The paper by Jomova et al. investigates the ability of quercetin to complex with, or chelate, copper ions, and reports that quercetin binds copper ions through its 5-hydroxy-4-keto chelating site. The Cu(II)–quercetin complex is shown to scavenge oxidative radicals more strongly than does quercetin by itself. Once quercetin chelates copper, the copper’s ability to form hydroxyl radicals through the Fenton reaction becomes weak. The paper also reports that quercetin, only at high concentrations, protects against oxidative DNA damage, including nicking and linearization.

Overall, the paper is an observational study. The paper will benefit from restructuring, providing a better focus, providing better rationales and methodological details, and referring to primary citations.

Comments: It seems at parts, the paper should be written more clearly or present a clear message so as not to confuse or mislead the readers. To achieve this, I suggest: • Therefore, the authors should present their paper as a purely chemical study with a strong focus on the molecular characterisation of the interaction between quercetin and copper, providing the DNA-damage and intercalation studies as examples of effects afforded by quercetin. • Thus, the authors should remove references to any disease model. Any reference to the therapeutic potential of quercetin in Alzheimer’s disease or cancer seems to be highly speculative in light of the data presented in this paper and without any substantive pharmacodynamics or pharmacokinetic measurements of quercetin, for example, in the brain tissue. In addition, the effect of quercetin to protect DNA against oxidative damage appears to be too short-lived and too insignificant at the concentrations of quercetin used to warrant a discussion of its potential use in any disease model, let alone chronic degenerative diseases or cancer. • It seems the message of the paper about quercetin’s ability to intercalate DNA structures is quite confusing and not clearly presented. The abstract presents conflicting statements about whether this happens or not and how. • The authors should provide additional, conclusive data to prove that quercetin intercalates DNA, for example, by single-molecule force spectroscopy (see Almaqwashi, A. A. et al. DNA intercalation optimized by two-step molecular lock mechanism. Sci. Rep. 6, 37993; doi: 10.1038/srep37993 (2016)). • The authors should clearly present the rationale for performing certain experiments to help readers focus. For example, it is not clear why the authors have decided to test whether quercetin intercalates DNA or why authors have decided to identify the responsible ROS species. • The authors should quantify the DNA-protective effects of the various concentrations of quercetin by densitometry. It seems that at the quercetin concentrations used, this protective effect is insignificant and short-lived. How could this be a potential therapeutic effect? Is there any in vivo or in vitro evidence that quercetin can penetrate nuclei? • The authors are encouraged to seek editorial help in writing their paper and in using the English conventions of scientific reporting. For example, a comma is used for decimal point according to European conventions, and at some parts, the full stop is used to show decimal points according to English conventions; this is inconsistent. In addition, the discussion of Job’s plot seems to be disrupted by lines 124–127, which discuss DPPH and ABTS results. • It is best to present the structure of rutin and the Job’s plots. • It is not clear why certain methodological decisions were taken. For example, why was methanol used? How much was the final concentration of methanol (v/v) in mixtures with DNA?