Substituent Effects in Chain-Breaking Aryltellurophenol Antioxidants.

2-Aryltellurophenols substituted in the aryltelluro or phenolic parts of the molecule were prepared by lithiation of the corresponding tetrahydropyran-protected 2-bromophenol, followed by reaction with a suitable diaryl ditelluride then deprotection. In a two-phase system containing N-acetylcysteine as a co-antioxidant in the aqueous phase, all of the compounds quenched lipid peroxyl radicals more efficiently than α-tocopherol, with three to five-fold longer inhibition times. Thus, these compounds offer better and longer-lasting antioxidant protection than recently prepared alkyltellurophenols.

Chain-Breaking Phenolic 2,3-Dihydrobenzo[b]selenophene Antioxidants: Proximity Effects and Regeneration Studies.

Phenolic 2,3-dihydrobenzo[b]selenophene antioxidants bearing an OH-group ortho (9), meta (10, 11) and para (8) to the Se were prepared by seleno-Claisen rearrangement/intramolecular hydroselenation. meta-Isomer (11) was studied by X-ray crystallography. The radical-trapping activity and regenerability of compounds 8-11 were evaluated using a two-phase system in which linoleic acid was undergoing peroxidation in the lipid phase while regeneration of the antioxidant by co-antioxidants (N-acetylcysteine, glutathione, dithiothreitol, ascorbic acid, tris(carboxyethyl)phosphine hydrochloride) was ongoing in the aqueous layer.

Selenium- and Tellurium-Based Antioxidants for Modulating Inflammation and Effects on Osteoblastic Activity.

Increased oxidative stress plays a significant role in the etiology of bone diseases. Heightened levels of H2O2 disrupt bone homeostasis, leading to greater bone resorption than bone formation. Organochalcogen compounds could act as free radical trapping agents or glutathione peroxidase mimetics, reducing oxidative stress in inflammatory diseases.

Nitro-, Azo-, and Amino Derivatives of Ebselen: Synthesis, Structure, and Cytoprotective Effects.

Novel azo-bis-ebselen compounds 7 were prepared by reduction of 7-nitro-2-aryl-1,2-benzisoselenazol-3(2H)-ones 3 and 6 with sodium benzenetellurolate, NaTeCH, and by reaction of 2-bromo-3-nitrobenzamides with NaSe. The X-ray structure of 7b showed that the molecule, due to strong intramolecular secondary Se···N interactions, is completely planar. Azo-compounds 7 upon further reaction with NaTeCH were reductively cleaved to provide 2 equiv of the corresponding aromatic amine.

Regenerable Radical-Trapping Tellurobistocopherol Antioxidants.

Tellurobistocopherols 9-11 were prepared by lithiation of the corresponding bromotocopherols, reaction with tellurium tetrachloride and reductive workup. Compounds 9-11 quenched linoleic-acid-derived peroxyl radicals much more efficiently than α-tocopherol in a chlorobenzene/water two-phase system. N-Acetylcysteine or tris(2-carboxylethyl)phosphine as co-antioxidants in the aqueous phase could regenerate the tellurobistocopherols and increase their inhibition times.

Alkyltelluro Substitution Improves the Radical-Trapping Capacity of Aromatic Amines.

The synthesis of a variety of aromatic amines carrying an ortho-alkyltelluro group is described. The new antioxidants quenched lipidperoxyl radicals much more efficiently than α-tocopherol and were regenerable by aqueous-phase N-acetylcysteine in a two-phase peroxidation system. The inhibition time for diaryl amine 9 b was four-fold longer than recorded with α-tocopherol.

Ebselen and analogs as inhibitors of Bacillus anthracis thioredoxin reductase and bactericidal antibacterials targeting Bacillus species, Staphylococcus aureus and Mycobacterium tuberculosis.

Background: Bacillus anthracis is the causative agent of anthrax, a disease associated with a very high mortality rate in its invasive forms.

Methods: We studied a number of ebselen analogs as inhibitors of B. anthracis thioredoxin reductase and their antibacterial activity on Bacillus subtilis, Staphylococcus aureus, Bacillus cereus and Mycobacterium tuberculosis.

Multifunctional Antioxidants: Regenerable Radical-Trapping and Hydroperoxide-Decomposing Ebselenols.

Regenerable, multifunctional ebselenol antioxidants were prepared that could quench peroxyl radicals more efficiently than α-tocopherol. These compounds act as better mimics of the glutathione peroxidase enzymes than ebselen. Production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in human mononuclear cells was considerably decreased upon exposure to the organoselenium compounds.

The Cellular Thioredoxin-1/Thioredoxin Reductase-1 Driven Oxidoreduction Represents a Chemotherapeutic Target for HIV-1 Entry Inhibition.

Background: The entry of HIV into its host cell is an interesting target for chemotherapeutic intervention in the life-cycle of the virus. During entry, reduction of disulfide bridges in the viral envelope glycoprotein gp120 by cellular oxidoreductases is crucial. The cellular thioredoxin reductase-1 plays an important role in this oxidoreduction process by recycling electrons to thioredoxin-1.

Regenerable Thiophenolic Radical-Trapping Antioxidants.

Diphenyl disulfides carrying alkyltelluro groups in the o-, m-, and p-positions were prepared using ortho-lithiation and lithium halogen exchange reactions. The novel antioxidants showed only minimal inhibitory effect on the azo-initiated peroxidation of linoleic acid in chlorobenzene until reduced to the corresponding thiophenols by tris(2-carboxyethyl)phosphine (TCEP). The best in situ generated thiophenol (from 7c) under these conditions quenched peroxyl radicals more efficiently than α-tocopherol with an almost 3-fold increase in inhibition time.

Effect of a Bromo Substituent on the Glutathione Peroxidase Activity of a Pyridoxine-like Diselenide.

In search for better mimics of the glutathione peroxidase enzymes, pyridoxine-like diselenides 6 and 11, carrying a 6-bromo substituent, were prepared. Reaction of 2,6-dibromo-3-pyridinol 5 with sodium diselenide provided 6 via aromatic nucleophilic substitution of the 2-bromo substituent. LiAlH4 caused reduction of all four ester groups and returned 11 after acidic workup.

Regenerable antioxidants-introduction of chalcogen substituents into tocopherols.

To improve the radical-trapping capacity of the natural antioxidants, alkylthio-, alkylseleno-, and alkyltelluro groups were introduced into all vacant aromatic positions in β-, γ- and δ-tocopherol. Reaction of the tocopherols with electrophilic chalcogen reagents generated by persulfate oxidation of dialkyl dichalcogenides provided convenient but low-yielding access to many sulfur and selenium derivatives, but failed in the case of tellurium. An approach based on lithiation of the appropriate bromo-tocopherol, insertion of chalcogen into the carbon-lithium bond, air-oxidation to a dichalcogenide, and final borohydride reduction/alkylation turned out to be generally applicable to the synthesis of all chalcogen derivatives.

Scavenging effect of Trolox released from brushite cements.

In this study a brushite cement was doped with the chain-breaking antioxidant Trolox. The effect of the antioxidant on the physical properties of the cement was evaluated and the release of Trolox was monitored by UV spectroscopy. The ability of the Trolox set free to scavenge reactive oxygen species (ROS) released by macrophages was determined in vitro using a luminol-amplified chemiluminescence assay.

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.

Catalytic antioxidants: regenerable tellurium analogues of vitamin E.

In an effort to improve the chain-breaking capacity of the natural antioxidants, an octyltelluro group was introduced next to the phenolic moiety in β- and δ-tocopherol. The new vitamin E analogues quenched peroxyl radicals more efficiently than α-tocopherol and were readily regenerable by aqueous N-acetylcysteine in a simple membrane model composed of a stirring chlorobenzene/water two-phase system. The novel tocopherol analogues could also mimic the action of the glutathione peroxidase enzymes.

Ebsulfur is a benzisothiazolone cytocidal inhibitor targeting the trypanothione reductase of Trypanosoma brucei.

Trypanosoma brucei is the causing agent of African trypanosomiasis. These parasites possess a unique thiol redox system required for DNA synthesis and defense against oxidative stress. It includes trypanothione and trypanothione reductase (TryR) instead of the thioredoxin and glutaredoxin systems of mammalian hosts.

In search of catalytic antioxidants--(alkyltelluro)phenols, (alkyltelluro)resorcinols, and bis(alkyltelluro)phenols.

The quenching of peroxyl radicals by ortho-(alkyltelluro)phenols occurs by a more complex mechanism than formal H-atom transfer. In an effort to improve on this concept, we have prepared (alkyltelluro)resorcinols and bis(alkyltelluro)phenols and evaluated their catalytic chain-breaking and preventive antioxidative properties. The in situ formed trianion produced from 2-bromophenol and 3 equiv of tert-butyllithium was allowed to react with dialkyl ditellurides to provide ortho-(alkyltelluro)phenols in low yields.

Multi-faceted reactivity of alkyltellurophenols towards peroxyl radicals: catalytic antioxidant versus thiol-depletion effect.

Hydroxyaryl alkyl tellurides are effective antioxidants both in organic solution and aqueous biphasic systems. They react by an unconventional mechanism with ROO(·) radicals with rate constants as high as 10(7)  M(-1)  s(-1) at 303 K, outperforming common phenols. The reactions proceed by oxygen atom transfer to tellurium followed by hydrogen atom transfer to the resulting RO(·) radical from the phenolic OH.

Turning pyridoxine into a catalytic chain-breaking and hydroperoxide-decomposing antioxidant.

Vitamin B6 is involved in a variety of enzymatic transformations. Some recent findings also indicate an antioxidant role of the vitamin in biological systems. We set out to turn pyridoxine (1a) into a catalytic chain-breaking and hydroperoxide-decomposing antioxidant by replacing the 2-methyl substituent with an alkyltelluro group.

Inhibition of bacterial thioredoxin reductase: an antibiotic mechanism targeting bacteria lacking glutathione.

Increasing antibiotic resistance makes the identification of new antibacterial principles an urgent task. The thioredoxin system including thioredoxin reductase (TrxR), thioredoxin (Trx), and NADPH plays critical roles in cellular DNA synthesis and defense against oxidative stress. Notably, TrxR is very different in structure and mechanism in mammals and bacteria.

Extraction of antioxidants from spruce (Picea abies) bark using eco-friendly solvents.

Introduction: Antioxidants are known to avert oxidation processes and they are found in trees and other plant materials. Tree bark is a major waste product from paper pulp industries; hence it is worthwhile to develop an extraction technique to extract the antioxidants.

Objective: To develop a fast and environmentally sustainable extraction technique for the extraction of antioxidants from bark of spruce (Picea abies) and also to identify the extracted antioxidants that are abundant in spruce bark.

Long-lasting antioxidant protection: a regenerable BHA analogue.

Introduction of an octyltelluro group ortho to the phenolic moiety in 3-tert-butyl-4-hydroxyanisole (BHA) was found to significantly improve the antioxidant characteristics of the material. In contrast to BHA and the corresponding ortho-substituted octylthio- (9c) and octylseleno (9b) derivatives, the organotellurium 9a was regenerable when assayed for its capacity to inhibit azo-initiated peroxidation of linoleic acid in a chlorobenzene/water two-phase system containing N-acetylcysteine as a stoichiometric reducing agent, and peroxyl radicals were quenched more efficiently than with α-tocopherol. In the homogeneous phase, inhibition of styrene autoxidation occurred with a rate constant kinh as large as 1 × 10(7) M(-1) s(-1) but with a low (n = 0.

Organochalcogen substituents in phenolic antioxidants.

Little is known about the ED/EW character of organochalcogen substituents and their contribution to the O-H bond dissociation enthalpy (BDE) in phenolic compounds. A series of ortho- and para-(S,Se,Te)R-substituted phenols were prepared and investigated by EPR, IR, and computational methods. Substituents lowered the O-H BDE by >3 kcal/mol in the para position, while the ortho-effect was modest due to hydrogen bonding ( approximately 3 kcal/mol) to the O-H group.

Exploring a synthetic organoselenium compound for antioxidant pharmacotherapy--toxicity and effects on ROS-production.

The organoselenium antioxidant 1 was previously found to act as a catalytic antioxidant in a two-phase lipid peroxidation system. In aqueous environment, selenide 1 quenched ABTS-radicals more efficiently than Trolox and ascorbic acid. The selenide dose-dependently scavenged reactive oxygen and nitrogen species more efficiently than Trolox for neutrophils and PMA-stimulated macrophages, with 50% inhibitory concentrations in the low micromolar range.

Catalytic chain-breaking pyridinol antioxidants.

The synthesis of 3-pyridinols carrying alkyltelluro, alkylseleno, and alkylthio groups is described together with a detailed kinetic, thermodynamic, and mechanistic study of their antioxidant activity. When assayed for their capacity to inhibit azo-initiated peroxidation of linoleic acid in a water/chlorobenzene two-phase system, tellurium-containing 3-pyridinols were readily regenerable by N-acetylcysteine contained in the aqueous phase. The best inhibitors quenched peroxyl radicals more efficiently than alpha-tocopherol, and the duration of inhibition was limited only by the availability of the thiol reducing agent.