The hydrolysis of the anti-cancer ruthenium complex NAMI-A affects its DNA binding and antimetastatic activity: an NMR evaluation

The coordination of the antimetastatic agent NAMI-A, [H(2)im][trans-RuCl4(dmso-S)(Him)], (Him = imidazole; dmso = dimethyl sulfoxide), to the DNA model base 9-methyladenine (9-MeAde) was investigated in water. NMR spectroscopy was first applied for the study of the molecular stability and hydrolysis of NAMI-A in aqueous solution over a range of pH (3.0-7.4) and chloride ion concentrations (0-1 M) at 37.0degreesC. In physiological conditions (phosphate buffer, pH 7.4) NAMI-A disappears from the solution in 15 min due to chloride and dmso hydrolysis, leading to uncharacterised poly-oxo Ru species. Conversely, at lower pH (3.0-6.0) and in water (pHsimilar to5.5), only a partial dinso hydrolysis occurs, slowly forming the [trans-RuCl4(H2O)(Him)](-) complex. This latter species coordinates to 9-MeAde (via the N7 of 9-MeAde), forming the [trans-RuCl4(9-MeAde)(Him)](-) complex. NAMI-A and [trans-RuCl4(H2O)(Him)](-) give -comparable intracellular ruthenium concentrations and accumulate in KB cells (human mouth carcinoma) and accumulate these at the G(2)/M phase, while poly-oxo Ru species do not, and their cell uptake is reduced to 50%. On the contrary, G(2)/M arrest and protein content in the murine metastatic cell line metGM, are not influenced by NAMI-A hydrolysis. Hydrolysed NAMI-A species apparently are easier taken up by the metGM cells, showing intracellular ruthenium concentrations one order of magnitude greater than those of intact NAMI-A. Therefore, it is proposed that the selective antimetastatic activity of NAMI-A during-in vivo experiments can be attributed to its hydrolysed species. (C) 2003 Elsevier Inc. All rights reserved.