C O M M U N I C A T I O N S
Scheme 1. Reaction of 8 with MMI and MSeI
Table 2. Initial Rates (v0) for the Reduction of H2O2 in the
Presence of Selenium Catalystsa
no.
compound
GPxb
MSeIox (5)
Ebselen (6)
7
GPx + MSeIox
ebselen + MSeIox
7 + MSeIox
v0 (µM min-1
)
1
2
3
4
5
6
7
30.55 ( 0.87
81.05 ( 0.40
78.46 ( 0.63
132.70 ( 2.84
106.69 ( 3.97
150.56 ( 3.53
195.52 ( 2.03
readily cleaved by DTT to produce 11. This suggests that, although
MMI and MSeI can form the corresponding selenenyl sulfides and
diselenides with stable selenenyl iodides, the resulting compounds
are not stable under reducing conditions. This is in agreement with
the recent observations that MSeI exhibits very weak inhibition
on ID-1 even at higher concentrations.5c
a Conditions: GSH, 1 mM; EDTA, 1 mM; GSSG reductase, 0.6 unit/
mL; NADPH, 0.2 mM; H2O2, 1 mM; selenium catalysts, 0.025 mM; in 0.1
M potassium phosphate buffer, pH 7.3. b GPx: 5 nM.
In summary, we have shown that the selenium analogues of anti-
thyroid drugs exhibit their anti-thyroid activity by a mechanism
different from that of MMI. The inhibition of TPO by selenium
compounds is mainly due to their ability to act as GPx mimics,
and the insensitivity of ID-1 toward MSeI is due to the inability of
the drug to form a stable -Se-Se- bond. This study suggests that
suitably designed selenium compounds may solve the problems
associated with PTU and MMI, which are irreversible inhibitors
of TPO. Alternatively, the anti-thyroid drugs, together with GPx,
may constitute a defense system against reactive oxygen species
in the thyroid gland.
that some of the anti-thyroid drugs may inhibit the thyroid hormone
biosynthesis by reducing H2O2 (GPx-like activity), because the
oxidation of iron center in TPO by H2O2 is the first step in thyroid
hormone synthesis. Therefore, we focused our attention on the GPx
activity of MSeIox and some related compounds. Interestingly,
MSeIox exhibited high GPx activity, providing a novel mechanism
for its inhibitory action. The activity of MSeIox was found to be
comparable to that of ebselen (6),10 a well-known GPx mimic (Table
2). On the other hand, the sulfur analogue, MMI, did not show
any noticeable activity under identical experimental conditions.
The high GPx activity of 5-7 suggests that the selenium
analogues of the anti-thyroid drugs and other GPx mimics inhibit
the LPO activity by reducing H2O2 and these compounds may also
act as antioxidants and protect cells from oxidative damage. It has
been suggested that an increase in the H2O2 concentration in the
thyroid could damage the gland and be an important factor in the
pathophysiology of myxedematous cretinism.11
Acknowledgment. This study was supported by the Department
of Science and Technology (DST), New Delhi, India.
Supporting Information Available: Experimental procedures
(PDF) and X-ray data for 5 and 7 (CIF). This material is available free
References
We also studied the effect of 3 and 5 on the GPx activity of the
natural enzyme and some GPx mimics because the electrophilic
reactivity of selenium in the selenenic acid (E-SeOH) intermediate
in the GPx cycle is similar to that of the E-SeI intermediate in the
deiodinase cycle. Therefore, the anti-thyroid drugs may interfere
with GPx by reacting with the E-SeOH to form stable -Se-S-
or -Se-Se- bonds. As it can be seen from Table 2, the activities
of GPx, ebselen (6), and compound 7 in the presence of MSeIox
are almost equal to the sum of the initial reduction rates observed
in the individual cases. The sulfur compound, MMI, also did not
inhibit the GPx or the model compounds, suggesting that the anti-
thyroid drugs do not interfere with other selenoenzymes such as
GPx in the thyroid gland.
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agents such as dithiothreitol (DTT). It should be mentioned that
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1). The reactions of selenenyl iodides with selenourea derivatives
have not been studied previously, although the reactivity of
selenenyl iodides toward thiourea drugs has been reported.4b
Reactions of MMI and MSeI with 8 in the presence of NEt3
afforded the selenenyl sulfide (9) and diselenide (10), respectively.
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(6) Crystal data for 5 (C8H10N4Se2): Mr ) 320.12, monoclinic, space group
C2/c, a ) 12.618(7), b ) 7.536(4), c ) 11.418(6) Å, â ) 97.446(9)°, V
) 1076.5(10) Å3, Z ) 4, Fcalcd ) 1.975 Mg/m3, Mo KR radiation (λ )
0.71073 Å), T ) 293(2) K; R1 ) 0.0349, wR2 ) 0.0995 (I > 2σ(I)); R1
) 0.0387, wR2 ) 0.1021 (all data). Crystal data for 7 (C16H20N2O3Se):
Mr ) 367.30, triclinic, space group P, a ) 9.486(6), b ) 9.965(6), c )
10.953(6) Å, R ) 91.403(9); â ) 111.942(8); γ ) 118.051(8)°, V ) 821.8-
(8) Å3, Z ) 2, Fcalcd ) 1.484 Mg/m3, Mo KR radiation (λ ) 0.71073 Å),
T ) 293(2) K; R1 ) 0.0264, wR2 ) 0.0674 (I > 2σ(I)); R1 ) 0.0297,
wR2 ) 0.0693 (all data).
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