The previously described 2-aryl-4-chloro-3-iodoquinolines were prepared following literature procedure and in turn converted to the corresponding hitherto unknown 2-aryl-3-iodo-4-(phenylamino)quinoline derivatives using aniline in refluxing ethanol. These 2-aryl-3-iodo-4-(phenylamino)quinolines were reacted with allybromide in ethanol at room temperature to afford 4-(N,N-allylphenylamino)-2-aryl-3-iodoquinoline derivatives. The 2-aryl-3-iodo-4-(phenylamino)quinoline and 4-(N,N-allylphenylamino)-2-aryl-3-iodoquinoline derivatives were subjected to metal-catalysed carbon-carbon bond formations. Palladium(0)-copper iodide catalysed Sonogashira cross-coupling of 2-aryl-3-iodo-4-(phenylamino)quinoline with terminal alkynes afforded series of 1,2,4-trisubstituted 1H-pyrrolo[3,2-c]quinolines in a single step operation. On the other hand, the 4-(N,N-allylphenylamino)-2-aryl-3-iodoquinoline derivatives were found to undergo palladium-catalysed intramolecular Heck reaction to yield the corresponding 1,3,4-trisubstituted 1H-pyrrolo[3,2-c]quinolines. All new compounds were characterized by using a combination of NMR (1H and 13C), IR, mass spectroscopic techniques as well as elemental analysis. / Chemistry / MSc. (Chemistry)

The previously described 2-aryl-4-chloro-3-iodoquinolines were prepared following literature procedure and in turn converted to the corresponding hitherto unknown 2-aryl-3-iodo-4-(phenylamino)quinoline derivatives using aniline in refluxing ethanol. These 2-aryl-3-iodo-4-(phenylamino)quinolines were reacted with allybromide in ethanol at room temperature to afford 4-(N,N-allylphenylamino)-2-aryl-3-iodoquinoline derivatives. The 2-aryl-3-iodo-4-(phenylamino)quinoline and 4-(N,N-allylphenylamino)-2-aryl-3-iodoquinoline derivatives were subjected to metal-catalysed carbon-carbon bond formations. Palladium(0)-copper iodide catalysed Sonogashira cross-coupling of 2-aryl-3-iodo-4-(phenylamino)quinoline with terminal alkynes afforded series of 1,2,4-trisubstituted 1H-pyrrolo[3,2-c]quinolines in a single step operation. On the other hand, the 4-(N,N-allylphenylamino)-2-aryl-3-iodoquinoline derivatives were found to undergo palladium-catalysed intramolecular Heck reaction to yield the corresponding 1,3,4-trisubstituted 1H-pyrrolo[3,2-c]quinolines. All new compounds were characterized by using a combination of NMR (1H and 13C), IR, mass spectroscopic techniques as well as elemental analysis. / Chemistry / MSc. (Chemistry)

Les récepteurs de l'adrénomédulline sont fortement exprimés dans les capillaires alvéolaires humains et fournissent une cible moléculaire pour l'imagerie de la circulation et de l'embolie pulmonaire. Au cours des années précédentes, le dérivé DFH12 marqué au 99mTc (PulmoBind) a démontré son potentiel en tant qu'agent d'imagerie SPECT de l'hypertension pulmonaire dans des études cliniques de phase I et II. L’objectif principal de mon projet est de développer le nouvel analogue DFH17 pour l’imagerie TEP des récepteurs de l'adrénomédulline via la méthode de l’Al18F. Pour atteindre cet objectif, un système d’élution semi-automatique a été conçu pour produire l’Al18F concentré directement dans le vial de réaction. En utilisant des tests de complexation avec le chélateur NOTA, des conditions optimales ont été trouvées pour le radiomarquage du DFH17 avec l’Al18F. La combinaison du rapport Al/DFH17 1:3 dans l'éthanol 50% a permis de produire le [18F]AlF-DFH17 avec des puretés radiochimiques et chimiques élevées. Les études TEP avec le [18F]AlF-DFH17 ont démontré un rapport élevé poumon-bruit de fond ainsi qu’une grande stabilité in vivo chez le rat, le chien et le primate. Des captations différenciées dans les poumons des trois espèces ont aussi été détectées par imagerie TEP et leurs différences ont été associées à des variations de la composant RAMP2. Compte tenu de l’importante captation pulmonaire, de la stabilité in vivo et de la dosimétrie favorable, le nouveau dérivé [18F]AlF-DFH17 est un excellent candidat potentiel en tant que traceur TEP des récepteurs adrénomédulline humains. L’expression des récepteurs AT1 de l’angiotensine II est altérée dans plusieurs maladies cardiovasculaires et rénales, telles la défaillance cardiaque, rénale et l’hypertension ainsi que dans certains cancers. Auparavant, le dérivé [11C]méthyl-Candesartan a démontré un potentiel comme agent d'imagerie TEP de l'AT1R rénal mais une proportion élevée du signal TEP correspondait à une liaison non-spécifique d'un radiométabolite hydrophobe. Dans ce travail, l’objectif principal est de développer le nouveau dérivé [18F]fluorobenzyl-Candesartan en utilisant le 4[18F]fluoroiodobenzène ([18F]FIB) avec un profil métabolique et de biodistribution potentiellement meilleurs. Pour atteindre cet objectif, des paramètres réactionnels de fluorination tels que le solvant, la quantité de précurseur, le catalyseur et la température ont été optimisés permettant la radiosynthèse du [18F]FIB avec des rendements et pureté élevés. Ensuite, le couplage du [18F]FIB au dérivé alcyne-trityl-Candesartan a été évalué en utilisant la réaction de Sonogashira suivie d'une détritylation acide. Suite à l’étude de plusieurs conditions de couplage, le rendement de radioconversion a été légèrement augmenté en utilisant le catalyseur Pd(PPh3)4/CuI et K2CO3 comme base. Les meilleures conditions de fluorination et de couplage ont été automatisées pour le module de synthèse Synthra® RNPlus Research. La production du [18F]FB-Candesartan été atteinte avec de faibles rendements et activités molaires en raison de la formation d’impuretés ayant des structures et temps de rétention par HPLC similaires à ceux de notre traceur. Des études supplémentaires afin d'améliorer le rendement, la purification par HPLC et l'activité molaire se sont avérées infructueuses pour l’instant. D’autres expériences devront être effectuées à cette fin. En conclusion, l'utilisation de la réaction de Sonogashira pour produire le [18F]FB-Candersartan avec des rendements et des activités molaires élevées s'est avérée difficile. / Adrenomedullin receptors are highly expressed in human alveolar capillaries and provide a molecular target for imaging the integrity of pulmonary microcirculation. In previous years, the 99mTc-labeled DFH12 derivative (PulmoBind) demonstrated its potential as a SPECT imaging agent of pulmonary hypertension in phase I and II clinical trials. In this work, we aimed to develop a NOTA-derivatized adrenomedullin analog (DFH17), radiolabeled with aluminum fluoride ([18F]AlF), for PET imaging of pulmonary microcirculation. To achieve this goal, highly concentrated [18F](AlF)2+ was produced from purified 18F using a semi-automatic system. Using inexpensive complexation assays with NOTA, optimal conditions at each step of the process were determined facilitating the radiolabeling optimization of DFH17. Furthermore, combining the Al-to-DFH17 1:3 ratio in 50% ethanol as co-solvent, allowed [18F]AlF-DFH17 production in high radiochemical and chemical purities. PET/CT and biodistribution demonstrated high [18F]AlF-DFH17 lung-to-background ratio and in vivo stability in rats, dog and primate. Contrasted inter-species uptake in the lungs associated with variations of RAMP2 were also detected by PET imaging. Considering high lung uptake, in vivo stability and favorable dosimetry observed in the monkey, the novel AM derivative [18F]AlF-DFH17 exhibits an excellent potential as a PET tracer of human AM receptors. Alterations of the expression levels of AT1R has been linked to cardiac and renal diseases, such as cardiac and renal failures, hypertension and some type of cancers. Previously, [11C]methyl-Candesartan displayed potential for PET imaging of AT1Rs, but a high proportion of PET signal corresponded to non-specific binding from a 11C-labeled hydrophobic metabolite. In this work, the main objective was to develop the novel derivative [18F]fluorobenzyl-Candesartan, with potentially better metabolic profile and biodistribution, using 4-[18F]fluoroidobenzene ([18F]FIB) as prosthetic group. To pursue this goal, radiofluorination parameters such as solvent, amount of precursor, type of catalyst and temperature were optimized to reliably synthesize [18F]FIB in high yield and purity. Coupling of [18F]FIB to the alkyne-trityl-Candesartan was evaluated using the Sonogashira cross-coupling reaction followed by an acid deprotection. After studying several Pd-cross-coupling conditions, the radioconversion yield was slightly increased by means of a Pd(PPh3)4/CuI catalyst and K2CO3 as base in DMF. Therefore, the best reaction conditions for [18F]FIB fluorination and its coupling to alkyne-Candesartan followed by an acid hydrolysis, was fully automated for Synthra® RNPlus Research synthesis module. In general, the synthesis of [18F]FB-Candesartan was achieved in low yields and molar activities due to the formation of structurally-close by-product(s) with similar HPLC retention time. Additional studies to further improve the yield, HPLC purification and molar activity (MA) have been unsuccessful. Other experiments will need to be performed to this end. In conclusion, the use of Sonogashira cross-coupling reaction to produce [18F]FB-Candesartan in high yields and molar activities was found to be challenging.

There are two general ways to introduce functionalities into a polymeric structure: functionalization of the monomeric units before polymerization and postfunctionalization of the preformed polymer. Building libraries of polymers with different functionalities can be completed with significantly less effort by the second method, as each postfunctionalization of a single batch of polymeric backbone can involve as little as one synthetic step. One method of building a polymeric backbone for postfunctionalization involves the synthesis of hyperbranched conjugated polymers (HCPs) from AB2 monomeric units. A polymer formed from n AB2 monomeric units should contain n reactive B groups, which act as sites of functionalization. Utilizing this principle, two different hyperbranched poly(phenylene vinylene-phenylene ethynylene) scaffolds were synthesized and studied in both their inherent properties and functionalization. The first HCP synthesized was compared against a monomeric cruciform model and a linear polymer with a similar structure. The hyperbranched polymer has red-shifted absorption and emission in comparison to the cruciform model and linear polymer. The HCP quenches paraquat more efficiently than the linear polymer by a factor of about two, suggesting a greater rate of energy transfer. The functionalization of HCPs was studied; iodine groups decorating the HCPs were replaced with terminal alkynes by Pd-catalyzed coupling, providing a library of 24 differently functionalized HCPs. Elemental analyses of the postfunctionalized polymers show nearly complete substitution of the iodine groups. The postfunctionalized polymers show increased fluorescence compared to the original iodine decorated polymers, due to the loss of the heavy atom effect inducing iodine groups. The emissions of the postfunctionalized polymers in solution show a strong dependence on the groups attached to the conjugated structures, with emission maxima ranging from 505 nm to 602 nm; quantum yields range from 0.7% to 25%. Solid-state emission studies show stronger and more red-shifted spectra compared to emissions observed in solution.

Après quelques rappels bibliographiques (biologiques et chimiques) sur les rétinoïdes et sur l'angiogenèse (chapitre I), ce travail décrit, dans un premier temps, la synthèse du composé B2, un analogue du DHA (Acide DocosaHexaènoïque) (chapitre II). Du fait de l'activité rétinoïdienne et anti-angiogénique du DHA, de tels analogues (plus stables que le DHA lui-même) pourraient être intéressants dans le domaine de la lutte contre le cancer. Le chapitre III est consacré à l'étude de plusieurs nouvelles réactions multicomposants palladocatalysées permettant de générer, en une seule étape, deux ou trois liaisons Carbone-Carbone de manière totalement régio- et stéréo-sélective à partir des produits souvent commerciaux que sont les halogénures benzyliques et les alynes terminaux. Ces réactions aboutissent à des produits dont le squelette carboné est de type ényne. Le chapitre IV présente les résultats obtenus pour certains de ces énynes dans quatre tests biologiques. Les tests effectués sont : l'affinité pour les récepteurs des oestrogènes, la modulation de l'activité luciférase dans les cellules MELN, l'activité antileishmannienne et la cytotoxicité. Certains produits présentent des activités encourageantes.

A number of novel isoindoline nitroxides have been synthesised using a variety of synthetic techniques. Several carbon-carbon bond forming methodologies, including the first examples of Heck and Sonogashira coupling applied to the isoindoline nitroxide class, were utilised to give novel robust aromatic frameworks. Palladium-catalysed Heck coupling of brominated nitroxides and ester-substituted olefins generates novel nitroxides possessing extended conjugation. Hydrolysis of the nitroxide esters gave the corresponding carboxylic acids, which showed enhanced water solubility. Sonogashira coupling of an iodo-isoindoline nitroxide gave several novel alkynesubstituted nitroxides in high yield. Subsequent coupling of a deprotected ethynyl nitroxide with aromatic iodides gave acetylene-linked nitroxides and an acetylene linked nitroxide dimer. A butadiyne linked dinitroxide was successfully synthesised via Eglinton oxidative coupling of two ethynyl nitroxides. The synthesis of a novel water-soluble dicarboxy nitroxide was achieved by base hydrolysis of a dinitrile. Functional group interconversion furnished anhydride and imide substituted nitroxides from the diacid. Subjecting the imide to the Hofmann rearrangement gave an unexpected brominated amino-carboxy nitroxide. The dicarboxy nitroxide and the brominated amino-carboxy nitroxide were both shown to have a protective effect on Ataxia-Telangiectasia cells, indicating a possible role as antioxidants in the treatment of this disease. A fluorescein nitroxide was successfully synthesised through the condensation of the anhydride substituted nitroxide and resorcinol. After limited success using a variety of other techniques, Buchwald-Hartwig amination was able to furnish a rhodamine nitroxide, via a triflate-fluorescein nitroxide. The extended aromatic nitroxides possess suppressed fluorescence and we have described these systems as profluorescent. The profluorescent nitroxides were found to have significantly lower quantum yields than the non-radical analogues and displayed a substantial increase in fluorescence intensity upon radical trapping, making them useful probes for free radical reactions.

Le travail présenté dans ce manuscrit est consacré à la synthèse et à l'évaluation pharmacologique de quelques δ-valérolactones. Une première séquence réactionnelle a permis d'accéder aux analogues synthétiques des kavalactones avec de bons rendements en développant notamment des réactions de couplage par activation aux micro-ondes. Diverses modulations ont ensuite été réalisées par des couplages de type Heck, Suzuki et Sonogashira. Parallèlement une deuxième séquence réactionnelle a été mise au point au départ d'alcools allyliques en utilisant une réaction tandem isomérisation-aldolisation avec divers aldéhydes pour entrer différents substituants en position 3, 5 et 6 du cycle lactonique. Notre intérêt s'est aussi porté sur la chimie combinatoire, pour préparer des petites chimiothèques de δ-valérolactones. Nous avons utilisé le couplage de Heck suivi d'une aldolisation/lactonisation à partir d'un support fluoré. Les avantages de ce support fluoré ont permis de simplifier les étapes de purification. La séquence réactionnelle choisie n'a cependant été validée qu'en solution. Concernant l'aspect biologique, l'évaluation de l’activité cytotoxique in vitro de 34 δ-valérolactones seul un composé présente une cytotoxicité modérée sur les lignées cancéreuses B16 et A375M (CI50 < 10μM). Les effets inhibiteurs in vitro sur le sang total permettent de souligner l'intérêt thérapeutique éventuel de cette famille de molécules dans le traitement de l’inflammation. Enfin le test à l'acide acétique in vivo pour évaluer l’activité analgésique de quelques composés a montré une forte inhibition pour l'hétérocycle 131 (69,4%). / A pesquisa e desenvolvimento de medicamentos é um processo complexo e longo que se inicia com a pesquisa básica de um novo composto bioativo em modelos experimentais in vitro e pré-clinicos. Neste trabalho descreve-se a síntese de d-valerolactonas e avaliação biológica. Uma primeira rota sintética permitiu obter análogos das kavalactones com bons rendimentos através de reações de aldolisação e acoplamentos do tipo Heck e Suzuki com o auxílio do forno de microondas. Paralelamente outra estratégia sintética foi realizada através de modulações no anel aromático ligado ao núcleo lactônico, com reações do tipo Heck, Suzuki e Sonogashira, com excelentes rendimentos. Outra sequência reacional foi desenvolvida a partir de álcoois alílicos utilizando a reação conhecida como tandem isomerisação/aldolisação com diversos aldeídos obtendo lactonas substituídas em posição 3, 5 e 6 do ciclo lactônico. Objetivou-se também neste estudo, a partir do princípio da química combinatória, preparar uma pequena quimioteca de d-valerolactones. Para tanto se desenvolveu uma seqüência reacional a partir do suporte fluorado em função das vantagens deste método em relação à Síntese Orgânica em Fase Sólida (SOFS), esta rota sintética foi acompanhada em solução. No que se refere ao aspecto biológico, foram avaliados 35 compostos sintetizados sobre a atividade citotóxica. No entanto apenas um composto apresentou uma leve atividade (CI50 < 10μM) sobre as linhagens celulares testadas (A-375M e B16). Em relação à avaliação antiinflamatória in vitro observou-se atividade interessante sobre o composto 61 na inbição do TNFa no sangue total. A avaliação do potencial antinociceptivo dos 10 compostos testados (5, 129-137) demonstrou um perfil promissor, sendo que o composto 131 apresentou uma inibição mais expressiva (69,4%) em relação aos outros compostos. Os resultados químicos e biológicos promissores aqui demonstrados indicam a viabilidade em utilizar essa classe química estudada para encontrar substâncias mais ativas as quais podem representar uma nova entidade terapêutica. / This work describes the synthesis and the pharmacological evaluation of various δ-valerolactone derivatives. We first prepared some kavalactone analogues in good yields using microwave-promoted palladium-catalyzed coupling reactions. Several modulations have been done using Heck, Suzuki and Sonogashira reactions. At the same time, we developed a synthetic pathway starting from allylic alcohols and involving a tandem isomerisation-aldolisation reaction with various aldehydes in order to introduce diversity at the C-3, C-5 and C-6 positions of the valerolactone. We focused on the combinatorial chemistry in order to obtain a library of δ-valerolactone derivatives. The Heck coupling was followed by an isomerisation-aldolisation reaction using a fluorated support. The purification steps were much easier using fluorated supports. However, so far this synthetic pathway is only valid in solution. We then tested 34 d-valerolactones analogues to determine their in vitro cytotoxic activity and discovered that one d-valerolactone was slightly active (CI50 < 10μM) on two cell lines (A-375M and B16). Moreover, the in vitro inhibitor effects on whole blood sample showed that δ-valerolactone derivatives might have an interesting antiinflammatory activity. Finally, the in vivo acetic acid test evaluating the analgesic activity of several compounds displayed a high inhibition for the heterocyclic 131 (69.4%).

Le travail présenté dans ce manuscrit est consacré à la synthèse et à l'évaluation pharmacologique de quelques δ-valérolactones. Une première séquence réactionnelle a permis d'accéder aux analogues synthétiques des kavalactones avec de bons rendements en développant notamment des réactions de couplage par activation aux micro-ondes. Diverses modulations ont ensuite été réalisées par des couplages de type Heck, Suzuki et Sonogashira. Parallèlement une deuxième séquence réactionnelle a été mise au point au départ d'alcools allyliques en utilisant une réaction tandem isomérisation-aldolisation avec divers aldéhydes pour entrer différents substituants en position 3, 5 et 6 du cycle lactonique. Notre intérêt s'est aussi porté sur la chimie combinatoire, pour préparer des petites chimiothèques de δ-valérolactones. Nous avons utilisé le couplage de Heck suivi d'une aldolisation/lactonisation à partir d'un support fluoré. Les avantages de ce support fluoré ont permis de simplifier les étapes de purification. La séquence réactionnelle choisie n'a cependant été validée qu'en solution. Concernant l'aspect biologique, l'évaluation de l’activité cytotoxique in vitro de 34 δ-valérolactones seul un composé présente une cytotoxicité modérée sur les lignées cancéreuses B16 et A375M (CI50 < 10μM). Les effets inhibiteurs in vitro sur le sang total permettent de souligner l'intérêt thérapeutique éventuel de cette famille de molécules dans le traitement de l’inflammation. Enfin le test à l'acide acétique in vivo pour évaluer l’activité analgésique de quelques composés a montré une forte inhibition pour l'hétérocycle 131 (69,4%). / A pesquisa e desenvolvimento de medicamentos é um processo complexo e longo que se inicia com a pesquisa básica de um novo composto bioativo em modelos experimentais in vitro e pré-clinicos. Neste trabalho descreve-se a síntese de d-valerolactonas e avaliação biológica. Uma primeira rota sintética permitiu obter análogos das kavalactones com bons rendimentos através de reações de aldolisação e acoplamentos do tipo Heck e Suzuki com o auxílio do forno de microondas. Paralelamente outra estratégia sintética foi realizada através de modulações no anel aromático ligado ao núcleo lactônico, com reações do tipo Heck, Suzuki e Sonogashira, com excelentes rendimentos. Outra sequência reacional foi desenvolvida a partir de álcoois alílicos utilizando a reação conhecida como tandem isomerisação/aldolisação com diversos aldeídos obtendo lactonas substituídas em posição 3, 5 e 6 do ciclo lactônico. Objetivou-se também neste estudo, a partir do princípio da química combinatória, preparar uma pequena quimioteca de d-valerolactones. Para tanto se desenvolveu uma seqüência reacional a partir do suporte fluorado em função das vantagens deste método em relação à Síntese Orgânica em Fase Sólida (SOFS), esta rota sintética foi acompanhada em solução. No que se refere ao aspecto biológico, foram avaliados 35 compostos sintetizados sobre a atividade citotóxica. No entanto apenas um composto apresentou uma leve atividade (CI50 < 10μM) sobre as linhagens celulares testadas (A-375M e B16). Em relação à avaliação antiinflamatória in vitro observou-se atividade interessante sobre o composto 61 na inbição do TNFa no sangue total. A avaliação do potencial antinociceptivo dos 10 compostos testados (5, 129-137) demonstrou um perfil promissor, sendo que o composto 131 apresentou uma inibição mais expressiva (69,4%) em relação aos outros compostos. Os resultados químicos e biológicos promissores aqui demonstrados indicam a viabilidade em utilizar essa classe química estudada para encontrar substâncias mais ativas as quais podem representar uma nova entidade terapêutica. / This work describes the synthesis and the pharmacological evaluation of various δ-valerolactone derivatives. We first prepared some kavalactone analogues in good yields using microwave-promoted palladium-catalyzed coupling reactions. Several modulations have been done using Heck, Suzuki and Sonogashira reactions. At the same time, we developed a synthetic pathway starting from allylic alcohols and involving a tandem isomerisation-aldolisation reaction with various aldehydes in order to introduce diversity at the C-3, C-5 and C-6 positions of the valerolactone. We focused on the combinatorial chemistry in order to obtain a library of δ-valerolactone derivatives. The Heck coupling was followed by an isomerisation-aldolisation reaction using a fluorated support. The purification steps were much easier using fluorated supports. However, so far this synthetic pathway is only valid in solution. We then tested 34 d-valerolactones analogues to determine their in vitro cytotoxic activity and discovered that one d-valerolactone was slightly active (CI50 < 10μM) on two cell lines (A-375M and B16). Moreover, the in vitro inhibitor effects on whole blood sample showed that δ-valerolactone derivatives might have an interesting antiinflammatory activity. Finally, the in vivo acetic acid test evaluating the analgesic activity of several compounds displayed a high inhibition for the heterocyclic 131 (69.4%).

Le travail présenté dans ce manuscrit est consacré à la synthèse et à l'évaluation pharmacologique de quelques δ-valérolactones. Une première séquence réactionnelle a permis d'accéder aux analogues synthétiques des kavalactones avec de bons rendements en développant notamment des réactions de couplage par activation aux micro-ondes. Diverses modulations ont ensuite été réalisées par des couplages de type Heck, Suzuki et Sonogashira. Parallèlement une deuxième séquence réactionnelle a été mise au point au départ d'alcools allyliques en utilisant une réaction tandem isomérisation-aldolisation avec divers aldéhydes pour entrer différents substituants en position 3, 5 et 6 du cycle lactonique. Notre intérêt s'est aussi porté sur la chimie combinatoire, pour préparer des petites chimiothèques de δ-valérolactones. Nous avons utilisé le couplage de Heck suivi d'une aldolisation/lactonisation à partir d'un support fluoré. Les avantages de ce support fluoré ont permis de simplifier les étapes de purification. La séquence réactionnelle choisie n'a cependant été validée qu'en solution. Concernant l'aspect biologique, l'évaluation de l’activité cytotoxique in vitro de 34 δ-valérolactones seul un composé présente une cytotoxicité modérée sur les lignées cancéreuses B16 et A375M (CI50 < 10μM). Les effets inhibiteurs in vitro sur le sang total permettent de souligner l'intérêt thérapeutique éventuel de cette famille de molécules dans le traitement de l’inflammation. Enfin le test à l'acide acétique in vivo pour évaluer l’activité analgésique de quelques composés a montré une forte inhibition pour l'hétérocycle 131 (69,4%). / A pesquisa e desenvolvimento de medicamentos é um processo complexo e longo que se inicia com a pesquisa básica de um novo composto bioativo em modelos experimentais in vitro e pré-clinicos. Neste trabalho descreve-se a síntese de d-valerolactonas e avaliação biológica. Uma primeira rota sintética permitiu obter análogos das kavalactones com bons rendimentos através de reações de aldolisação e acoplamentos do tipo Heck e Suzuki com o auxílio do forno de microondas. Paralelamente outra estratégia sintética foi realizada através de modulações no anel aromático ligado ao núcleo lactônico, com reações do tipo Heck, Suzuki e Sonogashira, com excelentes rendimentos. Outra sequência reacional foi desenvolvida a partir de álcoois alílicos utilizando a reação conhecida como tandem isomerisação/aldolisação com diversos aldeídos obtendo lactonas substituídas em posição 3, 5 e 6 do ciclo lactônico. Objetivou-se também neste estudo, a partir do princípio da química combinatória, preparar uma pequena quimioteca de d-valerolactones. Para tanto se desenvolveu uma seqüência reacional a partir do suporte fluorado em função das vantagens deste método em relação à Síntese Orgânica em Fase Sólida (SOFS), esta rota sintética foi acompanhada em solução. No que se refere ao aspecto biológico, foram avaliados 35 compostos sintetizados sobre a atividade citotóxica. No entanto apenas um composto apresentou uma leve atividade (CI50 < 10μM) sobre as linhagens celulares testadas (A-375M e B16). Em relação à avaliação antiinflamatória in vitro observou-se atividade interessante sobre o composto 61 na inbição do TNFa no sangue total. A avaliação do potencial antinociceptivo dos 10 compostos testados (5, 129-137) demonstrou um perfil promissor, sendo que o composto 131 apresentou uma inibição mais expressiva (69,4%) em relação aos outros compostos. Os resultados químicos e biológicos promissores aqui demonstrados indicam a viabilidade em utilizar essa classe química estudada para encontrar substâncias mais ativas as quais podem representar uma nova entidade terapêutica. / This work describes the synthesis and the pharmacological evaluation of various δ-valerolactone derivatives. We first prepared some kavalactone analogues in good yields using microwave-promoted palladium-catalyzed coupling reactions. Several modulations have been done using Heck, Suzuki and Sonogashira reactions. At the same time, we developed a synthetic pathway starting from allylic alcohols and involving a tandem isomerisation-aldolisation reaction with various aldehydes in order to introduce diversity at the C-3, C-5 and C-6 positions of the valerolactone. We focused on the combinatorial chemistry in order to obtain a library of δ-valerolactone derivatives. The Heck coupling was followed by an isomerisation-aldolisation reaction using a fluorated support. The purification steps were much easier using fluorated supports. However, so far this synthetic pathway is only valid in solution. We then tested 34 d-valerolactones analogues to determine their in vitro cytotoxic activity and discovered that one d-valerolactone was slightly active (CI50 < 10μM) on two cell lines (A-375M and B16). Moreover, the in vitro inhibitor effects on whole blood sample showed that δ-valerolactone derivatives might have an interesting antiinflammatory activity. Finally, the in vivo acetic acid test evaluating the analgesic activity of several compounds displayed a high inhibition for the heterocyclic 131 (69.4%).

The 2-aryl-6,8-dibromoquinazolin-4(3H)-ones were prepared in a single-pot operation by condensing 6,8-dibromoanthranilamide and aryl aldehydes in the presence of molecular iodine in ethanol. Treatment of the 2-aryl-6,8-dibromoquinazolin-4(3H)-ones with thionylchloride in the presence of dimethylformamide afforded the corresponding 2-aryl-4-chloro-6,8-dibromoquinazolines. Palladium(0)-copper iodide catalysed Sonogashira cross-coupling reaction of 2-aryl-4-chloro-6,8-dibromoquinazolines with terminal alkynes at room temperature afforded series of 2-aryl-6,8-dibromo-4-(alkynyl)quinazolines. Further transformation of the 2-aryl-6,8-dibromo-4-(phenylethynyl)quinazolines via Suzuki-Miyaura cross-coupling with arylboronic acids occurred without selectivity to afford the corresponding 2,6,8-triaryl-4-(phenylethynyl)quinazolines. The compounds were characterized using a combination of NMR (1H and 13C) and IR spectroscopic techniques as well as mass spectrometry. The absorption and emission properties of 2,6,8-triaryl-4-(phenylethynyl)quinazolines were determined in solution. / Chemistry / M.Sc. (Chemistry)