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DNA Cleavage Induced by Photoexcited Antimalarial Drugs: A Photophysical and Photobiological Study
Author(s) -
Aloisi Gian Gaetano,
Amelia Matteo,
Barbafina Arianna,
Latterini Loredana,
Elisei Fausto,
Dall’Acqua Francesco,
Vedaldi Daniela,
Faccio Anita,
Viola Giampietro
Publication year - 2007
Publication title -
photochemistry and photobiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.818
H-Index - 131
eISSN - 1751-1097
pISSN - 0031-8655
DOI - 10.1111/j.1751-1097.2007.00084.x
Subject(s) - chemistry , dna , flash photolysis , intercalation (chemistry) , singlet oxygen , photochemistry , pyrimidine , stereochemistry , reaction rate constant , biochemistry , kinetics , oxygen , organic chemistry , physics , quantum mechanics
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 K a ∼ 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‐β‐ 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.