Interactions of dinuclear transition metal compounds with DNA nucleobases and related nitrogen donor ligands

Mononuclear transition metal compounds such as cisplatin, iproplatin and carboplatin are well known for their extraordinarily high carcinostatic activity. Years of research have been devoted to the elucidation of their mechanism of action. The generally accepted model is the inhibition of DNA replication by the covalent binding of two adjacent guanine bases through their respective N 7 atoms to the platinum metal center. Other transition metal compounds are known to exhibit considerable anticancer activity that is also attributed to direct metal-DNA interactions. In this vein, we are investigating the preferred DNA binding sites as well as the exact binding modes of dinuclear transition metal carboxylates of the type M2(O 2CR)4, M2X4(O2CR)2 and M2(DTolF)2(O2CCF3) 2 (M = Ru, Rh and Re R = CH3, CH2, CH3, CH2CH2CH3 DTolF = di-p-tolylformamidinate X = halide). Recent studies in our laboratories have elucidated unprecedented bridging modes for the model nucleobases 9-ethylguanine and 9-ethyladenine. In addition, the synthesis and spectroscopic characterization of the reaction products of these metal compounds with the twelve base pair oligonucleotide, d(5'-CCT CTG GTC TCC-3'), have been performed. Other studies involving the polymerase chain reaction (PCR) indicate that the DNA replication process is inhibited by covalent metal binding to the template strand. The PCR results along with 1H NMR spectroscopic, HPLC and X-ray crystallographic results will be presented.