Chemistry of the Thyroid Gland: Thyroid Hormones and Antithyroid · PDF fileChemistry of the Thyroid Gland: Thyroid Hormones and Antithyroid Drugs G. Mugesh Department of Inorganic

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


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


Selenenyl Iodide – Non-existent Compound?


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)


Cooper, D. S. N. Engl. J. Med. 2005, 352, 905.

Interactions of Antithyroid Drugs with Iodine


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


E = O, does not exist; E = Te, very unstable

- 4.8 ppm

JSe-C113-C NMR: = 220 Hz

C-Se single bond, 1Jse-c ~ 110-140 Hz; C=Se double bond, 1Jse-c ~ 220-240 Hz

Roy, Nethaji & Mugesh, J. Am. Chem. Soc. 2004, 126, 2712.

Roy & Mugesh, J. Am. Chem. Soc. 2005, 127, 15207.

Roy, Das & Mugesh, Inorg. Chim. Acta. 2007, 360, 303.

1.848 Å


N

NSe

Me

N

NSe

MeI3

N

NSe

Me

N

NSe

Me2IH H

H


Roy, Nethaji, & Mugesh, Org. Biomol. Chem., 2006, 4, 2883.

Hydrolysis by Metallo-β-Lactamases

MoxalactamCefazolin

S

NO

HN H

S

N NN

N

Me

OHO

O

OH

O

NO

HN O H

Me

S

N NN

N

Me

ONaO

NaOO

HOO

S

NO

HN H

S

N N

S

OHO

O

CH3

NN

N

N

Cefamandole

S

NO

HN H

O

ONaO

O

O

HN

S

CO2H

OH

HN

OOH

S

ON

S

CO2H

HN

OOH

S

O

OH

S

mβl

Cephalothin

O

NO

HN O H

Me

S

N NN

NMe

ONaO

NaOO

HOO

O

NO

HN O H

Me

ONaO

NaOO

HOO

OH

mβl

SH

NN N

N Me

MTTMoxalactam


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+


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.


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.



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.



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


J. Biol. Chem. 2004, 279, 25, 26411 - 26416.


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


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.


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


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




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


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


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.



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.







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


Se Se NH... Me

Se Se N... Me

Se Se

Effect of Se…N interactions on 77Se NMR

Compound rSe1··Se2/ (Å) rSe2··N/ (Å) <Se1-Se2-N (º) qSe1 qSe2 E (kcal.mol-1)

nN→σ*Se―Se

1 2.467 2.337 167.14 0.133 0.450 21.16

2 2.472 2.327 167.14 0.129 0.452 37.16

3 2.471 2.337 167.00 0.130 0.448 37.75

4 2.495 2.250 167.34 0.104 0.477 47.51

5 2.426 2.629 164.65 0.172 0.294 14.79

6 2.431 2.593 165.08 0.165 0.294 16.61

7 2.432 2.586 165.46 0.164 0.290 16.91

8 2.434 2.583 164.71 0.162 0.289 17.37

Geometry optimization: B3LYP/6-31+G**; NBO analyses: B3LYP/6-311++G**

AIM image of 1

DFT Calculations

Se Se NH... RSe Se N... R

1, R = Me2, R = Et3, R = nPr4, R = iPr

5, R = Me6, R = Et7, R = nPr8, R = iPr


2

Compound rSe··S/ (Å) rS··N/ (Å) <Se-S-N (º) qSe qS E (kcal.mol-1)

nN→σ*Se―S

9 2.924 2.549 172.15 0.268 0.252 12.77

10 2.293 2.557 172.13 0.268 0.251 12.44

11 2.294 2.552 172.13 0.268 0.2578 12.67

12 2.301 2.518 172.11 0.258 0.253 13.97

13 2.284 2.734 168.2 0.271 0.165 7.75

14 2.289 2.688 168.94 0.264 0.164 9.23

15 2.293 2.659 169.38 0.260 0.161 10.10

16 2.287 2.719 168.15 0.267 0.162 8.68

AIM image of 9

Se S NH..... RSe S N..... R

9, R = Me10, R = Et11, R = nPr12, R = iPr

13, R = Me14, R = Et15, R = nPr16, R = iPr

DFT Calculations

10



Compound rS··Se/ (Å) rSe··N/ (Å) <S-Se-N (º) qS qSe E (kcal.mol-1)

nN→σ*S―Se

17 2.372 2.284 165.94 0.017 0.518 41.70

18 2.3 77 2.273 165.95 0.012 0.522 43.70

19 2.376 2.283 166.00 0.012 0.519 40.85

20 2.394 2.229 166.11 0.003 0.537 49.94

21 2.318 2.582 164.54 0.054 0.357 16.72

22 2.322 2.557 164.74 0.049 0.357 18.96

23 2.322 2.556 164.97 0.050 0.355 18.20

24 2.324 2.549 164.28 0.047 0.351 18.78

AIM image of 17

S Se NH.... RS Se N.... R

17, R = Me18, R = Et19, R = nPr20, R = iPr

21, R = Me22, R = Et23, R = nPr24, R = iPr

DFT Calculations

18



Acknowledgement

Department of Science and Technology (DST), New Delhi

Alexander von Humboldt Foundation, Germany

Thank You

Gouriprasanna Roy

Debasis Das

A. Tamilselvi

Debasish Manna



Far-IR spectra

FT-Raman spectra

110 : normally attributed to the symmetric stretching of I – symmetric ion – one Raman active band.

143 : the anti-symmetric stretching may become Raman active.

3-

141: ν(I-I) stretching vibration mode.

Di-iodine vapor gives a strong band at 216, which appears at 180 in the solid state.

This band shifts to lower wavenumbers upon coordination to a donor atom, reflecting a reduction in the I-I bond order.

I can exist as a real I entity or an I ·I adduct.3- -

23-

ν

(cm )- -1

I

277 274141

MSeI

MSeI.I2

100150200250300

0.6

0.8

1.0


Roy, Nethaji, & Mugesh, Org. Biomol. Chem., 2006, 4, 2883.

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Chemistry of the Thyroid Gland: Thyroid Hormones and Antithyroid · PDF fileChemistry of the Thyroid Gland: Thyroid Hormones and Antithyroid Drugs G. Mugesh Department of Inorganic