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

Reactions of the anticancer active dirhodium tetraacetate (1), Rh-2(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 Rh-2(AcO)(4)(L-HHis)(2)center dot 2H(2)O(2) confirmed the axial coordination of histidine imidazole groups (average Rh-N-axial 2.23 angstrom). These adducts, however, were found to be unstable in solution over time (24 h). Heating Rh-2(AcO)(4) -histidine solutions to 40 degrees C (near body temperature) or 95 degrees C accelerated the formation of Rh-2(II)(AcO)(2)(His)(2) and Rh-III(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 C-13 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 Rh-2(AcO)(4) are formed. X-ray absorption spectroscopy showed almost the same Rh-Rh distance (2.41 +/- 0.01 angstrom) for the Rh-2(AcO)(4) units as in 2, and a contribution from an axial thiol coordination (Rh-S-axial 2.62 +/- 0.05 angstrom). The Rh-2(AcO)(4) - HSA complex was found to decompose partially (similar to 15%) over 24 h at ambient temperature. The partial decomposition of Rh-2(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.