Model Studies on a Carprofen Derivative as Dual Photosensitizer for Thymine Dimerization and (6–4) Photoproduct Repair

Abstract

Cyclobutane pyrimidine dimers (CPD) and (6-4) photoproducts are among the main UV-induced DNA lesions. Both types of damage are mostly repaired in prokaryotes by photolyase enzymes. The repair mechanism of (6-4) photolyases has still not been fully elucidated, but it is assumed that back rearrangement to the oxetane occurs prior to repair. In this work, a non-steroidal anti-inflammatory drug derivative corresponding to the dechlorinated methyl ester of carprofen (namely methyl 2-(carbazol-2-yl)propanoate, PPMe) has been used to achieve the photosensitized cycloreversion of model oxetanes (formally resulting from photocycloaddition between benzophenone and 1,3-dimethylthymine or 2'-deoxyuridine), by employing fluorescence spectroscopy, laser flash photolysis, HPLC and NMR. Although PPMe is able to photoinduce the cycloreversion of both oxetanes, the fluorescence quenching of PPMe is faster for the 2'-deoxyribose-containing oxetane; this underlines the importance of the structure in such studies. Moreover, PPMe was shown to photoinduce the formation of thymidine cyclobutane dimers through a triplet-triplet energy transfer from a vibrationally excited state, as suggested by the enhanced PPMe triplet quenching by thymidine with increasing temperature. These results reveal a dual role of PPMe in DNA photosensitization, in that it photoinduces either damage or repair.

Photoinduced Damage to Cellular DNA: Direct and Photosensitized Reactions†

“…There is an abundant literature on the TTET-mediated formation of CPDs in ds DNA by several photosensitizers, including acetone (142), acetophenone (54,142), benzophenone (54,143), carprofen (144), fenofibric acid (143), fluoroquinolones (92,93,145), ketoprofen (143) and three pyridopsoralen derivatives (146,147). The predominant CPD photoproduct of the latter photosensitized reactions was found to be cis-syn T<>T, in agreement with the fact that thymine exhibits the lowest triplet energy (E T ) among nucleobases (148).…”

Photosensitised pyrimidine dimerisation in DNA

“…31,50 Similar observations have been reported for NSAIDs containing the BP chromophore, such as ketoprofen (KP) and its derivatives. 51,52,54,55 Similarly, a photocycloaddition product identified as an oxetane has been 55 described after irradiation of cytosine in acetone-aqueous (1:1) solutions. …”

Regiochemical memory in the adiabatic photolysis of thymine-derived oxetanes. A combined ultrafast spectroscopic and CASSCF/CASPT2 computational study

“…[14][15][16][17][18][19][20][21] Previously, the photoinduced cycloreversion of oxetanes generated from 1,3-dimethylthymine (DMT) and carbonyl compounds has been investigated as a model for the photoenzymatic repair of DNA PPs. [22][23][24][25][26][27][28][29][30] Direct photolysis of some oxetane derivatives was observed to result in a rare adiabatic cleavage leading to the triplet excited state of the corresponding carbonyl species, along with ground state DMT. 24,30 A more recent work has proposed that cycloreversion takes place in a stepwise manner from the singlet excited state, with population of the triplet excited carbonyl at a later stage.…”