Reactional dynamics of the triplet excited state and radical species of the antitumor drug pazelliptin in aqueous media and with respect to nucleic acids: a laser photolysis and pulsed radiolysis study.

Summary The activity of the antitumor drug pazelliptin (pze) does not seem to be due only to its intercalation in dna, but would require a metabolic activation leading to the formation of radical species. A part of this work deals with the study of the reaction dynamics of such species in solution and towards dna. Experimentally, pze radicals are generated by pulsed radiolysis or laser-photolysis methods using the possibility of two-photon photoionization of the drug. These two complementary studies have allowed us to characterize by transient absorption spectroscopy measurements, the reactivity of the pze radicals in these different protonation states and to propose a mechanism of action of the drug towards dna involving its radical species and the active oxygen species. Furthermore, we have shown that pze is a photosensitizer of dna degradation by measuring single and double strand breaks. The investigation of the molecular mechanisms responsible for this process led us to characterize the photophysical and photochemical properties of the triplet state of pze in solution and complexed to nucleic acids. The results allowed us to propose a mode of action of the drug through a charge transfer oxidation of dna from the triplet state of pze.