Structural and Energetic Properties of Organometallic Ruthenium(II) Diamine Anticancer Compounds and Their Interaction with Nucleobases.

We rationalize the chemoselectivity of the monofunctional ruthenium anticancer compound [(η(6)-arene)Ru(II)(en)(OH2)](2+) (en=ethylenediamine; arene=benzene 1, p-cymene 2) toward guanine, using static DFT (BP86) and MP2 calculations together with Car-Parrinello molecular dynamics. The calculated binding energies for the three investigated nucleobases (G, A, C) decreases in the order G(N7) ≫ C(O2) ∼ C(N3) > A(N7) > G(O6) > OH2. The G(N7) complex is the most stable product due to a hydrogen bond of its O6 with one of the H2N-amine groups of en, while the corresponding NH2-H2N(en) interaction in the adenine complex is repulsive. A very low rotational barrier of 0.17 kcal/mol (BP86) and 0.64 kcal/mol (MP2) was calculated for the arene rotation in [(η(6)-C6H6)Ru(en)(Cl)](+) (3) allowing complexes containing arenes with bulky side chains like p-cymene to minimize steric interactions with, e.g., DNA by simple arene rotation. All [(η(6)-arene)Ru(en)(L)](2+) compounds exist in two stable conformers obtained for different diamine dihedral angle (NCCN) orientation, which, in the case of asymmetric ligands L, differ by up to ∼2.8 kcal/mol. Car-Parrinello dynamics reveal a chelating transition state for the interconversion between N7 and O6 binding of guanine to [(η(6)-arene)Ru(en)](2+).