Reactive oxygen species in aerobic decomposition of thiourea dioxides

Article abstract of DOI:10.1039/a907816i

Thiourea dioxides decompose in air-saturated alkaline solutions to give dithionite, S₂O₄^2-. Kinetics of decomposition of aminoiminomethanesulfinic acid (AIMSA), methylaminoiminomethanesulfinic acid (MAIMSA) and dimethylaminoiminomethanesulfinic acid (DMAIMSA) were studied in alkaline solutions under aerobic and anaerobic conditions. No dithionite was formed in strictly anaerobic conditions. Dithionite, however, was formed in the presence of KO₂ and H₂O₂ under anaerobic conditions. The rate of decomposition was fastest for DMAIMSA and slowest for MAIMSA. The proposed mechanism involves the initial formation of the dioxosulfate(2-) ion, SO₂^2-, through the heterolytic cleavage of the C-S bond. The dioxosulfate(2-) ion then reacts with dioxygen to give a series of reactive oxygen species: Superoxide, peroxide and the hydroxyl radical. The expected dismutation of Superoxide is important only in weakly alkaline solutions of pH less than 10. It is suggested, for the first time, that the reactive oxygen species and the sulfur leaving groups may be responsible for the toxicity observed in most thioureas. The Royal Society of Chemistry 2000.

Full text of DOI:10.1039/a907816i

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Reactive oxygen species in aerobic decomposition of thiourea
dioxides†
Serge A. Svarovsky,a Reuben H. Simoyi*a and Sergei V. Makarovb
a Department of Chemistry, West Virginia University, Morgantown, WV 26506-6045, USA
b Department of Physical Chemistry, Institute of Chemistry and Technology, Ivanovo,
Engels Str. 7, 153460 Russia
Received 28th September 1999, Accepted 15th December 1999
Thiourea dioxides decompose in air-saturated alkaline solutions to give dithionite, S2O42Ϫ. Kinetics of decomposition
of aminoiminomethanesulfinic acid (AIMSA), methylaminoiminomethanesulfinic acid (MAIMSA) and dimethyl-
aminoiminomethanesulfinic acid (DMAIMSA) were studied in alkaline solutions under aerobic and anaerobic
conditions. No dithionite was formed in strictly anaerobic conditions. Dithionite, however, was formed in the
presence of KO2 and H2O2 under anaerobic conditions. The rate of decomposition was fastest for DMAIMSA and
2Ϫ
slowest for MAIMSA. The proposed mechanism involves the initial formation of the dioxosulfate(2Ϫ) ion, SO2
,
through the heterolytic cleavage of the C–S bond. The dioxosulfate(2Ϫ) ion then reacts with dioxygen to give a series
of reactive oxygen species: superoxide, peroxide and the hydroxyl radical. The expected dismutation of superoxide
is important only in weakly alkaline solutions of pH less than 10. It is suggested, for the first time, that the reactive
oxygen species and the sulfur leaving groups may be responsible for the toxicity observed in most thioureas.
Here we report on the kinetic studies of aerobic decomposition
of thiourea dioxide, N-methylthiourea dioxide, and N,NЈ-
dimethylthiourea dioxide in aqueous solutions.
Introduction
It is well known that many thioureas are toxins.2,3 Substituted
thioureas and thiourea itself are known to exhibit a number of
pharmacological effects in toxicity and metabolic effects.3 The
main in vivo transformations of thioureas involve oxygenation
of the sulfur atom followed by nucleophilic substitution or
elimination reactions to give sulfinic and sulfonic acids.4 It is
known that S-oxygenation of thioureas results in the formation
of genotoxic products.5 The major products of oxidation,
however, are the corresponding aminoiminomethanesulfinic
acids (thiourea dioxides).6 It was hypothesized that nucleophilic
reactions of thiourea dioxides may be related to the reactions
that lead to the toxicity of thioureas.3 Animal studies on the
chronic toxicity of thiourea have shown that when it is admin-
istered in drinking water it induces thyroid adenomas and
carcinomas in rats.7 The tumorigenicity of thiourea has been
attributed to its strong antithyroid activity which leads to
a disruption of the pituitary–thyroid hormonal regulatory
system.8 Thiourea inhibits thyroid peroxidase which results in
an increased release of thyrotropin from the pituitary.9
Subtle differences in substituted thioureas can impart vastly
different degrees of toxicity. For example, while α-naphthyl-
thiourea produces pulmonary edema and pleural effusion in
rats, its oxidation gives α-naphthylurea, an innocuous sub-
stance to rats.10 In general, thioureas which substantially
desulfurize during the metabolic processes, have been found to
be the most toxic as is the case with α-naphthylthiourea. Thio-
ureas that do not desulfurize and maintain a thione group as a
metabolic end-product are generally non-toxic.11 It is reason-
able to assume, then, that the observed toxicity may arise
from either the sulfur-containing leaving groups or the reactive
oxygen species they generate.12
Experimental
Materials
Aminoiminomethanesulfinic acid (AIMSA), methylurea, N,NЈ-
dimethylurea, potassium superoxide, hydrogen peroxide, and
α-isonitrosopropiophenone (ISPF) were purchased from
Aldrich and used without further purification. Methylthiourea
and 1,3-dimethyl-2-thiourea were purchased from Fluka and
used as received. Superoxide dismutase (SOD) and catalase
were purchased from Sigma.
Methylaminoiminomethanesulfinic acid (MAIMSA) was
prepared according to a literature procedure by oxidation of
methylthiourea with hydrogen peroxide.13
N,NЈ-Dimethyl-
aminoiminomethanesulfinic acid (DMAIMSA) was prepared
by oxidation of 1,3-dimethyl-2-thiourea with hydrogen
peroxide following the procedure used for the synthesis of
MAIMSA.
Instrumentation
Conventional kinetics experiments were performed on a Perkin-
Elmer Lambda 2S UV/Vis spectrophotometer. A Hi-Tech
Scientific SF-DX2 stopped-flow spectrophotometer was used
to measure induction times and to follow faster reactions.
The products of MAIMSA and DMAIMSA decomposition
were analyzed on a JNM GX-270 (JEOL) NMR spectrometer.
GC-MS were measured with a Hewlett-Packard Model 5980
GC-MS using a mass selective detector.
Surprisingly, there are no data available on toxic effects of
inorganic sulfur-containing leaving groups released from thio-
urea dioxides in nucleophilic substitution/elimination reactions.
Since these groups are strong reductants,10 their reactions in
vivo may potentially lead to the observed toxicity of thioureas.
Methods
All experiments were performed at 25 0.2 ЊC. Temperature
control was maintained with a NesLab RTE-101 thermostat.
Reactions were run at an ionic strength of 0.5 M (NaCl). A
mixture of acetic acid, phosphoric acid, and boric acid plus
NaOH (Britton–Robinson system)14 was used for the prepar-
ation of buffer solutions. In most reactions, however, a fixed
† Nonlinear dynamics in chemistry derived from sulfur compounds.
Part 33.1
DOI: 10.1039/a907816i
J. Chem. Soc., Dalton Trans., 2000, 511–514
This journal is © The Royal Society of Chemistry 2000
511

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0.5 M NaOH aqueous solution was used as the reaction
medium. Decomposition of AIMSA and MAIMSA solutions
was followed by measuring absorbance at 270 nm where the
absorption coefficients of AIMSA and MAIMSA in water were
found to be 489 and 521 MϪ1 cmϪ1 respectively. DMAIMSA
decomposition was monitored by measuring absorbance at
263 nm where the absorption coefficient was found to be 475
MϪ1 cmϪ1. Due to deprotonation of the sulfinic acids (pKa-
(AIMSA) = 8.01),15 their absorption coefficients were higher at
high pH conditions and hence had to be determined separately
for solutions with different pH. Possible intermediates of
aerobic decomposition of the sulfinic acids (superoxide, hydro-
gen peroxide and dithionite) also absorb significantly at 270 nm
(ε = 1330, 11016 and 2365 MϪ1 cmϪ1 respectively). Therefore we
were unable to use experimental traces at 270 nm obtained in
air-saturated solutions in our calculations of the rate constants
at this wavelength. Dithionite formation was followed at 315
nm (ε = 8043 MϪ1 cmϪ1).17
Urea, methylurea, and N,NЈ-dimethylurea were assayed
with α-isonitrosopropiophenone (ISPF) reagent.18 In control
experiments AIMSA, MAIMSA, and DMAIMSA were assayed
with ISPF, and none gave a positive test. The decomposition
products of these sulfinic acids were also assayed with the ISPF
reagent and all gave the distinctive pink color for the presence
of corresponding ureas.
AIMSA did not show any reasonable NMR spectrum,
and neither did its decomposition products. MAIMSA and
DMAIMSA, however, each showed a single peak in each case
representing the methyl protons. After decomposition, both
MAIMSA and DMAIMSA yielded methylurea and N,NЈ-
dimethylurea respectively. This was confirmed by comparing
the chemical shifts of the methyl protons of authentic samples
of methylurea and N,NЈ-dimethylurea with the decomposition
products of MAIMSA and DMAIMSA under identical pH
conditions. In addition, the presence of methylurea and N,NЈ-
dimethylurea as the only detectable carbon-containing products
of MAIMSA and DMAIMSA was independently confirmed
by GC-MS. This shows that the decomposition of these sulfinic
acids in alkaline conditions results in the cleavage of the C–S
bond while leaving the rest of the organic backbone intact.
Fig. 1 (A) Formation of dithionite in the reaction of aerobic AIMSA
decomposition in 0.5 M NaOH air-saturated solution. [AIMSA]0 = (a)
0.6 mM; (b) 1 mM; (c) 3 mM; (d) 4.6 mM; (e) 6 mM. (B) Variation of
the maximum dithionite concentration formed with respect to initial
AIMSA concentrations. At high AIMSA concentrations the limiting
factor is the amount of dissolved oxygen in solution, hence the satur-
ation is observed.
This proposed mechanism, reactions (2)–(4), however, was
not supported by our experimental data since we could not
observe any influence of sulfite on the rate of dithionite form-
Results and discussion
ation in alkaline solutions. McGill and Lindstrom22 assumed
Ϫ
Decomposition of air-saturated alkaline solutions of amino-
iminomethanesulfinic acid (AIMSA), N-methylaminoimino-
methanesulfinic acid (MAIMSA), and N,NЈ-dimethylamino-
iminomethanesulfinic acid (DMAIMSA) is accompanied by
that the presence of the SO2
anion-radical supports
᝽
homolytic cleavage of the carbon–sulfur bond of AIMSA but
they did not mention a possible role of oxygen in these
processes.
2Ϫ
the formation of dithionite S2O4 (λmax = 315 nm, ε315 = 8043
By varying [AIMSA]0 at fixed pH our experimental results
M
Ϫ1 cmϪ1 19 which is preceded by an induction period (Fig. 1A).
)
showed
that
if
[AIMSA]0 ӷ [O2]0
(with
standard
[O2]0 = 2.4 × 10Ϫ4 M in air-saturated aqueous solution and
2.15 × 10Ϫ4 M in 0.5 M NaOH),23 the maximum concentration
of S2O42Ϫ attained during the reaction reached a constant value
Table 1 summarizes the major characteristics of the kinetic
traces shown in Fig. 1A.
2Ϫ
S2O4 is known to exist in equilibrium with anion-radical
Ϫ 19
of about 1.4 × 10Ϫ4 M and did not depend on [AIMSA]0
(Fig. 1B). In all our experiments, [S2O4
SO2
.
᝽
2Ϫ
]
was found to be
max
2Ϫ
Ϫ
S2O4
2 SO2
(1)
᝽
limited by the amount of oxygen initially present in solution. It
was reasonable to assume, then, that oxygen was involved in the
formation of S2O42Ϫ. Indeed, under rigorously anaerobic con-
ditions dithionite was not formed at all. Further experimental
data showed that oxygen did not affect the kinetics of AIMSA
decomposition monitored at 270 nm. The 270 nm wavelength is
the maximum in the absorption peak of AIMSA.
The equilibrium of reaction (1) lies heavily to the right in
aprotic solvents (CH3CN, DMSO, etc.). In aqueous protic
solutions the equlibrium constant has been quoted as being
between 1.4 × 10Ϫ9 M and 1.4 × 10Ϫ6 M.20
Budanov and co-workers21 explained the presence of
dithionite in the alkaline decomposition of thiourea dioxide by
the following reaction scheme that is initiated by the heterolytic
cleavage of the C–S bond:
These results seem to suggest that dithionite and the anion-
Ϫ
radical SO2 are products of the reaction of oxygen with
᝽
some sulfur-containing product of AIMSA decomposition.
A possibility is the dioxosulfate(2Ϫ) ion, SO22Ϫ, which is
formed during heterolytic cleavage of the C–S bond.24
(NH )(HN᎐)C–S(᎐O)OH ϩ OHϪ
᎐
᎐
2
Ϫ
(NH2)2CO ϩ HSO2
2 HSO3Ϫ ϩ HSϪ
S2O42Ϫ ϩ H2O
(2)
(3)
(4)
2Ϫ
The reaction of SO2 with O2 is very fast and produces the
SO2 Ϫ radical-ion:25
Ϫ
᝽
3 HSO2
HSO2Ϫ ϩ HSO3
SO22Ϫ ϩ O2 → SO2 Ϫ ϩ O2
(5)
Ϫ
Ϫ
᝽
᝽
512
J. Chem. Soc., Dalton Trans., 2000, 511–514

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Table 1 Summary of the data presented in Fig. 1a
[AIMSA]0/M
1 × 10Ϫ3
2 × 10Ϫ3
3 × 10Ϫ3
6 × 10Ϫ3
Induction period/s
202
101
66
33
Zero-order ratea/M sϪ1
2.67 × 10Ϫ7
1.03 × 10Ϫ4
7.06 × 10Ϫ7
1.35 × 10Ϫ4
1.12 × 10Ϫ6
1.41 × 10Ϫ4
2.06 × 10Ϫ6
1.48 × 10Ϫ4
2Ϫ
[S2O4
]
a/M
max
a Concentration of S2O42Ϫ was calculated based on ε315(S2O42Ϫ) = 8043 MϪ1 cmϪ1
.
Ϫ
The SO2 radical-ion, in turn, is known to react with oxygen
᝽
with a nearly diffusion-controlled rate constant of 2.4 × 109
26
M
Ϫ1 sϪ1
:
Ϫ
SO2 Ϫ ϩ O2 → SO2 ϩ O2
(6)
᝽
᝽
Both reactions (5) and (6) proceed during the induction
period and produce the reactive oxygen species superoxide. If
SO22Ϫ and SO2 Ϫ were to react with oxygen alone one would not
᝽
observe any formation of dithionite when all the oxygen in
solution is consumed. Since formation of dithionite proceeds
after the induction period there should be some reaction of
2Ϫ
Ϫ
SO2 with O2 or with the product of its dismutation: per-
᝽
oxide. Superoxide is known to be very stable in strongly alkaline
solutions27 and does not significantly dismutate in the time
frame of our experiments. Therefore, we can assume that direct
reaction of SO2 and SO2 with O2 (accumulated during
the induction period) commences after the induction period:
2Ϫ
Ϫ
Ϫ
᝽
᝽
2Ϫ
SO22Ϫ ϩ O2 Ϫ → SO2 Ϫ ϩ O2
(7)
(8)
᝽
᝽
2Ϫ
SO2 Ϫ ϩ O2 Ϫ → SO2 ϩ O2
᝽
᝽
This conclusion has been confirmed by independent kinetic
studies of the reaction between AIMSA and potassium super-
oxide (KO2) under anaerobic conditions. Fig. 2A shows that
kinetic traces at 315 nm resemble those obtained in air-
saturated solutions without KO2 (Fig. 1A). If [KO2]0 = 0 or
[KO2]0 ӷ [AIMSA]0, dithionite is not formed at all (see trace
(f)).
Reactions (7) and (8) produce another reactive oxygen
species: peroxide. Peroxide’s influence on the formation of
S2O42Ϫ in the absence of oxygen in strongly alkaline solutions is
very similar to that of superoxide (Fig. 2B).28 Stoichiometries of
the reactions of SO22Ϫ and SO2 Ϫ with peroxide are as follows:
᝽
Fig. 2 (A) Formation of dithionite in the reaction of anaerobic
decomposition of 1.2 mM AIMSA in 0.5 M NaOH in the presence of
KO2: (a) 0.1 mM; (b) 0.14 mM; (c) 0.35 mM; (d) 0.7 mM; (e) 7 mM.
No dithionite was formed without KO2. (B) Formation of dithionite in
the reaction of anaerobic decomposition of 1.2 mM AIMSA in 0.5 M
NaOH in the presence of H2O2: (a) 0.11 mM; (b) 0.22 mM; (c) 0.44
mM; (d) 0.88 mM; (e) 1.1 mM; (f) 4.4 mM. No dithionite was formed
without H2O2.
Ϫ
Ϫ
SO22Ϫ ϩ O22Ϫ ϩ 2 H2O → SO2 ϩ 3 OH ϩ OH (9)
ؒ
᝽
SO2 Ϫ ϩ O2 ϩ 2 H2O → SO2 ϩ 3 OH ϩ OH (10)
2Ϫ
Ϫ
ؒ
᝽
Reactions (9) and (10) produce the most reactive oxygen
species in the reaction sequence: the hydroxyl radical. It may
disappear in a variety of pathways including the well-known,
nearly diffusion-controlled reaction with sulfite [SO2(aq)]29
formed in reactions (6), (8), and (10). Indeed, addition of OH
radical traps such as sodium formate or tert-butyl alcohol did
not influence the kinetics of dithionite formation in the case of
aerobic AIMSA decomposition.
At fixed [O2]0 and pH, the duration of the induction period
depends solely on the initial concentration of AIMSA (Fig. 1A,
Table 1). The data shown in Table 1 clearly indicate that higher
concentrations of the substrate quickly form dithionite, and
that there is a precise reciprocal relationship between con-
centration of substrate and the length of the induction period.
This can be easily explained by invoking pseudo first-order
In the absence of oxygen, we have found that the pseudo first-
order rate constant for AIMSA decomposition in 0.5 M NaOH
was 6.25 × 10Ϫ4
s
Ϫ1. A zero-order law for dithionite formation
(PFO) rate constant of AIMSA decomposition: kobs
[AIMSA]0 × kPFO, where kPFO = k[OHϪ]. Since kPFO at [OHϪ] =
0.5 M is constant (6.25 × 10Ϫ4 Ϫ1), kobs will increase linearly
=
observed in Fig. 1A can be explained by the fact that in the time
frame when actual dithionite formation takes place (linear rise)
the concentration of AIMSA decreases rather insignificantly
(ca. 10% in trace (b)). Therefore, it can be assumed that the rate
s
with concentration of AIMSA. As a result, the time taken to
consume all of the oxygen in solution will decrease reciprocally
to kobs. It is important to note that during the induction period
every molecule of AIMSA is an origin for two oxygen consum-
2Ϫ
of heterolysis of AIMSA to yield SO2 (which then is very
rapidly converted to SO2Ϫ) remains nearly constant. Indeed,
when the time period of dithionite formation increases the
deviation from zero-order kinetics becomes more and more evi-
dent (Fig. 1A).
2Ϫ
ing species, SO2 and SO2Ϫ, hence the following relationship
can be used to estimate the induction period (T): T = [O2]0/
2kPFO[AIMSA]0. The calculated value (172 s for [AIMSA]0 =
J. Chem. Soc., Dalton Trans., 2000, 511–514
513

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acid showed significant production of the sulfite anion-radical
which can cause substantial damage to DNA.32 Further work
in this area will include an extension of these kinetic and mech-
anistic studies to other thiourea dioxides and nucleophiles.
Acknowledgements
We acknowledge the National Science Foundation through
grant number CHE-9632592 for financial support. S. V. M. is
grateful to the Russian Foundation for Basic Research for
financial support (grant no. 98-03-32802).
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Fig. 3 Formation of dithionite during aerobic decomposition of 1.2
mM AIMSA in a buffer solution at pH 9.9: (a) without enzymes; (b) 1.5
µM SOD; (c) 0.125 µM catalase.
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(Fig. 1A), due to partial contribution of superoxide to the con-
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kinetic curves of dithionite formation (Fig. 3, trace (a)).
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at pH 9.9 (Fig. 3, trace (b)). This effect can be explained by the
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:
᝽
2 O2 Ϫ ϩ H2O → O2 ϩ HO2Ϫ ϩ OHϪ
(11)
᝽
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position process as well as the enhanced stability of AIMSA at
Ϫ
pH near 7. But even in this case, reactions of SO22Ϫ and SO2
᝽
with O2 will yield significant accumulation of toxic reactive
Ϫ
2Ϫ
ؒ
oxygen species O2 , OH and O2
.
᝽
All of the dependences mentioned above were also observed
for MAIMSA and DMAIMSA. Measurements of the rates of
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anaerobic conditions revealed substantially different and
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s
Ϫ1; 1.56 × 10Ϫ4 sϪ1 and 5.04 × 10Ϫ3 sϪ1
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and MAIMSA. The decomposition rate of MAIMSA was the
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Conclusions
The results reported in this study show that the toxicity of
thioureas might be partially attributed to in vivo reactions
of SO22Ϫ and SO2 Ϫ with oxygen resulting in the production of
᝽
a series of reactive oxygen species: O2 Ϫ, O2Ϫ, and OH .
ؒ
᝽
These reactive oxygen species, especially the hydroxyl radical,
can cause DNA damage. In some of our previous work,31 our
experiments on the decomposition of hydroxymethanesulfinic
Paper a907816i
514
J. Chem. Soc., Dalton Trans., 2000, 511–514