Mechanisms of reactions of Ru(iii)-based drug NAMI-A and its aquated products with DNA purine bases: a DFT study

Abstract

It is believed that Ru(III)-based drugs including NAMI-A and KP1019, which have entered clinical trials, are hydrolysed readily in vivo to form a number of more reactive aquated complexes which then react with the biological targets. However, no conclusive report on this matter is available in the literature. Therefore, the mechanisms of reactions of NAMI-A and its mono- and di-aquated products (in which one/two chloride ligands are replaced by one/two water molecules) at the N7 site of guanine as well as the reaction of mono-aquated NAMI-A at the N7 site of adenine have been investigated using density functional theory. The present contribution provides the detailed structural properties of reactant complexes (RCs), transition states (TSs) and product complexes (PCs) involved in these reactions obtained at the M06-2X/(LanL2DZ+6-31G**) level of theory in the gas phase as well as the energetics and rate constants obtained at the M06-2X/(LanL2DZ+6-311+G**) level of theory in the gas phase and aqueous media. The solvent effect of aqueous media was estimated using the conductor-like polarisable continuum model (CPCM). It is found that both the mono- and di-aquated products of NAMI-A are more reactive than NAMI-A itself toward the N7 site of guanine. It is further found that the mono-aquated NAMI-A reacts with the N7 site of adenine more favourably than with the N7 site of guanine, the barrier energy and rate constant of its reaction with adenine (guanine) being 22.67 (27.15) kcal mol⁻¹ and 1.46 × 10⁻⁴ s⁻¹ (7.55 × 10⁻⁸) in aqueous media. It shows that NAMI-A is first hydrolysed to form more reactive aquated complexes which then react with the biological targets like adenine and guanine. Thus, the present study is expected to be helpful in understanding the mechanisms of analogues of NAMI-A, and other Ru-based drugs also.