关键词: 氯乙基亚硝基脲; DNA单链断裂; 密度泛函理论; MΦller-Pleset微扰理论

Abstract:

Density functional theory(DFT) and Mller-Pleset perturbation(MP) theory methods were carried out to investigate the mechanism of single strand break following the alkylation of DNA base induced by chloroethylnitrosoureas(CENUs). A multiple-step process, involving the decomposition of CENUs, the alkylation on DNA base, the hydrolysis of N—glycosidic bond, the ring-opening reaction of basic sites and the elimination of phosphodiester finally leading to the DNA strand break, has been examined. The geometries of stationary points(reactions, intermediates, transition states and product) were optimized at B3LYP/6-31++G** level. For simulating the reaction in cellular environment, the optimization or single energy computations were performed with the conductor-like polarizable continuum model(CPCM) model in water. The potential energy curve of the whole reactions was ploted by B3LYP/6-31++G** and MP2/6-311++G** computation respectively, then the results showed that the energy barrier of phosphodiester elimination reaction was the maximal value in the processes, while that of the alkylation reaction was the minimum. So a conclusion from theoretical analysis, which was consisted with the kinetics experimental phenomenon, was drawed that the alkylation reaction would be completed as soon as CENUs decomposed, and then the alkylated base would eliminate from the strand in a short time, however, the final DNA single strand break reaction would be a much more time-consuming process after the generation of the abasic sites.

Key words: Chloroethylnitrosoureas(CENUs); DNA single strand break; Density functional theory(DFT); Mller-Pleset perturbation theory