Reactivity Studies on a Cobalt(III) Complex Towards the Development of Catechol-Based Bioreductive Prodrugs

The current treatments for cancer – chemo and radiotherapy – find resistance in solid tumours because of a hypoxic condition (low concentration of oxygen) that limit their efficiency. However, the hypoxic environment can be exploited for the development of bioreductive prodrugs. In this approach, a compound could circulate intact through the body, being selectively activated in the reductive environment of a tumour, with subsequent release of a cytotoxic ligand. Compounds like catechols, with antitumor potential, and cobalt complexes, whose metallic center has an inert (+3) and a labile (+2) oxidation state, are being investigated for the development of such systems. In this way, we present the synthesis (Scheme 1), characterization and preliminary reactivity assays of a cobalt(III) complex with tris(pyridin-2-ylmethyl)amine (TPA) and tetracholocatechol (TCC) ligands, [Co(TPA)(TCC)]ClO4 (1), as model for catechol-based bioreductive prodrugs.The complex was fully characterized by single crystal X-ray diffraction, IR, UV-Vis, ESI-MS and CHN elemental analysis. Cyclic voltammetry analysis revealed a pair of waves at -0.99V and -0.58V vs Fc/Fc+, assigned to irreversible metal centered (Co3+/Co2+) reduction and oxidation processes, respectively. Reactivity assays, monitorated by UV-Visible spectroscopy in phosphate buffer at pH 6.2, 7.0 and 7.4, with ascorbic acid (reducing agent), under argon and oxygenated atmospheres, at 25 oC, showed no significant changes in the spectra during 24 hours, which indicates that both reduction and ligand dissociation did not take place. Additional studies are in progress to evaluate the reduction of 1 by other reducing agents.