Anthracyclines and their model quinones

The most basic structural model for anthracyclines adriamycin (doxorubicin) and daunomycin (daunorubicin) was considered to be tiie strongly intramolecularly hydrogen-bonded naphthazarin (5,8-dihydroxy-1,4-naphthoquinone) (Section 3.2). It is usually customary to study the way in which such simple quinones form radicals in order to gain insight into the way more complex quinones might produce toxic and other effects. This is more so as the radical centres in the complex molecules are usually located in these simpler model structures. Treatment of naphthazarin will also demonstrate how various data may be compiled and compared. 

In aqueous solution, naphthazarin (NZH2) can exist in the fully protonated form (NZH2), anionic form (NzH ) or dianionic form (Nz ) depending on the pH. 

The ESR studies also established that the pK 13.8 could be assigned to the transition NzH2 NzH , and that the structure of the semiquinone was a strongly intramolecularly hydrogen-bonded highly symmetric structure where the unpaired electron is delocalised over the entire ring structure (Section 3.2). 

The one-electron reduction potential (E ) values were calculated at several pH values using several redox standards. From these measurements, e) = - 109 mV vs NHE at 25°C was established. A E versus pH plot shows a region independent of pH, i.e. no proton involved in the reduction process, confirming the above structural assignments. 

In many cases, semiquinones are present at appreciable concentrations in solutions containing quinones and the corresponding hydroquinone. In the case of naphthazarin, the NzH2 form was found to be extremely stable in the weakly alkaline solutions unlike at the two extremes of the pH range when the disproportionation of the semiquinone was complete. The reaction (23) was studied over the entire pH range 1-14. Within pH 6 to 11, the disproportionation was incomplete and the semiquinone was stable over himdreds of milhseconds at least. The equihbrium concentration of the semiquinone was measured and the equilibrium constant K q was calculated. Such stability constants were related to the one-electron reduction potentials for the quinone and the semiquinone (at 25°C) via the expression  

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