Interaction of anti-thyroid drugs with iodine: The isolation of two unusual ionic compounds derived from Se-methimazole

Article abstract of DOI:10.1039/b604060h

The inhibition of lactoperoxidase (LPO)-catalyzed iodination of l-tyrosine by the anti-thyroid drug methimazole (MMI) and its selenium analogue (MSeI) is described. MSeI inhibits LPO with an IC₅₀ value of 12.4 M, and this inhibition could be completely reversed by increasing the peroxide concentration. In addition to the inhibition, MSeI reacts with molecular iodine to produce novel ionic diselenides, and the nature of the species formed in this reaction appear to be solvent-dependent. The formation of ionic species in the reaction is confirmed by single-crystal X-ray studies, FT-IR and FT-Raman spectroscopic investigations. This study provides the first experimental evidence that MSeI not only effectively inhibits the LPO-catalyzed iodination of tyrosine, but also reacts with I₂ to produce novel ionic diselenides. These results also suggest that MSeI reacts with iodine, even in its oxidized form, to form ionic diselenides containing iodide or polyiodide anions, which might be effective intermediates in the inhibition of thyroid hormones. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b604060h

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Interaction of anti-thyroid drugs with iodine: the isolation of two unusual ionic
compounds derived from Se-methimazole†
Gouriprasanna Roy, Munirathinam Nethaji and G. Mugesh*
Received 20th March 2006, Accepted 15th June 2006
First published as an Advance Article on the web 30th June 2006
DOI: 10.1039/b604060h
The inhibition of lactoperoxidase (LPO)-catalyzed iodination of L-tyrosine by the anti-thyroid drug
methimazole (MMI) and its selenium analogue (MSeI) is described. MSeI inhibits LPO with an IC50
value of 12.4 lM, and this inhibition could be completely reversed by increasing the peroxide
concentration. In addition to the inhibition, MSeI reacts with molecular iodine to produce novel ionic
diselenides, and the nature of the species formed in this reaction appear to be solvent-dependent. The
formation of ionic species in the reaction is confirmed by single-crystal X-ray studies, FT-IR and
FT-Raman spectroscopic investigations. This study provides the first experimental evidence that MSeI
not only effectively inhibits the LPO-catalyzed iodination of tyrosine, but also reacts with I2 to produce
novel ionic diselenides. These results also suggest that MSeI reacts with iodine, even in its oxidized
form, to form ionic diselenides containing iodide or polyiodide anions, which might be effective
intermediates in the inhibition of thyroid hormones.
Introduction
The molecular interactions of anti-thyroid drugs (1 and 3,
Scheme 1) with iodine have been subjected to many investigations
because these drugs inhibit thyroid hormone synthesis by forming
donor–acceptor complexes with iodine1 or by interacting with
an active iodine species of thyroid peroxidase (TPO), a heme
enzyme, which catalyzes the iodination of tyrosine residues of
thyroglobulin.2 In addition, 6-n-propyl-2-thiouracil (PTU, 1) can
also inhibit the deiodination reactions catalyzed by type I iodothy-
ronine deiodinase (ID-I).3 Recently, the selenium analogues of
anti-thyroid drugs 2 (PSeU) and 4 (MSeI) attracted considerable
attention4 because these compounds may inhibit thyroid hormone
synthesis by a mechanism different from that of the sulfur
analogues.5 Recent experimental and theoretical studies suggest
that the selenium compound 4 does not exist as a true selone or
selenol, but it exists in a zwitterionic form.5b Interestingly, this
compound, in contrast to the sulfur analogue, is found to be
unstable under aerobic conditions and is readily oxidized to the
diselenide 5.5 Therefore, the effect of the selenium compounds on
the iodination of tyrosine and the identification of the products
formed in the reactions of these compounds with iodine are crucial
in understanding the mechanism of action of these drugs in vivo.
In this paper, we describe the inhibition of lactoperoxidase (LPO)-
catalyzed iodination of L-tyrosine by 3 and 4, and the isolation
of two novel cationic species from the reaction of 4 and 5 with
molecular iodine.
Scheme 1 Chemical structures of some anti-thyroid drugs and their iodine
complexes.
Results and discussion
The enzyme inhibition experiments were carried out with Fe-
containing lactoperoxidase (LPO), since it is readily available
in purified form. Furthermore, LPO has been shown to behave
very similarly to TPO with respect to iodination of thyroglobulin,
the natural substrate, and other iodide acceptors. Therefore, the
iodination of tyrosine was studied by using an LPO/H2O2/I−
assay, and the initial rates for the conversion of L-tyrosine to 3-
iodo-L-tyrosine (Scheme 2) were determined by an HPLC method.
As the formation of 3,5-diiodo-L-tyrosine was also observed in the
reaction, only the initial 5–10% of the conversion was followed, for
which only a trace amount of the diiodo compound was produced.
The decrease in the concentration of L-tyrosine was followed by
measuring the peak area at 277 nm, and the amount of tyrosine
present in the solution at a given time was calculated from the
calibration plot obtained by injecting known concentrations of
L-tyrosine. The effect of compound 4 on the iodination reaction
Department of Inorganic & Physical Chemistry, Indian Institute of Science,
Bangalore, 560 012, India. E-mail: mugesh@ipc.iisc.ernet.in; Fax: +91-80-
2360 1552/2360 0683
† Electronic supplementary information (ESI) available: Details of theo-
retical calculations, UV-Vis spectra of 5 with iodine, and far-IR spectra for
compounds 5–7. See DOI: 10.1039/b604060h
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(ABTS), this suggests that the selenium analogue may inhibit the
LPO by a different mechanism. The diselenide 5, on the other
hand, did not show any significant inhibition under identical
conditions. Although weak inhibition of LPO by 5 was observed
during the initial period of the reaction, a reliable IC50 value could
not be obtained.
To understand the effect of the peroxide substrate on the
reaction rate and the inhibition, the LPO activity was determined
at various concentrations of hydrogen peroxide. In addition, the
effect of peroxide on the inhibition of LPO-catalyzed iodination
by anti-thyroid drugs 3 and 4 was evaluated by carrying out the
experiments at various concentrations of H2O2. The initial rates
(v0) derived from various concentrations of H2O2 were plotted
against the concentration of H2O2. Although the LPO activity
was inhibited by 4 at lower concentrations of H2O2, the enzyme’s
activity could be completely recovered by increasing the H2O2
concentration (Fig. 3). These results suggest that the concentration
of H2O2 has a dramatic effect on the inhibition of iodination
reaction by compound 4 (Fig. 1).
Scheme 2 Iodination of L-tyrosine by the LPO/peroxide/iodide system.
was determined at various concentrations of 4 under identical
experimental conditions (Fig. 1).
Fig. 1 Decrease in the amount of tyrosine with time: (a) control; (b) 6 lM
of 4; (c) 9 lM of 4; (d) 12 lM of 4; (d) 15 lM of 4 and (e) 20 lM of 4.
The IC50 values for the inhibition of LPO-catalyzed iodination
of L-tyrosine by the test compounds were also determined by
following the same procedure. The initial rates for the iodination
reaction were determined at various concentrations of inhibitors.
The inhibition curves obtained by plotting the percentage control
activity against the concentration of inhibitors are shown in Fig. 2.
As expected, MMI exhibited a strong inhibition, with an IC50 value
of 5.2 lM, which is comparable with the IC50 value obtained for
the LPO-catalyzed oxidation reaction.5 The selenium analogue (4)
also showed a strong inhibition, with an IC50 value of 12.4 lM,
which is consistent with the effect of this compound on peroxidase-
catalyzed oxidation reactions.5 Similarly to the LPO-catalyzed
oxidation of 2,2ꢀ-azino-bis(3-ethylbenzathiazoline sulfonic acid)
Fig. 3 Effect of H2O2 on the inhibition of LPO by 4: (a) 0 lM; (b) 20 lM;
(c) 30 lM; (d) 40 lM.
Because the oxidation of MMI to the corresponding disulfide
by TPO/H2O2/I− system is associated with the reaction of MMI
with I2,6 we have investigated the interaction of 4 and 5 with iodine.
It has been reported that I2 chemically oxidizes MMI to produce
ionic disulfides that exist in two different protonated forms.6a It
is not known whether the selenium analogue of MMI, in its
reduced form, also undergoes such oxidation by I2 to produce ionic
species. Therefore, we carried out the experiments with the reduced
species (4), which exists in its zwitterionic form.5b The reaction of
4 with I2 in CH2Cl2 produced red-brown crystals. Interestingly,
the X-ray crystal structure shows the formation of compound 6,
−
which consists of a monocation containing a diselenide and I3
as counterion (Fig. 4). This is in contrast to the reaction of MMI
with I2 in CH2Cl2, which afforded a disulfide-containing dication
−
and I8 as counterions.
The formation of 6 is interesting from a chemical point of
view, as only one of the imidazole rings undergoes oxidation.
It should be mentioned that the N-methylation on MMI has
been shown to abolish its TPO inhibitory activity.7 Freeman
et al. have shown that the reaction of the N-methylated derivative
(1,3-dimethylimidazole-2-thione) with I2 does not produce any
disulfide, but that it produces a 1 : 1 thione–I2 charge-transfer
Fig. 2 Inhibition of LPO-catalyzed iodination of tyrosine by MMI (3)
and MSeI (4).
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Fig. 5 FT-Raman spectra of (a) compound 6, (b) compound 5, and (c)
compound 7.
Fig. 4 ORTEP diagram of compound 6 (with 50% probability ellipsoids),
showing two monocations stabilized by triiodide anions.
The single-crystal X-ray studies confirm the proposed structure
adduct.8 The N-methylated derivative of 4 (1,3-dimethylimidazole-
2-selone), on the other hand, produces a hypervalent “T-shaped”
compound containing an I–Se–I moiety.9 Therefore, the existence
of 4 in its selenolate (zwitterionic) form is probably responsible for
its different reactivity toward iodine. Stable open-chain cationic
diselenide species are very uncommon in the literature, and to the
best of our knowledge no structural information is available for
complexes derived from the reactions of selenium analogues of
anti-thyroid drugs with iodine.
The chemical oxidation of 4 by I2 suggests that compound 5,
which exists in the oxidized form of 4, may not produce any ionic
species. To test this, compound 5 was treated with I2 in a 1 : 2
molar ratio in CH2Cl2. This reaction yielded a brown solution;
from which dark brown crystals were obtained on standing
at room temperature. Surprisingly, the X-ray crystal structure
shows the formation of a monocationic species, which is identical
with that obtained from the reaction of 4 with I2 (Fig. 4). The
formation of a cationic species in this reaction is quite unexpected,
because the reactions of iodine with diselenides generally produce
selenenyl iodide species or charge-transfer complexes consisting
of diselenide–molecular iodine adducts.10 However, the biological
significance of the reaction between 5 and molecular iodine is still
not clear, as compound 5 does not show any significant effect on
the LPO-catalyzed iodination reaction.
of 6 (Fig. 4), which consists of two independent diselenide
˚
˚
monocations (Se–Se: 2.382 A; 2.364 A). These diselenide cations
interact with their symmetry equivalents through N–H · · · N
hydrogen bonds to form dimeric units with an overall charge of
+2 (Fig. S3, ESI†). The charge balance in the crystals is achieved
−
by the presence of two I3 anions. The two C–Se bond lengths in
˚
each subunit are almost equal (C–Se: 1.886–1.890 A), although
only one of the five-membered rings in each subunit is protonated.
However, the I–I bond lengths observed differ significantly from
˚
the corresponding I–I bond length of I2 in the solid state (2.715 A).
The two I–I bond lengths of the I3− species in complex 6 range from
2.888 A to 2.925 A, indicating a slight distortion of the I3− moiety.
This distortion is probably responsible for additional bands in the
FT-Raman spectrum of the complex (vide supra).
˚
˚
In the reaction between 5 and I2 in dichloromethane, the
concentrations of I2 do not appear to change the nature of
products. During our attempts to oxidize the second ring using
various concentrations of I2 up to an excess, only the monocation
was obtained as a stable product. However, the choice of solvent
has been found to have a large influence on the nature of products
formed. The reaction of 5 with I2 in a 1 : 2 molar ratio in water
produced a mixture containing both monocation (6) and dication
(7) as confirmed by single-crystal X-ray studies (Fig. 6). In contrast
to the monocation, the charge balance in a crystal of the dication
is achieved by two I− anions. In compound 7, the average C–Se
The far-IR spectrum of complex 6 shows a distinct band
at 135 cm−1 for the m(I–I) stretching vibration mode (Fig. S1,
ESI†). This is in agreement with the fact that I2 gives a strong
band at 180 cm−1 in the solid state, which shifts to lower
wavenumbers upon coordination to a donor atom, reflecting a
reduction in the I–I bond order.1b The FT-Raman spectrum of the
complex in the m(I–I) region shows intense peaks at 164, 143, and
110 cm−1. In addition, a weak band is observed around 67 cm−1
(Fig. 5). The band at 110 cm−1 can be certainly assigned to the
m1 symmetric stretching of I3−, which being a symmetrical ion
normally exhibits only one Raman-active band. However, when a
distortion of I3− occurs, the antisymmetric stretching may become
Raman-active, and additional bands at higher (140–130 cm−1)
and at lower frequencies (80–70 cm−1) may be observed.1b,11
Therefore, the relatively weak bands at 143 cm−1 and 67 cm−1 can
be attributed to the antisymmetric stretching and deformation
˚
bond length of 1.895 A is comparable with that of the diselenide
5b
˚
5 (1.880 A), but this is significantly longer than the average C–
˚
Se bond length (1.848 A) found in compound 4, which exists in
a zwitterionic form.12 The FT-Raman spectrum of compound 7
Fig. 6 ORTEP diagram of compound 7 (with 50% probability ellipsoids),
showing a dication stabilized by two iodide ions.
−
motions (respectively) of the I3 ion (Fig. 5a).
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shows no peaks in the region of lower wavenumbers (Fig. 5c),
indicating the absence of any triiodide or polyiodide species in the
crystals.
was used to measure the electronic absorption spectra. 13C (100.5
MHz) and 1H (400 MHz) NMR spectra were recorded on Bruker
Avance 400 (400 MHz NMR) spectrometers. Elemental analyses
were performed on a ThermoFinigan FLASH EA 1112 CHNS
analyser.
To understand further the nature of the interaction between the
diselenide and iodine, we carried out density functional theory
(DFT) calculations on compounds 6 and 7.13–15 The bond lengths
and angles are in good agreement with the experimental data.13
The Kohn–Sham HOMO and LUMO calculations14–17 show that
the energy gap between the HOMO and LUMO in 7 is much
higher than that of 6 (Fig. 7), indicating that the dication is more
stable than the monocation. However, these results cannot be
correlated directly with our experimental observations because
the formation of the monocation and/or dication appears to be
highly solvent-dependent. The free energy calculations (Table S5,
ESI†) for the formation of complexes 6 and 7 in the gas phase and
in water suggest that the solvent effect is more predominant for
the monocation 6 than for the dication 7.
Synthesis of 3-methyl-2-((1-methyl-1H-imidazol-2-yl)diselanyl)-
1H-imidazol-3-ium triiodide (6). To a solution of 5 (1.00 g, 3.12
mmol) in CH2Cl2 (30 mL) was added a solution of I2 (1.58 g, 6.25
◦
mmol) in CH2Cl2 (70 mL) dropwise under nitrogen at 0 C. The
red-brown solution was stirred at room temperature for 3 h. The
resulting solution was concentrated to give a red-brown solid
product in quantitative yield. The product was recrystallized from
CH2Cl2 to give black crystals. Yield: 98%, mp 146–148 ◦C, IR
(KBr) (cm−1): 3440vs, 3103m, 2922s, 2848w, 1618w, 1456s, 1404w,
1
1308w, 1267s, 1122s, 1018w, 945w, 762vs, 681s, 669s. H NMR
(400 MHz, CDCl3): d 7.39 (s, 2H), 7.24 (s, 2H), 3.91 (s, 6H).
13C NMR (100.5 MHz, CDCl3): d 30.3, 35.5, 124.1, 127.5, 133.6,
161.67. Anal. Calcd for C8H11N4Se2I3: C, 13.69; H, 1.58; N 7.98.
Found: C, 13.96; H, 1.82; N, 8.04.
Synthesis of 2,2ꢀ-diselandiylbis(3-methyl-1H-imidazol-3-ium)
iodide (7). To a solution of 5 (1.00 g, 3.12 mmol) in H2O (100 mL)
was added solid I2 (1.58 g, 6.25 mmol) in H2O (70 mL) dropwise.
The red brown solution was stirred at room temperature for 3 h.
After filtration, the black filtrate was separated and concentrated.
The compound was recrystallized in CH2Cl2. Yield 1.6 g (88%),
mp 193–195 ◦C, IR (KBr) (cm−1): 3418w, 3148m, 3101vs, 3057vs,
3026vs, 2963s, 2822m, 2730w, 2686w, 2520w, 1726w, 1638w, 1568s,
1479vs, 1361m, 1294vs, 1149s, 1104m, 1023w, 919m, 863.91w,
1
771vs, 759s, 675s, 630vs. H NMR (400 MHz, CDCl3): d 7.39
(s, 2H), 7.24 (s, 2H), 3.91 (s, 6H). Anal. Calcd for C8H12N4Se2I2:
C, 16.68; H, 2.10; N 9.73. Found: C, 17.02; H, 2.64; N, 10.01.
Fig. 7 Kohn–Sham HOMO–LUMO diagrams of monocation 6 (a and
b) and dication 7 (c and d).
X-Ray Crystallography
Conclusions
X-Ray crystallographic studies were carried out on a Bruker CCD
diffractometer with graphite-monochromatized Mo-Ka radiation
In summary, the first experimental evidence reported here suggests
that the selenium analogue of MMI not only effectively inhibits
the LPO-catalyzed iodination of tyrosine, but also reacts with I2 to
produce novel ionic diselenides. The inhibition of LPO by 4 could
be completely reversed by increasing the H2O2 concentration This
study reveals that MSeI reacts with iodine, even in its oxidized
form, to form ionic diselenides containing iodide or polyiodide
anions, which might be effective intermediates in the inhibition of
thyroid hormones.
˚
(k = 0.71073 A) controlled by a Pentium-based PC running on
the SMART software package. (SMART, version 5.05; Bruker
AXS: Madison, WI, 1998). Single crystals were mounted at room
temperature on the ends of glass fibers, and data were collected at
room temperature. The structures were solved by direct methods
and refined using the SHELXTL software package.18 In general,
all non-hydrogen atoms were refined anisotropically. Hydrogen
atoms were assigned idealized locations. Empirical absorption
corrections were applied to all structures using SADABS.19,20
Experimental
Crystal data for 6. C8H11N4Se2I3, Mr = 701.8, monoclinic,
space group P21/n, a = 15.484(6), b = 12.017(5), c = 19.604(8)
General
3
A, b = 105.509(6); V = 3515(2) A , Z = 8, qcalcd = 2.65 Mg m−3,
˚
˚
˚
All reactions were carried out under a N2 atmosphere using
Schlenk techniques. Melting points were determined in open tubes
on a Buchi melting point B-540 apparatus and are uncorrected.
Infrared spectra were obtained as KBr discs with a JASCO FT/IR-
410 spectrometer in the 4000–400 cm−1 region and with a Perkin–
Elmer spectrometer GX (FT-IR system) in the 400–50 cm−1
region. A Perkin–Elmer Lambda 5 UV/Vis spectrophotometer
Mo-Ka radiation (k = 0.71073 A), T = 293(2) K, GOF = 1.019,
R1 = 0.036, wR2 = 0.085 (I > 2r(I)); R1 = 0.049, wR2 = 0.093
(all data). The structure was solved by a direct method (SIR-92)18
and refined by a full-matrix least-squares procedure on F2 for all
reflections (SHELXL-97).19,20 CCDC reference number 256230.
For crystallographic data in CIF or other electronic format see
DOI: 10.1039/b604060h.
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Crystal data for 7. C8H12N4Se2I2, Mr = 575.9, triclinic, space
(b) C. D. Antoniadis, S. K. Hadjikakou, N. Hadjiliadis, M. Kubicki
and I. S. Butler, Eur. J. Inorg. Chem., 2004, 4324–4329 and references
therein; (c) M. C. Aragoni, M. Arca, F. Demartin, F. A. Devillanova,
A. Garau, F. Isaia, V. Lippolis and G. Verani, Dalton Trans., 2005,
2252–2258.
2 D. S. Cooper, Lancet, 2003, 362, 459–468; D. S. Cooper,
N. Engl. J. Med., 2005, 352, 905–917 and references therein.
3 (a) M. J. Berry, L. Banu and P. R. Larsen, Nature, 1991, 349, 438–440;
(b) M. J. Berry, J. D. Kieffer, J. W. Harney and P. R. Larsen, J. Biol.
Chem., 1991, 266, 14155–14158; (c) J. Ko¨hrle, Methods Enzymol., 2002,
347, 125–167; J. Ko¨hrle, Thyroid, 2005, 15, 841–843.
4 (a) T. J. Visser, E. Kaptein and H. Y. Aboul-Enein, Biochem. Biophys.
Res. Commun., 1992, 189, 1362–1367; (b) A. Taurog, M. L. Dorris, L. J.
Guziec and F. S. Guziec, Jr., Biochem. Pharmacol., 1994, 48, 1447–1453;
(c) A. Taurog, M. L. Dorris, W.-X. Hu and F. S. Guziec, Jr., Biochem.
Pharmacol., 1995, 49, 701–709.
¯
˚
group P1, a = 6.6979(1), b = 10.3741(2), c = 12.158(3) A, a
◦
3
˚
= 68.916(3); b = 82.135(3); c = 78.816(3) , V = 771.16(1) A ,
Z = 2, qcalcd = 2.48 Mg m−3, Mo-Ka radiation (k = 0.71073
˚
A), T = 293(2) K, GOF = 1.03; R1 = 0.023, wR2 = 0.056
(I > 2r(I)); R1 = 0.026, wR2 = 0.058 (all data). The structure was
solved by a direct method (SIR-92)18 and refined by a full-matrix
least-squares procedure on F2 for all reflections (SHELXL-97).19,20
CCDC reference number 293611. For crystallographic data in CIF
or other electronic format see DOI: 10.1039/b604060h.
Lactoperoxidase (LPO)-catalyzed iodination of L-tyrosine
Inhibition of LPO-catalyzed iodination of L-tyrosine. This
procedure, using various concentrations of MSeI (4) was carried
out by an HPLC method. The incubation mixtures for the HPLC
analysis contained KI (1 × 10−3 M), L-tyrosine (1 × 10−3 M),
hydrogen peroxide (1 × 10−3 M) and LPO enzyme (1 lg) in
0.05 M phosphate buffer, pH 7.4. The mixture was incubated at
room temperature and aliquots (10 lL) injected onto the HPLC
column and eluted with a gradient solvent system (0.1% TFA in
water–MeCN). The decrease in the amount of tyrosine (lg) was
calculated from the calibration plot. The chromatograms were
extracted at 277 nm.
5 (a) G. Roy, M. Nethaji and G. Mugesh, J. Am. Chem. Soc., 2004, 126,
2712–2713; (b) G. Roy and G. Mugesh, J. Am. Chem. Soc., 2005, 127,
15207–15217.
6 (a) M. C. Aragoni, M. Arca, F. Demartin, F. A. Devillanova, A. Garau,
F. Isaia, V. Lippolis, V and G. Verani, J. Am. Chem. Soc., 2002, 124,
4538–4539; (b) C. D. Antoniadis, G. J. Corban, S. K. Hadjikakou,
N. Hadjiliadis, M. Kubicki, S. Warner and I. S. Butler, Eur. J. Inorg.
Chem., 2003, 1635–1640; (c) V. Daga, S. K. Hadjikakou, N. Hadjiliadis,
M. Kubicki, J. H. Z. dos Santos and I. S. Butler, Eur. J. Inorg. Chem.,
2002, 1718–1728; (d) G. J. Corban, S. K. Hadjikakou, N. Hadjiliadis, M.
Kubicki, E. R. T. Tiekink, I. S. Butler, E. Drougas and A. M. Kosmas,
Inorg. Chem., 2005, 44, 8617–8627.
7 T. J. Visser, E. Van Overmeeren, D. Fekkes, R. Docter and G.
Hennemann, FEBS Lett., 1979, 103, 314–318.
8 F. Freeman, J. W. Ziller, H. N. Po and M. C. Keindl, J. Am. Chem. Soc.,
1988, 110, 2586–2591.
The effect of hydrogen peroxide concentration on the inhibition
(Fig. 3). In this HPLC assay, the incubation mixtures contained
KI (1 × 10−4 M), L-tyrosine (9 × 10−4 M) and LPO enzyme (1.5 lg)
in 0.05 M phosphate buffer, pH 7.4. The mixtures were incubated
at room temperature and aliquots (10 lL) were injected onto the
HPLC column and eluted with a gradient solvent system (0.1%
TFA in water–MeCN). The formation of the monoiodotyrosine
was followed at 295 nm.
9 M. C. Aragoni, M. Arca, A. J. Blake, F. A. Devillanova, W.-W. du
Mont, A. Garau, F. Isaia, V. Lippolis, G. Verani and C. Wilson, Angew.
Chem., Int. Ed., 2001, 40, 4229–4232 and references therein.
10 W.-W. du Mont, A. Martens von Salzen, F. Ruthe, E. Seppa¨la¨, G.
Mugesh, F. A. Devillanova, V. Lippolis and N. Kuhn, J. Organomet.
Chem., 2001, 623, 14–28 and references therein.
11 P. Deplano, J. R. Ferraro, M. L. Mercuri and E. F. Trogu, Coord. Chem.
Rev., 1999, 188, 71–95 and references therein.
12 The X-ray crystal structure of 4 suggests that the compound does not
have a true selone moiety, but that it exists in a zwitterionic form in
which the selenium carries a negative charge and one of the nitrogen
atoms in the five-membered ring is protonated. The average C–Se bond
Theoretical calculations
All calculations were performed using the Gaussian98 suite of
quantum chemical programs.13 The hybrid Becke 3–Lee–Yang–
Parr (B3LYP) exchange correlation functional was applied for
DFT calculations.14 Geometries were fully optimized at the B3LYP
level of theory using 6-31G(d) basis sets. All stationary points were
characterized as minima by the corresponding Hessian indices.
The HOMO calculations were done at the B3LYP/6-31G(d)
level. The solvent effect was included in the calculations at the
same level using Tomasi’s polarizable continuum model (PCM) in
aqueous solution.15 All structures were characterized as potential
energy minima at the B3LYP level by verifying that all vibrational
frequencies were real.
˚
˚
length of 1.848 A is shorter than a C–Se single bond (1.94 A), but
˚
significantly longer than a C–Se double bond (1.74 A). This indicates
that the C–Se bond in compound 4 has only partial double bond
character. G. Roy, D. Das and G. Mugesh, Inorg. Chim. Acta, submitted.
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We thank Prof. T. N. Guru Row for helpful discussions. This study
was supported by the Department of Science and Technology
(DST), and the Council of Scientific and Industrial Research
(CSIR), New Delhi, India. GR acknowledges the CSIR for a
research fellowship.
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