Free Radical Intermediates in the Reduction of Quinoxaline N-Oxide Antitumor Drugs: Redox and Prototropic Reactions

Abstract

The free radical intermediates formed on one-electron reduction of imidazo[1,2-a]quinoxaline N-oxides RB91724 (I), RB90740 (II), and RB93918 (III) were investigated by pulse radiolysis. Reaction with radiolytically-generated CO2•- radical anions produced the N-oxide radicals. The radicals decayed by second-order kinetics, but the lifetimes of the radicals of I increased with increasing pH, whereas the lifetimes of the radicals of II and III were not significantly affected by pH (pH 4−11). The pKa values of the protonated radicals were measured as 7.4, 6.2, and 5.5 for I, II, and III, respectively. The radicals reacted with oxygen, with rate constants of 1.6, 3.2, and 1.8 × 108 dm3 mol-1 s-1 for I, II, and III, respectively, at pH 7.4. From redox equilibria with viologens and 1-methylnicotinamide, the one-electron reduction potential of I was estimated to be −0.70 V, and those for II and III were estimated as ∼−0.80 V vs NHE, i.e., much lower than the corresponding value for the benzotriazine dioxide tirap...