Photosensitization of anticancer agents--8. One-electron reduction of mitoxantrone: an EPR and spectrophotometric...

An efficient method of one-electron reduction of the anticancer agent mitoxantrone is described. The method depends on illumination of a suitable photosensitizer absorbing blue light [acriflavine, anthrapyrazole, or Ru(bpy)2+(3)] in the presence of the drug and an electron donor, such as NAD(P)H, in deaerated solutions. An EPR spectrum, assigned to a semiquinone of mitoxantrone, is generated under these conditions and identified by spectral simulation. Decay of this species, attributed to a radical-radical reaction, gives a second order rate constant of 1.7 x 10(2) M-1 s-1 in organic media [dimethylsulfoxide (DMSO)/pH 8 buffer, 1:1 vol/vol] but is more rapid (approximately 10(4) M-1 s-1) in aqueous media under comparable conditions. The considerably decreased lifetime of the mitoxantrone radical at pH 5 is attributed to an additional electron transfer, promoted by protonation of the radical, and/or to an accelerated recombination of neutral radicals, leading to an EPR-silent species. Parallel spectrophotometric studies on the generation of the mitoxantrone reduced species by photosensitized reduction are described. The method offers convenient access to a key radical species involved in the metabolism and possible mode of action of this clinical anticancer agent.