The influence of gold(i) on the mechanism of thiolate, disulfide exchange

Article abstract of DOI:10.1039/c6dt01400c

The mechanism of gold(i)-thiolate, disulfide exchange was investigated by using initial-rate kinetic studies, 2D (¹H-¹H) ROESY NMR spectroscopy, and electrochemical/chemical techniques. The rate law for exchange is overall second order, first order in gold(i)-thiolate and disulfide. 2D NMR experiments show evidence of association between gold(i)-thiolate and disulfide. Electrochemical/chemical investigations do not show evidence of free thiolate and are consistent with a mechanism involving formation of a [Au-S, S-S], four-centered metallacycle intermediate during gold(i)-thiolate, disulfide exchange.

Full text of DOI:10.1039/c6dt01400c

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The influence of gold(I) on the mechanism of
thiolate, disulfide exchange†
Cite this: DOI: 10.1039/c6dt01400c
Received 11th April 2016,
Accepted 20th June 2016
Gamage S. P. Garusinghe, S. Max Bessey, Alice E. Bruce* and Mitchell R. M. Bruce*
DOI: 10.1039/c6dt01400c
www.rsc.org/dalton
The mechanism of gold(I)-thiolate, disulfide exchange was investi-
We and others have shown that the thiophilic metal ions,
gated by using initial-rate kinetic studies, 2D (1H–1H) ROESY NMR Zn2+ and Au+ can participate in thiolate-disulfide
spectroscopy, and electrochemical/chemical techniques. The rate exchange.10–14 We have been investigating metal-mediated
law for exchange is overall second order, first order in gold(I)-thio- thiol-disulfide exchange reactions to understand the mechan-
late and disulfide. 2D NMR experiments show evidence of associ- ism, rate, redox potential and other electronic properties (e.g.
ation between gold(I)-thiolate and disulfide. Electrochemical/ dielectric effects of solvents).15–17 Our goal is to assess the like-
chemical investigations do not show evidence of free thiolate and lihood that Zn2+ and Au+ can influence cellular redox pro-
are consistent with a mechanism involving formation of a [Au–S, cesses involving thiol-disulfide exchange.
S–S], four-centered metallacycle intermediate during gold(I)-thiolate,
Zinc is an essential transition metal that plays an important
role in cellular antioxidant defense.18,19 Although Zn2+ is not a
redox active metal ion, coordination environments with
cysteine thiol ligands permit reversible redox reactions leading
to release and binding of Zn2+.20–25 For example, release of
Zn2+ from metallothionein is proposed to occur via inter-
actions of the protein with glutathione disulfide, which
increases in concentration during oxidative stress.26,27 Such a
mechanism is supported by studies on small molecule zinc
thiolate complexes, which undergo thiolate-disulfide
exchange.10,28,29 In addition, calculational results suggest a
role for Zn2+ in protein-thiolate, disulfide exchange.30
Gold(I) has been used for more than 100 years in the treat-
ment of rheumatoid arthritis (RA) and is currently a focus of
research aimed at developing new approaches for treatment of
cancer and other diseases.31–39 Although there have been
numerous studies on the biological activity of gold drugs, their
mechanism of action is not fully understood. Gold(I) has a
high affinity for sulfur and selenium and cellular targets for
gold compounds primarily include cysteine and/or selenocys-
teine-containing proteins.31,32,34 Early studies demonstrated
that gold accumulates in inflamed synovial tissues,32,40 and
similarly to other heavy metals, Au+ ions lead to expression of
thionein.41 Studies also indicate that bio-released gold(I) ions
and the orally active RA drug, auranofin, exhibit anti-inflam-
matory activity in mouse models for brain injuries.42,43 More
recent studies have demonstrated that Au+ triggers release of
Zn2+ from a zinc finger protein.44 In addition, thioredoxin
reductase, a selenoenzyme in the thioredoxin system that is
integral to cellular redox regulation, has been identified as a
target for gold compounds.32,34,45–47
disulfide exchange.
Thiol-disulfide exchange is an essential feature of structural
and functional modifications that occur in many proteins. For-
mation of mixed disulfides between proteins and glutathione
or cysteine is thought to play a role in cell signalling and regu-
latory pathways that are important in oxidative stress, apopto-
sis and aging.1–4 For example, S-glutathionylation, which
protects proteins against irreversible oxidation, can occur via
exchange of glutathione disulfide with protein sulfhydryls to
create a mixed protein-glutathione disulfide.5 The mechanism
of thiol-disulfide exchange is generally accepted as consisting
of deprotonation of thiol, followed by SN2 attack of thiolate on
disulfide, and proceeds through a transition state with a linear
orientation of the three sulfur atoms.6–8
While it has been noted that metals, such as Hg2+ exert
deleterious effects by directly inducing oxidative stress,9 other
authors have pointed out that metals may impart protection
against oxidation through their interaction with cysteine
thiolate. This has led us to the interesting question: are
metals capable of inserting into the thiol-disulfide exchange
reaction, and if so, what is the effect on the mechanism of
the reaction?
University of Maine, Department of Chemistry, Orono, ME 04469-5706, USA.
E-mail: abruce@maine.edu, mbruce@maine.edu
†Electronic supplementary information (ESI) available: Additional experimental
details are provided for initial rate experiments, free thiolate trapping studies,
2D (1H–1H) NOESY and ROESY NMR spectroscopy, and DFT calculations. See
DOI: 10.1039/c6dt01400c
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ꢀ
ðCH3OÞ3PO þ CH3C6H4Sꢀ ! CH3SC6H4CH3 þ ðCH3OÞ2PO2
We report here kinetic and mechanistic studies for the
exchange reaction of Ph3PAuSC6H4R (R = CH3, NO2) and
O2NC6H4SSC6H4NO2 which provide insight into the influence
of gold(I) on the mechanism of thiolate, disulfide exchange.
The method of initial rates48 was used to study the reaction
of Ph3PAuSC6H4CH3 with O2NC6H4SSC6H4NO2 (eqn (1)) in
acetonitrile. The choice of acetonitrile comes from other pre-
liminary work, which examined the influence of solvent on the
reaction of phosphine gold thiolates and disulfides. In DMSO
solution, a side reaction occurs that produces Ph3PvO.17 In
contrast, Ph3PvO does not form in acetonitrile and the reac-
tion proceeds cleanly to the product gold(I)-thiolate and mixed
disulfide shown in eqn (1) at early stages of the reaction, while
at longer reaction times the symmetric disulfide,
CH3C6H4SSC6H4CH3, forms.15 The reaction was monitored by
1H NMR array spectroscopy for the first 10 minutes and rates
were calculated using the initial formal concentrations of reac-
tants at t = 0. The rate of disappearance of the gold(I)-thiolate
reactant, which was measured relative to an internal standard,
mirrors the rate of appearance of mixed disulfide. The data are
shown in Table S1 and Fig. S1 (see ESI†). Analysis of the
results reveals a rate law that is overall second order, first
order in [Ph3PAuSC6H4CH3] and [O2NC6H4SSC6H4NO2] with
kobs = 0.422 0.014 M−1 s−1 (eqn (2)).
ð3Þ
In contrast, CH3SC6H4CH3 was not detected in the 1H NMR
of
a mixture of a 10-fold excess of TMP (50 mM)
Ph3PAuSC6H4CH3 (5 mM) and O2NC6H4SSC6H4NO2, (5 mM)
even after 40 hours. (We note that within 15 hours, the gold(I)
thiolate complex has completely reacted via thiolate disulfide
exchange, i.e. eqn (1).) Similarly, the self-exchange reaction of
Ph3PAuSC6H4NO2 (5 mM) and O2NC6H4SSC6H4NO2 (5 mM),
was monitored in the presence of TMP (50 mM) with no evi-
dence of formation of CH3SC6H4NO2 up to 40 hours. Finally,
the rate of gold-thiolate disulfide exchange for 1.27 mM
[Ph3PAuSC6H4CH3] and 1.17 mM [O2NC6H4SSC6H4NO2] was
measured in the absence and in the presence of 4 mM TMP.
Results indicate that the rate of exchange is unaffected by the
addition of TMP. However, interpretation of these results is
somewhat limited by the slow kinetics of the reaction of TMP
with free thiolate. Therefore we turned to electrochemical tech-
niques for the detection of thiolate.
Electrochemical studies
Cyclic voltammetry (CV) experiments were conducted first to
determine the potentials at which free thiolate vs. gold(I)-thio-
late oxidizes. Oxidation of free thiolate has been shown to
occur at significantly lower potentials than when it is co-
ordinated to metals.51–53 For example, Savéant et al.,53
measured the formal potentials of aryl thiolates (ArS•/ArS−)
using fast microelectrode cyclic voltammetry in acetonitrile
and determined that the formal potential for the oxidation of
p-methylbenzenethiolate occurs at +0.04 V (vs. SCE). In com-
parison, oxidation of the coordinated thiolate ligand in
Ph3PAuSC6H4CH3 occurs at >+0.55 V.51,52 We note that due to
the irreversible nature of these sulfur-based redox couples, the
peak oxidation potentials observed in cyclic voltammetry
studies vary depending on scan rate (e.g. 20–500 mV s−1),
working electrode (Pt, GC), solvent (CH3CN, CH2Cl2) and elec-
trode adsorption effects.51,52 Accordingly, when making a com-
parison of the redox properties of sulfur-containing
compounds, it is useful to employ the same experimental con-
ð1Þ
ꢀd½Ph3PAuSC6H4CH3 ꢁ
¼ kobs½Ph3PAuSC6H4CH3ꢁ½ðO2NC6H4SÞ2ꢁ
dt
ð2Þ
Since the mechanism of metal-free thiol-disulfide exchange
involves attack of thiolate on disulfide in the rate determining
step, we considered the possibility that free thiolate, which
might form via dissociation from the gold(I) complex, is
responsible for the reaction with disulfide. To examine this
possibility, we conducted several lines of investigation: (1)
chemical thiolate trapping, (2) electrochemical studies, (3)
kinetics studies in the presence and absence of air and (4)
kinetic studies in the presence of added thiolate.
ditions. For example, Fig.
1 shows the CV scans of
Ph3PAuSC6H4CH3 and [Me4N][SC6H4CH3], both at concen-
trations of 1.9 mM in 0.1 M TBAH/CH3CN solutions at 250 mV
Chemical thiolate trapping studies
We selected trimethylphosphate [(CH3O)3PO, TMP] as a chemi- s−1. Oxidation of free thiolate (−0.003 V vs. Ag/AgCl; Fig. 1b),
cal thiolate trap, since TMP has been shown to react with free occurs 750 mV lower in potential than the metal-coordinated
thiolate.49,50 In a control experiment, CD3CN solutions of thiolate (+0.76 V vs. Ag/AgCl) (Fig. 1a).
0.25 mM TMP and 0.05 mM [Me4N][SC6H4CH3], prepared in
A similar comparison of CVs of 1.9 mM Ph3PAuSC6H4NO2
an Ar-filled drybox, showed clear evidence in the 1H NMR of and 1.9 mM [Me4N][SC6H4NO2] is shown in Fig. S2 (see ESI†).
formation of dimethylphosphate (DMP; doublet at 3.36 ppm) Oxidation of free thiolate ([−SC6H4NO2]: +0.42 V vs. Ag/AgCl;
within 15 minutes. Additional aliquots of [Me4N][SC6H4CH3] Fig. S2b†), occurs 720 mV lower than the metal-thiolate
(to a concentration of 0.55 mM) and longer reaction times (Ph3PAuSC6H4NO2: +1.14 V vs. Ag/AgCl; Fig. S2a†).
(24 hours) were required to detect a significant amount of the Constant potential electrolysis experiments were conducted
methylated sulfur compound, CH3SC6H4CH3 (singlets at 2.44 to determine whether there was a significant amount of free
and 2.28 ppm, respectively) (eqn (3)).
thiolate in solutions of Ph3PAuSC6H4CH3. Fig. S3† shows
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conditions (2.61 mM Ph3PAuSC6H4CH3 and 2.50 mM
O2NC6H4SSC6H4NO2 solutions). The rate constants of a set of
two anaerobic and three air experiments, show no significant
differences in the calculated rate constants: 0.41 M−1 s−1 vs.
0.42 M−1 s−1, respectively.
Kinetic studies with added thiolate
The effect of micromolar amounts of added thiolate on the
gold(I) thiolate disulfide exchange reaction was also deter-
mined. Reaction kinetics were measured for solutions of
1.21 mM Ph3PAuSC6H4CH3 and 1.23 mM O2NC6H4SSC6H4NO2
with 5, 10, 20, 40 and 70 μM [Me4N][SC6H4CH3]. At the lowest
levels of added thiolate (5, 10 and 20 μM) the reaction rate is
essentially unchanged, while at higher levels there is a slight
increase in rate (e.g. 2× at 70 μM). Since the rate constant for
free thiolate disulfide exchange is estimated to be 104 M−1 s−1
in acetonitrile,54 if free thiolate was mechanistically the reac-
tive species, addition of free thiolate would be predicted to
lead to dramatic increases in the rate of exchange, which is
not observed. Preliminary evidence by NMR suggests that the
addition of free thiolate results in exchange of the gold bound
thiolate and may lead to the formation of a new gold complex.
Further experiments are required to understand this process.
Taken together, the trapping experiments involving TMP,
the electrochemical studies and kinetic experiments with
added thiolate indicate that free thiolate is not detectable in
any significant quantity either from solutions of gold(I)-thio-
late, or during the gold(I)-mediated thiolate, disulfide
exchange reactions in acetonitrile. We note that other similar
studies such as zinc(II)-thiolate, disulfide exchange in DMSO,10
and gold(I)-thiolate, disulfide exchange in CH2Cl2,11 have
arrived at similar conclusions.
Fig. 1 Cyclic voltammograms of (a) 1.9 mM Ph3PAuSC6H4CH3 and (b)
1.9 mM [Me4N][SC6H4CH3] in 0.1 M TBAH/CH3CN in a two-compart-
ment cell. Pt vs. Ag/AgCl|Pt, 250 mV s−1. The background current is light
gray.
current vs. time traces during constant potential electrolyses
experiments performed near 0 V vs. Ag/AgCl (in Ar-purged,
stirred CH3CN solutions). Fig. S3a† shows the current as a
function of time for a 1.9 mM Ph3PAuSC6H4CH3 solution held
at 0.0 V, while Fig. S3b† shows the significant anodic current
observed for oxidation of 1.9 mM [Me4N][SC6H4CH3] at
+0.05 V. The trace for the gold compound registers essentially
what is observed without metal complex and demonstrates
that there is not an appreciable amount of free thiolate in solu-
tions of Ph3PAuSC6H4CH3. However, this procedure does not
allow us to detect trace amounts of free thiolate (≤10 μM).
Differential pulse voltammetry (DPV) was used to detect
lower levels of free thiolate in solutions of Ph3PAuSC6H4CH3.
A detection limit of approximately 1.5 μM for free thiolate (at
−0.1 V vs. Ag/AgCl) was estimated from a series of experiments
on different concentrations of [Me4N][SC6H4CH3]. In experi-
ments under anaerobic conditions, there was no evidence of
the presence of free thiolate in 2.0, 3.0 or 4.0 mM solutions of
Ph3PAuSC6H4CH3. DPV experiments were also conducted to
qualitatively determine the effect of O2 on solutions of thio-
late. A 100 μM solution of [Me4N][SC6H4CH3], prepared under
argon, showed a persistent DPV signal that when subsequently
exposed to O2, decreased and completely disappeared within
15 minutes.
To gain additional mechanistic insight, the self-exchange
reaction shown in eqn (4) was studied using 2D (1H–1H)
ROESY NMR spectroscopy carried out in solutions of 5.0 mM
Ph3PAuSC6H4NO2 and 5.0 mM NO2C6H4SSC6H4NO2 in CD3CN.
A star is used in eqn (4) to label the self-exchange reaction.
Numbered hydrogen atoms on the thiolate and disulfide moi-
eties are used to discuss the 2D NMR spectra.
ð4Þ
Kinetics studies in the presence and
absence of air
There are two different colors of off-diagonal cross-peaks in
The DPV experiment suggests that if free thiolate forms in the 2D (1H–1H)-ROESY NMR spectrum (Fig. 2A). The blue
acetonitrile solutions of Ph3PAuSC6H4CH3, the thiolate would peaks are indicative of association while the red peaks indicate
oxidize, resulting in decomposition of the gold complex. We exchange. The blue cross-peaks B1 and B2 at the intersections
have observed that CD3CN solutions of Ph3PAuSC6H4CH3 pre- of H2–H3 and H1–H4 indicate intermolecular NOE’s caused
pared in air are stable for at least 24 hours, as evidenced by 1H by association between gold(I)-thiolate and disulfide. The blue
NMR; i.e. no decomposition is observed. Further, kinetic cross-peaks B3 and B4 at the intersection of H1–H2 and H3–
experiments were conducted to measure the rate of exchange H4 are also caused by association, but these occur via intra-
under anaerobic conditions (2.53 mM Ph3PAuSC6H4CH3 molecular NOE’s between adjacent aromatic protons. (Note:
and 2.59 mM O2NC6H4SSC6H4NO2 solutions) vs. aerobic the H4 protons are partially obscured by aromatic protons on
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and H2–H3 at a distance of 3.13 Å and performed a DFT calcu-
lation to minimize the structure.58 The result is illustrated in
Fig. 2B, which shows a cartoon rendered with Autodesk 3DS
MAX 2013. (SN stands for the nucleophilic sulfur, SC is the
central sulfur, and SL is the leaving sulfur.) The SN–Au bond
length (2.36 Å) is typical of lengths in Au(I)-thiolate complexes.
The nucleophilic sulfur (SN) approaches the disulfide sulfur
(SC) at a distance 5.34 Å. The SC–SL bond length is 2.07 Å while
the SL⋯Au distance is 4.20 Å. When the constraints on the
H1–H4 and H2–H3 distances are removed and the structure is
reoptimized, the disulfide and gold complex move apart, but
the orientation is similar to the conformation shown in Fig. 2b
(see S4b†). The H2–H3 distance increases from 3.13 Å to
3.59 Å, while the H1–H4 distance increases to 6.28 Å. The
SN⋯SC and SL⋯Au distances also increase significantly.
The conformation shown in Fig. 2b was estimated to be
approximately 13 kJ mol−1 higher in energy than the separated
reactants and approximately 9 kJ mol−1 higher than the mini-
mized structure without constraints on the H1–H4 and H2–H3
distances. This suggests that the conformation shown in
Fig. 2b would be accessible at room temperature. Further,
such an association can be imagined to lead to gold(I)-thiolate,
disulfide exchange through a (Au–SN, SC–SL) 4-centered metal-
lacycle arrangement. We note that this arrangement is nearly
identical to the calculation recently reported for the transition
state involving zinc(II)-thioredoxin, glutathione disulfide
exchange.30 The metal-mediated mechanism differs signifi-
cantly from non-metal thiol-disulfide exchange, which pro-
ceeds through a linear arrangement of sulfurs. This difference
in mechanism is expected to lead to a different dependence of
rates as a function of solvent for metal vs. non-metal mediated
thiol-disulfide exchange, which is currently being investigated.
Finally, based on our results, we suggest that further studies
are needed to eliminate the possibility that trace free thiolate
at levels below 100 nM may influence gold(I)-thiolate, disulfide
exchange in acetontrile.
Fig. 2 A. 2D (1H–1H)-ROESY NMR spectrum of involving
Ph3PAuSC6H4NO2 and NO2C6H4SSC6H4NO2. B. A cartoon to help visu-
alize the intermolecular association (dashed lines) between
Ph3PAuSC6H4NO2 and NO2C6H4SSC6H4NO2, generated from a mini-
mized DFT calculation by tethering H1–H4 and H2–H3 distances at
3.1 Å (suggested from 2D (1H–1H)-ROESY NMR results).
the Ph3P ligand.) The red cross peaks, R1 and R2 indicate
chemical exchange between H1–H3 and H2–H4 respectively,
and arise from “nonproductive” thiolate disulfide exchange
between Ph3PAuSC6H4NO2 and NO2C6H4SSC6H4NO2 (eqn (4)).
A key feature of the 2D (1H–1H) ROESY spectrum is the set
of blue cross peaks, B1 and B2, indicating intermolecular
long-range interactions between H2–H3 and H1–H4. The dis-
tances between these spatially close nuclei can be estimated,55
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