An Organodiselenide with Dual Mimic Function of Sulfhydryl Oxidases and Glutathione Peroxidases: Aerial Oxidation of Organothiols to Organodisulfides

Article abstract of DOI:10.1021/acs.orglett.8b02756

A novel organodiselenide, which mimics sulfhydryl oxidases and glutathione peroxidase (GPx) enzymes for oxidation of thiols by oxygen and hydrogen peroxide, respectively, into disulfides has been presented. The developed catalyst oxidizes an array of organothiols into respective disulfides in practical yields by using aerial O₂ to avoid any reagents/additives, base, and light source. The synthesized diselenide also catalyzes the reduction of hydrogen peroxide into water by following the GPx enzymatic catalytic cycle with a reduction rate of 49.65 ± 3.7 μM·min^-1.

Full text of DOI:10.1021/acs.orglett.8b02756

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
An Organodiselenide with Dual Mimic Function of Sulfhydryl
Oxidases and Glutathione Peroxidases: Aerial Oxidation of
Organothiols to Organodisulfides
Vandana Rathore, Aditya Upadhyay, and Sangit Kumar*
Department of Chemistry, Indian Institute of Science Education and Research (IISER) Bhopal, Bhopal By-pass Road, Bhauri,
Bhopal 462 066, Madhya Pradesh India
S
* Supporting Information
ABSTRACT: A novel organodiselenide, which mimics sulfhydryl oxidases and
glutathione peroxidase (GPx) enzymes for oxidation of thiols by oxygen and
hydrogen peroxide, respectively, into disulfides has been presented. The
developed catalyst oxidizes an array of organothiols into respective disulfides in
practical yields by using aerial O2 to avoid any reagents/additives, base, and
light source. The synthesized diselenide also catalyzes the reduction of
hydrogen peroxide into water by following the GPx enzymatic catalytic cycle
with a reduction rate of 49.65 3.7 μM·min−1.
Heavier organochalcogens also catalyze oxidation reac-
he disulfide bond plays a vital role in biological functions
Tof large molecules such as peptides and proteins. The tions,11−13 particularly, oxidation of organothiols into disul-
1
fides. However, these require strong oxidizing reagents, namely
peroxides, or are performed under UV irradiation.13 Con-
sequently, many organothiols with complex functionalities
have not been converted into their respective disulfides.
Moreover, peptide and protein modification using reagents and
subsequent purification steps are undesirable. Therefore, a
mild protocol for the oxidation of thiols is needed.
In living cells, the sulfhydryl oxidase (SOX) family of
flavoenzymes catalyzes the direct and facile oxidation of thiols
into disulfides (Scheme 1, eq 1).14 Disulfide bond formation
occurs first with thiol−disulfide exchange reaction followed by
shuttling of electrons from reduced thiols to the oxidized
disulfide member of the protein disulfide isomerase (PDI)
family. This results in the reduction of conserved cysteine−S−
structure and stability of various antibodies; human immuno-
globulin G1 antibody is also associated with the disulfide
linkage.2 The formation and transfer of disulfide bond is an
important event in the maturation of the proteins present in
both eukaryotic and prokaryotic cells.3 Besides its vital role in
living cells, the disulfide bond is an important parameter for
the construction of novel proteins in the laboratory by
chemical synthesis and semisynthesis. Moreover, the disulfide
bonds or corresponding thiols in proteins have become an
important component of therapeutic agents for the treatment
of several diseases such as cancer and autoimmune diseases.4
The formation of the disulfide S−S bond is a fundamental step
toward accessing a wide range of organic molecules, which are
prevalent in the industry, namely pharmaceuticals, agro-
chemicals, and pesticides.5 Furthermore, disulfide bonds have
been used as ligands for the isolation of soft metals, particularly
Hg, Cd, Zn, etc.6
Scheme 1. Routes to Organodisulfides
Because of their significance in chemistry and biology,
numerous transition-metal (TM)-catalyzed7 or TM-free8−10
methods have been developed for the oxidation of organothiols
̈
into disulfides. Recently, Noel and co-workers have reported
aerobic oxidation of organothiols by using visible-light
irradiation and a sensitizer eosin Y.10a Subsequently, a
visible-light-induced photocatalytic aerobic oxidation of thiols
has been achieved by the same group utilizing titanium dioxide
nanoparticle as a heterogeneous photocatalyst.10b Nonetheless,
high catalyst loading or specially designed ligands are essential
to achieve an optimum yield of the disulfide due to its inherent
chalcophilic nature, which poisons the TM catalysts.
Received: August 28, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02756
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Organic Letters
Letter
a
S−cysteine motifs in the PDIs. Subsequently, the PDIs are
reoxidized by the flavoenzyme endoplasmic reticulum oxidase
1, which transfers electrons via flavin adenine dinucleotide
(FAD) onto oxygen leading to de novo disulfide generation
and concomitant release of hydrogen peroxide (Figure S2).
The selenium-containing glutathione peroxidase (GPx)
selenoenzyme and related mimics catalyze the reduction of
hydrogen peroxide and organic hydroperoxide to water and
alcohols, respectively, by using glutathione GSH as the
stoichiometric reductant in this process (Scheme 1, eq 2).15
Here, in continuation of our work on organochalcogens,16
we report an organodiselenide 1a that exhibits the function of
sulfhydryl oxidases and glutathione peroxidases enzymes
depending on the available substrate. The developed enzyme
mimic catalyzes the oxidation of organothiols into organo-
disulfides by aerial oxygen and peroxide with the concomitant
release of hydrogen peroxide and water, respectively. In
addition, mechanistic understanding of the reaction was
investigated by 77Se NMR, CV, mass spectrometry, control
experiments, EPR spectroscopy, and DFT.
Table 1. Optimization of the Reaction Conditions
b
c
entry
catalyst
solvent
CH3CN
time (h) conv and yield (%)
1
2
1a, 5 mol %
7
7
99 and 90
99 and 97, 96
d
1a
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN+H2O
CH3CN
3
4
5
6
7
8
9
10
11
12
13
1b
1c
1d
1e
1f
1g
7
7
20
35
12
9
15
15
ND
7
ND
10
92
trace
12
12
12
12
12
12
14
7
The diselenide catalyst 1a was synthesized from 2-amino-
phenyl diselenide 1b (Scheme 2). 2-Aminophenyl diselenide
Scheme 2. Synthesis of Diselenide Catalyst 1a
1h, 1i
1j
1k
1a
1a
7
7
e
14
a
The reactions were carried out using thiol 0.1 mmol and catalyst
(0.01 mmol, 1 mol %) in an open NMR tube for indicated time.
b
c
Determined by 1H NMR spectroscopy. Isolated. ND: not detected.
d
e
Yield at 2 mmol scale. Reaction was carried out under inert
atmosphere.
tested organoselenium compounds were effective for the aerial
oxidation of thiols (entries 3−9, Table 1). To our surprise,
organoditelluride 1j20 also provided only 7% oxidation of thiols
(entry 10, Table 1). Next, aerial oxidation of p-toluenethiol
was studied in the presence of 1k lacking selenium, 2-
aminophenyl diselenide 1b, Schiff base 1c, and 2-hydrox-
yphenyl diselenide 1f lacking one or both functionalities
among phenolic, amino, and selenium. 2-Aminophenyl
diselenide 1b provided 20% oxidation of thiol into disulfide
2a (entry 3, Table 1), and Schiff base 1c lacking NH
functionality and 2-hydroxyphenyl diselenide 1f afforded 35
and 15% of the oxidation product respectively (entries 4 and 7,
Table 1). In the absence of a selenium catalyst, oxidation of p-
toluenethiol could not be realized (entry 11, Table 1). The
radical quencher 1k afforded only 10% conversion of p-
toluenethiol (entry 12, Table 1). The aerial oxidation of thiol
can also be carried out in water and acetonitrile solvent
mixture (entry 13, Table 1). The conversion of thiol into
disulfide 2a was not observed under inert atmosphere, and
only traces of disulfide 2a were observed as expected (Table 1,
entry 14).
1b was obtained in gram quantity by following the reported
procedure16a by careful variation in the stoichiometry of
reagents, providing the diselenide 1b in isolated 70% yield.
Next, the addition of 2-aminophenyl diselenide 1b to o-
salicylaldehyde in toluene in the presence of a catalytic amount
of acetic acid under reflux conditions in a Dean−Stark
apparatus provided the Schiff base 1c17 quantitatively. The
reduction of the CN bond in 1c by an excess of NaBH4
provided the desired diselenide catalyst 1a in 85% yield.
Diselenides 1d, 1e,18a and 1f,18a selenides 1h−1i,18b Spector’s
catalyst 1g,19 and ditelluride 1j,20 used in this study, were
synthesized by following the methods described in the
1
literature. During our H NMR study on the reaction of
diselenide 1a with p-toluenethiol, complete oxidation of p-
toluenethiol into p-toluene disulfide 2a was observed along
with the formation of H2O (entry1, Table 1). Moreover, 1 mol
% of diselenide 1a was sufficient for the oxidation of p-
toluenethiol and led to 96% isolated yield of 2a (entry 2, Table
1). Next, Spector’s catalyst 1g and other diselenides 1b−f,
which act as efficient GPx mimics19 for the reduction of
hydrogen peroxides using thiol substrate, were studied under
the same conditions for the purpose of comparison (entries 3−
8, Table 1). Similarly, monoselenides 1h and 1i, which reduced
the peroxyl radicals21 in a catalytic manner exploiting thiol as a
sacrificial cosubstrate reductant, have been studied under
similar conditions (entry 9, Table 1). Surprisingly, none of the
Next, various organothiols were tested for aerial oxidation in
the presence of 1 mol % of the enzyme mimic 1a. A variety of
aromatic thiols, namely thiophenols containing OH, OMe,
NH2, CH2OH, Cl, Br, F, thionaphthols, heteroaryl thiols 2-
mercaptobenzothiazole, 2-mercaptopyridine, 2-mercaptothio-
phene, and alkyl thiols, were oxidized into respective disulfides
B
DOI: 10.1021/acs.orglett.8b02756
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Scheme 4. 77Se NMR Study on the Reaction of Diselenide
1a with p-Toluenethiol and O2
2b−2y practically (Scheme 3). The biologically relevant thiols
such as homocysteine, cysteine, N-acetylcysteine, and gluta-
a,b
Scheme 3. Aerial Oxidation of Various Organothiols
Next, a solution of diselenide 1a with 2 equiv of p-
toluenethiol in CD3CN was purged with oxygen for 7 h, and
the resulting reaction mixture was studied by 77Se NMR in
which a peak at 747 ppm was observed and seems to
correspond to formation of selone 3c, and additional an
unidentified peak at 818 ppm was also observed (see the
Supporting Information).
Next, an EPR study was carried out on air exposed
diselenide 1a in the solid phase and an oxygen-purged (15
min) solution of 1a (Figure 1). The EPR spectrum shows a
a
The reaction was carried out using 2 mmol of organothiol and 1a
b
(0.02 mmol) in CH3CN (5 mL) at rt. Reaction was conducted in
CH3CN + H2O mixture (1:1). Isolated yields.
thione were studied next in the series. The reaction, realized to
be sluggish in acetonitrile, resulted in the formation of the
impure product. The reaction progressed smoothly in a water/
acetonitrile mixture (1:1), thus providing the corresponding
disulfides 2z−ac in substantial yields.
Figure 1. (a) EPR spectrum of 1a after O2 purged in CH3CN. (b)
Cyclic voltammogram of 1a (2 mM) in CH3CN using SCE, scan rate
10 mV s−1 in TBAPF6.
Next, we showed that the newly synthesized mimic can
reduce hydrogen peroxide oxidant into water by benzenethiol
cosubstrate into benzene disulfide by following the first-order
reaction with a reduction rate of 49.65 3.7 μM·min−1, which
is comparable with the studied GPx mimic phenyl diselenide
signal at 3354 G. The reaction of p-toluenethiol with N-tert-
butyl-α-phenylnitrone (PBN), a radical-trapping reagent,
under similar conditions shows an EPR signal (Figure S13),
which infers that oxidation of p-toluenethiol proceeds via a
radical pathway.
The cyclic voltammogram of 1a shows a redox potential of
+0.44 V (Figure 1b). The observed oxidation potential of 1a is
+0.50 V, and oxygen has a reduction potential Ered (O2/H2O2)
of 0.65 V (vs SCE), which suggests that O2 is strong enough
for the oxidation of 1a by +0.15 V.
DFT calculations were performed to predict the feasible
path for aerial oxidation of thiol by diselenide 1a. Several paths
were considered for diselenide 1a (see the Supporting
Information), and the tentative mechanism of the reaction is
depicted in Scheme 5. Diselenide reacts with 1 equiv of the
thiol to produce selenenyl sulfide 3a and selenol 3b. Selenenyl
sulfide 3a may further react with an additional molecule of
thiol to produce selenol 3b, expectedly.
1d (reduction rate = 24
1.86 μM·min−1) and Spector’s
catalyst 1g (reduction rate = 128.34 13.3 μM·min−1).20
The reaction of diselenide mimic 1a with p-toluenethiol was
monitored by 77Se NMR spectroscopy as 77Se nuclei is NMR
active, sensitive to the electronic environment, and helpful in
establishing the intermediates involved in the reaction. 77Se
NMR of diselenide 1a exhibits a signal at 400 ppm (Scheme
4). The addition of an excess of p-toluenethiol to the catalyst
1a produced a new weak signal at 478 ppm, which corresponds
to the selenenyl sulfide 3a, and the expected signal due to
selenol 3b was not observed presumably due to the oxidation
into diselenide 1a. The generation of selenol 3b was indirectly
established by trapping it with methyl iodide, which results in
the formation of RSeCH3 (δ 109 ppm). Methyl selenide 3ba
has also been isolated (see the Supporting Information).
Attempts to isolate selenenyl sulfide 3a were unsuccessful and
seem to undergo disproportionation diselenide 1a and p-
toluene disulfide 2a (see the Supporting Information).
The oxidation of 3b by O2 would afford selone 3c and
hydrogen peroxide by electron transfer followed by proton
C
DOI: 10.1021/acs.orglett.8b02756
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Organic Letters
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Scheme 5. Mechanism for 1a-Catalyzed Oxidation of Thiol
by Air and Peroxide
Aditya Upadhyay: 0000-0003-4072-062X
Sangit Kumar: 0000-0003-0658-8709
a
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from DST-SERB New
Delhi (EMR/2015/000061). V.R. [23/12/2012(ii)EU-V] and
A.U. acknowledge UGC and IISER Bhopal, respectively, for
fellowships. We thank Professor Deepak Chopra and the
editorial office (proofreading of the manuscript), Miss Evelin
L. Verghese and Mr. Satya R. Jena (CV study), and Mr. Saurav
K. Veedu (isolation of intermediate).
a
Calculated relative Gibb’s free energy (ΔG° in kJ mol−1) obtained at
the DFT-B3LYP(6-311+G(d,p)) level using the CPCM model in
acetonitrile.
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AUTHOR INFORMATION
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Corresponding Author
*E-mail: sangitkumar@iiserb.ac.in.
ORCID
Vandana Rathore: 0000-0001-7815-6513
D
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