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

Enhancing herbicides sorption in sodic soils through biochar amendment : A promising approach for sustainable agriculture

This study is essential for assessing the binding capacity of Prosopis wood biochar to commonly used herbicides, Pretilachlor and Pendimethalin. Understanding their sorption dynamics at varying biochar application rates and exposure times is crucial for sustainable and effective herbicide management in intensively farming agricultural fields and for reducing environmental contamination. The Prosopis wood biochar was produced in an earthen kiln at 300-350°C. The batch experiment was conducted to study the sorption potential of biochar additions at rates of 0, 5, and 10 t ha-1. The herbicides were added to the homogenized soil-biochar mixes at zero, whole, twice, and four times the recommended dose. The sorption of the herbicides by soil biochar mixture was studied for 12 and 24 hours. The result showed that Pendimethalin sorption increased with biochar application rate, requiring 24 hours for 95% sorption at 4X dose without biochar (77.95 mg/kg soil) and 12 hours with 10 t/ha biochar (75.82 mg/kg soil). The Kd value increased with biochar application (0.57-77.95 mg/kg soil) and decreased with pendimethalin application (77.95-3.04 mg/kg soil). Maximum sorption (95%) was attained within 12 hours for 1X and 2X rates and 24 hours for 4X rates when biochar was added. This demonstrated that although pendimethalin residue in the soil can be immobilized by adding biochar within 8 hours at lower rates, more than 24 hours were required when pendimethalin was applied at higher rates or repeatedly. Biochar can be used to reduce pendimethalin leaching in agricultural fields, especially sodic soils, at higher application rates.

2,2′-(Diselane-1,2-di­yl)dinicotinamide N,N′-dimethyl­formamide disolvate

The asymmetric unit of the title compound, C12H10N4O2Se2·2C3H7NO, contains two solvent mol­ecules and two half mol­ecules of the dinicotinamide, each of which sits on a center of symmetry passing through the middle of the Se—Se bond. In each mol­ecule, the two pyridyl groups and diseleno group are approximately coplanar (r.m.s. deviations from planarity for all non-H atoms = 0.011 and 0.008 Å in the two mol­ecules). Inter­molecular N—H⋯O hydrogen bonds stablilize the crystal packing

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

5,5′-Seleno­bis­(2-hy­droxy­benzaldehyde)

In the title mol­ecule, C14H10O4Se, the dihedral angle between the two benzene rings is 74.6 (1)°. Both hy­droxy­benzaldehyde groups form intra­molecular O—H⋯O hydrogen bonds. In the crystal, pairs of mol­ecules are linked by pairs of weak C—H⋯π(arene) inter­actions, forming centrosymmetric dimers. In addition, mol­ecules are linked by π–π stacking inter­actions, with a centroid–centroid distance of 3.785 (2) Å, forming chains along the c axis

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

5-Benzyl­idene-2,3-diphenyl-1,2-selenaphosphole-2-selenide

The title compound, C23H19PSe2, has a central five-membered twist C3PSe ring conformation. One phenyl ring substituent, attached to an sp 2 carbon, is approximately coplanar with the C3PSe ring whilst the other organic substituents, attached to an sp 3-carbon and a PV atom, lie on the same side of the ring

Structural characterization of angiotensin I-converting enzyme in complex with a selenium analogue of captopril

Human somatic angiotensin I-converting enzyme (ACE), a zinc-dependent dipeptidyl carboxypeptidase, is central to the regulation of the renin–angiotensin aldosterone system. It is a well-known target for combating hypertension and related cardiovascular diseases. In a recent study by Bhuyan and Mugesh [Org. Biomol. Chem. (2011) 9, 1356–1365], it was shown that the selenium analogues of captopril (a well-known clinical inhibitor of ACE) not only inhibit ACE, but also protect against peroxynitrite-mediated nitration of peptides and proteins. Here, we report the crystal structures of human testis ACE (tACE) and a homologue of ACE, known as AnCE, from Drosophila melanogaster in complex with the most promising selenium analogue of captopril (SeCap) determined at 2.4 and 2.35 Å resolution, respectively. The inhibitor binds at the active site of tACE and AnCE in an analogous fashion to that observed for captopril and provide the first examples of a protein–selenolate interaction. These new structures of tACE–SeCap and AnCE–SeCap inhibitor complexes presented here provide important information for further exploration of zinc coordinating selenium-based ACE inhibitor pharmacophores with significant antioxidant activity