Chemistry of the Thyroid Gland: Thyroid Chemistry of the Thyroid Gland: Thyroid Hormones and Antithyroid Drugs Hormones and Antithyroid Drugs G. Mugesh Department of Inorganic & Physical Chemistry Indian Institute of Science Bangalore 560 012, INDIA Bioinorganic and Biomimetic Chemistry Humboldt Kolleg, IIA Bangalore, February 2-5, 2011
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Chemistry of the Thyroid Gland: Thyroid Chemistry of the Thyroid Gland: Thyroid Hormones and Antithyroid DrugsHormones and Antithyroid Drugs
G. MugeshDepartment of Inorganic & Physical Chemistry
Indian Institute of Science
Bangalore 560 012, INDIA
Bioinorganic and Biomimetic Chemistry
Humboldt Kolleg, IIA Bangalore, February 2-5, 2011
Hormones and Thyroid Gland
Humboldt Kolleg, IIA Bangalore, February 2-5, 2011
Image taken from: http://www.biodiagnostiki.com
Thyroxine (T4)
O
CO2HH
NH2
I
I
I
I
HO
I I
TPO TPO
tyrosine thyroxineI I
thyroglobulin
HO CH
HHO C
H
HHO C
H
HHO C
H
HI
I I
I
C
H
HO C
H
HHO
I
I I
I
Thyroid Hormone Synthesis
Hyperthyroidism – anti-thyroid drugs
E-Se H+ E-SeI
DTTredDTToxI +
GTGE-Se-Au
T4
O
CO2HH
NH2
I
I
I
I
HO
T3
O
CO2HH
NH2
I
II
HO
PTU
N
NS
H O
CH2CH2CH3
SeE
I
H O2 2
IODINERecommended Daily Intake
Thyroid
Humboldt Kolleg, IIA Bangalore, February 2-5, 2011
Selenenyl Iodide – Non-existent Compound?
Humboldt Kolleg, IIA Bangalore, February 2-5, 2011
W. E. Dasent, Nonexistent compounds, Marcel Dekker, New York (1965) .
Se Se
R
R
+ I I Se I
R2
172 + 150 = 322 kJ/mol 2 x 150 = 300 kJ/mol
Isodesmic Equation
For a long time, uncharged covalent selenium iodides have been regarded as non-existent .
Se
SeSe
Se
I
I
I
I
du Mont, et al. Angew. Chem. Int. Ed. 1987, 26, 780.
trisyl
Se
Me3Si SiMe3
SiMe3
Se
supermesityl
Anti-thyroid Drugs – Treatment for Hyperthyroidism
N N
S
H H
O
N N
S
Me H N N
S
Me O
O
N N
S
H H
OMe
PTU MTU
MMI CBZ
Inhibition of thyroid peroxidase (TPO) by coordination to iron
Donor-acceptor complexes with molecular iodine
PTU and MTU – Block T4T3 conversion (ID-I)
Humboldt Kolleg, IIA Bangalore, February 2-5, 2011
Cooper, D. S. N. Engl. J. Med. 2005, 352, 905.
Interactions of Antithyroid Drugs with Iodine
Humboldt Kolleg, IIA Bangalore, February 2-5, 2011
Isaia et al. J. Am. Chem. Soc. 2002, 124, 4538. J. Med. Chem. 2008, 51, 4050.
S
N N Me
MMI
H
S
N N Me
MMI.I2
H
II
SN
NMe
H
SNH
NMe
I2 3I2
MMI-dication
I82-
NN
SHH
O
PTU
I2NN
SHH
O
PTU.I2
II
Hadjiliadis et al. Eur. J. Inorg. Chem. 2003, 1635.
Se-MMI – Tautomeric Structures
NN Me
EH
NN Me
E
HNHN Me
Se
(2b) E = Se
(1b) E = S(2a) E = Se(1a) E = S
Humboldt Kolleg, IIA Bangalore, February 2-5, 2011
Humboldt Kolleg, IIA Bangalore, February 2-5, 2011
Tautomeric Forms of MTT and MDT
N
N NN
SH
N
NS
CH3
SH
CH3 N
N NN
S
N
NS
CH3
S
CH3
H
H
MTT
MDTTyrosine Thyroxine (T4)
Anti-thyroid drugs
TPO
OI
II
IHO
NH2
CO2H
Thyroid Gland
HONH2
HO2C
I-/H2O2
N N
S
H3C H
MMI
Roy, G.; Mugesh. G. J. Am. Chem. Soc. 2005, 127, 15207.
Roy, G.; Nethaji, M.; Mugesh, G. J. Am. Chem. Soc. 2004, 126, 2712.
Bhuyan, B. J.; Mugesh, G. Inorg. Chem. 2008, 47, 6569.
L-tyrosineCO2H
NH2
OH
CO2H
NH2
OH
ILPO
H2O2, I
3-iodo-L-tyrosine
CO2H
NH2
OH
I
3,5-diiodo-L-tyrosine
I+
Humboldt Kolleg, IIA Bangalore, February 2-5, 2011
Inhibition of LPO-catalyzed Iodination
L-tyrosineCO2H
NH2
OH
CO2H
NH2
OH
ILPO
H2O2, I
3-iodo-L-tyrosine
CO2H
NH2
OH
I
3,5-diiodo-L-tyrosine
I+
No Compound Structure IC50 values (μM)
1 MMI 4.09 ± 0.56
2 MTT 7.29 ± 0.77
3 MDT 3.04 ± 0.65
N
N NN
S
CH3H
N
NS
CH3
S
H
NN
S
CH3H
Tamilselvi & Mugesh, ChemMedChem, 2009, 4, 512.
Humboldt Kolleg, IIA Bangalore, February 2-5, 2011
Sulfur-Iodine Interactions
S
NO
HN
S NN
SOHO
O
CH3
NN
NN mβl
SH
N
NS
S
NO
HN
OHO
O
NN
NN
OH
CH3
SN
N S
Me
I S
NN
S
Me
I5H
HS
NN
S
Me
II
SN N
S Me
I2HH
S
N
NS
Me
II
HI
II
I
S
N
NS
CH3
H
I2
Tamilselvi, A.; Mugesh, G.
Bioorg. Med. Chem. Lett. 2010, 20, 3692.
Humboldt Kolleg, IIA Bangalore, February 2-5, 2011
Humboldt Kolleg, IIA Bangalore, February 2-5, 2011
Sulfur-Iodine Interactions
S
N
NS
MDT
Me
H
MTDT
N
N
N
S
Me
O H
O
H
Thione-Iodine complexes (a) DMETT.I2
(b) MMI.I2, (c) MDT.I2, (d) PTU-I2
(e) MTDT-I2, (f) free iodine
0.2 0.4 0.6 0.8 1.0 1.240
80
120
160
200
240
(f)
(e)(d)
(c)(b)
(a)
Ra
ma
n S
hif
t (c
m-1)
I-I Bond Order
Tamilselvi, A.; Mugesh, G.
Bioorg. Med. Chem. Lett. 2010, 20, 3692.
Thyroid hormone binding in Transthyretin (TTR)
Halogen binding sites P1, P2, P3 and their symmetry related pairs P1', P2', P3' in thyroid
hormone transport protein Transthyretin. T4 (ball and stick - red) binding is greatly influenced by charged residues Lys15 and
Glu54 in P1 pocket.
Humboldt Kolleg, IIA Bangalore, February 2-5, 2011
Humboldt Kolleg, IIA Bangalore, February 2-5, 2011
Hydrogen bonding with Lys15 and Glu54
4-phenolic hydroxyl group forms water
mediated hydrogen bond to Ser117.
5'-I atom of phenolic ring interacts with Leu110 backbone N atom in P3 pocket
(I…..N, 3.5 Å) 3’- I atom interacts with the carbonyl oxygen of Ala109 in P2 pocket formed by other
monomer of the protein (I…..O, 2.8 - 3.3 Å)
Acta Cryst. 1996, D52, 758-765.
Halogen bonding in human TTR-T4 complex
Halogen Bonding
Binding of T3 with TTR
Humboldt Kolleg, IIA Bangalore, February 2-5, 2011
J. Biol. Chem. 2004, 279, 25, 26411 - 26416.
Humboldt Kolleg, IIA Bangalore, February 2-5, 2011
3'-I interacts directly with Ser117 side chain hydroxyl (I….O, 2.86 Å) although a series of contacts with 108-110 and 117- 119 residues are possible with distances between 2.86 Å & 3.72 Å)
Superimposed structure of T4 (thick line) and T3 (light line) bound to human TTR. Amino acids are represented by single letter codes.
J. Biol. Chem. 1992, 267, 1, 353-357.
Binding of 3,3’-T2 with human TTR
Affinity
100 %
0.07 %
0.01%
The binding affinity decreases upon removal of iodines.
J. Biol. Chem. 1992, 267, 1, 353-357.
Binding of Thyroid Hormones to TTR
O
CO2HH
NH2
I
I
I
I
HO
O
CO2HH
NH2
II
HO
O
CO2HH
NH2
I
HO
T4
T2
T1
Humboldt Kolleg, IIA Bangalore, February 2-5, 2011
O
CO2HH
NH2
I
I
I
HO
O
CO2HH
NH2
I
II
HOT3
rT3
active hormone
Iodothyronine Deiodinases
T2
ID-1ID-3ID-2
ID-3ID-2
T4
T3
O
CO2HH
NH2
I
I
I
I
HO
O
CO2HH
NH2
I
II
HO
O
CO2HH
I
I
I
HO
rT3
O
CO2HH
NH2
II
HO
ID-1
NH2
ID-1
outer ring
inner ring
ACTIVATION
INACTIVATION
INACTIVATION
Behne et al. BBRC, 1990, 173, 1143; Berry et al. Nature 1991, 349, 438.
The entire body metabolism depends on the amount of thyroid hormones produced.
produces the active thyroid hormone
protects tissues from an excess of thyroid hormone.
Humboldt Kolleg, IIA Bangalore, February 2-5, 2011
Iodothyronine Deiodinase Mimics
OH
II
R
O
I
R
I
H
OH
I
R
R'SeH
-RSeI
O
CO2MeH
NHCOPrn
I
I
I
I
HO O
CO2MeH
NHCOPrn
I
I
H
I
HONEt3, CDCl350 oC, 7 days
SeH
R
R R
R
R = 2,6-diisopropylphenyl
65 %
(BpqSeH)
OMe
II
OPh
BpqSeH, NEt3
CDCl3, 50 oC, 5 daysno deiodination
Goto et al. Angew. Chem. Int. Ed. 2010, 49, 545.
Enol-keto tautomerism is required
Outer ring iodines are more reactive
than the inner-ring ones
Humboldt Kolleg, IIA Bangalore, February 2-5, 2011
T4
O
CO2HH
NH2
I
I
I
I
HO
rT3
O
CO2HH
NH2
H
I
I
I
HO
phosphate buffer
pH 7.5, 37 oC
SH SeH
T3
O
CO2HH
NH2
I
II
HO
T2
O
CO2HH
NH2
H
II
HO
phosphate buffer
pH 7.5, 37 oC
Inner-ring Deiodination
Physiologically relevant conditions
Highly specific to inner-ring deiodination
Manna and Mugesh, Angew. Chem. Int. Ed. 2010, 49, 9246 - 9249.
Quantitative conversion of T4 to rT3 in 30 h
Iodothyronine Deiodinase Mimics
Humboldt Kolleg, IIA Bangalore, February 2-5, 2011
Iodothyronine Deiodinase Mimics
SH SH SH SeH NH
SeH SH
1 2 3
N
SeH
SH SePh
4 5
The rate of deiodination is highly pH dependent. A thiol adjacent to selenol is important for the
deiodination. Replacing -SeH with -SH reduces the activity.
0
20
40
60
80
100
T2T3rT3T4
321321
Compound
Rel
ativ
e A
ctiv
ity
4 6 8 10 12
0.5
1.0
1.5
2.0
2.5
3.0
3.5
rate
(µM
/min
)
pH
Humboldt Kolleg, IIA Bangalore, February 2-5, 2011
Picture 13
Possible Mechanism
Positive charge on inner–ring iodine decreases upon deiodination of T4.
Halogen bonding may play an important role in the inner-ring deiodination.
Possible mechanism
Humboldt Kolleg, IIA Bangalore, February 2-5, 2011
SH SeH
O
I
I
...
- rT3SH Se I
- HI
S Se
(T4)
SH SH SH SeH SeH SeH
SH SH NH
SH SeH NH
SeH SeH NH
Se SH Se SeH
Does an increase in reactivity change the selectivity??
Manna and Mugesh, Unpublished results.
Iodothyronine Deiodinase Mimics
Humboldt Kolleg, IIA Bangalore, February 2-5, 2011
121
91
141
1.61.6
6
0
3 2 5
8 9 10
6 7
T4
rT3
T2
SeH SeHSeH SeH N
H
T4
rT3
T2
An increase in the reactivity does not change the selectivity, but it leads to further deiodination.
rT3 undergoes a further deiodination to form T2.
Iodothyronine Deiodinase Mimics
Humboldt Kolleg, IIA Bangalore, February 2-5, 2011
Manna and Mugesh, Unpublished results.
Iodothyronine Deiodinase Mimics
Humboldt Kolleg, IIA Bangalore, February 2-5, 2011
Manna and Mugesh, Unpublished results.
T2
ID-1ID-3ID-2
ID-3ID-2
T4
T3
O
CO2HH
NH2
I
I
I
I
HO
O
CO2HH
NH2
I
II
HO
O
CO2HH
I
I
I
HO
rT3
O
CO2HH
NH2
II
HO
ID-1
NH2
ID-1
outer ring
inner ring
SeH SeH
SeH
HSe
SeH
HSe
SeH SeH
SeH
HSe
Humboldt Kolleg, IIA Bangalore, February 2-5, 2011