The reduction of (ImH)[trans-RuIIICl4(dmso)(Im)] under physiological conditions: preferential reaction of the reduced complex with human serum albumin
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A systematic study of the reduction of (ImH)[trans-RuCl4(dmso)(Im)] (NAMI-A; dmso is dimethyl sulfoxide, Im is imidazole), a promising antimetastasing agent, by l-ascorbic acid under physiological conditions is reported. Under blood plasma conditions (pH 7.4, 0.1–0.15 M NaCl , 37 °C) the rapid reduction of trans-[RuIIICl4(dmso)(Im)]− results in the formation of trans-[RuIICl4(dmso)(Im)]2− within seconds, and is followed by successive dissociation of the chloride ligands, whereas neither dmso nor imidazole ligands are released during the reaction. Under our experimental conditions, the formation of the ascorbate dianion is the rate-determining step, and once it has formed it reacts rapidly with NAMI-A. Moreover, the NAMI-A complex is very unstable at physiological pH (7.4); therefore, the hydrolysis of NAMI-A cannot be excluded as a competing reaction. During hydrolysis, aquated derivatives via stepwise dissociation of chloride and dmso ligands are formed, and most of these species have a higher redox potential and are expected to be even more easily reduced by ascorbic acid. Thus, it is very likely that the reduced form of NAMI-A or the reduction products of its hydrolytic derivatives react with albumin. The reaction of reduced NAMI-A with human serum albumin leads to the formation of stable adducts, with a binding efficiency very similar to that of the parent complex, viz., 3.2 ± 0.3 and 4.0 ± 0.4 mol of Ru(II) and Ru(III) per mole of albumin, respectively, however with a significantly higher reactivity.
KeywordsNAMI-A Antimetastatic drug Ascorbic acid Albumin Hydrolysis
The authors gratefully acknowledge financial support from the Deutsche Forschungsgemeinschaft (SFB 583), the European Commission for the AQUACHEM Research Training Network (contract no. MRTN-CT-2003-503864) and the Polish Ministry of Science and Higher Education (grant PB-1283/T09/2005/29). They kindly acknowledge Wiesław Knap and Halina Mrowiec for performing the ICP-MS experiments.
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