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 } ...
The aerobic reaction between glutathione (HA) and dirhodium(II) tetraacetate, Rh(AcO) (AcO = CHCOO), in aqueous solution (pH 7.4) breaks up the direct Rh-Rh bond and its carboxylate framework, as evidenced by UV-Vis spectroscopy. After purifying the reaction product using size exclusion chromatography, electrospray ionization mass spectrometry (ESI-MS) of the solution showed binuclear [Formula: see text] and [Formula: see text] ions. Evaporation yielded a solid compound, [Formula: see text], for which Rh K-edge extended X-ray absorption fine structure (EXAFS) spectroscopy revealed ~ 2 Rh-O (2.08 ± 0.02 Å) and ~ 4 Rh-S (2.33 ± 0.02 Å) bond distances around each Rh center, and the Rh··Rh distance 3.11 ± 0.02 Å, close to that in dirhodium(III) complexes with three bridging thiolates connecting [Formula: see text] units. The C CPMAS NMR spectrum of the Rh-glutathione complex showed a change ∆δ > 6 ppm in the chemical shift of the COO signal, indicating some carboxylate coordination to the Rh(III) ions. This study shows that under aerobic conditions glutathione enables oxidation of Rh(AcO) and thus reduces its antitumor efficiency. The reaction of Rh(AcO) with glutathione was investigated by ESI-MS, UV-Vis, C NMR and X-ray absorption spectroscopy, revealing that glutathione breaks down the carboxylate framework enabling oxidization of the [Formula: see text] core to Rh(III) dimeric units, bridged by three thiolates.
The potential chemotherapeutic properties coupled to photochemical transitions make the family of fac-[Re(CO) 3 (N,N) X] 0/+ (N,N = a bidentate diimine such as 2,2′-bipyridine (bpy); X = halide, H 2 O, pyridine derivatives, PR 3 , etc.) complexes of special interest. We have investigated reactions of the aqua complex fac-[Re(CO) 3 (bpy)(H 2 O)](CF 3 SO 3) (1) with potential anticancer activity with the amino acid l-cysteine (H 2 Cys), and its derivative N-acetyl-l-cysteine (H 2 NAC), as well as the tripeptide glutathione (H 3 A), under physiological conditions (pH 7.4, 37 °C), to model the interaction of 1 with thiolcontaining proteins and enzymes, and the impact of such coordination on its photophysical properties and cytotoxicity. We report the syntheses and characterization of fac-[Re(CO) 3 (bpy)(HCys)]•0.5H 2 O (2), Na(fac-[Re(CO) 3 (bpy)(NAC)]) (3), and Na(fac-[Re(CO) 3 (bpy)(HA)])•H 2 O (4) using extended X-ray absorption spectroscopy, IR and NMR spectroscopy, electrospray ionization spectrometry, as well as the crystal structure of {fac-[Re(CO) 3 (bpy)(HCys)]} 4 •9H 2 O (2 + 1.75 H 2 O). The emission spectrum of 1 displays a variance in Stokes shift upon coordination of l-cysteine and N-acetyl-l-cysteine. Laser excitation at λ = 355 nm of methanol solutions of 1-3 was followed by measuring their ability to produce singlet oxygen (1 O 2) using direct detection methods. The cytotoxicity of 1 and its cysteine-bound complex 2 was assessed using the MDA-MB-231 breast cancer cell line, showing that the replacement of the aqua ligand on 1 with l-cysteine significantly reduced the cytotoxicity of the Re(I) tricarbonyl complex. Probing the cellular localization of 1 and 2 using X-ray fluorescence microscopy revealed an accumulation of 1 in the nuclear and/or perinuclear region, whereas the accumulation of 2 was considerably reduced, potentially explaining its reduced cytotoxicity.
X-ray fluorescence microscopy confirms the necessity of vacant axial sites in dirhodium(ii) carboxylates for their cellular uptake and cytotoxicity.
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