One-electron reduction of adriamycin and daunomycin: Short-term stability of the semiquinones

Pulse radiolysis studies of the one-electron reduction of adriamycin have now been extended to daunomycin. The daunomycin semiquinone has a p K a for phenolic dissociation of 2.8 ± 0.1. Measurement of the one-electron reduction potential using several redox references at pH values within the range pH 6 to 12 indicated no significant difference between the semiquinones of adriamycin and those of daunomycin. A value of E 7 1 = −341 ± 15 mV (vs NHE) fitted the complete set of data for both compounds, with a p K a of the NH 3 + group of the sugar moiety of 9.2 ± 0.1. Measurement of equilibria between the semiquinones and the parent quinones and their fully reduced products showed a maximum semiquinone stability around pH 9. At pH 7 the stability constant is 0.04 for both adriamycin and daunomycin. From the equilibrium and E 1 data, the second one-electron and the two-electron reduction potentials have been calculated over the pH range 7 to 12. E 7 2 is −260 ± 15 mV and E 7 m is −300 ± 15 mV for both compounds. The p K a values for the reduced anthracyclines have been calculated from the equilibrium data in the approximate pH range 7–12 to be 8.1 ± 0.1 and 9.0 ± 0.2 for the first two hydroxy groups and the two possible combinations for the ionization of the sugar NH 3 + groups, with the remaining two hydroxy groups ionizing above pH 14.