Conformational Flexibility and Halogen Bonding in Thyroid Hormones

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Conformational Flexibility and Halogen Bonding in Thyroid Hormones and their Metabolites Santanu Mondal, and Govindasamy Mugesh Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.6b00945 • Publication Date (Web): 30 Aug 2016 Downloaded from http://pubs.acs.org on September 2, 2016

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Crystal Growth & Design

Conformational Flexibility and Halogen Bonding in Thyroid Hormones and their Metabolites Santanu Mondal and Govindasamy Mugesh* Department of Inorganic and Physical Chemistry, Indian Institute of Science, Bangalore-560012, India. KEYWORDS. Conformation • Halogen bonding • Iodothyronamine • Thyroid hormone • X-Ray crystal structure

ABSTRACT. Iodothyronamines (TAMs) are endogenous thyroid hormone (TH) metabolites, which are proposed to be bio-synthesized by decarboxylation of β-alanine side chain of THs. Iodothyronine deiodinases (DIOs) mediate phenolic and tyrosyl ring deiodinations of thyroid hormones and play an important role in thyroid hormone homeostasis. These enzymes also accept iodothyronamines as substrates for deiodination, but the binding affinities of TAMs to DIOs are lower than that of THs. In this paper, we report, for the first time, the formation of halogen bonding in various iodothyronamines by using single crystal X-ray studies. We also describe the conformational changes that take place in the structures of THs and TAMs upon deiodination. Density Functional Theory calculations were performed to understand the halogen bonded assembly and their biological implications.

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INTRODUCTION Thyroid gland in the human endocrine system produces L-thyroxine (T4) as a prohormone. Three isoforms of the selenocysteine-containing enzymes, iodothyronine deiodinases (DIOs), play an important role in maintaining the thyroid hormone levels throughout the body.1-5 Type 1 deiodinase (DIO1) catalyzes both the phenolic (5') and tyrosyl ring (5) deiodination of T4 to form 3,3',5-triiodothyronine (T3) and 3,3',5'-triiodothyronine (rT3), respectively. In contrast, type 2 (DIO2) and type 3 (DIO3) deiodinase catalyze selective phenolic and tyrosyl ring deiodination of T4, respectively. Both T3 and rT3 undergo further deiodinations by all three enzymes to form the biologically inactive metabolite L-thyronine (T0) as shown in Scheme 1.6-11 In addition to the enzyme-catalyzed deiodination pathways, thyroid hormones (THs) also undergo decarboxylation of β-alanine side chain to form iodothyronamines (TAMs). Although a total of nine iodothyronamine derivatives are possible, only 3-iodothyronamine (3-T1AM) and thyronamine (T0AM) were detected so far in the serum of various organisms.12 These metabolites have been shown to induce a decrease in the body temperature (hypothermia) and cardiac output (bradycardia), when injected to mouse in pharmacological doses.12,13 3-T1AM is also known to activate trace amine-associated receptor, an orphan G-protein coupled receptor.14 Recently, TAMs have been identified as substrates for DIOs.15 However, some of the THs and TAMs do not undergo deiodination by these enzymes (Scheme 1),15,16-21 indicating that the change in the structure and conformations of THs upon decarboxylation may alter the binding of TAMs at the enzyme active site. Recently, we reported that T4 can exist in different conformations in the solid state.22 These two different solid forms have been studied by single crystal and powder X-ray diffraction, 13C NMR and Raman spectroscopy. Interestingly, the two forms showed different solubility and


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Scheme 1. Deiodination of thyroid hormones and iodothyronamines by DIOs. I HO

O

I

DIO 1, DIO 3

DIO 1, DIO 2 I

R= CO2H / H

H R

T4, R= CO2H

I

T4AM, R= H

HO

O I

I

H

NH2

H

HO DIO 1, DIO 2

DIO 1, DIO 3

H R R= CO2H / H

R= CO2H / H

I

rT3, R= CO2H

R= CO2H

I

I

H

HO

H

O I

3',5'-T2, R= CO2H

HO

H

R= CO2H / H

H

I

H

R= CO2H / H

DIO 3

H HO

DIO 1

O H

H

3'-T1, R= CO2H

H R

3'-T1AM, R= H

H

3-T1AM, R= H

DIO 1

O H

H

T0AM, R= H

H R NH2

DIO 3

H

T0, R= CO2H

H

I

3-T1, R= CO2H

NH2 HO

R= CO2H

NH2

3,5-T2AM, R= H

DIO 1, DIO 3 R= CO2H / H

R= CO2H / H DIO 1, DIO 2

O

I

3,5-T2, R= CO2H

NH2

3,3'-T2AM, R= H

I

H R

H R 3,3'-T2, R= CO2H

NH2

O H

I

H R

HO

NH2

H

H

3',5'-T2AM, R= H

H R

DIO 1 R= CO2H

I O

I

T3AM, R= H

R= CO2H / H DIO 1, DIO 3

HO

I

T3, R= CO2H

NH2

rT3AM, R= H

O

H R

R= H

NH2

optical rotation in different solvents. The relative orientations of two iodinated phenyl rings and the amino acid moiety in T4 have been shown to affect the halogen bonding ability of the iodine atoms.22 The conformation-dependent halogen bonding may also play an important role in the binding of T4 to its transport protein transthyretin (TTR).23 Although iodothyronamines exhibit different binding behavior to their transport protein, apolipoprotein B-100 (apoB-100),24 the involvement of iodine atoms of iodothyronamines in halogen bonding is not known. In this


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paper, we report on the X-ray structures and solid state conformations of different iodothyronamines and compare them with that of thyroid hormones. We also discuss the different types of halogen bonding interactions and its biological implications. RESULTS AND DISCUSSION Iodothyronamines were synthesized by following a procedure reported by Scanlan and coworkers with minor modifications (Scheme S01, Supporting Information).25 All the iodothyronamines and T3 were recrystallized as trifluoroacetate salts. The diiodo derivative 3,5T2 was recrystallized in the zwitterionic form, but our attemps to crystalize T4AM were unsuccessful. Needle-shaped crystals of trifluoroacetate salt of T3 were obtained by slow evaporation of a mixture of T3 and trifluoroacetic acid (TFA) in ethyl acetate and diethylether. The crystals were of monoclinic space group P 21.26 The torsional angles, which are mostly used to describe the conformations of thyroid hormones and their metabolites, are shown in Figure 1A. The torsional angles χ1 and χ2 determine the orientation of the β-alanine side chain with respect to tyrosyl ring and phenolic ring. In T4-diethanolamine salt, both the cisoid and transoid conformers of T4 were observed in the unit cell.27 The β-alanine side chain and phenolic ring of thyroid hormones are placed in the same face and opposite faces of the plane of tyrosyl ring in the cisoid and transoid conformers, respectively. In contrast to the structure of T4, only transoid conformer is observed in the single crystal X-ray structure of trifluoroacetate salt of T3 (Figure 1B). An interesting characteristic of the structure of thyroid hormones is the mutual perpendicularity of the tyrosyl ring and phenolic ring. This unique conformation of the diphenyl ether linkage is important for the biological activity of T4.28,29 The two torsional angles, φ and φ' (Figure 1A), appear to control the perpendicular arrangement of the phenolic and tyrosyl rings, with one iodine atom in the phenolic ring occupying a position close to the tyrosyl ring in T4.


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Figure 1. (A) Different torsional angles used for defining the conformations of T3. The atomnumbering scheme, shown for T3, is applicable for all the thyroid hormones and their metabolites. Hydrogen atoms are omitted for clarity. C-I bond lengths (Å) and C4-O3-C1' bond angles (⁰) in the ball and stick model of single crystal X-ray structures of T3 (B), T3AM (C) and rT3AM (D). Only one conformer of rT3AM has been shown. Trifluoroacetate and water are omitted for clarity. Although for an ideal mutual perpendicularity between the two rings, the values of φ and φ' are expected to be 90⁰ and 0⁰, respectively, both the values deviate from the ideal ones. Therefore, the values of φ and φ' indicate the “swinging” and “twisting” of the phenolic ring about the C4O3 and O3-C1' axes, respectively. The values of φ and φ' for the trifluroacetate salt of T3 are 88.4⁰ and 20⁰, respectively (Table 1). Unlike T4, the 3'-iodine atom in T3 can occupy both the


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positions, which are close to the tyrosyl ring (proximal conformer) or away from the tyrosyl ring (distal conformer). Both the proximal and distal conformers of zwitter-ionic form of T3 have been reported earlier.30,31 In contrast, only the distal conformer was observed for 3,5,3'-triiodo-Lthyronine methyl ester and only the proximal conformer has been observed for 3,5,3'-triiodo-Lthyronine hydrate hydrochloride.32,33 For the trifluoroacetate salt of T3, we observed only the proximal conformer (Figure 1B). Table 1. Conformational parameters (χ1, χ2, φ and φ') for different thyroid hormone metabolites. χ1 (⁰)

χ2 (⁰)

φ (⁰)

φ' (⁰)

T3

-72.8

-78.8

88.4

20.0

T3AM

-164.7

-73.4

97.7

-2.0

rT3[a][b]

52, 52

105, 104

8, -6

86, 87

rT3AM[b]

167.7, 178.9

-56.7, -94.2

109.8, 107.2

-26.0, -13.0

3,5-T2

-57.3

-55.1

114.1

-30.7

3,5-T2AM

-171.5

-69.0

104.4

-33.9

3,3'-T2AM

-176.9

-48.8

112.8

-20.7

3',5'-T2AM

-179.4

89.6

119.2

-40.8

3-T1AM

178.1

-69.8

102.3

-22.8

3'-T1AM[b]

-174.7, 173.0

-88.2, -92.2

164.2, 49.9

-72.7, 45.9

T0AM

179.3

-87.1

142.8

-73.1

[a] The values have been taken from previously reported structure.34 [b] Two values for each parameter correspond to two independent conformers observed in the asymmetric unit.

It is interesting to note that T3AM, the decarboxylated metabolite of T3, also adopts more stable transoid geometry similar to T3 (Figure 1C).26 However, on removal of the carboxyl


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group from T3, the aminoethyl side chain in T3AM becomes almost parallel to the plane of tyrosyl-ring (Figure 1B and 1C). In agreement with this observation, χ1 changes from -72.8⁰, in T3, to -164.7⁰, in T3AM (Table 1). Although the “swinging” of the phenolic-ring about C4-O3 axis is almost similar in T3AM (97.7⁰) and T3 (88.4⁰), the “twisting” of the phenolic-ring about the O3-C1' axis is significantly less in T3AM (-2⁰) than in T3 (20⁰) (Table1). These observations indicate that the decarboxylation of β-alanine side chain of T3 increase the mutual perpendicularity between the two iodinated phenyl rings in T3AM. T3AM has been previously crystallized as a bis(salicylato)borate salt.35 Although the structure of this salt exhibits twistskewed geometry of the tyrosyl and phenolic ring as well as proximal conformation of the 3'iodine atom as observed in the structure of trifluoroacetate salt, the aminoethyl side chain and the phenolic ring exhibited cisoid geometry with respect to the tyrosyl ring. This observation indicates that the counter anion has significant effect on the conformation of T3AM. The tyrosyl ring C-I bonds in T3AM are slightly elongated (average bond length 2.092 Å) than in T3 (average bond length 2.084 Å) whereas the phenolic ring C-I bond is significantly elongated in T3AM (2.131 Å) than in T3 (2.078 Å). Interestingly, unlike T3, T3AM does not undergo phenolic ring deiodination by DIO1.15 The conformational flexibility and internal dynamics in thyroid hormones in solution has been studied earlier by NMR spectroscopy.36-38 Similar to the three-dimensional structures of thyroid hormones observed in the X-ray structures, these studies also indicated the roughly perpendicular arrangement of the two iodinated rings and the rapid movement of the phenolic ring about the diphenyl ether linkage. As discussed earlier, rotation of the phenolic ring about the O3-C1' bond in T3 gives rise to the formation of proximal and distal conformers. Temperature-dependent NMR spectroscopic investigation indicated that in solution, T3 adopts both the distal and


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proximal conformations with almost equal populations, which is contrast to our observation that both T3 and T3AM exhibit proximal conformation in the solid state. The rotational energy barrier between these two conformations was calculated to be about 36 kJmol-1 and this energy barrier was shown to be independent of the nature of the side chain functionalities.39,40 These observations indicate that in solution, T3AM may also behave similarly to T3. Interestingly, conversion between the cisoid and transoid conformers of thyroid hormones has also been observed in solution and NMR experiments suggested that these two conformers are almost equally populated in solution.38 It is possible that depending on the crystallization medium and intermolecular interactions, the transoid conformer of trifluoroacetate salts of T3 and T3AM crystallize out favorably. Although the conformations of tyrosyl and phenolic ring (φ and φ') of T3 bound to the receptor and transport proteins are more or less similar to that observed in the crystal structure of trafluoroacetate salt of T3, the conformations of amino acid side chain (χ1, χ2 and ψ) are observed to be significantly different in the bound and free forms of T3.41-44 It should be noted that the tyrosl and phenolic ring of T3 bound to the receptor TRα1 (human) adopts a conformation (φ = 86.3⁰ and φ' = 20.6⁰), which is almost similar to that observed in the crystal structure of trafluoroacetate salt of T3.41 It is known that rT3AM can be bio-synthesized either by decarboxylation of rT3 or by tyrosyl ring deiodination of T4AM by DIO1 or DIO3. Two independent conformations were observed in the assymmetric unit of rT3AM.45 Both the conformers adopt transoid geometry (Figure 1D). These observations are very similar to those observed in the crystal structure of rT3 by Okabe and coworkers.34 Similar to the decarboxylation of T3, the decarboxylation of rT3 makes the aminoethyl side chain in rT3AM almost parallel to the plane of tyrosyl ring (χ1=52⁰ in rT3; χ1= 167.7⁰ and 178.9⁰ in rT3AM, Table 1). The change in χ2 is almost negligible between T3 and


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T3AM, whereas χ2 changes significantly on decarboxylation of rT3 to rT3AM (Table 1). A comparison of φ and φ' angles in rT3 with those in T3, T3AM and rT3AM reveal some interesting structural features of rT3. In T3, T3AM or rT3AM, φ and φ' are close to 90⁰ and 0⁰, whereas in rT3, they are close to 0⁰ and 90⁰ (Table 1). However, deviation in the values of φ and φ' from the ideal values, that is 90⁰ and 0⁰, respectively, are higher in rT3AM than in T3AM (Table 1), indicating that the mutual perpendicularity between two phenyl rings is more in T3AM than in rT3AM. In rT3, phenolic ring C-I bonds (average C-I bond length 2.12 Å) are more elongated than tyrosyl ring C-I bond (average bond length 2.00 Å).34 By contrast, in T3, the tyrosyl ring C-I bonds (average bond length 2.084 Å) are more elongated than the phenolic ring C-I bond (bond length 2.078 Å) (Figure 1B). These observations indicate that the tyrosyl and phenolic ring iodine atoms of T3 and rT3, respectively, are easier to remove than the iodine atoms on the other ring. In rT3AM, C-I bonds in both the tyrosyl (bond length 2.093 Å) and phenolic ring (average bond length 2.094 Å) are of almost similar length. Comparison of these C-I bond lengths with those in rT3 suggests that the removal of phenolic ring iodine atom from rT3 is easier than from rT3AM but the removal of tyrosyl ring iodine atom from rT3AM is easier than from rT3. These results are quite similar to the observed rates of deiodination of thyroid hormones and iodothyronamines by DIOs.15 However, in addition to the C-I bond strength, the positive charge on the iodine atom and the strength of Se···I halogen bonding also plays important role in the C-I bond activation and deiodination of thyroid hormones. Solid state crystal packing of thyroid hormones and iodothyronamines shows extensive Hbonding generally involving the amine group, 4'-OH group, carboxylic acid group (for thyroid hormones) and trifluoroacetate moiety (Figures S19B and S20, Supporting Information). In addition to these H-bonding interactions, the most interesting feature of the crystal packing of


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thyroid hormones and iodothyronamines is the I···I non-covalent interactions. Intermolecular halogen···halogen (X···X) interactions are extensively studied in halogenated phenols, halobenzoic acids, halogenated thiacalix[4]arenes and many other halogenated systems.46-54 Furthermore, X¯···X interactions have been discovered as the pillars for anion recognition processes.52-54 Recently, our studies on the halogen bond-mediated deiodination of thyroid hormones and dehalogenation of halogenated nucleosides have attracted significant research attention.55-60 We have shown that in addition to the Se···I halogen bonding, I···I interactions can also help in polarizing C-I bonds and in the deiodination of thyroid hormones by deiodinase mimics.26 Depending on the angular contacts of the halogen atoms involved in the interaction, two different kinds of X···X interactions have been proposed in the literature.61,62 In type I interactions, the values of θ1 and θ2, that is the C-X1···X2 and X1···X2-C angles (Figure 2A), respectively, are almost identical. These contacts appear due to a close packing of the molecules and it is common for all the halogens. Type I X···X interactions are generally not considered as halogen bonding63-65 interactions. Type II contacts are generally recognized by the perpendicular arrangements of the two C-X bonds i.e. θ1~180⁰ and θ2~90⁰ (Figure 2A). These interactions are called halogen bonding because the lateral negative potential of one halogen interacts with the positively charged σ-hole66,67 of the other halogen atom. There are some X···X interactions that lie in between the type I and type II interactions. These are termed as quasi-type I/type II X···X interactions. In a recent review, Desiraju and co-workers have summarized the criteria for different types of X···X interactions.62 For type I interactions, |θ1-θ2| should be in between 0⁰15⁰, whereas for type II interactions, |θ1-θ2| should be greater than 30⁰. X···X interactions having |θ1-θ2| between 15⁰ and 30⁰ can be termed as quasi-type I/type II. Two types of I···I interactions are observed in the crystal packing of T3. Both of these


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Figure 2. (A) Schematic representations of type I and type II X···X interactions. (B) Capped stick model of crystal packing of T3 indicating two types of I···I interactions. Hydrogen atoms are omitted for clarity. (C) NBO analysis of the type II I···I interaction in T3 indicating the natural charges on each iodine atoms. interactions are observed between the adjacent layers of T3. Interestingly, only tyrosyl ring iodine atoms form these I···I contacts. The orientations of the T3 molecules in the adjacent layers appeared to be antiparallel to each other. Each 5-iodine atoms of T3 in one layer form two identical I···I contacts with the 5-iodine atoms of two T3 molecules in the adjacent layer as shown in Figure 2B. Similarly, 3-iodine atoms of T3 in one layer also form two identical I···I contacts with 3-iodine atoms of two T3 molecules in the adjacent layer. However, I···I contacts


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formed by 3-iodine atoms are weaker (I···I distance, 3.861 Å) than those formed by 5-iodine atoms (I···I distance, 3.643 Å). These distances are 2.5% and 8%, respectively, shorter than the sum of the van der Waals radii of iodine (1.98 Å). These I···I interactions were categorized by analyzing the values of θ1 and θ2 (Figure 2B, insets). The contacts formed by the 5-iodine atom (I···I distance, 3.643 Å) appear to be of type II category with a |θ1-θ2| of 73.4⁰ whereas the contacts formed by 5'-iodine atom (I···I distance, 3.861 Å) appear to be of type III or quasi type I/type II category with a |θ1-θ2| of 26.6⁰. For these I···I interactions, two adjacent layers of T3 are brought close to each other by water mediated hydrogen bonds between 4'-OH group and carboxylic acid group, 4'-OH group and trifluoroacetate, and salt bridge interaction between αamine group and trifluoroacetate (Figure S19B, Supporting Information). To understand the electronic nature of the type II I···I halogen bonds, natural bond orbital (NBO) analysis, using B3LYP hybrid functional, 6-311G** basis set for iodine and 6-31+G* basis set for all other atoms, was carried out on the I···I bonded T3 molecules. As each T3 molecule, in one layer, forms two identical type II I···I halogen bonds with two T3 molecules in the adjacent layer, coordinates of such three T3 molecules were taken from the crystal structure. The overall positive charge on the iodine atoms IA, IB and IC are 0.296, 0.239 and 0.228 respectively (Figure 2C). The NBO calculations on the individual T3 molecules, involved in the type II I···I interaction, using the same level of theory and basis sets afforded the charges on IA, IB and IC as 0.261, 0.260 and 0.260, respectively. These results indicate that IA and IB act as halogen bond acceptors (electron donors) in the IA···IB and IB···IC interactions, respectively. As these I···I interactions extend through the three-dimensional crystal packing, all the iodine atoms involved in the type II interaction can be considered as a halogen bond donor as well as a halogen bond acceptor. Although the I···I distances for all the type II interactions are same


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(3.643 Å), the strength of the halogen bonding between each pair of the iodine atoms appeared to be slightly different. For the assembly shown in Figure 2C, the interaction energy between IA and IB is 5.66 Kcal/mol whereas the energy between IB and IC is 6.14 Kcal/mol. By contrast to type II interaction, in type III I···I interaction, both the iodine atoms donate electron density to the σhole of the other iodine atom (Figure S26, Supporting Information). However, in each set of type III interactions, the donation of electron density is more favoured in one direction. These type of interactions are probably facilitated by relaxation from almost perpendicular arrangements of two C-I units observed in type II interactions. Type III I···I interactions in T3 are 2.5-2.8 times weaker than the type II I···I interactions. In contrast to T3, T3AM does not show I···I interactions in their solid state crystal packing. However, rT3AM shows both type I and type II I···I interactions in the crystal packing. Interestingly, only the phenolic-ring iodine atoms take part in these I···I interactions. In the asymmetric unit, two rT3AM molecules are hydrogen bonded via 4'-OH groups (Figure S20B, Supporting Information). Both the 3'- and 5'-iodine atoms of rT3AM, in each layer, form a type II I···I contact with the 5'- and 3'-iodine atoms, respectively, of rT3AM molecules in the adjacent layers as shown in Figure 3A. However, the geometries (θ1, θ2 and I···I distance) of these two type II contacts are not identical. One set of type II interactions are identified by I···I distance of 3.662 Å and |θ1-θ2| of 58.8⁰ whereas the other set is recognized by I···I distance of 3.727 Å and |θ1-θ2| of 57.4⁰. These two interatomic distances are 7.5% and 5.9%, respectively, shorter than the sum of the Van der Waals radii of iodine (1.98 Å). Type I contacts, as shown in Figure 3A, has an I···I distance of 3.747 Å and |θ1-θ2| of 12.8⁰. The NBO analysis on the halogen-bonded assembly has been carried out by following a similar procedure as described for T3. In Figure 3B, the interactions among the four iodine atoms are


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Figure 3. (A) Capped stick model of crystal packing of rT3AM indicating the geometries of type I and type II I···I interactions. Trifluoroacetate and water molecules are omitted for clarity. (B) NBO analysis of the type I and type II I···I interactions in rT3AM. Hydrogen atoms are omitted for clarity. The table indicates the natural charges on each iodine atoms at the halogen bonded (X-bonded) and isolated state, and the halogen bonding (X-bonding) energies. (C) Space filling model of crystal packing of rT3AM indicating that both the I···I halogen bonding and H-bonding involving rT3AM, trifluoroacetate and water molecules help in close packing of rT3AM molecules.


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shown. The directions of arrow indicate the donation of electron density from one iodine atom to the σ-hole of other. The positive charge on IA and IB, 0.222 and 0.214, respectively, in the isolated state changes to 0.188 and 0.221, respectively, after halogen bonding interaction (Figure 3B, see table). Similarly, the positive charge on IC and ID, 0.210 and 0.231, respectively, in the isolated state changes to 0.208 and 0.200, respectively, after halogen bonding interaction. The direction of transfer of electron density from one iodine atom to another has been derived from the NBO calculation. The interaction energy between IA and IB is 5.05 Kcalmol-1 whereas the same between IC and ID is 4.24 Kcalmol-1. Type I interaction between IB and IC involves a very weak electron donation from IC to IB with interaction energy of 1.3 Kcal.mol-1. Together with Hbonding among rT3AM, trifluoroacetate and water molecules, I···I halogen bonding interaction helps in close packing of layers of rT3AM (Figure 3C). The diiodo derivative, 3,5-T2, with both the iodine atoms in the tyrosyl ring, is an important metabolite of thyroid hormones. Chronic administration of 3,5-T2 in wistar rats has been shown to exhibit selective thyromimetic activity68 with a decrease in thyroidal iodide uptake, thyroperoxidase (TPO)-activity, NADPH oxidase 4 (NOX 4)-activity, Dio1-activity and with an increase in expression of thyroid stimulating hormone (TSH) receptor and dual oxidase (DUOX)-activity.69 3,5-T2 treatment of rats also resulted in decrease in TSH, T3 and T4 concentration in a dose dependent manner. 3,5-T2 administration to rats receiving fat enriched diet reduced both the adiposity and body-weight gain without affecting the serum TSH, T3 and T4 concentration.70 This compound has also been shown to have significant thyromimetic activity in in vitro assays involving nuclear receptors (TRs) and GH3 cells.71 However, the biosynthesis of 3,5-T2 is still not clear. Although in many experiments T3 has been excluded as substrate for phenolic-ring deiodination by DIO1, homogenates of NCLP-6E monkey


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hepatocarcinoma cells expressing DIO1 enzymatic activity were reported to mediate phenolicring deiodination of T3 to produce 3,5-T2.16,17 Solution state structure of 3,5-T2 was investigated earlier by spin-lattice relaxation time analysis of 1H and

13

C NMR spectra, and

13

C nuclear

overhauser enhancement factors.38 Cody and co-workers reported the first crystal structure of a 1:1 complex of 3,5-T2 and N-methylacetamide.72 In the present study, we obtained the crystal structure of the zwitterionic form of 3,5-T2. Similar to the N-acetamide salt,72 the zwitterionic form of 3,5-T2 also exhibits a transoid geometry of the phenolic ring and the amino acid backbone with respect to the tyrosyl ring (Figure 4A). Removal of one iodine atom from the phenolic ring of T3 changes the values of χ1 and χ2 from -72.8⁰ to -57.3⁰ and from -78.8⁰ to -55.1⁰, respectively (Table 1). Interestingly, in 3,5-T2 both the swinging and twisting of the phenolic ring about C4-O3 and O3-C1' axis, respectively, is significantly different from those in T3 (see the values of φ and φ' from Table 1). Furthermore, it should be noted that in 3,5-T2, the twisting of phenolic ring is in the opposite direction compared to that in T3. Removal of carboxyl group from 3,5-T2 makes the aminoethyl side chain of 3,5-T2AM coplanar with the tyrosyl ring (Figure 4A and 4B). In agreement, similar to the decarboxylation of T3 to T3AM, the value of χ1 changes from -57.3⁰ in 3,5-T2 to -171.5⁰ in 3,5-T2AM. By contrast to the differences in the values of χ1 and χ2 between T3 and 3,5-T2, these torsional angles were found to be almost similar in T3AM and 3,5-T2AM (Table 1). Although φ is almost similar in T3AM and 3,5- T2AM, φ' values are significantly different in these two thyroid hormone metabolites. It should be noted that the average C-I bond lengths for tyrosyl ring iodine atoms are almost similar in 3,5-T2AM (2.089 Å) and T3AM (2.084 Å). 3,3'-T2AM and 3',5'-T2AM are two diiodinated iodothyronamines which can be biosynthesized by tyrosyl ring deiodination of T3AM and rT3AM, respectively, by DIO1.15


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Figure 4. C-I bond lengths (Å) and C4-O3-C1' bond angles (⁰) in the ball and stick model of single crystal X-ray structures of 3,5-T2 (A), 3,5-T2AM (B), 3,3'-T2AM (C) and 3',5'-T2AM (D). Trifluoroacetate and water molecules are omitted for clarity. (E) Ball and stick model of solid state crystal packing of 3,5-T2AM indicating the geometries of type II I···I and F···I interactions. Hydrogen atoms and water molecules are omitted for clarity.


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Phenolic ring deiodination of rT3AM by DIO1 can also produce 3,3'-T2AM. Like T3AM and rT3AM, 3,3'-T2AM also exists in the transoid geometry (Figure 4C). Interestingly, the 3'-iodine atom in 3,3'-T2AM adopts distal position with respect to the tyrosyl position. This observation indicates that the removal of one tyrosyl ring iodine from T3AM, in which 3'-iodine adopts proximal position, results in rotation of the phenolic ring around O3-C1' bond to place the 3'iodine in a distal position. This structural rearrangement results in change in swinging and twisting of the phenolic ring of 3,3'-T2AM by about 15-20⁰ compared to T3AM (Table 1). However, the arrangement of the phenolic ring of 3,3'-T2AM is almost identical to that in rT3AM (see the values of φ and φ' from Table 1), indicating that the phenolic ring deiodination of rT3AM to 3,3'-T2AM does not affect the mutual perpendicularity of the two substituted phenyl rings. By contrast, tyrosyl ring deiodination of rT3AM to 3',5'-T2AM changes the φ and φ' by almost 12⁰ and 27⁰, respectively (Table 1). Surprisingly, unlike all other iodothyronamine derivatives, 3',5'-T2AM exhibits a cisoid geometry of phenolic ring and aminoethyl side chain with respect to tyrosyl ring (Figure 4D). In agreement with this, the sign of χ2 is opposite to that observed in other iodothyronamine metabolites (Table 1). All the diiodo thyroid hormone derivatives and their metabolites show extensive H-bonding involving water molecules and trifluoroacetate (for iodothyronamines) moieties (Figures S21S24, Supporting Information). However, among the di-iodinated iodothyronamines, only 3,5T2AM forms I···I interactions in the crystal packing. These interactions are type II in nature with I···I distances of 3.779 Å and |θ1-θ2| of 44.2⁰ (Figure 4E). This non-covalent I···I distance is 4.6% shorter than the sum of the van der Waals radii of the iodine (1.98 Å). In the isolated state, the positive charge on IA and IB (Figure 4E) are 0.257 and 0.254, respectively. After formation of


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halogen bonding by donation of electron density from IA to the σ-hole of IB, the charges on IA and IB become 0.267 and 0.226, respectively. NBO calculations, using the similar basis sets and hybrid functional as discussed earlier, on this halogen-bonded assembly gave the interaction energy between IA and IB as 3.61 Kcal/mol. Another interesting feature of the crystal packing of 3,5-T2AM is the inter-halogen F···I halogen bonding interaction between trifluoroacetate and 3,5-T2AM (Figure 4E). These contacts are also type II in nature with F···I distance of 3.261 Å and |θ1-θ2| of 44.8⁰. These F···I distances are 5.5% shorter than the sum of van der Waals radii of fluorine (1.47 Å) and iodine (1.98 Å). For these interactions, the electron density is transferred from fluorine atoms (halogen bond acceptor) to the σ-hole of iodine atoms (halogen bond donor). A similar type II O···I halogen bonding was also observed in the crystal packing of 3,3'-T2AM (Figure S23, Supporting Information). Phenolic ring deiodination of 3,3'-T2AM by DIO1 as well as tyrosyl ring deiodination of 3,5T2AM by DIO1 and DIO3 produces 3-iodothyronamine (3-T1AM).15 The other monoiodo metabolite 3'-T1AM is produced by tyrosyl ring deiodination of 3,3'-T2AM by DIO3 as well as by phenolic ring deiodination of 3',5'-T2AM by DIO1 and DIO2. 3-T1AM further undergoes tyrosyl ring deiodination by DIO3 to produce the completely deiodinated metabolite T0AM whereas 3'-T1AM does not undergo any further deiodination to form T0AM (Scheme 1).15 By contrast, 3'-T1 undergo phenolic deiodination by DIO1 to form T0 whereas 3-T1 does not undergo deiodination to form T0.16-21 These observations clearly indicate that the decarboxylation of β-alanine side chain of the thyroid hormones changes the substrate specificity of the DIOs. Recently, Scanlan and co-workers have identified apolipoprotein B-100 (apoB100), the protein component of several low density lipoprotein particles, to be a specific transporter (KD = 17 nM) of 3-T1AM with a 3-T1AM/apoB-100 stoichiometry of 1:1.24 They


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found 3'-T1AM and T0AM to be very weak competitive inhibitors of binding of 3-T1AM to apoB-100 with IC50 values of 259 nM and 268 nM, respectively. However, the three dimensional structures and conformations of 3-T1AM, 3'-T1AM and T0AM are not known. It is possible that 3-T1AM has the optimized structure and conformational parameters for its maximum transport and physiological activity. Trifluoroacetate salt of 3-T1AM crystallizes in monoclinic space group P 21/C. The transoid conformation of 3-T1AM exhibits antiparallel arrangement of the amino group (χ1 = 178.1⁰ and χ2 = -69.8⁰) with respect to the tyrosyl ring (Figure 5A and Table 1). The “swinging” (φ) of the phenolic-ring about C4-O3 axis is 102.3⁰ whereas the twisting (φ') of the same about O3-C1' axis is -22.8⁰ (Table 1). Removal of the tyrosyl ring iodine from 3,5-T2AM decreases the φ' by almost 11⁰ without affecting φ much (Table 1). In contrast, removal of phenolic ring iodine from 3,3'-T2AM

decreases the φ by almost 10⁰ without affecting φ' much. These observations

indicate that the removal of tyrosyl and phenolic ring iodine atoms from 3,5-T2AM and 3,3'T2AM, respectively, have nearly opposite effects on the conformations of the deiodinated product 3-T1AM. The other monoiodo metabolite 3'-T1AM crystallizes in monoclinic space group P 21/n. Interestingly, two independent conformations were observed in the asymmetric unit of 3'-T1AM. Both the conformations have transoid geometry of the phenolic ring and the aminoethyl side chain with respect to the tyrosyl ring (Figure 5B). However, analysis of the positions of the iodine atom revealed that in one conformation 3'iodine atom is close to tyrosyl ring (proximal conformer), whereas in the other conformer, the same is away from the tyrosyl ring (distal conformer). The swinging of phenolic ring about C4O3 axis is 164.2⁰ in the proximal conformer whereas the same in distal conformer is 49.9⁰


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(Table1). The twisting of the phenolic ring about O3-C1' axis is -72.7⁰ in the proximal conformer whereas the same in the distal conformer is 45.9⁰. Therefore, the presence of the iodine atom in

Figure 5. Bond lengths (Å) and C4-O3-C1' bond angles (⁰) in the ball and stick model of X-ray crystal structures of 3-T1AM (A), 3'-T1AM (B) and T0AM (C). Both the proximal and distal conformers of 3'-T1AM are shown. (D) Ball and stick model of crystal packing of 3-T1AM indicating the geometries of type I I···I interaction. Trifluoroacetate and water molecules are omitted from all the structures for clarity. the phenolic ring significantly affects the “twisting” and “swinging” of the same ring compared to 3-T1AM and other iodothyronamine metabolites. These significant structural differences between 3-T1AM and 3'-T1AM may account for different substrate specificities of DIO1


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towards monoiodothyroanmines described earlier (Scheme 1). Completely deiodinated thyronamine (T0AM) also shows transoid conformation (Figure 5C). The “twisting” and “swinging” of the phenolic-ring are 142.8⁰ and -73.1⁰, respectively (Table 1). In the crystal packing of 3-T1AM, type I I···I interactions, with a I···I distance of 3.708 Å and |θ1-θ2| of 0⁰, were observed (Figure 5D). This non-bonded distance between two iodine atoms is 6.4% shorter than the sum of the van der Waals radii of iodine (1.98 Å). However, 3'-T1AM does not form I···I contacts in the crystal packing. Although the completely deiodinated species T0AM shows similar physiological activities like 3-T1AM, T0AM was found to be less potent than 3-T1AM in inducing hypothermia, bradycardia and hyperglycemia.12,13 Structural and conformational differences between T0AM and 3-T1AM may affect their binding to the receptors and transport proteins. It is known that the backbone nitrogen atom of Leu110 in transthyretin plays an important role in the binding of thyroxine by forming a N···I halogen bond.23 Iodine atom in the 3-position of 3-T1AM may form halogen bonding interaction with receptor and transport protein and this may increase the affnity of 3T1AM to receptors and transport proteins compared to T0AM. However, further studies including co-crystal structures of 3-T1AM and T0AM with transport protein or receptor are requirred to understand the different physiological activites of these interesting decarboxylated thyroid hormone metabolites. CONCLUSIONS In this paper, we have discussed the structures and conformations of iodothyronamines and some of the thyroid hormones. Iodothyronamines are decarboxylated thyroid hormone metabolites and we have shown that the decarboxylation of β-alanine side chain of thyroid hormones affects the three-dimensional structure of iodothyronamines significantly. Iodothyronamines are recognised


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as substrates of iodothyronine deiodinses (DIOs), although some of the deiodinated iodothyronamines are not accepted by DIOs as substrates. We have shown that the deiodination of iodothyronamines results in significant alterations in the conformation of the deiodinated product which can account for the different substrate specificities of DIOs. These crystal structures would help in understanding the importance of conformational parameters in the binding of thyroid hormones and iodothyronamines to their transport proteins and cellular receptors. The presence of I···I halogen bonding in the crystal packing of thyroid hormones and iodothyronamines uncovers the potential of the iodine atoms in the these hormones to form halogen bonding with donor atoms from receptors or enzymes. EXPERIMENTAL SECTION Synthesis: Iodothyronamines have been synthesized using a similar procedure reported by Scanlan et al. with minor modifications.25 T4AM. N-t-BOC-3,3',5,5'-tetraiodothyronamine (200 mg, 0.24 mmol) was stirred with 1:4 v/v mixture of trifluoroacetic acid and dichloromethane for 1h. The solvent was evaporated under vacuum to yield a yellowish white sticky solid. T4AM was purified from the crude reaction mixture by reverse-phase HPLC using a C18 column (Atlantis, 250 × 19 mm, 10µm) and 70% methanol/water as mobile phase. T4AM containing fractions were lyophilized to yield a white solid in 90% yield. 1H NMR (d4-MeOH) δ (ppm): 7.89 (s, 2H), 7.10 (s, 2H), 3.22 (t, J = 7.6 Hz, 2H), 2.94 (t, J = 7.6 Hz, 2H); 13C NMR (d4-MeOH) δ (ppm): 153.3, 151.6, 150.7, 141.0, 138.6, 126.2, 91.1, 84.7, 40.4, 31.8; ESI-MS (m/z) calculated for C14H11NO2I4 [M+H]+: 733.7047, found 733.9314.


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T3AM. This compound was synthesized by using N-t-BOC-3,3',5-triiodothyronamine (200 mg, 0.28 mmol) as described earlier for T4AM. Yield: 92%. 1H NMR (d4-MeOH) δ (ppm): 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) δ (ppm): 153.9, 152.5, 149.9, 141.0, 138.2, 125.6, 116.8, 115.0, 91.4, 83.4, 40.5, 31.8; ESI-MS (m/z) calculated for C14H13NO2I3 [M+H]+: 607.8080, found 607.7704. rT3AM. This compound was synthesized by using N-t-BOC-3,3',5'-triiodothyronamine (200 mg, 0.28 mmol) as described earlier for T4AM. Yield: 95%. 1H NMR (d4-MeOH) δ (ppm): 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), 2.94 (t, J = 7.6 Hz, 2H);

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C NMR (d4-MeOH) δ (ppm): 156.0, 152.6, 151.3, 140.5, 135.0, 130.7, 129.0,

119.8, 88.8, 84.5, 40.7, 32.3; ESI-MS (m/z) calculated for C14H13NO2I3 [M+H]+: 607.8080, found 607.7794. 3,3'-T2AM. This compound was synthesized by using N-t-BOC-3,3'-diiodothyronamine (200 mg, 0.34 mmol) as described earlier for T4AM. Yield: 93%. 1H NMR (d4-MeOH) δ (ppm): 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 (t, J = 7.6 Hz, 2H);

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C NMR (d4-MeOH) δ (ppm): 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; ESI-MS (m/z) calculated for C14H14NO2I2 [M+H]+: 481.9114, found 481.8453. 3,5-T2AM. This compound was synthesized by using N-t-BOC-3,5-diiodothyronamine (200 mg, 0.34 mmol) as described earlier for T4AM. Yield: 90%. 1H NMR(d4-MeOH) δ (ppm): 7.86 (s, 2H), 6.70 (d, J = 8.8 Hz, 2H), 6.56 (d, J = 8.8 Hz, 2H), 4.63 (s, br, 2H), 3.31 (t, J = 1.2 Hz, 2H), 2.93 (d, br, J = 6.8 Hz, 2H);

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C NMR (d4-MeOH) δ (ppm): 154.3, 152.5, 150.0, 140.9, 137.8,


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116.3, 115.9, 91.6, 40.5, 31.8; ESI-MS (m/z) calculated for C14H13NO2I2 [M+H]+: 481.9114, found 481.8681. 3',5'-T2AM. This compound was synthesized by using N-t-BOC-3',5'-diiodothyronamine (200 mg, 0.34 mmol) as described earlier for T4AM. Yield: 94%. 1H NMR (d4-MeOH) δ (ppm): 7.39 (s, 2H), 7.29 (d, J = 8.4 Hz, 2H), 6.96 (d, J = 8.4 Hz, 2H), 3.19 (t, J = 7.6 Hz, 2H), 2.96 (t, J = 8 Hz, 2H);

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C NMR (d4-MeOH) δ (ppm): 157.1, 152.6, 151.5, 132.1, 130.5, 130.0, 118.9, 84.4,

41.0, 32.9; ESI-MS (m/z) calculated for C14H13NO2I2 [M+H]+: 481.9114, found 481.8962. 3-T1AM. This compound was synthesized by using N-t-BOC-3-iodothyronamine (200 mg, 0.56 mmol) as described earlier for T4AM. Yield: 95%. 1H NMR (d4-MeOH) δ (ppm): 7.79 (d, J = 2 Hz, 1H), 7.19 (dd, J = 6.4 Hz, 1H), 6.77-6.83 (m, J = 9.2 Hz, 4H), 6.71 (d, J = 8.4 Hz, 1H), 3.14 (t, J = 8 Hz, 2H), 2.88 (t, J = 7.6 Hz, 2H); 13C NMR (d4-MeOH) δ (ppm): 157.7, 154.3, 149.3, 140.1, 133.1, 130.1, 120.5, 117.6, 116.3, 87.5, 40.8, 32.3; ESI-MS (m/z) calculated for C14H14NO2I1 [M+H]+: 356.0147, found 356.0094. 3'-T1AM. This compound was synthesized by using N-t-BOC-3'-iodothyronamine (200 mg, 0.56 mmol) as described earlier for T4AM. Yield: 91%. 1H NMR (d4-MeOH) δ (ppm): 7.30 (d, J = 2.8 Hz, 1H), 7.23 (d, J = 8.8 Hz, 2H), 6.88-6.91 (m, J = 2.8 Hz, 3H), 6.83 (d, J = 8.8 Hz, 1H), 3.15 (t, J = 8.4 Hz, 2H), 2.92 (t, J = 8 Hz, 2H);

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C NMR (d4-MeOH) δ (ppm): 158.0, 153.8,

150.0, 131.2, 130.2, 130.1, 120.9, 118.2, 115.0, 83.3, 41.0, 32.8; ESI-MS (m/z) calculated for C14H14NO2I1 [M+H]+: 356.0147, found 356.0525. T0AM. This compound was synthesized by using N-t-BOC-thyronamine (200 mg, 0.87 mmol) as described earlier for T4AM. Yield: 96%. 1H NMR (d4-MeOH) δ (ppm): 7.21 (d, J = 8.4 Hz, 2H), 6.87 (t, J = 10.4 Hz, 4H), 6.79 (d, J = 8.8 Hz, 2H), 3.15 (t, J = 8 Hz, 2H), 2.91 (t, J = 8 Hz,


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2H); 13C NMR (d4-MeOH) δ (ppm): 158.6, 154.1, 149.4, 130.6, 130.1, 121.1, 117.7, 116.2, 41.1, 32.8; ESI-MS (m/z) calculated for C14H15NO2 [M+H]+: 230.1181, found 230.0648. Computational Method: All the DFT calculations were performed in Gaussian03 and Gaussian09 suites of quantum chemical programme using the hybrid Becke 3-Lee-Yang-Parr (B3LYP) exchange correlation functional.73-76 For the analysis of the I···I halogen bonding, coordinates have been taken from the crystal structure of the thyroid hormones and iodothyronamines. Natural Bond Orbital (NBO) calculations77,78 were performed using 6-31+G* basis sets except iodine for which 6-311G** basis set was used. Single-crystal X-Ray crystallography: T3, T3AM, 3'-T1AM were recrystallized as trifluoroacetate salt from a 1:1 mixture of ethyl acetate-di ethyl ether by slow evaporation method. rT3AM, 3,5-T2AM, 3,3'-T2AM, 3',5'-T2AM, 3-T1AM and T0AM were recrystallized as trifluoroacetate salt from a 3:1 methanol-water solution. 3,5-T2 was recrystallized as zwitter-ion from an ammoniacal mixture of water and methanol (1:3). The single crystal X-ray diffraction data were collected on a Bruker SMART APEX CCD diffractometer utilizing SMART/SAINT software.79 Intensity data were collected using graphite-monochromatized Mo-Kα radiation of wavelength 0.71073 Å at room temperature. All the structures were solved by SHELX-97 program incorporated in WinGX. Empirical absorption corrections were applied with SADABS.80,81 T3.CF3CO2. C17H13NO8F3I3, Fw = 796.98, Monoclinic P21, a = 15.124(3) Å , b = 5.0451(10) Å, c = 16.052(3) Å, α= 90⁰, β= 103.409(12)⁰, γ = 90⁰, V = 1191.5(4) Å3, Z = 2, MoKα radiation (λ = 0.71073 Å), T = 296(2) K, ρcalcd (gcm-3) = 2.222, µ (MoKα) (mm-1) = 4.000, Collected reflections = 7017, Unique reflections = 3357, GOF (F2) = 0.957, R1a = 0.0578, wR2b = 0.1373.


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T3AM.CF3CO2. C16H13NO4F3I3, Fw = 720.97, Monoclinic P 21/C, a = 6.565(4) Å , b = 11.892(8) Å, c = 27.565(18) Å, α= 90⁰, β= 89.92(4)⁰, γ = 90⁰, V = 2152(2) Å3, Z = 4, MoKα radiation (λ = 0.71073 Å), T = 296(2) K, ρcalcd (gcm-3) = 2.225, µ (MoKα) (mm-1) = 4.403, Collected reflections = 5070, Unique reflections = 1967, GOF (F2) = 0.901, R1a = 0.0732, wR2b = 0.2089. rT3AM.CF3CO2. C16H15N1O5F3I3, Fw = 738.99, Triclinic P -1, a = 8.6684(5) Å , b = 9.1810(5) Å, c = 31.3546(18) Å, α= 88.003(2)⁰, β= 83.224(2)⁰, γ = 62.305(2)⁰, V = 2193.5(2) Å3, Z = 4, MoKα radiation (λ = 0.71073 Å), T = 296(2) K, ρcalcd (gcm-3) = 2.238, µ (MoKα) (mm-1) = 4.325, Collected reflections = 11565, Unique reflections = 7322, GOF (F2) = 1.029, R1a = 0.0446, wR2b = 0.1090. 3,5-T2AM.CF3CO2. C16H16NO5F3I2, Fw = 613.10, Monoclinic C 2/c, a = 14.9418(2) Å , b = 10.3139(15) Å, c = 26.3434(4) Å, α= 90⁰, β= 92.614(4)⁰, γ = 90⁰, V = 4055.5(10) Å3, Z = 8, MoKα radiation (λ = 0.71073 Å), T = 296(2) K, ρcalcd (gcm-3) = 2.008, µ (MoKα) (mm-1) = 3.154, Collected reflections = 6294, Unique reflections = 5023, GOF (F2) = 1.055, R1a = 0.0370, wR2b = 0.0822. 3,5-T2. C15H13NO4I2, Fw = 525.06, orthorhombic P212121, a = 6.0404(17) Å , b = 12.8126(3) Å, c = 24.8761(5) Å, α= 90⁰, β= 90⁰, γ = 90⁰, V = 1925.3(8) Å3, Z = 4, MoKα radiation (λ = 0.71073 Å), T = 296(2) K, ρcalcd (gcm-3) = 1.811, µ (MoKα) (mm-1) = 3.281, Collected reflections = 3851, Unique reflections = 2613, GOF (F2) = 1.079, R1a = 0.0703, wR2b = 0.2385. 3,3'-T2AM.CF3CO2. C16H15NO5F3I2, Fw = 612.09, Monoclinic C 2/c, a = 28.792(5) Å , b = 8.390(5) Å, c = 16.654(5) Å, α= 90⁰, β= 92.033(5)⁰, γ = 90⁰, V = 4021(3) Å3, Z = 8, MoKα radiation (λ = 0.71073 Å), T = 296(2) K, ρcalcd (gcm-3) = 2.022, µ (MoKα) (mm-1) = 3.181,


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Collected reflections = 6162, Unique reflections = 4960, GOF (F2) = 1.013, R1a = 0.0306, wR2b = 0.0758. 3',5'-T2AM.CF3CO2. C16H14NO4F3I2, Fw = 595.08, Triclinic P -1, a = 5.5691(6) Å , b = 10.3724(11) Å, c = 17.6633(18) Å, α= 78.671(6)⁰, β= 85.729(5)⁰, γ = 79.229(5)⁰, V = 982.06(18) Å3, Z = 2, MoKα radiation (λ = 0.71073 Å), T = 296(2) K, ρcalcd (gcm-3) = 2.012, µ (MoKα) (mm-1) = 3.250, Collected reflections = 6149, Unique reflections = 4278, GOF (F2) = 1.056, R1a = 0.0365, wR2b = 0.0977. 3-T1AM.CF3CO2. C16H17NO5F3I1, Fw = 487.21, Monoclinic P 21/c, a = 15.4185(4) Å , b = 14.7521(4) Å, c = 8.7484(19) Å, α= 90⁰, β= 106.186(13)⁰, γ = 90⁰, V = 1910.9(8) Å3, Z = 4, MoKα radiation (λ = 0.71073 Å), T = 296(2) K, ρcalcd (gcm-3) = 1.694, µ (MoKα) (mm-1) = 1.729, Collected reflections = 6081, Unique reflections = 3093, GOF (F2) = 1.006, R1a = 0.0493, wR2b = 0.1414. 3'-T1AM.CF3CO2. C16H15NO4F3I1, Fw = 469.19, Monoclinic P21/n, a = 12.158(2) Å , b = 9.3054(17) Å, c = 32.979(6) Å, α= 90⁰, β= 92.357(12)⁰, γ = 90⁰, V = 3728(11) Å3, Z = 8, MoKα radiation (λ = 0.71073 Å), T = 296(2) K, ρcalcd (gcm-3) = 1.672, µ (MoKα) (mm-1) = 1.766, Collected reflections = 11436, Unique reflections = 3013, GOF (F2) = 0.931, R1a = 0.0831, wR2b = 0.3050. T0AM.CF3CO2. C16H16NO4F3, Fw = 343.30, Monoclinic P21/c, a = 16.9525(2) Å , b = 11.7547(14) Å, c = 8.0149(10) Å, α= 90⁰, β= 93.763(4)⁰, γ = 90⁰, V = 1593.7(3) Å3, Z = 4, MoKα radiation (λ = 0.71073 Å), T = 296(2) K, ρcalcd (gcm-3) = 1.431, µ (MoKα) (mm-1) = 0.125, Collected reflections = 4979, Unique reflections = 2326, GOF (F2) = 1.008, R1a = 0.0630, wR2b = 0.2062. ASSOCIATED CONTENT


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Supporting Information. Synthesis schemes, 1H and 13C NMR spectra, mass spectra, ORTEP diagrams, crystal packing, H-bonding interactions have been included. This material is available free of charge via the Internet at http://pubs.acs.org. AUTHOR INFORMATION Corresponding Author *Email: [email protected] Funding Sources This study was supported by Science and Engineering Research Board (SERB), New Delhi, India. ACKNOWLEDGMENT This study was financially supported by Science and Engineering Research Board (SERB), India. S. Mondal thanks Indian Institute of Science, Bangalore for a research fellowship, Division of Chemical Sciences, IISc for single-crystal X-Ray diffraction (SCXRD) facility and Dr. Arun Kumar Bar for his training on solving crystal structures. G. Mugesh thanks SERB for the J. C. Bose National Fellowship (Grant No. SB/S2/JCB-067/2015). REFERENCES (1)

Behne, D.; Kyriakopoulos, A.; Meinhold, H.; Köhrle, J.; Biochem. Biophys. Res. Commun. 1990, 173, 1143-1149.

(2)

Berry, M. J.; Banu, L.; Larsen, P. R. Nature 1991, 349, 438-440.


29


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 30 of 38

(3)

Larsen, P. R.; Berry, M. J. Annu. Rev. Nutr. 1995, 15, 323.

(4)

Leonard, J. L.; Köhrle, J. “Intracellular Pathways of Iodothyronine Metabolism” in The Thyroid; Braverman, L. E.; Utiger, R. D. Eds.; Lippincott-Raven, Philadelphia, 1996, p. 144.

(5)

Germain, D. L. St.; Galton, V. A. Thyroid 1997, 7, 655. (f) Mondal, S.; Raja, K.; Schweizer, U.; Mugesh, G. Angew. Chem. Int. Ed. 2016, 7606-7630.

(6)

Bianco, A. C.; Salvatore, D.; Gereben, B.; Berry, M. J.; Larsen, P. R. Endocr. Rev. 2002, 23, 38-89.

(7)

Köhrle, J. Methods Enzymol. 2002, 347, 125-167.

(8)

Kuiper, G. G. J. M.; Kester, M. H. A.; Peeters, R. P.; Visser, T. J. Thyroid 2005, 15, 787798.

(9)

Visser, T. J.; Schoenmakers, C. H. H. Acta Med Austriaca 1992, 19, 18–21.

(10)

Köhrle, J. Mol. Cell. Endocrinol. 1999, 151, 103-119.

(11)

Köhrle, J.; Jakob, F.; Contempré, B.; Dumont, J. E. Endocr. Rev. 2005, 26, 944-984.

(12)

Scanlan, T. S.; Suchland, K. L.; Hart, M. E.; Chiellini, G.; Huang, Y.; Kruzich, P. J.; Frascarelli, S.; Crossley II, D. A.; Bunzow, J. R.; Ronca-Testoni, S.; Lin, E. T.; Hatton, D.; Zucchi, R.; Grandy, D. K. Nat. Med. 2004, 10, 638-642.

(13)

Doyle, K. P.; Suchland, K. L.; Ciesielski, T. M. P.; Lessov, N. S.; Grandy, D. K.; Scanlan, T. S.; Stenzel-poore, M. P. Stroke 2007, 38, 2569-2576.


30

Page 31 of 38

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(14)

Zucchi, R.; Chiellini, G.; Scanlan, T. S.; Grandy, D. K. Br. J. Pharmacol. 2006, 149, 967978.

(15)

Piehl, S.; Heberer, T.; Balizs, G.; Scanlan, T. S.; Smits, R.; Koksch, B.; Köhrle, J. Endocrinology 2008, 149, 3037-3045.

(16)

Sorimachi, K.; Cahnmann, H. J. Horm. Metab. Res. 1979, 11, 233-237.

(17)

Sorimachi, K.; Robbins, J. Biochim. Biophys. Acta 1979, 583, 443-453.

(18)

Chopra, I. J. Endocrinology 1981, 108, 464-471.

(19)

Otten, M. H.; Hennemann, G.; Docter, R.; Visser, T. J. Endocrinology 1984, 115, 887894.

(20)

Smallridge, R. C.; Whorton, N. E. Metabolism 1984, 33, 1034-1038.

(21)

Sorimachi, K.; Niwa, A.; Yasumura, Y. Endocrinol. Jpn. 1980, 27, 631-636.

(22)

Mondal, S.; Mugesh, G. Angew. Chem. Int. Ed. 2015, 54, 10833-10837.

(23)

Wojtczak, A.; Cody, V.; Luft, J. R.; Pangborn, W. Acta Crystallogr. Sect. D 2001, 57, 1061-1070.

(24)

Roy, G.; Placzek, E.; Scanlan, T. S. J. Biol. Chem. 2012, 287, 1790-1800.

(25)

Hart, M. E.; Suchland, K. L.; Miyakawa, M.; Bunzow, J. R.; Grandy, D. K.; Scanlan, T. S. J. Med. Chem. 2006, 49, 1101-1112.

(26)

Mondal, S.; Mugesh, G. Chem. Eur. J. 2014, 20, 11120-11128.

(27)

Cody, V. Acta Crystallogr. Sect. B 1981, 37, 1685-1689.


31


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 32 of 38

(28)

Selenkow, H. A.; Asper, S. P. Jr. Physiol. Rev. 1955, 35, 426-474.

(29)

Jorgensen, E. C. Pharmacol. Ther. Part B 1976, 2, 661-682.

(30)

Camerman, N.; Camerman, A. Science 1972, 175, 764-766.

(31)

Cody, V.; Duax, W. L. Science 1973, 181, 757-758.

(32)

Cody, V. J. Med. Chem. 1975, 18, 126-129.

(33)

Camerman, A.; Camerman, N. Acta Crystallogr. Sect. B 1974, 30, 1832-1840.

(34)

Okabe, N.; Fujiwara, T.; Yamagata, Y.; Tomita, K. I. Biochim. Biophys. Acta 1982, 717, 179-181.

(35)

Cody, V. Acta Crystallogr. Sect. C 1984, 40, 1214-1217.

(36)

Gale, D. J.; Craik, D. J.; Brownlee, R. T. C. Magn. Reson. Chem. 1988, 26, 275-280.

(37)

Duggan, B. M.; Craik, D. J. J. Med. Chem. 1996, 39, 4007-4016.

(38)

Duggan, B. M.; Craik, D. J. J. Med. Chem. 1997, 40, 2259-2265.

(39)

Camerman, N.; Fawcett, J. K.; Reynolds, W. F.; Camerman, A. Nature 1975, 253, 50-51.

(40)

Emmett, J. C.; Pepper, E. S. Nature 1975, 257, 334-336.

(41)

Nascimento, A. S.; Gomes Dias, S. M.; Nunes, F. M.; Aparício, R.; Ambrosio, A. L. B.; Bleicher, L.; Figueira, A. C. M.; Santos, M. A. M.; de Oliveira Neto, M.; Fischer, H.; Togashi, M.; Craievich, A. F.; Garratt, R. C.; Baxter, J. D.; Webb, P.; Polikarpov, I. J. Mol. Biol. 2006, 360, 586-598.


32

Page 33 of 38

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(42)

Kojetin, D. J.; Matta-Camacho, E.; Hughes, T. S.; Srinivasan, S.; Nwachukwu, J. C.; Cavett, V.; Nowak, J.; Chalmers, M. J.; Marciano, D. P.; Kamenecka, T. M.; Shulman, A. I.; Rance, M.; Griffin, P. R.; Bruning, J. B.; Nettles, K. W. Nat. Commun. 2015, 6, 8013.

(43)

Borel, F.; Hachi, I.; Palencia, A.; Gaillard, M. C.; Ferrer, J. L. FEBS J. 2014, 281, 15981612.

(44)

Eneqvist, T.; Lundberg, E.; Karlsson, A.; Huang, S.; Santos, C. R.; Power, D. M.; SauerEriksson, A. E. J. Biol. Chem. 2004, 279, 26411-26416.

(45)

CCDC 1420567 (rT3AM), 1420568 (3,5-T2), 1420569 (3,5-T2AM), 1420570 (3,3'T2AM), 1420571 (3',5'-T2AM), 1420572 (3-T1AM), 1420573 (3'-T1AM), 1420574 (T0AM) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre.

(46)

Mukherjee, A.; Desiraju, G. R. IUCrJ 2014, 1, 49-60.

(47)

Nygren, C. L.; Wilson, C. C.; Turner, J. F. C. J. Phys. Chem. A 2005, 109, 2586-2593.

(48)

Yamada, M.; Kanazawa, R.; Hamada, F. CrystEngComm 2014, 16, 2605-2614.

(49)

Mei, L.; Wang, C. -Z.; Wang, L.; Zhao, Y. -L.; Chai, Z. -F.; Shi, W.-Q. Cryst. Growth Des. 2015, 15, 1395-1406.

(50)

Berger, G.; Robeyns, K.; Soubhye, J.; Wintjensd, R.; Meyer, F. CrystEngComm 2016, 18, 683-690.

(51)

Metrangolo, P.; Meyer, F.; Pilati, T.; Resnati, G.; Terraneo, G. Chem. Commun. 2008, 1635-1637.


33


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 34 of 38

(52)

Brown, A.; Beer, P. D. Chem. Commun. 2016, DOI: 10.1039/c6cc03638d.

(53)

Lim, J. Y. C.; Cunningham, M. J.; Davis, J. J.; Beer, P. D. Chem. Commun. 2015, 51, 14640-14643.

(54)

Mele, A.; Metrangolo, P.; Neukirch, H.; Pilati, T.; Resnati, G. J. Am. Chem. Soc. 2005, 127, 14972-14973.

(55)

Manna, D.; Mugesh, G. Angew. Chem. Int. Ed. 2010, 49, 9246-9249.

(56)

Manna, D.; Mugesh, G. J. Am. Chem. Soc. 2011, 133, 9980-9983.

(57)

Manna, D.; Mugesh, G. J. Am. Chem. Soc. 2012, 134, 4269-4279.

(58)

Manna, D.; Mondal, S.; Mugesh, G. Chem. Eur. J. 2015, 21, 2409-2416.

(59)

Mondal, S.; Mugesh, G. Org. Biomol. Chem. 2016, DOI: 10.1039/c6ob01375a.

(60)

Mondal, S.; Manna, D.; Mugesh, G. Angew. Chem. Int. Ed. 2015, 54, 9298-9302.

(61)

Desiraju, G. R.; Parthasarathy, R. J. Am. Chem. Soc. 1989, 111, 8626-8627.

(62)

Mukherjee, A.; Tothadi, S.; Desiraju, G. R. Acc. Chem. Res. 2014, 47, 2514-2524.

(63)

Metrangolo, P.; Meyer, F.; Pilati, T.; Resnati, G.; Terraneo, G. Angew. Chem. Int. Ed. 2008, 47, 6114-6127.

(64)

Gilday, L. C.; Robinson, S. W.; Barendt, T. A.; Langton, M. J.; Mullaney, B. R.; Beer, P. D. Chem. Rev. 2015, 115, 7118-7195.

(65)

Parisini, E.; Metrangolo, P.; Pilati, T.; Resnati, G.; Terraneo, G. Chem. Soc. Rev. 2011, 40, 2267-2278.


34

Page 35 of 38

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(66)

“An Overview of σ-Hole Bonding, an Important and Widely-Occurring Noncovalent Interaction”: Politzer, P.; Murray, J. S. in Practical Aspects of Computational Chemistry Methods, Concepts, and Applications, Leszczynski, J.; Shukla, M. K. Eds.; Springer, Heidelberg, 2009, chap. 6.

(67)

Clark, T.; Hennemann, M.; Murray, J. S.; Politzer, P. J. Mol. Model. 2007, 13, 291-296.

(68)

Baxter, J. D.; Webb, P. Nat. Rev. Drug. Discov. 2009, 8, 308-320.

(69)

Padron, A. S.; Neto, R. A. L.; Pantaleão, T. U.; dos Santos, M. C. de S.; Araujo, R. L.; de Andrade, B. M.; Leandro, M. da S.; de Castro, J. P. S. W.; Ferreira, A. C. F.; de Carvalho, D. P. J. Endocrinol. 2014, 221, 415-427.

(70)

Ball, S. G.; Sokolov, J.; Chin, W. W. J. Mol. Endocrinol. 1997, 19, 137-147.

(71)

Lanni, A.; Moreno, M.; Lombardi, A.; de Lange, P.; Silvestri, E.; Ragni, M.; Farina, P.; Baccari, G. C.; Fallahi, P.; Antonelli, A.; Goglia, F. FASEB J. 2005, 19, 1552-1554.

(72)

Cody, V.; Duax, W. L.; Norton, D. A. Acta Crystallogr. Sect. B 1972, 28, 2244-2252.

(73)

Gaussian 03, Revision C.02, Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Montgomery, Jr., J. A.; Vreven, T.; Kudin, K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.;


35


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 36 of 38

Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian, Inc., Wallingford CT, 2004. (74)

Gaussian 09, Revision A.1, Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, Jr., J. A.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, N. J.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, Ö.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian, Inc., Wallingford CT, 2009.

(75)

Becke, A. D. J. Chem. Phys. 1993, 98, 5648-5652.

(76)

Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37, 785-789.

(77)

Reed, A. E.; Curtiss, L. A.; Weinhold, F. Chem. Rev. 1988, 88, 899-926.


36

Page 37 of 38

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(78)

Glendening, E. D.; Reed, J. E.; Carpenter, J. E.; Weinhold, F. NBO Program 3.1; Madison, WI, 1988.

(79)

Altomare, A.; Cascarano, G.; Giacovazzo, C.; Gualardi, A. J. Appl. Crystallogr. 1993, 26, 343-350.

(80)

Sheldrick, G. M. Acta Crystallogr. Sect. A 1990, 46, 467-473.

(81)

Sheldrick, G. M. SHELX-97, Program for the Refinement of Crystal Structures; University of Göttingen: Göttingen, Germany, 1997.


37


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 38 of 38

For Table of Contents Use Only Conformational Flexibility and Halogen Bonding in Thyroid Hormones and their Metabolites Santanu Mondal and Govindasamy Mugesh*

Crystal structures of Iodothyronamines and thyroid hormones reveal the potential of iodine atoms to form halogen bonding with halogen bond acceptors. Tyrosyl and phenolic ring deiodinations of the hormone metabolites lead to significant conformational changes.


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Conformational Flexibility and Halogen Bonding in Thyroid Hormones

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