Dissertations / Theses on the topic 'Quinones'

The 3,4-dihydro-1H-naphtho[2,3-c]pyran ring system is found in many natural products as the 5,10- or 6,9-quinones. These compounds have been synthesized by various research groups as a result of their wide range of biological activities. This thesis describes several investigations directed towards syntheses of compounds in this general area. Quinone A (16) and quinone A'(17), derived from the naturally occurring aphid insect pigments protoaphin-fb and protoaphin-sl respectively, were of particular interest. The first chapter describes the previous syntheses of some naphtho[c]pyrans including those relating to the aphid pigment derivatives, followed by the isolation and identification of the aphid pigments. Also described was the ability of these naphthopyranquinones to act as potential bioreductive alkylating or dealkylating agents. The latter part of the chapter deals with the syntheses of the racemates of the aphid pigment derivatives quinones A and A' and deoxyquinone as well as model studies toward the non-quinonoid cleavage product, glucoside B. The chapter concludes with the progress made towards the first asymmetric synthesis of these compounds. Chapter 2 reports the establishment of conditions which led to ortho or para regioselectivity in the intramolecular cyclisation of tethered lactaldehydes to form benzo[c]pyrans. This regioselectivity depended on whether either benzyl or tbutyldimethylsilyl was used as protecting group. This chapter also described a model for the control of stereochemistry leading to quinone A'. Chapter 3 describes the syntheses of naphthalenes as potential precursors to the naphthopyranquinones derived from the aphid insect pigments. This followed after problems were encountered in previous work with inappropriate protection in the oxidation of halogenated benzopyrans. Chapter 4 develops the first successful syntheses of enantiopure quinone A and quinine A' with the correct absolute stereochemistry. This involved the regioselective addition of 1,3-bis(trimethylsilyloxy)-1-methoxybuta-1,3-diene toselectively halogenated benzopyranquinones. The latter were obtained through complementary series of highly diastereoselective transformations based on 2,5- dihydroxyacetophenone as starting material and (R)-lactate from the chiral pool as the source of asymmetry.

The 3,4-dihydro-1H-naphtho[2,3-c]pyran ring system is found in many natural products as the 5,10- or 6,9-quinones. These compounds have been synthesized by various research groups as a result of their wide range of biological activities. This thesis describes several investigations directed towards syntheses of compounds in this general area. Quinone A (16) and quinone A’(17), derived from the naturally occurring aphid insect pigments protoaphin-fb and protoaphin-sl respectively, were of particular interest. The first chapter describes the previous syntheses of some naphtho[c]pyrans including those relating to the aphid pigment derivatives, followed by the isolation and identification of the aphid pigments. Also described was the ability of these naphthopyranquinones to act as potential bioreductive alkylating or dealkylating agents. The latter part of the chapter deals with the syntheses of the racemates of the aphid pigment derivatives quinones A and A’ Œ and deoxyquinone as well as model studies toward the non-quinonoid cleavage product, glucoside B. The chapter concludes with the progress made towards the first asymmetric synthesis of these compounds. Chapter 2 reports the establishment of conditions which led to ortho or para regioselectivity in the intramolecular cyclisation of tethered lactaldehydes to form benzo[c]pyrans. This regioselectivity depended on whether either benzyl or tbutyldimethylsilyl was used as protecting group. This chapter also described a model for the control of stereochemistry leading to quinone A’. Chapter 3 describes the syntheses of naphthalenes as potential precursors to the naphthopyranquinones derived from the aphid insect pigments. This followed after problems were encountered in previous work with inappropriate protection in the oxidation of halogenated benzopyrans. Chapter 4 develops the first successful syntheses of enantiopure quinone A and quinine A’ with the correct absolute stereochemistry. This involved the regioselective addition of 1,3-bis(trimethylsilyloxy)-1-methoxybuta-1,3-diene toselectively halogenated benzopyranquinones. The latter were obtained through complementary series of highly diastereoselective transformations based on 2,5- dihydroxyacetophenone as starting material and (R)-lactate from the chiral pool as the source of asymmetry.

Made available in DSpace on 2014-06-11T19:31:00Z (GMT). No. of bitstreams: 0 Previous issue date: 2008-05-09Bitstream added on 2014-06-13T21:01:54Z : No. of bitstreams: 1 kitagawa_rr_dr_araiq.pdf: 870535 bytes, checksum: 17b95c96b49379329e5dd238176afb22 (MD5)
Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
Quinonas são substâncias orgânicas amplamente distribuídas na natureza, encontradas em plantas, fungos e bactérias, associadas à atividade antitumoral e antimicrobiana. Recentemente, uma quinona (5-metoxi-3,4-diidroxantomegnina), estruturalmente semelhante à 1,4-naftoquinona, foi isolada dos capítulos de Paepalanthus latipes. O objetivo desse estudo foi avaliar atividades biológicas dessa quinona visando possível aplicação terapêutica. A 5-metoxi-3,4-diidroxantomegnina apresentou concentração inibitória mínima para Staphylococcus aureus e Enterococcus faecalis (197µM), mas não para Escherichia coli. Essa quinona demonstrou significativo índice citotóxico para células McCoy quando comparado ao da cisplatina. Nos ensaios utilizando linhagens tumorais de adenocarcinoma de pulmão (LP07) e mama (LM2), a maior citotoxicidade da 5-metoxi-3,4-diidroxantomegnina foi para a linhagem LP07. A associação com ácido ascórbico aumentou a citotoxicidade da 5-metoxi-3,4-diidroxantomegnina para células McCoy, LM2 e LP07 devido a um redox cílcico com formação de peróxido de hidrogênio. Visto que alguns antineoplásicos somente apresentam efeito citotóxico após biotransformação, a citotoxicidade da 5-metoxi-3,4-diidroxantomegnina na presença do sistema microssomal S9 foi avaliada e constatou-se que esse sistema de ativação metabólica não altera o potencial citotóxico da quinona. Óxido nítrico (NO) e fator de necrose tumoral-a (TNF-a) não foram detectados nos sobrenadantes de culturas de macrófagos tratados com 5-metoxi-3,4-diidroxantomegnina, portanto seu efeito tóxico, nesse sistema celular, não está relacionado com a produção desses mediadores. Entretanto, macrófagos tratados com essa quinona aumentaram significativamente a liberação de peróxido de hidrogênio. Nos testes de inibição dos...
Quinones are organic substances widely distributed in nature, found in plants, fungi and bacteria, associated with antitumoral and antimicrobial activities. Recently, a quinone (5-methoxy-3,4-dehydroxanthomegnin), structurally similar to 1,4-naphthoquinone, was isolated of the capitula of Paepalanthus latipes. The objective of this study was to evaluate biological activities of this quinone aiming a possible therapeutical application. The 5-methoxy-3,4-dehydroxanthomegnin showed minimal inhibitory concentration for Staphylococcus aureus and Enterococcus faecalis (197µM), but not for Escherichia coli. This quinone showed significative cytotoxic index for McCoy cells when compared with cisplatin. In the assays using tumoral cell lines of adenocarcinoma of lung (LP07) and breast (LM2), the largest cytotoxicity of the 5-methoxy-3,4-dehydroxanthomegnin was for LP07 line. The association with ascorbic acid increased the cytotoxicity of the 5-methoxy-3,4-dehydroxanthomegnin for McCoy cells, LM2 and LP07 due to redox cycling with hydrogen peroxide formation. Since some antineoplastic only present cytotoxic effect after biotransformation, the cytotoxicity of the 5-methoxy-3,4-dehydroxanthomegnin in the presence of the microssomal system S9 was evaluated and it was found that this system does not change the cytotoxic potential of the quinone. Nitric oxide (NO) and tumoral necrosis factor- α (TNF-α) were not detected in supernatants of macrophages treated with 5-methoxy-3,4-dehydroxanthomegnin, therefore its toxic effect, in this cell system, is not related to the production these mediators. However, macrophages treated with 5-methoxy-3,4-dehydroxanthomegnin increased hydrogen peroxide liberation significantly. The tests of inhibition of the mediators NO and TNF-α demonstrated that the 5-methoxy-3,4-dehydroxanthomegnin inhibits the release... (Complete abstract click electronic access below)

Les quinones sont des composés ubiquitaires naturels indispensables aux organismes vivants. Cependant leur métabolisation est considérée comme toxique en raison de leur réactivité élevée. Les quinones sont en effet facilement réductibles à un ou deux électrons. La métabolisation intracellulaire de ces quinones par des réductases à un électron telles que le cytochrome P450 réductase ou d'autres flavoprotéines génèrent des semiquinones instables à l'origine de la production de radicaux libres conduisant à un stress oxydant. Les quinones-réductases 1 et 2 (QR1 et QR2) catalysent leur réduction à deux électrons pour former des hydroquinones chimiquement plus stables. Cette propriété est à l'origine du caractère détoxifiant généralement associé aux quinone-réductases. Cependant des analyses antérieures ont montré que ce caractère détoxifiant était remis en cause pour certains types de quinones et dépendait, notamment, du type de cellules. Ainsi afin de mieux comprendre les mécanismes conduisant à la génération d'espèces réactives et compte tenu du lien évoqué dans la littérature entre QR2 et neurodégénérescence, des études ont été menées sur des neurones primaires et des neuroblastomes génétiquement modifiés pour surexprimer QR2. Ces études ont mis en évidence, par diverses techniques analytiques telles que la résonance paramagnétique électronique ou la LC-MS, une augmentation de la toxicité de la ménadione mais également de l'adrénochrome en présence de la quinone-réductase 2. Afin d'expliquer les caractères contradictoires de QR2 d'une cellule à l'autre nous avons proposé l'hypothèse qu'une coopération avec une enzyme de conjugaison pouvant réagir avec la forme réduite instable et empêcher sa réoxydation soit nécessaire pour effectivement détoxifier les quinones. Des analyses complémentaires (RPE, LCMS, fluorescence) menées sur des neuroblastomes surexprimant à la fois QR2 et une enzyme de conjugaison spécifique des para-hydroquinone (UGT) ont en effet mis en évidence une diminution du stress oxydant lorsque les deux enzymes sont co-exprimées
Quinones are ubiquitous compounds in nature. They are also one of the essential elements in living organisms. However, their metabolisms are considered as toxic because there are highly reactive. Their structure is easily reduced by one or two electrons. The intracellular metabolism of these quinones via one-electron reduction such as cytochrome P450 reductase or others flavoproteins generates an unstable semiquinones which leads to a burst of free radical production that results in oxidative stress. On the other hand, quinone-reductases 1 and 2 (QR1 and QR2) catalyze quinone reduction via two electrons to form hydroquinones that chemically more stable. This property is well-known as the detoxifying character of quinone-reductase enzymes. However, previous analyses have shown that this detoxifying effect was appeared only for certain types of quinones and depended, in particular, on the type of cells. Thus, in order to better understand the mechanisms leading to the generation of reactive species and in consideration to those links that were mentioned in the literature between QR2 and neurodegeneration, studies were conducted on primary neurons and neuroblastoma cells genetically modified to overexpress in QR2. These studies have shown, by various analytical techniques such as electron paramagnetic resonance or LC-MS, an increase in the toxicity of menadione but also of adrenochrome in the presence of quinone- reductase 2. In order to explain the contradictory characteristics of QR2 from one cell to another, we proposed a hypothesis that a cooperation with another conjugating enzyme, which could react with the unstable reduced form that prevent its reoxidation, is needed to effectively detoxify quinones. Additional analyses (RPE, LCMS, fluorescence) conducted on neuroblastoma cells overexpressing both QR2 and a para-hydroquinone specific conjugation enzyme (UGT) have shown a decrease in oxidative stress when both enzymes are co-expressed

ABSTRACT SYNTHESIS OF FERROCENYL QUINONES AND POLYQUINANES Eralp, Tugç
e M.S., Department of Chemistry Supervisor: Assoc. Prof. Dr. Metin Zora June 2005, 79 pages With the discovery of antitumor activity of ferrocene derivatives, research on new ferrocene derivatives have gained importance. For this purpose, we have investigated the synthesis of ferrocenyl quinones starting from squaric acid. Several quinone derivatives are known to have antitumor and antibiotic activities. In this research, by combining ferrocene and quinone moieties, we have targeted ferrocenyl quinones which are supposed to have enhanced potential antitumor activity. Thermolysis of ferrocenyl-substituted 4-alkynyl cyclobutenones, which have been prepared from ferrocenyl cyclobutenediones and alkynyllithiums, leads to the formation of ferrocenyl quinones and besides also cyclopentendiones are observed. Ferrocenyl cyclobutenediones have been prepared from known cyclobutenediones by nucleophilic addition of ferrocenyllithium followed by hydrolysis. A mechanism for the formation of ferrocenyl substituted quinones, involving first electrocyclic ring opening of alkynyl substituted cyclobutenone to ketene intermediate and then ring closure, has been proposed. Polyquinanes are widely found in nature and proved to have biological activity such as antibiotic activity. For the synthesis of ferrocenyl polyquinanes, starting from squaric acid, ferrocenyl substituted cyclobutenediones were prepared and reacted with alkenyllithium, and hydrolyzed to afford ferrocenyl substituted polyquinanes. A mechanism has been proposed that involves first the formation of cis- and trans-divinyl substituted cyclobutenes that produce cyclooctatriene-dienolate, upon hydrolysis of this dienolate, aldol-type transannular ring closure reaction takes place, producing polyquinanes.

Naturally occurring quinones have attracted considerable interest due to their widespread occurrence, structural diversity and often potent biological activities. The research outlined in this thesis involves the development of synthetic approaches to two novel naphthoquinone derivatives, both of which were discovered during investigations into the bioactive constituents of tropical plant species. Chapter 1 introduces the family of quinonoid compounds and also considers the important role that natural product synthesis can play in structural confirmation and in providing an adequate supply of compounds for further research. Chapter 2 describes the synthesis of elecanacin 36, an unusual cyclobuta-fused naphthalene-1,4-dione derivative which has been isolated from the bulbs of the iris Eleutherine americana Merr. et Heyne (Iridaceae), along with the isomeric and well-known pyranonaphthoquinones eleutherin 38 and isoeleutherin 39. Chapter 3 focuses on an approach to 3-hydroxymethylfuro[3,2-b]naphtho[2,3-d]furan-5,10-dione 37, which has been isolated from the wood of the tropical tree Crescentia cujete L. (Bignoniaceae) and incorporates a rare fully aromatic furofuran moiety.

Quinones attract the attention of chemists and biologists because of their unique structure and biological properties. Cancer is a leading cause of death worldwide, killing millions of people every year. Several antitumour agents, frequently employed in the treatment of different forms of cancer, contain in their structure the quinone motif, discovered to have marked cytotoxic effects. Chapter 1 presents an overview of the unique properties of quinones, with particular emphasis on their anticancer activity. Bioactivation of quinones by cellular reductive enzymes generates reactive oxygen species and/or alkylating species responsible for the cytotoxic effects of these compounds. Chapter 2 discusses the synthetic approaches to the novel quinone-containing natural product (+ )-terreusinone, recently isolated from the marine algicolous fungus Aspergillus terreus. Although the total synthesis of the natural product could not be accomplished, an innovative and efficient symmetric strategy, with a double Claisen rearrangement as the key step, led to the formation of the dipyrrolobenzoquinone core of ( + )-terreusinone. Chapter 3 describes the design, the synthesis and the biological evaluation of novel 2-unsubstituted indolequinones based on the structure of the indolequinones, previously synthesised in our group, that showed growth inhibitory activity against human pancreatic cancer cells in vitro and in vivo. Human thioredoxin reductase 1, a selenium-containing enzyme, was identified as the molecular target of these indolequinones. All the novel indolequinones made were tested for their anticancer activity in vitro against human pancreatic cancer and some of them were found very potent compounds at inducing inhibition of growth in human pancreatic cancer cells, confirming the potential use of these indolequinone-based compounds as a therapeutic approach to pancreatic cancer.

This thesis investigates the development of an HPLC assay for vitamin K, and the synthesis of carboxylic acid functionalised analogues of vitamin K and coenzyme Q. These analogues were used to investigate the feasibility of an immunoassay based method for the measurement of vitamin K. Chapter one outlines the biochemistry of vitamin K and coenzyme Q. The biological functions of these quinones and their proposed role in many diverse disease states are discussed. Chapter two contains a review of literature methods for the assay of vitamin K in plasma, food and tissue samples. The development of an HPLC assay for vitamin K using a metal catalyst, in the presence of an alcohol, to effect reduction of the quinine to the fluorescent hydro quinone for detection is presented. An investigation of a .number of metal catalyst/alcohol reduction systems showed platinum black/methanol to give the largest fluorescent response. The generality of this system towards a series of quinones showed that naphthoquinones (including vitamin K1, vitamin K3, 1,4-naphthoquinone and 2-hydroxy-1 ,4-naphthoquinone) were efficiently reduced, while the reduction of various benzoquinones (including CoQ-10 and CoQ-0) was also achieved. This chemistry was then applied to the measurement of vitamin K in both standard solutions and plasma samples, via an HPLC system with fluorescence detection. The synthesis of two side chain functionalised analogues of vitamin K (3.70 and 3.80) is presented in chapter three. Two synthetic routes to side chain functionalised vitamin K analogues were investigated. The first involved the conjugation of a functionalised allylic bromide (3.60) to a protected naphthoquinone core (3.11). The second approach developed involved the functionalisation of the natural isoprene side chain of vitamin K. This method was applied to a K vitamin synthesised via cuprate coupling of 3.11 and geranyl bromide, and to vitamin K2 (MK-4). The results of initial immunological studies are reported in chapter four. The production of antibodies recognising the naphthoquinone core of vitamin K was unsuccessful, postulated to be due to the 'bridge effect' leading to antibodies that recognise the isoprenoid side chain of the vitamin K analogue. From the results of these studies three short chain vitamin K analogues (4.5, and 4.7) were designed. Synthesis of 4.5 proceeded via oxidation of an aldehyde intermediate from the synthesis of 3.70. Compound 4.7 was obtained from the cuprate coupling of core 3.11 with ethyl bromoacetate, and subsequent functional group interconversions and deprotection. The coupling of analogues 3.70, 4.5, and 4.7 to protected lysine and a protected gly-lys dipeptide was investigated to model the coupling of these compounds to a carrier protein for immunological study. The conjugates produced (4.2, 4.4, and 4.13-4.15) were subsequently studied by NMR spectroscopy and mass spectrometry. The above synthetic work is applied to the structurally related quinone coenzyme Q and is presented in Chapter five. Using the synthetic methods developed for the synthesis of vitamin K analogues two carboxylic acid functionalised analogues of coenzyme Q (5.37 and 5.38) were synthesised. These analogues were also conjugated to protected lysine and gly-lys dipeptide, and studied by NMR spectroscopy and mass spectrometry.

This thesis will focus on two main research areas with the aim of developing and exploring the solar photochemical reactivity of quinones. In Chapter One, a review of quinone photochemistry is presented; this includes both cycloaddition reactions and hydrogen abstraction reactions. After a review of the relevant literature, the aims of the research are outlined and placed into context. Chapter Two details the development of a green photo Friedel-Crafts acylation for the preparation of acylated hydroquinones, which serve as versatile precursors for the synthesis of numerous biologically active quinone natural products. After a review of the relevant literature, the results of the research are discussed. Key achievements include the development of an accessible and ‘greener’ synthetic protocol employing a ‘sun-mimicking’ light source and trifluorotoluene as solvent. The factors influencing the regiochemical outcome of the acylation are also discussed. In Chapter Three, the photochemical oxidising ability of p-benzoquinone in both stoichiometric and substoichiometric quantities is investigated. In the introduction, a short review of the oxidising ability of the quinones - particularly DDQ - is presented and the enhanced oxidising ability of p-benzoquinone upon irradiation is discussed. The potential breadth of this underexploited oxidising ability is then investigated in the use of alcohol oxidation and C-H functionalisation protocols. Chapter Four summarises the results obtained in the thesis and outlines scope for further research in the area. In Chapter Five, full experimental details for the research are presented.

"Au cours des dernières années, les systèmes quinoniques hétérocycliques ont connu un essor fulgurant en raison du potentiel pharmacologique important déployé par certaines de ces substances naturelles. Devant l'intérêt accru suscité par ces composés, il devenait impératif de concevoir de nouvelles méthodes de synthèse, dans le but d'accéder à de plus grandes quantités de matériel biologiquement actif, mais aussi afin de préparer facilement des substances analogues. Des travaux antérieurs portant sur la préparation de xanthones naturelles ont permis de substituer des quinones halogénées par le salicylate de méthyle. Tirant profit de ces résultats, nous avons alors entrepris de développer une méthode de substitution nucléophile d'un groupe labile dans une quinone par une amine et ainsi effectuer la synthèse régiospécifique d'anilinoquinones jusqu'à maintenant inaccessibles par les méthodes classiques. Puisque les amines ont montré par le passé une très faible sélectivité face aux quinones, nous les avons transformées en sulfonamides de façon à leur conférer un caractère nucléophile et un comportement voisins de celui des salicylates. Une étude exhaustive de la réaction des esters N-mésylanthraniliques avec de nombreux substrats quinoniques en présence de fluorure de césium dans le N, N-diméthylformamide vient en effet confirmer la régiospécificité du processus (C. Mongrain, L. Lee et P. Brassard; Synthesis, 678, 1993). Dans la seconde partie de nos travaux, nous avons démontré l'importance des anilinoquinones dans la synthèse de substances hétérocycliques azotées. A l'aide de réactions simples et efficaces, nous avons complété la synthèse de nombreuses acridones et benz[b]acridones polyfonctionnalisées. L'approche explorée permet également de préparer diverses substances isomères difficilement accessibles par les méthodes couramment utilisées. Nous avons ainsi pu confirmer la régiospécificité de cette nouvelle approche. Cette étude a été complétée par la synthèse de quelques acridones naturelles afin d'apporter certaines précisions quant à la nature exacte des produits décrits dans la littérature, ainsi que par une étude de cytotoxicité (C. Mongrain et P. Brassard; Heterocycles, 36, 2109, 1993). Nous avons aussi contribué à l'élaboration de méthodes pour la synthèse de la phomazarine et de l'isophomazarine, deux 1-azaanthraquinones naturelles. Malgré les nombreux progrès effectués dans la synthèse de la phomazarine, nous avons été incapables de cycliser l'intermédiaire I, ce qui nous aurait permis de compléter la construction de l'hétérocycle azoté. Dans ce chapitre, nous décrivons aussi la préparation de nouveaux diènes et la formation d'aminoquinones à l'aide de la méthodologie des cycloadditions régiospécifiques développé dans notre laboratoire. Finalement, la cycloaddition du 2-butyl-l, 3-diméthoxy-ltriméthylsiloxybuta- l, 3-diène à la 6-chloro-4-hydroxy-2-méthoxycarbonylquinoléine-5,8-quinone a fourni le squelette tricyclique de base de l'isophomazarine dans lequel, seul la position 9 n'est pas convenablement substitué."
Québec Université Laval, Bibliothèque 2018

La quinone réductase 2 ou QR2 est une enzyme qui, comme son homologue QR1, joue un rôle de détoxification des quinones, molécules fortement réactives, en les réduisant en hydroquinones. Cependant, il a été observé au niveau cellulaire et tissulaire que l'activité de cette flavoprotéine pouvait avoir des effets délétères en déclenchant une surproduction d'espèces réactives de l'oxygène (ROS). D'autre part, on observe une surexpression ou une sous expression de QR2 dans certaines maladies neurodégénératives comme la maladie de Parkinson et la maladie d'Alzheimer. Dans ce contexte, ce travail a porté sur l'étude des espèces oxygénées réactives produites lors du cycle redox quinone / QR2 et leurs variations en fonction de la nature de la quinone, sur protéine purifiée et sur modèles cellulaires comparativement à QR1. Les propriétés d'oxydo-réduction des substrats, co-substrats et inhibiteurs de QR2 étudiées par électrochimie ont permis de les classer en fonction de leur capacité à être réduits. L'activité enzymatique de la protéine, qu'elle soit purifiée ou intracellulaire, a été suivie par différentes méthodologies (résonance paramagnétique électronique, spectroscopie UV-visible et de fluorescence, U(H)PLC-MS, microscopie confocale de fluorescence). La production du radical superoxyde est observée en présence de lignées cellulaires surexprimant ou non QR1 et QR2. Les quinones sont réduites enzymatiquement pour donner des hydroquinones via l'activité des quinones réductases (QR1 et QR2) et des semiquinones via l'activité de réductases à un électron (CytP540 réductase par exemple). La réoxydation de ces produits est responsable d'une production plus ou moins forte de radicaux superoxydes selon la structure initiale de la quinone et l'affinité pour les différentes réductases. La ménadione provoque une production cellulaire de superoxyde plus importante en l'absence de QR1 et QR2. Ces analyses ont également démontré que, comme son homologue QR1, QR2 est capable de réduire les ortho-quinones dont certaines catécholquinones (aminochrome, dopachrome, adrénochrome) reconnues pour leur toxicité neuronale
Quinone reductase 2 or QR2 is an enzyme that, like its counterpart QR1, plays a role in detoxification of the highly reactives quinones by reducing them into hydroquinones. On one hand, it has been observed at the cellular and tissue level that the activity of this flavoprotein could have deleterious effects by triggering an overproduction of reactive oxygen species (ROS). On the other hand, overexpression or under expression of QR2 has been observed in some neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease. In this context, this work focused on the study of reactive oxygen species produced during the quinone / QR2 redox cycle and their variations depending on the nature of the quinone, on both purified protein and cell models, in comparison to QR1. The redox properties of the substrates, co-substrates and inhibitors ok QR2 studied by electrochemistry allowed to classify them according to their capacity to be reduced. The enzymatic activity of the protein, either purified or intracellular, was followed by various methodologies (electron paramagnetic resonance, UV-visible and fluorescence spectroscopy, U(H)PLC-MS, confocal fluorescence microscopy). Production of superoxide radical is observed in the presence of cell lines overexpressing or not QR1 and QR2. Quinones are reduced enzymatically to form hydroquinones via the activity of quinone reductase (QR1 and QR2) and semiquinone via the activity of one electron reductases (e.g. CytP540 reductase). Reoxidation of these products is responsible for a greater or lesser production of the superoxide radical, according to the initial structure of the quinone and the affinity for different reductases. Menadione causes a higher production of cellular superoxide in the absence of QR1 and QR2. These analyzes have also shown that, like its counterpart QR1, QR2 is capable of reducing ortho-quinones including catecholquinones (aminochrome, dopachrome, adrenochrome) known for their neuronal toxicity

Les ortho-quinones monocétaliques, générées par déaromatisation oxydante de composés phénoliques, sont des synthons attractifs pour la synthèse de produits naturels. Ces composés ont la particularité de dimériser spontanément. Cependant, la présence d'un groupe acétate au niveau de la fonction cétale retarde cette dimérisation et permet ainsi l'exploitation de l'unité cyclohexa-2,4-diénone. L'introduction contrôlée d'un centre stéréogénique au niveau de la fonction cétale doit permettre le contrôle stéréochimique de différentes réactions sur l'unité cyclohexa-2,4-diénone. Afin de valider cette hypothèse, une nouvelle méthodologie de synthèse de ces ortho-quinones monocétaliques chirales a été envisagé par oxydation anodique. La spirolactonisation d'acides carboxyliques aromatiques modèles a tout d'abord été entreprise. Un effet gem-dialkyle est nécessaire pour assurer la cyclisation. Cependant, la présence d'une unité acyloxy cyclique n'empêche pas le processus de dimération et conduit à un produit de cycloaddition [4+2] puis [2+2] de façon régio- et stéréocontrôlée. Un nouveau type de substrats possédant un substituant bromé aux effets stabilisants à donc été considéré. L'oxydation anodique d'alcools phénoliques bromés chiraux a permis d'accéder de façon diastéréosélective aux composés bicétaliques. Une hydrolyse acide sélective de ces ortho-quinones bicétaliques a alors conduit à la première série d'ortho-quinones monocétaliques énantiomériquement pures. Une étude préliminaire de leur réactivité a permis de confirmer leur potentiel synthétique dans différentes transformations. Parmi les plus sélectives, l'addition nucléophile de PhMgBr a conduit à l'adduit correspondant avec un excès diastéréoisomérique de 90%.

The work reported is divided into two parts: fIrstly a section dealing with the preparation of some novel diazanaphthoquinones and their reactions, especially the Diels-Alder reaction, and secondly an account of some quinoxaline derivatives and their fluorescence properties. Quinoxaline quinones containing electron-donating groups at both the 2- and 3- position have shown a difference in their stability and their behaviour in the Diels-Alder reaction compared to the stability and the reactions of quinoxaline quinone. Symmetrical dienes in the Diels-Alder reaction yielded the initial addition products, which were resistant to oxidation, whereas unsymmetrical dienes produced fully aromatized products. Crown ether derivatives of 5,8-dimethoxyquinoxaline and the corresponding quinoxaline quinones were prepared. An improved method for the preparation of a fluorescent derivatising reagent is described. This compound was then used to prepare ion-responsive fluoroionophores containing monoazacrown ethers of different cavity sizes. The complexation of these fluoroionophores, in dichloromethane, was achieved by using perchlorates of alkali and alkaline earth metals. A strong correlation between the size of the metal ion and the cavity size of the crown ether was seen in the fluorescence quantum yields of the complex, and a fluoroionophore containing a diazacrown ether gave particularly noteworthy results. A bathochromic shift with a strong hyperchromic effect was the most important feature caused by complexation with metal ions for these fluoroionophores. Fluorescent open chain ethers (podands) were also prepared and their complexation with metal ions was studied. A strong bathochromic shift and a hypochromic effect was observed especially in their excitation spectra. A further novel fluorescent derivatising reagent was prepared by extending the conjugated system. This gave the expected improved results upon the preparation of the derivatives including fluoroionophores having crown ethers of different cavity sizes. However, the changes in fluorescence did not correlate with the relationship between the sizes of the metals ion and the cavity of the crown ether. Nevertheless, a large bathochromic shift was observed on complexation with metal ions.

L'énergie est un enjeu crucial pour les sociétés actuelles et le recours à des énergies alternatives est de jour. Or la photosynthèse apparaît comme une piste intéressante et les unités photosynthétiques comme des convertisseurs potentiels sélectionnés par l'Evolution. Lors de la photosynthèse électron poursuit son cheminement le long de la chaîne photosynthétique pour permettre la mise en marche des différents complexes enzymatiques nécessaires au maintien en vie de l'organisme photosynthétique. L'étape cinétiquement limitante de ce transfert électronique se situe en amont du cytochrome b6f. C'est cette limitation qui serait responsable des dommages encourus par les algues sous forte lumière connus sous le nom de photoinhibition. Ainsi pour ne pas compromettre la vie de l'algue unicellulaire Chlamydomonas reinhardtii, la stratégie mise en place durant ces travaux de thèse a été de dériver les électrons d'une manière sélective en amont de l'étape cinétiquement limitante. Pour cela des quinones exogènes ont été utilisées comme accepteurs d'électrons capables d'atteindre la chaîne photosynthétique, de récupérer les électrons et de venir s'oxyder à l'électrode polarisée. Une demi-pile a été mise en place et la stabilité du courant dans le temps étudiée. Une toxicité des quinones a en particulier été mise en évidence et serait responsable de la dégradation des performances du système au cours du temps. Les spectroscopies de fluorescence et d'absorption ont pu fournir des éléments de réponse. Des critères de choix de quinones ont été identifiés et partant de là, de la synthèse organique a été effectuée pour essayer de trouver un compromis entre dérivation et toxicité
Photosynthetic electron derivation on living organism using quinones : the case of Chlamydomonas reinhardtii Nowadays, energy is a major concern to societies and research is focusing on finding new sources of clean and sustainable energy. In this context, photosynthesis may be an appropriate way to meet this objective. Indeed solar light provides the chemical energy required by photosynthetic organisms to maintain their cellular activity. Taking advantage of photosynthesis to produce a photocurrent requires intercepting electrons exchanged in the oxidation/reduction processes occurring along the photosynthetic chain. This is why we consider here an electrochemical device involving a gold electrode able to derivate photosynthetic electrons from a population of Chlamydomonas reinhardtii algae. However photosynthsesis is a multi-speed process and a rate controlling step was identified just before the b6f complex. This is why the strategy of this work aimed at deriving electrons before the b6f cytochrom. This allows to relieve algae from stress under high light conditions. Known as efficient PSII acceptors, quinones were used as exogenous mediators to transfer the electrons from the photosynthetic chain to the electrode surface. Therefore, the resulting photocurrents under illumination, were commented and discussed in order to understand and define the best appropriate experimental conditions for this bio-solar generator. Quinones were shown to induce toxicity on algae. Focus was directed on finding the best chemical structure which would combine good derivation properties and little toxicity

La dysiarenone est un méroterpénoïde pseudo-dimérique, présentant un squelette 2-oxaspiro[bicyclo[3.3.1]nonane-9,1′-cyclopentane] inédit, isolé à partir de l'éponge marine Dysidea arenaria. Les septosones B et C partagent un motif rare de type spiro[4.5]décane. On observe une importante similarité entre les septosones B et C et l'un des pseudo-monomères de la dysiarenone. Le second pseudo-monomère nécessaire à la dimérisation est l'avarone, une quinone/hydroquinone sesquiterpénique bien connue de la littérature. L'objectif principal de cette thèse était de synthétiser le précurseur spirocyclique à travers diverses approches synthétiques dont une addition de Michael intramoléculaire bioinspirée d'un alcène trisubstitué sur une quinone. Finalement, la stratégie la plus aboutie, via un réarrangement semi-pinacolique de quinol, a rendu possible la synthèse de l'épi-spirocycle nécessaire à la dimérisation. Cet isomère possède une stéréochimie correspondant à celle des spiroetherones A et B, deux autres sesquiterpènes naphthoquinones spirocycliques isolées de Dysidea etheria. Une synthèse de la structure proposée de la spiroetherone A a été réalisée en 14 étapes et, après confirmation par analyse RX, celle-ci a permis de démontrer une attribution erronée de la structure originelle.Des tentatives d'épimérisation du centre spirocyclique de l'intermédiaire "ènedione" ont été menées afin d'étudier la synthèse des septosones B et C ainsi que de la dysiarenone ; cette approche permettrait également de valider l'hypothèse sur la structure exacte des sesquiterpènes naphthoquinones.Au cours de ces travaux, une méthode de formation de liaison C-O par transfert d'atome d'hydrogène (MHAT) entre un alcène trisubstitué et un substrat diméthyl-acétal-quinone a été découverte. Cette méthode a été appliquée à la synthèse totale de la dactyloquinone A, une quinone/hydroquinone sesquiterpénique possédant un noyau dihydropyrane, isolée de Dactylospongia elegans
Dysiarenone is a pseudo-dimeric meroterpenoid, featuring an unprecedented 2-oxaspiro[bicyclo[3.3.1]nonane-9,1'-cyclopentane] carbon skeleton, isolated from the marine sponge Dysidea arenaria. Septosones B and C share a rare spiro[4.5]decane motif. A significant similarity can be observed between septosones B and C and one of the pseudo-monomers of dysiarenone. The second pseudo-monomer required for dimerization is avarone, a sesquiterpene quinone/hydroquinone well known in the literature.The main objective of this thesis was to synthesize the spirocyclic precursor through various synthetic approaches, including a bioinspired intramolecular Michael addition of a trisubstituted alkene onto a quinone. Ultimately, the most successful strategy, via a semi-pinacol rearrangement of quinol, enabled the synthesis of the epi-spirocycle necessary for the dimerization. This isomer possesses the stereochemistry corresponding to that of spiroetherones A and B, two other spirocyclic sesquiterpene naphthoquinones isolated from Dysidea etheria. The proposed structure of spiroetherone A was synthesized in 14 steps and, after confirmation by X-ray analysis, demonstrated a misassignment of the original structure.Attempts at epimerizing the spirocyclic center of the "enedione" intermediate were carried out to explore the synthesis of septosones B and C as well as dysiarenone; this approach would also help validate the hypothese about the exact structure of the sesquiterpene naphthoquinones.In the course of this work, a method of C-O bond formation via hydrogen atom transfer (MHAT) between a trisubstituted alkene and a quinone dimethyl ketal substrate was discovered. This method was applied to the total synthesis of dactyloquinone A, a sesquiterpene quinone/hydroquinone with a dihydropyran ring, isolated from Dactylospongia elegans

This dissertation presents a detailed computational investigation into the vibrational properties of quinones involved in solar energy conversion processes in photosynthetic reaction centers. In particular, we focus on the vibrational properties of the ubiquinone molecule that occupies the QA binding site in purple bacterial photosynthetic reaction centers. To provide a foundation upon which to base computational studies of pigments in protein binding sites density functional theory based calculations of the vibrational properties of neutral ubiquinone in the gas phase and in solvent were undertaken. From single point energy calculations it was shown that at least eight ubiquinone conformers, each with slightly different FTIR spectra, could be present in solvent at room temperature. The calculated and experimental spectra for neutral ubiquinone in solution are very different from the spectra associated with ubiquinone in the QA binding in purple bacterial reaction centers. For this reason an ONIOM method was undertaken in which the pigment was treated using density functional theory based methods while the protein was treated using molecular mechanics. The ONIOM calculations not only modeled the experimental QA FTIR difference spectra but also resolved the long standing issue of whether a very strong hydrogen bond exists between the bound ubiquinone and the imidazole nitrogen of a histidine residue (HisM219). To further validate the usefulness of the ONIOM approach experimental isotope edited FTIR spectra obtained using purple bacterial reaction centers with a range of chainless symmetrical quinones incorporated were modeled. Again, the agreement between the calculated and experimental spectra is outstanding. We also modeled the vibrational properties of the ubisemiquinone anion radical both in solvent and in the QA binding site. Vibrational modes of ubisemiquinone display a greater degree of mixing of the various molecular groups of the molecule. Nonetheless the calculated FTIR spectra for ubisemiquinone in solution and in the QA site agree very well with that found experimentally. Vibrational frequencies of ubisemiquinone obtained from ONIOM calculated Raman spectra also agree very well with that found in experimental resonance Raman spectra associated with the ubisemiquinone anion radical in the QA binding site.

Increasing demand for lighter and more powerful batteries has driven research beyond lithium-ion batteries. One system that has received significant attention is lithium-oxygen. This system exploits the reduction of oxygen to lithium peroxide, to provide a theoretical specific energy of 3500 Wh kg-1. One of the major problems facing the lithium-oxygen battery is the passivation of the air electrode caused by insoluble lithium oxides and lithium carbonate formed from unstable electrolytes. These products are not fully oxidized during the charge step and accumulate within the electrode, causing the capacity to fade with each cycle. This work focuses on the use of quinones as solution based catalysts in non-aqueous electrolytes to facilitate the electron transfer of both the oxygen reduction reaction (ORR) and the oxygen evolution reaction (OER). The required overpotential for the ORR is shown to decrease by 400 mV and the discharge capacity increase by 100% by incorporating quinones into the electrolyte. Analysis of the carbon electrode by X-ray diffraction confirms lithium peroxide as the discharge product. Furthermore the evolution and consumption of oxygen during cycling has been demonstrated to require only two electrons per mole of oxygen using on-line mass spectrometry indicating that the dominant reaction is the formation of lithium peroxide.

Au cours de ce travail consacre a la synthese de produits naturels nous avons developpe de nouvelles strategies en serie terpene-quinones et hydroquinones. Une synthese par voie radicalaire a permis de realiser des syntheses des anhydrides chaetomelliques en une etape. La decarboxylation radicalaire de barton appliquee a des diacides carboxyliques a longue chaine a conduit a la premiere synthese de la tyromycine a. Une deuxieme strategie utilisant le tetramethoxybenzene et son oxydation en quinone a ete developpee montrant la demethylation selective de l'orthoquinone intermediaire. La serie de la maesanine a ete synthetisee par alkylation du tetramethoxybenzene sur la chaine bromee adequate suivie de l'oxydation par le can. Pour la synthese de l'ilimaquinone, un analogue de la cetone de wieland-miescher a ete alkyle par 1,2 equivalent de derive brome tetramethoxyle, avec une tres bonne stereoselectivite ; l'oxydation par le can conduit a l'ilimaquinone en 11 etapes avec un rendement global de 25%. La hyatellaquinone decrite dans la litterature a ete synthetisee a partir du sclanolide. L'olefine exocyclique pure a ete obtenue par epoxydation selective, qui donne un acces rapide a l'acetate d'albicanyle, l'albicanol, l'albicanal. L'alkylation et l'oxydation par le can conduisent a la hyatellaquinone, avec un rendement global de 9% en 9 etapes. Cette synthese a permis la revision de la stereochimie du produit naturel. La synthese stereoselective du coscinosulfate 12r et 13r a ete realisee par une aldolisation utilisant l'oxazolidinone d'evans. L'analyse des cristaux au rayons x de l'aldehyde intermediaire confirme la stereochimie du produit de synthese. L'allongement de la chaine laterale a pu etre realisee par l'alkylation de la sulfone par un compose brome allylique convenablement protege. La synthese confirme la stereochimie du produit naturel.

A thesis submitted in fulfilment of the requirements for the degree Magister Technologiae (Chemistry) in the Faculty of Applied Sciences, Department of Chemistry, Cape Peninsula University of Technology, 2008
Green et al. attempted to synthesize linear naphthopyranquinones from a naphthyl dioxolane using a TiCl4 as a catalyst. They managed to synthesise an angular naphthopyran as well as a linear naphthopyran in low yield. They showed that reducing the steric strain at position 1 of the naphthyl dioxolane afforded a low percentage yield of the linear naphthopyran plus an angular one. This thesis describes the synthesis of linear naphthopyrans with an improved percentage yield using TiCl4 as a catalyst. This was achieved by placing a OMe group of less steric hinderance at position 1 and a Br atom at position 4 of a naphthyl dioxolane. The OMe group at position 1 was to allow isomerisation to occur at position 2, and the Br atom was to inhibit isomerisation at position 4, thereby inhibiting the formation of the angular naphthopyran.

Recently, considerable interest has been devoted to the synthesis of new ferrocene derivatives since properly functionalized ferrocene derivatives could be potential antitumor substances. For this purpose, we have investigated the synthesis of ferrocenyl quinones starting from squaric acid. Thermolysis of ferrocenylsubstituted cyclobutenones, which have been prepared from ferrocenyl cyclobutenediones and alkenyllithiums, affords hydroquinones, which furnish, upon oxidation, ferrocenyl quinones. Ferrocenyl cyclobutenediones have been prepared from known cyclobutenediones by nucleophilic addition of ferrocenyllithiumfollowed by hydrolysis, Pd/Cu-cocatalyzed cross-coupling with (tri-n-butylstannyl)ferrocene or Friedel&
#8211
Crafts alkylation with ferrocene. A mechanism involving electrocyclic ring opening of alkenyl substituted cyclobutenone to dienylketene and consequent electrocyclic ring closure to cyclohexadienone followed by enolization has been proposed to account for the formation of ferocenyl substituted hydroquinones. Rocket design and production is one of the hottest topics in defense industry. On this subject, significant amount of investments have been done and excellent results were obtained. Among the burning rate catalysts for composite rocket propellants, ferrocene derivatives are one of the most famous ones. Although ferrocene derivatives are superior to some other burning rate catalysts, their use has some drawbacks arising from the tendency of migration in the bulk of the material and their sensitivity toward oxidation by air. With the aim of preventing the negative aspects of ferrocene derivatives, we have investigated the synthesis of EDA (ethylenediamine), TEP (tetraethylenepentamine) and DDI (dimeryl-diisocyanate) based ferrocene derivatives.

The work described in this thesis is mainly concerned with the accurate measurement of redox potentials for a series of covalently linked porphyrin-quinone molecules (P-Q), in non-aqueous media. These compounds (synthesised by Prof. J.R. Bolton and co-workers of the University of Western Ontario, Canada) are of interest as models for the primary photochemical step in the photosynthetic process. The redox potentials were measured by cyclic voltammetry and differential pulse voltammetry. These electrochemical redox potentials were used to estimate the energy of the excited charge-separated state (P^.+-Q^.-), and confirm that this state is likely to be photochemically produced from the excited singlet state of P-Q rather than the triplet state. As a prelude and postscript to the studies of the P-Q compounds, the electrochemical behaviour of several related but simpler compounds, both porphyrins and quinones, is described. This includes an invesigation of the solvent dependence of quinone reduction potentials in non-aqueous media. A simple linear equation, based on Swain's A+B solvent parameters, is proposed as a means of predicting quinone reduction potentials in different solvents. Finally, the electrode kinetics of some simple metallorporphyrin oxidations are studied using an a.c. technique. A non-linear fitting routine was used to optimise the rate constant values obtained.

Along this Thesis dissertation book, which is focused on the topic of Redox Flow Batteries, many efforts have been done in order to improve different aspects of the all-Vanadium Redox Flow batteries (VRFBs) technology, as monitoring each battery compartment, increasing operational temperature range, enhancing negative electrode to reduce side reactions and charge transfer towards V3+/V2+ redox reaction and also modifying positive electrode to obtain a faster VO2 /VO redox reaction. Vanadium technology was chosen over all redox flow technologies due to its mature development reaching the barrier to commercial breakthrough. The main targeted aspects about VRFBs have been: • Reference electrode implementation into a single cell device (battery) to study separately anolyte and catholyte in real working conditions. This set- up allows following the contribution of each one of the electrodes separately, and consequently knowing the limiting factor in the battery, in order to improve them. • Electrolyte modifications with catalytic quantities of an additive allowing a larger vanadium ion concentration being able to be solved into the electrolyte, as well as increase the operational temperature window. These improvements are done in order to increase the energy density of the system, and also allow the battery to work in a wider temperature range to adapt this system to broader climate areas without temperature control. • Electrodes enhancement: Initially, we will focus our attention into electrode modifications to enhance their electrochemical properties. Firstly, increasing functional groups on the electrode’s surface, which make them more electroactive towards vanadium redox reactions. Secondly, different catalysts are deposited to obtain faster vanadium redox reactions on a carbon-based structure (as graphite felt or carbon felt). o Anode, main lacks are large ohmic overpotential due to competing side reaction. - It has been done an exhaust study of different structures of the same material, as it is nanoparticles (NPs), single- nanorods (SNRs) and multi-nanorods assembly (MNRs). - Graphite and/or carbon felt enhancement using the synthesis of different catalyst (TiO2, TiO2:H, TiO2:iN, O and N groups) which help not only to make the negative redox reaction (V3+/V2+) faster and reduce the voltage drop, but also avoid side reactions (gas evolution) as can be hydrogen evolution reaction (HER). All of these help to elevate the reachable energy and power densities of the battery. o Cathode, which lacks of a fast kinetics. - Deposition of a catalyst over graphite felt, as it is ceria (CeO2), to aid the positive redox reaction (VO2 /VO ) making it faster, as well as improve the efficiencies and accessible capacity of the battery. Despite the fact that the systems described previously were already proposed several decades ago, they are still the subject of current research. These systems show several inconvenient related to the vanadium abundance, the cost of it, as well as the geopolitical impact caused by its mining. As a consequence, the implementation of organic redox active species is a first step in order to avoid these disadvantages. Organic molecules are abundant, tunable by synthetic pathways and an improved kinetic with the possibility of having two-electron transfer process (as happens to quinones)1,2. Such a battery has the potential to meet the demanding cost, durability, eco-friendliness, and sustainability requirements for grid-scale electrical energy storage. Furthermore, this system has been studied targeting on a Quinone-based redox flow battery. After the selection of the catholyte (benzoquinone-based molecules as p-benzoquinone, o-benzoquinone and disodium 4,5-dihydroxy-1,3- benzenedisulfonate) and anolyte (Anthraquinone-2,7-disulfonic acid disodium salt) in a methanosulfonic acid solvent, the next step has been improving the electrode technology on both single cell compartments to promote positive and negative redox reactions. In order to do that surface modification has been done, by means of nitrogen and oxygen functionalization using different methods. Finally, it has been commented the present of all-Vanadium and Aqueous Organic Redox Flow Batteries, as well as some future perspective of both technologies.
A lo largo de esta tesis doctoral, centrada en el tema de baterías de flujo, se ha puesto mucho empeño en la mejora y desarrollo de diferentes aspectos de la tecnología referente a baterías de flujo de vanadio (VRFBs). En este aspecto, se ha realizado el seguimiento de cada compartimento de la batería por separado durante el ciclado de la batería, el aumento del rango de temperatura de trabajo de la batería, la mejora del electrodo negativo mediante la inhibición de reacciones parasitas y reducción de los valores de transferencia de carga para la reacción redox relativa a V3+/V2+, al igual que la modificación del electrodo positivo para obtener un aumento de la velocidad de reacción del par redox VO2+/VO2+. Se eligió la tecnología referente a vanadio respecto a otras tecnologías de baterías de flujo como consecuencia de su madurez en cuanto a desarrollo, rozando la barrera de la expansión comercial a gran escala. Los principales aspectos tratados sobre las baterías de flujo de vanadio han sido: • Implementación de un electrodo de referencia no-comercial dentro de una batería con el objetivo de estudiar por separado el anolito y el catolito a lo largo del ciclado de la batería. Esta configuración permite seguir la contribución de cada uno de los electrodos a la reacción por separado, y en consecuencia saber cuál es el factor limitante dentro de la batería con el objetivo de mejorarlo. • Mejoras del electrolito mediante aditivos en cantidades catalíticas con el objetivo de permitir una mayor cantidad de iones vanadio capaz de ser disueltos y también aumentar el rango de temperatura donde la batería es capaz de trabajar. Estas mejoras se han realizado para aumentar la densidad de energía del sistema, y también ampliar la temperatura operacional de la batería con el fin de poder trabajar en un mayor número de zonas climáticas. • Mejoras de electrodo: Inicialmente la atención se centra en la modificación de electrodos para mejorar sus propiedades electroquímicas. Primero aumentando el número de grupos funcionales en la superficie del electrodo, lo que los hace estos electrodos más electro activos hacia las reacciones redox de vanadio. Seguidamente también se realiza el depósito de diferentes catalizadores para obtener reacciones redox de vanadio más rápidas sobre un substrato carbonoso, como pueden ser los fieltros de carbono o grafito. o Ánodo, cuya principal deficiencia es el elevado sobrepotencial óhmico como consecuencia de las reacciones parásitas. - Se ha realizado el estudio de diferentes estructuras del mismo material, como es el óxido de titanio en su fase rutilo, como nanopartículas (NPs), nanorods simples (SNRs) y ensamblaje de nanorods multiples (MNRs). - Mejora de sustratos de fieltro de grafito y de carbono mediante diferentes catalizadores (TiO2, TiO2:H, TiO2:N), además de mediante grupos funcionales (grupos O y N), lo cuales no solo facilitan la mejora de la reacción redox V3+/V2+ aumentando la velocidad de dicha reacción y reduce la caída de voltaje de la batería, sino que es capaz de inhibir las reacciones parásitas de evolución de gases, como puede ser la reacción de evolución de hidrógeno (HER). Todo esto ayuda a aumentar la densidad de energía y la densidad de potencia de la batería. o Cátodo, cuya principal deficiencia es la baja velocidad de reacción comparativamente con la reacción negativa. - Depósito de un catalizador, como es la Ceria (CeO2), sobre un fieltro de grafito, con el objetivo de mejorar la reacción redox positiva VO2+/VO2+ haciéndola más rápida, además de mejorar las eficiencias de la batería y la capacidad que esta puede alcanzar. A pesar que los sistemas de baterías de flujo de vanadio descritos han sido estudiados desde hace varias décadas, son aún objeto de estudio actual. Sin embargo, estos sistemas muestras diversos inconvenientes relacionados con la abundancia de vanadio, su elevado coste, además del impacto geopolítico causado por su extracción. Como consecuencia de estos hechos, la implementación de baterías de flujo con especies orgánicas como pares redox activos es un primer paso con el objetivo de evitar las desventajas de las baterías de flujo previamente descritas. Al contrario que el vanadio, las moléculas orgánicas son abundantes, pueden ser modificadas mediante diferentes caminos de síntesis y poseen una cinética mejorada que además incluye una transferencia de dos electrones en el proceso, como se produce en las quinonas, mientras que en las baterías de flujo de vanadio solo se da la transferencia de un único electrón. Dichas baterías orgánicas tienen el potencial de satisfacer las demandas de coste, durabilidad, medioambientalmente respetuoso, y requerimientos de sostenibilidad para el almacenamiento energético dentro de la red eléctrica. Más allá, este sistema se ha estudiado centrándose en moléculas como base quinona en las baterías de flujo, seleccionando como catolito moléculas con base benzoquinona (p-benzoquinone, o-benzoquinone y 4,5-dihidroxi-1,3- benzenedisulfonato) y la sal disódica del ácido antraquinone-2,7-disulfónico como anolito. Ambos materiales activos se han disuelto en una solución con el ácido metanosulfónico como disolvente que ayuda a mejorar las eficiencias y capacidad alcanzable por la batería, además de su estabilidad a lo largo de los ciclos. Paralelamente, con el objetivo de mejorar las reacciones de las moléculas orgánicas previamente mencionadas, diferentes modificaciones en la superficie de electrodos de fieltro de carbono se han realizado, como puede ser la funcionalización mediante grupos nitrógeno y/o oxígeno mediante varios métodos. Finalmente, una breve perspectiva de futuro de las tecnologías estudiadas, como son las baterías de flujo de vanadio y las nuevas baterías de flujo con compuestos orgánicos activos, para ello se ha tenido en cuenta el citado trabajo de tesis como además los datos presentes en la literatura al respecto de estos temas.

Tuberculosis is one of the world’s deadliest diseases. It is caused by the bacterium Mycobacterium tuberculosis. Two groups of samples: Quinones and Garlic polysulfide mixtures were assessed for their antituberculosis activity. The microtitre alamar blue (MABA) and microtitre presto blue assays (MPBA), on Mycobacterium tuberculosis were conducted to determine the minimum inhibitory concentrations (MICs). Twenty quinones and six garlic oil polysulfide mixtures were tested for their in vitro antimycobacterial activity and cytotoxicity. The antimycobacterial activity was tested on the H37Rv Mycobacterium tuberculosis strain and the cytotoxicity was tested on primary peripheral blood mononuclear cells and secondary U937 human monocytes. Six quinone samples showed antimycobacterial activity with minimum inhibitory concentrations less than 3.125 μg/ml and one garlic sample had a minimum inhibitory concentration of 2.5 μg/ml. Samples KM 108-1 and IL 143 had selective indices above 8 and KM 140 had a selective index of 55. Twenty quinone samples and six garlic polysulfide mixtures were also evaluated for their immune stimulatory effects as well as their liver protective activity. The immune response was assessed by evaluating the Th1/Th2 cytokine production levels by the peripheral blood mononuclear cells on exposure with various concentrations of the samples. The induced toxicity on Liver cells (C3A - hepatocytes), by acetaminophen, were used to assess the hepatoprotective efficacy of the samples. Three quinone compounds showed immune stimulatory effects (KM94, KM108-1 and KM117), and five showed significant hepatoprotective effects of 60-100% (KM108, KM140, AqsNH4, CB5 and IL107) at ¼ Inhibitory Concentration of 50%. Garlic samples G5 and G6 showed slight immune stimulatory effects, while G6 was found to be the only sample to have hepatoprotective activity of 22%, probably due to the higher amount of diallyl tetrasulfide within the mixture. All the quinone samples were evaluated for their subversive substrate activities on three flavoprotein disulfide reductases: Glutathiol, Mycothiol and Thioredoxin reductase. Glutathiol reductase is the human analog while Mycothiol and Thioredoxin are bacterial analogs. Substrate binding affinity was determined and it was found that quinones act as substrates for all three enzymes with the highest affinity for Thioredoxin reductase. Samples; Aqs and KM80 had half the maximum velocity (Km-value) of lower than 30 μM. It can also be concluded that anthraquinones had a higher affinity to these disulfide enzymes as compared to naphthoquinones.
Dissertation (MSc)--University of Pretoria, 2014.
National Research Foundation (NRF)
Plant Science
MSc
Unrestricted

Ce travail est consacre a la synthese par reactions de transfert monoelectronique de nouveaux agents pharmacologiques quinoniques. La premiere partie decrit la synthese d'agents alkylants quinoniques et l'etude de leur reactivite dans des reactions de c-alkylation avec l'anion du 2-nitropropane. Une etude mecanistique complete a permis de definir un mecanisme radicalaire en chaine bis-s r n1 en series benzo-, naphto- et anthraquinone et tetrakis-s r n1 en serie benzoquinone. L'extension a divers anions nitronates secondaires aliphatiques, cycliques et heterocycliques a donne a ces reactions un caractere general. La seconde partie est consacree a la reactivite de ces agents alkylants avec des nitroalcanes primaires conduisant a une nouvelle methode d'annellation. Cette methode permet la synthese de nouvelles dialkylquinones (naphtoquinones, anthraquinones, naphtacenediones) a partir de bis(chloromethyl)quinones possedant un cycle aromatique de moins. De plus, une nouvelle synthese de tetraalkylanthraquinones est decrite, par reaction de bis-annellation, a partir de la tetrakis(chloromethyl)benzoquinone. Enfin, dans la derniere partie, la reactivite originale d'un agent alkylant derive de la 2-methyl-1,4-naphtoquinone avec des nitroalcanes primaires est presentee. Celle-ci conduit aux produits de c-alkylation attendus ainsi qu'a des dialkylanthraquinones. Une etude de reactivite intramoleculaire de chloromethyl nitroalcanes quinoniques, prepares a partir des produits de c-alkylation precedents, cloture ce travail.

Dans le cadre d’un programme de recherche dédié à la découverte de petites molécules à visée anticancéreuse, nous avons envisagé de concevoir des composés originaux dérivés de quinones. Notre premier objectif a été d’élaborer des mimes non-peptidiques de la protéine Smac, susceptibles de participer à relancer le phénomène d’apoptose, dont la structure est rigidifiée par des contraintes conformationnelles. Par ailleurs, les kinases et les phosphatases, jouant des rôles complémentaires de phosphorylation / déphosphorylation dans le cadre du contrôle du cycle cellulaire notamment, apparaissent aussi comme des cibles intéressantes. Une étude attentive de leurs inhibiteurs connus nous a permis de mettre en avant des analogies structurales qui nous ont conduit à vouloir synthétiser des motifs fonctionnalisés de dérivés de naphtoquinones.L’introduction directe de chaînes latérales aliphatiques sur nos substrats, par création de liaisons de type C(sp2)–C(sp3), a été rendue possible grâce au développement d’une méthodologie de décarboxylation radicalaire. Dans les conditions réactionnelles mises au point, le couple Ag(I)/S2O82- est utilisé comme initiateur radicalaire et autorise la génération de radicaux alkyles par décarboxylation d’acides aminés. L’introduction directe de cycles aromatiques fonctionnalisés, via la création de liaisons de type C(sp2)–C(sp2), a été réalisée par l’intermédiaire de la génération de radicaux aryles issus de sels de diazonium stables ou d’anilines. Les procédés décrits dans ce manuscrit nous ont permis d’apporter certains éclaircissements sur la réactivité des substrats et sur les mécanismes réactionnels impliqués
In our ongoing course dedicated to the discovery of small anticancer molecules, we designed novel quinone derivatives. Our first objective was to fashion non-peptidic Smac mimics, able to trigger apoptosis in tumor cells, displaying a structure rigidified by conformational restrictions. Otherwise, the kinases and the phosphatases, acting as phosphorylating / dephosphorylating agents mostly in the control of the cell cycle, were thought to be other relevant biological targets. An intent study of their known inhibitors allowed us to underline trends in their chemical structure and made us plan the synthesis of functionalized naphthoquinones.A dedicated approach involving radical decarboxylation of amino acids allowed the introduction of aliphatic side chains on our substrates though C(sp2)–C(sp3) bond formation. Ag(I)/S2O82- was used as alkyl radical initiator and the direct C-H alkylation of the quinonic positions could take place. C(sp2)–C(sp2) bonds were created through aryl radicals generation from stable diazonium salts or anilines which allowed the direct C-H arylation of quinones. The procedures described along this manuscript let us formulate several advances on the substrates reactivity and on the reaction mechanisms involved

Orientador: Maria Stella Gonçalves Raddi
Banca: Iracilda Zeppone Carlos
Banca: Wagner Vilegas
Banca: Jairo kenupp Bastos
Banca: Mônica Tallarico Pupo
Resumo: Quinonas são substâncias orgânicas amplamente distribuídas na natureza, encontradas em plantas, fungos e bactérias, associadas à atividade antitumoral e antimicrobiana. Recentemente, uma quinona (5-metoxi-3,4-diidroxantomegnina), estruturalmente semelhante à 1,4-naftoquinona, foi isolada dos capítulos de Paepalanthus latipes. O objetivo desse estudo foi avaliar atividades biológicas dessa quinona visando possível aplicação terapêutica. A 5-metoxi-3,4-diidroxantomegnina apresentou concentração inibitória mínima para Staphylococcus aureus e Enterococcus faecalis (197µM), mas não para Escherichia coli. Essa quinona demonstrou significativo índice citotóxico para células McCoy quando comparado ao da cisplatina. Nos ensaios utilizando linhagens tumorais de adenocarcinoma de pulmão (LP07) e mama (LM2), a maior citotoxicidade da 5-metoxi-3,4-diidroxantomegnina foi para a linhagem LP07. A associação com ácido ascórbico aumentou a citotoxicidade da 5-metoxi-3,4-diidroxantomegnina para células McCoy, LM2 e LP07 devido a um redox cílcico com formação de peróxido de hidrogênio. Visto que alguns antineoplásicos somente apresentam efeito citotóxico após biotransformação, a citotoxicidade da 5-metoxi-3,4-diidroxantomegnina na presença do sistema microssomal S9 foi avaliada e constatou-se que esse sistema de ativação metabólica não altera o potencial citotóxico da quinona. Óxido nítrico (NO) e fator de necrose tumoral-a (TNF-a) não foram detectados nos sobrenadantes de culturas de macrófagos tratados com 5-metoxi-3,4-diidroxantomegnina, portanto seu efeito tóxico, nesse sistema celular, não está relacionado com a produção desses mediadores. Entretanto, macrófagos tratados com essa quinona aumentaram significativamente a liberação de peróxido de hidrogênio. Nos testes de inibição dos... (Resumo completo, clicar acesso eletrônico abaixo)
Abstract: Quinones are organic substances widely distributed in nature, found in plants, fungi and bacteria, associated with antitumoral and antimicrobial activities. Recently, a quinone (5-methoxy-3,4-dehydroxanthomegnin), structurally similar to 1,4-naphthoquinone, was isolated of the capitula of Paepalanthus latipes. The objective of this study was to evaluate biological activities of this quinone aiming a possible therapeutical application. The 5-methoxy-3,4-dehydroxanthomegnin showed minimal inhibitory concentration for Staphylococcus aureus and Enterococcus faecalis (197µM), but not for Escherichia coli. This quinone showed significative cytotoxic index for McCoy cells when compared with cisplatin. In the assays using tumoral cell lines of adenocarcinoma of lung (LP07) and breast (LM2), the largest cytotoxicity of the 5-methoxy-3,4-dehydroxanthomegnin was for LP07 line. The association with ascorbic acid increased the cytotoxicity of the 5-methoxy-3,4-dehydroxanthomegnin for McCoy cells, LM2 and LP07 due to redox cycling with hydrogen peroxide formation. Since some antineoplastic only present cytotoxic effect after biotransformation, the cytotoxicity of the 5-methoxy-3,4-dehydroxanthomegnin in the presence of the microssomal system S9 was evaluated and it was found that this system does not change the cytotoxic potential of the quinone. Nitric oxide (NO) and tumoral necrosis factor- α (TNF-α) were not detected in supernatants of macrophages treated with 5-methoxy-3,4-dehydroxanthomegnin, therefore its toxic effect, in this cell system, is not related to the production these mediators. However, macrophages treated with 5-methoxy-3,4-dehydroxanthomegnin increased hydrogen peroxide liberation significantly. The tests of inhibition of the mediators NO and TNF-α demonstrated that the 5-methoxy-3,4-dehydroxanthomegnin inhibits the release... (Complete abstract click electronic access below)
Doutor