Computed redox potentials and the design of bioreductive agents.

Anti-cancer agents that have been made selective for tumour cells by exploiting the known differences in the availability of oxygen between normal and transformed cells are a promising development in cancer chemotherapy. We have recently suggested a new type of bioreductive activity which would depend on a two-electron reduction. For rational design of such compounds, it is essential to be able to predict the redox potentials and the chemical modifications needed to produce the optimum redox value. Calculating redox potentials is a daunting task for the theoretician, however, as the effect of water solvation is clearly of major significance. Recent successful calculations of differences in the free energies of biologically important molecules in aqueous solution using the free-energy perturbation method prompted us to apply the technique to the computation of two-electron redox potentials. The results are accurate to within 20 mV, suggesting that we should be able to manipulate redox potentials by successfully predicting structures with the appropriate value.