X-ray absorption spectroscopy studies of the adducts formed between cytotoxic gold compounds and two major serum proteins

JBIC Journal of Biological Inorganic Chemistry - Tập 16 - Trang 491-499 - 2010
L. Messori1, A. Balerna2, I. Ascone3, C. Castellano4, C. Gabbiani1, A. Casini5, C. Marchioni6, G. Jaouen3, A. Congiu Castellano6
1Department of Chemistry, University of Florence, Sesto Fiorentino, Florence, Italy
2INFN-LNF, Frascati, Italy
3Chimie ParisTech, Laboratoire Charles Friedel, UMR CNRS 7223, Paris Cedex 05, France
4Dipartimento di Chimica Strutturale e Stereochimica Inorganica, Università degli Studi di Milano, Milan, Italy
5Institut des Sciences et Ingénierie Chimiques Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
6Dipartimento di Fisica, Università Sapienza, Rome, Italy

Tóm tắt

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 [Au2(6,6′-dimethyl-2,2′-bipyridine)2(μ-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.

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