Computational investigation of the carmustine (BCNU) alkylation mechanism using the QTAIM, IQA, and NBO models

Abstract

Although several studies have attempted to deduce by theoretical calculations the reaction mechanism of carmustine with DNA, no study has presented data on the reaction sites and the behavior of the electrons of the participating molecules. Thus, the objective of this paper is to apply the NBO (Natural Bond Orbital) model from the donor-acceptor point of view and the QTAIM (Quantum Theory: Atoms in Molecules) theory from the Laplacian of electronic density and the energy partition formalism IQA (Interacting Quantum Atoms) to quantify the interactions present in the alkylation between carmustine and DNA. The results showed that the decomposition of carmustine forms the chloroethyl ion and the 2-chloroethyldiazene hydroxide molecule, which subsequently breaks down to form 2-chloroethanol and N2. The NBO, QTAIM, and IQA data demonstrated that the ionic carbon of the chloroethyl ion suffers a nucleophilic attack from the O6-guanine. In the alkylation between intermediate 1,O6-ethanoguanine and cytosine, the bond between the CO of the intermediate ring breaks with a subsequent nucleophilic attack of the N of the cytosine with the C of the ring of the molecule 1,O6-ethanoguanine, forming a bridge of ethane between the guanine and cytosine bases.