Science and Biotechnology, University of Life Sciences in Lublin, 20-950 Lublin, Poland.
International Journal of Molecular Sciences
|June 12, 2026
Summary
The position of O-methylation on flavonols like quercetin significantly impacts their antioxidant and anti-inflammatory properties. Rhamnetin shows stronger antioxidant activity, while isorhamnetin inhibits cyclooxygenase-2 (COX-2) more effectively, influencing biological responses.
Area of Science:
- Biochemistry
- Pharmacology
- Toxicology
Background:
- Flavonols, a class of dietary polyphenols, possess biological activities modulated by structural features like O-methylation.
- Quercetin derivatives, isorhamnetin (3'-O-methylquercetin) and rhamnetin (7-O-methylquercetin), serve as models to investigate methylation's impact.
Purpose of the Study:
- To compare the antioxidant and cyclooxygenase-2 (COX-2) inhibitory activities of isorhamnetin and rhamnetin.
- To evaluate the in vivo effects of these flavonols on developmental toxicity, behavior, and oxidative stress responses.
Main Methods:
- Antioxidant capacity assessed via DPPH, ABTS, CUPRAC, and FRAP assays.
- In vitro COX-2 inhibition assays and molecular docking simulations.
- In vivo studies in zebrafish larvae, including developmental toxicity and a 6-hydroxydopamine (6-OHDA) induced neurotoxicity model.
Main Results:
- Rhamnetin demonstrated superior radical-scavenging and reducing activity in DPPH, ABTS, and FRAP assays.
- Isorhamnetin exhibited stronger COX-2 inhibition, with distinct binding interactions suggested by docking.
- Rhamnetin displayed lower developmental toxicity in zebrafish larvae compared to isorhamnetin at higher concentrations.
- Both compounds ameliorated 6-OHDA-induced locomotor deficits and modulated antioxidant enzymes.
Conclusions:
- The position of O-methylation critically influences flavonol antioxidant potential and COX-2 interactions.
- Methylation site affects organism-level responses, including developmental toxicity and neuroprotection under oxidative stress.
