Reactivity of Cys4 Zinc Finger Domains with Gold(III) Complexes: Insights into the Formation of “Gold Fingers”

• Published in: Inorganic chemistry 2015-04, Vol.54 (8), p.4104-4113
• Main Authors: Jacques, Aurélie, Lebrun, Colette, Casini, Angela, Kieffer, Isabelle, Proux, Olivier, Latour, Jean-Marc, Sénèque, Olivier
• Format: Article
• Language: English
• Subjects: Chemical Sciences; Coordination chemistry; Humans; Inorganic chemistry; Medicinal Chemistry; Molecular Structure; Organogold Compounds - chemistry; Zinc Fingers
• ISSN: 0020-1669; 1520-510X
• DOI: 10.1021/acs.inorgchem.5b00360

Gold­(I) complexes such as auranofin or aurothiomalate have been used as therapeutic agents for the treatment of rheumatoid arthritis for several decades. Several gold­(I) and gold­(III) complexes have also shown in vitro anticancer properties against human cancer cell lines, including cell lines resistant to cisplatin. Because of the thiophilicity of gold, cysteine-containing proteins appear as likely targets for gold complexes. Among them, zinc finger proteins have attracted attention and, recently, gold­(I) and gold­(III) complexes have been shown to inhibit poly­(adenosine diphosphate ribose)­polymerase-1 (PARP-1), which is an essential protein involved in DNA repair and in cancer resistance to chemotherapies. In this Article, we characterize the reactivity of the gold­(III) complex [AuIII(terpy)­Cl]­Cl2 (Auterpy) with a model of Zn­(Cys)4 “zinc ribbon” zinc finger by a combination of absorption spectroscopy, circular dichroism, mass spectrometry, high-performance liquid chromatography analysis, and X-ray absorption spectroscopy. We show that the Zn­(Cys)4 site of Zn·LZR is rapidly oxidized by Auterpy to form a disulfide bond. The Zn2+ ion is released, and the two remaining cysteines coordinate the Au+ ion that is produced during the redox reaction. Subsequent oxidation of these cysteines can take place in conditions of excess gold­(III) complex. In the presence of excess free thiols mimicking the presence of glutathione in cells, mixing of the zinc finger model and gold­(III) complex yields a different product: complex (AuI)2·LZR with two Au+ ions bound to cysteines is formed. Thus, on the basis of detailed speciation and kinetic measurements, we demonstrate herein that the destruction of Zn­(Cys)4 zinc fingers by gold­(III) complexes to achieve the formation of “gold fingers” is worth consideration, either directly or mediated by reducing agents.