Quantum chemical calculation of free radical substitution reaction mechanism of camptothecin

Abstract

Free radical substitution reaction, which has low energy barrier and takes place in mild reaction conditions, is an important method for camptothecin's modification. The experimental data show that the free radical substitution reaction of camptothecin has high site selectivity, and prefers to take place at site 7. Up to now, few researches focus on the mechanism of it. In this study, the differences of the reaction rate constant (k) for the reactions at different sites, such as site of 7, 9, 10, 11, 12, were investigated with B3LYP of density functional theory at the 6-31+G (d, p) base set level and CPCM aqueous solvent model. It was found that the substitution reaction can be carried out in two steps in acidic condition. First, the methyl radical attacks the corresponding site to form an intermediate having methyl radical combined with the camptothecin skeleton, and then a hydrogen atom was abstracted by the singlet oxygen to form methyl camptothecin, wherein the first step was the rate control step of the reaction. The results show that site 7 has the higherreaction rate constant (k) than other examined sites, indicating that the reaction tends to take place on site 7 position, which is in agreement with the experimental results.