**1. Introduction**

The urgency to overcome the biophysical and biomedical drawbacks of current chemotherapeutic treatments led the scientists to consider flavonoid metal complexes as viable options in cancer therapy. Both *in vitro* and *in vivo* studies report that flavonoids and their metal ion complexes exert pleiotropic effects on tumor promotion and progression.

Our work is an attempt to help the design of novel flavonoid‐metal ion complexes with improved pharmacological activity and a broader range of antitumor mechanisms of action. In this chapter, we have analyzed relevant data available in literature on the antitumor activity of the flavonoid‐metal ion complexes, regarding their cellular targets, their role in cancer cell death, growth and proliferation, and structure‐activity analysis.

A novel metal‐based compound with antitumor activity and promising clinical efficacy should meet the following criteria: (1) possess good intrinsic properties, molecular stability, allowing

the drug to arrive intact at the target cells; (2) exert efficient interaction with transport proteins in blood and membranes; (3) show good DNA‐binding properties; (4) have selective activity against cancerous cells over normal cells; and (5) preferably have activity against tumor cells that are resistant to cisplatin and derivatives. These aspects will be discussed in the following pages.

### **2. Flavonoids: general information, main classes, and chelating properties**

Flavonoids (from the Latin "flavus," yellow) are secondary plant metabolites naturally occurring in seeds, fruit skin, peel, and bark of plants [1]. Flavonoids are important components of the human diet, the major sources of flavonoids being apples, red fruits, onions, citrus fruits, nuts, and beverages such as tea, beer, and wine [2]. Although they are not considered nutrients, due to the variety of pharmacological activities in the mammalian body, flavonoids are more correctly referred to as "nutraceuticals" [3].

These compounds possess a common flavane (2‐phenyl‐benzo‐γ‐piran) nucleus, consisting of an aromatic A‐ring fused to a heterocyclic C‐ring, attached through a single carbon‐carbon bond to a benzene B‐ring (**Figure 1**).

According to the oxidation degree of the C‐ring, the hydroxylation pattern of the nucleus, and the C<sup>3</sup> substituent, the flavonoids can be categorized into seven subclasses: flavones, flavonols, flavanones, flavanols (catechins), flavanonols, isoflavones, anthocyanins, and anthocyanidins [4–6]. Thus, the total number of polyphenolic compounds exceeds 4000. In all these subclasses, rings B and C are linked at C2 , with the sole exception of the isoflavones (linked at C<sup>3</sup> ). Many flavonoids occur naturally as glycosides; the carbohydrate substituents include D‐glucose, L‐rhamnose, glucorhamnose, galactose, and arabinose [7]. **Table 1** lists the subclasses of flavonoids, and a set of representatives, to which we will refer to in this chapter.

Flavonoids possess three possible metal‐chelating sites that can bind metal ions: (i) the 3‐ hydroxy‐4‐ketone groups in the C‐ring, (ii) the 5‐hydroxy group in the A‐ring and 4‐carbonyl group in the C–ring, and (iii) 3',4'‐dihydroxy groups, located on the B‐ring (**Figure 2**).

**Figure 1.** Basic flavonoid structure.


the drug to arrive intact at the target cells; (2) exert efficient interaction with transport proteins in blood and membranes; (3) show good DNA‐binding properties; (4) have selective activity against cancerous cells over normal cells; and (5) preferably have activity against tumor cells that are resistant to cisplatin and derivatives. These aspects will be discussed in the following pages.

**2. Flavonoids: general information, main classes, and chelating properties**

Flavonoids (from the Latin "flavus," yellow) are secondary plant metabolites naturally occurring in seeds, fruit skin, peel, and bark of plants [1]. Flavonoids are important components of the human diet, the major sources of flavonoids being apples, red fruits, onions, citrus fruits, nuts, and beverages such as tea, beer, and wine [2]. Although they are not considered nutrients, due to the variety of pharmacological activities in the mammalian body, flavonoids are

These compounds possess a common flavane (2‐phenyl‐benzo‐γ‐piran) nucleus, consisting of an aromatic A‐ring fused to a heterocyclic C‐ring, attached through a single carbon‐carbon

According to the oxidation degree of the C‐ring, the hydroxylation pattern of the nucleus,

vonols, flavanones, flavanols (catechins), flavanonols, isoflavones, anthocyanins, and anthocyanidins [4–6]. Thus, the total number of polyphenolic compounds exceeds 4000. In all these

Flavonoids possess three possible metal‐chelating sites that can bind metal ions: (i) the 3‐ hydroxy‐4‐ketone groups in the C‐ring, (ii) the 5‐hydroxy group in the A‐ring and 4‐carbonyl group in the C–ring, and (iii) 3',4'‐dihydroxy groups, located on the B‐ring (**Figure 2**).

). Many flavonoids occur naturally as glycosides; the carbohydrate substituents include D‐glucose, L‐rhamnose, glucorhamnose, galactose, and arabinose [7]. **Table 1** lists the subclasses of flavonoids, and a set of representatives, to which we will refer to in this chapter.

substituent, the flavonoids can be categorized into seven subclasses: flavones, fla-

, with the sole exception of the isoflavones (linked

more correctly referred to as "nutraceuticals" [3].

bond to a benzene B‐ring (**Figure 1**).

306 Flavonoids - From Biosynthesis to Human Health

subclasses, rings B and C are linked at C2

**Figure 1.** Basic flavonoid structure.

and the C<sup>3</sup>

at C<sup>3</sup>


**Table 1.** Main flavonoid [21] subclasses.

**Figure 2.** Typical chelation sites in forming the flavonoid complexes [2].

Cornard and Merlin [8] have reported that in acidic conditions, the 3‐hydroxy‐4‐ketone or the 5‐hydroxy‐4‐keto groups of quercetin (Q) are involved in coordination, whereas in alkaline milieu, the second chelating site, 3',4'‐dihydroxy group, located on the B‐ring, is also involved.
