DNA structural distortions induced by ruthenium-arene anticancer compounds.

Organometallic ruthenium(II)−arene (RA) compounds combine a rich structural diversity with the potential to overcome existing chemotherapeutic limitations. In particular, the two classes of compounds [Ru(II)(η6-arene)X(en)] and [Ru(II)(η6-arene)(X)2(pta)] (RA-en and RA-pta, respectively; X = leaving group, en = ethylenediamine, pta = 1,3,5-triaza-7-phosphaadamantane) have become the focus of recent anticancer research. In vitro and in vivo studies have shown that they exhibit promising new activity profiles, for which their interactions with DNA are suspected to be a crucial factor. In the present study, we investigate the binding processes of monofunctional RA-en and bifunctional RA-pta to double-stranded DNA and characterize the resulting structural perturbations by means of ab initio and classical molecular dynamics simulations. We find that both RA complexes bind easily through their ruthenium center to the N7 atom of guanine bases. The high flexibility of DNA allows for fast accommodation of the ruth...