Thyroid hormone synthesis and anti-thyroid drugs: a Bioinorganic Chemistry approach

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 H2O2 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

Bioinorganic Chemistry in Thyroid Gland: Effect of Antithyroid Drugs on Peroxidase-Catalyzed Oxidation and Iodination Reactions

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

Selenium-containing enzymes in mammals: chemical perspectives

The chemical and biochemical route to the synthesis of the 21st amino acid in living systems, selenocysteine, is described. The incorporation of this rare amino acid residue into proteins is described with emphasis on the role of monoselenophosphate as selenium source. The role of selenocysteine moiety in natural mammalian enzymes such as glutathione peroxidase (GPx), iodothyronine deiodinase (ID) and thioredoxin reductase (TrxR) is highlighted and the effect of other amino acid residues located in close proximity to selenocysteine is described. It is evident from various studies that two amino acid residues, tryptophan and glutamine, appear in identical positions in all known members of the GPx family. According to the three-dimensional structure established for bovine GPx, these residues could constitute a catalytic triad in which the selenol group of the selenocysteine is both stabilized and activated by hydrogen bonding with the imino group of the tryptophan (Trp) residue and with the amido group of the glutamine (Gln) residue. The ID enzymes, on the other hand, do not possess any Trp or Gln residues in close proximity to selenium, but contain several histidine residues, which may play important roles in the catalysis. The TrxR enzymes also possess some basic histidines, but the most important amino acid residues are the cysteines which constitute the internal cofactor systems along with the catalytically active selenocysteine. The catalytic activity and substrate specificity of all three selenoenzymes are described. The reactivity of selenocysteine residues in selenoenzymes towards metal-based drugs such as goldthioglucose is also described

Anticancer property of Bryophyllum pinnata (Lam.) Oken. leaf on human cervical cancer cells

<p>Abstract</p> <p>Background</p> <p><it>Bryophyllum pinnata </it>(<it>B. pinnata</it>) is a common medicinal plant used in traditional medicine of India and of other countries for curing various infections, bowel diseases, healing wounds and other ailments. However, its anticancer properties are poorly defined. In view of broad spectrum therapeutic potential of <it>B. pinnata </it>we designed a study to examine anti-cancer and anti-Human Papillomavirus (HPV) activities in its leaf extracts and tried to isolate its active principle.</p> <p>Methods</p> <p>A chloroform extract derived from a bulk of botanically well-characterized pulverized <it>B</it>. <it>pinnata </it>leaves was separated using column chromatography with step- gradient of petroleum ether and ethyl acetate. Fractions were characterized for phyto-chemical compounds by TLC, HPTLC and NMR and Biological activity of the fractions were examined by MTT-based cell viability assay, Electrophoretic Mobility Shift Assay, Northern blotting and assay of apoptosis related proteins by immunoblotting in human cervical cancer cells.</p> <p>Results</p> <p>Results showed presence of growth inhibitory activity in the crude leaf extracts with IC₅₀at 552 μg/ml which resolved to fraction F4 (Petroleum Ether: Ethyl Acetate:: 50:50) and showed IC₅₀at 91 μg/ml. Investigations of anti-viral activity of the extract and its fraction revealed a specific anti-HPV activity on cervical cancer cells as evidenced by downregulation of constitutively active AP1 specific DNA binding activity and suppression of oncogenic c-Fos and c-Jun expression which was accompanied by inhibition of HPV18 transcription. In addition to inhibiting growth, fraction F4 strongly induced apoptosis as evidenced by an increased expression of the pro-apoptotic protein Bax, suppression of the anti-apoptotic molecules Bcl-2, and activation of caspase-3 and cleavage of PARP-1. Phytochemical analysis of fraction F4 by HPTLC and NMR indicated presence of activity that resembled Bryophyllin A.</p> <p>Conclusions</p> <p>Our study therefore demonstrates presence of anticancer and anti-HPV an activity in <it>B</it>. <it>pinnata </it>leaves that can be further exploited as a potential anticancer, anti-HPV therapeutic for treatment of HPV infection and cervical cancer.</p

Heteroatom-directed aromatic lithiation: a versatile route to the synthesis of organochalcogen (se, te) compounds

Chiral and achiral organochalcogen compounds bearing a heteroatom in close proximity are easily accessible via the directed aromatic lithiation route. The lithium chalcogenolates prepared by the insertion of selenium or tellurium into the C-Li bond are used to synthesize various chalcogen compounds such as Se/Te, N donor ligands, dichalcogenides, monomeric metal chalcogenolates, and macrocycles. The differences in the stability and reactivity of the organochalcogen compounds derived from various substrates are described in terms of electronic and stereochemical properties of donor atoms

Bioinorganic Chemistry in Thyroid Gland: Effect of Antithyroid Drugs on Peroxidase-Catalyzed Oxidation and Iodination Reactions

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. Copyright © 2006 G. Roy and G. Mugesh. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

Chemistry in thyroid gland: iodothyronine deiodinases and anti-thyroid drugs

The monodeiodination of the prohormone thyroxine (T4) to the biologically active hormone 3,5,3'-triiodothyronine (T3) is the first step in thyroid hormone action and the type I iodothyronine deiodinase (ID-I), an enzyme containing selenocysteine in its active site, is responsible for most of this conversion. ID-I is an integral membrane protein present in highest amounts in liver, kidney, and thyroid. In the deiodinase cycle, the selenol group of the enzyme (E-SeH) first reacts with T4 to form a selenenyl iodide (E-SeI) with a release of the deiodinated iodothyronine. Subsequent reaction of the E-SeI with a thiol of other cofactors releases I<SUP>-</SUP> and regenerates the active site. The thiourea drug, 6-n-propylthiouracil (PTU), reacts with the E-SeI intermediate to inhibit the enzyme active site regeneration. Owing to this property, PTU and related sulfur derivatives are often used in the acute treatment of severely hyperthyroid (Graves disease) patients and therefore commonly known as antithyroid drugs. Although the formation of a mixed selenenyl sulfide (ESe-S-PTU) adduct has been proposed to be a possible way of inhibition, it is still a matter of debate whether PTU reacts with a well-defined Se-I bond of it reacts with an equivalent species or directly with the enzyme active site. In view of this, the first successful model studies on the reactivity of PTU towards synthetic organoselenenyl iodides (RSeI) have been carried out and the results will be discussed as a basis for the deiodinase inhibition. On the basis of experimental data, a mechanism for the inhibition of ID-I by thiouracil drugs and possible amino acid residues responsible for the inhibition will be discussed