Kinetics and mechanism of the reactions of superoxide ion in solution. Part 6. Interaction of superoxide ion with adriamycin in aprotic and protic media

Abstract

The interaction of superoxide ion with adriamycin has been studied in aprotic and protic solutions by the use of electronic absorption and n.m.r. spectroscopy. It was found that superoxide ion reacted with adriamycin by one-electron transfer in both aprotic and protic media (in the latter case against the reduction potential) due to irreversible transformation of the adriamycin semiquinone via dimerisation and deglycosation. The one-electron mechanism was confirmed by electrochemical reduction of adriamycin and by its reduction with NaBH,, benzosemiquinone, and ascorbate. In both aprotic and protic media one-electron reduction of adriamycin by superoxide ion was favoured over deprotonation. The possible application of this mechanism to the reaction of 02-* with other anthraquinones was also considered.Free-radical reactions of adriamycin (AdrH,) and other anthracycline (AnthH,) antibiotics have been much studied in connection with the suggestion that both the anti-cancer effects 3*4 and the cardiotoxicity ' of these antibiotics may be accounted for by the generation of oxygen and semiquinone free radicals. It has been shown4-* that the incubation of anthracycline antibiotics with microsomes and mitochondria leads to a sharp increase in superoxide production, which was explained by the one-electron oxidation of antibiotic semiquinones by molecular oxygen [equation (l)].AnthH,-* + 0, AnthH, + 02-' (1)Chemical studies are not in full agreement with this proposal. Thus, although pulse-radiolysis studies 9,10 show that in aqueous solution equilibrium (1) must indeed be shifted to the right ( K , cu. lo3),'' we have previously found that in aprotic media (DMF) superoxide ion reacts with adriamycin practically irreversibly. We assumed that the reaction proceeds oiu a oneelectron transfer mechanism to form the adriamycin semiquinone which at the next stage forms a dimeric or oligomeric diamagnetic complex. Recently, our conclusion was questioned.I2'l3 The authors of these papers argued that 02-' reacts with anthracycline antibiotics oia the deprotonation reaction (2) and not oiu the one-electron transfer ( -1). 02-' +We re-investigated the interaction of superoxide ion with adriamycin in aprotic media (acetonitrile) and extended the study to water-acetonitrile solutions with a water content up to 900;. Acetonitrile was chosen as the aprotic solvent instead of dimethylformamide because in this solvent 02-* has a strongly marked maximum at 249 nm.I4

Synthesis and Chemistry of Quinone Methide Models for the Anthracycline Antitumor Antibiotics

“…The anthracycline antitumor antibiotics, such as adriamycin and daunomycin, are an important class of cancer chemotherapeutic agents, and yet their precise mode of action is not fully understood . These compounds, which are known to be DNA intercalators, may derive their anticancer activity via several different manifolds of action, including the following: (1) a radical based mechanism involving the formation of super oxide or other radicals from quinonoid redox chemistry; (2) an intercalation-based pathway involving DNA topoisomerase II; or (3) a mechanism involving alkylation of some critical biomolecule by a quinone methide, or other reactive intermediate 2d …”