New insights into the chemistry of fac-[Ru(CO)3]2 + fragments in biologically relevant conditions: The CO releasing activity of [Ru(CO)3Cl2(1,3-thiazole)], and the X-ray crystal structure of its adduct with lysozyme

Complexes of the general formula fac-[Ru(CO)3L3]2 +, namely CORM-2 and CORM-3, have been successfully used as experimental CO releasing molecules (CO-RMs) but their mechanism of action and delivery of CO remain unclear. The well characterized complex [Ru(CO)3Cl2(1,3-thiazole)] (1) is now studied as a potential model CO-RM of the same family of complexes using LC–MS, FTIR, and UV–vis spectroscopy, together with X-ray crystallography. The chemistry of [Ru(CO)3Cl2(1,3-thiazole)] is very similar to that of CORM-3: it only releases residual amounts of CO to the headspace of a solution in PBS7.4 and produces marginal increase of COHb after long incubation in whole blood. 1 also reacts with lysozyme to form Ru adducts. The crystallographic model of the lysozyme–Ru adducts shows only mono-carbonyl Ru species. [Ru(H2O)4(CO)] is found covalently bound to a histidine (His15) and to two aspartates (Asp18 and Asp119) at the protein surface. The CO release silence of both 1 and CORM-3 and their rapid formation of protein–Ru(CO)x(H2O)y (x = 1,2) adducts, support our hypothesis that fac-[Ru(CO)3L3] CO-RMs deliver CO in vivo through the decay of their adducts with plasma proteins.

fac-[Ru(CO)3Cl2(1,3-thiazole)] releases residual amounts of CO gas from its aqueous solutions, and forms marginal amounts of COHb when incubated with whole blood. In the presence of HEWL crystals at pH 4.5, [Ru(CO)(H2O)4]2 + fragments are found to coordinate His15, Asp18 and Asp119. This CO silent release profile emulates that of CORM-3.Figure optionsDownload as PowerPoint slide