Deiodination of Thyroid Hormones by Iodothyronine Deiodinase Mimics: Does an Increase in the Reactivity Alter the Regioselectivity?

Organoselenium compounds as functional mimics of iodothyronine deiodinase are described. The naphthyl-based compounds having two selenol groups are remarkably efficient in the inner-ring deiodination of thyroxine. The introduction of a basic amino group in close proximity to one of the selenol moieties enhances the deiodination. This study suggests that an increase in the nucleophilic reactivity of the conserved Cys residue at the active site of deiodinases is very important for effective deiodination.

Regioselective Deiodination of Thyroxine by Iodothyronine Deiodinase Mimics: An Unusual Mechanistic Pathway Involving Cooperative Chalcogen and Halogen Bonding

Iodothyronine deiodinases (IDs) are mammalian selenoenzymes that catalyze the conversion of thyroxine (T4) to 3,5,3'-triiodothyronine (T3) and 3,3',5'-triiodothyronine (rT3) by the outer- and inner-ring deiodination pathways, respectively. These enzymes also catalyze further deiodination of T3 and rT3 to produce a variety of di- and monoiodo derivatives. In this paper, the deiodinase activity of a series of pen-substituted naphthalenes having different amino groups is described. These compounds remove iodine selectively from the inner-ring of T4 and T3 to produce rT3 and 3,3'-diiodothyronine (3,3'-T2), respectively. The naphthyl-based compounds having two selenols in the pen-positions exhibit much higher deiodinase activity than those having two thiols or a thiol selenol pair. Mechanistic investigations reveal that the formation of a halogen bond between the iodine and chalcogen (S or Se) and the pen-interaction between two chalcogen atoms (chalcogen bond) are important for the deiodination reactions. Although the formation of a halogen bond leads to elongation of the C-I bond, the chalcogen bond facilitates the transfer of more electron density to the C-I sigma* orbitals, leading to a complete cleavage of the C-I bond. The higher activity of amino-substituted selenium compounds can be ascribed to the deprotonation of thiol/selenol moiety by the amino group, which not only increases the strength of halogen bond but also facilitates the chalcogen chalcogen interactions.

Regioselective Deiodination of Iodothyronamines, Endogenous Thyroid Hormone Derivatives, by Deiodinase Mimics

Iodothyronine deiodinases (IDs) are mammalian selenoenzymes that play an important role in the activation and inactivation pound 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 (T3AM) is deiodinated at the inner ring by naphthyl-based deiodinase mimics, which is similar to the deiodination of 3,3',5-triiodothyronine (T3). However, T3AM under-goes much slower deiodination than T3. Detailed experimental 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 center dot center dot center dot 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, T3AM, which does not have I center dot center dot I interactions, undergoes much slower deiodination.

Thiol cofactors for selenoenzymes and their synthetic mimics

The importance of selenium as an essential trace element is now well recognized. In proteins, the redox-active selenium moiety is incorporated as selenocysteine (Sec), the 21st amino acid. In mammals, selenium exerts its redox activities through several selenocysteine-containing enzymes, which include glutathione peroxidase (GPx), iodothyronine deiodinase (ID), and thioredoxin reductase (TrxR). Although these enzymes have Sec in their active sites, they catalyze completely different reactions and their substrate specificity and cofactor or co-substrate systems are significantly different. The antioxidant enzyme GPx uses the tripeptide glutathione (GSH) for the catalytic reduction of hydrogen peroxide and organic peroxides, whereas the larger and more advanced mammalian TrxRs have cysteine moieties in different subunits and prefer to utilize these internal cysteines as thiol cofactors for their catalytic activity. On the other hand, the nature of in vivo cofactor for the deiodinating enzyme ID is not known, although the use of thiols as reducing agents has been well-documented. Recent studies suggest that molecular recognition and effective binding of the thiol cofactors at the active site of the selenoenzymes and their mimics play crucial roles in the catalytic activity. The aim of this perspective is to present an overview of the thiol cofactor systems used by different selenoenzymes and their mimics.

Synthesis and characterization of some gold(I)-thiolate complexes having N-methylimidazole moiety

Antithyroid drugs inhibit the thyroid hormone synthesis by inactivating the thyroid peroxidase and/or iodothyronine deiodinase, which are involved in iodination and deiodination reactions. Gold(I) compounds also inhibit the thyroid hormone synthesis by interacting with the selenocysteine residue of iodothyronine deiodinase. However, the chemical reactions between these two different classes of compounds have not been studied. In this paper, we describe the interaction of therapeutic gold(I) compounds with the commonly used thiourea-based antithyroid drug, methimazole. It is observed that the gold(I) phosphine complexes (R(3)PAuCl, where R = Me, Et, Ph) react with methimazole only upon deprotonation to produce the corresponding gold(I)-thiolate complexes. Addition of PPh(3) to the gold(I)-thiolates produces (R(3)PAuPPh(3))(+) (R = Me or Et), indicating the possibility of ligand exchange reactions.

Antithyroid drugs and their analogues: synthesis, structure, and mechanism of action

Thyroid hormones are essential for the development and differentiation of all cells of the human body. They regulate protein, fat, and carbohydrate metabolism. In this Account, we discuss the synthesis, structure, and mechanism of action of thyroid hormones and their analogues. The prohormone thyroxine (14) is synthesized on thyroglobulin by thyroid peroxidase (TPO), a heme enzyme that uses iodide and hydrogen peroxide to perform iodination and phenolic coupling reactions. The monodeiodination of T4 to 3,3',5-triiodothyronine (13) by selenium-containing deiodinases (ID-1, ID-2) is a key step in the activation of thyroid hormones. The type 3 deiodinase (ID-3) catalyzes the deactivation of thyroid hormone in a process that removes iodine selectively from the tyrosyl ring of T4 to produce 3,3',5'-triiodothyronine (rT3). Several physiological and pathological stimuli influence thyroid hormone synthesis. The overproduction of thyroid hormones leads to hyperthyroidism, which is treated by antithyroid drugs that either inhibit the thyroid hormone biosynthesis and/or decrease the conversion of T4 to T3. Antithyroid drugs are thiourea-based compounds, which indude propylthiouracil (PTU), methimazole (MM I), and carbimazole (CBZ). The thyroid gland actively concentrates these heterocyclic compounds against a concentration gradient Recently, the selenium analogues of PTU, MMI, and CBZ attracted significant attention because the selenium moiety in these compounds has a higher nucleophilicity than that of the sulfur moiety. Researchers have developed new methods for the synthesis of the selenium compounds. Several experimental and theoretical investigations revealed that the selone (C=Se) in the selenium analogues is more polarized than the thione (C=S) in the sulfur compounds, and the selones exist predominantly in their zwitterionic forms. Although the thionamide-based antithyroid drugs have been used for almost 70 years, the mechanism of their action is not completely understood. Most investigations have revealed that MMI and PTU irreversibly inhibit TPO. PTU, MTU, and their selenium analogues also inhibit ID-1, most likely by reacting with the selenenyl iodide intermediate. The good ID-1 inhibitory activity of Pill and its analogues can be ascribed to the presence of the -N(H)-C(=O)- functionality that can form hydrogen bonds with nearby amino add residues in the selenenyl sulfide state. In addition to the TPO and ID-1 inhibition, the selenium analogues are very good antioxidants. In the presence of cellular reducing agents such as GSH, these compounds catalytically reduce hydrogen peroxide. They can also efficiently scavenge peroxynitrite, a potent biological oxidant and nitrating agent.

Halogen Bonding Controls the Regioselectivity of the Deiodination of Thyroid Hormones and their Sulfate Analogues

The type1 iodothyronine deiodinase (1D-1) in liver and kidney converts the L-thyroxine (T4), a prohormone, by outer-ring (5) deiodination to biologically active 3,3,5-triiodothyronine (T3) or by inner-ring (5) deiodination to inactive 3,3,5-triiodothronine (rT3). Sulfate conjugation is an important step in the irreversible inactivation of thyroid hormones. While sulfate conjugation of the phenolic hydroxyl group stimulates the 5-deiodination of T4 and T3, it blocks the 5-deiodination of T4. We show that thyroxine sulfate (T4S) undergoes faster deiodination as compared to the parent thyroid hormone T4 by synthetic selenium compounds. It is also shown that ID-3 mimics, which are remarkably selective to the inner-ring deiodination of T4 and T3, changes the selectivity completely when T4S is used as a substrate. From the theoretical investigations, it is observed that the strength of halogen bonding increases upon sulfate conjugation, which leads to a change in the regioselectivity of ID-3 mimics towards the deiodination of T4S. It has been shown that these mimics perform both the 5- and 5-ring deiodinations by an identical mechanism.

Remarkable Effect of Chalcogen Substitution on an Enzyme Mimetic for Deiodination of Thyroid Hormones

Iodothyronine deiodinases are selenoenzymes which regulate the thyroid hormone homeostasis by catalyzing the regioselective deiodination of thyroxine (T4). Synthetic deiodinase mimetics are important not only to understand the mechanism of enzyme catalysis, but also to develop therapeutic agents as abnormal thyroid hormone levels have implications in different diseases, such as hypoxia, myocardial infarction, critical illness, neuronal ischemia, tissue injury, and cancer. Described herein is that the replacement of sulfur/selenium atoms in a series of deiodinase mimetics by tellurium remarkably alters the reactivity as well as regioselectivity toward T4. The tellurium compounds reported in this paper represent the first examples of deiodinase mimetics which mediate sequential deiodination of T4 to produce all the hormone derivatives including T0 under physiologically relevant conditions.