The initiation and development of cancer which is known to be a leading cause of death worldwide is linked with DNA damage caused by a myriad of endogenous and exogenous agents including free radicals, reactive oxygen species (ROS), reactive nitrogen oxide species (RNOS), alkylating agents and ionizing radiation [1–5]. It is reported that these agents react with DNA bases and yield a plethora of modified DNA bases which can result the formation of mispairing of bases, abasic sites, strand-breaks, inter- and intra-strand DNA cross-links and DNA-protein cross-links [1, 4, 6, 5]. In addition to cancer, these DNA lesions, if not repaired, can cause several other lethal consequences including mutation, aging and neurodegenerative diseases [5, 2–4, 6]. Remarkably, anticancer drugs such as cisplatin, temozolamide, mechlorethamine etc. which are used to treat cancer also act by interacting with DNA bases [7–10].
Metal-based anticancer drugs and their interaction and reaction with DNA have gathered a lot of attention of researchers over the past few decades [10, 9, 11–14]. Ruthenium (Ru)-complexes are considered to be one of the most promising alternatives to the prevalent platinum (Pt)-based drugs due to their favourable toxicity, drug resistance and various remarkable properties [12, 15–17]. Therefore, a large number of Ru-complexes have been synthesised and tested for their anticancer activity to date [12, 18]. It is reported that two Ru-complexes, namely, NAMI-A [ImH[trans-RuCl4(DMSO-S) imidazole(Im)] and KP1019 [InH[trans-RuCl4(Indazole)2] have entered the clinical trials [18, 16, 19]. Ru-based drugs are, in general, believed to act via two mechanisms: activation-by-reduction and hydrolysis. Previous studies [20–28] on the hydrolysis of NAMI-A show that the first hydrolysis where one chloride (Cl−) ligand of NAMI-A is replaced by a water molecule is faster than its second hydrolysis. The hydrolyzed products of Ru-based drugs such as NAMI-A, ICR and KP1019 are reported to be more reactive towards biological molecules than their parent complexes [20–24, 29–31].
DNA is considered to be the prime pharmacological target for ruthenium and other metal-based anticancer drugs [9–12, 15, 16, 19, 20, 29, 31, 30]. The Ru-based drugs bind favorably to the N7 site of guanine [30, 29, 16, 19, 20]. Moreover, Ru-based drugs can also bind to other DNA bases such as adenine and cytosine [16, 17, 19, 29, 32]. Novakova et al. [33] showed that Ru-complex, mer-[Ru(III)(terpy)Cl3], formed DNA inter-strand cross-linking by coordinating specially with isolated guanine residues. P.M. van Vliet et al. [34] showed that the mer-[Ru(III)(terpy)Cl3] complex formed DNA inter-strand cross-linking in vitro via binding with two guanine bases in trans-configuration. Malina et al. [35] demonstrated that Ru-based drugs such as NAMI, KP1019 and ICR yielded bifunctional inter-strand crosslinks on double helical DNA with guanine as the prevalent binding site. It is noted that NAMI can produce bifunctional adducts affecting the conformation of DNA more efficiently as compared to KP1019 and ICR [35]. Extensive researches have been carried out both experimentally and theoretically to understand the mechanisms of action of Ru-based drugs but its therapeutic effect and specific pharmacological targets are not completely understood [36, 32, 30, 31, 29, 20, 19, 12].
In order to understand the DNA inter-strand cross-link formation capability of NAMI-A, we herein perform the density functional theoretic (DFT) calculations to investigate theoretically the structure and energetics of the formation of cross-linked DNA bases due to the reactions of mono-functional adduct of NAMI-A formed at the N7 site of guanine (hereafter denoted as GN7-NAMI-A) and each of the four DNA bases (as shown in Scheme 1). In view of the fact that Ru-based drugs bind predominantly with the N7 site of guanine and are hydrolyzed before reacting with any target, the GN7-NAMI-A (Fig. 1a) has been chosen as a reactant for the present study. The mechanisms of the formation of mono-functional adduct of NAMI-A at the N7 site of guanine can be found in our previous work [36].