Reactions of Antitumor Active Dirhodium(II) Tetraacetate Rh(2)(CH(3)COO)(4) with Cysteine and Its Derivatives

[Image: see text] We have combined results from several spectroscopic techniques to investigate the aerobic reactions of Rh(2)(AcO)(4) (AcO(–) = CH(3)COO(–)) with l-cysteine (H(2)Cys) and its derivatives d-penicillamine (3,3′-dimethylcysteine, H(2)Pen), with steric hindrance at the thiol group, and N-acetyl-l-cysteine (H(2)NAC), with its amino group blocked. Previous investigations have shown that antitumor active dirhodium(II) carboxylates may irreversibly inhibit enzymes containing a thiol group at or near their active sites. Also, cysteine, the only thiol-containing proteinogenic amino acid, interacts in vivo with this class of antitumor compounds, but structural information on the products of such reactions is lacking. In the present study, the reactions of Rh(2)(AcO)(4) and H(2)L were carried out in aqueous solutions at the pH of mixing (acidic) and at physiological pH, using the different mole ratios 1:2, 1:4, and 1:6, which resulted in the same products in increasing yields. Electrospray ionization mass spectrometry (ESI-MS) indicates formation of dimeric [Rh(III)(2)Pen(4)](2–) or oligomeric {Rh(III)(2)L(4)}(n) (L = Cys, NAC) complexes with bridging thiolate groups. Analyses of Rh K edge extended X-ray absorption fine structure (EXAFS) data reveal 3–4 Rh–S and 2–3 Rh–(N/O) bonds around six-coordinated Rh(III) ions at mean distances of 2.33 ± 0.02 and 2.09 ± 0.02 Å, respectively. In the N-acetyl-l-cysteine compound, the Rh(III)···Rh(III) distance 3.10 ± 0.02 Å obtained from the EXAFS spectrum supports trithiolate bridges between the Rh(III) ions, as was also found when using glutathione as ligand. In the cysteine and penicillamine complexes, double thiolate bridges join the Rh(III) ions, with the nonbridging Cys(2–) and Pen(2–) ligands in tridentate chelating (S,N,O) mode, which is consistent with the Δδ(C) = 7.3–8.4 ppm shift of the COO(–) signal in their carbon-13 cross polarization magic angle spinning (CPMAS) NMR spectra. For the penicillamine complex, the 2475.6 eV peak in its S K edge X-ray absorption near edge structure (XANES) spectrum shows partial oxidation, probably caused by peroxide generated from reduction of dissolved O(2), of thiolato to sulfenato (S=O) groups, which were also identified by ESI-MS for all three {Rh(III)(2)L(4)}(n) compounds.