Reactions of Potent Antitumor Complex <i>trans</i>-[Ru^IIICl₄(indazole)₂]^- with a DNA-Relevant Nucleobase and Thioethers: Insight into Biological Action

Reactions of the complex trans-[RuCl4(Hind)2]- (Hind = indazole), which is of clinical relevance today, with both the DNA model nucleobase 9-methyladenine (made) and the thioethers R2S (R = Me, Et), as models of the methionine residue in biological molecules possibly acting as nitrogen-competing sulfur-donor ligands for ruthenium atom, have been investigated to get insight into details of mechanism leading to antitumor activity. Three novel ruthenium complexes, viz., [RuIIICl3(Hind)2(made)], 1, [RuIICl2(Hind)2(Me2S)2], 2, and [RuIICl2(Hind)2(Et2S)2], 3, have been isolated as solids. Oxidation of 2 and 3 with hydrogen peroxide in the presence of 12 M HCl in chloroform afforded the monothioether adducts, viz., [RuIIICl3(Hind)2(Me2S)], 4, and [RuIIICl3(Hind)2(Et2S)], 5. By dissolution of 2 or 3 in DMSO, replacement of both R2S ligands by DMSO molecules occurred with isolation of trans,trans,trans-[RuIICl2(Hind)2(DMSO)2], 6. The products were characterized by elemental analysis, IR, UV−vis, electrospray mass spectrometry, cyclic voltammetry, and X-ray crystallography (1·CH2Cl2·CH3OH and 1·1.1H2O·0.9CH3OH, 2, and 5). The first crystallographic evidence for the monofunctional coordination of the 9-methyladenine ligand to ruthenium via N7 and the self-pairing of the complex molecules via H-bonding, using the usual Watson−Crick pairing donor and acceptor sites of two adjacent 9-methyladenine ligands, is reported. The electrochemical behavior of 1−5 has been studied in DMF and DMSO by cyclic voltammetry. The redox potential values have been interpreted on the basis of the Lever's parametrization method. The EL parameter was estimated for 9-methyladenine at 0.18 V, showing that this ligand behaves as a weaker net electron donor than imidazole (EL = 0.12 V). The kinetics of the reductively induced stepwise replacement of chlorides by DMF in 4 and 5 were studied by digital simulation of the cyclic voltammograms. The rate constant k1 has been determined as 0.9 ± 0.1 s-1, which obeys the first-order rate law, while k2 is concentration dependent (0.2 ± 0.1 M1-n·s-1 with n > 1 for 4 mM solutions of 4 and 5), indicating higher-order reactions mechanism.