Oxigênio molecular singlete [O2(1Δg)], uma espécie excitada, desempenha um papel importante em sistemas químicos e biológicos. É um poderoso eletrófilo, que reage com moléculas ricas em elétrons através de cicloadições [2+2], [4+2] e reações tipo ene. Ácidos graxos poliinsaturados, proteínas e DNA são alvos vulneráveis para o ataque de O2(1Δg). Os endoperóxidos de derivados de naftaleno são muito úteis e versáteis como fontes limpas de O2(1Δg), uma vez que são quase quimicamente inertes. Por outro lado, o desenvolvimento de novas fontes de O2(1Δg) ainda é uma tarefa desafiadora. Os derivados de naftaleno são capazes de armazenar O2(1Δg) por reação de cicloadiação [4+2] e liberá-lo em temperaturas amenas, o que os torna muito adequados para uso em estudos biológicos. A síntese destes compostos está baseada em modificações nos substituintes ligados nas posições 1 e 4 da estrutura do naftaleno. Na primeira parte deste trabalho, a síntese de três endoperóxidos derivados do naftaleno solúveis em água foi realizada. DHPNO2 e NDPO2 foram preparados de acordo com métodos similares descritos na literatura. A síntese de um novo endoperóxido dicatiônico derivado do naftaleno (NBTEO2) foi desenvolvida, contendo dois grupos de cloreto de amônio quaternário nas posições 1,4 do anel aromático. O intermediário chave na síntese dos três endoperóxidos é o BBMN, o qual foi preparado a partir da bromação radicalar do 1,4-dimetilnaftaleno. Nossos resultados têm indicado que este composto dicatiônico pode ser uma fonte química de O2(1Δg) em potencial, e pode ser explorado em estudos com mitocôndrias, onde o papel biológico de O2(1Δg) é investigado. A segunda parte deste trabalho foi dedicada a investigar a geração de O2(1Δg) através das reações entre hidroperóxidos de lipídeos (ácido oleico, linoleico e colesterol), hidroperóxidos orgânicos (cumeno e t-butila), bem como peróxido de hidrogênio com NO2+, utilizando o composto NO2BF4. Evidências da geração de O2(1Δg) foram obtidas através de medidas de emissão de luz na região do infravermelho próximo, no comprimento de onda de 1270 nm. Além disso, a prova inequívoca da presença de O2(1Δg) foi demonstrada através da caracterização espectral direta da emissão de luz no infravermelho próximo. O uso de azida de sódio como captador físico de O2(1Δg), juntamente com as medidas da quimiluminescência, contribuíram para identificar a geração desta espécie na reação entre hidroperóxidos de lipídeos e NO2BF4. Embora seja uma abordagem química, nossos resultados adicionaram informações importantes sobre a peroxidação lipídica, principalmente quando espécies reativas de nitrogênio estão envolvidas. O O2(1Δg) poderia ser gerado como um subproduto da peroxidação lipídica em condições onde espécies reativas de nitrogênio interagem com hidroperóxidos lipídicos. Isto pode contribuir para um melhor entendimento deste evento complexo com implicações fisiológicas ou fisiopatológicas. / Singlet molecular oxygen [O2(1Δg)], an excited species, plays an important role in chemical and biological systems. It is a powerfull electrophile, reacting with electron rich molecules through [2+2] cycloadditions, [4+2] cycloadditions and ene reactions. Polyunsaturated fatty acids, proteins and DNA are vulnerable targets for O2(1Δg) reaction. Naphthalene derivatives endoperoxides are very useful and versatile as a clean source of O2(1Δg), once they are almost chemically inert. On the other hand, developing new sources of O2(1Δg) are still a challenging task. Naphthalene derivatives are able to trap O2(1Δg) by [4+2] cycloaddition and release it in mild temperatures, which make them very suitable for biological studies. The synthesis of these compounds is based on modifications in substituents bonded in 1,4 positions of nafhthalene backbone. In the first part of present work, the synthesis of three water soluble naphthalene derivatives endoperoxides was performed. DHPNO2, NDPO2 were prepared according to similar methods described in the literature. A new di-cationic naphthalene derivative endoperoxide (NBTEO2) synthesis was developed, containing two quaternary ammonium chloride groups in 1,4-positions of aromatic ring. The key intermediate: for the synthesis of the three endoperoxides is the compound BBMN, which was prepared from radicalar bromination of 1,4-dimethylnaphthalene. Our results have indicated that this di-cationic compound can be a potential chemical source of O2(1Δg) and may be explored in mitochondrial studies where O2(1Δg) biological role is investigated. The second part of this work is dedicated to the investigation of generation of O2(1Δg) through reaction of lipid hydroperoxides (oleic acid, linoleic acids and cholesterol), organic hydroperoxides (cumene and t-butyl), as well as hydrogen peroxide with NO2+, using the compound NO2BF4. Evidences of generation of O2(1Δg) were obtained recording the monomol light emission measurement in near infrared region at wavelength of 1270 nm. Moreover, the proof of the presence of O2(1Δg) was unequivocally demonstrated by the direct spectral characterization of near-infrared light emission. The use of sodium azide as a physical quencher of O2(1Δg), associated to chemiluminescence measurements, contributed to identify the generation of this species in the reaction of lipid hydroperoxides and NO2BF4. Although, it is a chemical approach, our results add important information about lipid peroxidation, mainly when reactive species of nitrogen are involved. O2(1Δg) might be generate as a byproduct of lipid peroxidation, in conditions where reactive nitrogen species interact with lipid hydroperoxides. This might contribute to a better understand of this complex event and physiological or physiopathological implications

FundaÃÃo Cearense de Apoio ao Desenvolvimento Cientifico e TecnolÃgico / Empresa Brasileira de Pesquisa AgropecuÃria / As orquÃdeas sÃo plantas ornamentais que se destacam principalmente na floricultura devido à beleza, ao exotismo, à diversidade de cores, aos tamanhos e aos formatos de suas flores. A espÃcie Cattleya labiata e as do gÃnero Phalaenopsis apresentam uma grande oferta de opÃÃes de cores que tornam suas flores muito valorizadas e demandadas para comercializaÃÃo. Cattleya labiata à nativa do Nordeste brasileiro e suas floress sÃo levemente arroxeadas e perfumadas; enquanto que Phalaenopsis sp. produz flores brancas de longa durabilidade. A cultura de tecidos tem sido largamente empregada na multiplicaÃÃo massiva desses dois gÃneros. O estiolamento in vitro permite produzir grande nÃmero de plantas, reduzindo os riscos da ocorrÃncia de variaÃÃo somaclonal. Em razÃo disso, este trabalho teve como objetivo avaliar a influÃncia de diferentes ambientes de cultivo e de concentraÃÃes de BAP (6-benzilaminopurina) e ANA (Ãcido naftaleno acÃtico) no estiolamento in vitro das orquÃdeas Cattleya labiata e Phalaenopsis sp. PlÃntulas oriundas de sementes germinadas in vitro com aproximadamente + 1,0 cm de comprimento foram inoculadas em tubos de ensaio contendo 15,0 mL de meio de cultura MS, acrescido de diferentes concentraÃÃes de BAP (0,0; 2,0 e 4,0 mg L-1), ANA (0,0; 1,0 e 2,0 mg L-1) e ambientes de cultivo (sala de crescimento no escuro e com 16 horas de luz artificial), em esquema fatorial 2 x 3 x 3 (2 ambientes x 3 doses de BAP x 3 doses de ANA). Ao final de 150 dias, foram realizadas as seguintes avaliaÃÃes: a) nÃmero de brotos estiolados; b) nÃmero de nÃs por broto estiolado; c) comprimento da brotaÃÃo principal (cm); d) nÃmero de raÃzes e, e) massa seca total (g). O nÃmero de brotos estiolados e de nÃs (por broto estiolado) em plÃntulas de C. labiata e de nÃs por broto estiolado em Phalaenopsis sp. foram superiores no ambiente em ausÃncia de luz independente do fitorregulador utilizado, entretanto para o nÃmero de brotaÃÃes de Phalaenopsis sp. o ambiente luminoso foi o mais favorÃvel. A espÃcie C. labiata apresentou maior nÃmero de nÃs com a utilizaÃÃo de 2,0 mg L-1 de ANA na ausÃncia de BAP, e a orquÃdea Phalaenopsis sp. proporcionou maior nÃmero de nÃs com o emprego de 2,0 mg L-1 de ANA. Em plÃntulas de C. labiata e Phalaenopsis sp. a altura da brotaÃÃo principal foi superior em ambiente na ausÃncia de luz e, em contraste, o nÃmero de raÃzes e a massa seca total das plÃntulas foram superiores em ambiente na presenÃa de luz, sendo que para C. labiata esses resultados foram independentes do regulador de crescimento utilizado. / Orchids are ornamental plants that stand out mainly in floriculture due to the beauty, the exoticism, the diversity of colors, the sizes and shapes of their flowers. Cattleya labiata and species of the genus Phalaenopsis feature a wide range of color choices that make their flowers much valued and demanded for marketing. Cattleya labiata is native of the Brazilian Northeast and produces purplish and slightly fragrant flowers; and Phalaenopsis sp. produces white flowers for long lasting durability. Tissue culture is widely used in massive multiplication of genres. The in vitro etiolation allows to produce large numbers of plants, reducing the risk of somaclonal variation. For this reason, this study aimed to evaluate the influence of different cultivation environments and concentrations of BAP (6-benzylaminopurine) and NAA (naphthalene acetic acid) in vitro etiolation of the orchids Cattleya labiata and Phalaenopsis sp. Seedlings grown from seeds germinated in vitro with approximately + 1.0 cm in length were inoculated into test tubes containing 15.0 mL of MS medium supplemented with different concentrations of BAP (0.0, 2.0 and 4,0 mg L-1), NAA (0.0, 1.0 and 2.0 mg L-1) and culture environments (dark growth and room with artificial light) in a factorial 2 x 3 x 3 (2 environments x 3 doses of BAP x 3 doses of NAA). At the end of 150 days, the following evaluations were performed: a) number of etiolated shoots; b) number of nodes per etiolated shoot; c) length of the main sprout (cm); d) number of roots, and e) total dry mass (g). The number of etiolated shoots and nodes (per etiolated shoot) on seedlings of C. labiata and nodes per etiolated shoot in Phalaenopsis sp. were higher in the environment in the absence of light independent of the phytoregulator used, however the number of shoots of Phalaenopsis sp. the luminous environment was the most favorable. The species C. labiata showed a higher number of nodes with the use of 2.0 mg L-1 of NAA, in the absence of BAP, and Phalaenopsis sp. provided the highest number of nodes with the use of 2.0 mg L-1 of NAA. In seedlings of C. labiata and Phalaenopsis sp. the height of the main budding was higher in the environment in the absence of light, in contrast, the number of roots and total dry weight of seedlings were higher in luminous environment, and for C. labiata these results were independent regulator growth used.

L'étude des Hydrocarbures Aromatiques Polycycliques (PAH) a connu un intérêt croissant depuis une trentaine d'années, en raison notamment de leur possible présence dans le milieu interstellaire qui expliquerait l'observation des bandes d'émission IR encore non attribuées. Dans ce travail de thèse, la dynamique de refroidissement du cation naphtalène C10H8+, la plus petite molécule de la famille des PAH, est étudiée dans un anneau de stockage électrostatique, le Mini-Ring. La distribution en énergie interne des ions stockés est sondée en induisant la photo dissociation d'une fraction des ions par une excitation laser à la longueur d'onde 532 nm. La dynamique de refroidissement des cations photo-excités est observée en mesurant en fonction du temps le nombre de neutres émis par dissociation. La courbe de déclin du signal de neutres est directement reliée à la distribution en énergie interne des ions à l'instant de l'excitation laser. Cette distribution en énergie interne peut alors être déterminée à différents temps de stockage en analysant les courbes de déclin à l'aide d'un programme numérique développé pendant la thèse. L'évolution temporelle de la distribution met en évidence un processus de refroidissement rapide caractérisé par un taux de refroidissement compris entre 70 et 90 s−1 pour des énergies internes de 5.9 et 6.8 eV. Ce refroidissement rapide ne peut être expliqué par l'émission de photons infrarouges. Il est attribué à la "fluorescence de Poincaré" caractérisée par un processus de conversion interne inverse suivie de l'émission d'un photon dans le domaine du visible. Cette fluorescence de Poincaré ou fluorescence récurrente a été prédite il y a plus de 20 ans mais n'a jamais été mesurée directement à ce jour. Les taux de refroidissement mesurés lors de ce travail de thèse apportent une évidence indirecte de ce processus / The study of Polycyclic Aromatic Hydrocarbons (PAH) has been of increasing interest during the last thirty years: their possible presence in the interstellar medium is commonly invoked to explain the observation of still unassigned IR emission bands. In this thesis, the cooling dynamics of the naphthalene cations C10H8 +, the smallest molecule of the PAH family, is studied in an electrostatic storage ring, the Mini-Ring. Particularly, we consider the two main cooling processes for naphthalene cation, the dissociation and photon emission. Naphthalene molecules are ionized in an electron cyclotron resonance source (ECR), accelerated to 12 keV and then injected and stored in the Mini-Ring for several milliseconds. The internal energy distribution of the stored ions is probed by laser induced dissociation using an excitation wavelength at 532 nm. The cooling dynamics of the photo-excited cations is observed by measuring the number of emitted neutrals as a function of time. The decay curve of the neutral signal is directly related to the internal energy distribution of the ions at the excitation time. This internal energy distribution can then be determined at various storage times by analyzing the decay curves using a code developed during this thesis. The time evolution of the internal energy distribution shows a fast cooling process characterized by a cooling rate increasing from 70 to 90 s−1 for internal energies from 5.9 to 6.8 eV. This fast cooling process can’t be explained by infrared photons emission. It is attributed to the "Poincaré fluorescence " which involves an inverse internal conversion process followed by the emission of a visible photon. This fluorescence from thermally excited electron or recurrent fluorescence was predicted more than 20 years ago, but has never been measured directly up to now. The measured cooling rates in this thesis provide indirect evidence of this process

Ces travaux de thèse ont permis dans un premier temps, d'aborder différentes voies de synthèse d'un nouvel antipsychotique potentiel (F17464) proposé par les laboratoires Pierre Fabre. Trois stratégies basées sur des synthèses convergentes ont été initiées. La première stratégie repose sur une étape clé de métathèse croisée, la seconde sur une réaction de Sonogashira et la troisième aborde une nouvelle méthodologie d'alkylation des chromones en position 3. Ces méthodes nous ont permis d'accéder à des intermédiaires de synthèse originaux, utiles pour préparer la molécule F17464 en respectant les contraintes industrielles.Dans un deuxième temps, différents types de molécules polycycliques complexes ont été synthétisés par cascades réactionnelles palladocatalysées. Une série de naphtalènes condensés a été préparée par réaction domino palladocatalysée issue de cyclocarbopalladations successives suivies d'une activation C(sp2)-H. Plusieurs types de cycles à sept atomes de carbone condensés ont été synthétisés en une seule étape, à partir de substrats faciles d'accès, via des cascades réactionnelles cyclocarbopalladations/activation C(sp2) ou C(sp3)-H.Finalement, des cyclooctatriènes et des fenestradiènes ont été obtenus à partir du même substrat,en une seule étape, via des réactions en cascade débutant par une cyclocarbopalladation 4-exodigsuivie d'un couplage de Stille puis d'une addition d'alcynes sur une triple liaison s'achevant par des réactions d'électrocyclisations. La température est le seul paramètre réactionnel qui diffère dans la synthèse de ces deux polycycles complexes, à partir du même substrat. / This PhD thesis allowed us in the first part to develop different synthesic pathways to a new potential antipsychotic (F17464) invented by Pierre Fabre laboratories. Three strategies based on convergent syntheses are initiated. The key step of the first strategy is olefin cross metathesis. The second strategy rests on Sonogashira coupling and the third one involves a new methodology ofchromones alkylation in position 3. These methods allowed us access to novel synthetic intermediates, useful in the preparation of the F17464 molecule by following industrial confines.ln the second part, different types of polycyclic molecules were synthesized by palladium-catalyzed cascade reactions. A set of fused naphthalenes was prepared by palladium-catalyzed dominoreaction including cyclocarbopalladations followed by C(sp2)-H bond activation. Several types of fused seven-membered carbocycles were synthesized in a one-pot reaction from convenient substrates, via cascade reactions including cyclocarbopalladations followed by C(sp2 or sp3)-Hbond activation. Finally, cyclooctatrienes and fenestradienes were obtained also in a one-pot reaction from the same substrate via cascade reactions involving 4-exo-dig cyclocarbopalladation, followed by Stille coupling, alkyne addition onto a triple bond, finishing by electrocyclization reactions. Temperature is the only parameter that differs in the synthesis ôf the two complex polycycles starting from the same substrate.

I) Introduction p-Conjugated polymers inherently combine electronic properties of inorganic semiconductor crystals and material characteristics of organic plastics due to their special molecular design. This unique combination has led to developing new unconventional optoelectronic technologies and, further, resulted in the evolution of semiconducting polymers (SCPs) as fundamental components for novel electronic devices, such as organic field-effect transistors (OFETs), organic light-emitting diodes (OLEDs) and organic solar cells (OSCs).[1–5] Moreover, the material flexibility, capability for thin-film formation, and solution processibility additionally allow utilizing modern printing technologies for the large-scale fabrication of flexible, light-weight organic electronics. This especially enables to significantly increase the production speed and, moreover, to drastically reduce the costs per unit.[6, 7] In particular, transistors are the most important elements in modern functional electronic devices because of acting as electronic switches in logic circuits or in displays to control pixels. However, due to molecular arrangement and interactions, the electronic performance of SCPs cannot compete with the one of monocrystalline silicon which is used in state-of-the-art high-performance microtechnology.[5, 8] Nonetheless, intensive and continuing efforts of scientists focused on improving the performance of OFETs, with the special focus on the charge carrier mobility, by optimizing the polymer structure, processing conditions and OFET device architecture. By this, it was possible to identify crucial relationships between polymer structure, optoelectronic properties, microstructure, and OFET performance.[8] Nowadays, the interdisciplinary scientific success is represented by high-performance SCPs with charge carrier mobilities exceeding the value of amorphous silicon.[3, 9] However, further research is essential to enable developing the next generation of electronic devices for application in healthcare, safety technology, transportation, and communication. II) Objective and Results Within the scope of this doctoral thesis, current high-performance p-conjugated SCPs should be studied comprehensively to improve the present understanding about the interdependency between molecular structure, material properties and charge transport. Therefore, the extensive research approaches focused on different key aspects of high charge carrier mobility polymers for organic transistors. The performed investigations comprised the impact of, first, novel design concepts, second, precise structural modifications and, third, synthetic and processing conditions and led to the major findings listed below. 1. The design concept of tuning the p-conjugation length allows to gradually modulate physical material properties and demonstrates that a strong localization of frontier molecular orbitals in combination with a high degree of thin-film ordering can provide a favorable platform for charge transport in p-conjugated semiconducting polymers.[1] 2. The replacement of thiophene units with thiazoles in naphthalene diimide-based p- conjugated polymers allows to increase interchain interactions and to lower frontier molecular orbitals. This compensates the potentially detrimental enhancement of backbone torsion and drives the charge transport to unipolar electron transport, whereas mobility values are partially comparable with those of the respective thiophene containing analogs. 3. p-Conjugated diketopyrrolo[3,4-c]pyrrole-based copolymers can be synthesized within fifteen minutes what, in combination with avoiding aqueous washings and optimizing processing conditions, allowed an increase in morphological and energetic order and, thus, improved the charge transport properties significantly. III) Conclusion The key findings of this doctoral thesis provide new significant insights into important aspects of designing, synthesizing and processing high charge carrier mobility polymers. By this, they can guide future research to further improve the performance of organic electronic devices - decisive for driving the development and fabrication of smart, functional and wearable next-generation electronics. References [1] T. Erdmann, S. Fabiano, B. Milián-Medina, D. Hanifi, Z. Chen, M. Berggren, J. Gierschner, A. Salleo, A. Kiriy, B. Voit, A. Facchetti, Advanced Materials 2016, 28 (41), 9169–9174, DOI:10.1002/adma.201602923. [2] Y. Karpov, T. Erdmann, I. Raguzin, M. Al-Hussein, M. Binner, U. Lappan, M. Stamm, K. L. Gerasimov, T. Beryozkina, V. Bakulev, D. V. Anokhin, D. A. Ivanov, F. Günther, S. Gemming, G. Seifert, B. Voit, R. Di Pietro, A. Kiriy, Advanced Materials 2016, 28 (28), 6003–6010, DOI:10.1002/adma.201506295. [3] A. Facchetti, Chemistry of Materials 2011, 23 (3), 733–758, DOI:10.1021/cm102419z. [4] A. J. Heeger, Chemical Society Reviews 2010, 39, 2354–2371, DOI:10.1039/B914956M. [5] H. Klauk, Chemical Society Reviews 2010, 39, 2643–2666, DOI:10.1039/B909902F. [6] S. G. Bucella, A. Luzio, E. Gann, L. Thomsen, C. R. McNeill, G. Pace, A. Perinot, Z. Chen, A. Facchetti, M. Caironi, Nature Communications 2015, 6, 8394, DOI:10.1038/ncomms9394. [7] H. Sirringhaus, T. Kawase, R. H. Friend, T. Shimoda, M. Inbasekaran, W. Wu, E. P. Woo, Science 2000, 290 (5499), 2123–2126, DOI:10.1126/science.290.5499.2123. [8] D. Venkateshvaran, M. Nikolka, A. Sadhanala, V. Lemaur, M. Zelazny, M. Kepa, M. Hurhangee, A. J. Kronemeijer, V. Pecunia, I. Nasrallah, I. Romanov, K. Broch, I. McCulloch, D. Emin, Y. Olivier, J. Cornil, D. Beljonne, H. Sirringhaus, Nature 2014, 515 (7527), 384–388, DOI:10.1038/nature13854. [9] S. Holliday, J. E. Donaghey, I. McCulloch, Chemistry of Materials 2014, 26 (1), 647–663, DOI: 10.1021/cm402421p.

Masters of Science / Fumonisins, carcinogenic mycotoxins produced by various Fusarium species, occur naturally in maize and maize-based food products. They are hazards for animal and human health as they cause cancer in rodents and have been associated with oesophageal cancer and neural tube defects in humans. The most abundant naturally occurring fumonisins analogues in maize are fumonisin B1, B2 and B3 (FB1, FB2 and FB3). For analytical determination, they mostly require suitable extraction, clean-up and pre or post-column derivatization together with reversed-phase HPLC separation. o- Phthaldialdehyde (OPA) had been adopted as the most widely used derivatization reagent for fumonisins as they lack useful chromophores or fluorophores. Alternative derivatization reagents, naphthalene-2,3- dicarboxaldehyde (NDA) and dansyl chloride (DnS-Cl), were investigated in this study. / South Africa

Thyroid hormones (THs; T4 and T3), secreted from thyroid gland, play an important role in human growth and development. T3 (3,5,3′-triiodothyronine) is the active hormone and the conversion of T4 (3,3′,5,5′-tetraiodothyronine) to T3 in cells is mediated by iodothyronine deiodinases enzymes (DIOs). DIOs are selenocysteine containing enzymes and are classified into three types (DIO1, DIO2 and DIO3). DIO1 catalyzes the outer-ring deiodination (ORD; T3 formation) and inner-ring deiodination (IRD; rT3 formation) reactions, involving in the activation (T4 to T3 conversion) and inactivation (T4 to rT3 conversion), respectively. DIO2 and DIO3 catalyse the ORD and IRD reactions, respectively. This homeostasis is regulated tightly and any deviation would lead to diseases like hyperthyroidism or hypothyroidism. Recently it is of interest to many research groups to develop iodothyronine deiodinase mimics and we have developed naphthalene-based peri-substituted thioselenol pair at 1,8-positions (1.25), which remove iodine selectively from inner-ring of T4. When selenium atom is substituted in place of sulfur (selenol-selenol pair; 1.26), the deiodination activity was ca. 90 times faster than with 1.25. This thesis deals with various aspects of the effect of substituents on the naphthalene-1,8-diselenol and solvent effect on the thyroid hormone deiodination by naphthalene-based iodothyronine deiodinase mimics. Figure 1. (A) Deiodination reactions by DIOs. (B) Chemical structure of 1.25 and 1.26. The thesis consists of five chapters. The first chapter provides a general overview about sialoproteins, thyroid hormone biosynthesis, thyroid hormone metabolism, halogen bonding, iodothyronine deiodinase mimics and proposed mechanisms for the deidoination of thyroid hormones. This chapter also introduces peri-naphthalene-1,8-diselenol (1.26), which is the key compound in this thesis and discusses about proposed mechanism for the deiodination of thyroxine involving co-operative halogen bonding and chalcogen bonding mechanism. Figure 2. (A) TH action. (B) Proposed mechanism for the deiodination of T4 by 1.26 involving cooperative halogen bonding and chalcogen bonding. Chapter 2 discusses about the synthesis, characterization and deiodination activity of a series of naphthalene-based peri-substituted-1,8-diselenols (Figure 3). These diselenols regioselectivity remove iodine from inner ring of thyroxine and other thyroid hormones, (T3 and 3, 5-T2). Substitution with different groups on the naphthalene ring did not change the regioselectivity of deiodination, indicating that the deiodination activity does not depend on the nature of substituents. Secondary or tertiary amine side chain group attached at the 2nd position of the naphthalene ring showed better activity. It is due to the secondary interaction, which facilitates the iodine removal. It was further confirmed with the substitutions at the 4th position of the ring to discriminate the possibility of electronic effect. The higher deiodination rate owing to the t-butyl group at second position of the ring also suggests that the steric effect may also play a role in the deiodination reaction (Figure 4). It is proposed that peri substituted naphthalene-1,8-diselenols remove iodine from thyroid hormones through halogen bonding-chalcogen bonding mechanism (Figure 2). The investigation of Se···Se bond distance from the crystal structures and through DFT calculation and NMR experiment showed that the stronger chalcogen bond could be the reason for the increase in the reactivity observed with substituted peri-naphthalene-1,8-diselenols. Figure 3. peri-substituted naphthalene-1,8-diselenols used for the study. Figure 4. Relative deiodinase activity of substituted-peri-naphthalene-1,8-diselenols with T4. In Chapter 3, we have discussed about the effect of chalcogen atom substitution in a series of deiodinase mimics on the deiodination of thyroid hormones. Moving from thiol-selenol pair (1.25) to selenol-selenol pair (1.26) in naphthalene based peri-substituted mimics, an increase in the activity was observed. In this chapter, we have shown that substituting with tellurium, as tellurium-thiol pair (3.3) and ditellurol (3.4) increases the reactivity of deiodination to several times and also regioselectivity of deiodination is changed from IRD in the case of 1.26 to both IRD and ORD for 3.3 and 3.4. The presence of two tellurol moieties (3.4) or a thiol-tellurol pair (3.3) can mediate sequential deiodination of T4, to produce all the possible thyroid hormone derivatives under physiologically relevant conditions (Figure 5). This study provided the first experimental evidence that the regioselectivity of the thyroid hormone deiodination is controlled by the nucleophilicity and the strength of halogen bond between the iodine and chalcogen atoms. Figure 5. (A) HPLC chromatograms of deiodination reaction of T4 with 3.3 and 3.4. (B) Chemical structure of 3.3 and 3.4. (C) Sequential deiodination reaction of T4 by 3.3 and 3.4. Chapter 4 describes the effect of alkyl conjugation at 4′-OH position of THs on the deiodination by iodothyronine mimics. In addition to the deiodination, iodothyronines undergo conjugation with sulfate and glucuronic acid group at 4′-hydroxyl position. Conjugation alters the physico-chemical properties of iodothyronines. For example, it is known that sulfate conjugation increases the rate of deiodination to a large extend. We have conjugated alkyl group at 4′-hydroxyl position of iodothyronines and investigated the deiodination reactions with reported peri-substituted naphthalene-1,8-diselenols. We observed that similar to sulfated thyroid hormones O-methylthyroxine also undergoes both phenolic and tyrosyl ring deiodination reactions and overall the rate of deiodination is increased at least by 5 times as compared with T4 under identical conditions. The phenolic iodine removal is favored by conjugation as compared to the tyrosyl ring iodine, which is similar to the observation made for T4S. Interestingly, when the acetamide group is conjugated at 4′-OH position, the regioselectivity of deiodination is changed exclusively to 5′-iodine. DFT calculations show that the positive potential on the iodine increase upon conjugation, which leads to stronger halogen bonding interaction with selenol, might be the reason for the change in the regioselectivity of deiodination. Figure 6. (A) HPLC chromatogram of deiodination reaction of T4(Me) with 1.26. (B) Initial rate comparison of T4 and T4(Me).(C) HPLC chromatogram of deiodination reaction of T4(AA) with 1.26 showing the formation of T3(AA) (ORD product). (D) Electron potential map of T4, T4(Me) and T4(AA) showing the increase in electro positive potential on 5′-iodine upon conjugation. Chapter 5 deals with the solvent effect on the deiodination reactions of THs by iodothyronine deiodinase mimics. As discussed in the earlier chapters, the deiodination reaction of thyroxine by naphthalene based-1,8-diselenols under physiological conditions produce, rT3 (IRD) as the only observable products. Surprisingly, when the deiodination reaction was performed in DMF or DMSO in the presence of 1.26, the regioselectivity of reaction was changed and the formation of both T3 (ORD) and rT3 was observed. In DMF or in DMSO, the deiodination reactivity of 1.26 was found to be 1000 fold higher than the reaction performed in phosphate buffer at pH 7.4. Figure 7. (A) HPLC chromatogram for the deiodination reaction of T4 in DMF by 1.26 showing both IRD and ORD. (B) A comparison of initial rate for the deiodination reactions of T4, T3 and 3,5-T2 in DMF and in DMSO by 1.26. (C) HPLC chromatograms for the deiodination reaction of T4 in DMF by 1.26 in the presence of TEMPO, showing the inhibition of deiodination (i) 0 mM TEMPO (ii) 10 mM of TEMPO (iii) 30 mM TEMPO. (D) HPLC chromatograms for the deiodination reaction of T4 in DMSO by 1.26 in the presence of TEMPO showing the inhibition of deiodination (i) 0 mM TEMPO (ii) 10 mM of TEMPO (iii) 30 mM TEMPO. 3,5-DIT was not denominated under physiological conditions, however, in DMF and in DMSO, 3,5-DIT was deiodinated by 2.4 to produce 3-MIT. We also observed that the control reactions in DMF or DMSO also showed a little deiodination activity. The very high reactivity observed in the presence of DMF or DMSO implied that the mechanism of denomination in these solvents may be different. It has been reported that DMSO or DMF radicals can be formed with small amounts of a base. Reaction mixture consisting of NaBH4 (for generating selenol from diselenide) and NaOH (T4 solution) may facilitate the radical formation. We also performed the reaction in the presence of TEMPO (free radical scavenger) and observed the inhibition of deiodination reaction. However, it is not clear whether the radical pathway could be one of the possible mechanisms of deiodination in these solvents by compounds 1.26 and 2.4. Further studies are required to propose a radical mechanism in different solvents such as DMF and DMSO.

Comme le naphtalène a récemment émergé comme un socle fondamental en chimie médicinale, le développement de méthodologies menant à des plateformes fonctionnalisées basées sur du naphtalène est devenu un centre d’intérêt majeur de la communauté scientifique. En effet, des conditions expérimentales optimisées sur le benzène ou d’autre noyaux aromatiques ne peuvent pas toujours être transposées au naphtalène. Ces dernières peuvent parfois conduire à des résultats différents, possiblement dû à l’aromaticité plus faible de ce bicycle aromatique.Dans ce contexte, cette thèse s’articule autour du naphtalène et de ses dérivés. Des méthodes variées permettant une fonctionnalisation sélective de différentes positions de cette plateforme, ainsi que des stratégies de synthèses d’architectures polycycliques ont été développées.Notre attention s’est ensuite portée sur des précurseurs du naphtalène, en particulier sur les tetralones. En utilisant une méthode basée sur l’utilisation d’un groupe directeur éphémère, la position 8 de ce bicycle a été arylée, et les différents composés ainsi obtenus ont pu être convertis en d’autre plateformes polycycliques. En complément, des calculs DFT ont permis d’expliquer la régiosélectivité observée lors de la synthèse de fluorenones étendues, et d’étudier le mécanisme d’arylation dirigée des tetralones. / Because naphthalene has recently emerged as a fundamental platform in medicinal chemistry, the development of methodologies leading to diversely functionalised naphthalene-based platforms has become a prime concern of the scientific community. Indeed, experimental conditions previously optimised for benzene and other aromatic rings cannot always be applied to naphthalene. These methods can sometimes lead to different results, as a consequence of the lower aromaticity of the naphthalene core.In this context, this thesis is dedicated to the naphthalene and its derivatives. Various methods to selectively functionalise the different positions of the naphthalene core and synthetic pathways to extended polycyclic architectures were developed.Next, we focused on naphthalene precursors, especially on tetralones. Using a strategy involving a transient directing group, the position 8 of these bicycles was successfully arylated and the resulting compounds were successfully converted into other polycyclic platforms. In addition, DFT calculation have been used to explain the regioselectivity observed during the synthesis of extended fluorenones, and to study the mechanism of directed arylation of tetralones.

I) Introduction p-Conjugated polymers inherently combine electronic properties of inorganic semiconductor crystals and material characteristics of organic plastics due to their special molecular design. This unique combination has led to developing new unconventional optoelectronic technologies and, further, resulted in the evolution of semiconducting polymers (SCPs) as fundamental components for novel electronic devices, such as organic field-effect transistors (OFETs), organic light-emitting diodes (OLEDs) and organic solar cells (OSCs).[1–5] Moreover, the material flexibility, capability for thin-film formation, and solution processibility additionally allow utilizing modern printing technologies for the large-scale fabrication of flexible, light-weight organic electronics. This especially enables to significantly increase the production speed and, moreover, to drastically reduce the costs per unit.[6, 7] In particular, transistors are the most important elements in modern functional electronic devices because of acting as electronic switches in logic circuits or in displays to control pixels. However, due to molecular arrangement and interactions, the electronic performance of SCPs cannot compete with the one of monocrystalline silicon which is used in state-of-the-art high-performance microtechnology.[5, 8] Nonetheless, intensive and continuing efforts of scientists focused on improving the performance of OFETs, with the special focus on the charge carrier mobility, by optimizing the polymer structure, processing conditions and OFET device architecture. By this, it was possible to identify crucial relationships between polymer structure, optoelectronic properties, microstructure, and OFET performance.[8] Nowadays, the interdisciplinary scientific success is represented by high-performance SCPs with charge carrier mobilities exceeding the value of amorphous silicon.[3, 9] However, further research is essential to enable developing the next generation of electronic devices for application in healthcare, safety technology, transportation, and communication. II) Objective and Results Within the scope of this doctoral thesis, current high-performance p-conjugated SCPs should be studied comprehensively to improve the present understanding about the interdependency between molecular structure, material properties and charge transport. Therefore, the extensive research approaches focused on different key aspects of high charge carrier mobility polymers for organic transistors. The performed investigations comprised the impact of, first, novel design concepts, second, precise structural modifications and, third, synthetic and processing conditions and led to the major findings listed below. 1. The design concept of tuning the p-conjugation length allows to gradually modulate physical material properties and demonstrates that a strong localization of frontier molecular orbitals in combination with a high degree of thin-film ordering can provide a favorable platform for charge transport in p-conjugated semiconducting polymers.[1] 2. The replacement of thiophene units with thiazoles in naphthalene diimide-based p- conjugated polymers allows to increase interchain interactions and to lower frontier molecular orbitals. This compensates the potentially detrimental enhancement of backbone torsion and drives the charge transport to unipolar electron transport, whereas mobility values are partially comparable with those of the respective thiophene containing analogs. 3. p-Conjugated diketopyrrolo[3,4-c]pyrrole-based copolymers can be synthesized within fifteen minutes what, in combination with avoiding aqueous washings and optimizing processing conditions, allowed an increase in morphological and energetic order and, thus, improved the charge transport properties significantly. III) Conclusion The key findings of this doctoral thesis provide new significant insights into important aspects of designing, synthesizing and processing high charge carrier mobility polymers. By this, they can guide future research to further improve the performance of organic electronic devices - decisive for driving the development and fabrication of smart, functional and wearable next-generation electronics. References [1] T. Erdmann, S. Fabiano, B. Milián-Medina, D. Hanifi, Z. Chen, M. Berggren, J. Gierschner, A. Salleo, A. Kiriy, B. Voit, A. Facchetti, Advanced Materials 2016, 28 (41), 9169–9174, DOI:10.1002/adma.201602923. [2] Y. Karpov, T. Erdmann, I. Raguzin, M. Al-Hussein, M. Binner, U. Lappan, M. Stamm, K. L. Gerasimov, T. Beryozkina, V. Bakulev, D. V. Anokhin, D. A. Ivanov, F. Günther, S. Gemming, G. Seifert, B. Voit, R. Di Pietro, A. Kiriy, Advanced Materials 2016, 28 (28), 6003–6010, DOI:10.1002/adma.201506295. [3] A. Facchetti, Chemistry of Materials 2011, 23 (3), 733–758, DOI:10.1021/cm102419z. [4] A. J. Heeger, Chemical Society Reviews 2010, 39, 2354–2371, DOI:10.1039/B914956M. [5] H. Klauk, Chemical Society Reviews 2010, 39, 2643–2666, DOI:10.1039/B909902F. [6] S. G. Bucella, A. Luzio, E. Gann, L. Thomsen, C. R. McNeill, G. Pace, A. Perinot, Z. Chen, A. Facchetti, M. Caironi, Nature Communications 2015, 6, 8394, DOI:10.1038/ncomms9394. [7] H. Sirringhaus, T. Kawase, R. H. Friend, T. Shimoda, M. Inbasekaran, W. Wu, E. P. Woo, Science 2000, 290 (5499), 2123–2126, DOI:10.1126/science.290.5499.2123. [8] D. Venkateshvaran, M. Nikolka, A. Sadhanala, V. Lemaur, M. Zelazny, M. Kepa, M. Hurhangee, A. J. Kronemeijer, V. Pecunia, I. Nasrallah, I. Romanov, K. Broch, I. McCulloch, D. Emin, Y. Olivier, J. Cornil, D. Beljonne, H. Sirringhaus, Nature 2014, 515 (7527), 384–388, DOI:10.1038/nature13854. [9] S. Holliday, J. E. Donaghey, I. McCulloch, Chemistry of Materials 2014, 26 (1), 647–663, DOI: 10.1021/cm402421p.

SIRT1 and SIRT2 are two NAD⁺-dependent deacetylases which negatively modulate the activity of p53, a protein which is involved in cell cycle arrest, senescence and apoptosis following genotoxic stress. Part I of the thesis describes the exploration of the chemical space around a reported unselective and modest inhibitor of SIRT1 and SIRT2 with the aim of improving the selectivity and potency of the inhibitor against the two isoforms. Particular emphasis is placed upon understanding the mode of binding of the novel analogues within the active site of the enzymes. Chapter 1 reviews the physiological roles of class III NAD⁺-dependent deacetylases, also known as sirtuins. In particular, the application of SIRT1 and SIRT2 inhibitors as potential anticancer agents is described. Amongst these, only cambinol and the tenovins showed in vivo activity in a mouse xenograft model. Previously only one analogue of cambinol had been reported in the literature. Chapter 2 describes the development of a small collection of novel cambinol analogues (First Generation Studies). The role played by different substituents at the phenyl group and at the N-1 of the thiouracil core is discussed. Along with the synthesis and structure activity relationship (SAR) associated with the core structure, in-cell experiments intended to confirm the activity of the most active compounds are reported. Chapter 3 provides a rationalisation for the SAR discussed in Chapter 2. Based on computational molecular modelling studies (GOLD), the activity of the most potent and selective SIRT2 inhibitors is explained. Two series of novel cambinol analogues were designed (Second and Third Generation Analogues) in order to assess further the proposed binding mode. Chapter 4 focuses on the development of the “Second Generation” analogues, characterised by the presence of lipophilic substituents at the sulfur atom and at the N-3 position of the thiouracil core. The synthesis, biological evaluation and SAR are discussed in detail. Chapter 5 reports the development of the “Third Generation” analogues, characterised by either a benzyl group or para-alkoxy-substituted benzyl group at the N-1 position of cambinol. Once again, the synthesis, biological evaluation and SAR data are presented. An improved understanding of the mode of binding of the novel compounds is proposed based on molecular dynamics (MD) studies. Indole-based alkaloids, such as Vincristine and Vinblastine, are well known for their anticancer activity. Recently, the anticancer activity of members of the calycanthaceous family of alkaloids has been discovered. Part II of the thesis focuses on model studies aimed at developing the total synthesis of one of these compounds, perophoramidine. Chapter 7 provides an overview of the calycanthaceous alkaloid family of natural products, including their biological properties. The structural features of perophoramidine, along with the previously reported synthetic studies are outlined. Chapter 8 describes the synthesis of an advanced intermediate in the total synthesis of dehaloperophoramidine, a structural analogue of perophoramidine Problems encountered, optimisation studies and the synthesis of a re-designed intermediate are also reported in this chapter.