title: DNA cleavage induced by photoexcited antimalarial drugs: a photophysical and photobiological study.
abstract: The interactions and the photosensitizing activity of three antimalarial drugs quinine (Q), mefloquine (MQ) and quinacrine (QC) toward DNA was studied. Evidences obtained by absorption and emission spectroscopy and by linear dichroism measurements indicate that these derivatives bind the macromolecule with a high affinity (binding constants Ka approximately 10(5) M(-1)). The absorption characteristics of the drugs changed markedly by addition of DNA and their fluorescence was quenched with rate constants higher than that of diffusion. The geometry of binding involves predominantly the intercalation into the double helix. The DNA photocleavage properties of antimalarials was investigated using plasmid DNA as a model, at different [drug]/ [DNA] ratios. The results indicate that mainly MQ and Q are able to induce significant photodamage to DNA. In particular the marked effect of the former drug is evidenced after treatment of photosensitized DNA by two base excision repair enzymes, formamydo-pyrimidine glycosilase (Fpg) and Endonuclease III (Endo III). From a mechanistic point of view, experiments carried out in different experimental conditions indicate that these drugs photoinduce DNA damage through singlet oxygen and/or radical cation production. These findings are further supported by the determination of two photoproducts of 2'-deoxyguanosine, which are diagnostic for Type I and Type II pathways, namely 2,2-diamino(2-deoxy-beta-D-erythro-pentofuranosyl)-4-amino-5(2H)-oxazolone and (R,S)4-hydroxy-8-oxo-4,8-dihydro-2'-deoxyguanosine (4-OH-8-oxo-dGuo). Laser flash photolysis experiments carried out in the presence of DNA indicates that the excitation produces mainly the triplet state for Q and the triplet and radical cation for QC. Moreover the singlet and triplet states and radical cations of the drugs are quenched by 2'-deoxyguanosine monophosphate. The absorbances of these transients decrease with increasing DNA concentration.
authors.affiliation: Department of Chemistry and CEMIN (Centro di Eccellenza sui Materiali Innovativi Nanostrutturati), University of Perugia, Perugia, Italy.
authors.forename: Gian Gaetano
authors.initials: GG
authors.lastname: Aloisi
authors.forename: Matteo
authors.initials: M
authors.lastname: Amelia
authors.forename: Arianna
authors.initials: A
authors.lastname: Barbafina
authors.forename: Loredana
authors.initials: L
authors.lastname: Latterini
authors.forename: Fausto
authors.initials: F
authors.lastname: Elisei
authors.forename: Francesco
authors.initials: F
authors.lastname: dall'Acqua
authors.forename: Daniela
authors.initials: D
authors.lastname: Vedaldi
authors.forename: Anita
authors.initials: A
authors.lastname: Faccio
authors.forename: Giampietro
authors.initials: G
authors.lastname: Viola
mesh_terms: D000962:Antimalarials / Q000494:pharmacology*; D053837:DNA Cleavage / Q000187:drug effects* / Q000528:radiation effects; D004249:DNA Damage / Q000187:drug effects / Q000528:radiation effects; D015767:Mefloquine / Q000494:pharmacology; D010782:Photolysis; D017319:Photosensitizing Agents / Q000494:pharmacology; D010957:Plasmids; D011796:Quinacrine / Q000494:pharmacology; D011803:Quinine / Q000494:pharmacology
chemical_list: D000962:Antimalarials; D017319:Photosensitizing Agents; D011803:Quinine; D011796:Quinacrine; D015767:Mefloquine