Theoretical Study on the Photo-Oxidation and Photoreduction of an Azetidine Derivative as a Model of DNA Repair

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.

Spatial and Temporal Resolution of the Oxygen-Independent Photoinduced DNA Interstrand Cross-Linking by a Nitroimidazole Derivative

“…The magnitudes have been computed with the M06-2X/6-31++G(d,p) method according to previous works on related systems. 56 , 57 …”

“… a Asterisks denote that the species is considered in the lowest-lying singlet or doublet state (S 1 for 1 and D 2 for 4 ), at its corresponding equilibrium geometry. The magnitudes have been computed with the M06-2X/6-31++G­(d,p) method according to previous works on related systems. , …”

“…Solvent effects (water) were considered using the polarizable continuum model (PCM). As indicated in Table , the (photo)­redox reactions were tackled with the M06-2X/6-31++G­(d,p) method since previous DNA-related works showed that this level of theory properly describes these types of reactions, as compared to experimental observations. , The B3LYP-PCM/6-31G*method was initially chosen to calculate the activation energy and energy difference between the reactants and products of the radical addition of 4 to the C5 and C6 positions of thymine. Frequency calculations were carried out on top of the converged minima and TSs to check the absence of any negative eigenvalue of the Hessian or the presence of only one, respectively.…”

Reductive Photocycloreversion of Cyclobutane Dimers Triggered by Guanines

“…This magnitude considers and connects the excitation of G and OG, the eT process to CPD, and the kinetics of the cyclobutane ring opening (see more details on this approach to model the phenomenon in our previous work, Navarrete-Miguel et al). 44 Note that the release of energy occurring in the eT to generate the charged species G •+ or OG •+ and CPD •− , (ΔE red )*, is clearly higher as compared to the small energy barrier needed to break the ring in the CPD •− system, ΔE ⧧ . The total energy balance, ΔE pc ⧧ , is more negative for OG, which should contribute to favoring the phenomenon in OG.…”