title: Photosensitization of DNA strand breaks by three phenothiazine derivatives.
abstract: The interaction and the photosensitizing activity of three phenothiazine derivatives, fluphenazine hydrochloride (FP), thioridazine hydrochloride (TR), and perphenazine (PP), toward DNA were studied. Evidences obtained from various spectroscopic studies such as fluorimetric and linear dichroism measurements indicate that these derivatives bind to the DNA at least in two ways: intercalation and external stacking on the DNA helix, depending on their relative concentrations. Irradiation of supercoiled plasmid DNA in the presence of these phenothiazines leads to single strand breaks. The DNA photocleavage appears to be due to externally bound molecules rather than to those intercalated. The highest photocleavage activity was observed with PP and TR whereas FP was less efficient. The efficiency of the photocleavage in aerated and deaerated solutions does not change thus indicating that an involvement of singlet oxygen can be excluded. Primer extension analysis of plasmid DNA irradiated in the presence of phenothiazines indicates that photocleavage of DNA occurs predominantly at Gua and Cyt residues. Laser flash experiments carried out in the presence of 2'-deoxyguanosine 5'-monophosphate reveal an efficient electron transfer between the nucleotide and the radical cations produced by photoionization of the phenothiazines. In the presence of DNA, an electron transfer process takes place within the laser pulse from the lowest singlet state of phenothiazines to the DNA bases; the time-resolved measurements showed that the back-electron transfer is a negligible decay pathway for the charged species.
authors.affiliation: Department of Pharmaceutical Sciences, University of Padova, via Marzolo 5 Padova, Italy. giampietro.viola.1@unipd.it
authors.forename: Giampietro
authors.initials: G
authors.lastname: Viola
authors.forename: Loredana
authors.initials: L
authors.lastname: Latterini
authors.forename: Daniela
authors.initials: D
authors.lastname: Vedaldi
authors.forename: Gian Gaetano
authors.initials: GG
authors.lastname: Aloisi
authors.forename: Francesco
authors.initials: F
authors.lastname: Dall'Acqua
authors.forename: Nadia
authors.initials: N
authors.lastname: Gabellini
authors.forename: Fausto
authors.initials: F
authors.lastname: Elisei
authors.forename: Arianna
authors.initials: A
authors.lastname: Barbafina
mesh_terms: D000818:Animals; D001483:Base Sequence; D004247:DNA / Q000737:chemistry* / Q000528:radiation effects; D004249:DNA Damage; D005476:Fluphenazine / Q000737:chemistry; D007834:Lasers; D008027:Light; D008969:Molecular Sequence Data; D010546:Perphenazine / Q000737:chemistry; D010640:Phenothiazines / Q000737:chemistry*; D010777:Photochemistry; D017319:Photosensitizing Agents / Q000737:chemistry*; D012474:Salmon; D013816:Thermodynamics; D013881:Thioridazine / Q000737:chemistry; D014466:Ultraviolet Rays
chemical_list: D010640:Phenothiazines; D017319:Photosensitizing Agents; D004247:DNA; D010546:Perphenazine; D013881:Thioridazine; D005476:Fluphenazine