15N Chemically Induced Dynamic Nuclear Polarization (15N‐CIDNP) Investigations of the Peroxynitrite Decay and Nitration of N‐Acetyl‐L‐tyrosine

During the decay of (¹⁵N)peroxynitrite (O?¹⁵NOO ^? ) in the presence of N‐acetyl‐L ‐tyrosine (Tyrac) in neutral solution and at 268 K, the ¹⁵N‐NMR signals of ¹⁵NO and ¹⁵NO show emission (E) and enhanced absorption (A) as it has already been observed by Butler and co‐workers in the presence of L ‐tyrosine (Tyr). The effects are built up in radical pairs [CO , ¹⁵NO ]^S formed by O? O bond scission of the (¹⁵N)peroxynitrite? CO₂ adduct (O?¹⁵NO? OCO ). In the absence of Tyrac and Tyr, the peroxynitrite decay rate is enhanced, and ¹⁵N‐CIDNP does not occur. This is explained by a chain reaction during the peroxynitrite decay involving N₂O₃ and radicals NO ^. and NO . The interpretation is supported by ¹⁵N‐CIDNP observed with (¹⁵N)peroxynitrite generated in situ during reaction of H₂O₂ with N‐acetyl‐N‐(¹⁵N)nitroso‐dl ‐tryptophan ((¹⁵N)NANT) at 298 K and pH 7.5. In the presence of Na¹⁵NO₂ at pH 7.5 and in acidic solution, ¹⁵N‐CIDNP appears in the nitration products of Tyrac, 1‐(¹⁵N)nitro‐N‐acetyl‐L ‐tyrosine (1‐¹⁵NO₂‐Tyrac) and 3‐(¹⁵N)nitro‐N‐acetyl‐L ‐tyrosine (3‐¹⁵NO₂‐Tyrac). The effects are built up in radical pairs [Tyrac ^. , ¹⁵NO ]^F formed by encounters of independently generated radicals Tyrac ^. and ¹⁵NO . Quantitative ¹⁵N‐CIDNP studies show that nitrogen dioxide dependent reactions are the main if not the only pathways for yielding both nitrate and nitrated products.     

Cocrystals of 6‐methyl‐2‐thiouracil: presence of the acceptor–donor–acceptor/donor–acceptor–donor synthon

The results of seven cocrystallization experiments of the antithyroid drug 6‐methyl‐2‐thiouracil (MTU), C₅H₆N₂OS, with 2,4‐diaminopyrimidine, 2,4,6‐triaminopyrimidine and 6‐amino‐3H‐isocytosine (viz. 2,6‐diamino‐3H‐pyrimidin‐4‐one) are reported. MTU features an ADA (A = acceptor and D = donor) hydrogen‐bonding site, while the three coformers show complementary DAD hydrogen‐bonding sites and therefore should be capable of forming an ADA/DAD N—H...O/N—H...N/N—H...S synthon with MTU. The experiments yielded one cocrystal and six cocrystal solvates, namely 6‐methyl‐2‐thiouracil–2,4‐diaminopyrimidine–1‐methylpyrrolidin‐2‐one (1/1/2), C₅H₆N₂OS·C₄H₆N₄·2C₅H₉NO, (I), 6‐methyl‐2‐thiouracil–2,4‐diaminopyrimidine (1/1), C₅H₆N₂OS·C₄H₆N₄, (II), 6‐methyl‐2‐thiouracil–2,4‐diaminopyrimidine–N,N‐dimethylacetamide (2/1/2), 2C₅H₆N₂OS·C₄H₆N₄·2C₄H₉NO, (III), 6‐methyl‐2‐thiouracil–2,4‐diaminopyrimidine–N,N‐dimethylformamide (2/1/2), C₅H₆N₂OS·0.5C₄H₆N₄·C₃H₇NO, (IV), 2,4,6‐triaminopyrimidinium 6‐methyl‐2‐thiouracilate–6‐methyl‐2‐thiouracil–N,N‐dimethylformamide (1/1/2), C₄H₈N₅⁺·C₅H₅N₂OS⁻·C₅H₆N₂OS·2C₃H₇NO, (V), 6‐methyl‐2‐thiouracil–6‐amino‐3H‐isocytosine–N,N‐dimethylformamide (1/1/1), C₅H₆N₂OS·C₄H₆N₄O·C₃H₇NO, (VI), and 6‐methyl‐2‐thiouracil–6‐amino‐3H‐isocytosine–dimethyl sulfoxide (1/1/1), C₅H₆N₂OS·C₄H₆N₄O·C₂H₆OS, (VII). Whereas in cocrystal (I) an R₂²(8) interaction similar to the Watson–Crick adenine/uracil base pair is formed and a two‐dimensional hydrogen‐bonding network is observed, the cocrystals (II)–(VII) contain the triply hydrogen‐bonded ADA/DAD N—H...O/N—H...N/N—H...S synthon and show a one‐dimensional hydrogen‐bonding network. Although 2,4‐diaminopyrimidine possesses only one DAD hydrogen‐bonding site, it is, due to orientational disorder, triply connected to two MTU molecules in (III) and (IV).     

A Non‐damaging Method to Analyze the Configuration and Dynamics of Nitrotyrosines in Proteins

Often, deregulation of protein activity and turnover by tyrosine nitration drives cells toward pathogenesis. Hence, understanding how the nitration of a protein affects both its function and stability is of outstanding interest. Nowadays, most of the in vitro analyses of nitrated proteins rely on chemical treatment of native proteins with an excess of a chemical reagent. One such reagent, peroxynitrite, stands out for its biological relevance. However, given the excess of the nitrating reagent, the resulting in vitro modification could differ from the physiological nitration. Here, we determine unequivocally the configuration of distinct nitrated‐tyrosine rings in single‐tyrosine mutants of cytochrome c. We aimed to confirm the nitration position by a non‐destructive method. Thus, we have resorted to ¹H‐¹⁵N heteronuclear single quantum coherence(HSQC) spectra to identify the ³J(N? H) correlation between a ¹⁵N‐tagged nitro group and the adjacent aromatic proton. Once the chemical shift of this proton was determined, we compared the ¹H‐¹³C HSQC spectra of untreated and nitrated samples. All tyrosines were nitrated at ε positions, in agreement to previous analysis by indirect techniques. Notably, the various nitrotyrosine residues show a different dynamic behaviour that is consistent with molecular dynamics computations.     

Cocrystals of 6‐propyl‐2‐thiouracil: N—H...O versus N—H...S hydrogen bonds

In order to investigate the relative stability of N—H...O and N—H...S hydrogen bonds, we cocrystallized the antithyroid drug 6‐propyl‐2‐thiouracil with two complementary heterocycles. In the cocrystal pyrimidin‐2‐amine–6‐propyl‐2‐thiouracil (1/2), C₄H₅N₃·2C₇H₁₀N₂OS, (I), the `base pair' is connected by one N—H...S and one N—H...N hydrogen bond. Homodimers of 6‐propyl‐2‐thiouracil linked by two N—H...S hydrogen bonds are observed in the cocrystal N‐(6‐acetamidopyridin‐2‐yl)acetamide–6‐propyl‐2‐thiouracil (1/2), C₉H₁₁N₃O₂·2C₇H₁₀N₂OS, (II). The crystal structure of 6‐propyl‐2‐thiouracil itself, C₇H₁₀N₂OS, (III), is stabilized by pairwise N—H...O and N—H...S hydrogen bonds. In all three structures, N—H...S hydrogen bonds occur only within R₂²(8) patterns, whereas N—H...O hydrogen bonds tend to connect the homo‐ and heterodimers into extended networks. In agreement with related structures, the hydrogen‐bonding capability of C=O and C=S groups seems to be comparable.     

6‐Propyl‐2‐thiouracil versus 6‐methoxymethyl‐2‐thiouracil: enhancing the hydrogen‐bonded synthon motif by replacement of a methylene group with an O atom

The understanding of intermolecular interactions is a key objective of crystal engineering in order to exploit the derived knowledge for the rational design of new molecular solids with tailored physical and chemical properties. The tools and theories of crystal engineering are indispensable for the rational design of (pharmaceutical) cocrystals. The results of cocrystallization experiments of the antithyroid drug 6‐propyl‐2‐thiouracil (PTU) with 2,4‐diaminopyrimidine (DAPY), and of 6‐methoxymethyl‐2‐thiouracil (MOMTU) with DAPY and 2,4,6‐triaminopyrimidine (TAPY), respectively, are reported. PTU and MOMTU show a high structural similarity and differ only in the replacement of a methylene group (–CH₂–) with an O atom in the side chain, thus introducing an additional hydrogen‐bond acceptor in MOMTU. Both molecules contain an ADA hydrogen‐bonding site (A = acceptor and D = donor), while the coformers DAPY and TAPY both show complementary DAD sites and therefore should be capable of forming a mixed ADA/DAD synthon with each other, i.e. N—H…O, N—H…N and N—H…S hydrogen bonds. The experiments yielded one solvated cocrystal salt of PTU with DAPY, four different solvates of MOMTU, one ionic cocrystal of MOMTU with DAPY and one cocrystal salt of MOMTU with TAPY, namely 2,4‐diaminopyrimidinium 6‐propyl‐2‐thiouracilate–2,4‐diaminopyrimidine–N,N‐dimethylacetamide–water (1/1/1/1) (the systematic name for 6‐propyl‐2‐thiouracilate is 6‐oxo‐4‐propyl‐2‐sulfanylidene‐1,2,3,6‐tetrahydropyrimidin‐1‐ide), C₄H₇N₄⁺·C₇H₉N₂OS⁻·C₄H₆N₄·C₄H₉NO·H₂O, (I), 6‐methoxymethyl‐2‐thiouracil–N,N‐dimethylformamide (1/1), C₆H₈N₂O₂S·C₃H₇NO, (II), 6‐methoxymethyl‐2‐thiouracil–N,N‐dimethylacetamide (1/1), C₆H₈N₂O₂S·C₄H₉NO, (III), 6‐methoxymethyl‐2‐thiouracil–dimethyl sulfoxide (1/1), C₆H₈N₂O₂S·C₂H₆OS, (IV), 6‐methoxymethyl‐2‐thiouracil–1‐methylpyrrolidin‐2‐one (1/1), C₆H₈N₂O₂S·C₅H₉NO, (V), 2,4‐diaminopyrimidinium 6‐methoxymethyl‐2‐thiouracilate (the systematic name for 6‐methoxymethyl‐2‐thiouracilate is 4‐methoxymethyl‐6‐oxo‐2‐sulfanylidene‐1,2,3,6‐tetrahydropyrimidin‐1‐ide), C₄H₇N₄⁺·C₆H₇N₂O₂S⁻, (VI), and 2,4,6‐triaminopyrimidinium 6‐methoxymethyl‐2‐thiouracilate–6‐methoxymethyl‐2‐thiouracil (1/1), C₄H₈N₅⁺·C₆H₇N₂O₂S⁻·C₆H₈N₂O₂S, (VII). Whereas in (I) only an AA/DD hydrogen‐bonding interaction was formed, the structures of (VI) and (VII) both display the desired ADA/DAD synthon. Conformational studies on the side chains of PTU and MOMTU also revealed a significant deviation for cocrystals (VI) and (VII), leading to the desired enhancement of the hydrogen‐bond pattern within the crystal.     

Reactions of Stable α‐Chlorosulfanyl Chlorides with CS‐Functionalized Compounds

The smooth reaction of 3‐chloro‐3‐(chlorosulfanyl)‐2,2,4,4‐tetramethylcyclobutanone ( 3 ) with 3,4,5‐trisubstituted 2,3‐dihydro‐1H‐imidazole‐2‐thiones 8 and 2‐thiouracil ( 10 ) in CH₂Cl₂/Et₃N at room temperature yielded the corresponding disulfanes 9 and 11 (Scheme 2), respectively, via a nucleophilic substitution of Cl^? of the sulfanyl chloride by the S‐atom of the heterocyclic thione. The analogous reaction of 3‐cyclohexyl‐2,3‐dihydro‐4,5‐diphenyl‐1H‐imidazole‐2‐thione ( 8b ) and 10 with the chlorodisulfanyl derivative 16 led to the corresponding trisulfanes 17 and 18 (Scheme 4), respectively. On the other hand, the reaction of 3 and 4,4‐dimethyl‐2‐phenyl‐1,3‐thiazole‐5(4H)‐thione ( 12 ) in CH₂Cl₂ gave only 4,4‐dimethyl‐2‐phenyl‐1,3‐thiazol‐5(4H)‐one ( 13 ) and the trithioorthoester derivative 14 , a bis‐disulfane, in low yield (Scheme 3). At ?78°, only bis(1‐chloro‐2,2,4,4‐tetramethyl‐3‐oxocyclobutyl)polysulfanes 15 were formed. Even at ?78°, a 1 : 2 mixture of 12 and 16 in CH₂Cl₂ reacted to give 13 and the symmetrical pentasulfane 19 in good yield (Scheme 5). The structures of 11, 14, 17 , and 18 have been established by X‐ray crystallography.     

Inhibition of peroxynitrite- and peroxidase-mediated protein tyrosine nitration by imidazole-based thiourea and selenourea derivatives

In the present study, the synthesis and characterization of a series of N-methylimidazole-based thiourea and selenourea derivatives are described. The new compounds were also studied for their ability to inhibit peroxynitrite (PN)- and peroxidase-mediated nitration of protein tyrosine residues. It has been observed that the selenourea derivatives are more efficient than the thiourea-based compounds in the inhibition of protein nitration. The higher activity of selenoureas as compared to that of the corresponding thioureas can be ascribed to the zwitterionic nature of the selenourea moiety. Single crystal X-ray diffraction studies on some of the thiourea and selenourea derivatives reveal that the C=S bonds in thioureas possess more of double bond character than the C=Se bonds in the corresponding selenoureas. Therefore, the selenium compounds can react with PN or hydrogen peroxide much faster than their sulfur analogues. The reactions of thiourea and selenourea derivatives with PN or hydrogen peroxide produce the corresponding sulfinic or seleninic acid derivatives, which upon elimination of sulfurous/selenous acids produce the corresponding N-methylimdazole derivatives.     

Potential energy surface of the reaction of imidazole with peroxynitrite: Density functional theory study

This article presents a theoretical investigation of the reaction mechanism of imidazole nitration by peroxynitrite using density functional theory calculations. Understanding this reaction mechanism will help in elucidating the mechanism of guanine nitration by peroxynitrite, which is one of the assumed chemical pathways for damaging DNA in cells. This work focuses on the analysis of the potential energy surface (PES) for this reaction in the gas phase. Calculations were carried out using Hartree–Fock (HF) and density functional theory (DFT) Hamiltonians with double‐zeta basis sets ranging from 6‐31G(d) to 6‐31++G(d,p), and the triple‐zeta basis set 6‐311G(d). The computational results reveal that the reaction of imidazole with peroxynitrite in gas phase produces the following species: (i) hydroxide ion and 2‐nitroimidazole, (ii) hydrogen superoxide ion and 2‐nitrosoimidazole, and (iii) water and 2‐nitroimidazolide. The rate‐determining step is the formation of a short‐lived intermediate in which the imidazole C₂ carbon is covalently bonded to peroxynitrite nitrogen. Three short‐lived intermediates were found in the reaction path. These intermediates are involved in a proton‐hopping transport from C₂ carbon to the terminal oxygen of the ? O? O moiety of peroxynitrite via the nitroso (ON? ) oxygen. Both HF and DFT calculations (using the Becke3–Lee–Yang–Parr functional) lead to similar reaction paths for proton transport, but the landscape details of the PES for HF and DFT calculations differ. This investigation shows that the reaction of imidazole with peroxynitrite produces essentially the same types of products (nitro‐ and nitroso‐) as observed experimentally in the reaction of guanine with peroxynitrite, which makes the former reaction a good model to study by computation the essential characteristics of the latter reaction. Nevertheless, the computationally determined activation energy for imidazole nitration by peroxynitrite in the gas phase is 84.1 kcal/mol (calculated at the B3LYP/6‐31++G(d,p) level), too large for an enzymatic reaction. Exploratory calculations on imidazole nitration in solution, and on the reaction of 9‐methylguanine with peroxynitrite in the gas phase and solution, show that solvation increases the activation energy for both imidazole and guanine, and that the modest decrease (15 kcal mol^?1) in the activation energy, due to the adjacent six member ring of guanine, is counterbalanced by solvation. These results lead to the speculation that proton tunneling may be at the origin of experimentally observed high reaction rate of guanine nitration by peroxynitrite in solution. © 2005 Wiley Periodicals, Inc. Int J Quantum Chem, 2005     

trans–cisS‐Benzyl dithiocarbazate

In the crystal structure of the title compound, C₈H₁₀N₂S₂, the mol­ecules are linked by N—H?S hydrogen bonds between the imino group and the thione‐S atoms to form a chain along the b axis. The di­thio­carb­azate moiety is rotated by 85.8 (2)° with respect to the phenyl ring.     

pH‐Dependent Nitrotyrosine Formation in Ribonuclease A is Enhanced in the Presence of Polyethylene Glycol (PEG)

Protein nitration can occur as a result of peroxynitrite‐mediated oxidative stress. Excess production of peroxynitrite (PN) within the cellular medium can cause oxidative damage to biomolecules. The in vitro nitration of Ribonuclease A (RNase A) results in nitrotyrosine (NT) formation with a strong dependence on the pH of the medium. In order to mimic the cellular environment in this study, PN‐mediated RNase A nitration has been carried out in a crowded medium. The degree of nitration is higher at pH 7.4 (physiological pH) compared to pH 6.0 (tumor cell pH). The extent of nitration increases significantly when PN is added to RNase A in the presence of crowding agents PEG 400 and PEG 6000. PEG has been found to stabilize PN over a prolonged period, thereby increasing the degree of nitration. NT formation in RNase A also results in a significant loss in enzymatic activity.     

Chromatographic determination of 6-substituted 2-thiouracyls,thyreostatic preparations

Optimum conditions (borate buffer solution pH 9.18, voltage 20 kV) were selected for the separation and quantitative determination of antithyroid preparations, 6-R-2-thiouracyls, where R = H (TU), CH₃ (MTU), n-C₃H₇ (PTU) by capillary zone electrophoresis in a quartz capillary 60 cm (effective length of 50 cm) × 75 μm. The procedure allows for the estimation of the concentration of substances in the ranges 1.3–103, 1.4–114, and 1.7–136 μg/mL, respectively, with detection limits of 0.93, 0.73, and 0.86 μg/mL for TU, MTU, and PTU, respectively. The procedure of the gas chromatographic-mass spectrometric determination of PTU with an analytical range of 10–50 μg/mL and a detection limit of 5.22 μg/mL is developed.     

Pyridoxine‐Derived Organoselenium Compounds with Glutathione Peroxidase‐Like and Chain‐Breaking Antioxidant Activity

One of the vitamin B6 vitamers, pyridoxine, was modified to incorporate selenium in various oxidation states in place of the methyl group in position 2. Such compounds were conveniently accessed by treatment of bis‐4,5‐(carboethoxy)‐2‐iodo‐3‐pyridinol with disodium diselenide and LiAlH₄‐reduction. After work‐up, selone 7 was isolated in good yield as an air‐stable crystalline material. Hydrogen bonding to the neighboring hydroxyl group, as revealed by the short intramolecular Se ??? H distance in the crystal structure is likely to provide extra stabilization to the compound. Computational studies showed that selone 7 is more stable than the corresponding selenol tautomer by 12.2 kcal mol^?1. Hydrogen peroxide oxidation of the selone 7 afforded diselenide 12 , and, on further oxidation, seleninic acid 13 . Treatment of the seleninic acid with thiophenol provided an isolable selenosulfide 14 . The glutathione peroxidase‐like properties of the pyridoxine‐derived compounds were assessed by using the coupled reductase method. Seleninic acid 13 was found to be twofold more active than ebselen. The chain‐breaking capacity of the pyridoxine compounds were studied in a water/chlorobenzene membrane model containing linoleic acid as an oxidizable substrate and N‐acetylcysteine as a thiol reducing agent. Diselenide 15 could match α‐tocopherol when it comes to reactivity towards peroxyl radicals and inhibition time.     

Stickstoffmonoxid,Superoxid und Peroxynitrit: Radikalchemie im Organismus

^˙NO is an arginine‐derived signal molecule which together with prostacyclin is involved in blood vessel relaxation. Superoxide (^˙O2‐) being a radical like ^˙NO, almost quantitatively traps ^˙NO under formation of peroxynitrite, which is able to oxidatively modify biomolecules. Already submicromolar concentrations of peroxynitrite selectively cause a tyrosine nitration and inactivation of prostacyclin synthase. The mechanism of this nitration could be explained by a heme‐thiolate‐catalyzed homolytic cleavage of peroxynitrite followed by the formation of a ferryl/^˙NO2 intermediate. By this nitration reaction the superoxide radical gains a new function as a signal molecule with antagonistic actions to ^˙NO. Inflammatory conditions upregulate ^˙NO and superoxide in many cells and by the generating higher levels of peroxynitrite cause pathophysiological effects. Such oxidative changes may be a future target for pharmacological interventions by suitable antioxidants.     

Direct Resonance Raman Characterization of a Peroxynitrito Copper Complex Generated from O2 and NO and Mechanistic Insights into Metal‐Mediated Peroxynitrite Decomposition

We report the formation of a new copper peroxynitrite ( PN ) complex [Cu^II(TMG₃tren)(κ¹‐OONO)]⁺ ( PN1 ) from the reaction of [Cu^II(TMG₃tren)(O₂^.?)]⁺ ( 1 ) with NO^._(g) at ?125 °C. The first resonance Raman spectroscopic characterization of such a metal‐bound PN moiety supports a cis κ¹‐(^?OONO) geometry. PN1 transforms thermally into an isomeric form ( PN2 ) with κ²‐O,O′‐(^?OONO) coordination, which undergoes O?O bond homolysis to generate a putative cupryl (LCu^II?O^.) intermediate and NO₂^.. These transient species do not recombine to give a nitrato (NO₃^?) product but instead proceed to effect oxidative chemistry and formation of a Cu^II–nitrito (NO₂^?) complex ( 2 ).     

糖尿病和硝化条件下胰岛素受体及底物酪氨酸磷酸化的研究

利用新颖的定量核磁共振(³¹P NMR)法和免疫印迹法研究了四氧嘧啶诱导的糖尿病状态下以及酪氨酸经过氧亚硝酸根供体SIN-1硝化条件下大鼠肝脏胰岛素受体(IR)的自磷酸化和受体底物1(IRS1)的磷酸化。结果表明,四氧嘧啶诱导的糖尿病大鼠肝脏中IR自磷酸化水平削弱了,硝化对大鼠肝脏中IR自磷酸化的影响依赖于SIN-1浓度,根据IRS1磷酸化位点基序设计的多肽的硝化完全抑制了其磷酸化,提示酪氨酸硝化可能干扰胰岛素磷酸化信号通路。     

Synthesis of 1,2,4‐triazolo[1,5‐d]‐1,2,4‐triazine‐5‐thiones

In an attempt to discover bicyclic compounds containing the 1,2,4‐triazine moiety, 1,2,4‐triazolo[1,5‐d]‐1,2,4‐triazine‐5‐thiones from one pot reaction of arylnitriles with 4‐amino‐1,2,4‐triazine‐3‐thione‐5‐one in the presence of potassium tert‐butoxide were synthesized.     

Synthesis of 4‐(Phenylamino)quinazoline‐2(1H)‐selones and Diselenides from Isoselenocyanates: Dimroth Rearrangement of an Intermediate

The reaction of anthranilonitriles 8 with phenyl isoselenocyanates ( 1a ) in dry pyridine under reflux gave 4‐(phenylamino)quinazoline‐2(1H)‐selones 9 (Scheme 2). They are easily oxidized and converted to diselenides of type 11 . The analogous reaction of 8a with phenyl isothiocyanate ( 1b ) yielded the quinazoline‐2(1H)‐thione 10 (Scheme 2). A reaction mechanism via a Dimroth rearrangement of the primarily formed intermediate is presented in Scheme 3. The molecular structures of 10 and 11a have been established by X‐ray crystallography. Unexpectedly, no selone or diselenide was obtained in the case of the reaction with 3‐aminobenzo[b]furan‐2‐carbonitrile ( 14 ). The only product isolated was the selenide 16 (Scheme 4), the structure of which has been established by X‐ray crystallography.     

Oxidative demetalation of Fischer alkoxy carbene complexes with stoichiometric pyridine N-oxide and NaBH4-promoted demetalation of Fischer iminocarbene complexes with sulfur and selenium

Oxidation of Fischer alkoxy carbene complexes were systematically investigated with stoichiometric pyridine N-oxide (PNO) under mild conditions, forming ester products in good to excellent yields from the corresponding monocarbene complexes. Fischer alkoxy biscarbene complexes efficiently underwent stepwise oxidative demetalation under controlled conditions, resulting in ester-monocarbene and diester products, respectively. This oxidation protocol has demonstrated a generally efficient method to oxidize Fischer alkoxy carbene complexes under mild conditions, providing a new route to novel monocarbene complexes from Fischer biscarbene complexes. In the presence of NaBH₄, reactions of Fischer iminocarbene complexes with elemental sulfur or selenium in ethanol at ambient temperature regioselectively afforded thione or selone complexes by insertion of a sulfur or selenium atom into the MC bonds in Fischer carbene complexes, and metal-free selone was also obtained. The molecular structures of the iminocarbene complexes and selone derivatives were confirmed by X-ray crystallographic study. The NaBH₄-promoted demetalation protocol suggests a potential new route to demetalate Fischer aminocarbene complexes.     

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.