Effect of reduction potential on the rate of reduction of nitroacridines by xanthine oxidase and by dihydro-flavin mononucleotide

Abstract

The cytotoxicity of many nitroaromatic compounds is mediated by bioreduction. There is a correlation between the one-electron-reduction potentials and cytotoxic potencies of simple nitroheterocycles such as nitroimidazoles, but no such correlation is observed with DNA-binding nitroacridines related to the drug nitracrine. A study of the reduction of 1-nitroacridines by the enzyme xanthine oxidase and by reduced flavin mononucleotide, FMNH₂(as a model of the enzyme's active site) has been undertaken to explore the redox dependence in this series. The values of V_max,/K_m for reduction by xanthine oxidase, XOD, and the second-order rate constants of reduction by FMNH₂, analysed using Marcus electron-transfer theory, indicate a correlation between reduction potential and the rate of reduction, but suggest that the potential-energy barrier for electron transfer is small relative to that imposed by requirements for association, orientation and desolvation of the reactants. The close similarity in Marcus parameters for reduction by FMNH₂ and by XOD suggests that reduction occurs by a similar mechanism in each case. The free-energy change for electron transfer, ΔG^‡_o, is only 1–2 kJ mol^–1. It appears that the rate of reduction is unlikely to be the only determinant of hypoxic cytotoxicity for the nitroacridines, although the applicability of findings with XOD to other nitroreductases is uncertain.