Journal of Inorganic Biochemistry 85 (2001) 67–76 www.elsevier.nl / locate / jinorgbio Redox and ligand exchange reactions of potential gold(I) and gold(III)-cyanide metabolites under biomimetic conditions a a b c Annapurna J. Canumalla , Norah Al-Zamil , Matthew Phillips , Anvarhusein A. Isab , b, * C. Frank Shaw III a Department of Chemistry, The University of Wisconsin — Milwaukee, WI, 43201-0413, USA b Department of Chemistry –Moore 337, Eastern Kentucky University, Richmond, KY, 40475-3102, USA c Department of Chemistry, King Fahd University of Petroleum and Minerals, Dhahran, Saudi Arabia Received 8 August 2000; received in revised form 9 November 2000; accepted 11 November 2000 Abstract 2 Biomimetic pathways for the oxidation of [Au(CN) ] , a gold metabolite, and further cyanation of the gold(III) products to form 2 2 13 Au(CN) were investigated using C NMR and UV–Visible spectroscopic methods. Hypochlorite ion, an oxidant released during the 4 2 oxidative burst of immune cells, was employed. The reaction generates mixed dicyanoaurate(III) complexes, trans-[Au(CN) X ] , where 2 2 2 2 X represents equilibrating hydroxide and chloride ligands, and establishes the chemical feasibility of dicyanoaurate oxidation by OCl 2 to gold(III) species. This oxidation reaction suggests a new procedure for synthesis of H[Au(CN) Cl ]. Reaction of trans-[Au(CN) X ] 2 2 2 2 2 2 2 2 2 (X 5Cl and Br ) or [AuCl ] with HCN in aqueous solution at pH 7.4 leads directly to [Au(CN) ] without detection of the 4 4 2 anticipated [Au(CN) X ] intermediates, which is attributed to the cis- and trans-accelerating effects of the cyanides. The reduction of x 42x 2 [Au(CN) ] by glutathione and other thiols is a complex, pH-dependent process that proceeds through two intermediates and ultimately 4 2 generates [Au(CN) ] . These studies provide further insight into the possible mechanisms of an immunogenically generated gold(I) / 2 gold(III) redox cycle in vivo.  2001 Elsevier Science B.V. All rights reserved. Keywords: Aurocyanide; Auricyanide; Hypochlorite; Cis effects; Trans effects; Gold; Biological redox reactions 1. Introduction drugs in the blood and urine of chrysotherapy patients [6,9]. As a result of the two tightly bound cyanide ligands, 2 Gold(I) drugs have been used for the treatment of [Au(CN) ] is relatively unreactive towards ligand ex- 2 rheumatoid arthritis since the 1920s despite the fact that change reactions with other gold binding ligands. Recent ¨ their exact mechanism of action remains unknown [1–5]. equilibrium and Mossbauer studies indicate non-covalent 2 Other gold complexes show activity against HIV [6] and association of intact [Au(CN) ] ions with the transport 2 2 malaria [7]. Two recent advances in understanding the protein, serum albumin, to form albumin–[Au(CN) ] 2 n metabolism of gold in vivo may provide insight into the adducts [10–12]. The binding is labile and easily revers- 4 21 3 21 generation of the pharmacologically active species. First, ible ( K 55.5310 M ; K 57.0310 M ) [10,12] ex- 1 2 the gold(I) drugs and / or their metabolites react in vivo plaining the presence of significant amounts of 2 with cyanide, resulting in the formation of [Au(CN) ] in body fluids of chrysotherapy patients. 2 2 dicyanoaurate(I), [Au(CN) ] [1,2,8]. The cyanide is Second, although gold(I) is the primary oxidation state 2 2 generated from thiocyanate and hypochlorite, OCl , dur- found in vivo [13], there is immunological evidence for the ing the oxidative burst of macrophages and other immune generation of gold(III) metabolites [14–16]. Biomimetic cells, and for some patients even larger amounts are studies indicate that the oxidation of gold(I) thiomalate and 2 2 absorbed from tobacco smoke. The [Au(CN) ] ion has gold(I) thioglucose [10,17] by OCl , which is released 2 been identified as a common metabolite of the gold(I) when cells are induced to undergo the oxidative burst at inflammed sites, is rapid and thermodynamically feasible resulting in the formation of gold(III) species. These *Corresponding author. Tel.: 11-859-622-1456; fax: 11-859-622- studies have been extended to the second generation 8197. 2 E-mail address: cheshaw@eku.edu (C.F. Shaw III). gold(I) drug, auranofin [18]. Since OCl is involved in 0162-0134 / 01 / $ – see front matter  2001 Elsevier Science B.V. All rights reserved. PII: S0162-0134(00)00224-5