**6. Interactions of flavonoids metal complexes with nucleic acids**

The ability of small molecules to interact with DNA ranks among the most important mechanisms of action enabling antitumor activity, since intercalation between adjacent base pairs inhibits DNA replication. Most of the flavonoids and their metal complexes show affinity toward nucleic acids. Flavonoids bind DNA as a result of electrostatic interactions, as is the case of quercetin [97] and morin [98 and references therein]. Their complexes, on the other hand, are bulkier, and display more diversified mechanisms of interaction with DNA, including "major" or "minor groove" binding and/or intercalation. Due to their structural planarity, flavonoid complexes are prone to act as intercalators [99]. Moreover, the emergence of electrostatic interactions between the metal cation and anionic phosphate groups of DNA structure stabilizes the adducts formed between the complexes and DNA. It is considered that the DNA base pairs remove the flavonoid molecules in the metal complex, since the binding affinity between the negatively charged phosphate groups and the positively charged metal ions is stronger than that between the flavonoid molecule and the metal center [100, 101]. In most cases, active compounds possess quasi‐planar structures, with a medium‐sized planar area and hydrophobic character [82]. A selection of the metal complexes of flavonoids that interact with DNA is presented in **Table 5**.

Another aspect regarding DNA interaction refers to the complexes' cleavage activity. This property can benefit their antitumor activity, but can also cause oxidative DNA damage (and consequently cell death) in normal cells [22]. Therefore, efforts toward increasing the complexes' selectivity against cancer cells are of prior importance.

The development of electrochemical DNA biosensors has been of high interest in this field, since metal flavonoid complexes show promising results in DNA recognition. Flavonoid complex‐based biosensors can be useful in several domains, such as transducing DNA hybridization, drug design, and diagnosis [102, 103, 105].



ds: double‐stranded; CT‐DNA: calf thymus DNA; RLS: resonance light scattering; *Γ*<sup>s</sup> : saturation coverage value; GC: guanine‐cytosine; SC: supercoiled; NC: nicked circular form.

**Table 5.** Selection of flavonoid metal complexes‐DNA interaction studies.

**Complex Comments Ref.**

moderate intercalative manner. Fe(quer)2

conditions, via oxidative pathway.

activity on plasmid DNA (pBR322) under physiological

The interaction of NiR with DNA was studied using fluorescence spectra and agarose gel electrophoresis. The complex can intercalate moderately between DNA base pairs and shows significant, dose‐dependent cleavage activity on pBR322 plasmid DNA from the SC form to the

The complex shows cleavage activity toward CT‐DNA via an oxidative mechanism with higher efficacy in the presence of

into the double‐helix DNA; according to the Hill model for cooperative binding, the equilibrium dissociation constant and the binding stoichiometry were calculated to be *K* = 2.5 × 10−5 M

studies indicate that the complex binds to DNA via a weak

Intercalation was proposed as the mode of binding of the ligand, the complex with salmon sperm dsDNA via cyclic and square wave voltammetry, UV‐vis spectroscopy techniques.

studies indicate that morin interacts with DNA in a non‐

studied by means of cyclic voltammetry and fluorescence spectroscopy. The complex interacts with DNA via intercalation and nonspecific electrostatic interaction.

 was used for the construction of an electrochemical DNA biosensor for DNA hybridization detection, showing

By means of UV‐vis spectrophotometry, cyclic voltammetry, and synchronous fluorescence spectroscopy, an intercalative

The equilibrium constant of the exchange process in the intercalation reaction was found to be approximately 5 × 10−1; 35% of the bound complex was not involved in

proposed based on the quenching effect of DNA on the RLS

intensity of Tb(III)/Eu(III)‐quercetin system.

 M−1 The UV‐vis, fluorescence and CD spectral measurements revealed that both the complex and the ligand interact with CT‐DNA via intercalation. The binding affinity

M−1 at 20°C.

with salmon sperm dsDNA was

= 1.82 ± 0.2 × 105

M−1

= 2 × 103

reducing agents (ascorbate/hydrogen peroxide).

means of electrochemical methods. Cd(mor)2

values: **(1)**: 1.58, **(2)**: 2.29, **(3)**: 3.20 × 105

R3

relatively good sensitivity and selectivity.

binding mode was proposed. *K*<sup>b</sup>

of the complex is stronger than that of free ligand.

shows cleavage

can intercalate

M−1 at 298 K. Other

[40]

[52]

[101]

[102]

[103]

[104]

[105]

[59, 70]

[106]

[100]

Fe(II)‐quercetin complex Fe(quer)2 The interaction of the complex with DNA occurs in a

NC form.

Cd(II)‐morin complex Cd(mor)2 The interaction with salmon sperm dsDNA was studied by

Co(II)‐morin complex Co(mor)2 Competitive experiments, viscosity, and electrochemical

*K*b

Cu<sup>2</sup> R3

R<sup>3</sup> The interaction of Cu<sup>2</sup>

= 1.5 × 10<sup>6</sup>

intercalation.

Tb(III)/Eu(III)‐quercetin system A sensitive method for the determination of CT‐DNA is

and *m* = 1.761, respectively.

partial intercalation. *K*<sup>b</sup>

intercalative manner [98].

Ni(II)‐rutin (R) complex metal:ligand

318 Flavonoids - From Biosynthesis to Human Health

molar ratio 1:2 (NiR)

Fe(III) chlorobis(flavonolato) (methanol) complex metal:ligand molar ratio 1:2 Fe(III)‐(3hf)

Morin **(1)** Cu(II)‐morin complex **(2)**

Cu(II)‐rutin (R) complex Cu2

Cu(II)‐quercetin complex metal:ligand molar ratio 1:2

Cu(II)‐hesperetin complex *K*<sup>b</sup>

Morin‐β‐CD **(3)**

Regarding the interaction of the complexes with RNA, a few studies have been cited in the literature. La(III)‐quercetin complex enhances binding to plant viral satellite dsRNA [109]. Both quercetin and the complex interact with dsDNA, dsRNA, and ssRNA. The affinities of La(III)‐ quercetin for dsDNA and dsRNA were significantly higher compared to the free ligand, revealing significant impact of La(III) in binding to polynucleotides, most likely due to the electrostatic interactions between La(III) and the phosphate groups surrounding binding sites. Similar results were observed for interactions of the La(III)‐quercetin complex with ssRNA [110].

Undisputedly, there is a consistent amount of experimental evidence regarding the interaction of flavonoids and their metal complexes with nucleic acids. However, some details with respect to the binding sites in the DNA structure need further investigations. There appears that the complexes possess higher affinity toward GC‐rich sequences in DNA [111], but this assumption needs to be backed up by more data.
