Synthesis, characterization and biological activities of mononuclear Co(III) complexes as potential bioreductively activated prodrugs

Aiming to investigate the use of tridentate ligands to develop new bireductively activated prodrugs, two N2O-donor ligands (HL1: [(2-hydroxybenzyl)(2-(imidazol-2-yl)ethyl)]amine; and HL2: [(2-hydroxybenzyl)(2-(pyridil-2-yl)ethyl]amine) were used to synthesize new Co(III) complexes, 1 and 2. Both complexes were characterized by X-ray crystallography, mass spectrometry, electrochemistry, IR, UV–visible and 1H NMR spectroscopies. Electrochemical data in methanol revealed that the Co(III) → Co(II) reduction of 1 (−0.84 V vs. normal hydrogen electrode – NHE) is more positive than 2 (−1.13 V vs. NHE), while it was expected to be more negative due to better σ-donor ability of imidazole ring in HL1, compared to pyridine in HL2. Considering that reduction processes on Co(III) center may involve the lowest unoccupied molecular orbital (LUMO), it might play an important role on the electronic properties of the complexes, and could explain the observed redox potentials. Then, geometry optimizations of 1 and 2 were performed using the density functional theory (DFT), and different group participation in their LUMO is demonstrated. Using Saccharomyces cerevisiae cells as eukaryotic model, it is shown that in situ generated reduced species, 1red and 2red, have high capacity to inhibit cellular growth, with IC50 (0.50 mM for both complexes) lower than cisplatin IC50 (0.6 mM) at the same time of exposure. Regarding to their ability to promote S. cerevisiae cells death, after 24 h, cells became susceptible only when exposed to 1red and 2red: (i) at concentrations higher than 0.5 mM in a non-dose dependence, and (ii) in anaerobic metabolism. These data reveal the potential of 1 and 2 as bioreductively activated prodrugs, since their oxidized forms do not present expressive activities when compared to their reduced forms.