DNA Interactions of Monofunctional Organometallic Ruthenium(II) Antitumor Complexes in Cell-free Media

摘要

Modifications of natural DNA in a cell-free medium by antitumor monodentate Ru(II) areneudcompounds of the general formula [(eta 6-arene)Ru(en)Cl]+ (arene ) biphenyl, dihydroanthracene,udtetrahydroanthracene, p-cymene, or benzene; en ) ethylenediamine) were studied by atomic absorption,udmelting behavior, transcription mapping, circular and linear dichroism, plasmid unwinding, competitiveudethidium displacement, and differential pulse polarography. The results indicate that these complexesudbind preferentially to guanine residues in double-helical DNA. The data are consistent with DNA bindingudof the complexes containing biphenyl, dihydroanthracene, or tetrahydroanthracene ligands that involvesudcombined coordination to G N7 and noncovalent, hydrophobic interactions between the arene ligand andudDNA, which may include arene intercalation and minor groove binding. In contrast, the single hydrocarbonudrings in the p-cymene and benzene ruthenium complexes cannot interact with double-helical DNA byudintercalation. Interestingly, the adducts of the complex containing p-cymene ligand, which has methyludand isopropyl substituents, distort the conformation and thermally destabilize double-helical DNA distinctlyudmore than the adducts of the three multiring ruthenium arene compounds. It has been suggested that theuddifferent character of conformational alterations induced in DNA, and the resulting thermal destabilization,udmay affect differently further “downstream” effects of damaged DNA and consequently may result inuddifferent biological effects of this new class of metal-based antitumor compounds. The results point to audunique profile of DNA binding for Ru(II) arene compounds, suggesting that a search for new anticancerudcompounds based on this class of complexes may also lead to an altered profile of biological activity inudcomparison with that of metal-based antitumor drugs already used in the clinic or currently on clinicaludtrials.