A DFT study of both the hydrolytic degradation and protonation of semustine in variation conditions of pH and interaction of drug with DNA nucleobases

Semustine as an anti-cancer medicine is decomposed by hydrolysis under pH-dependent conditions, forming chlorocarbonium ion and interaction with nucleic acid molecules. This medicine can prevent the growth of cancer cells. In this study, the hydrolysis of medicine under various conditions is investigated, to find out the energy differences and the effects of an acidic condition on its activation energy. The mechanisms of protonation, degradation, and interaction with DNA bases were treated using density functional theory (B3LYP) and by utilizing the complete basis set 6–31 + G(d) method in gas phase. Also, in order to clarify the role of the acidic conditions on the increased stability and mechanism of the drug, the protonation of all possible sites was investigated. The obtained results depicted that the protonation of the oxygen of the carbonyl group (O1) is the preferable site for protonation that would stabilize the system by about 20.27 kcal mol−1 more than the next favorable protonation site (N1). The comparison of the hydrolysis rates indicates that the tendency to hydrolysis of medicine under acidic conditions increases by protonation of O1 site. While the rate of degradation enhances by decreasing of pH, it never comes to a complete halt under basic conditions. In order to investigate the medicine interaction with the bases of DNA profile, the mechanism of chlorocarbonium ion interaction was examined with the bases of DNA. The outcome indicates that the values of energies for O6 and N7 of guanine are − 70.26 kcal mol−1 and − 55.19 kcal mol−1, respectively, and probably the drug exerts its anti-cancer effect through interaction with these sites.