# Co(II) Complex of Quercetin-Spectral, Anti-/Pro-Oxidant and Cytotoxic Activity in HaCaT Cell Lines
## 1 Introduction  
Flavonoids are a category of plant hydroxylated phenolic compounds with an aromatic ring structure and include quercetin [1; 2; 3]. The highest concentrations of quercetin were reported in unsweetened cocoa powder (20.10 mg/100 g); fruits such as apples (with skin 4.42 mg/100 g) and raw cranberries (14.00 mg/100 g); and vegetables such as raw onions (13.27 mg/100 g), raw broccoli (3.21 mg/100 g), and raw spinach (4.86 mg/100 g). The concentration of quercetin in beverages such as green tea (2.69 mg/100 g), black tea (1.99 mg/100 g), and red wine (0.84 mg/100 g) was also determined [4]. Quercetin possesses a variety of biological properties (Figure 1), but low water solubility and bioavailability limits its use as a drug or food supplement [5; 6; 7; 8; 9]. However, new formulations of quercetin, such as metal complexes of quercetin, may be able to overcome these limitations. Figure 1: Biological properties of quercetin [5; 6; 7; 8; 9]. According to the literature, quercetin has a protective effect against oxidant damage (lipid peroxidation, DNA and protein damage). Oxidant damage can contribute to the development of many of civilization's diseases such as diabetes, coronary artery disease, Alzheimer's disease, Parkinson's disease or even cancer [10; 11]. Quercetin is probably the most powerful scavenger of reactive oxygen species and reactive nitrogen species [12]. In certain cases, it is more powerful than vitamin C, due to the 3-OH and 3 \({}^{\prime}\), 4\({}^{\prime}\)-catechon groups, proving to be ten times stronger for peroxynitrite than the known peroxynitrite scavenger, esbelen [13]. The mechanism of action for quercetin can include increasing antioxidant defense and the inhibition of enzymes involved in the generation of reactive oxygen species (ROS) or scavenging ROS [14]. Recently, there have been many reports in the literature regarding the high antioxidant properties of metal ion complexes with quercetin, e.g., copper(II), iron(II) [15; 16], cobalt(II), cadmium(II) [17], magnesium(II) [18], and nickel(II)-quercetin complexes [19]. Cu(II), Fe(II), Co(II) and Cd(II) complexes of quercetin showed higher antioxidant properties than ligands alone [15; 16; 19; 20; 21], whereas for Pb(II) and Sb(II)-quercetin complexes, the opposite effect was reported [22; 23]. The type of metal coordination by quercetin may explain the different antioxidant properties of these complexes compared to ligand. Quercetin is one of the most widely investigated polyphenols with well-known anticancer properties. Its anti-proliferative mechanisms include, modulating apoptosis-inducing factors, and surviving signaling pathways. The conjugation of quercetin and transition metal ions promotes its anticancer activity due to the favorable geometric spatial orientation of the active site, with the addition of the metal ion [24]. [PERSON] and others [24] described the anticancer activity of a Ni(II)-quercetin complex, suggesting that its mechanism of action relies on DNA intercalation. [PERSON] and [PERSON] [25] investigated the activity of a Zn(II)-quercetin complex in relation to human bladder cancer cells (BFTC-905), where the concentration of \(\geq\)12.5 uM effectively inhibited their invasiveness. In another study, a Ge(IV)-quercetin complex showed cytotoxicity in SPC-A-1, EC9706, HeLa and PC-3 cancer cell lines [26]. As reported in [24], the DNA intercalation of metal-quercetin complexes is probably the main mechanism of their anticancer properties. The heterobimetallic complexes, in the potential cytotoxic therapy, are noteworthy, and include Cu(II)/Sn2(IV)-quercetin and Zn(II)/Sn2(IV)-quercetin. Their unique mechanism of action is a dual mode of binding to DNA and presents cleavage properties. High DNA binding affinity is achieved via: (a) electrostatic interactions of Sn(IV) ions coordinating the oxygen atoms of the phosphate backbone and (b) covalent binding of Cu(II)/Zn(II) to N-3/N-7 nucleobase positions [26].