Abstract
Photocycloreversion plays a central role in the study of the repair of DNA lesions, reverting them into the original pyrimidine nucleobases. Particularly, among the proposed mechanisms for the repair of DNA (6-4) photoproducts by photolyases, it has been suggested that it takes place through an intermediate characterized by a four-membered heterocyclic oxetane or azetidine ring, whose opening requires the reduction of the fused nucleobases. The specific role of this electron transfer step and its impact on the ring opening energetics remain to be understood. These processes are studied herein by means of quantum-chemical calculations on the two azetidine stereoisomers obtained from photocycloaddition between 6-azauracil and cyclohexene. First, we analyze the efficiency of the electron-transfer processes by computing the redox properties of the azetidine isomers as well as those of a series of aromatic photosensitizers acting as photoreductants and photo-oxidants. We find certain stereodifferentiation favoring oxidation of the cis-isomer, in agreement with previous experimental data. Second, we determine the reaction profiles of the ring-opening mechanism of the cationic, neutral, and anionic systems and assess their feasibility based on their energy barrier heights and the stability of the reactants and products. Results show that oxidation largely decreases the ring-opening energy barrier for both stereoisomers, even though the process is forecast as too slow to be competitive. Conversely, one-electron reduction dramatically facilitates the ring opening of the azetidine heterocycle. Considering the overall quantum-chemistry findings, N,N-dimethylaniline is proposed as an efficient photosensitizer to trigger the photoinduced cycloreversion of the DNA lesion model.
Highlights
The direct absorption of ultraviolet light causes the most abundant lesions in DNA, namely cyclobutane pyrimidine dimers (CPD) and (6-4) photoproducts (6-4PP) [1,2,3]
The 1,2-hydride shift in the C2-C4 position leads to a species whose C1-C2 bond scission is much more energetic. Considering these results, it is reasonable to think that the ring opening reaction triggered by the initial N3-C4 cleavage is probably more efficient for the transAZT-CH cation, even though the energy barriers (>30 kcal mol-1) are still large and p1r0edofic1t4 slow ring-opening reactions with the photo-oxidants considered in this work
Considering these results, it is reasonable to think that the ring opening reaction triggered by the initial N3-C4 cleavage is probably more efficient for the trans-AZT-CH cation, even though the energy barriers (>30 kcal mol−1) are still large and predict slow ring-opening reactions with the photo-oxidants considered in this work
Summary
The direct absorption of ultraviolet light causes the most abundant lesions in DNA, namely cyclobutane pyrimidine dimers (CPD) and (6-4) photoproducts (6-4PP) [1,2,3]. DNA photoreduction has been mainly associated with photorepair, the significance of oxidative processes has long been proven in relation to the long-range charge transport [16,17,18] Taking this context, the photoreactivity of azetidine intermediates is important to determine their photostability under photosensitization conditions and to evaluate the ability of some photo-oxidants to act as photolyase mimics. 0.96 0.27 (6.2) 0.24 (5.6) N.D. DCN and DCA have similar and less negative Ered,0,Phs than CNN, which implies a higher ability to accept one electron from the AZT-CH in the photo-oxidation process. DCN and DCA have similar and less negative Ered,0,Phs than CNN, which implies a higher ability to accept one electron from the AZT-CH in the photo-oxidation process This trend is captured in the computed AEA, which is clearly lower for CNN. The stereopreference for the cis-AZT-CH isomer in the photo-oxidation process is maintained for all the Phs, in agreement with the experimental determinations
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