A semiempirical computational study of electron transfer reactivity of one‐ vs. two‐ring model systems for anthracycline pharmacophores. I. A rationale for mode of action

Abstract

The redox capacities of 5-hydroxy-1,4-naphthaquinone (VI), 5-8-dihydroxy-1,4-naphthaquinone (VII), and 5,8-dihydroxy-1,4-naphthaquinone imine (VIII) as model systems for the pharmacophore of aclacinomycin A, adriamycin/daunomycin, and 5-iminodaunomycin (5IDN), respectively, along with 1,4-naphthaquinone (V), 1,4-benzoquinone (IV), and 1,4-benzoquinone imine (IX), have been investigated by the AM1 semiempirical method. The reduction activation of the parent (Q) model systems to their various redox states [quinone radical anion (Q−2), semiquinone (QH˙), semiquinone anion (QH−), and hydroquinone (QH2)], the redox capacities of the redox states, and the intermolecular electron self-exchange processes between the redox states and electron transfer reactions from the redox states to molecular oxygen have been examined using reaction enthalpies, adiabatic ionization potentials and electron affinities, and absolute and adiabatic electronegativities. Keto—enol transformations and the effects of solvation and H bonding on keto–enol tautomers of VI and of the hydroquinones of VI and VIII have also been assessed. The results indicate that the reactivity of VIII, relative to that of VII, may not be diminished. VI, however, appears to be less reactive than VII, and this suggests clues for the reduced toxicities of aclacinomycin A. Overall, the results suggest that the experimentally observed reduced cardiotoxic effects of 5IDN may be explained by changes in electron configuration and/or electron density and in geometry, such as changes in planarity that accompany enol to keto transformations in the reduction by product of 5IDN (Bird et al.7)—that is, between the hydroquinone (II) of naphthacenedione (I) and naphthacenone (III). Moreover, the results suggest that the two-electron reduction product, Q−2, of the drugs can be the reductant that produces reactive dioxygen species, such as O2−˙ and HO2˙, via electron transfer to molecular oxygen as opposed to QH˙ and QH2, which have been postulated to be responsible for electron transfer. This possibly new role for Q−2 may be important in cardioxicity, particularly in aprotic and/or hydrophobic media. © 1996 by John Wiley & Sons, Inc.