An ebselen like catalyst with enhanced GPx activity via a selenol intermediate

Article abstract of DOI:10.1039/c4ob00027g

The reaction of KSeO^tBu with 2-iodo-arylbenzamides gave benzamide ring-substituted, quinine-derived isoselenazolones 1b-1d. The reaction of PhSH with ortho-methyl-substituted isoselenazolone 1b gave selenol 3b, which is oxidized by H₂

Full text of DOI:10.1039/c4ob00027g

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An ebselen like catalyst with enhanced GPx activity
via a selenol intermediate†
Shah Jaimin Balkrishna,a Shailesh Kumar,a Gajendra Kumar Azad,b
Bhagat Singh Bhakuni,a Piyush Panini,a Navjeet Ahalawat,a Raghuvir Singh Tomar,b
Michael R. Dettyc and Sangit Kumar*a
Cite this: Org. Biomol. Chem., 2014,
12, 1215
Received 4th January 2014,
Accepted 8th January 2014
DOI: 10.1039/c4ob00027g
www.rsc.org/obc
The reaction of KSeOtBu with 2-iodo-arylbenzamides gave benz-
amide ring-substituted, quinine-derived isoselenazolones 1b–1d.
The reaction of PhSH with ortho-methyl-substituted isoselenazo-
lone 1b gave selenol 3b, which is oxidized by H2O2 to regenerate
1b. Isoselenazolone 1b shows a high rate (0.33 × 103 µM min−1) of
oxidation of PhSH with H2O2, which is ∼103-fold more active than
ebselen (1a) and ≥30-fold more active than the other isoselenazo-
lones of this study. Compound 1b shows less inhibition of the
growth of yeast cells than 1a.
The selenoenzyme glutathione peroxidase (GPx) is present in
the human body and functions as a catalytic antioxidant for
the reduction of various hydroperoxides using glutathione as
the stoichiometric co-reductant. The reactive site of GPx con-
tains selenocysteine (CySeH), which is responsible for the high
catalytic activity for the reduction of hydroperoxides
(Scheme 1).1 The GPx mimic ebselen (1a) or 2-phenyl-1,2-benz-
isoselenazol-3(2H)-one (PZ 51) is a biologically non-toxic (LD50
= 6.81 g kg−1), well-studied organoselenium compound with
anti-inflammatory and antioxidant therapeutic properties as
well as the potential to treat indications such as bipolar dis-
order.2,3 The diverse remedial properties of 1a are apparently
due to its catalytic ability in reduction of hydroperoxides
together with its low toxicity. Unfortunately, 1a is a relatively
inefficient catalyst for the reduction of hydroperoxides, which
encourages making attempts to synthesize effective GPx-mimics
with improved catalytic activity for the reduction of peroxides
Scheme 1 GPx reaction site and generation of selenol.
while maintaining low toxicity. The poor catalytic reactivity of 1a
is presumably due to the lack of reactivity of selenenylsulfide 2a
to produce selenol 3a when it reacts with an additional mole-
cule of thiol (eqn (1), Scheme 1).4 The generation of a selenol by
the reaction of an organothiol with an organoselenium com-
pound is a challenging task in general and from isoselenazo-
lones in particular.5–7 Several N-substituted isoselenazolones
have been described; however, none appear to form a stable
selenol upon their reaction with organothiols.8–13 Therefore,
these isoselenazolones are limited in their catalytic activity for
the reduction of H2O2 via an ebselen-like pathway.
Isoselenazolones with additional benzamide ring function-
ality have not been studied as GPx mimics presumably due to
difficulties in their synthesis. Here, in continuation of our
work on organochalcogen chemistry,14 we describe the syn-
thesis of isoselenazolones containing a quinine moiety and
the facile generation of selenol 3b by the reaction of isoselena-
zolone 1b with PhSH (eqn (2)). The catalytic activity of various
isoselenazolones as GPx mimics was also studied, with 1b
showing much greater catalytic activity than ebselen (1a).
N-Quininamine-substituted [N-(1S)-(6-methoxyquinolin-4-yl)-
aDepartment of Chemistry, Indian Institute of Science Education and Research
Bhopal (IISER), Indore bypass Road, Bhopal, MP 462 066, India.
E-mail: sangitkumar@iiserb.ac.in
bDepartment of Biological Sciences, Indian Institute of Science Education and
Research Bhopal (IISER), Indore bypass Road, Bhopal, MP 462 066, India
cDepartment of Chemistry, University at Buffalo, The State University of New York,
Buffalo, New York 14260, USA
†Electronic supplementary information (ESI) available: Characterization data,
NMR and mass spectra on 1a–1r and CIF files for 1b, 1c, and 1e, DFT calcu-
lations and geometry optimization on 2b, 2c and 2e, GPx-activities, kinetic
studies, toxicity tests. CCDC numbers 930741, 930742 and 953729 are for 1b, 1c
and 1e respectively. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c4ob00027g
((2S,4S,5R)-5-vinyl-quinuclidin-2-yl)methyl]
isoselenazolones
1b–1d were prepared using KSeOtBu as the source of selenium15
and in higher yields (71% vs. 55% for 1b, 84% vs. 72% for 1c
and 70% vs. 60% for 1d) in comparison to copper-catalyzed
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spectrometry.16 An equimolar mixture of isoselenazolone 1b
and PhSH in CD3OD gave a small peak at −0.2 ppm due to
selenol 3b (Table 1). Surprisingly, formation of the expected
selenenylsulfide 2b was not observed by 77Se NMR. Addition of
a second equiv. of PhSH to the stoichiometric reaction mixture
of 1b and PhSH gave a sharp peak at 4.8 ppm. A freshly pre-
pared solution of 1b and PhSH was monitored by mass spec-
trometry and showed the formation of selenenylsulfide 2b
(m/z 629.1615 + H+) which suggests that the reaction proceeds
via the formation of selenenylsulfide 2b. However, this is a tran-
sient intermediate in the formation of selenol 3b. Selenol 3b is
stable for at least two weeks in solution as 77Se NMR shows a
constant signal at −0.9 ppm. Signals due to the formation of
diselenide 4b or isoselenazolone 1b were not observed.
The 77Se NMR chemical shift of 3b is similar to reported
77Se NMR chemical shifts of N,N-dimethylbenzylamine selenol
(9.9 ppm),6b the aryl-selenol BmtSeH (6 ppm),7a and a
camphor-derived selenol (−49 ppm).9a However, the 77Se NMR
chemical shift of 3b is upfield relative to PhSeH (145 ppm).
Several other isoselenazolones (1a–1c, 1e, and 1n) were
reacted with PhSH and results are summarized in Table 1. Iso-
selenazolone 1c having a quininamine moiety and lacking the
ortho-CH3 substituent forms only selenenylsulfide 2c in the
presence of 1–3 equivalents of PhSH (entries 3 and 4, Table 1).
However, ortho CH3-substituted isoselenazolones 1e gave sele-
nenylsulfides 2e and diselenide 4e when reacted with one and
two equivalents of PhSH. Similarly, 1n gave 2n and 4n with
one equivalent of PhSH (entry 7, Table 1). In contrast, addition
of a second equivalent of PhSH led to complete conversion of
2n into diselenide 4n (entry 8, Table 1).
The formation of diselenides 4e and 4n could occur via
either of two processes: oxidation of the respective selenols 3e
and 3n or disproportionation of selenenylsulfides 2e and 2n.17
Mixtures of isoselenazolones 1b, 1e, or 1n and PhSH
(1 : 2 molar ratios) were reacted with CH3I. Indeed, complete
conversion of in situ generated selenol 3b into the corres-
ponding methylselenide was observed. In contrast, isoselena-
zolones 1e and 1n failed to produce the corresponding
methylselenides under similar conditions. This implies that
the formation of diselenides 4e and 4n occurred by the dispro-
portionation of selenenylsulfides 2e and 2n rather than via the
formation of the corresponding selenols (Scheme 3).
Scheme 2 Synthesis of isoselenazolones.
Se–N bond formation reactions (eqn (3), Scheme 2). The use of
KSeOtBu as a selenium source is more efficient for the syn-
thesis of isoselenazolones bearing polar functionality. In the
copper catalyzed methodology, separation of the copper-1,10-
phenanthroline catalyst from the polar quininamine-derived
isoselenazolones 1b–1d was difficult. Using KSeOtBu as the
source of Se, quininamine-derived isoselenazolones 1b–1d
were obtained in higher yield with fewer side products.
However, the use of KSeOtBu was only applicable to 2-iodo-
and selected 2-bromobenzamides. KSeOtBu was unreactive
with 2-chlorobenzamides as substrates. The isoselenazolones
ebselen (1a) and 1e–1r were prepared by the Cu-catalyzed Se–N
bond forming reaction (eqn (4), Scheme 2).14a,b The isoselena-
zolone structure was confirmed by 77Se NMR (Table 1) and
X-ray structural studies of 1b, 1c and 1e.
The reaction between PhSH and isoselenazolones was
monitored by 77Se NMR spectroscopy and mass
Table 1 Reaction of isoselenazolones with PhSHa
Entry
1 (δ)
[PhSH]
2 (δ)
3 (δ)
4 (δ)
1
1
2
3, 4
5
6
7
8
1a (912)
1b (851)
1b (851)
1c (858)
1e (859)
1e (859)
1n (889)
1n (889)
1
1
2
2
1
2
1
2
2a (591)
2b (—)
2b (—)
2c (589)
2e (496)
2e (496)
2n (454)
2n (—)
3a (—)
3b (−0.2)
3b (4.8)
3c (—)
3e (—)
3e (—)
3n (—)
3n (—)
4b (—)
4b (—)
4b (—)
4c (—)
4e (416)
4e (416)
4n (405)
4n (401)
a Reaction was carried out in CD3OD using 1 equiv. of PhSH with 1.
(—) Not observed.
Scheme 3 Proposed generation of selenol 3b from 1b.
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Fig. 1 Optimized structures of 2b and 2e. Se⋯O 3.811 Å (CvO), Se⋯N
2.825 Å (tert-N quininamine), Se⋯N (NH) in 2b. Se⋯O 2.42 Å (CvO) in
2e. Se⋯O 4.083 Å (CvO), Se⋯N 2.79 Å (tert-N), Se⋯N (NH) in 2c.
Fig. 2 Initial rates of PhSSPh formation in the presence of catalysts 1a,
1b, 1c, 1e and 1n.
DFT calculations on the related selenenylsulfides 2b, 2c, 2e,
2f and 2n were performed to study the nature of Se⋯O/N inter-
actions (Fig. 1) as these interactions appear to be important,
not only in the stabilization of the selenol functionality
(Scheme 1), but also in its formation from the corresponding
selenenylsulfide. Short Se⋯O/N interactions increase electron
density on selenium, which should then favor the nucleophilic
attack of PhS− at sulfur rather than at selenium in the
selenenylsulfide intermediate leading to the selenol and
disulfide.6a,c,9a,18 However, other factors must also be con-
sidered. In selenenylsulfide 2c, intramolecular Se⋯O and
Se⋯N distances are favorable for the generation of selenol
3c,19 but neither 3c nor diselenide 4c is observed.
We next examined the antioxidant properties of isoselena-
zolones 1a–1r for the reduction of H2O2 in the presence of
PhSH as a co-reductant in CH3OH according to eqn (6).
From the data in Table 2 and Fig. 2, isoselenazolone 1b,
which forms selenol 3b, shows a much higher initial rate of
oxidation of PhSH (vo = 331 µM min−1) when compared to
the remainder of the isoselenazolones of this study.20 Isosele-
nazolone 1b is 103-fold more active than ebselen 1a and
30-fold more active than quininamine-based isoselenazolones
1c and 1e. Also, 1b is 475 times more active than the diphenyl
diselenide. We have also evaluated the influence of an external
base triethylamine (0.05 mM) on the GPx activity of 1b and 1c.
However, the external base gave no significant change in cata-
lytic activity of 1b and 1c (entries 5 and 7, Table 2). In other
systems, the introduction of a methoxy group into an aromatic
ring enhances the antioxidant property of catalysts.21 In this
context, we have synthesized a series of methoxy-substituted
isoselenazolones 1d and 1i–1p. However, these catalysts
showed ≤5% of the antioxidant activity of 1b.
Isoselenazolones 1a, 1c, 1d, 1g, 1h, 1p and 1q, which form
only selenenylsulfides with PhSH via 77Se NMR studies, are
poor catalysts for this reaction based on vo, whereas isoselena-
zolones 1e, 1f, and 1i–1o which form diselenides with PhSH
are intermediate in catalytic activity relative to 1b.
To further understand the mechanism of Gpx activity of the
isoselenazolone 1b, the effects of catalyst and H2O2 concen-
trations on vo were examined. Initial values of vo increased lin-
early with respect to catalyst concentration indicating a first-
order dependence of GPx activity on catalyst concentration. As
the concentration of H2O2 increased, values of vo increased,
but became constant with no further increase in vo with
increasing H2O2 concentration. The effect of changing per-
oxide concentration is consistent with the formation of an oxi-
dized intermediate whose subsequent reduction limits the rate
of turnover in the system.
To establish the catalytic cycle, selenol 3b was treated with
one equivalent of H2O2 in CD3OD and the resulting mixture
was examined by 77Se NMR and mass spectrometry. A signal
was observed at 1093 ppm in the 77Se NMR and is attributed
to selenenic acid (R-SeOH) 5b (based on the observed m/z
536.1489) and a second signal at 851 ppm corresponding to
isoselenazolone 1b. The addition of a second equivalent of
PhSH to selenenic acid 5b led to the formation of 1b and 2b.
The catalytic cycle for 3b reacting with PhSH and H2O2 is sum-
marized in Scheme 4.
Table 2 GPx like activity of isoselenazolonesa
Entry
Cat.
vo (µM min−1
)
Entry
Cat.
vo (µM min−1
)
1
2
3
4
5
6
7
8
(PhSe)2
1a
0.7 0.1
0.4 0.02
331 2b
1.6 0.1
332 2b
12
13
14
15
16
17
18
19
20
21
22
1h
1i
1j
1k
1l
1m
1n
1o
1p
1q
1r
13
17
13
17
13
14
1
2
1
1
1
2
1b
Et3Nc
1b + Et3Nc
1c
11
1
1c + Et3Nc
12.2 0.7
4.0 0.2
11.7 0.3
15
1.2 0.3
0.20 0.02
10
1d
1e
1f
1
9
10
11
11
21
2
1
1g
0.40 0.03
3
a The initial rates (vo) for the oxidation of PhSH (1 mM) with H2O2
(3.75 mM) in the presence of a catalyst (0.01 mM) were determined in
CH3OH by monitoring the UV absorption at 305 nm due to the
formation of phenyl disulfide. b vo obtained by a Lineweaver–Burk plot.
c Concentration of Et3N was 0.05 mM.
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stabilizes 3b, which regenerates 1b following reaction with
H2O2. In a comparison of ebselen (1a) and 1b, the growth of
yeast cells in the presence of 1b was comparable to the DMSO
control and was significantly higher than that in the presence
of 1a. Currently, we are investigating the catalytic role of
selenol for various biological activities involving thioredoxin
reductase and deiodinase enzymes in which selenol function-
ality is critical for activity.
Scheme 4 Catalytic cycle for 1b.
Acknowledgements
We are thankful to DAE-BRNS, Mumbai, DST-New Delhi,
DRDO-New Delhi, and IISER Bhopal for funding. SJB, SK, and
BSB thank IISER Bhopal for fellowships. MRD thanks the US
Office of Naval Research (award N0014-09-1-0217) for partial
support of this research.
Fig. 3 Yeast cells growth in the presence of catalysts.
Ebselen (1a) is the most widely studied GPx-mimic in orga-
noselenium chemistry and has demonstrated low toxicity in
biological studies. We compared the effects of 1a and 1b on
the growth of yeast cells to compare relative toxicities.22 The
dose-dependent effect of various concentrations of isoselenazo-
lones on the growth of yeast cells was observed over a 72 h time
period (for more details, please see ESI,† S174–S175).23 Fig. 3a
compares ebselen (1a) with isoselenazolone 1b and shows a
higher growth of cells in the presence of 1b compared to 1a.
These results were validated by growth curve analysis in
liquid culture as shown in Fig. 3b (please see ESI,† S175–S179
for experimental data).24 Yeast cells were treated with an
increasing dose of either 1a or 1b (10, 20 and 30 µM) and
growth was monitored at OD600 nm for 11 h at regular intervals.
It is apparent that the OD600 nm value for 1b (0.85 0.01) is sig-
nificantly higher than that for 1a (0.26 0.01). From growth
curve analysis, doubling time for the growth of yeast cells was
also calculated in the presence of 1a and 1b. It was signifi-
cantly higher for 1a (278 12 min) compared to 1b (124
3 min), further suggesting that 1b inhibits cell growth to a
lesser extent than ebselen (1a).
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Conclusions
In summary, the reaction of isoselenazolones with additional
substituents on the benzamide ring with PhSH has been inves-
tigated. Isoselenazolone 1b bearing an ortho-methyl group on
the benzamide ring and an N-quininamine group gave selenol
3b in the presence of PhSH. The remainder of the isoselenazo-
lones of this study formed either selenenylsulfides or disele-
nides upon reaction with PhSH. We have also shown that short
intramolecular Se⋯N/O interactions are not sufficient for the
generation of selenol from selenenylsulfide. The high GPx-like
activity of isoselenazolone 1b, which forms selenol intermedi-
ate 3b, suggests that the presence of the bulky N-quininamine
substituent and the ortho-CH3 benzamide substituent
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22 Yeast cells serve as an eukaryotic cell model to assess the
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