Selenium Analogues of Antithyroid Drugs – Recent Developments

Abstract

Thyroxine (T4), the main secretory hormone of the thyroid gland, is produced on thyroglobulin by thyroid peroxidase (TPO)/H(2)O(2)/iodide system and deiodinated to its active form (T3) by a selenocysteine-containing enzyme, iodothyronine deiodinase (ID). The activation of thyroid-stimulating hormone (TSH) receptor by auto-antibodies leads to 'hyperthyroidism', a life-threatening disease which is treated by antithyroid drugs such as 6-propyl-2-thiouracil (PTU) and methimazole (MMI). The present review describes the biological activities of a number of S/Se derivatives bearing the methimazole pharmacophore. It is shown that the isosteric substitutions in the existing drugs lead to compounds that can effectively and reversibly inhibit the heme-containing lactoperoxidase (LPO). In contrast to methimazole, the selenium analogue, MSeI, does not interfere with the enzyme directly, but it inhibits LPO by reducing the H(2)O(2) that is required for the oxidation of the Fe-center in LPO. These studies reveal that the degradation of the intracellular H(2)O(2) by the Se analogues of antithyroid drugs may be beneficial to the thyroid gland, as these compounds may act as antioxidants and protect thyroid cells from oxidative damage. Because the drugs with an action essentially on H(2)O(2) can reversibly inhibit the thyroid peroxidase, such drugs could be of great importance in the treatment of hyperthyroidism.

Selenium and the thyroid

“…Structure-activity relationships were identified, providing relevant information on the mechanism of action of TPO and deiodinases, as well as allowing development and testing of Se-based antithyroid drugs that selectively interfere with TPO or deiodinases [41]. As the current antithyroid drugs, which are based on thiourea pharmacophores (e.g.…”

Se- and S-Based Thiouracil and Methimazole Analogues Exert Different Inhibitory Mechanisms on Type 1 and Type 2 Deiodinases

“…The seleno-analogue of MMI, methylselenoimidazole, however, has proven to be a slightly better inhibitor, although even at a dose of 0.3 m M only a 28% inhibition of the D1 activity was found [22]. Roy and Mugesh [14] showed that this methylselenoimidazole is not stable in air and easily oxidizes to its diselenide (C4). In our hands the coupling of two methylselenoimidazole molecules via their selenium, C4, showed to be most potent with an IC 50 of approximately 0.4 m M , hence better than its precursor.…”

“…Due to the higher nucleophilicity of Se [11], it was suggested that Se analogues might form an enzyme-Se-Se analogue more effectively than the enzyme-Se-S analogue [12,13], hence inhibit D1 activity even more prominently. On the other hand, the enzyme-Se-Se analogue might more easily be reduced by high levels of thiols (DTT) compared to the enzyme-Se-S-PTU complex [14,15,16]. In fact, the selenium analogue of PTU (PTU-Se) was quite similar, or only slightly more potent in its capacity to inhibit D1 activity compared to the classical PTU (PTU-S) [10,12].…”

Modeling and simulation analysis of propyl-thiouracil (PTU), an anti-thyroid drug on thyroid peroxidase (TPO), thyroid stimulating hormone receptor (TSHR), and sodium iodide (NIS) symporter based on systems biology approach

“…TPO cooperates in iodination of tyrosyl residues in thyroglobulin and other proteins (Ruf and Carayon 2006;Kessler et al 2008). TPO is excited by TSH and inhibited by propylthiouracil (PTU) and methimazole (MMI) (Roy and Mugesh 2008).…”