Calculation of one-electron reduction potentials for nitroheterocyclic hypoxia-selective agents

Theoretical one-electron reduction potentials, E(1), have been determined for a set of eight nitroarene hypoxic cell radiosensitisers using a combination of classical statistical mechanics and quantum mechanical methods. Gas-phase electron affinities were calculated using ab initio Hartree-Fock calculations and relative hydration energies were computed using the free energy perturbation (FEP) method. The results were used to estimate the relative one-electron reduction potentials for these molecules in solution. In general, the computed results are in good agreement with experiment although further work is required to determine the limitations of the method. Nevertheless, the method shows sufficient promise to be of value in the rational design of improved oxidative agents for use as hypoxia-selective radiosensitisers and bioreductivity activated cytotoxins.