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 bhnq(2-)
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 bhnq(2-) was observed for the reaction of 1 with
ascorbic acid. For 2, the dissociation of bhnq(2-) 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.