The Kinetics and Mechanism of the Reaction Between Serum Albuminand Auranofin (and its Isopropyl Analogue) In Vitro

Abstract

The first detailed kinetic study of in vitro reactions between serum albumin and the secondgeneration gold drug Auranofin [Et3PAuSATg triethylphosphine-(2,3,4,6-tetra-O-acetyl-l-8-Dglucopytanosato-S-) gold(I)] and its tri-i-propylphosphine analogue, .iPr3PAuSATg, are reported. The reactions were investigated using Penefsky spun columns and NMR saturation transfer kinetics. Based on the Penefsky column data, the binding of the Et3PAuSATg to AIbSH (0.600 mM) was complete when gold concentrations were limiting: 0.093, 0.151, and 0.225 mM. The reaction is biphasic. The fast phase is defined by a first order rate constant, (k 2.94 _+ 0.24 x 10-2 sec"1) and accounts for 95% of the Au(I) bound. This phase is first order with respect to albumin, and zero order with respect to auranofin. A minor, slower step (k 2 2.26 _+ 0.26 x 10-3 sec"1), which accounts for only 5% of the reaction, is also first order with respect to albumin, and zero order with

Physiological and pathological changes in the redox state of human serum albumin critically influence its binding properties

“…There are antiarthritic drugs like auranofin (Et 3 PAu‐ S ‐actylthioglucose), which are based on compounds containing gold(I) complexes and a thiol moiety. Cys34 is the principal binding site of auranofin on albumin and different adducts have been found ( Coffer et al ., 1987 ; Shaw, 1989 ; Dhubhghaill et al ., 1992 ; Roberts et al ., 1996 ). A complex series of reactions is involved in the albumin binding of this group of compounds to HMA and HNA ( Shaw, 1989 ; Roberts et al ., 1996 ) including ligand exchange and liberation of acetylthioglucose, which may in turn modify the redox situation on Cys34.…”

Role of Tyr84 in controlling the reactivity of Cys34 of human albumin

“…Thus, the state of Cys34 is an important origin for heterogeneity in albumin. There has been much interest in the Cys34 site, because not only does it act as a physiological antioxidant [5,6], but also as a binding site for a wide variety of biologically and clinically important small molecules, such as gold(I) antiarthritic drugs [7,8], platinum(II) anticancer drugs [9,10], mercurials [11], as well as a variety of drugs which bind as mixed disulfides, including captopril (an antihypertensive) [12] and disulfiram (an alcohol‐abuse drug) [13]. Importantly, 82% of nitric oxide in blood (≈ 7 µ m ) is transported as an S ‐nitrosothiol at Cys34 [14].…”

Integrated experimental/computational approaches to characterize the systems formed by vanadium with proteins and enzymes

“…180 Therefore, based on MS and 1 H NMR evidence, it was concluded that Cys34 was the first residue to interact with the Au I (PEt 3 ) + fragment. [180][181][182] Auration of Cys34 has been recently reported by X-ray crystallography, 183 as well as further evidence of the affinity of Auranofin toward thiols. 184,185 Docking studies, integrating spectroscopic/spectrometric data, allow the confirmation of this binding with F max = 41.8 (Fig.…”