Reactions of the metallodrug auranofin [(1-thio-.beta.-D-glucopyranose-2,3,4,6-tetraacetato-S)(triethylphosphine)gold] with biological ligands studied by radioisotope methodology

Ecker, David J.; Hempel, Judith C.; Sutton, Bridget M.; Kirsch, R.; Crooke, Stanley T.

doi:10.1021/ic00238a009

Cited by 30 publications

(15 citation statements)

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“…This phenomenon has been observed only with the Penefsky column data. Previously reported conventional gel filtration studies, 9,15,34 with gold in excess of albumin, consistently found that the Au binding ability is equivalent to the mercaptalbumin concentration (Au/Alb TOT ) SH titer). We are able to reproduce these earlier results when the albumin and auranofin preparations from the Penefsky column studies are resolved on a conventional column.…”

Section: Resultsmentioning

confidence: 97%

“…‡ Simulation Dynamics Inc. X Abstract published in AdVance ACS Abstracts, November 15, 1995. (1) Hill, D. T.; Sutton, B. M. Cryst. Struct The resulting albumin-gold complex has been well characterized by 31 P-NMR, 9-12 1 H-NMR, 13,14 chromatography, 9,15 and radioisotope methods 15 and is well established. 16 It is a linear dicoordinate Au(I) complex with bond lengths of 227 pm for Au-S and 230 pm for Au-P. 9 The isopropyl and methyl analogues of auranofin (R 3 PAuSATg, R ) Me and iPr) undergo similar reactions.…”

Section: Introductionmentioning

confidence: 99%

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Kinetics and Mechanism of the Reaction between Serum Albumin and Auranofin (and Its Isopropyl Analogue) in Vitro

et al. 1996

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The first detailed kinetic study of in vitro reactions between serum albumin and the secondgeneration gold drug 3,4,glucopytanosato-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 respect to auranofin. For .iPr3PAuSATg, only the first step was observed, k 1.4 +_ 0.1 x 10 -2 s "1 and is first order in albumin and independent of iPr3PAuSATg concentration. 31p.NMR saturation transfer experiments utilizing the auranofin analogue, .iPr3PAuSATg, under equilibrium conditions with excess .iPr3PAuSATg and ATgSH yielded second order rate constants for both the forward (1.0 x 102 M " sec"1) and the reverse (3.9 x 101 M "1 sec"1) directions. A multi-step mechanism involving a conformationally altered albumin species to which gold binds was developed using the steady-state approximation. The mechanism accounts for the different reaction orders observed under the two set of conditions. A rate determining conformational change on the albumin governs the reaction as monitored by the Penefsky columns. A second order reaction of R3PAuSATg at Cys-34 is observed under the NMR conditions. These results are the first quantitative determination of auranofin-albumin reaction kinetics and the first mechanistic study of the reaction.A novel binding mechanism, association of auranofin in the pocket of albumin-disulfide species can be detected by Penefsky and HummeI-Dreyer gel chromatographic techniques, but not by conventional gel-exclusion chromatography. This complex albumin-auranofin complex is weaklybound and readily dissociates.

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Section: Resultsmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Kinetics and Mechanism of the Reaction between Serum Albumin and Auranofin (and Its Isopropyl Analogue) in Vitro

et al. 1996

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“…[Au(PEt 3 )] + , the classical mitochondriotropic cation in gold(I)-based drugs, inhibits proliferation at the submicromolar concentrations tested, both as a component of compound 1 and when delivered as HSA-1 . ACRAMTU appears to serve as a readily exchangeable carrier ligand, similar to the thioglucose ligand in auranofin, and does not appear to be essential for the inhibitory activity of 1 in CD8 + cells. We took advantage of the thiourea–thiol ligand exchange chemistry to modify cysteine thiol in rHSA with [Au(PEt 3 )] + .…”

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confidence: 99%

Human Serum Albumin-Delivered [Au(PEt₃)]⁺ Is a Potent Inhibitor of T Cell Proliferation

Dean

Yang

Liu

et al. 2017

ACS Med. Chem. Lett.

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“…The antiarthritic activity of gold(I) compounds may be related to the high affinity and selectivity of gold(I) for sulfhydryl sulfur as a biological ligand [16]. Since gold(I) is extremely labile, these gold(I) complexes after their administration, undergo several ligand exchange reactions in the body with biofluids, cells and proteins [10,[17][18][19][20]. The high affinity of gold(I) for sulfur and selenium ligands suggests that proteins including enzymes and transport proteins will be critical in vivo targets.…”

Section: Introductionmentioning

confidence: 99%

“…The phosphorus-31 nucleus with 100% natural abundance and high sensitivity makes 31 P NMR the most widely used technique for investigating the reactions of auranofin [29]. The 31 P chemical shift is sensitive to the nature of the trans coordinated ligand and release of Et 3 P can be monitored by observation of Et 3 PO resonance [18,19,24,25,33]. Changes in intensity of the resonances with time are helpful to follow the kinetics of the exchange reactions [34].…”

Section: Introductionmentioning

confidence: 99%

Applications of NMR spectroscopy in understanding the gold biochemistry

Isab

Ahmad²

2006

Journal of Spectroscopy

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Gold-based drugs have been successfully used for the treatment of rheumatoid arthritis. When administered, they undergo ligand exchange reactions in the body with biofluids, cells and proteins. NMR spectroscopy is a very useful technique for probing these ligand exchange reactions under physiological conditions. The strength of the binding ligands can be estimated by studying the chemical shift changes in13C and31P NMR. It is also a powerful method for investigating the kinetics and thermodynamics of the exchange reactions of gold drugs with biomolecules. The purpose of this review report is to highlight the importance of NMR spectroscopy in the study of gold biochemistry and to bridge the fairly large gap in the progress of this interesting area of bioinorganic chemistry.

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Reactions of the metallodrug auranofin [(1-thio-.beta.-D-glucopyranose-2,3,4,6-tetraacetato-S)(triethylphosphine)gold] with biological ligands studied by radioisotope methodology

Cited by 30 publications

References 1 publication

Kinetics and Mechanism of the Reaction between Serum Albumin and Auranofin (and Its Isopropyl Analogue) in Vitro

Kinetics and Mechanism of the Reaction between Serum Albumin and Auranofin (and Its Isopropyl Analogue) in Vitro

Human Serum Albumin-Delivered [Au(PEt₃)]⁺ Is a Potent Inhibitor of T Cell Proliferation

Applications of NMR spectroscopy in understanding the gold biochemistry

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Reactions of the metallodrug auranofin [(1-thio-.beta.-D-glucopyranose-2,3,4,6-tetraacetato-S)(triethylphosphine)gold] with biological ligands studied by radioisotope methodology

Cited by 30 publications

References 1 publication

Kinetics and Mechanism of the Reaction between Serum Albumin and Auranofin (and Its Isopropyl Analogue) in Vitro

Kinetics and Mechanism of the Reaction between Serum Albumin and Auranofin (and Its Isopropyl Analogue) in Vitro

Human Serum Albumin-Delivered [Au(PEt3)]+ Is a Potent Inhibitor of T Cell Proliferation

Applications of NMR spectroscopy in understanding the gold biochemistry

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Human Serum Albumin-Delivered [Au(PEt₃)]⁺ Is a Potent Inhibitor of T Cell Proliferation