Regioselective deiodination of iodothyronamines, endogenous thyroid hormone derivatives, by deiodinase mimics

Article abstract of DOI:10.1002/chem.201403248

Iodothyronine deiodinases (IDs) are mammalian selenoenzymes that play an important role in the activation and inactivation￡ of thyroid hormones. It is known that iodothyronamines (TnAMs), produced by the decarboxylation of thyroid hormones, act as substrates for deiodinases. To understand whether decarboxylation alters the rate and/or regioselectivity of deiodination by using synthetic deiodinase mimics, we studied the deiodination of different iodothyronamines. The triiodo derivative 3,3,5-triiodothyronamine (T3 AM) is deiodinated at the inner ring by naphthyl-based deiodinase mimics, which is similar to the deiodination of 3,3,5-triiodothyronine (T3). However, T3 AM undergoes much slower deiodination than T3. Detailed experimental and theoretical investigations suggest that T3 AM forms a weaker halogen bond with selenium donors than T3. Kinetic studies and single-crystal X-ray structures of T3 and T3 AM reveal that intermolecular I...I interactions may play an important role in deiodination. The formation of hydrogen- and halogen-bonding assemblies, which leads to the formation of a dimeric species of T3 in solution, facilitates the interactions between the selenium and iodine atoms. In contrast, T3 AM, which does not have I...I interactions, undergoes much slower deiodination.

Full text of DOI:10.1002/chem.201403248

DOI: 10.1002/chem.201403248
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Enzyme Models
Regioselective Deiodination of Iodothyronamines, Endogenous
Thyroid Hormone Derivatives, by Deiodinase Mimics
Santanu Mondal and Govindasamy Mugesh*[a]
Abstract: Iodothyronine deiodinases (IDs) are mammalian
selenoenzymes that play an important role in the activation
and inactivation£ of thyroid hormones. It is known that io-
dothyronamines (TnAMs), produced by the decarboxylation
of thyroid hormones, act as substrates for deiodinases. To
understand whether decarboxylation alters the rate and/or
regioselectivity of deiodination by using synthetic deiodi-
nase mimics, we studied the deiodination of different iodo-
thyronamines. The triiodo derivative 3,3’,5-triiodothyron-
amine (T3AM) is deiodinated at the inner ring by naphthyl-
based deiodinase mimics, which is similar to the deiodina-
tion of 3,3’,5-triiodothyronine (T3). However, T3AM under-
goes much slower deiodination than T3. Detailed experi-
mental and theoretical investigations suggest that T3AM
forms a weaker halogen bond with selenium donors than
T3. Kinetic studies and single-crystal X-ray structures of T3
and T3AM reveal that intermolecular I···I interactions may
play an important role in deiodination. The formation of hy-
drogen- and halogen-bonding assemblies, which leads to
the formation of a dimeric species of T3 in solution, facili-
tates the interactions between the selenium and iodine
atoms. In contrast, T3AM, which does not have I···I interac-
tions, undergoes much slower deiodination.
Introduction
Iodothyronine deiodinases (IDs) are mammalian selenoen-
zymes that play an important role in the maintenance of the
thyroid-hormone level in the body by employing various acti-
vation and deactivation pathways.[1] Type-1 and -2 deiodinases
(ID-1 and ID-2) catalyse the conversion of the prohormone l-
thyroxine (T4) into biologically active 3,5,3’-triiodothyronine
(T3) by means of phenolic ring (5’) deiodination. ID-1 and type-
3 deiodinase (ID-3) can convert T4 into the biologically inactive
hormone 3,3’,5’-triodothyronine (rT3) by tyrosylring (5) deiodi-
nation. ID-1 ID-2, and ID-3 also further catalyse the deiodina-
tion of T3 or rT3 to 3,3’-diiodothyronine (3,3’-T2; Scheme 1).[2,3]
In addition to deiodination, the thyroid hormones also under-
go decarboxylation to produce the corresponding iodothyron-
amines (TnAMs).
Scheme 1. Deiodination of thyroid hormones (THs) and iodothyronamines
(TnAMs) by IDs.
Recent studies have shown that TnAMs act as endogenous
signalling molecules, although the exact physiological role of
these compounds has not been identified. 3-Iodothyronamine
(3-T1AM) and thyronamine (T0AM) have been detected in the
plasma of various organisms.[4a] When injected into mice, 3-
T1AM induces a decrease in the body temperature (hypother-
mia) and cardiac output (bradycardia) in pharmacological dose-
s.[4a,b] Interestingly, only the metabolites 3-T1AM and T0AM
have been detected in plasma, thus indicating that TnAMs,
with more iodine atoms, may be deiodinated by IDs. Recently,
TnAMs have been identified as substrates of all three types of
ID.[5] It should be noted that T4AM and T3AM do not undergo
5’-deiodination by ID-1, and the reason for the inability of ID-
1 to catalyse phenolic-ring deiodination of these two metabo-
lites is still unknown.
Recently, we showed that naphthyl-based compound 1, with
a thiol and selenol pair, selectively removes iodine atoms from
the tyrosyl ring of T4 and T3 to produce rT3 and 3,3’-T2, re-
spectively, under physiologically relevant conditions.[6] Replace-
ment of the selenol group in 1 by a thiol group (i.e., 2) results
in a decrease in the deiodination activity. On the other hand,
[a] S. Mondal, Prof. Dr. G. Mugesh
Department of Inorganic and Physical Chemistry
Indian Institute of Science, Bangalore 560012 (India)
E-mail: mugesh@ipc.iisc.ernet.in
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201403248.
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which is in agreement with our earlier reports that rT3 and
3,3’-T2 do not undergo deiodination by 3 under identical ex-
perimental conditions.
The deiodination of T4 by a naphthyl-based diselenol has
been explained on the basis of co-operative action of halogen
bonding (between one of the selenol groups and iodine atom)
and chalcogen bonding (between two selenol groups).[9] As
T3AM has three surface-exposed iodine atoms, the selenol
group can form halogen bonding with any of the iodine
atoms. However, 3 selectively removes one iodine atom from
the inner ring of T3AM to produce 3,3’-T2AM. Due to aniso-
tropic-charge distribution, halogen atoms contain a significant
amount of positive potential (s-hole) surrounded by a belt of
negative potential.[10] The s-hole in an iodine atom is responsi-
ble for the formation of a halogen bond with electron donors.
To understand the regioselectivity of deiodination, we carried
out DFT calculations. Geometries were optimised by using the
B3LYP level of theory and 6-31+G* basis sets for all the atoms,
except iodine for which the 6-311G** basis set was used.
Interestingly, natural-bond orbital (NBO) analysis shows that
the natural charges on the two inner-ring iodine atoms of
T3AM are different (0.199 and 0.203 a.u.), and these charges
are significantly different from that of the outer-ring iodine
atom (0.190 a.u.). Therefore, the s-hole in the inner-ring iodine
atoms can be considered to be more electropositive than the
outer-ring iodine atom. To understand the ability of these
iodine atoms to form halogen bonds, we used the methyl sele-
nolate (MeSeꢀ) ion as an electron donor. As expected, the
MeSeꢀ ions form halogen bonds with both inner- and outer-
ring iodine atoms, which is similar to the formation of halogen
bonds between halogen atoms and various other electron
donors, as reported earlier.[10,11] Although the C-I-Se bond
angle is approximately 1808, the C-Se-I bond angle is approxi-
mately 908 (Figure 3). A comparison of the Se···I distances ob-
tained for the outer- and inner-ring iodine atoms indicates that
the inner-ring iodine atoms form much stronger halogen
bonds with the MeSeꢀ ion than the outer-ring iodine atom, al-
though both distances are shorter than the sum of the van der
Waals radii of the iodine and selenium atoms (3.88 ꢁ). As
Figure 1. Chemical structures of functional mimics of ID-3.
replacement of the thiol moiety by a selenol group (i.e., 3;
Figure 1) leads to an increase in the deiodination activity, with-
out any change in regioselectivity.[7] As mentioned earlier, the
carboxyl group in the b-alanine side chain of T4 affects the de-
iodination of T4AM by ID-1 significantly. Deiodination of iodo-
thyronamines was carried out by ID-3 mimics to understand
the effect of the carboxyl group on deiodination. Interestingly,
the presence of a carboxyl group facilitates the deiodination of
T3 by forming a dimer through hydrogen bonding and weak
I···I halogen bonding.
Results and Discussion
T4AM, T3AM, rT3AM, and 3,3’-T2AM were synthesised by fol-
lowing the procedure of Scanlan and co-workers with minor
modifications.[8] The deiodination of thyroid hormones and io-
dothyronamines by means of deiodinase mimics in the pres-
ence of dithiothreitol (DTT) was monitored by HPLC. The
amount of deiodinated compounds produced in these reac-
tions was quantified by comparing the peak area with that of
standard samples. Due to the low solubility of iodothyron-
amines in phosphate buffer (100 mm, pH 7.00), 20% (v/v) ace-
tonitrile was added to the phosphate buffer. Under these assay
conditions, T4 readily underwent selective deiodination of the
tyrosyl ring in 5 by 3 to produce rT3. However, when T4AM
was used as a substrate for deiodination, no deiodinated prod-
uct could be detected probably due to the low solubility of
T4AM in the assay mixture (Figure 2a). As reported earlier, the
deiodination of T3 by 3 produced 3,3’-T2 as the only deiodi-
nated product.[7] Under similar experimental conditions, T3AM
was deiodinated selectively at the tyrosyl ring by 3 to produce
3,3’-T2AM (Figure 2b), thus indicating that the removal of the
carboxyl group from the b-alanine side chain of T3 does not
alter the regioselectivity of the deiodination. On the other
hand, rT3AM and 3,3’-T2AM did not undergo deiodination,
Figure 2. HPLC chromatogram for the deiodination of a) T4AM and b) T3AM
by 3. Assay conditions: T4AM or T3AM (0.3 mm), 3 (1.2 mm), DTT (15 mm),
NaBH4 (30 mm), phosphate buffer (100 mm, pH 7.00), 20% (v/v) acetonitrile,
378C.
Figure 3. A comparison of the Se···I distances, CꢀI bond lengths [ꢁ], and C-I-
Se and C-Se-I angles [8] for the a) outer-ring and b) inner-ring iodine atoms
in the halogen-bonded adducts of T3AM with the MeSeꢀ ion.
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a result, the inner-ring CꢀI bond is significantly more elongat-
ed (2.326 ꢁ) than the outer-ring CꢀI bond (2.283 ꢁ). In free
T3AM, the inner- and outer-ring CꢀI bond lengths were 2.129
and 2.126 ꢁ, respectively.
The halogen-bonding energy between the MeSeꢀ ion and
the inner-ring iodine atom calculated in the gas phase is
59.03 kcalmolꢀ1, which is higher than that observed for the in-
teraction of the MeSeꢀ ion with the outer-ring iodine atom
(46.53 kcalmolꢀ1). The ability of the inner-ring iodine atoms to
form stronger halogen bonds with the selenium atom may ac-
count for the selective inner-ring deiodination of T3AM by 3.
Because the removal of an iodine atom from T3AM decreases
the positive potential on the iodine atom, 3,3’-T2AM does not
undergo any further deiodination by 3 (see Table S02 in the
Supporting Information). In agreement with this outcome, the
interaction energy between the MeSeꢀ ion and the iodine
atoms of 3,3’-T2AM (51.38 and 51.7 kcalmolꢀ1 for the inner
and outer rings, respectively) are lower than that observed for
the inner-ring iodine atom of T3AM (59.03 kcalmolꢀ1).
Figure 4. a) Chemical structure of 4. b) ORTEP diagram of a single-crystal X-
ray structure of 5, indicating Se···S noncovalent interactions. The thermal el-
lipsoids are drawn at 30% probability. c) 77Se NMR spectrum of 4 in chloro-
form/methanol (1:1). Chemical-shift values [ppm] are cited with respect to
(CH3)2Se as an external standard.
When T4AM was used as a substrate, no deiodination by 3
was observed. It is known that T4AM undergoes inner-ring de-
iodination by ID-1 and ID-3 to produce rT3AM. However, ID-
1 does not catalyse the outer-ring deiodination of T4AM, al-
though this enzyme can remove an iodine atom from the
outer ring of T4 to produce T3. To understand the unexpected
behaviour of T4AM towards 3, we carried out DFT calculations
on T4AM and the MeSeꢀ ion. Interestingly, an inner-ring iodine
atom of T4AM forms a halogen bond with the MeSeꢀ ion with
an interaction energy of 62.89 kcalmolꢀ1, which is higher than
that observed for T3AM. Therefore, it is expected that T4AM
should undergo inner-ring deiodination readily by 3. When
T4AM was added to the assay mixture, the solution became
turbid, thus indicating that the solubility of T4AM in 20% (v/v)
acetonitrile and phosphate buffer is lower than that of T4 and
T3AM. When the deiodination reaction was carried out in
100% acetonitrile, T4AM underwent deiodination by 3 to pro-
duce rT3AM, T3AM, and a small of amount of 3,3’-T2AM (see
Figure S22 in the Supporting Information). These observations
indicate that the solvent has a remarkable effect in deiodina-
tion reactions.
Figure 5. Initial rates of deiodination of T3 and T3AM by 3 and 4 under
identical conditions. Assay conditions: T3 or T3AM (0.3 mm), mimic
(1.2 mm), DTT (15 mm), NaBH4 (30 mm), phosphate buffer (100 mm, pH 7.00),
20% (v/v) acetonitrile, 378C.
acts with the selenium atom, which is similar to the Se···N in-
teractions in the secondary-amine-substituted deiodinase
mimics reported earlier (Figure 4b).[12] The presence of the
noncovalent Se···S interaction in 4 can be understood from the
chemical shifts in the 77Se NMR spectra (Figure 4c). The signal
for the selenol group adjacent to the sulfur moiety in 4 (d=
102 ppm) is significantly shifted upfield relative to the other
selenol group (d=205 ppm) in the same compound or 3 (d=
156 ppm). These results indicate a more nucleophilic character
of the selenol group adjacent to the sulfur atom of the thio-
acetal moiety relative to the other selenol group.
Interestingly, the initial rates of deiodination of T3AM by 3
and 4 are almost 11- and 8-fold, respectively, less than that of
T3 (Figure 5), thus indicating that the removal of the carboxyl
group from the b-alanine side chain of T3 decreases the rate
of deiodination without affecting the regioselectivity. This out-
come is in agreement with the report of Kçhrle and co-workers
that the rates of outer- and inner-ring deiodination of iodo-
thyronamines by deiodinases are lower than that of thyroid
hormones.[5] To understand the difference in the reactivity of
the iodine atoms in T3 and T3AM, we carried out DFT calcula-
tions on T3 and T3AM with the MeSeꢀ ion. The Se···I distance
for the outer-ring iodine atom in T3 (3.018 ꢁ) is slightly shorter
than that in T3AM (3.024 ꢁ). In contrast, the Se···I distance for
the inner-ring iodine atom in T3 (2.942 ꢁ) is significantly short-
er than that in T3AM (2.955 ꢁ; Figures 3 and 6). As a result, the
inner-ring CꢀI bond in T3 is more elongated (2.338 ꢁ) relative
to T3AM (2.326 ꢁ). Consequently, the energies for the nonco-
valent interactions between the MeSeꢀ ion and the inner-ring
iodine atom is 62.58 and 59.03 kcalmolꢀ1 for T3 and T3AM, re-
Our earlier reports showed that the introduction of a secon-
dary-amine moiety in proximity to one of the selenol groups in
3 led to increase in deiodinase activity relative to 3. Herein, we
report the effect of the sulfur-containing thioacetal moiety 4
(Figure 4a) in proximity to one of the selenol groups in 3.
Compound 4 was freshly prepared by reducing the corre-
sponding diselenide 5 (Figure 4b) with sodium borohydride.
Interestingly, 4 was 1.8- and 2.3-fold more active than 3 in the
deiodination of T3 to 3,3’-T2 and T3AM to 3,3’-T2AM
(Figure 5). With the help of a lone pair of electrons, the sulfur
atoms of the thioacetal moiety in 4, may interact with the
proximal selenol group during the reaction. As co-operative
halogen and chalcogen bonding is important for deiodination,
the donation of electron density by the sulfur atoms further
strengthens the chalcogen bonding, and hence halogen bond-
ing, thus facilitating the deiodination reactions. Single-crystal
X-ray studies of 5 indicate that one of the sulfur atoms inter-
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Figure 6. A comparison of the Se···I distances, CꢀI bond lengths [ꢁ], and C-I-
Se and C-Se-I angles [8] for the a) outer-ring and b) inner-ring iodine atoms
in the halogen-bonded adducts of T3 with the MeSeꢀ ion.
spectively. Therefore, the inner-ring deiodination of T3 by the
selenium compounds is expected to be faster than that of
T3AM. However, the marginal difference in the halogen-bond
energy may not be sufficient to explain the 7–11-fold increase
in the rate of deiodination of T3. To this end, we carried out
detailed kinetic experiments.
To understand the differences in the rate of deiodination of
T3 and T3AM, we determined the activation-energy barrier for
the reactions from Arrhenius plots (see below).[13] Briefly, the
effect of temperature on the deiodination of T3 and T3AM by
4 was studied over a temperature range of 303–318 K at
pH 7.[14] These experiments indicate that the rate of deiodina-
tion of T3 and T3AM increases with temperature (Figure 7). In-
terestingly, there was no change in regioselectivity up to
318 K.
Figure 7. Effect of temperature on the initial rate of deiodination of a) T3
and b) T3AM by 4. Assay conditions: T3 or T3AM (0.3 mm), 4 (1.2 mm), DTT
(15 mm), NaBH4 (30 mm), phosphate buffer (100 mm, pH 7), and 20% (v/v)
acetonitrile.
As none of the intermediates in the deiodination reaction is
isolable, an overall rate constant instead of the rate constant
for the rate-determining step may be used. For this purpose,
we determined the order of the deiodination reactions.[15] De-
tailed kinetic experiments indicate that deiodination of T3 is
overall a third-order reaction, that is, second order with respect
to T3 and first order with respect to 4. In contrast, deiodination
of T3AM is overall a second-order reaction, that is, first order
with respect to T3AM and first order with respect to 4 (Fig-
ure 8a,b). From the Arrhenius plot, the activation energies for
the deiodination of T3 and T3AM is calculated to be 63.6 and
53.3 kJmolꢀ1, respectively (Figure 9). These observations sug-
gest that the rate of deiodination of T3 should be lower than
that of T3AM. However, the collision frequency or pre-expo-
nential factor[16] for T3 is two-fold higher (1.99ꢂ103) than for
T3AM (0.89ꢂ103). Structural preorganisation of T3 in solution
is probably responsible for the facile and effective attack of
the selenol moiety in 4 on the T3 iodine atoms (see below).
As discussed earlier, the deiodination of T3 is second order
with respect to T3, whereas the deiodination of T3AM is first
order with respect to T3AM, although both the deiodination
reactions are first order with respect to diselenol 4. Therefore,
in the two independent reactions, one molecule of 4 may in-
teract with two molecules of T3 or one molecule of T3AM, re-
spectively.[17] Alternatively, T3 molecules may interact noncova-
lently with each other to form a dimeric species before the re-
action with 4. In such case, a decrease in the concentration of
T3, that is, an increase in the molecular separation, should lead
to the formation of a monomeric T3 species in solution. To un-
derstand the effect of concentration on the intermolecular in-
teractions, we carried out UV/Vis spectroscopic experiments at
different concentrations of T3 and T3AM. The UV/Vis spectra
of T3 (at 0.5 mm concentration), showed lmax =322 nm and
a small hump at around l=289 nm (Figure 10a). When the
concentration was decreased, the lmax value remained un-
changed up to 0.2 mm. A further decrease in the concentration
of T3 shifted the lmax value to a lower wavelength (lmax
=
296 nm). Interestingly, at lower concentrations, T3 exhibited
a shoulder at around l=322 nm, which gradually disappeared
upon further dilution, thus indicating the presence of two spe-
cies in equilibrium with each other. The species that exhibits
lmax =322 nm appears to be the T3 dimer, whereas the T3 mo-
nomer exhibits lmax =296 nm. In contrast, the absorption spec-
tra of T3AM (Figure 10b) shows only one peak at l=296 nm
over a wide concentration range of 0.05–0.5 mm, thus indicat-
ing the presence of only the monomeric species.
As the concentration of T3 (0.3 mm) used for the deiodinase
assays is identical to the concentration that helps the forma-
tion of a dimer species, the reaction of selenol is expected to
occur with the dimeric form of T3. This behaviour is consistent
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Figure 8. Determination of the order of the deiodination reactions of a) T3
and b) T3AM by 4. R1: initial rate for T3 or T3AM (0.3 mm); R2: initial rate
for T3 or T3AM (0.6 mm); R3: initial rate for T3 or T3AM (0.3 mm). Although
the concentration of 4 used for determining R1 and R2 was 0.3 mm, it was
0.6 mm for R3. KT3 and KT3AM: the rate constant for the deiodination reactions
of T3 and T3AM, respectively. The concentrations of DTT and NaBH4 used
were 15 and 7.5 mm, respectively. The reactions were carried out in phos-
phate buffer (100 mm, pH 7) and 20% (v/v) acetonitrile at 378C.
Figure 10. Concentration-dependent UV/Vis absorption spectra of a) T3 and
b) T3AM. The spectra of T3 and T3AM were recorded in 20% (v/v) acetoni-
trile in phosphate buffer (100 mm, pH 7.0).
with the results of the kinetic experiments, which show that
the deiodination reaction is second order with respect to T3.
On the other hand, the reaction between T3AM and the sele-
nol group should occur with the monomeric form of T3AM be-
cause no dimer formation was observed up to the concentra-
tion of 0.5 mm. Therefore, the deiodination reaction is first-
order with respect to T3AM (see above). Interestingly, when
the kinetic experiments were carried out for the deiodination
reaction at 0.08 mm concentration, the reaction was first order
with respect to T3 when T3 exists only as a monomeric species
(see Figure S23 in the Supporting Information), thus indicating
that the intermolecular interactions in solution have a signifi-
cant effect on the deiodination kinetics.
To understand the intermolecular interactions in T3 and
T3AM further, we determined the single-crystal X-ray struc-
tures of these two compounds. The crystal structure of T3 indi-
cates the presence of closely packed layers with extensive hy-
drogen bonding with trifluoroacetate ions and water (Fig-
ure 11a). The carboxyl group in the b-alanine side chain in one
molecule forms water-mediated hydrogen bonding with the
4’-OH group of the neighbouring molecule. Interestingly, the
two inner-ring iodine atoms interact with the inner-ring iodine
atoms of the neighbouring molecule, and each iodine atom
forms a bifurcated halogen bond. The I···I distances of 3.86 and
3.64 ꢁ are shorter than the sum of the van der Waals radii
(3.96 ꢁ). However, the outer-ring iodine atom is not involved in
I···I halogen bonding. These observations indicate that the
inner-ring iodine atoms in T3 are more susceptible to halogen
Figure 9. Arrhenius plots for the deiodination of a) T3 and b) T3AM by 4.
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It is known that one or more histidine (His) resi-
dues in the active site of ID-1 plays an important role
in the deiodination reaction of thyroid hormones in
addition to the cysteine (Cys) and Sec (selenocys-
teine) residues. Kçhrle and others have shown an en-
hancement in nucleophilicity of the Sec residue in
the active site of ID-1 by the formation of an imida-
zolium–selenolate ion pair.[20] His residues at the 158
and 174 positions in human ID-1 are conserved in ID-
2 and ID-3, although the formation of the imidazoli-
um–selenolate ion pair has not been proposed for
ID-3.[2a] Goto et al. reported that the outer-ring deio-
dination of N-butyrylthyroxine methyl ester by a steri-
Figure 11. Single-crystal X-ray structures that indicate a) intermolecular hydrogen and
halogen bonding in T3 and b) hydrogen bonding in T3AM.
bonding than the outer-ring iodine atom. Similar to T3, the
crystal packing of T3AM also indicates the presence of hydro-
gen bonding between the 4’-OH group, protonated amine
group, and the trifluoroacetate carboxylate ion (Figure 11b).
However, no I···I interactions were observed in T3AM, thus indi-
cating that the iodine atoms in this compound do not favour
halogen bonding.
As some of the intermolecular interactions found in the crys-
tal structure may break down in solution and the kinetic data
support the formation of a dimer in solution, we presume that
a dimeric form is responsible for the observed reactivity of T3.
Figure 12. a) Structure of I···I halogen-bonded dimer of T3 for NBO analysis.
b) Possible mode of interaction of the T3 dimer with a selenol group.
It has been shown that the dimeric form of T3 favours the
attack of the selenol group on the inner-ring iodine atom of
T3. Therefore, along with hydrogen bonding, I···I halogen
bonding may take part in the formation of dimeric species of
T3 in solution. Previously, halogen bonding in solution has
been reported for the formation of supramolecular gels, trans-
membrane transport of anions, anion recognition and coordi-
nation, and the design of efficient inhibitors of enzymes.[18] The
halogen–halogen (Br···Br and I···I) interaction in solution is also
known to be an important factor for the assembly of crystalline
nanoparticles in aqueous suspension by both 3-bromo- and 3-
iodocarbazoles.[19] Therefore, to understand the effect of I···I in-
teractions on the reactivity of an inner-ring iodine atom, we
carried out DFT calculations on the dimeric form by using the
coordinates obtained from X-ray data (after removing the tri-
fluoroacetate ion and water). The two T3 molecules, in which
the iodine atoms interact with each other with an I···I distance
of 3.64 ꢁ (Figure 12a), were considered for the calculations.
The NBO analysis indicates that the inner-ring iodine atoms in
individual T3 molecules have similar charges (0.260 a.u.). How-
ever, upon interaction with each other, the charge on IA be-
comes significantly more positive than on IB (0.276 versus
0.217 a.u., respectively). These observations indicate that one
iodine atom acts as an electron donor (halogen-bond accept-
or), whereas the other iodine atom acts as an electron accept-
or (halogen-bond donor). The iodine atom that carries more
positive charge is expected to form a stronger halogen bond
with a selenium atom (in the selenol group) than the one that
has a less positive charge (Figure 12b). Thus, intermolecular I···I
halogen bonding may facilitate the attack of the selenol group
on T3 relative to T3AM.
cally hindered selenol group takes place only in the presence
of triethylamine.[21] This outcome has been explained by the in-
crease in the nucleophilicity of the selenol group by trimethyl-
amine. We also noticed that the inner-ring deiodination of T3
or T3AM can be enhanced by adding trimethylamine to the re-
action mixture. The NBO analysis indicates that the positive po-
tential (0.207 a.u.) on the inner-ring iodine atoms of T3 is in-
creased with halogen bonding to trimethylamine (0.217 a.u.).
Furthermore, the CꢀI bond of the inner-ring iodine atom in T3
(2.127 ꢁ) is significantly elongated in the presence of trimethyl-
amine (2.139 ꢁ). The electron density, donated by the halogen-
bond acceptor triethylamine, becomes delocalised on the
phenyl ring and makes the iodine atom more susceptible to-
wards deiodination. These observations indicate that any halo-
gen-bond acceptor can polarise the CꢀI bond.
Conclusion
The regioselective deiodination of iodothyronamines by syn-
thetic deiodinase mimics has been described. A sulfur atom in
proximity to a selenol group in naphthyl-based compounds
enhances the deiodinase activity. The rate of deiodination of
3,3’,5-triiodothyronine (T3) was 8–11-fold higher than that of
3,3’,5-triiodothyronamine (T3AM). Detailed kinetic experiments
indicate that the deiodination reactions of T3 and T3AM are
second order with respect to T3 and first order with respect to
T3AM. However, the order of the reaction depends on the con-
centration of T3 because the reaction is first order with respect
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the mixture at 08C, which was warmed to room temperature over
12 h. The mixture was diluted with excess dichloromethane,
washed with water (5ꢂ), dried over anhydrous sodium sulfate, and
evaporated under reduced pressure to give a dark-brown liquid.
The crude product was purified by column chromatography with
petroleum ether/diethyl ether as the eluent to give 5 as a dark-
brown solid in 35% yield. 1H NMR (CDCl3): d=7.51 (d, J=8.4 Hz,
1H), 7.44 (t, J=6.8 Hz, 2H), 7.33 (d, J=8 Hz, 1H), 7.24–7.28 (q, J=
5.6 Hz, 1H), 5.87 (s, 1H), 3.61–3.67 (m, 2H), 3.41–3.45 ppm (m, 2H);
13C NMR (CDCl3): d=141.4, 141.3, 139.7, 137.6, 132.9, 129.1, 128.0,
125.2, 123.6, 122.8, 58.9, 41.0 ppm; 77Se NMR (CDCl3): d=453,
382 ppm.
to T3 at lower concentrations, thus indicating that intermolec-
ular interactions play an important role in deiodination. Single-
crystal X-ray studies of T3 indicated the presence of novel I···I
halogen bonds, which are absent in the crystal structure of
T3AM. These observations suggest that not only the halogen
bond between the iodine and selenium atoms, but also I···I in-
termolecular interactions, facilitate deiodination of thyroid hor-
mones.
Experimental Section
Synthesis of T4AM: N-tert-butoxycarbonyl-3,3’,5,5’-tetraiodothyr-
onamine (200 mg, 0.24 mmol) was stirred in 1:4 (v/v) mixture of tri-
fluoroacetic acid and dichloromethane for 1 h. The solvent was
evaporated under vacuum to yield a yellow–white sticky solid.
T4AM was purified from the crude reaction mixture by using a re-
verse-phase HPLC with a C18 column (Atlantis; 250ꢂ19 mm, I.D.=
10 mm) and methanol/water (70:30) as the mobile phase. T4AM-
containing fractions were lyophilised to yield a white solid in 90%
General procedure
Tyramine, iodine monochloride (ICl), triisopropylborate, tetrabutyl-
ammonium fluoride (TBAF), borontrifluoride diethyletherate
(BF3·Et2O), ethanedithiol, selenium powder, T4, rT3, T3, and acetoni-
trile were purchased from Sigma–Aldrich. n-Butyllithium (nBuLi)
was obtained from Acros Chemical Co. (Belgium). Dithiothreitol
(DTT) and anhydrous cupric acetate were obtained from Alfa Aesar.
Trifluoroacetic acid (TFA) and precoated silica-gel plates were pur-
chased from Merck. Liquid-state NMR spectra were recorded in
1
yield. H NMR ([D4]MeOH): d=7.89 (s, 2H), 7.10 (s, 2H), 3.22 (t, J=
7.6 Hz, 2H), 2.94 ppm (t, J=7.6 Hz, 2H); 13C NMR ([D4]MeOH): d=
153.3, 151.6, 150.7, 141.0, 138.6, 126.2, 91.1, 84.7, 40.4, 31.8 ppm;
MS (ESI): m/z calcd for C14H11NO2I4: 733.7 ([M+H]+); found 734.06.
CDCl3, [D4]MeOH, or [D6]DMSO as a solvent. H, 13C, and 77Se NMR
1
spectra were obtained using a Bruker 400 MHz NMR spectrometer
(400, 100.56, 76.29 MHz, respectively). Chemical-shift values are
cited with respect to SiMe4 as an internal (1H and 13C) and Me2Se
as an external (77Se) standard. Column chromatography was carried
out in glass columns or in an automated flash-chromatography
system (Biotage) by using preloaded silica cartridges. HPLC experi-
ments were performed on a Waters Alliance system (Milford, MA,
USA) consisting of a 2695 separation module and a 2996 photo-
diode-array detector. HPLC sample vials (1.7 mL) were used to
carry out the deiodinase assays, and a built-in auto-sampler was
used for sample injection. The HPLC system was controlled by EM-
POWER software (Waters corporation, Milford, MA, USA). Single-
crystal X-ray diffraction data were obtained from a Bruker Kappa
Apex II X-ray diffractometer with a CCD detector. Compounds 20
and 21 were synthesised by following a reported procedure.[7,9]
Synthesis of T3AM: This compound was synthesised by using N-
tert-butoxycarbonyl-3,3’,5-triiodothyronamine (200 mg, 0.28 mmol)
as described earlier for T4AM in 92% yield. 1H NMR ([D4]MeOH):
d=7.89 (s, 2H), 7.00 (d, J=2.8 Hz, 1H), 6.78 (d, J=8.8 Hz, 1H),
6.64–6.67 (dd, J=6.4 Hz, 1H), 3.23 (t, J=8 Hz, 2H), 2.95 (t, J=
7.2 Hz, 2H); 13C NMR ([D4]MeOH): d=153.9, 152.5, 149.9, 141.0,
138.2, 125.6, 116.8, 115.0, 91.4, 83.4, 40.5, 31.8; MS (ESI): m/z calcd
for C14H13NO2I3: 607.81 ([M+H]+); found: 607.77.
Synthesis of rT3AM: This compound was synthesised by using N-
tert-butoxycarbonyl-3,3’,5’-triiodothyronamine (200 mg, 0.28 mmol)
1
as described earlier for T4AM in 95% yield. H NMR [D4]MeOH): d=
7.85 (s, 1H), 7.31 (s, 3H), 6.91 (d, J=8.4 Hz, 1H), 4.64 (br, s, 2H),
3.19 (t, J=7.6 Hz, 2H), 2.9 ppm (t, J=7.6 Hz, 2H); 13C NMR
([D4]MeOH): d=156.0, 152.6, 151.3, 140.5, 135.0, 130.7, 129.0, 119.8,
88.8, 84.5, 40.7, 32.3 ppm; MS (ESI): m/z calcd for C14H13NO2I3:
607.81 ([M+H]+); found: 607.71.
Deiodination assays
Synthesis of 3,3’-T2AM: This compound was synthesised by using
N-tert-butoxycarbonyl-3,3’-diiodothyronamine (200 mg, 0.34 mmol)
as described earlier for T4AM in 93% yield. 1H NMR ([D4]MeOH):
d=7.81 (d, J=2 Hz, 1H), 7.22–7.24 (q, J=4 Hz, 2H), 6.84 (t, J=
2.8 Hz, 1H), 6.78 (d, J=8.4 Hz, 1H), 3.16 (t, J=8 Hz, 2H), 2.91 ppm
(t, J=7.6 Hz, 2H); 13C NMR ([D4]MeOH): d=157.0, 153.9, 149.9,
140.3, 133.9, 130.4, 129.4, 120.2, 118.5, 115.1, 88.0, 83.4, 40.8,
32.3 ppm; MS (ESI): m/z calcd for C14H14NO2I2: 481.91 ([M+H]+);
found: 481.85.
The deiodination reactions of thyroid hormones and iodothyron-
amines were carried out in a mixture of 20% (v/v) acetonitrile and
phosphate buffer (100 mm, pH 7.00) at 378C in the presence of
15 mm DTT. Acetonitrile was used to increase the solubility of iodo-
thyronamines in phosphate buffer at physiological pH values. The
selenol compounds (1.2 mm) were freshly prepared by reducing
the corresponding diselenide with sodium borohydride. To deter-
mine the initial rate of deiodination, the deiodination of thyroid
hormones or iodothyronamines (0.3 mm) was followed during the
initial period (ca. 10%) of the reaction. The deiodinated products
were analysed by using reverse-phase HPLC (Princeton C18
column; 150ꢂ5 mm, I.D.=5 mm) with gradient elution and aceto-
nitrile/ammonium acetate/acetic acid buffer (15 mm, pH 4) as the
mobile phase. The formation of deiodinated products was moni-
tored at l=275 nm, and the yields of their formation were calcu-
lated from the corresponding peak areas.
Single-crystal X-ray crystallography
Compound 5 was recrystallised from chloroform by using the
slow-evaporation method. Dark-brown crystals were filtered,
washed with petroleum ether, and dried under high vacuum. T3
was recrystallised with trifluoroacetic acid from a solution of dieth-
yl ether and ethyl acetate (1:1). The needle-shaped white crystals
obtained from the solution were dried under vacuum. T3AM was
also recrystallised as a trifluoroacetate salt by following a similar
procedure. The single-crystal X-ray diffraction data of 5, T3, and
T3AM were collected on a Bruker SMART APEX CCD diffractometer
by utilizing SMART/SAINT software.[22] Intensity data were collected
by using graphite-monochromatised MoKa radiation of wave-
Synthesis
Synthesis of 5: 1,2-Ethanedithiol (46 mg, 0.49 mmol) was added to
a solution of 21 (100 mg, 0.32 mmol) in dry dichloromethane
(20 mL). The resulting solution was cooled to 08C. Borontrifluoride
diethyl etherate (80 mL, 45–50% solution) was added dropwise to
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man, R. D. Utiger), Lippincott-Raven, Philadelphia, 1996, p. 144; f) D. L.
St. Germain, V. A. Galton, Thyroid 1997, 7, 655–668.
[2] a) A. C. Bianco, D. Salvatore, B. Gereben, M. J. Berry, P. R. Larsen, Endocr.
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167; c) G. G. J. M. Kuiper, M. H. A. Kester, R. P. Peeters, T. J. Visser, Thyroid
2005, 15, 787–798.
[3] a) T. J. Visser, C. H. H. Schoenmakers, Acta Med. Austriaca 1992, 19, 18–
21; b) J. Kçhrle, Mol. Cell. Endocrinol. 1999, 151, 103–119; c) J. Kçhrle, F.
Jakob, B. Contemprꢃ, J. E. Dumont, Endocr. Rev. 2005, 26, 944–984.
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zich, S. Frascarelli, D. A. Crossley II, J. R. Bunzow, S. Ronca-Testoni, E. T.
Lin, D. Hatton, R. Zucchi, D. K. Grandy, Nat. Med. 2004, 10, 638–642;
b) K. P. Doyle, K. L. Suchland, T. M. P. Ciesielski, N. S. Lessov, D. K. Grandy,
T. S. Scanlan, M. P. Stenzel-poore, Stroke 2007, 38, 2569–2576.
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Endocrinol. 2008, 149, 3037–3045.
[6] D. Manna, G. Mugesh, Angew. Chem. 2010, 122, 9432–9435; Angew.
Chem. Int. Ed. 2010, 49, 9246–9249.
[7] D. Manna, G. Mugesh, J. Am. Chem. Soc. 2011, 133, 9980–9983.
[8] M. E. Hart, K. L. Suchland, M. Miyakawa, J. R. Bunzow, D. K. Grandy, T. S.
Scanlan, J. Med. Chem. 2006, 49, 1101–1112.
[9] D. Manna, G. Mugesh, J. Am. Chem. Soc. 2012, 134, 4269–4279.
[10] P. Metrangolo, F. Meyer, T. Pilati, G. Resnati, G. Terraneo, Angew. Chem.
2008, 120, 6206–6220; Angew. Chem. Int. Ed. 2008, 47, 6114–6127.
[11] P. Auffinger, F. A. Hays, E. Westhof, P. S. Ho, Proc. Natl. Acad. Sci. USA
2004, 101, 16789–16794.
[12] CCDC-992507 (T3), -992508 (T3AM), -992509 (5) contain the supple-
mentary crystallographic data for this paper. These data can be ob-
tained free of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
[13] To understand the kinetics of the deiodination of T3 and T3AM, the ac-
tivation energy was determined from the Arrhenius equation: lnK=
lnAꢀEa/RT (K is the rate constant; A is the pre-exponential factor, which
indicates the frequency of collisions between reactants; Ea is the activa-
tion energy; R is the universal gas constant; and T is the temperature in
K); a plot of lnK versus 1/T is expected to produce a straight line with
a negative slope of magnitude Ea/R and an intercept lnA; a) R. D.
Levine, in Molecular Reaction Dynamics, Cambridge University Press,
2005; b) K. J. Laidler, in Chemical Kinetics, Third Edition, Harper & Row,
New York, 1987, p. 42.
[14] For calculating the rate constants (K), the initial rate of deiodination
was determined at different temperatures in the range 303–318 K.
[15] For a bimolecular reaction between A and B, the rate of reaction (R)=
K[A]n1[B]n2, where n1 and n2 are the orders of reaction with respect to A
and B, respectively; therefore, to determine the rate constant from the
rate of deiodination, it is necessary to know the order of the deiodina-
tion reactions; the order of deiodination reactions was determined by
following a procedure shown in Scheme S03 in the Supporting Infor-
mation: a) R. H. Petrucci, W. S. Harwood, F. G. Herring in General Chemis-
try, 8edth edPrentice-Hall, 2002, p. 585–586; b) P. Atkins, J. D. Paula in
Physical Chemistry, 8edth ed W. H. Freeman and Company, New York,
2006, p. 797–798.
[16] a) R. Chang in Physical Chemistry for the Biosciences, University Science
Books, Sausalito, CA, 2005; b) P. Atkins, J. D. Paula in Physical Chemistry
for the Life Sciences, Alexandria, VA, 2006.
[17] Probability of obtaining three reactant molecules (two molecules of T3
and one molecule of selenol) in suitable orientations for effective colli-
sion is expected to be less than bringing together two reactant mole-
cules (one molecule of T3AM and one molecule of selenol); as the
third-order deiodination reaction of T3 is expected to be slower than
the deiodination of T3AM, the reaction of one molecule of selenol with
two separate molecules of T3 may be excluded.
length 0.71073 ꢁ at room temperature. All the structures were
solved by using the SHELX-97 program incorporated in WinGX. Em-
pirical absorption corrections were applied with SADABS.[23,24] All
the non-hydrogen atoms were refined by anisotropic-displacement
coefficients except one carbon atom (C10) in the phenolic ring of
T3. The hydrogen atoms on the carbon, nitrogen, and oxygen
atoms were included in geometric positions and given thermal pa-
rameters are equivalent to 1.2ꢂ the atoms to which they were at-
tached.
Crystal data for 5: C13H10S2Se2, Mr =388.27, monoclinic, P21/c, a=
12.0408(13), b=11.0451(11), c=10.3597(11) ꢁ; a=90, b=
112.223(3), g=908; V=1275.4(2) ꢁ3, Z=4, MoKa radiation (l=
0.71073 ꢁ),
T=273(2) K,
1calcd =2.022 gcmꢀ3
,
m(MoKa)=
6.097 mmꢀ1; collected reflections=2978, unique reflections=2138,
GOF (F2)=1.041, R1[a] =0.0441, wR2[b] =0.1045.
Crystal data for T3·CF3CO2: C17H13NO8F3I3, Mr =796.98, monoclinic,
P21, a=15.124(3), b=5.0451(10), c=16.052(3) ꢁ; a=90, b=
103.409(12), g=908; V=1191.5(4) ꢁ3, Z=2, MoKa radiation (l=
0.71073 ꢁ),
T=296(2) K,
1calcd =2.222 gcmꢀ3
,
m(MoKa)=
4.000 mmꢀ1; collected reflections=7017, unique reflections=3357,
GOF (F2)=0.957, R1[a] =0.0578, wR2[b] =0.1373.
Crystal data for T3AM·CF3CO2: C16H13NO4F3I3, Mr =720.97, mono-
clinic, P21/C, a=6.565(4), b=11.892(8), c=27.565(18) ꢁ; a=90, b=
89.92(4), g=908; V=2152(2) ꢁ3, Z=4, MoKa radiation (l=
0.71073 ꢁ),
T=296(2) K,
1calcd =2.225 gcmꢀ3
,
m(MoKa)=
4.403 mmꢀ1; collected reflections=5070, unique reflections=1967,
GOF (F2)=0.901, R1[a] =0.0732, wR2[b] =0. 2089.
[a] R1=Sj jFo jꢀjFc j j/SjFo j. [b] wR2 ={S[w(Fo ꢀFc2)2]/S[w(Fo ) ]}1/2
.
2
2 2
Computational methods
All the DFT calculations were performed by using the Gaussian03
and Gaussian09 suites of quantum-chemical programs.[25] The
hybrid Becke 3-Lee–Yang–Parr (B3LYP) exchange correlation func-
tional was used to predict the molecular geometries with mini-
mum energy.[26] All the hormones and hormone metabolites were
optimised at the B3LYP level using 6–31+G* basis sets for all the
atoms, except iodine for which the 6–311G** basis set was used.
Frequency calculations were performed for each optimised geome-
try at the same level of theory by using the same basis sets to
ensure that there was a minimum on the potential-energy surface.
NBO calculations[27] were performed by using 6–311+G** basis
sets, except iodine for which the 6–311G** basis set was used.
Acknowledgements
This study was supported by the Department of Science and
Technology (DST), New Delhi. G.M. acknowledges the DST for
the award of a Swarnajayanti Fellowship, and S.M. thanks the
Indian Institute of Science for a research fellowship.
Keywords: enzyme models · hormones · iodine · noncovalent
interactions · selenium
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Received: April 25, 2014
Published online on && &&, 0000
Chem. Eur. J. 2014, 20, 1 – 10
www.chemeurj.org
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ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers! ÞÞ

Full Paper
FULL PAPER
Modelling what you want: Whereas
3,3’,5-triiodothyronine (T3) forms a di-
meric structure in solution through hy-
drogen bonding and weak intermolecu-
lar I···I halogen bonding, such interac-
tions are also observed for 3,3’,5-triiodo-
thyronamine (T3AM; see figure). The
attack of a selenol group at the iodine
atom is, therefore, more favored for the
dimeric T3 than the monomeric T3AM.
&
Enzyme Models
S. Mondal, G. Mugesh*
&& – &&
Regioselective Deiodination of
Iodothyronamines, Endogenous
Thyroid Hormone Derivatives, by
Deiodinase Mimics
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Chem. Eur. J. 2014, 20, 1 – 10
www.chemeurj.org
10
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!