Selenium analogues of antithyroid drugs–recent developments

enzyme (Figure 1), 2006

Propylthiouracil (PTU) and methimazole (MMI) are the most commonly used antithyroid drugs. The available data suggest that these drugs may block the thyroid hormone synthesis by inhibiting the thyroid peroxidase (TPO) or diverting oxidized iodides away from thyroglobulin. It is also known that PTU inhibits the selenocysteine-containing enzyme ID-1 by reacting with the selenenyl iodide intermediate (E-SeI). In view of the current interest in antithyroid drugs, we have recently carried out biomimetic studies to understand the mechanism by which the antithyroid drugs inhibit the thyroid hormone synthesis and found that the replacement of sulfur with selenium in MMI leads to an interesting compound that may reversibly block the thyroid hormone synthesis. Our recent results on the inhibition of lactoperoxidase (LPO)-catalyzed oxidation and iodination reactions by antithyroid drugs are described.

Journal of the American Chemical Society, 2005

Syntheses and characterization of the selenium analogue (MSeI) of anti-thyroid drug methimazole and a series of organoselenium compounds bearing N-methylimidazole pharmacophore are described. In contrast to the sulfur compound that exists predominantly in its thione form, the selenium analogue exists in a selenol form, which spontaneously oxidizes in air to produce the corresponding diselenide. The reduction of the diselenide by GSH or NaBH4 affords the biologically active selenol, which effectively inhibits the lactoperoxidase (LPO) activity in vitro. The monoselenides having N-methylimidazole moiety are found to be much less active than the selenol, suggesting that the presence of a selenol moiety is important for the LPO inhibition. The kinetic and mechanistic studies reveal that MSeI inhibits the LPO activity by reducing the H2O2, providing a novel method to reversibly inhibit the enzyme. Although MSeI strongly inhibits LPO, the enzyme's activity can be completely recovered by increasing the H2O2 concentration. On the other hand, the inhibition by methimazole (MMI), the sulfur analogue, cannot be reversed by increasing the H2O2 concentration, leading to a complete inactivation of the enzyme. The reversible inhibition of LPO by some of the selenium derivatives is correlated with their glutathione peroxidase (GPx) activity, and the high GPx activity of the selenium compounds as compared with their sulfur analogues suggests that the selenium derivatives may protect the thyroid gland from oxidative damage.

Journal of Chemical Sciences, 2006

Hydrogen peroxide, generated by thyroid oxidase enzymes, is a crucial substrate for the thyroid peroxidase (TPO)-catalysed biosynthesis of thyroid hormones, thyroxine (T4) and triiodothyronine (T3) in the thyroid gland. It is believed that the H 2 O 2 generation is a limiting step in thyroid hormone synthesis. Therefore, the control of hydrogen peroxide concentration is one of the possible mechanisms for the inhibition of thyroid hormone biosynthesis. The inhibition of thyroid hormone synthesis is required for the treatment of hyperthyroidism and this can be achieved by one or more anti-thyroid drugs. The most widely used anti-thyroid drug methimazole (MMI) inhibits the production of thyroid hormones by irreversibly inactivating the enzyme TPO. Our studies show that the replacement of sulphur in MMI by selenium leads to a selone, which exists predominantly in its zwitterionic form. In contrast to the sulphur drug, the selenium analogue (MSeI) reversibly inhibits the peroxidase-catalysed oxidation and iodination reactions. Theoretical studies on MSeI reveal that the selenium atom in this compound carries a large negative charge. The carbon-selenium bond length in MSeI is found to be close to single-bond length. As the selenium atom exhibits a large nucleophilic character, the selenium analogue of MMI may scavenge the hydrogen peroxide present in the thyroid cells, which may lead to a reversible inhibition of thyroid hormone biosynthesis.

Biochemical and Biophysical Research Communications, 1992

Type I iodothyronine deiodinase (ID-l) is a selenoenzyme, which is important for the conversion of the prohormone thyroxine (T4) to the bioactive thyroid hormone 3,3',5triiodothyronine (T3). 2-Thiouracil derivatives inhibit ID-I by interaction with an enzyme form generated during catalysis. We have now tested the potential inhibitory effects of the selenocompounds 6-methyl-(MSU) and 6-propyl-2-selenouracil (PSU) in comparison with their thioanalogs 6-methyl-(MTU) and 6-propyl-2-thiouracil (PTU) on rat liver ID-I activity using 3,3',5'-triiodothyronine (reverse T3, rT3) as substrate and dithiothreitol (DlT) as cofactor. All compounds showed dose-dependent inhibition of ID-I with IC, values of 1,0.5,0.4 and 0.2 BM for MTU, MSU, PTU and PSU, respectively. Our results further suggest that these inhibitions are uncompetitive with substrate and competitive with cofactor. The high potency of selenouracils may be due to reaction with a substrate-induced enzyme selenenyl iodide intermediate under formation of a stable enzyme-selenouracil diselenide. 0 1992 Academic Press, 1°C.

Inorganica chimica acta, 2007

In this paper, the synthesis and characterization of thiones and selones having N,N-disubstituted imidazole are described. Experimental and theoretical studies were performed on a number of selones, which suggest that these compounds exist as zwitterions in which the selenium atom carries a large negative charge. The structures of selones were studied in solution by 77 Se NMR spectroscopy and the 77 Se NMR chemical shifts for the selones show large upfield shifts in the signals, confirming the zwitterionic structure of the selones in solution. The thermal isomerization of some S-and Se-substituted methyl and benzyl imidazole derivatives to produce the thermodynamically more stable N-substituted derivatives are described. A structure-activity correlation was attempted on the inhibition of LPO-catalyzed oxidation and iodination reactions by several thiouracil compounds, which indicate that the presence of an n-propyl group in PTU is important for an efficient inhibition. In contrast to the S-and Se-substituted derivatives, the selones produced by thermal isomerization exhibited efficient inhibition, indicating the importance of reactive selone (zwitterionic) moiety in the inhibition. The inhibition data on carbimazole (CBZ) support the assumption that CBZ acts as a prodrug, requiring a conversion to methimazole (MMI) for its inhibitory action on thyroid peroxidase.

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.

Endocrinology, 1997

The bioactivity of thyroid hormone is determined to a large extent by the monodeiodination of the prohormone T 4 by the hepatic selenoenzyme type I iodothyronine deiodinase (ID1), i.e. by outer ring deiodination (ORD) to the active hormone T 3 , or by inner ring deiodination (IRD) to the inactive metabolite rT 3. ID1 also catalyzes the IRD of T 3 and the ORD of rT 3 , both to T 2 , as well as the deiodination of different iodothyronine sulfates, e.g. IRD of T 3 S and ORD of T 2 S. Previous studies have indicated important differences in catalytic specificity between dog ID1 (dID1) and human ID1 (hID1), in particular with respect to the ORD of rT 3. This study was done to investigate the relationship between structure and catalytic function of this enzyme by comparing the deiodination of T 4 , T 3 , rT 3 , T 3 S, and T 2 S by native dID1 and hID1 in liver microsomes as well as by recombinant wild-type, chimeric and mutated d/hID1 enzymes expressed in HEK293 cells. With both native and recombinant wild-type enzymes, the substrate specificity was T 3 S Ͼ T 2 S Ϸ rT 3 Ͼ Ͼ T 4 Ͼ T 3 for dID1, and rT 3 Ͼ Ͼ T 2 S Ϸ T 3 S Ͼ T 4 Ϸ T 3 for hID1. Whereas ORD of T 4 and of T 4 , T 3 , and T 3 S showed relatively little variation between the different d/hID1 constructs, large differences were found for the ORD of rT 3 and T 2 S. Both reactions were favored by the presence of the amino acids G, E and, in particular, F, present in hID1 at positions 45, 46, and 65, instead of the dID1 residues N, G, and L, respectively. However, although ORD of rT 3 was not affected by the presence (hID1) or absence (dID1) of the TGMTR(48-52) sequence, the ORD of T 2 S was markedly inhibited by the presence of this sequence. Therefore, we have identified structural elements in ID1 that have substrate-specific impacts on deiodination. Our results suggest the specific interaction of the mono-substituted inner ring of the substrates rT 3 and T 2 S but not the disubstituted inner ring of T 3 , T 3 S, or T 4 , with the aromatic ring of F65 in ID1, perhaps byinteractions. (Endocrinology 138: 213-219, 1997)

FEBS Letters, 1994

The prohormone thyroxine (T4) is activated by outer ring deiodination (ORD) to 3,3',5_triiodothyronine (T3) and both hormones are degraded by inner ring deiodination (IRD) to 3,3',5'-triiodothyronine (rT3) and 3,3'-diiodothyronine, respectively. Indirect evidence suggests that the type I iodothyronine deiodinase (ID-I) in liver has both ORD and IRD activities, with preference for rT3 and sulfated iodothyronines as substrates. To establish this, we have compared the ORD of rT3 and IRD of T3 and T3 sulfate by homogenates of cells transfected with rat ID-I cDNA and by rat liver microsomes. In both preparations rT3 is the preferred substrate, while deiodination of T3 is markedly accelerated by its sulfation. Kinetic analysis provided similar K

Endocrinology and Metabolism, 2021

Thyroid hormone (TH) signaling is strictly regulated by iodothyronine deiodinase activity, which both preserves the circulating levels of the biologically active triiodothyronine (T3) and regulates TH homeostasis at the local level, in a cell- and time-dependent manner. Three deiodinases have been identified—namely iodothyronine deiodinase 1 (DIO1), DIO2, and DIO3—that differ in their catalytic properties and tissue distribution. The deiodinases represent a dynamic system that changes in the different stages of life according to their functions and roles in various cell types and tissues. Deiodinase activity at the tissue level permits cell-targeted fine regulation of TH homeostasis, mediating the activation (DIO1 and DIO2) and inactivation (DIO3) of THs. Deiodinase homeostasis is the driving force that leads T3-target cells towards customized TH signaling, which takes into account both the hormonal circulating levels and the tissue-specific response. This review analyzes the comple...

Journal of medicinal chemistry, 2008