Binding of histidine and human serum albumin to dirhodium(II) tetraacetate.

Abstract Reactions of the anticancer active dirhodium tetraacetate (1), Rh2(AcO)4 (AcO− = CH3COO−), with the amino acid histidine (HHis) and human serum albumin (HSA) were monitored over time and different metal: ligand ratios using UV-vis spectroscopy and/or electro-spray ionization mass spectrometry. Initially, histidine formed 1:1 and 1:2 adducts in aqueous solutions. The crystal structure of Rh2(AcO)4(L-HHis)2·2H2O (2) confirmed the axial coordination of histidine imidazole groups (average Rh-Naxial 2.23 A). These adducts, however, were found to be unstable in solution over time (24 h). Heating Rh2(AcO)4 –histidine solutions to 40 °C (near body temperature) or 95 °C accelerated the formation of RhII2(AcO)2(His)2 and RhIII(His)2(AcO) complexes. The corresponding pH change from neutral to mildly acid (pH 4–5) indicates deprotonation of histidine NH3+ groups due to coordination to Rh ions, which simultaneously bind to histidine COO− groups, as evidenced by 13C NMR spectroscopy. In the case of HSA with 16 histidine and one cysteine residues, UV-vis spectroscopy indicates that mono- and di-histidine HSA adducts with Rh2(AcO)4 are formed. X-ray absorption spectroscopy showed almost the same Rh-Rh distance (2.41 ± 0.01 A) for the Rh2(AcO)4 units as in 2, and a contribution from an axial thiol coordination (Rh-Saxial 2.62 ± 0.05 A). The Rh2(AcO)4 – HSA complex was found to decompose partially (~15%) over 24 h at ambient temperature. The partial decomposition of Rh2(AcO)4 both through coordination to histidine or to human serum albumin, the most abundant protein in blood plasma, is a factor to consider for its efficacy as a potential anticancer agent.