Antioxidant Properties and Radical Production Capability of the Potential Antitumor V(IV)O Complexes Formed by Flavonoid Ligands

Oxidovanadium(IV) complexes of flavonoids were shown to be promising antitumor agents against several cancer cell lines1. Unfortunately, the mode of action of these compounds in the inhibition of cancer cell proliferation is still elusive. A possible mechanism would be related to the oxidative stress on the tumor cells by generating ROS species and leading, at the end, to the apoptosis. On the other hand, one of the properties of flavonoid ligands is their activity as antioxidants which may be exploited in the prevention of tumors. All of these aspects must be taken into account when the potential pharmacological action of flavonoid complexes is studied. In this work the antioxidant properties and the radical production capability of some VIVO complexes formed by flavonoid ligands were examined. In particular, the bis-chelated species of quercetin (que), [VO(que)2]2-, and morin (mor), [VO(mor)2], were evaluated for their capability to reduce the stable radical 1,1-diphenyl-2-picrylhydrazyl (DPPH) and produce the hydroxyl radical oOH by Fenton-like reactions, where the reducing agent is VIVO2+. The results were compared with those displayed by other VIVO complexes, such as [VO(H2O)5]2+, [VO(acac)2] (acac = acetylacetonate) and [VO(cat)2]2- (cat = catecholate). The studies showed that the capability of the VIVO flavonoids complexes to reduce DPPH is much larger than that of the VIVO species formed by non-antioxidant ligands and it is due mainly to the flavonoid molecule. Through the 5,5-dimethyl-1-pyrroline N-oxide (DMPO) trapping assay of the hydroxyl radical it was possible to demonstrate that, in acidic aqueous solution, [VO(H2O)5]2+ is as effective as [Fe(H2O)6]2+ in promoting Fenton reaction and, depending on the concentration, can be even more effective than iron. Moreover in the system containing [VO(acac)2], the adduct DMPO-OH is produced, demonstrating that also metal complexes, and not only "free" metal ions, as usually reported in the literature, are able to give Fenton-like reactions generating significant amounts of hydroxyl radicals. When VIVO complexes of flavonoids were taken into account, the amount of hydroxyl radicals produced in Fenton-like reactions is significantly lower because of the antioxidant properties of the ligands, and depends on the specific structure of the flavonoid and on the capability to reduce H2O2 to give oOH. Finally, we can say that it could be possible to modulate the production of ROS species by vanadium complexes changing the features of the ligand coordinated to the VIVO2+ ion, such as the entity, nature and position of the substituents and the number of phenolic groups.