## 2 Iron Chelators Design and Redox Activity of Iron
### Thermodynamics, Stability, Sensitivity and Lipophilicity  
The selectivity and stability of the chelator complex are essential when designing a chelator. The ligands, as discussed above, can change the electrode potential of iron complexes but can also influence the stability of the complex. Chelators must form at least two (bidentate) coordination bonds to the metal, and iron can achieve up to a maximum of six (hexadentate) coordination bonds. They usually contain ligands of nitrogen, oxygen and sulphur [26]. The number of chelate rings affects stability, with an increasing number resulting in increased stability; this is the chelate effect [27]. Thermodynamically, this is favourable, as it has entropic and enthalpic contributions due to the increase in the strength of the binding site caused by an increase in electron density. Thus, the binding of a chelator with a hexadentate coordination number is also redox stable as it saturates the Fe coordination sphere and binds iron in a (1 chelator: 1 iron) ratio. The redox stability of hexadentate chelators can be proven as hydroxyl radical formation requires a free unbonded coordination site in Fenton chemistry; therefore, hexadentate chelators do not perform Fenton chemistry [24; 28]. Iron chelators such as bidentate chelators bind iron in a (3 chelator: 1 iron) ratio and tridentate chelators in a (2 chelator: 1 iron) ratio, which can leave co-ordination sites free [29]. The bidentate and tridentate chelators are more kinetically labile as they can form these partially dissociated complexes. For example, a bidentate chelator might only bind to iron twice, leaving a site free. This results in the weaker chelators that might not bind with all the coordination sites being more reactive, increasing Fenton chemistry and ROS [26]. Bidentate, tridentate and hexadentate chelators can be seen in Figure 3, all occupying a full coordination site. Therefore, the stability of these ligands goes in the order of hexadentate > tridentate > bidentate [30]. The stability of these compounds can be ascertained by looking at the pFe\({}^{3+}\) values, which is the negative logarithm concentration of free Fe (III). This also considers the ligand protonation, denticity, and stoichiometries and shows that hexadentate chelators are more stable than bidentate and tridentate ligands [31]. Thermodynamic stability depends on the bonding interaction, where the metal-ligand interaction can be described as Lewis acid-base interaction [32]. Chelators can be designed for either Fe (III) or Fe (II). High spin Fe (III) acts as a hard acid as it has a tri-positive cation ratio of 0.65 A, a high electron density, and binds hard ligands such as oxygen. Oxygen donor atoms can also stabilise the chelator, and thus it is much less likely to redox cycle [33]. In contrast, Fe (II) has a lower electron density and prefers softer ligands such as nitrogen, which can be reduced in physiological conditions by enzymes in the cell [30]. Due to this redox activity, they can participate in Fenton chemistry and generate ROS. It is important to note that ligands that prefer Fe (II) have an affinity for other bivalent metals [34]. Contrastingly ligands that prefer Fe (III) cations prefer cations such as gallium that are not commonly seen in the human body. This is why Fe (III) chelators are becoming more popular in a clinical setting for iron overload diseases [35]. Ligands that bind both are more likely to favour Fe (II), which prefers soft donors. These soft donors would be more likely to catalyse the Fenton reaction leading to the production of hydroxy radicals and are an attractive option for cancer by increasing ROS [29]. Lipophilicity refers to the affinity a molecule has for an aqueous environment, usually determined by its log \(p\)-value, the logarithm of solute concentration in octanol over unionized solute concentration in water [36]. Lipophilicity is crucial as it allows the uptake of the drug in the gastrointestinal tract to reach the target site to release its therapeutic effect [37].