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Chapter 1 introduces the phenomenon of oxygen toxicity and the central role played by oxygen free radicals, most notably the superoxide radical anion. The technique of spin trapping, whereby reactive free radicals are studied and identified, is then introduced. The synthesis of improved spin traps for superoxide by the preparation of 1-pyrroline 1-oxides bearing a C-3 ester or alkyl halide substituent is then discussed. Chapter 2 describes the preparation of 2-(prop-2-enyl)-aldehydes, 2-dimethoxymethylaldehydes and a 2-phenylthiomethylaldehyde. Bromination of 5,5-dimethyl-1-(prop-2-enyl)-1-pyrroline 1-oxide did not give rise to addition at the C=C double bond but recovery of the nitrone and a hydroxamic acid. Similarly, hydrohalogenation of the alkenyl-nitrone did not lead to addition at the C=C double bond. The preparation and utility of 3-(ethoxycarbonylprop-2-enyl)-5,5-dimethyl-1-pyrroline 1-oxide is then described. Chapter 3 details the preparation of 3-dimethoxymethyl-1-pyrroline 1-oxides. Acid-catalysed deprotection of these nitrone acetals did not result in the formation of the expected 3-aldehydo-5,5-dimethyl-1-pyrroline 1-oxides. Chapter 4 deals with the preparation of 5,5-dimethyl-3-phenylthiomethyl-1-pyrroline 1-oxide. Conversion of the phenylthiomethyl group to an iodomethyl group led to the loss of the nitrone. Chlorination of the nitrone gave 4-methyl-4-nitro-2-phenylthiomethylpentanoic acid. Oxidation of 5,5-dimethyl-3-ethoxycarbonyl-1-hydroxypyrrolidine resulted in the dimeric nitrone 3,3'-bis(ethoxycarbonyl)-5,5,5',5'-tetramethyl-3,3'-bi-1-pyrrolinyl 1,1-dioxide being isolated. Chapter 5 concerns the synthetic utility of α-bromoaldehydes. The preparation of 5,5-dimethyl-3-benzenesulphonyl-1-pyrroline 1-oxide is then described. Alkylation of the nitrone in the presence of sodium hydride with methylbromoacetate gave the C-3 disubstituted nitrone, 3-benzenesulphonyl-5,5-dimethyl-3-methoxycarbonylmethyl-1-pyrroline 1-oxide. Chapter 6 concerns the spin trapping reactions of the nitrones prepared in this thesis. The ESR spectra of the hydrogen atom adducts showed the magnetic non-equivalence of the β-hydrogens owing to the presence of the C-3 substituent. Spin trapping of the <I>t</I>-butoxy radical was found to be stereospecific. Apparent selectivity for the hydroxyl radical was found as no spin adducts were detected with the superoxide radical anion.

In the framework of Ph.D. thesis the evaluation of radical reactions of four groups of secondary amines R1–NH–R2 in the presence of some selected types of agents was performed using EPR spectroscopy. First group was represented by peroxoagents (3-chloroperbenzoic acid, tBuO2 radicals), the second group involved compounds of PbIV+ (PbO2, Pb(OAc)4) functioning as hydrogen-abstracting agents. In the presence of peroxyagents the formation of corresponding aminoxyl radicals R1–NO–R2 was demonstrated. In the case of surplus of tBuO2 radicals these radicals enter the consecutive reactions which products are new types of secondary aminoxyls. By the interpretation of reaction mechanism the intermediary formation of nitrones was assumed. These function in later steps of the reaction as spin traps for tBuO2 radicals. By the study of radical mechanism of amines R1–NH–R2 initiated by PbIV+ agents was proved, that these compounds hydrogen atom not only from –NH– group under formation of aminyl radicals, but also from C–H bonds in substituents R1, R2 (the formation of C-radicals). Because both groups of the radicals formed are characterized by high reactivity, their identification was possible only using spin-trapping method. In the course of the investigation of radical reactions of secondary amines the big amount of experimental EPR spectra was obtained. These exhibited in many cases very high hyperfine structure. Due to this fact it was necessary to perform the detailed evaluation on the basis of spectral simulation. Except of some special cases using this approach the interpretation of majority of registered EPR spectra was interpreted and EPR parameters were summarized in tables.

Le but de cette thèse consistait en l’amélioration de l’activité thérapeutique d’agents anti-radicalaires synthétiques de type nitroxyde et nitrone. Ces deux classes d’antioxydants synthétiques ont été choisies pour leur très bonne activité de piégeurs de radicaux libres, des substances particulièrement délétères et impliquées à l’heure actuelle dans un grand nombre de pathologies. Dans une première partie de ce travail, des nitroxydes ont été fonctionnalisés par des transporteurs amphiphiles dérivés de la lysine et de l’acide aspartique, puis une deuxième approche a consisté en la modification d’une nitrone, l’alphaphényl-N-tert-butyl-nitrone (PBN) par des groupements polaires et apolaires. Les études physico-chimiques ont ensuite permit de caractériser les propriétés d’auto-assemblage en milieux aqueux de ces composés ainsi que leur caractère hydrophobe et leurs propriétés antioxydantes. Enfin, des études biologiques ont mis en évidence les propriétés protectrices de ces molécules vis-à-vis des phénomènes de stress oxydant sur des modèles in vitro et in vivo. / The goal of this thesis was to improve the therapeutic activity of synthetic nitroxide and nitrone antioxidant agents. Free radicals are very reactive and toxic species that are associated to a large number of pathologies. In the first part of this work, nitroxides were grafted to lysine- and aspartic acid- based amphiphilic carriers. The second part, consisted inthe functionalization of the α-phenyl-N-tert-butyl-nitrone (PBN) by hydrophilic and lipophilic groups. For both series of compounds the self-aggregation properties in water as well as their hydrophobic character and antioxidant properties were determined. Finally, biological studies demonstrated the protective properties of these molecules against oxidative stress in vitro and in vivo models.

Les nitrones sont de composés diamagnétiques qui additionnent les radicaux libres pour former des adduits nitroxyde détectables par résonance paramagnétique électronique (RPE). Récemment les nitrones linéaires telles que l’α-phényl-N-tert-butylnitrone (PBN) et ses dérivés ont été proposées comme nouvelles thérapeutiques dans des pathologies à stress oxydant. Dans ce contexte nous avons synthétisé une vingtaine de PPNs originales, dérivés β-phosphorylés de la PBN, dont le groupe phényle a été substitué par des groupes ayant des effets électroniques sur la fonction nitrone ou a été conçu de manière à former un fragment phénolique présent dans certains antioxydants naturels. Il s’agissait de combiner le bon outil de détection des radicaux que sont les PPNs aux éventuels effets antioxydants et donneurs de NO● de ces nitrones. Nous avons réalisé une évaluation des propriétés antioxydantes des nouvelles PPNs au moyen de différents tests biochimiques ainsi qu'une étude par RPE permettant de déterminer leur réactivité in vitro sur plusieurs types de radicaux libres d'intérêt biologique. Nous avons sélectionné les PPNs ayant les meilleures propriétés afin d'examiner leur impact pharmacologique dans un modèle d'endothélium aortique de rat soumis à un stress oxydant. Dans une deuxième partie, nous avons greffé sur certaines des PPNs synthétisées des chaînes alkyles de différentes longueurs dont la terminaison triphénylphosphonium confère à ces nitrones une affinité particulière pour la mitochondrie, principale source cellulaire de production radicalaire. Nous avons ensuite évalué par RPE la capacité de ces 5 nouvelles mito-PPNs à piéger les radicaux libres alkyle et alcoxy in vitro. / Nitrones are diamagnetic compounds commonly used as probes to monitor biological free radical formation by the spin trapping (ST)/electron paramagnetic resonance coupling (EPR). In addition the growing interest in the therapeutic potential of α-phenyl-N-tert-butylnitrone (PBN) derivatives led researchers to develop analogs having improved protective properties and bioavailability. Among these, PPNs are β-phosphorylated analogues of PBN which form more persistent spin adducts than PBN toward oxygen-centered radicals. In this context we have synthesized twenty new hybrid PPNs having their aromatic ring substituted either by groups which can bring electronic and steric effects to the nitrone function or mimic natural antioxidant moieties. We evaluated the antioxidant properties of the new PPNs with a series of specific assays and we used ESR to study PPNs properties in ST toward a wide array of biologically-relevant free radicals, and their intrinsic nitric oxide releasing properties. The most promising compounds were than tested as vasorelaxant and antioxidant free radicals detectors in rat aortic rings. Protection by PPNs was assessed by measuring vascular response preservation and biochemical indices in aortic tissue. The second purpose dealt with the synthesis of new mitochondrial targeted PPNs with the aim to reach the primary biological source of endogenous production of free radicals. Using EPR we have assessed their ability to scavenge alkyl and alkoxy free radicals in vitro which allowed us to envisage a potential use of this probe against lipid peroxidation at mitochondrial level.

Le but de cette thèse consistait en l'amélioration de l'activité thérapeutique d'agents anti-radicalaires synthétiques de type nitroxyde et nitrone. Ces deux classes d'antioxydants synthétiques ont été choisies pour leur très bonne activité de piégeurs de radicaux libres, des substances particulièrement délétères et impliquées à l'heure actuelle dans un grand nombre de pathologies. Dans une première partie de ce travail, des nitroxydes ont été fonctionnalisés par des transporteurs amphiphiles dérivés de la lysine et de l'acide aspartique, puis une deuxième approche a consisté en la modification d'une nitrone, l'alphaphényl-N-tert-butyl-nitrone (PBN) par des groupements polaires et apolaires. Les études physico-chimiques ont ensuite permit de caractériser les propriétés d'auto-assemblage en milieux aqueux de ces composés ainsi que leur caractère hydrophobe et leurs propriétés antioxydantes. Enfin, des études biologiques ont mis en évidence les propriétés protectrices de ces molécules vis-à-vis des phénomènes de stress oxydant sur des modèles in vitro et in vivo.

Within the PhD. thesis the problems of H-transfer from selected types of phenols, aromatic secondary amines and compounds with acidic CH bond were investigated. This process was initiated by the action of redox agents, mostly PbO2, in nonpolar solvents. The abstraction of hydrogen atom results in the formation of radical intermediates, which were detected by EPR spectroscopy. Because in most cases, highly unstable radicals were produced, it was neccessary to apply the technique of indirect detection, so called spin trapping. This method enables to interpret the character of generated radicals on the basis of EPR parameters of radical adducts, which are formed by their reaction with suitably chosen compounds, spin traps, which are added to the reaction system. As spin traps, the aromatic nitrosocompounds were preferentially used. Due to the fact that EPR spectra of radical adducts were in most cases very complex, their interpretation was possible only using the computer simulation. Based on this approach, new information about the character of addition of phenoxyl tradicals to aromatic nitrosocompounds, stability of alkyl substituents in methyl substituted phenols and character of C-radicals, generated from substituted coumarines and beta-diketones, was obtained. Simultaneously, the small ability of nitrogen radicals, primary products of the splitting of NH bond, to enter the reaction with spin traps was proved by aromatic secondary amines.

In the frame of submitted diploma thesis dealing with the radical products of the decomposition of different X-H bonds, primary attention was focused on the detection of radical intermediates from decomposed N-H bonds. This access was realized with secondary amines of N-alkylaniline group, as well as with other structures R1-NH-R2. The aim was to confirm the formation of unstable aminyl radicals R1-N•-R2, which is possible by using spin-trapping method. In the series of experiments, where the compounds of lead and cobalt, as well as stable radical DPPH were applied as initiators of the decomposition, the unambiguous evidence for aminyl radicals was found only in the case of N-alkylanilines. With other secondary amines the detection of aminyl radicals is an open problem, because their adducts with nitrosobenzene are in very low concentration. Besides the study of the decomposition of N-H bonds also the products of the decomposition of phenolic O-H bonds, as well as products of the decomposition of C-H bonds in alkylsubstituents in phenols was studied.

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Cette étude a pour but d’explorer le comportement de radicaux centrés sur des atomes de soufre dans des silices nanostructurées de type hexagonales 2D. Une large variété de silices a été synthétisée en jouant sur la nature et la charge en précurseurs organiques. La synthèse de silices de type SBA-15 fonctionnalisées avec des précurseurs de radicaux sulfanyle, sulfinyle et sulfonyle a été réalisée grâce au procédé sol-gel. Ces matériaux nanostructurés ont permis de fortement exalter la persistance des radicaux formés en leur sein.Des radicaux alkyl- et arylsulfanyle ont été formés par photolyse de thiols greffés dans des silices. Ces radicaux ont été piégés par la tert-butylphénylnitrone et les adduits de spin ainsi formés ont vu leur temps de vie grandement augmenter par rapport aux mêmes expériences conduites à partir de précurseurs non greffés. L’observation directe du radical arylsulfanyle à température ambiante a pu être réalisée, le temps de demi-vie pouvant aller jusqu’à plusieurs jours, même en présence de dioxygène.Des précurseurs contenant un motif diazène greffés dans une silice ont permis la formation et l’observation directe de radicaux arylsulfanyle, arylsulfinyle et arylsulfonyle par photolyse à température ambiante et par thermolyse à 200 °C. Selon les conditions, des temps de demi-vie de plusieurs heures ont été enregistrés. / The aim of this study is to explore the behavior of sulfur-centered radicals in 2D-hexagonal nanostructured silicas. A large variety of silicas was synthesized by varying the nature and the loading of organic precursors. Synthesis of SBA-15 silicas functionalized with sulfanyl, sulfinyl and sulfonyl radicals precursors was achieved according to the sol-gel process. These nanostructured materials led to a dramatic enhancement in the lifetime of generated confined radicals.Alkyl- and arylsulfanyl radicals were formed by photolysis of thiols grafted in silicas. These radicals were trapped by tert-butylphenylnitrone and the resulting spin-adducts got their lifetime strongly enhanced as compared to the same experiment conducted with non-grafted precursors. Direct observation of arylsulfanyl radicals at room temperature was also achieved, the half-lifetime of which was recorded to be several days, even in the presence of dioxygen.Precursors containing a diazene framework grafted onto silica enabled the formation and direct observation of arylsulfanyl, arylsulfinyl and arylsulfonyl radicals by both photolysis at room temperature and thermolysis at 200 °C. Depending on the conditions, half-lifetimes of several hours were recorded for these radicals.