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In recent years, there has been increasing interest in damaged DNA and RNA nucleobases. These damaged nucleobases can cause DNA mutation, resulting in various diseases such as cancer. Alkylating agents are mutagenic and carcinogenic in a variety of prokaryotic and eukaryotic organisms. The present study employs density functional theory (DFT/B3LYP) with the 6-311++G(d,p) basis set to investigate the effect of chemical damage in O-alkyl pyrimidines such as O-methylthymine, O-methylcytosine and O-methylthymine. We compared the intrinsic properties, such as proton affinities, gas phase acidities, equilibrium tautomerization and nucleobase pair's hydrogen bonding properties, of these molecules with those in the normal nucleobases thymine and cytosine. The results are of interest for chemical reasons and also possibly for biological purposes since biological media can be quite non-polar. Furthermore, we found that N1-H of O-methylthymine is less acidic than N1-H of thymine, suggesting that alkyl DNA glycosylase enzyme cannot discriminate this damaged nucleobase from a normal thymine nucleobase. This result indicates that the conjugated base anion of O-methylthymine would be a worse leaving group and O-methylthymine is repaired in genome by demethylation rather than enzyme-catalyzed excision at N1. [ABSTRACT FROM AUTHOR]

Thiotepa ( N,N′, N″-triethylenethiophosphoramide) and its major metabolite (Tepa) as trifunctional alkylating agents has recently been used in cancer therapy. In vivo and vitro studies show the possible pathways of alkylation of DNA by Thiotepa and Tepa. Two pathways are suggested, but the main pathway of mechanism remains unclear. In pathway 1, forming cross-links with DNA molecules can be carried out via two different mechanisms. In first mechanism, these agents undergo the ring opening reaction which is initiated by protonating aziridine, which then becomes the main target of nucleophilic attack by the N7-Guanine of DNA. The second probable mechanism is ring opening of aziridyl group by nucleophilic attack of N7-Guanine without initial protonation. Thiotepa and Tepa in pathway 2, act as a cell penetrating carrier for aziridine, which is released via hydrolysis. The released aziridine can form a cross-link with N7-Guanine. In this study, we calculated the activation free energy and kinetic rate constant for alkylating the Guanine via the first pathway to determine the most precise mechanism by applying density functional theory using B3LYP method. We carried out geometrical optimizations with the conductor-like polarizable continuum model to account for the solvent effect, and the results were compared with those in the gas phase. Hyperconjugation stabilization factors that affect on stability of generated transition state were investigated by natural bond order analysis. Furthermore, quantum theory of atoms in molecules analysis was performed to extract the bond critical points properties because the electron densities can be considered as a good description of the strength of different types of interactions. [ABSTRACT FROM AUTHOR]

The cation radicals of DNA constituents generated by the ionizing radiation initiate the alteration of the bases, which is one main type of cytotoxic DNA lesions. These cation radical spices are known for their role in producing nucleic acid strand break, and it is important to identify the cation radical formation at particular atomic site in these molecules so that the major pathway for the nucleic acid damage may be trapped. In the present study, we explored theoretically energetic, structural, and electronic properties of the possible radicals formed via proton atom abstraction at various sites of sugar part of deoxycytidine cation radical by employing density functional theory at B3LYP/6-311++G (d,p) level. The computation revealed 0.0-22.6 kcal/mol energy disparity in these radicals. Radical-centered carbon increases the extent of bonding with its adjacent atoms. This tendency should be important in predicting the reactivity of sugar-based radicals. Based on DFT calculations, sugar radicals of deoxycytidine have following stability order: raH1′ > raH2′ > raH4′ > raH3′ > raH5′ > raO5′H > raO3′H. Furthermore, influence of cation radical formation on acidities of multiple sites in deoxycytidine nucleosides was investigated. For instance upon cation radical formation, ΔH of O3′H and O5′H sites of deoxycytidine varies from 348.6 and 351.5 to 228.8 and 227.5 kcal/mol, respectively. [ABSTRACT FROM AUTHOR]