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The motivation of this work was to probe whether coordination of esculetin to cobalt(III) could lead to a complex with the required properties to function as a redox-activated drug delivery platform, selective for hypoxic environments. The complex [Co(esc)(py2en)]ClO4·(CH3OH)2 (1) was obtained and fully characterized by CHN elemental analysis, single-crystal Xray diffractometry, UV/Vis and fluorescence spectroscopy, and ESI mass spectrometry. The redox behavior of 1 was evaluated by cyclic and square wave voltammetry analyses in MeCN and PBS buffer, which revealed distinct potentials for the Co3+/Co2+ processes in aqueous and organic solutions. In PBS, the potential is within the accepted ideal range (-0.2 to -0.4 V vs. SHE) for reduction in biological systems. Thus, a selective release of the coumarin ligand in a hypoxic environment upon reduction was simulated by investigating reactions of 1 with sodium dithionite in argon-, air-, and O2-saturated atmospheres. An [O2]-dependent dissociation of esculetin was monitored over a 72 h period at 25 °C by UV/Vis spectroscopy and confirmed by fluorescence spectroscopy and ESI-MS data. These results provide strong evidence of a hypoxia-selective, redox-activated mechanism for the release of esculetin from this cobalt(III) complex. [ABSTRACT FROM AUTHOR]

Our group has recently initiated a study on the development of new prototypes for bioreductive prodrugs, based on Co(III) complexes with the ligand 2,2′-bis(3-hydroxy-1,4-naphthoquinone), H2bhnq. The focus of this work is to investigate the dissociation of bhnq−2 from the complex upon reduction, and the effects of pH, redox potential, oxygen concentration and nature of the auxiliary ligands on this reaction. The bhnq2− ligand is a “non-cytotoxic” agent that was chosen as a probe for the reactivity studies due to its suitable chromophoric properties, at the same time that it resembles more cytotoxic naphthoquinones relevant for cancer therapy. In this way, two Co(III) complexes [Co(bhnq)(L1)]BF4·H2O (1) and [Co(bhnq)(L2)]BF4·H2O (2) (L1= N,N′-bis(pyridin-2-ylmethyl)ethylenediamine and L2= N,N′-dimethyl-N,N′-bis(pyridin-2-ylmethyl)ethylenediamine) were synthesized and fully characterized. The gallium analogs [Ga(bhnq)(L1)]NO3·3H2O (3) and [Ga(bhnq)(L2)]NO3·3H2O (4) were also prepared for helping with the assignments of the redox properties of the cobalt complexes and the structure of 2. Cyclic voltammetry analysis revealed a pH-independent quasi-reversible Co(III)/Co(II) process at −0.22 and −0.08V vs NHE for 1 and 2, respectively. An O2-dependent dissociation of bhnq2− was observed for the reaction of 1 with ascorbic acid. For 2, the dissociation of bhnq2− was found to be independent on the concentration of O2 and faster than in 1, with little influence of the pH on both complexes. The difference in reactivity between 1 and 2 and their redox properties, among other factors, suggests that 1 undergoes redox cycling, pointed out as a key feature for a prodrug to achieve hypoxic selectivity. [ABSTRACT FROM AUTHOR]