A study on the properties and reactivity of naphthoquinone-cobalt(III) prototypes for bioreductive prodrugs

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), H(2)bhnq. 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 center dot H2O (1) and [Co(bhnq)(L2)]BF4 center dot 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 center dot 3H(2)O (3) and [Ga(bhnq)(L2)] NO3 center dot 3H(2)O (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 -0.08 V vs NHE for 1 and 2, respectively. An O-2-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 O-2 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. (c) 2013 Elsevier Inc. All rights reserved.