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.

Keywords: DNA repair; azetidine; density functional theory; electron transfer; photochemistry; redox properties; ring opening.

Figure 1

Structure of the cis- and trans- azetidine stereoisomers and the photosensitizers (Phs) studied in this work, classified according to their capacity to photo-oxidize or photoreduce the azetidine-cyclohexene model (AZT-CH) [19].

Figure 2

Scheme of the processes that take place during the ring-opening mechanism of the AZT-CH system. Phs_S0 = photosensitizer in the ground state, Phs_S1 = vertical absorption energy of the S₁ state of the photosensitizer, Phs_S1,min = energy of the S₁ state of the photosensitizer at its equilibrium geometry, S_CS^+/− = charge separated state of the photosensitizer and the AZT-CH system, AZT-CH_TS^+/− = transition state of the AZT-CH cationic or anionic state, azaU-CH^+/− = charge-separated reaction products, E_S1 = adiabatic electronic transition energy for the S₁ state of the photosensitizer, ΔE_redox = redox energy difference between AZT-CH and the photosensitizers in the excited state, ΔE^‡ = activation energy, ΔE = energy difference between reactants and products in the charge separated state, ΔE_pc^‡ = overall ability of the Phs to induce the cycloreversion of AZT-CH.

Figure 3

Opening of the azetidine ring of the cis-AZT-CH system in the gas-phase. The reaction profile corresponds to the reduced system with a net charge of −1 and doublet multiplicity. ‡ indicates transition state.

Figure 4

Opening of the azetidine ring of the trans-AZT-CH system in the gas-phase. The reaction profile corresponds to the reduced system with a net charge of −1 and doublet multiplicity. ‡ indicates transition state.

Figure 5

Opening of the azetidine ring of the cis-AZT-CH system in the gas-phase. The reaction profile corresponds to the oxidized system with a net charge of +1 and doublet multiplicity. Only the C₁-C₂ bond break is shown, the N₃-C₄ bond cleavage is displayed in a different figure and is common to both cis- and trans- isomers. ‡ indicates transition state.

Figure 6

Opening of the azetidine ring of the trans-AZT-CH system in the gas-phase. The reaction profile corresponds to the oxidized system with a net charge of +1 and doublet multiplicity. Only the C₁-C₂ bond break is shown, the N₃-C₄ bond cleavage is displayed in a different figure and is common to both cis- and trans- isomers. ‡ indicates transition state.

Figure 7

N₃-C₄ scission of the AZT-CH system in the gas-phase. Relaxed scan of the N₃-C₄ coordinate (left hand side), minimum energy path (MEP, center) from the highest-energy point of the scan, and linear interpolation of internal coordinates (LIIC, right hand side) between the last point of the MEP and the optimized products. The reaction profile corresponds to the oxidized system with a net charge of +1 and doublet multiplicity. The N₃-C₄ bond cleavage is common to both cis- and trans- isomers, and the transition state-like structure corresponds to a N₃-C₄ distance of 2.35 Å. Energies are relative to the trans-AZT-CH cation. ‡ indicates transition state.

Figure 8

Opening of the azetidine ring of the trans-AZT-CH system in the gas-phase initiated by the N₃-C₄ bond breaking. The reaction profiles correspond to the oxidized system with a net charge of +1 and doublet multiplicity, and have been obtained through relaxed scans of the N₃-C₄ bond distance, LIIC between relevant structures, and MEP determinations. The initial points for both MEP profiles were computed through relaxed scan calculations of the C₁-C₂ bond distance freezing the N₃-C₄ coordinate at 2.959 Å to avoid the return of the system to the reagents region. The hydrogen atom that undergoes the 1,2-hydride shift is highlighted with green dashed circles. The pathway that connects the last MEP structure to the products minimum shown in Figure 7 has not been computed. ‡ indicates transition state.