XAS studies of the adducts formed between cytotoxic gold compounds and two major serum proteins

• Published in: J. Biol. Inorg. Chem (ISSN: 0949-8257), vol. 16, num. 3, p. 491–499
• Springer Verlag, 2011

Gold metallodrugs form a class of promising antiproliferative agents showing a high propensity to react with proteins. We exploit here X-ray absorption spectroscopy (XAS) methods [both X-ray absorption near-edge spectroscopy (XANES) and extended X-ray absorption fine structure (EXAFS)] to gain insight into the nature of the adducts formed between three representative gold(I, III) metallodrugs (i.e., auranofin, [Au(2,2'-bipyridine)(OH)(2)](PF6), Aubipy, and dinuclear [Au-2(6,6'-dimethyl-2,2'-bipyridine)(2)(mu-O)(2)](PF6)(2), Auoxo6) and two major plasma proteins, namely, bovine serum albumin (BSA) and human serum apotransferrin (apoTf). The following metallodrug-protein systems were investigated in depth: auranofin/apoTf, Aubipy/BSA, and Auoxo6/apoTf. XANES spectra revealed that auranofin, upon protein binding, conserves its gold(I) oxidation state. Protein binding most probably takes place through release of the thiosugar ligand and its subsequent replacement by a thiol (or a thioether) from the protein. This hypothesis is independently supported by EXAFS results. In contrast, the reactions of Aubipy with serum albumin and of Auoxo6 with serum apoTf invariantly result in gold(III) to gold(I) reduction. Gold(III) reduction, clearly documented by XANES, is accompanied, in both cases, by release of the bipyridyl ligands; for Auoxo6 cleavage of the gold-gold dioxo bridge is also observed. Gold(III) reduction leads to formation of protein-bound gold(I) species, with deeply modified metal coordination environments, as evidenced by EXAFS. In these adducts, the gold(I) centers are probably anchored to the protein through nitrogen donors. In general, these two XAS methods, i.e., XANES and EXAFS, used here jointly, allowed us to gain independent structural information on metallodrug/protein systems; detailed insight into the gold oxidation state and the local environment of protein-bound metal atoms was achieved in the various cases.

Keywords: X-ray absorption spectroscopy ; Gold compound ; Protein ; Cytotoxicity ; Platinum(Iv) Anticancer Agents ; Human Blood-Plasma ; Gold(Iii) Complexes ; Binding Properties ; Solution Chemistry ; Bipyridyl Ligands ; Crystal-Structure ; Cancer-Cells ; Albumin ; Metallodrugs

Reference

• EPFL-ARTICLE-161924
• doi:10.1007/s00775-010-0748-5
• View record in Web of Science

Record created on 2010-12-22, modified on 2017-05-12