Glutathione peroxidase (GPx)-like antioxidant activity of the organoselenium drug ebselen: unexpected complications with thiol exchange reactions

The factors that are responsible for the relatively low glutathione peroxidase (GPx)-like antioxidant activity of organoselenium compounds such as ebselen (1, 2-phenyl-1,2-benzisoselenazol-3(2H)-one) in the reduction of hydroperoxides with aromatic thiols such as benzenethiol and 4-methylbenzenethiol as cosubstrates are described. Experimental and theoretical investigations reveal that the relatively poor GPx-like catalytic activity of organoselenium compounds is due to the undesired thiol exchange reactions that take place at the selenium center in the selenenyl sulfide intermediate. This study suggests that any substituent that is capable of enhancing the nucleophilic attack of thiol at sulfur in the selenenyl sulfide state would enhance the antioxidant potency of organoselenium compounds such as ebselen. It is proved that the use of thiol having an intramolecularly coordinating group would enhance the biological activity of ebselen and other organoselenium compounds. The presence of strong S...N or S...O interactions in the selenenyl sulfide state can modulate the attack of an incoming nucleophile (thiol) at the sulfur atom of the -Se-S- bridge and enhance the GPx activity by reducing the barrier for the formation of the active species selenol.     

Synthesis, characterization, and antioxidant activity of some ebselen analogues

Simple synthetic routes for several analogues of the anti-inflammatory organoselenium drug, ebselen, are described. The compounds are characterized by (1)H, (13)C, and (77)Se NMR spectroscopy and mass spectral techniques and, in some cases, by single-crystal X-ray diffraction studies. The glutathione peroxidase (GPx)-like antioxidant activity has been studied by using H(2)O(2), tBuOOH, and Cum-OOH as substrates, and thiophenol (PhSH, 4-Me-C(6)H(4)SH) and glutathione (GSH) as cosubstrates. Density functional theory (DFT) calculations have been performed on these systems to understand the effects of various substituents on the (77)Se NMR chemical shifts; these results have been compared with the experimental data. The experimental and theoretical results suggest that the presence of a phenyl substituent on the nitrogen atom is important for the antioxidant activity of ebselen. While ebselen and its analogues are poor catalysts in aromatic thiol assays, these compounds exhibit high GPx activity when GSH is used as the cosubstrate. The poor catalytic activity of ebselen analogues in the presence of aromatic thiols such as PhSH and 4-Me-C(6)H(4)SH can be ascribed to the undesired thiol exchange reaction that takes place at the selenium center due to SeO nonbonding interactions. To understand the effects of different peroxides on the catalytic activities, we have determined the initial rates at various concentrations of GSH and peroxides. These data suggest that the nature of peroxide has little effect on the catalytic efficiencies, although the initial reaction rates observed with hydrogen peroxide were found to be higher than that with tBuOOH and Cum-OOH. In contrast to the effect of peroxides, the nature of thiols appears to have a dramatic effect on the catalytic activity of ebselen and its related derivatives.     

New hypocholesterolemic abietamide derivatives. II. Synthesis and hypocholesterolemic activity of N-phenyl-delta 8-dihydroabietamides

A series of N-phenyl-delta 8-dihydroabietamide analogs were prepared and tested for hypocholesterolemic activity. The effects of substituents of the phenyl moiety on the activities were quantitatively analyzed by using various substituent parameters. The activities were enhanced by the electron-donating effect of ortho and para substitutents and the bulkiness of ortho substituents. A combination of 2,6-dimethylaniline with resin acids other than delta 8-dihydroabietic acid produced lower activities than N-(2,6-dimethylphenyl)-delta 8-dihydroabietamide, abietane-type carboxamides being somewhat stronger than pimarane-type carboxamides. The conversion of the carboxamide group to other groups resulted in more or less of a decrease in activity, giving evidence that the carboxamide group is important to hypocholesterolemic activity.     

Synthesis of a new seleninic acid anhydride and mechanistic studies into its glutathione peroxidase activity

Starting from low toxic salicyloylglycine, a new seleninic acid anhydride 7 that lacks SeN or SeO non-bonded interactions was synthesized. This compound exhibits a fourfold higher glutathione peroxidase-like (GPx-like) activity than ebselen and inhibits plant and mammalian 12/15-lipoxygenases at lower micromolar concentrations. Because of these pharmacological properties, 7 may constitute a new lead compound for the development of anti-inflammatory low-molecular-weight seleno-organic compounds. Analyzing the redox products of 7 with glutathione (GSH) and tBuOOH, we identified three potential catalytic cycles (A, B, C) of GPx-like activity that are interconnected by key metabolites. To study the relative contribution of these cycles to the catalytic activity, we prepared selected reaction intermediates and found that the activity of seleninic acid anhydride 7 and of the corresponding diselenide 11 and selenol 14 compounds were in the same range. In contrast, the GPx-like activity of monoselenide 9 was more than one order of magnitude lower. These data suggested that cycles A and B may constitute the major routes of GPx-like activity of 7, whereas cycle C may not significantly contribute to catalysis.     

A simple and efficient strategy to enhance the antioxidant activities of amino-substituted glutathione peroxidase mimics

The glutathione peroxidase (GPx) activities of some diaryl diselenides incorporating tertiary amino groups were studied with H(2)O(2), Cum-OOH, and tBuOOH as substrates and with PhSH as thiol co-substrate. Simple replacement of a hydrogen atom with a methoxy group dramatically enhances the GPx activity. The introduction of methoxy substituents ortho to selenium in N,N-dialkylbenzylamine-based compounds makes the basicity of the amino groups perfect for the catalysis. The presence of 6-OMe groups prevents possible SeN interactions in the selenols, increasing their zwitterionic characters. The methoxy substituents also protect the selenium in the selenenic acid intermediates from overoxidation to seleninic acids or irreversible inactivation to selenonic acid derivatives. The additional substituents also play a crucial role in the selenenyl sulfide intermediates, by preventing thiol exchange reactions-which would normally lead to an inactivation pathway-at the selenium centers. The strengths of SeN interactions in the selenenyl sulfide intermediates are dramatically reduced upon introduction of the methoxy substituents, which not only reduce the thiol exchange reactions at selenium but also enhance the nucleophilic attack of the incoming thiols at sulfur. The facile attack of thiols at sulfur in the selenenyl sulfides also prevents the reactions between the selenenyl sulfides and H(2)O(2) that can regenerate the selenenic acids (reverse-GPx cycle). These studies reveal that the simple 6-OMe groups play multiple roles in each of the catalytically active intermediates by introducing steric and electronic effects that are required for efficient catalysis.     

Steric and electronic effects in capsule-confined green fluorescent protein chromophores

The turn-on of emission in fluorescent protein chromophores sequestered in an "octaacid" capsule is controlled by stereoelectronic effects described by a linear free energy relationship. The stereochemical effects are governed by both the positions and volumes of the aryl substituents, while the electronic effects, including ortho effects, can be treated with Hammett σ parameters. The use of substituent volumes rather than A values reflects packing of the molecule within the confines of the capsule.     

Unexpected fragmentation of beta-substituted meso-tetraphenylporphyrins induced by high-energy collisional activation

The protonated molecules and radical cations of meso-tetraphenylporphyrins with beta-pyrrolic substituents, when formed by fast atom bombardment (FAB) and subjected to high-energy collisions, give rise to unexpected fragment ions. The reaction involves hydrogen migration from the ortho position of the phenyl ring to the a atom of the substituent, with formation of an intramolecular, six-membered ring. The process is analogous to condensed-phase cyclizations described for the same type of compounds. The fragmentation requires the presence of a double bond in the substituent group attached to the pyrrolic ring. A rearrangement process involving anchimeric assistance by the phenyl group (analogous to an ortho effect) is proposed for the formation of these ions.     

Synthesis, structure, and glutathione peroxidase-like activity of amino acid containing ebselen analogues and diaryl diselenides

The synthesis of some ebselen analogues and diaryl diselenides, which have amino acid functions as an intramolecularly coordinating group (Se···O) has been achieved by the DCC coupling procedure. The reaction of 2,2'-diselanediylbis(5-tert-butylisophthalic acid) or the activated ester tetrakis(2,5-dioxopyrrolidin-1-yl) 2,2'-diselanediylbis(5-tert-butylisophthalate) with different C-protected amino acids (Gly, L-Phe, L-Ala, and L-Trp) afforded the corresponding ebselen analogues. The used precursor diselenides have been found to undergo facile intramolecular cyclization during the amide bond formation reaction. In contrast, the DCC coupling of 2,2'-diselanediyldibenzoic acid with C-protected amino acids (Gly, L/D-Ala and L-Phe) affords the corresponding amide derivatives and not the ebselen analogues. Some of the representative compounds have been structurally characterized by single-crystal X-ray crystallography. The glutathione peroxidase (GPx)-like activities of the ebselen analogues and the diaryl diselenides have been evaluated by using the coupled reductase assay method. Intramolecularly stabilized ebselen analogues show slightly higher maximal velocity (V(max)) than ebselen. However, they do not show any GPx-like activity at low GSH concentrations at which ebselen and related diselenides are active. This could be attributed to the peroxide-mediated intramolecular cyclization of the corresponding selenenyl sulfide and diaryl diselenide intermediates generated during the catalytic cycle. Interestingly, the diaryl diselenides with alanine (L,L or D,D) amide moieties showed excellent catalytic efficiency (k(cat)/K(M)) with low K(M) values in comparison to the other compounds.     

取代基物化参数及其在药物定量构效关系中的应用

把取代基电性、立体及疏水性物化参数组合建立一种新取代基描述方法, 对环尿素类和N,N-二甲基-2-溴苯乙胺类衍生物进行结构表征. 对训练样本集通过逐步回归筛选变量, 所建多元线性回归方程R2分别为0.853和0.960, 留一法交互检验Rcv2分别为0.723和0.901；用预测集样本作外部预测, 所得Qext2分别为0.7617和0.7653. 结果显示：环尿素类化合物结构中苯环邻位立体、间位疏水、对位疏水及立体因素对该类药物抗HIV活性产生阻抑作用； N,N-二甲基-2-溴苯乙胺类苯环上取代基立体因素及对位给电子效应有利于提高肾上腺素能阻断活性.     

Unexpected fragmentation of β-substituted meso-tetraphenylporphyrins induced by high-energy collisional activation

The protonated molecules and radical cations of meso-tetraphenylporphyrins with β-pyrrolic substituents, when formed by fast atom bombardment (FAB) and subjected to high-energy collisions, give rise to unexpected fragment ions. The reaction involves hydrogen migration from the ortho position of the phenyl ring to the atom of the substituent, with formation of an intramolecular, six-membered ring. The process is analogous to condensed-phase cyclizations described for the same type of compounds. The fragmentation requires the presence of a double bond in the substituent group attached to the pyrrolic ring. A rearrangement process involving anchimeric assistance by the phenyl group (analogous to an ortho effect) is proposed for the formation of these ions.     

Prevention of Racemization of the Chiral Carbon in the Episelenonium ION Intermediate: Steric Protection and Electron-Withdrawing Effect

To prevent the racemization of the chiral carbon in the episelenonium ion intermediate bearing an aryl group on the selenium atom, both the bulky substituent(s) on the ortho position(s) of the aryl group and electron-with-drawing substituent(s) in the aryl group are found to play an important role.     

立体拥挤二苯基卡宾分子结构的电子效应

通过对二苯基重氮甲烷的光照射产生了一系列具有对称对位取代基的三线态二(2,6-二甲苯基)卡宾.用电子顺磁共振波谱对其进行了研究.通过对不同粘度的基质(matrix)中零磁场分裂参数D和E的测定,依据电子自旋离域取代基常数σr对三线态二苯基卡宾的分子结构的取代基效应进行了分析.并通过对卡宾的热消失温度及其室温脱气苯溶液中寿命的测定,对三线态二(2,6-二甲苯基)卡宾的稳定性进行了定量考察.结果表明,对卡宾中心的自旋电子具有离域效应的取代基使三线态二(2,6-二甲苯基)卡宾采取低能稳定的直线型结构,且显示了更好的热稳定性和更长的寿命.     

Conformational arm-wrestling: battles for stereochemical control in benzamides bearing matched and mismatched chiral 2- and 6-substituents

The orientation of a tertiary amide group adjacent to an aromatic ring may be governed by the stereochemistry of an adjacent chiral substituent. With a chiral substituent in both ortho positions, matched/mismatched pairs of isomers result. Evidence for matched stereochemistry is provided by the clean NMR spectra of single conformers, while mismatching gives poor or unexpected selectivities in the formation of chiral substituents, or mixtures of amide conformers. Attempts to use the match-mismatch effect to select for racemic pairs of enantiomeric substituents, and hence develop a "racemate-sequestering" reagent, are described, along with the use of "matching" to scavenge a single enantiomer of a diamine from material of incomplete enantiomeric purity.     

二苯基卡宾反应性的取代基效应

用激光闪光光解法对室温溶液中产生的三线态二苯基卡宾进行了直接观察,并通过对产生的三线态二苯基卡宾寿命的测定以及与氧气反应速率常数的考察,就邻位及对位的取代基效应进行了初步探讨。     

2-苯基-苯并异硒唑酮-3及其衍生物的合成和抗肿瘤活性的初步研究

微量元素硒能防治克山病、大骨节病、肿瘤及心血管病等。目前,普遍认为在哺乳动物体内存在着一种重要的含硒酶即谷胱甘肽过氧化物酶(GSH-Px),阻由于其结构的复杂性,限制了对它的研究。而有关硒酶模拟化合物2-苯基-苯并异硒唑酮-3(简称Ebselen)的生物活性已见诸报道,它是具有类似谷胱甘肽过氧化物酶生物活性的小分子有机硒化合物,具有极     

O,O-二乙基亚磷酰基异氰酸酯与亚苄基苯胺的反应研究

O,O-二乙基亚磷酰基异氰酸酯与亚苄基苯胺反应,当亚苄基苯胺分子中苯环上具有邻位取代基时,产物不是稳定的1,3,4-二氮磷杂环戊烷衍生物,却是α-(O,O-二乙基)膦酰基苄基苯胺.这可能是由于邻位取代基的立体效应阻碍了环加成反应,且中间体水解之故.所得化合物均经元素分析、IR、H、N、AF及MS谱证实.     

Production and Characterization Te-Peptide by Induced Autolysis of Saccharomyces Cerevisiae

Recently, the interest in mimicking functions of chalcogen-based catalytic antioxidants like selenoenzymes, has been increased. Various attempts had been done with selenium, but very few attempts were carried out with tellurium. Bio-complex formation and characterization of tellurium was not tried earlier by using any organism. The present study was focused on tellurium peptide production, characterization, and bioactivity assessment especially Mimetic to glutathione peroxidase (GPx). The production was achieved by the autolysis of total proteins obtained from Saccharomyces cerevisiae ATCC 7752 grown with inorganic tellurium. The GPx-like activity of the hydrolyzed tellurium peptide was increased when prepared by autolysis, but decreased when prepared by acid hydrolysis. Tellurium peptide produced by autolysis of the yeast cell showed increased GPx-like activity as well as tellurium content. Tellurium peptide showed little toxicity, compared to highly toxic inorganic tellurium. The results showed the potential of tellurium peptide as an antioxidant that can be produced by simple autolysis of yeast cells.     

THE SULFENAMIDE CHIRAL UNIT. TORSIONAL BARRIERS IN TRINITROBENZENESULFENAMIDES AND PERHALOBENZENSULFENAMIDES

Abstract

The free energies of activation for degenerate racemization of sulfenamides, measured by DNMR spectroscopy provide information about the N-S formal single bond since stereomutation is accomplished by torsion about this bond. The S-N torsional barrier in benzenesulfenamides (arSNR¹R²) is singnificantly increased by the presence of substituents which are electron withdrawin (by resonance). However, while the barrier is increased by para and^a/single ortho substituent, the introduction of a second ortho substituent lowers the barrier.     

Silyl-directed, iridium-catalyzed ortho-borylation of arenes. A one-pot ortho-borylation of phenols, arylamines, and alkylarenes

The regioselectivity of the borylation of arenes catalyzed by the combination of 4,4'-di-tert-butylbipyridine (dtbpy) and [Ir(cod)Cl]2 has typically been governed by steric effects. We describe a strategy that makes use of a new substituent for ortho-functionalization to overcome this bias. We show that arenes containing hydrosilyl substituents on an atom attached to the arene ring undergo borylation at the position ortho to the hydrosilyl group. Using iridium-catalyzed formation of silyl ethers and silylamines from silanes and either phenols or arylamines, we have developed the ortho-borylation into a one-pot conversion of free phenols and monoprotected anilines into hydroxy- and amino-substituted organoboron derivatives.     

Electronic and hydrogen bonding effects on the chain-breaking activity of sulfur-containing phenolic antioxidants

A kinetic and thermodynamic investigation of phenols para-substituted with thiyl (SR), sulfinyl (SOR), and sulfonyl (SO(2)R) groups and ortho-substituted with thiyl groups is reported. The effect of the sulfur substituents on the O-H bond dissociation enthalpy values, BDE(O-H), was measured by means of the EPR radical equilibration technique and the reactivity toward peroxyl radicals, k(inh), of these phenolic antioxidants was determined by inhibited autoxidation studies. An inverse correlation between these two parameters was found. A p-SMe substituent decreased the BDE(O-H) value to a lesser extent than a p-OMe group (-3.6 vs -4.4 kcal/mol), whereas the effect of the same groups in an ortho position showed an opposite trend (-0.85 vs -0.2 kcal/mol). The latter result is explained in terms of the different strength of the intramolecular hydrogen bond between the OH proton and the sulfur or oxygen substituents in ortho derivatives. ESI-MS analysis of the products formed by reacting the sulfides with peroxyl radicals from the azoinitiator AIBN revealed the formation of a complex mixture of products, which may play an important role in determining the overall antioxidant activity of the parent compounds.