Computational investigation of the carmustine (BCNU) alkylation mechanism using the QTAIM, IQA, and NBO models
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ORIGINAL RESEARCH
Computational investigation of the carmustine (BCNU) alkylation mechanism using the QTAIM, IQA, and NBO models S. H. D. M. Faria 1,2
&
J. G. Teleschi 2
&
L. Teodoro 2
&
M. O. Almeida 3
Received: 13 April 2020 / Accepted: 30 July 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
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,O6ethanoguanine 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. Keywords Potential energy surface . Carmustine . Chloroethyl ion . 1,O6-ethanoguanine . Guanine-cytosine pair
Introduction 1,3-Bis(2-chloroethyl)-1-nitrosourea, or carmustine (BCNU), is an important alkylating agent used in the treatment of brain tumors due to its lipophilicity that allows it to cross the bloodbrain barrier [1]. Its high antitumor potential is related to its ability to cross-link between chains deoxyribonucleic acid; this characteristic being evidenced by the study of the reaction Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11224-020-01604-x) contains supplementary material, which is available to authorized users. * S. H. D. M. Faria [email protected] 1
Instituto de Química, Universidade Estadual de Campinas (UNICAMP), Rua Josué de Castro, 126 - Cidade Universitária, Campinas, SP 13083-861, Brazil
2
Universidade Paulista (UNIP), Av. Comendador Enzo Ferrari, 280 – Swift, Campinas, SP 13045-770, Brazil
3
Centro de Ciências Naturais e Humanas, Universidade Federal do ABC (UFABC), Rua Santa Adélia, 166, Bairro Bangu, Santo André, SP 09210-170, Brazil
kinetics of BCNU with DNA published in 1977 by Kurt W. Kohn [2]. Four years later, Tong and Ludlum [3] isolated and characterized the molecules of N7-(2-chloroethyl)guanine and diguanylethane in DNA that have been reacted with BCNU. In the authors’ view, the formation of cross-links consisting of 2-carbon bridges such as tho
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