## 2 Iron Chelators Design and Redox Activity of Iron
### Thermodynamics, Stability, Sensitivity and Lipophilicity
Lipophilicity is essential when designing a chelator, as it can utilise passive transport to cross biological barriers. There are two routes an oral drug such as an iron chelator can take either through the portal vein or the intestinal tract. If they are small and soluble, they can travel through the portal vein, where enzymes metabolise them in the liver [38]. The second is through the lymphatic system, bypassing the metabolism in the liver, increasing its bioavailability [39]. Lipophilicity is vital for it to pass through the lymphatic system. The addition of lipids, or a more lipid ligand, can help an iron chelator's bioavailability in three ways: the alteration of the intestinal milieu, recruitment of the lymphatic drug transport system and interaction with the enterocytes transport process [2; 40]. In theory, chelators with high lipophilicity can enter the cells more efficiently and therefore bind to the labile iron inhibiting it from many processes such as direct inhibition of the R2 subunit of ribonucleotide reductase (RR) [41]. As discussed above, the size of the chelator is also important since if it is above a specific molecular weight, roughly 500 Daltons, it will not be absorbed through the gastrointestinal tract. Additionally, most hexadentate chelators have more than 5 high hydrogen bond donors and 10 hydrogen bond acceptors, resulting in poorer absorption or permeation [42]. This limits which chelators can be used; typically, hexadentate chelators such as bidentate and tridentate have lower molecular weights. Therefore, they are more orally available than hexadentate chelators which struggle to be absorbed and enter cells. An example of this is deferoxamine; a hexadentate chelator that does not quickly enter or leave cells [43]. Therefore, the design of a chelator for its use is clinically significant. Chelators that should be used in iron overload diseases should be redox inactive and are therefore typically hexadentate ones. However, the production of ROS species by iron chelators, where their complexes participate in redox cycling, has been shown to kill cancer cells by causing DNA damage. Consequently, bidentate or tridentate iron chelators with soft donors can typically bind to both Fe\({}^{2+}\) and Fe\({}^{3+}\). They are an attractive option as they can form complexes that redox cycle and produce excess ROS which can be toxic to cancer cells. Bidentate and  
Figure 3: (**A,B**) show deferiprone, the bidentate chelator, bound to iron occupying its full coordination in a 3:1 ratio (3 deferiprone: 1 iron) and its 3D arrangement are, respectively, optimised. (**C,D**) show the tridentate chelator deferasirov bound to iron in a ratio of 2:1 (2 deferasirov to 1 iron). These chelators are more likely to be redox-active than hexadentate chelators as they can leave sites free for Fenton chemistry. (**E,F**) show the hexadentate chelator bound with iron Ferrioxamine B. Ferrioxamine is not redox-active, as it binds iron 1:1 and therefore cannot leave any sites free. tridentate chelators are less stable; however, this ability to develop dissociated complexes with iron allows its kinetic lability and participation in Fenton chemistry.