Donor-acceptor conjugated polymers opened a new era for conjugated polymer research due to the abundant selection and combination of different conjugated units. This class of polymers function as semiconductor materials with potential application in plastic consumer electronics. The frontier molecular orbital energies of the polymers are generally determined by the selection of donor and acceptor units in the backbone structure, and their substituents. The side chains attached to the backbone not only affect the solubility of the materials, but also their self-assembly and morphological characteristics, which indirectly govern optoelectronic properties. It is important therefore to consider backbone architectures and the side chains together, to control (opto)-electronic properties for specific applications, while also maintaining solution processability without disrupting solid-state packing. The research presented in this dissertation focuses largely on the side chains: how the bulk and position of side chains affect the (opto)-electronic properties of select donor-acceptor (D-A) conjugated polymers. More precisely the intent is to vary the size and position of branches in the alkyl side chains of donor-acceptor polymers, in the attempt to solubilize poorly soluble polymers, without disrupting self-assembly of the polymer backbones into close p-stacks. After an introductory chapter 1, chapter 2 mainly focuses on the synthesis and structure-property study of polymers with 2,3,5,6-tetrafluorobenzene (TFB) as the acceptor motif and benzo[1,2-b:4,5-b′]dithiophene (BDT) as donor units carrying solubilizing substituents. TFB units were chosen based on previous observations that this acceptor unit imparts particularly poor solubility to various donor-acceptor copolymers. The current study indicates that bulky branches placed close to the polymer backbone could solubilize the PBDTTFB copolymers without altering the absorption profile and oxidation potentials. Optical, wide-angle x-ray diffraction (WAXD) and solubility studies shows that solubility is closely related to branching size and position. As the branch size in increased, the solubility of these polymers undergoes a step-change. The third chapter mainly focuses on the structure-property study of D-A polymers with thienopyrroledione (TPD) as acceptor. Unlike TFB, this acceptor can carry additional side chains that can compete with the space-filling demands of the donor unit side chains. As donor, the rigid BDT unit was compared with 3,3’-dialkoxy-2,2’bithiophene (RO2T2) units which have a similar size, but contain a “swiveling” central σ-bond. Bulkiness of side chains attached to the T2 units should be expected to have a more severe impact, possibly causing the two thiophene units of the T2 units to twist out of plane. It was demonstrated that alkoxy side chains with bulky branches in close proximity to the polymer backbones does not disrupt conjugation in these polymers. The UV-Vis absorption spectra of RO2T2-TPD polymers were red-shifted (more than 120 nm) in comparison to PBDTTPD polymers due to the smaller Eg (energy gap), which might be attributed to the expected higher energy HOMO imparted by the donor unit. The π-π stacking of polymers with BDT units was little affected by the bulky side chains. However, the π-π stacking of polymers with RO2T2 units was much more sensitive to side-chain bulk, with high degree of order and close π-π stacking only if proper local free spacing exists for side-chain interdigitation. Chapter 4 reports efforts to study polymers from the same set of RO2T2 monomers studied in Chapter 3, but without acceptor units that might otherwise drive self-assembly. RO2T2 homopolymers were synthesized via the Grignard metathesis (GRIM) method. Further, copolymers were prepared with RO2T2 units alternating with thiophene, thieno[3,2-b]thiophene or bithiophene. The spectroscopic studies suggest these polymers with bulky side chains exhibit some varying level of backbone conjugation. Somewhat surprisingly, despite an expected decrease in the strength of intermolecular donor-acceptor interactions, the solubilities were in some cases low, but varied with volume fraction of side chains. Further, even for polymers that appear to easily dissolve, aggregation in solution is so extensive as to give ensembles “too large” for characterization by GPC and or solution NMR. Oxidation potentials seem essentially insensitive to any of the structural variables (governed mostly by the backbone RO2T2 units).

Les HAP sont des polluants ubiquitaires de l'environnement. Certains d'entre eux, comme le benzo[a]pyrène (B[a]P) sont cancérigènes pour l'homme. Il est donc primordial d'évaluer l'exposition des individus au B[a]P. Pour cela, la mesure des adduits de l'ADN est d'un intérêt majeur puisqu'elle permet de quantifier la dose génotoxique. Deux voies métaboliques du B[a]P conduisent à la formation de divers adduits de l'ADN. Afin de définir de nouveaux biomarqueurs d'exposition, nous avons cherché à identifier la nature chimique des adduits majoritairement formés dans des modèles cellulaires de kératinocytes et d'hépatocytes humains exposés au B[a]P. Pour cela, une méthode analytique par chromatographie liquide haute performance couplée à la spectrométrie de masse en mode tandem a été mise au point pour permettre le dosage spécifique de sept adduits, avec une limite de détection de l'ordre de 1 adduit/108 nucléosides normaux. Les adduits majoritaires sont les adduits stables du diol-époxyde du B[a]P (BPDE), et les cinétiques de formation et de réparation sont différentes entre les deux types cellulaires. Chez l'homme, la méthode analytique développée ne nous a pas permis de mettre en évidence ces adduits que ce soit dans l'urine de sujets exposés professionnellement aux HAP ou dans l'ADN lymphocytaire de sujets fumeurs. De plus les nucléosides oxydés dans l'urine s'avèrent ne pas être de bons biomarqueurs d'effet des HAP. Les adduits stables du BPDE apparaissent donc comme des biomarqueurs pertinents de l'exposition au B[a]P, mais il est nécessaire d'améliorer la limite de détection de notre méthode pour permettre leur dosage chez l'homme.

Lic.-avh. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 2 uppsatser.

[pt] Este trabalho apresenta a síntese e caracterização de 11-tosil-6,6a,11, 11-tetraidro-5H-benzo[a]carbazois análogos ao LQB223, um composto previamente sintetizado em nosso grupo de pesquisa que tem ação anticâncer e antileishmanial in vitro e ação antimalarial in vitro e in vivo. A etapa chave da reação para a obtenção dos 5-metoxi-11a-N-arilsulfonil-tetrahidro-5H-benzo[a]carbazol (97a), 6-metoxi-11a-N-arilsulfonil-tetrahidro-5H-benzo[a]carbazol (97b) e 7-metoxi-11a-N-arilsulfonil-tetrahidro-5H-benzo[a]carbazol (97c) envolve uma reação de aza-arilação de Heck catalisada por paládio na presença de carbonato de prata e acetona entre o N-tosil-o-iodoanilina (55b) e dihidronaftalenos substituídos (100a, 100b, e 100c), preparados previamente a partir de tetralonas comerciais (84a, 84b, 84c). Os compostos 5-hidroxi-11a-N-arilsulfonil-tetrahidro-5H-benzo[a]carbazol (98a), 6-hidroxi-11a-N-arilsulfonil-tetrahidro-5H-benzo[a]carbazol (98b) e o 7-hidroxi-11a-N-arilsulfonil-tetrahidro-5H--benzo[a]carbazol (98c) foram obtidos através da desproteção das metoxilas com BBr3 em rendimentos quantitativos. Todos os compostos foram avaliados quanto a ação anticâncer em linhagens de leucemia que apesentam o fenótipo MDR lucena e FEPS e em linhagem de leucemia K562 e nas linhagens de câncer de mama MCF-7, que expressa o receptor de estrogênio, e MDA-MD231.Dentre os compostos preparados, o composto 6-metoxi-11a-N-arilsulfonil-tetrahidro-5H-benzo[a]carbazol (97b) foi tão ativo quanto o LQB223 frente a ação antileucêmica nas linhagens K562, lucena e FEPS, entretanto foi mais eficaz que o LQB223 nas linhagens de MCF-7 (IC50 igual 5,93 mais ou menos 3,58 MiM) e MDA-MD231 (IC50 igual 8,29 mais ou menos 2,08 MiM), apresentando um nível baixo de toxicidade para as células sadias. Por outro lado, o composto 6-hidroxi-11a-N-arilsulfonil-tetrahidro-5H-benzo[a]carbazol (98b), apesar de ser muito ativo em linhagens de câncer mama, possui um alto nível de toxicidade para células sadias e composto 7-hidroxi-11a-N-arilsulfonil-tetrahidro-5H-benzo[a]carbazol (98c) foi eficaz em MDA-MD231 (IC50 igual 4,84) porém ainda não foi avaliado quanto a toxicidade em células sadias. Os dados sugerem que os compostos oxigenados 97b e 98c direciona a ação para o câncer de mama. / [en] This work describes the synthesis and characterization of the 11a-N-arylsulfonil-tetrahydro-5H-benzo[a]carbazoles analogous to LQB223, a previously synthesized compound by our research group that has anti-cancer and antileishmanial activity in vitro and antimalarial activity in vitro and in vivo. The key step of the reaction for obtaining the 5-methoxy-11a-N-arylsulfonil-tetrahydro-5H-benzo[a]carbazole (97a), 6-methoxy-11a-N-arylsulfonil-tetrahydro-5H-benzo[a]carbazole (97b) and 7-methoxy-11a-N-arylsulfonil-tetrahydro-5H-benzo[a]carbazole (97c) is the palladium catalyzed Heck aza-arylation reaction in the presence of silver carbonate and acetone from N-tosyl-o-iodoaniline (55b) and substituted dihydronaphthalenes (100a, 100b and 100c), previously prepared from commercial tetralones (84a, 84b and 84c). The compounds 5-hydroxy-11a-N-arylsulfonil-tetrahydro-5H-benzo[a]carbazole (98a), 6-hydroxy-11a-N-arylsulfonil-tetrahydro-5H-benzo[a]carbazole (98b) and 7-hydroxy-11a-N-arylsulfonil-tetrahydro-5H-benzo[a]carbazole (98c) were obtained by deprotection with BBr3 in yields quantitative. All compounds were evaluated for anticancer activity in K562, FEPS and Lucena leukemia cell lines, which exhibit the MDR phenotype, and in breast cancer cell lines MCF-7, which expresses the estrogen receptor, and MDA-MD231.Among the compounds prepared, the compound 97b is as active as LQB223 for the antileukemic activity on K562 lines, and Lucena FEPs, however it is more effective than the LQB223 in MCF-7 (IC50 equal 5.93 plus/minus 3.58 MiM) and MDA-MD231 (IC50 equal 8.29 plus/minus 2.08 uM) breast cancer lines, with low level of toxicity to healthy cells. The compound 98b presents similar activity to 97b but is toxic. The compound 98c is effective in MDA-MD231 (IC50 equal 4,84) but, level of toxicity to healthy cells was not test yet. The reports suggest that the oxygenation pattern in the 3 position directs to the anticancer activity to the breast cancer lines.

Benzo[a]pyrene (BaP), is one of the most potent mutagens and carcinogens known. It requires metabolic activation through cytochrome P450 (CYP)1A1 to yield the ultimate carcinogenic metabolite, benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE). BPDE can bind to DNA and form predominantly covalent (+) trans adducts at the N2 position of guanine causing DNA damage. Rutaecarpine (RTC) is an herbal medicine that has been used to treat several diseases such as headache, hypertension, gastrointestinal disorders, amenorrhea, and anti-inflammation. It has also been reported as a potent inducer of CYP enzymes, including CYP1A1, and CYP1A2. The mechanisms underlying up-regulation of CYP1A1 by RTC is dependent on aryl hydrocarbon receptors. Meanwhile, RTC can inhibit the activity of CYP1A1, CYP1A2 and CYP1B1. To investigate the effect of RTC on the BaP-induced DNA damage, we analyzed the CYP1A1 enzyme activity and DNA damage level in two cell lines, namely mucoepidermoid pulmonary carcinoma cells (H292) and hepatocellular carcinoma cells (Hep3B). The cells either were treated with only 5 μM BaP or 1.25, 2.5, 5 and 10 μM RTC, respectively; or were co-administrated 5 μM BaP and one of the four concentrations of RTC for 24 hours. Ethoxyresorufin-O-deethylase (EROD) assay was used to detect CYP1A1 enzyme activity. The results showed that both BaP and RTC significantly (p<0.05) induced CYP1A1 enzyme activity when administered separately, with RTC induction exhibiting a concentration-dependent manner. Interestingly, co-administration of RTC with BaP, especially at high concentration (10 μM) of RTC, induced less CYP1A1 enzyme activity compared to either only RTC or BaP administration. MuseTM Multi-Color DNA Damage kit was used to evaluate the DNA damage level in cells. The data showed that the DNA damage induced by BaP alone was about 2-fold higher (p&;lt;0.05) than that by concurrent administration of RTC and BaP. In conclusion, our data showed that although both RTC and BaP are inducers of CYP1A1 enzyme, their co-administration will reduce CYP1A1 enzyme activity compared with BaP administration alone. The DNA damage kit results supported that there is a potential protective effect of RTC against BaP-induced DNA damage in both H292 and Hep3B cells.

Le benzo-a-pyrène (BaP) est un hydrocarbure aromatique polycyclique (HAP) cancérogène pour l’homme, qui contamine toutes les sphères de notre environnement. Son métabolite, le BaP-7,8-diol-9,10-époxyde (BPDE) est considéré comme son cancérogène ultime. Le BPDE se lie à l’ADN, formant des adduits qui doivent être réparés et qui seraient responsables des dommages à l’ADN et de la cancérogenèse induite par le BaP. Les adduits BPDE-ADN et les dommages à l’ADN (bris simple-brin [BSB] à l’ADN, aberrations chromosomiques [AC], échanges entre chromatides-sœurs [ÉCS] et micronoyaux [MN]) ont été mesurés dans les lymphocytes humains exposés à de faibles concentrations de BaP, provenant de jeunes volontaires non-fumeurs et en santé. Suite à l’exposition au BaP, le niveau d’adduits BPDE-ADN et la fréquence des AC et des MN augmentent significativement, puis diminuent aux concentrations les plus élevées de BaP testées, suggérant une induction du métabolisme de phase II du BaP. Lors de la mesure des ÉCS, nous obtenons une courbe dose-réponse linéaire, indiquant la production d’un autre type de lésions devant être réparées par le système de réparation par recombinaison homologue. Ces lésions pourraient être des bris à l’ADN ou des bases oxydées (8-OH-dG), ce qui est suggéré par l’analyse des corrélations existant entre nos biomarqueurs. Par ailleurs, la comparaison de la courbe dose-réponse des hommes et des femmes montre que des différences existent entre les sexes. Ainsi, les ÉCS, les AC et les MN sont significativement augmentés chez les hommes à la plus faible concentration de BaP, alors que chez les femmes cette augmentation, quoique présente, est non significative. Des différences interindividuelles sont également observées et sont plus importantes pour les adduits BPDE-ADN, les MN et les AC, alors que pour les ÉCS elles sont minimes. Les analyses statistiques effectuées ont permis d’établir que quatre facteurs (niveau d’exposition au BaP, adduits BPDE-ADN, fréquence des AC et nombre de MN par cellule micronucléée) expliquent jusqu’à 59 % de la variabilité observée dans le test des ÉCS, alors qu’aucun facteur significatif n’a pu être identifié dans le test des AC et des MN. L’analyse du mécanisme de formation de nos biomarqueurs précoces permet de suggérer que les bris à l’ADN et les bases oxydées devraient être classées comme biomarqueurs de dose biologique efficace, au sein des biomarqueurs d’exposition, dans le continuum exposition-maladie du BaP, étant donné qu’ils causent la formation des biomarqueurs de génotoxicité (ÉCS, AC et MN). Par ailleurs, le test des AC et des MN ont permis de confirmer l’action clastogénique du BaP en plus de mettre en évidence des effets aneugènes affectant surtout la ségrégation des chromosomes lors de la division cellulaire. Ces effets aneugènes, reliés à l’étape de progression dans la cancérogenèse, pourraient être particulièrement importants puisque l’exposition au BaP et aux HAP est chronique et dure plusieurs années, voire des décennies. La compréhension des mécanismes régissant la formation des biomarqueurs étudiés dans cette étude, ainsi que des relations existant entre eux, peut être appliquée à de nombreux contaminants connus et émergents de notre environnement et contribuer à en évaluer le mode d’action. / Benzo-a-pyrene (BaP) is a polycyclic aromatic hydrocarbon (PAH) classified as carcinogenic to human, and is present throughout our environment. Metabolic activation of BaP leads to production of BaP-7,8-diol-9,10-epoxide (BPDE), considered as its ultimate carcinogenic metabolite. BPDE can bind to DNA, forming BPDE-DNA adducts at the origin of BaP-induced DNA damage and carcinogenesis. BPDE-DNA adducts and DNA damages (DNA single-strand breaks [SSBs], chromosomal aberrations [CAs], sister chromatid exchanges [SCEs] and micronuclei [MNs]) are measured in human lymphocytes exposed to low BaP concentrations, taken from non-smoking healthy young subjects. Following BaP exposure, BPDE-DNA adduct levels, as well as CA and MN frequencies raise significantly, and then decrease to the higher BaP concentrations tested, suggesting metabolic enzyme saturation or induction of BaP phase II metabolism. As for SCEs test, a linear dose response curve is obtained, suggesting that production of additional DNA lesions requiring homologous recombination repair may occur. These lesions could be DNA breaks or oxidized DNA bases (8-OH-dG), as indicated by correlation analysis performed between our biomarkers. Additionally, when comparing the dose-response curves for men and women separately, some differences show up. Indeed, SCEs, CAs, and MNs are significantly increased in men at the lowest BaP concentration tested, while in women, this increase is present but not significant. Interindividual differences are also present and are more considerable for BPDE-DNA adducts, MNs and CAs, whereas they are very low for SCEs. Statistical analysis showed that four factors (BaP exposure level, BPDE-DNA adducts, CA frequency and number of MN per micronucleated cell) significantly explained up to 59 % of observed variability in SCE test, while no such factors could explain the observed variability in CA and MN test. Following analysis of mechanisms underlying the formation of early biomarkers, we suggest a modification of the Exposure-Disease Continuum of BaP. We propose that DNA breaks and oxidized DNA bases should be classified as biomarkers of biologically effective dose (part of the exposure biomarkers), as their presence are at origin of early biomarkers of genotoxicity (SCEs, CAs and MNs). On the other hand, CA and MN tests confirmed clastogenic properties of BaP, and highlighted aneugenic effects influencing mostly chromosome segregation during cell division. These aneugenic effects, linked to the progression step of carcinogenesis, could be of particular importance given that exposure to BaP and other PAHs (smoking, occupational exposure) are chronic and may last for decades. Understanding the mechanisms playing a role in early biomarkers formation, as well as the relations existing between them, can be largely applied in our environment to many known and emerging contaminants, thus contributing to characterize their mode of action.

Le benzo-a-pyrène (BaP) est un hydrocarbure aromatique polycyclique (HAP) cancérogène pour l’homme, qui contamine toutes les sphères de notre environnement. Son métabolite, le BaP-7,8-diol-9,10-époxyde (BPDE) est considéré comme son cancérogène ultime. Le BPDE se lie à l’ADN, formant des adduits qui doivent être réparés et qui seraient responsables des dommages à l’ADN et de la cancérogenèse induite par le BaP. Les adduits BPDE-ADN et les dommages à l’ADN (bris simple-brin [BSB] à l’ADN, aberrations chromosomiques [AC], échanges entre chromatides-sœurs [ÉCS] et micronoyaux [MN]) ont été mesurés dans les lymphocytes humains exposés à de faibles concentrations de BaP, provenant de jeunes volontaires non-fumeurs et en santé. Suite à l’exposition au BaP, le niveau d’adduits BPDE-ADN et la fréquence des AC et des MN augmentent significativement, puis diminuent aux concentrations les plus élevées de BaP testées, suggérant une induction du métabolisme de phase II du BaP. Lors de la mesure des ÉCS, nous obtenons une courbe dose-réponse linéaire, indiquant la production d’un autre type de lésions devant être réparées par le système de réparation par recombinaison homologue. Ces lésions pourraient être des bris à l’ADN ou des bases oxydées (8-OH-dG), ce qui est suggéré par l’analyse des corrélations existant entre nos biomarqueurs. Par ailleurs, la comparaison de la courbe dose-réponse des hommes et des femmes montre que des différences existent entre les sexes. Ainsi, les ÉCS, les AC et les MN sont significativement augmentés chez les hommes à la plus faible concentration de BaP, alors que chez les femmes cette augmentation, quoique présente, est non significative. Des différences interindividuelles sont également observées et sont plus importantes pour les adduits BPDE-ADN, les MN et les AC, alors que pour les ÉCS elles sont minimes. Les analyses statistiques effectuées ont permis d’établir que quatre facteurs (niveau d’exposition au BaP, adduits BPDE-ADN, fréquence des AC et nombre de MN par cellule micronucléée) expliquent jusqu’à 59 % de la variabilité observée dans le test des ÉCS, alors qu’aucun facteur significatif n’a pu être identifié dans le test des AC et des MN. L’analyse du mécanisme de formation de nos biomarqueurs précoces permet de suggérer que les bris à l’ADN et les bases oxydées devraient être classées comme biomarqueurs de dose biologique efficace, au sein des biomarqueurs d’exposition, dans le continuum exposition-maladie du BaP, étant donné qu’ils causent la formation des biomarqueurs de génotoxicité (ÉCS, AC et MN). Par ailleurs, le test des AC et des MN ont permis de confirmer l’action clastogénique du BaP en plus de mettre en évidence des effets aneugènes affectant surtout la ségrégation des chromosomes lors de la division cellulaire. Ces effets aneugènes, reliés à l’étape de progression dans la cancérogenèse, pourraient être particulièrement importants puisque l’exposition au BaP et aux HAP est chronique et dure plusieurs années, voire des décennies. La compréhension des mécanismes régissant la formation des biomarqueurs étudiés dans cette étude, ainsi que des relations existant entre eux, peut être appliquée à de nombreux contaminants connus et émergents de notre environnement et contribuer à en évaluer le mode d’action. / Benzo-a-pyrene (BaP) is a polycyclic aromatic hydrocarbon (PAH) classified as carcinogenic to human, and is present throughout our environment. Metabolic activation of BaP leads to production of BaP-7,8-diol-9,10-epoxide (BPDE), considered as its ultimate carcinogenic metabolite. BPDE can bind to DNA, forming BPDE-DNA adducts at the origin of BaP-induced DNA damage and carcinogenesis. BPDE-DNA adducts and DNA damages (DNA single-strand breaks [SSBs], chromosomal aberrations [CAs], sister chromatid exchanges [SCEs] and micronuclei [MNs]) are measured in human lymphocytes exposed to low BaP concentrations, taken from non-smoking healthy young subjects. Following BaP exposure, BPDE-DNA adduct levels, as well as CA and MN frequencies raise significantly, and then decrease to the higher BaP concentrations tested, suggesting metabolic enzyme saturation or induction of BaP phase II metabolism. As for SCEs test, a linear dose response curve is obtained, suggesting that production of additional DNA lesions requiring homologous recombination repair may occur. These lesions could be DNA breaks or oxidized DNA bases (8-OH-dG), as indicated by correlation analysis performed between our biomarkers. Additionally, when comparing the dose-response curves for men and women separately, some differences show up. Indeed, SCEs, CAs, and MNs are significantly increased in men at the lowest BaP concentration tested, while in women, this increase is present but not significant. Interindividual differences are also present and are more considerable for BPDE-DNA adducts, MNs and CAs, whereas they are very low for SCEs. Statistical analysis showed that four factors (BaP exposure level, BPDE-DNA adducts, CA frequency and number of MN per micronucleated cell) significantly explained up to 59 % of observed variability in SCE test, while no such factors could explain the observed variability in CA and MN test. Following analysis of mechanisms underlying the formation of early biomarkers, we suggest a modification of the Exposure-Disease Continuum of BaP. We propose that DNA breaks and oxidized DNA bases should be classified as biomarkers of biologically effective dose (part of the exposure biomarkers), as their presence are at origin of early biomarkers of genotoxicity (SCEs, CAs and MNs). On the other hand, CA and MN tests confirmed clastogenic properties of BaP, and highlighted aneugenic effects influencing mostly chromosome segregation during cell division. These aneugenic effects, linked to the progression step of carcinogenesis, could be of particular importance given that exposure to BaP and other PAHs (smoking, occupational exposure) are chronic and may last for decades. Understanding the mechanisms playing a role in early biomarkers formation, as well as the relations existing between them, can be largely applied in our environment to many known and emerging contaminants, thus contributing to characterize their mode of action.

Les travaux réalisés au cours de cette thèse ont consisté en l’élaboration d’édifices multi-chromophoriques pour des applications en cellules solaires organiques. La conception de ces nouveaux matériaux a été guidée par trois paramètres : (i) l’augmentation de la planéité pour une meilleure organisation intermoléculaire ; (ii) la modulation de la fenêtre spectrale d’absorption pour capter un maximum de photons ; (iii) l’enrichissement électronique des matériaux pour faciliter la séparation des charges. Notre choix s’est porté sur les hydrocarbures aromatiques polycycliques, de part leurs propriétés structurantes bien connues. La synthèse du 2-bromodibenzo[g,p]chrysène a été réalisée par des réactions de type Scholl intramoléculaires, puis sa dérivatisation a permis de synthétiser des matériaux correspondants. La mono-fonctionnalisation d’un synthon benzo[1,2-b:3,4-b’:5,6-b’’]trithiophène a également été effectuée. Des BODIPYs dithiényles α-fusionnés ont ensuite été synthétisés selon une procédure originale de couplages oxydants intramoléculaires, permettant d’obtenir des composés plans, fonctionnalisés et fonctionnalisables, tout en contournant la chimie contraignante du pyrrole. L’obtention de dyades et triades à base de DPPs, de BODIPY et de triphénylamines ont permis d’obtenir des composés panchromatiques et d’étudier les phénomènes d’extinction de la fluorescence par spectroscopies statiques et ultrarapides. Un dernier projet a porté sur des édifices de type D-A-D à base de BODIPYs et amines aromatiques tertiaires. / The projects developed in this thesis consisted in the elaboration of multi-chromophoric scaffolds towards applications in bulk heterojunction organic solar cells. The design of the materials was guided by three main parameters: (i) the increase of the planarity to observe a better intermolecular organization; (ii) the broadening of the spectral absorption window in order to maximize the number of absorbed photons; (iii) the increase of the electronic density in order to facilitate the charge separation. First, the structural properties of mono-functionalized polycyclic aromatic hydrocarbons (PAH) were investigated with the synthesis of 2-bromodibenzo[g,p]chrysene by Scholl type reactions, followed by its functionalization and the development of related materials. Then we also focused on another PAH: benzo[1,2-b:3,4-b’:5,6-b’’]trithiophene and its subsequent functionalization. α-Fused dithienyl BODIPYs were then built according to an original procedure based on intramolecular oxidative coupling reactions. Substituted and functionalizable planar compounds were obtained bypassing the instability of the pyrrole ring chemistry. Subsequently, the elaboration of dyads and triads based on DPPs, BODIPY and triphenylamines led to the examination of the fluorescence quenching process by static and ultrafast spectroscopies. A last project consisted in the study and applications of D-A-D edifices based on BODIPYs and ternary aromatic amines.

L’exposition prénatale à différents agents toxiques est généralement étudiée en considérant le placenta comme une barrière entre la mère et le fœtus ; nous le considérons en tant qu’organe cible des agents toxiques. Pour ce faire, nous avons sélectionné un modèle cellulaire de trophoblastes adapté aux études toxicologiques. En clinique, des pathologies de la grossesse sont associées à des modifications de la sécrétion de l’hormone placentaire lactogène hPL et de l’hormone gonadotrope chorionique hCG. Nos travaux in vitro ont permis de faire le lien entre une exposition à des micropolluants (le mono(2-ethylhexyl) phtalate, un perturbateur endocrinien, et le benzo(a)pyrene, un carcinogène) et ces observations cliniques. Les biomarqueurs de sécrétion hormonale (hPL et hCG hyperglycosylée) et de dégénérescence (activation du purinorécepteur P2X7) que nous avons identifiés permettent de détecter l’exposition et le risque suite à une exposition à des polluants. / Prenatal exposure to pollutants is commonly evaluated using placenta as a barrier between mother and fetus. Here, we consider placenta as a target organ for toxic agents. To achieve this, we selected a trophoblastic cell model, which is adapted to toxicological studies. In clinical studies, pregnancy pathologies are associated to changes in human placental lactogen (hPL) and human chorionic gonadotropin (hCG) secretions. Our in vitro work links exposure to micropollutants (mono(2-ethylhexyl)phthalate, an endocrine disruptor, and benzo(a)pyrene, a carcinogen) and clinical observations. We identified biomarkers of hormonal secretion (hPL and hyperglycosylated hCG) and degeneration (P2X7 receptor activation), which enable the evaluation of exposure and risk attached to exposure to pollutants.

Orientador: Márcia Cristina Bisinoti / Coorientador: Eduardo Alves de Almeida / Banca: Gisela de Aragão Umbuzeiro / Banca: Gustavo Orlando Bonilla Rodriguez / Resumo: As substâncias húmicas aquáticas possuem grande importância ambiental por terem a capacidade de complexar íons metálicos presentes no ambiente influenciando a disponibilidade dos mesmos, tornando-os geralmente menos tóxicos para a biota. As Metalotioneínas (MT) apresentam a característica de regular metais nos organismos aquáticos, sendo induzidas na presença de metais e outros compostos e, portanto utilizadas como biomarcador ambiental. O benzo[a]pireno é oriundo de fontes biogênicas, pirogênicas e petrogênicas e seu efeito na indução de MT em tilápias é desconhecido. Neste contexto, foi avaliada a indução de MT em peixes expostos a metais tóxicos individualmente e na mistura, na ausência e presença de substâncias húmicas aquáticas (SHA), bem como na presença de benzo[a]pireno. Neste trabalho foram feitas a otimização e padronização do método para quantificação de metalotioneínas em fígado e brânquias de peixes empregando a técnica de Cromatografia Líquida de Alta Eficiência com Detector de Fluorescência (HPLC-FD). Também foi avaliada a influência do tempo de duração dos ensaios na indução de metalotioneínas em peixes expostos a metais de interesse ambiental durante 3, 7 e 14 dias. Tilápias do Nilo (Oreochromis niloticus) foram alocadas em aquários individuais e submetidas à exposição a concentrações regulamentadas pela resolução Conama 357/2005 para rios Classe 2, Classe 3 e 5 vezes Classe 3 de Cádmio, Cobre, Chumbo, Ferro e Benzo[a]pireno isoladamente, bem como a mistura dos metais na presença e ausência de SHA. A concentração de metal "livre" foi acompanhada durante os experimentos de exposição empregando o Sistema de Ultrafiltração com Fluxo Tangencial. Em todas as amostras de água dos experimentos de exposição e no tecido muscular dos peixes utilizados foram realizadas a... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: The aquatic humic substances have great environmental importance to have the ability to complex metal ions present in the environment influencing their availability, making them generally less toxic to biota. Metallothioneins (MT) have the characteristic of regular metals on aquatic organisms being induced in the presence of metals and other compounds and therefore used as a biomarker environment. Benzo[a]pyrene is formed by biogenic sources, pyrogenic and petrogenic and its effect on the induction of MT in tilapia is unknown. In this context, we evaluated the induction of MT in fish exposed to toxic metals (Fe, Cu, Cd and Pb) individually and all these metal combined in the absence and presence of humic substances (SHA), as well as in the presence of benzo[a]pyrene. In this work we made the optimization and standardization of the method for quantification of metallothionein in liver and gills of fish employing the technique of High Performance Liquid Chromatography with Fluorescence Detector (HPLC-FD). We also evaluated the influence of the duration of the tests in the induction of metallothionein in fishes exposed to metals of environmental interest for 3, 7 and 14 days. Nile tilapia (Oreochromis niloticus) were placed in individual aquaria and subjected to exposure to concentrations regulated by CONAMA 357/2005 Resolution for rivers Class 2, Class 3 and 3 fold the concentrations to Class 3 for Cadmium, Copper, Lead, Iron and Benzo[a]pyrene separately, and all these metals combined in the presence and absence of SHA. The concentration of free metal was monitored during the exposure experiments using a Tangential Flow Ultrafiltration System (TFUS). In all samples of water exposure experiments and in the muscle tissue of fishes were quantified total metal employing a Graphite Furnace Atomic Absorption Spectrophotometer... (Complete abstract click electronic access below) / Mestre