DNA-damaging agents remain one of the most important chemotherapeutic strategies for the treatment of cancer(1). The drugs designed for this purpose generally contain two leaving groups that, by means SN2 reactions, form cross-linking DNA complexes of type (1,2)-intrastrand, (1,3)-intrastrand or (1,2’)-interstrand. In this kind of chemical transformations, the nucleophile (Nu:)—a DNA base, in most cases guanine (G) and, into a lesser extent, adenine (A)—attacks the chemotherapeutic reagent, which acts as an electrophile, to release a leaving group (Lg). Thus, assuming Nu:= G and Lg = Cl, the general reaction is DNA-G + E-Cl → DNA-G(+)-E+ Cl(-) (Figure 1).
Although this reaction implicates in serious harm to the double-helix structure those damages can be reversed by repair pathways in cancer cells, thus limiting the therapeutic success of these reagents, especially in further rounds of chemotherapy(2). To address this issue, platinum-based compounds, named Aurkine, were synthetized, based on increasing the number of electrophilic positions (En), that must generate interstrand crosslink adducts that should result in irreversible lesions in the DNA of cancer cells. Within this context, we have applied computational chemistry methods based on Quantum Mechanics (QM) and Molecular Dynamics (MD), for a better understanding how those compounds compromise the structure of a DNA sequence. These studies have given us insights on the structural distortions induced by these drug candidates as well as to predict the kinetics of these processes via successive SN2 reactions on guanine residues.
