Structural and Energetic Properties of Organometallic Ruthenium(II) Diamine Anticancer Compounds and Their Interaction with Nucleobases Christian Gossens, Ivano Tavernelli, and Ursula Rothlisberger* Institut des Sciences et Inge ´ nierie Chimiques, Ecole Polytechnique Fe ´ de ´ rale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland Received January 17, 2007 Abstract: We rationalize the chemoselectivity of the monofunctional ruthenium anticancer compound [(η 6 -arene)Ru(II)(en)(OH 2 )] 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) > OH 2 . The G(N7) complex is the most stable product due to a hydrogen bond of its O6 with one of the H 2 N-amine groups of en, while the corresponding NH 2 -H 2 N(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 -C 6 H 6 )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+ . Introduction The discovery of cisplatin [Pt(NH 3 ) 2 (Cl) 2 ] 1 as an anticancer drug 2,3 has stimulated the search for other transition-metal complexes with even higher activity. 4 In the last decades, this search resulted mainly in related platinum based complexes which made their way to the clinics. 5 However, problems related to toxicity, selectivity, and resistance have limited their therapeutic application. 6 More recently, ruthe- nium complexes have attracted particular attention because of their potentially high in vivo antitumor activity and selectivity, together with their low general toxicity. Some of these compounds have already entered clinical trials. 7,8 Whereas inorganic ruthenium coordination complexes have been investigated for some years, organoruthenium com- pounds have moved into the focus of anticancer research only recently. So far, all of these complexes are based on a ruthenium(II) containing organometallic moieties of the type [(η 6 -arene)Ru] 2+ , 9-12 [(η 5 -cyclopentadienyl)Ru] + , 13,14 or [(1,4,7- trithiacyclononane)Ru] 2+ . 15 The remaining three coordination sites in these pseudo-octahedral complexes, which exhibit a so-called “piano stool” geometry, can be occupied by various monodentate or chelating ligands. A common feature to all these compounds is the presence of at least one leaving group, as for instance the chloro ligand in [(η 6 -arene)Ru(en)(Cl)] + (where en)ethylenediamine). It was shown experimentally that these chloro species hydro- lyze like cisplatin only at very low chloride concentration (e.g., inside a human cell), while no hydrolysis occurs at higher chloride concentrations (e.g., in the human blood stream). 16 As for cisplatin, the cellular (nuclear) DNA is considered the most relevant biological target, and it was shown experimentally that a hydrolyzed ruthenium arene diamine can indeed bind to oligonucleotides. 17 Crystal structures have been published showing such binding of [(η 6 - arene)Ru(en)] 2+ (arene)biphenyl; 5,8,9,10-tetrahydroan- thracene; 9,10-dihydroanthracene) to the N7 atom of guanine * Corresponding author e-mail: ursula.roethlisberger@epfl.ch. 1212 J. Chem. Theory Comput. 2007, 3, 1212-1222 10.1021/ct6003577 CCC: $37.00 © 2007 American Chemical Society Published on Web 03/29/2007