Reactions of Antitumor Active Dirhodium(II) TetraacetateRh2(CH3COO)4 with Cysteine and ItsDerivatives

摘要

We have combined results from several spectroscopic techniques to investigate the aerobic reactions of Rh2(AcO)4 (AcO^– = CH3COO^–) with l-cysteine (H2Cys) and its derivatives d-penicillamine (3,3′-dimethylcysteine, H2Pen), with steric hindrance at the thiol group, and N-acetyl-l-cysteine (H2NAC), 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 Rh2(AcO)4 and H2L 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^III2Pen4]^2– or oligomeric {Rh^III2L4}n (L = Cys, NAC) complexes with bridging thiolate groups. Analyses of Rh K edge extended X-ray absorption fine structure (EXAFS) datareveal 3–4 Rh–S and 2–3 Rh–(N/O) bondsaround 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 EXAFSspectrum supports trithiolate bridges between the Rh(III) ions, aswas also found when using glutathione as ligand. In the cysteine andpenicillamine 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 consistentwith the ΔδC = 7.3–8.4 ppm shift ofthe COO^– signal in their carbon-13 cross polarizationmagic 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 peroxidegenerated from reduction of dissolved O2, of thiolato tosulfenato (S=O) groups, which were also identified by ESI-MSfor all three {Rh^III₂L₄}_n compounds.