How environment affects drug activity: Localization, compartmentalization and reactions of a vanadium insulin-enhancing compound, dipicolinatooxovanadium(V)

The chemical and biological properties of a simple and traditional V(5+) coordination complex, dipicolinatooxovanadium(V) (abbreviated [VO2dipic]−), are described in order to present a hypothesis for a novel mode of action wherein a hydrophobic membrane environment plays a key role. Specifically, we propose that the compartmentalization and both chemical and biological transformations of vanadium-complexes direct whether beneficial or toxic effects will be observed with this class of compounds. This concept is based on the formation of high levels of uncontrollable reactive oxygen species (ROS) from one-electron reactions or alternative events possibly initiated by a two-electron reaction which may be directly or indirectly beneficial by reducing the high levels of ROS. The properties of dipicolinatooxovanadium(V) compounds in aqueous solution (D.C. Crans, et al., Inorg. Chem. 39 (2000) 4409–4416) are very different from those in organic solvents (S.K. Hanson, et al., J. Am. Chem. Soc. 131 (2009) 428–429) and these differences may be key for their mode of action. Since other vanadium complexes are known to hydrolyze upon administration, the low stability of the aqueous complex requires entrapment in hydrophobic environments for such a complex to exist sufficiently long to have an effect. The suggestion that the environment changes the reactivity of the compounds is consistent with the very different modes of action by which one complex act. In short, a novel hypothesis is presented for a mode of action of vanadium compounds based on differences in properties resulting from environmental conditions. These considerations are supported by recent evidence supporting a role for membranes and signal transduction events (D.A. Roess, et al. Chem. Biodivers. 5 (2008) 1558–1570) of the insulin-enhancing properties of these compounds.