Antioxidant activity of the new thiosulfinate derivative, S-benzyl phenylmethanethiosulfinate, from Petiveria alliacea L.

Article abstract of DOI:10.1039/b715727d

The antioxidant effects of the new thiosulfinate derivative, S-benzyl phenylmethanethiosulfinate (BPT), against the oxidation of cumene and methyl linoleate (ML) in chlorobenzene were studied in detail using HPLC. The results showed that BPT provided effe

Full text of DOI:10.1039/b715727d

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Antioxidant activity of the new thiosulfinate derivative, S-benzyl
phenylmethanethiosulfinate, from Petiveria alliacea L.
Youji Okada,a Kaoru Tanaka,b Eisuke Satoc and Haruo Okajima*a
Received 11th October 2007, Accepted 28th January 2008
First published as an Advance Article on the web 18th February 2008
DOI: 10.1039/b715727d
The antioxidant effects of the new thiosulfinate derivative, S-benzyl phenylmethanethiosulfinate (BPT),
against the oxidation of cumene and methyl linoleate (ML) in chlorobenzene were studied in detail using
HPLC. The results showed that BPT provided effective inhibition with a well-defined induction period
under these oxidation conditions, and it was found that the stoichiometric factor (n), the number of
peroxyl radicals trapped by one antioxidant molecule, of BPT is about 2. We then undertook a thorough
investigation aimed at elucidating the active structural site of BPT. Various model compounds, such as
diphenyl disulfide, dibenzyl disulfide, S-phenyl benzenethiosulfinate and S-ethyl phenylmethanethiosul-
finate, were used which provided evidence that the benzylic hydrogen of BPT is mainly associated with the
peroxyl radical scavenging. Moreover, we measured the rate constant for the reaction of BPT with peroxyl
radicals derived from cumene and ML in chlorobenzene, and based on these measurements, BPT reacts
with these peroxyl radicals with a rate constant of kinh = 8.6 × 103 and 6.2 × 104 M−1 s−1, respectively.
Introduction
It is generally known that garlic extract exhibits antioxidant
activity against lipid peroxidation.1–10 We reported that garlic
extracts inhibit methyl linoleate (ML) oxidation in an acetonitrile
solution, and the antioxidant activity is mostly due to the presence
of allicin (1f) (Fig. 1), one of the main thiosulfinates in garlic.11
More recently, we also showed that allicin (1f) inhibits the
oxidation of cumene and ML in chlorobenzene, and this ability is
characterized by a reaction with the peroxyl radical derived from
cumene and ML with the rate constants (kinh) 2.6 × 103 M−1 s−1
and 1.6 × 105 M−1 s−1, respectively.12 However, the antioxidant
activity of allicin (1f) is weaker than that of a-tocopherol (a-toc).
Fig. 1 Chemical structures of thiosulfinates (1) and related organosulfur
compounds (2) used in this study.
In addition, we elucidated that allicin (1f) antioxidant activity
requires a combination of an allyl group and an –S(O)S- group,
and that the antioxidant properties of allicin (1f) are due to the
fact that the transfer of the allylic hydrogen of allicin (1f) causes
scavenging of the chain-carrying peroxyl radicals of the substrates
forming hydroperoxides.12 Our present aim is to compare the
antioxidant activity and antioxidative mechanism of allicin (1f)
with those of other thiosulfinate derivatives.
Petiveria alliacea L. is widely distributed throughout the South
and Central Americas, and has commonly been used in folk
medicines.13–15 It has been reported that various preparations
made from these plants exhibit anti-inflammatory, antimicrobial,
anticancer and stimulant effects. It is interesting to note that
the root of this plant contains various thiosulfinate compounds,
and S-benzyl phenylmethanethiosulfinate (BPT) (1b) is the most
abundant thiosulfinate found in this extract.15 BPT (1b) is believed
to possess antibacterial and antifungal activities, however, as far as
we know, reliable data on its antioxidant activities are lacking. This
paper is the first report on kinetic and mechanistic investigations
of the new thiosulfinate derivative, BPT (1b), as an antioxidant.
Experimental
Materials
Cumene, 2,2ꢀ-azobis(isobutyronitrile) (AIBN), 1,1-diphenyl-2-
picrylhydrazyl (DPPH), and chlorobenzene were obtained from
Wako Pure Chemical Industries (Osaka, Japan). AIBN was
recrystallized from methanol, and cumene was purified on a
silica-gel column before use. ML was purchased from the Sigma
Chemical Co. (St. Louis, MO, USA) and purified on a silica-gel
column before use. Dibenzyl disulfide (2b) and diphenyl disulfide
(2a) were obtained from the Aldrich Chemical Co. (Milwaukee,
WI, USA). a-Toc was purchased from the Kanto Chemical Co.
aDepartment of Analytical Chemistry, Faculty of Health Sciences,
Kyorin University, 476 Miyasita-cho, Hachioji, Tokyo, 192-8508, Japan.
E-mail: okajima@kyorin-u.ac.jp; Fax: +81-42-691-1094; Tel: +81-42-691-
0011
bDepartment of Medical Information Engineering, Faculty of Health Sci-
ences, Kyorin University, 476 Miyasita-cho, Hachioji, Tokyo, 192-8508,
Japan. E-mail: tanaka@kyorin-u.ac.jp; Fax: +81-42-682-1033; Tel: +81-
42-691-0011
cDepartment of Analytical Chemistry, Faculty of Pharmaceutical Sciences,
Aomori University, 2-3-1 Kobata, Aomori, Aomori 030–0943, Japan
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(Tokyo, Japan) and used without purification. All other reagents
were of the highest grade commercially available.
30 ◦C in air. Samples (0.5 mL) were withdrawn from the mixture at
known intervals during the induction period and were immediately
reduced to ML hydroxides (MLOH) by the addition of 1.0 mL of
2 mM triphenylphosphine in chlorobenzene to these samples. The
analysis was performed using silica-gel HPLC (1.0 mL min−1 n-
hexane + 1.0% 2-propanol, Supelco SUPELCOSIL LC-Si 5 lm
250 × 4.6 mm column) and peaks in MLOH were detected at
234 nm.21
Synthesis of BPT (1b) from dibenzyl disulfide (2b)
BPT (1b) was chemically synthesized from dibenzyl disulfide (2b)
using the method of Cruz-Villalon.16 The synthesized BPT (1b)
was purified by preparative HPLC (10 mL min−1 methanol +
30% H2O) using a UV detector at 254 nm with an RP-C18
column (particle size 10 lm; 19 × 300 mm; Waters lBondapakTM).
BPT (1b) was identified by comparing its mass spectrum to
that reported by Kubec et al.; MS m/z (relative intensity): 263
(MH+, 20%), 139 (C6H5CH2SO+, 10).15 A Micromass ZQ mass
spectrometer (Waters) equipped with an atmospheric pressure
chemical ionization (APCI) source was used in the positive
ionization mode. The mass ionization conditions were as follows:
desolvation temperature, 400 ◦C; source temperature, 120 ◦C; cone
voltage, 9V; and desolvation gas flow, 160 L h−1.
Calculation of bond dissociation enthalpy (BDE) values
The calculation of the BDE values of BPT (1b) was performed
by the Gaussian 03 program (Gaussian, Inc., Carnegie, PA,
USA) as follows: geometrical optimization and determination
of the vibrational frequencies were performed using HF/6-
31+G(2d,p).22 The single-point electronic energies were obtained
using B3LYP/6-31+G(2d,p).
S-Phenyl benzenethiosulfinate (1a) and S-ethyl phenyl-
methanethiosulfinate (1d, 1e) were also synthesized from diphenyl
disulfide (2a) and benzyl ethyl disulfide (2c), respectively, in the
same way as described above. However, the benzyl ethyl disulfide
(2c) was synthesized using the method of Mugesh et al.17 The
purification and confirmation of these compounds were performed
following the procedure given above.
Results and discussion
Inhibitory effect of BPT (1b) against cumene and ML oxidation
The effects of BPT (1b) as an antioxidant against cumene and
ML oxidation have been investigated in chlorobenzene, which has
proven useful in quantitative assays of the chemical activities of
antioxidants against lipid peroxidation. In fact, these experimental
conditions are frequently employed as a simple means to determine
the rate constants for peroxyl radical trapping by antioxidants.23,24
We previously determined the rate constants kinh for the reaction
of allicin (1f) with peroxyl radicals.12 Therefore, at this time, we
decided to study the antioxidant activity of BPT (1b) under these
conditions using HPLC.
Cumene and ML oxidation in chlorobenzene solution
In a typical experiment, either cumene (5.35 M) or ML (91 mM)
was incubated in chlorobenzene in the presence of an appropriate
amount of BPT (1b) at 30 ◦C in air. A solution of AIBN (23 mM
for cumene and 40 mM for ML) in chlorobenzene was added to
this reaction mixture.18,19 The rates of the substrate oxidations were
followed by measuring the peroxides generated from each substrate
using reverse phase HPLC (0.3 mL min−1 methanol + 15% water,
Shiseido CAPCELLPAK C18 5 lm 3.0 × 150 mm column), and
peaks were detected at 260 nm for cumene hydroperoxide (CHP)
and at 234 nm for ML hydroperoxide (MLOOH). At the same time,
the consumption of BPT (1b) was analyzed using a C18 HPLC with
a UV detector at 254 nm.
Fig. 2 shows the increase in traces of CHP by BPT (1b)’s
inhibition of the cumene oxidation initiated by AIBN. BPT
(1b) displayed a very clear induction period during cumene
oxidation. The induction period ended when the BPT (1b) had
Reactivity of BPT (1b) toward DPPH
DPPH (50 lM) and BPT (1b) (25 lM) were dissolved in
chlorobenzene at 30 ◦C. The rate of the DPPH-scavenging reaction
was monitored at 517 nm using a spectrophotometer. In the same
way, DPPH (50 lM) and BPT (1b) (50 lM) were dissolved in
methanol in the presence of Mg(ClO4)2 (0.2 M) and monitored at
516 nm using a spectrophotometer.20 The consumption of BPT
(1b) (0.5 mM or 1.0 mM) by reaction with DPPH (1.0 mM)
was analyzed using an HPLC equipped with an RP-C18 column
(0.3 mL min−1 methanol + 25% water, Shiseido CAPCELLPAK
C18 5 lm 3.0 × 150 mm column), and BPT (1b) was detected by
its UV absorption at 254 nm.
Fig. 2 Inhibitory effect of BPT (1b) on the oxidation of cumene induced
by AIBN in chlorobenzene. Cumene (5.35 M) was oxidized at 30 ◦C in
chlorobenzene in air with AIBN (23 mM) in the absence (a) and presence
(b) of 20 lM, and (c) 30 lM BPT (1b). The CHP was measured by HPLC.
Analysis of MLOOH isomers
The oxidation of ML (91 mM) was performed in chlorobenzene
with AIBN (40 mM) in the presence of BPT (1b) (50 lM) at
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been exhaustively consumed, and the rates of oxidation after the
induction period were almost the same as those in the absence of
BPT (1b). A very similar behavior was exhibited when BPT (1b)
was added to the ML oxidation system (Fig. 3). In addition, we
examined the effect of BPT (1b) as a hydroperoxide decomposer in
chlorobenzene at 30 ◦C. However, it was found that BPT (1b) had
no significant effect on the decomposition of CHP or MLOOH
(data not shown).
Fig. 4 Inhibitory effects of 1d and 1e on the oxidation of cumene induced
by AIBN in chlorobenzene. Cumene (5.35 M) was oxidized at 30 ◦C in
chlorobenzene in air with AIBN (23 lM) in the absence (a) and presence
(b) of 30 lM 1e, and (c) 30 lM 1d.
the contribution of BPT (1b)’s hydrogen atoms to its antioxidant
activity.
BPT (1b) was added to the ML oxidation induced by AIBN in
chlorobenzene, and then the MLOOH isomers formed during oxi-
dation were reduced by triphenylphosphine to their corresponding
alcohols, which were analyzed by HPLC. As shown in Fig. 5, the
Fig. 3 Inhibitory effect of BPT (1b) on the oxidation of ML induced
by AIBN in chlorobenzene. ML (91 mM) was oxidized at 30 ◦C in
chlorobenzene in air with AIBN (40 mM) in the absence (a) and presence
(b) of 30 lM, and (c) 50 lM BPT (1b). The MLOOH was measured by
HPLC.
Structure–antioxidant activity relationship of BPT (1b)
To elucidate the active structural site of the BPT (1b) as an
antioxidant, we studied the relationship between the structure
and antioxidant activity of BPT (1b) against cumene oxidation
in chlorobenzene at 30 ◦C.
The results indicated that the diphenyl disulfide (2a), diben-
zyl disulfide (2b) and S-phenyl benzenethiosulfinate (1a) had
no significant antioxidant activity, though BPT (1b) has fairly
strong activity at the same concentration (data not shown).
Similarly, as shown in Fig. 4, C6H5CH2S(O)SCH2CH3 (1e) was
much less efficient in suppressing cumene oxidation. However,
CH3CH2S(O)SCH2C6H5 (1d) was more effective in inhibiting the
oxidation of cumene than 1e. It is evident from these results that
the –S(O)S–CH2C6H5 portion of BPT (1b) is an essential site for
its antioxidant activities.
Antioxidant mechanism of BPT (1b)
The ratios of MLOOH isomers are known to be remarkably
different during ML oxidation in the presence of hydrogen-
donating antioxidants.21 That is, the amount of cis, trans-MLOOH
increases and the trans, trans-MLOOH decreases with increasing
concentrations of hydrogen-donating antioxidants, which results
in a decrease in the cis, trans to trans, trans (c, t : t, t) ratio
of the formed MLOOH. Therefore, we analyzed the ratios of
the MLOOH isomers in the presence of BPT (1b) to confirm
Fig. 5 Distribution of geometric isomers of the MLOH. ML (91 mM)
was oxidized at 30 ◦C in chlorobenzene in air with AIBN (40 mM) in the
absence (a) and presence (b) of 50 lM BPT (1b). Sample (0.5 ml) was
withdrawn from the mixture after 30 min and was reduced to MLOH by
adding triphenylphosphine to the sample. The MLOH was analyzed by
HPLC.
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c, t : t, t ratio of the MLOOH formed during the uninhibited AIBN-
initiated oxidation of ML in chlorobenzene remained constant at
0.16 from 5 to 30 min. However, the addition of 50 lM BPT (1b)
to this reaction mixture induced a c, t : t, t ratio of about 0.23
over the course of the induction period. This fact suggests that the
hydrogen atom of BPT (1b) may at least contribute to determining
its antioxidant activity.
Furthermore, we have also extended the investigation to the
radical-scavenging mechanism of BPT (1b). It is well known that
there are two mechanisms for the radical-scavenging reactions of
antioxidants: a one-step hydrogen atom transfer and an electron
transfer followed by a proton transfer.25 In addition, the electron-
transfer mechanism is known to be accelerated in the presence
of Mg2+.20 We then examined the effect of Mg2+ on the radical-
scavenging rate of BPT (1b) in methanol according to the method
of Nakanishi et al.20 As shown in Fig. 6, the rate of the DPPH-
scavenging reaction with BPT (1b) was not affected by the addition
of Mg2+. This shows that the radical-scavenging reactions of BPT
(1b) proceed via a one-step hydrogen atom transfer.
of BPT (1b), by measuring its reactivity with DPPH. DPPH has
often been used in estimating of the reactivity of antioxidants
with radicals and can also be used to estimate antioxidant
stoichiometries.27 Therefore, we measured the rate of reduction
of DPPH by BPT (1b) and the amount of unreacted BPT (1b)
remaining after the BPT (1b) was mixed with equimolar quantities
of DPPH in chlorobenzene. As shown in Fig. 7, it was found that
50% of the BPT (1b) remained, despite the fact that DPPH was
completely reduced by the BPT (1b). This result clearly shows that
the n for BPT (1b) is almost 2.0 in chlorobenzene at 30 ◦C.
Fig. 7 Consumption of BPT (1b) and DPPH by reaction of BPT (1b)
with DPPH in chlorobenzene. DPPH (1.0 mM) was reduced at 30 ◦C in
chlorobenzene in air in the presence of (a) and (c) 1.0 mM, and (b) and (d)
0.5 mM BPT (1b). BPT (1b) and DPPH were measured by HPLC.
It is obvious from the results of the Gaussian 03 calculation
that the S–S bond of BPT (1b) was significantly weaker after the
benzylic hydrogen atom of BPT (1b) was abstracted by radicals.
That is, the BDE value of the S–S bond of BPT (1b) was calculated
to be 34.8 kcal mol−1, while that of the corresponding radical
(1c) obtained by the abstraction of a benzylic hydrogen atom
was only slightly above 0 kcal mol−1. This means that BPT (1b)
may have decomposed after the benzylic hydrogen atom of BPT
(1b) was abstracted by radicals. It is suggested that the products
arising from the decomposition of BPT (1b) by loss of a benzylic
hydrogen atom would contribute to determining the n value. In
fact, we detected some products using LC-MS after the reaction
of BPT (1b) with DPPH. However, their structures have not yet
been characterized. The structure of the products formed from
BPT (1b) during the reaction with DPPH needs to be further
examined in detail.
Fig. 6 Reactivity of BPT (1b) toward DPPH in the presence of Mg2+ in
methanol. DPPH (50 lM) was reduced at 30 ◦C in methanol under air in
the absence (a) and presence (b) of 0.2 M Mg(ClO4)2, (c) 50 lM BPT (1b),
and (d) 0.2 M Mg(ClO4)2 and 50 lM BPT (1b).
To further explore the contribution of the BPT (1b) hydrogen
atom, we calculated the BDE values of the benzylic C–H bond
of BPT (1b) using Gaussian 03. Because the one-step hydrogen
atom transfer mechanism is governed by BDE to a large extent,26
we focused our attention on the BDE values of the benzylic C–H
bond of BPT (1b). As a result, the BDE value of the benzylic C–H
bond of C6H5–CH2–S(O)SCH2C6H5 (1b) was 93.0 kcal mol−1, and
that of C6H5CH2S(O)S–CH2–C6H5 (1b) was 88.9 kcal mol−1. This
result shows that the benzylic hydrogen atom of C6H5CH2S(O)S–
CH2–C6H5 (1b) could contribute to its antioxidant activities,
consistent with the observation that CH3CH2S(O)SCH2C6H5 (1d)
was capable of more effectively inhibiting cumene oxidation than
C6H5CH2S(O)SCH2CH3 (1e).
Determination of rate constants (kinh) for the scavenging reaction of
BPT (1b) with peroxyl radicals
We determined the rate constants for the scavenging of peroxyl
radicals, kinh, by BPT (1b) for comparison with those of another
antioxidant. We first experimentally measured the s and Rinh, the
length of the induction period, and the rate of hydroperoxide
formation during the course of the induction periods of the cumene
Determination of stoichiometric factor (n)
In order to determine the rate constants for the scavenging of
peroxyl radicals by BPT (1b), we measured the stoichiometric
factor n, the number of peroxyl radicals trapped by one molecule
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Table 1 Summary of antioxidant activity of BPT (1b), allicin (1f) and a-toc
n
kp/M−1 s−1
Ri/M s−1
2.5 × 10−9
5.3 × 10−9
R
inh/M s−1
s/s
k
inh/M−1 s−1
Cumene oxidation system
30 lM BPT (1b)
25 lM allicin (1f)
25 lM a-toc
ML oxidation system
50 lM BPT (1b)
50 lM allicin (1f)
50 lM a-toc
2.0
1.0
2.0
4.6 × 10−9
3.7 × 10−8
3.9 × 10−10
4.8 × 10−9
3.6 × 10−9
2.7 × 10−10
5766
2788
20286
8.6 × 103
2.6 × 103
1.2 × 105
6.2 × 104
1.6 × 105
1.1 × 106
0.18
2.0
1.0
2.0
2895
2659
18948
62
and ML oxidations induced by BPT (1b). We then determined
the rate of radical chain initiation (Ri) by the inhibitor method,
using a-toc as the reference antioxidant: Ri = 2[a-toc]/s. The kinh
values were determined by a previously used method, following
eqn (1),28,29
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(1)
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where ROOH, RH, IH and kp are the substrate hydroperoxide,
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in chlorobenzene at 30 C were 0.18 M−1 s−1 and 62 M−1 s−1,
2005, 10, 96–102.
respectively.30,31 The kinh can be determined by introducing each
value into eqn (1). The kinh, n, Rinh and s versus the cumene and ML
oxidations in chlorobenzene at 30 ◦C are summarized in Table 1 for
comparison to those of allicin (1f) and a-toc. The kinh values gave
the rate constants for BPT (1b) with the peroxyl radicals derived
from cumene and ML of 8.6 × 103 M−1 s−1 and 6.2 × 104 M−1 s−1.
This is about three times that of allicin (1f) and one-fourteenth
that of a-toc in the cumene oxidation system and about half that
of allicin (1f) and one-seventeenth that of a-toc in the ML system.
Based on the above results, BPT (1b) is chemically less reactive
toward the peroxyl radical than a-toc, but it was found that
BPT (1b) reacts with peroxyl radicals derived from cumene about
3 times faster than allicin (1f). In the ML oxidation system, BPT
(1b) has half the antioxidant activity of allicin (1f). However,
this kinh indicates the value for one peroxyl radical trapped by
one molecule of BPT (1b). As described above, one molecule
of BPT (1b) can scavenge two molecules of peroxyl radicals. In
addition, we obtained valuable data about the mechanism of the
thiosulfinate derivative as an antioxidant, that is, the benzyl group
would be more effective as an antioxidant of the thiosulfinate
derivatives than the allyl group, and one molecule of BPT (1b) can
scavenge two molecules of radical.
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It is generally believed that the oxidative modification of
biological molecules leads to tissue damage and eventually to
various diseases.32,33 The action of BPT (1b) as a radical-scavenging
antioxidant, first discovered in this study, could contribute to a
decrease in the development of these diseases.
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