Antioxidant action of organic sulfites—II. Esters of sulfurous acid as primary antioxidants

The effect of esters of sulfurous acid as primary antioxidants was examined. Different aliphatic, aromatic, open-chain and cyclic sulfites were synthesized. The reactions of organic sulfites with RO₂ and RO radicals, the chain carriers of the autoxidation of hydrocarbons and polymers, were simulated by means of the thermal decomposition of azobisisobutyronitrile (AIBN) in the presence of oxygen and of di-tert-butylperoxalate (DTBPO). The reactivity of organic sulfites with 2-cyanoisopropylperoxyl radicals is low. Only aromatic sulfites are able to trap peroxyl radicals; however, they are not very effective primary antioxidants. The reactions of the organic sulfites with tert-butoxyl radicals generally lead to an increase in the rate of decomposition of DTBPO, as determined from rate constants measured at 50 °C. A decomposition of DTBPO induced by liberated tert-butyl radicals in the presence of alkyl sulfites is very probable. Alkyl sulfites and aromatic sulfites with aliphatic groups act mainly as hydrogen donors in reactions with alkoxyl and peroxyl radicals.     

The reactivity of air-stable pyridine- and pyrimidine-containing diarylamine antioxidants

We recently reported a preliminary account of our efforts to develop novel diarylamine radical-trapping antioxidants (Hanthorn et al. J. Am. Chem. Soc.2012, 134, 8306-8309), wherein we demonstrated that the incorporation of ring nitrogens into diphenylamines affords compounds that display a compromise between H-atom transfer reactivity to peroxyl radicals and stability to one-electron oxidation. Herein, we report the results of thermochemical and kinetic experiments on an expanded set of diarylamines (see the accompanying paper, DOI: 10.1021/jo301013c ), which provide a more complete picture of the structure-reactivity relationships of these compounds as antioxidants. Nitrogen incoporation into a series of alkyl-, alkoxyl-, and dialkylamino-substituted diphenylamines raises their oxidation potentials systematically with the number of nitrogen atoms, resulting in overall increases of 0.3-0.5 V on going from the diphenylamines to the dipyrimidylamines. At the same time, the effect of nitrogen incorporation on their reactivity toward peroxyl radicals was comparatively small (a decrease of only 6-fold at most), which is also reflected in their N-H bond dissociation enthalpies. Rate constants for reactions of dialkylamino-substituted diarylamines with peroxyl radicals were found to be >10(7) M(-1) s(-1), which correspond to the pre-exponential factors that we obtained for a representative trio of compounds (log A ～ 7), indicating that the activation energies (E(a)) are negligible for these reactions. Comparison of our thermokinetic data for reactions of the diarylamines with peroxyl radicals with literature data for reactions of phenols with peroxyl radicals clearly reveals that diarylamines have higher inherent reactivities, which can be explained by a proton-coupled electron-transfer mechanism for these reactions, which is supported by theoretical calculations. A similar comparison of the reactivities of diarylamines and phenols with alkyl radicals, which must take place by a H-atom transfer mechanism, clearly reveals the importance of the polar effect in the reactions of the more acidic phenols, which makes phenols comparatively more reactive.     

Kinetics and structure-activity relationship of dendritic bridged hindered phenol antioxidants to protect styrene against free radical induced peroxidation

A series of dendritic poly(amido-amine) (PAMAM) bridged hindered phenols antioxidants were synthesized. The active antioxidant group (3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionic acid) was attached to two generations of PAMAM dendrimers, and their structure was verified by nuclear magnetic resonance (NMR) and fourier transform infrared spectra (FT-IR). The antioxidant abilities of the dendritic phenols to inhibit the oxidation of styrene were evaluated and the relationships between the length of core, the generation of dendrimers and the antioxidant activities were established. The reaction kinetics of scavenging peroxyl radicals was followed by oxygen consumption. The inhibition time (t_inh) values showed the dendritic phenols had the ability of scavenging peroxyl radicals, and that the antioxidant ability increased with the increasing length of the core and the generation. The kinetic analysis demonstrated that dendritic phenols could slow the rate of styrene peroxidation induced by AIBN, as shown by the number of trapping ROO· (n), and this role was in accordance with that of the t_inh values.     

Dissociation energies of O-H and N-H bonds in hybrid antioxidants

The dissociation energies of O-H and N-H bonds have been determined for ten aminophenoltype (HOArAmH) hybrid antioxidants. The bond dissociation energies D _O-H and D _N-H have been estimated from experimental kinetic data (rate constants of the reactions of peroxyl radicals with these antioxidants and their alkyl-substituted derivatives) by the intersecting-parabolas method. Kinetic data for the reactions of peroxyl radicals with HOArAmH, ROArAmH, and HOArAmR compounds were used. The following D _O-H and D _N-H values (kJ/mol) were obtained: for 4-hydroxydiphenylamine, D _O-H = 338.8 and D _N-H = 355.9; for 4-hydroxyphenyl-2-naphthylamine, D _O-H = 335.4 and D _N-H = 353.6; for 6-hydroxy-1,2-dihydro-2,2,4-tri-methylquinoline, D _O-H = 338.0 and D _N-H = 348.2; for 9-hydroxy-1,2-dihydro-2,3,4-trimethylquinoline, D _O-H = 329.7 and D _N-H = 383.3; for 6-hydroxy-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline, D _O-H = 324.4 and D _N-H = 345.3; for 8-hydroxy-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline, D _O-H = 329.4 and D _N-H = 380.6; for 5-hydroxyimidazole, D _O-H = 356.4 and D _N-H = 368.4; for 5-hydroxy-2-methylimidazole, D _O-H = 351.3 and D _N-H = 362.6; for 5-hydroxy-4,6-dimethylimidazole, D _O-H = 346.7 and D _N-H = 357.3; for 5-hydroxy-2,4,6-trimethylimidazole, D _O-H = 347.7 and D _N-H = 358.7.     

Chain-breaking antioxidant activity of phosphite esters

The inhibition of the autoxidation of hydrocarbons and polypropylene by aliphatic, aromatic, sterically hindered and cyclic phosphites has been studied by means of volumetric and ³¹P-NMR techniques. The antioxidant activity of phosphites depends on the rate of their reactions with peroxyl radicals and on the way they react with alkoxyl radicals. Only those phosphites which react by substitution to give free aryloxyl radicals are effective as chain-breaking antioxidants.The reaction modes of various phosphites with various peroxyl and alkoxyl radicals have been studied in some model reactions and the relationship between structure, reaction mechanism and antioxidant activity has been elucidated.     

How lipid unsaturation, peroxyl radical partitioning, and chromanol lipophilic tail affect the antioxidant activity of α-tocopherol: direct visualization via high-throughput fluorescence studies conducted with fluorogenic α-tocopherol analogues

The preparation of two highly sensitive fluorogenic α-tocopherol (TOH) analogues which undergo >30-fold fluorescence intensity enhancement upon reaction with peroxyl radicals is reported. The probes consist of a chromanol moiety coupled to the meso position of a BODIPY fluorophore, where the use of a methylene linker (BODIPY-2,2,5,7,8-pentamethyl-6-hydroxy-chroman adduct, H(2)B-PMHC) vs an ester linker (meso-methanoyl BODIPY-6-hydroxy-2,5,7,8-tetramethylchromane-2-carboxylic acid, H(2)B-TOH) enables tuning their reactivity toward H-atom abstraction by peroxyl radicals. The development of a high-throughput fluorescence assay for monitoring kinetics of peroxyl radical reactions in liposomes is subsequently described where the evolution of the fluorescence intensity over time provides a rapid, facile method to conduct competitive kinetic studies in the presence of TOH and its analogues. A quantitative treatment is formulated for the temporal evolution of the intensity in terms of relative rate constants of H-atom abstraction (k(inh)) from the various tocopherol analogues. Combined, the new probes, the fluorescence assay, and the data analysis provide a new method to obtain, in a rapid, parallel format, relative antioxidant activities in phospholipid membranes. The method is exemplified with four chromanol-based antioxidant compounds differing in their aliphatic tails (TOH, PMHC, H(2)B-PMHC, and H(2)B-TOH). Studies were conducted in six different liposome solutions prepared from poly- and mono-unsaturated and saturated (fluid vs gel phase) lipids in the presence of either hydrophilic or lipophilic peroxyl radicals. A number of key insights into the chemistry of the TOH antioxidants in lipid membranes are provided: (1) The relative antioxidant activities of chromanols in homogeneous solution, arising from their inherent chemical reactivity, readily translate to the microheterogeneous environment at the water/lipid interface; thus similar values for k(inh)(H(2)B-PMHC)/k(inh)(H(2)B-TOH) in the range of 2-3 are recorded both in homogeneous solution and in liposome suspensions with hydrophilic or lipophilic peroxyl radicals. (2) The relative antioxidant activity between tocopherol analogues with the same inherent chemical reactivity but bearing short (PMHC) or long (TOH) aliphatic tails, k(inh)(PMHC)/k(inh)(TOH), is ~8 in the presence of hydrophilic peroxyl radicals, regardless of the nature of the lipid membrane into which they are embedded. (3) Antioxidants embedded in saturated lipids do not efficiently scavenge hydrophilic peroxyl radicals; under these conditions wastage reactions among peroxyl radicals become important, and this translates into larger times for antioxidant consumption. (4) Lipophilic peroxyl radicals show reduced discrimination between antioxidants bearing long and short aliphatic tails, with k(inh)(PMHC)/k(inh)(TOH) in the range of 3-4 for most lipid membranes. (5) Lipophilic peroxyl radicals are scavenged with the same efficiency by all four antioxidants studied, regardless of the nature of their aliphatic tail or the lipid membrane into which they are embedded. These data underpin the key role the lipid environment plays in modulating the rate of reaction of antioxidants characterized by similar inherent chemical reactivity (arising from a conserved chromanol moiety) but differing in their membrane mobility (structural differences in the lipophilic tail). Altogether, a novel, facile method of study, new insights, and a quantitative understanding on the critical role of lipid diversity in modulating antioxidant activity in the lipid milieu are reported.     

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 10⁷ 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. The reaction rates do not reflect the electronic properties of the ring substituents and, because the reactions occur in a solvent cage, quenching is more efficient when the OH and TeR groups have an ortho arrangement. In the presence of thiols, hydroxyaryl alkyl tellurides act as catalytic antioxidants towards both hydroperoxides (mimicking the glutathione peroxidases) and peroxyl radicals. The high efficiency of the quenching of the peroxyl radicals and hydroperoxides could be advantageous under normal cellular conditions, but pro‐oxidative (thiol depletion) when thiol concentrations are low.     

Do garlic-derived allyl sulfides scavenge peroxyl radicals?

The chain-breaking antioxidant activities of two garlic-derived allyl sulfides, i.e. diallyl disulfide (1), the main component of steam-distilled garlic oil, and allyl methyl sulfide (3) were evaluated by studying the thermally initiated autoxidation of cumene or styrene in their presence. Although the rate of cumene oxidation was reduced by addition of both 1 and 3, the dependence on the concentration of the two sulfides could not be explained on the basis of the classic antioxidant mechanism as with phenolic antioxidants. The rate of oxidation of styrene, on the other hand, did not show significant changes upon addition of either 1 or 3. This unusual behaviour was explained in terms of the co-oxidant effect, consisting in the decrease of the autoxidation rate of a substrate forming tertiary peroxyl radicals (i.e. cumene) upon addition of little amounts of a second oxidizable substrate giving rise instead to secondary peroxyl radicals. The relevant rate constants for the reaction of ROO(.) with 1 and 3 were measured as 1.6 and 1.0 M(-1) s(-1), respectively, fully consistent with the H-atom abstraction from substituted sulfides. It is therefore concluded that sulfides 1 and 3 do not scavenge peroxyl radicals and therefore cannot be considered chain-breaking antioxidants.     

Study of phenolic compounds as natural antioxidants by a fluorescence method

Much work has been carried out in recent years on the beneficial effect of phenolic compounds as natural antioxidants which help to neutralize free radicals. In fact, researchers have focused their attention on the pathological role of free radicals in a variety of diseases, among which the most important are atherosclerosis and cancer. Thus, among the components of the so-called 'Mediterranean Diet', phenolic compounds have received increased attention as epidemiological studies have shown that consumption of foods and beverages rich in phenolics is correlated with reduced incidence of heart disease. In this study, four phenolic compounds: (1) 3,4,5-trihydroxybenzoic acid (gallic acid); (2) trans 3,4',5-trihydroxystilbene (trans-resveratrol); (3) 3,3',4',5,7-pentahydroxyflavone (quercetin) and its glycoside (4) 3,3',4',5,7-pentahydroxyflavone-3-rutinoside (Rutin) have been subjected to antioxidant study by a fluorimetric assay. In this method, the rate of peroxidation induced by 2,2'-azobis (2-methylpropionamidine) dihydrochloride was monitored through the loss of fluorescence of the protein B-phycoerythrin (B-PE). Under appropriate conditions, the loss of B-PE fluorescence in the presence of reactive species is an index of oxidative damage of the protein. The inhibition of the action of reactive species by phenolic compounds, reflected in the protection against the loss of B-PE fluorescence in the fluorimetric assay, is a measure of its antioxidant capacity against the reactive species. The antioxidant effects of phenolic compounds have been investigated at different concentrations to relate activity to structural effects. It has been observed that the fluorescence decay due to peroxyl radical attack on B-PE decreases exponentially with time. As a reference compound for antioxidant capacity we used 6-hydroxy-2,5,7,8-tetramethyl-chroman-2-carboxylicacid (trolox), a water soluble tocopherol analogue. This compound reacts rapidly with peroxyl radicals, and, until the trolox is consumed, no loss in phycoerythrin fluorescence is observed. A linear correlation of the net protection value with the concentration of trolox was demonstrated. The phenolic compounds studied react with peroxyl radicals in a similar way to trolox. Quercetin and rutin were shown to have strong antioxidant activities. The results obtained here are in agreement with previous studies confirming that quercetin is the most antioxidant of the four polyphenolics.     

Peroxyesters as precursors to peroxyl radical clocks

The reactions of peroxyl radicals are at the center of the oxidative degradation of essentially all petroleum-derived hydrocarbons and biological lipids and consequently, the inhibition of these processes by radical-trapping antioxidants. Recently described peroxyl radical clocks offer a simple, convenient, and inexpensive method of determining rate constants for H-atom transfer reactions to peroxyl radicals, greatly enabling the kinetic and mechanistic characterization of compounds with antioxidant properties. We follow up our preliminary communication on the development of a methodology utilizing tert-butyl styrylperacetate as a precursor to a versatile peroxyl radical clock with the present paper, wherein we describe a novel naphthyl analogue, which provides for much improved product resolution for analysis, and provide the complete details associated with its development and application. Using this new precursor, and with consideration of the expanded set of reaction products, inhibition rate constants were measured for a variety of representative phenolic and diarylamine radical-trapping antioxidants. We also provide details for the use of this methodology for the determination of mechanistic information, such as kinetic solvent effects, Arrhenius parameters, and kinetic isotope effects.     

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.     

Thiophenols,Promising Scavengers of Peroxyl Radicals: Mechanisms and kinetics

The activity of 12 thiophenols as primary antioxidants in aqueous solution has been studied using density functional theory. Twelve different substituted thiophenols were tested as peroxyl radicals scavengers. Single electron transfer (SET) and formal hydrogen transfer (FHT) were investigated. The SET mechanism was found to be the main mechanism, with rate constants that are close to the diffusion limit, which means that these thiophenolic compounds have the capacity to scavenge peroxyl radicals before they can damage biomolecules. All 12 thiophenolic compounds react faster with methylperoxyl than with hydroperoxyl radicals. In addition, it was found that pH plays an important role in the reactivity of these compounds. © 2019 Wiley Periodicals, Inc.     

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. Thiol consumption in the aqueous phase was found to correlate inversely to the inhibition time and the availability of thiol is the limiting factor for the duration of antioxidant protection. The proposed mechanism for quenching of peroxyl radicals involves O‐atom transfer from peroxyl to Te followed by H‐atom transfer from amine to alkoxyl radical in a solvent cage.     

Why is the order reversed? peroxyl‐scavenging activity and fats‐and‐oils protecting activity of vitamin E

The orders of relative tocopherol biopotency, scavenging activity of lipid peroxyl radicals, and quenching activity of singlet oxygen are as follows: jalpha‐tocopherol > β‐tocopherol ? γ‐tocopherol > δ‐tocopherol. However, the reverse is the case for the activity to protect fats and oils from oxidation: jalpha‐tocopherol < β‐tocopherol < γ‐tocopherol δ‐tocopherol. The reason for this reverse has been studied by measuring weight gains of solutions including methyl linoleate and various antioxidants at daily intervals. Antioxidant activity is expressed as an induction period in days. Induction periods are compared with the second‐order rate constants for scavenging of an aroxyl radical by the antioxidants. A plot of the logarithm of the second‐order rate constant vs. the induction period is found to give a good linear fit, and the slope is negative. From these results, it is considered that the larger the peroxyl‐radical‐scavenging activity of a tocopherol, the more favorable the production of the tocopheroxyl radical, and thus the more efficient the oxidation of fats and oils by the tocopheroxyl radical. This is not the case for tocopherols in vivo, because vitamin C and ubiquinol reduce tocopheroxyl radicals formed from tocopherols. © 2005 Wiley Periodicals, Inc. Int J Chem Kinet 37: 605–610, 2005     

The effect of ring nitrogen atoms on the homolytic reactivity of phenolic compounds: understanding the radical-scavenging ability of 5-pyrimidinols

Six substituted 5-pyrimidinols were synthesized, and the thermochemistry and kinetics of their reactions with free radicals were studied and compared to those of equivalently substituted phenols. To assess their potential as hydrogen-atom donors to free radicals, we measured their O-H bond dissociation enthalpies (BDEs) using the radical equilibration electron paramagnetic resonance technique. This revealed that the O-H BDEs in 5-pyrimidinols are, on average, about 2.5 kcal mol(-1) higher than those in equivalently substituted phenols. The results are in good agreement with theoretical predictions, and confirm that substituent effects on the O-H BDE of 5-pyrimidinol are essentially the same as those on the Obond;H BDE in phenol. The kinetics of the reactions of these compounds with peroxyl radicals has been studied by their inhibition of the AIBN-initiated autoxidation of styrene, and with alkyl and alkoxyl radicals by competition kinetics. Despite their larger O-H BDEs, 5-pyrimidinols appear to transfer their phenolic hydrogen-atom to peroxyl radicals as quickly as equivalently substituted phenols, while their reactivity toward alkyl radicals far exceeds that of the corresponding phenols. We suggest that this rate enhancement, which is large in the case of alkyl radical reactions, small in the case of peroxyl radical reactions, and nonexistent in the case of alkoxyl radical reactions, is due to polar effects in the transition states of these atom-transfer reactions. This hypothesis is supported by additional experimental and theoretical results. Despite this higher reactivity of 5-pyrimidinols towards radicals compared to phenols, electrochemical measurements indicate that they are more stable to one-electron oxidation than equivalently substituted phenols. For example, the 5-pyrimidinol analogues of 2,4,6-trimethylphenol and butylated hydroxytoluene (BHT) were found to have oxidation potentials approximately 400 mV higher than their phenolic counterparts, but reacted roughly one order of magnitude faster with alkyl radicals and at about the same rate with peroxyl radicals. The 5-pyrimidinol structure should, therefore, serve as a useful template for the rational design of novel air-stable radical scavengers and chain-breaking antioxidants that are more effective than phenols.     

Organophosphorus antioxidants—VIII. Kinetics and mechanism of the reaction of organic phosphites with peroxyl radicals

Trialkyl phosphites react with cyanoisopropylperoxyl radicals, generated by thermolysis of azobis(isobutyronitrile) in the presence of oxygen, to give the corresponding phosphates with rate constants of the order of 10³ M⁻¹ sec⁻¹ at 65°C. Phenyl phosphites are oxidized also. A small amount of cyanoisopropyl phosphite is formed by substitution of the phosphite by alkyloxyl radicals leading to phenoxyl radicals. Sterically hindered aryl phosphites react with cyanoisopropylperoxyl radicals to yield the corresponding phosphates and alkoxyl radicals which in a second step react with phosphite by substitution releasing a sterically hindered phenoxyl radical. Therefore, sterically hindered phosphites are capable of acting as chain-terminating primary antioxidants. Because the rate constants of reaction of these phosphites with peroxyl radicals are only in the range of 10² M⁻¹ sec⁻¹ and 100 times smaller than those of phenols, phosphites should be less active as primary antioxidants than phenols.     

Optimization of conditions for the extraction of antioxidants from solid parts of medicinal plants

The extraction of phenolic antioxidants from solid plant raw materials (bark and roots) under the action of an electric current was studied. A relationship between the amount and antioxidant activity of extracted phenolic compounds with the particle size and the procedure of grinding plant raw material was found. The most complete extraction of phenols was reached in experiments with ground samples. The resulting extracts from the bark of arrowwood (Viburnum opulus L.) and the root of burnet (Sanguisorba officinalis L.) were superior to the extracts obtained by circulation extraction in a Soxhlet extractor in terms of the antioxidant activity, and they increased the stability of sunflower oil to oxidation by a factor of 2–3.     

On‐line HPLC method for screening of antioxidants against superoxide anion radical from complex mixtures

A practical approach for rapidly screening antioxidants against superoxide anion radicals from complex mixtures was developed based on the quantitative difference in active compounds before and after their reaction. To test the effectiveness of the approach, seven flavonoids with antioxidative properties were investigated both individually and in a mixture. Using the approach, antioxidants could be rapidly separated and screened with a ranked order of activities in the meantime. The radical scavenging activities were in the following order: quercetin > kaempferol > fisetin > puerarin > luteolin > rutin > baicalein. The order of activity was conducted by comparing the scavenging ratio of the antioxidant, which was completely consistent with the results obtained from the traditional electronic spin resonance. Then, the method was successfully applied to black tea extracts. This approach is fast and convenient for screening, isolating, and analyzing potential antioxidants from a mixture with good quantitative and reproducible ability.     

Kinetics and mechanism of peroxyl radical reactions with nitroxides

Cyclic nitroxides (>NO*) are stable radicals of diverse size, charge, lipophilicility, and cell permeability, which provide protection against oxidative stress via various mechanisms including SOD-mimic activity, oxidation of reduced transition metals and detoxification of oxygen- and nitrogen-centered radicals. However, there is no agreement regarding the reaction of nitroxides with peroxyl radicals, and many controversies in the literature exist. The question of whether nitroxides can protect by scavenging peroxyl radicals is important because peroxyl radicals are formed in biological systems. To further elucidate the mechanism(s) underlying the antioxidative effects of nitroxides, we studied by pulse radiolysis the reaction kinetics of piperidine, pyrrolidine, and oxazolidine nitroxides with several alkyl peroxyl radicals. It is demonstrated that nitroxides mainly reduce alkyl peroxyl radicals forming the respective oxoammonium cations (>N+=O). The most efficient scavenger of peroxyl radicals is 2,2,6,6-tetramethylpiperidine-N-oxyl (TPO), which has the lowest oxidation potential among the nitroxides tested in the present study. The rate constants of peroxyl reduction are in the order CH2(OH)OO*>CH3OO*>t-BuOO*, which correlate with the oxidation potential of these peroxyl radicals. The rate constants for TPO vary between 2.8x10(7) and 1.0x10(8) M-1 s-1 and for 3-carbamoylproxyl (3-CP) between 8.1x10(5) and 9.0x10(6) M-1 s-1. The efficacy of protection of nitroxides against inactivation of glucose oxidase caused by peroxyl radicals was studied. The results demonstrate a clear correlation between the kinetic features of the nitroxides and their ability to inhibit biological damage inflicted by peroxyl radicals.     

Optimization of the antioxidant activity of hydroxy-substituted 4-thiaflavanes: a proof-of-concept study

The design and the synthesis of a new family of hydroxy-4-thiaflavanes, in which the reactive phenolic OH is ortho to the sulfur atom of the benzofused oxathiin ring, allowed to prepare antioxidants that show rate constants for the reaction with peroxyl radicals (k(inh)), and bond dissociation energies (BDE), of the ArO-H group identical to those of α-tocopherol, the main component of vitamin E and the most effective lipophilic antioxidant known in nature. The peculiar conformation of the six-membered heterocyclic ring prevents the formation of an intramolecular hydrogen bond between the OH group and the S atom, while ensuring a good stabilization by electron donation of the phenoxyl radical formed after the reaction with peroxyl radicals. The preparation of these compounds was achieved through an inverse electron demand hetero Diels-Alder reaction of styrenes with o-thioquinones, in turn prepared from accurately designed 1,3-dihydroxy arenes. Properly arranging the substitution pattern on the aromatic ring, as in derivatives 9 and 11, allowed to reach values of k(inh) up to 4.0×10(6) M(-1) s(-1) and BDE((OH)) of 77.2 kcal mol(-1). This approach represents an innovative way to obtain highly active antioxidants without using strongly electron donating alkylamino groups which are associated with adverse toxicological profiles.