Binding of Organometallic Ruthenium Anticancer Complexes to DNA: Thermodynamic Base and Sequence Selectivity

Organometallic ruthenium(II) complexes [(eta(6)-arene) Ru(en) Cl][PF6] (arene = benzene (1), p-cymene (2), indane (3), and biphenyl (4); en = ethylenediamine) are promising anticancer drug candidates both in vitro and in vivo. In this paper, the interactions between ruthenium(II) complexes and 15-mer single- and double-stranded oligodeoxynucleotides (ODNs) were thermodynamically investigated using high performance liquid chromatography (HPLC) and electrospray ionization mass spectroscopy (ESI-MS). All of the complexes bind preferentially to G(8) on the single strand 5'-CTCTCTT7G(8)T(9)CTTCTC-3' (I), with complex 4 containing the most hydrophobic ligand as the most reactive one. To the analogs of I (changing T7 and/or T-9 to A and/or C), complex 4 shows a decreasing affinity to the G(8) site in the following order:-AG(8)T-(K: 5.74 x 10(4) M-1) >-CG(8)C-> -TG(8)A->-AG(8)A->-AG(8)C->-TG(8)T-(I)approximate to-CG(8)A-(K: 2.81 x 10(4) M-1). In the complementary strand of I, the G bases in the middle region are favored for ruthenation over guanine (G) bases in the end of oligodeoxynucleotides (ODNs). These results indicate that both the flanking bases (or base sequences) and the arene ligands play important roles in determining the binding preference, and the base-and sequence-selectivity, of ruthenium complex in binding to the ODNs.