calixarenes and ethylenediamine

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)(eta(6)-arene)X(en)] and [Ru(II)(eta(6)-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 ruthenium complexes into the major groove. Once bound to the host, however, the two complexes induce different DNA structural distortions. Strain induced in the DNA backbone from RA-en complexation is released by a local break of a Watson-Crick base-pair, consistent with the experimentally observed local denaturation. The bulkier RA-pta, on the other hand, bends the DNA helix toward its major groove, resembling the characteristic DNA distortion induced by the classic anticancer drug cisplatin. The atomistic details of the interactions of RA complexes with DNA gained in the present study shed light on some of the anticancer properties of these compounds and should assist future rational compound design.

Topics: Adamantane; Antineoplastic Agents; Binding Sites; Calixarenes; Computer Simulation; DNA; Ethylenediamines; Guanine; Models, Chemical; Models, Molecular; Molecular Conformation; Organometallic Compounds; Organophosphorus Compounds; Ruthenium; Stereoisomerism; Water