The reactivity of redox states of model systems for anthracycline pharmacophores were examined by the AM1 semiempirical approach. The redox states examined were quinone (Q), quinone radical anion (Q ), semiquinone radical (QH ), semiquinone anion (QH"), and hydroquinone (QH2), while the model systems were 1,4-benzoquinone (I), 1,4-naphthaquinone (II), hydroxy-naphthaquinone (III) and dihydroxy-naphthaquinone (IV), which are all part of the pharmacophores of several anthracyciines. The imine and/or diimine derivatives of 1,4-benzoquinone and dihydroxy-naphthaquinone were also investigated. The relative reactivity of Q, Q' , QH, QH, and QH2 were examined by utilizing absolute electronegativity and chemical hardness data. In all cases, Q' and QH were found to be the most reactive species suggesting that these redox states are probably the ones tnat transfer their electrons to molecular oxygen thereby generating reactive oxygen species. The imine and diimine analogs were shown to have higher reactivity. This strongly suggests that 5-iminodaunomycin, a C-5 imine derivative of daunomycin, which has been described as redox-incapacitated, should not be less reactive than daunomycin. Based on electronegativity data, there were no specific reactivity trend observed for redox states of the four quinone systems (l-IV); however, absolute hardness data suggested that Q" was the most reactive intermediate for all four systems. SOMO and LUMO energies, absolute electronegativities and chemical hardness values, and reaction enthalpies (for the electron attachment to Q) of 12 disubstituted naphthaquinones were also correlated with their experimental reduction potentials using a least squares analysis. When all 12 points were included, the correlation coefficients obtained were: 0.28 (SOMO energies), 0.40 (LUMO energies), 0.41 (absolute hardness), 0.53 (electronegativity), and 0.57 (reaction enthalpies). In all cases, exclusion of three points gave better correlations with coefficients in the range of 0.73-0.91. In general, SOMO and LUMO energies and reaction enthalpies decreased with increasing reduction potential and absolute hardness and electronegativity values increased with increasing reduction potential. Since experimental reduction potentials have been shown to correlate with antitumor activity, this study shows the various electronic properties considered in this study should also correlate with antitumor activity, and thus can be used to generate a data base for structure-activity correlations and for new drug design purposes.