FREE-RADICAL INTERMEDIATES IN THE REDUCTION OF QUINOXALINE N-OXIDE ANTITUMOR DRUGS - REDOX AND PROTOTROPIC REACTIONS

The free radical intermediates formed on one-electron reduction of imi dazo[1,2-a]quinoxaline N-oxides RB91724 (I), RB90740 (II), and RB93918 (III) were investigated by pulse radiolysis. Reaction with radiolytic ally-generated CO2.- radical anions produced the N-oxide radicals. The radicals decayed by second-order kinetics, but the lifetimes of the r adicals of I increased with increasing pH, whereas the lifetimes of th e radicals of II and III were not significantly affected by pH (pH 4-1 1). The pK(a) values of the protonated radicals were measured as 7.4, 6.2, and 5.5 for I, II, and III, respectively. The radicals reacted wi th oxygen, with rate constants of 1.6, 3.2, and 1.8 x 10(8) dm(3) mol( -1) s(-1) for I, II, and III, respectively, at pH 7.4. From redox equi libria with viologens and 1-methylnicotinamide, the one-electron reduc tion potential of I was estimated to be -0.70 V, and those for II and III were estimated as similar to-0.80 V vs NHE, i.e., much lower than the corresponding value for the benzotriazine dioxide tirapazamine (-0 .45 V). Radicals were also generated by reduction with deoxyribose rad icals. Steady-state gamma-radiolysis and product analysis indicated a chain mechanism for the reduction of the drugs.