Please note that the structures do not display correctly in the pdf document. Therefore the original manuscript in MSWord has also been uploaded. Please contact us email if you cannot view these files. / Sonogashira cross-coupling of 2-aryl-4-chloro-3-iodoquinoline derivatives with stoichiometric amount of terminal alkynes in the presence of bis(triphenylphosphine)palladium(II)chloride and copper iodide in triethylamine afforded the 3-(alkynyl)-2-aryl-4-chloroquinoline, exclusively. On the other hand, the 2-aryl-4-chloro-3-iodoquinolines with excess (2.5 equiv.) of terminal alkynes in the presence of PdCl2(PPh3)2-CuI catalyst mixture and NEt3 in dioxane-water (3:1 v/v) afforded the 2-aryl-3,4-bis(alkynyl)quinoline derivatives in a one-step operation. Further transformation of the 2-aryl-3-(alkynyl)-4-chloroquinoline via Suzuki cross-coupling reaction with boronic acid derivatives in the presence of tetrakis(triphenylphosphine)palladium and tricyclohexylphosphine as a ligand in dioxane-water (3:1 v/v) afforded the 2,4-diaryl-3-(alkynyl)quinolines in moderate to high yields. The 2-aryl-3-(alkynyl)-4-chloroquinolines were also transformed to the corresponding 2-aryl-4-(methylamino)-3-(alkynyl)quinoline derivatives using methylamine in ethanol under reflux. / Chemistry / M.Sc.

Please note that the structures do not display correctly in the pdf document. Therefore the original manuscript in MSWord has also been uploaded. Please contact us email if you cannot view these files. / Sonogashira cross-coupling of 2-aryl-4-chloro-3-iodoquinoline derivatives with stoichiometric amount of terminal alkynes in the presence of bis(triphenylphosphine)palladium(II)chloride and copper iodide in triethylamine afforded the 3-(alkynyl)-2-aryl-4-chloroquinoline, exclusively. On the other hand, the 2-aryl-4-chloro-3-iodoquinolines with excess (2.5 equiv.) of terminal alkynes in the presence of PdCl2(PPh3)2-CuI catalyst mixture and NEt3 in dioxane-water (3:1 v/v) afforded the 2-aryl-3,4-bis(alkynyl)quinoline derivatives in a one-step operation. Further transformation of the 2-aryl-3-(alkynyl)-4-chloroquinoline via Suzuki cross-coupling reaction with boronic acid derivatives in the presence of tetrakis(triphenylphosphine)palladium and tricyclohexylphosphine as a ligand in dioxane-water (3:1 v/v) afforded the 2,4-diaryl-3-(alkynyl)quinolines in moderate to high yields. The 2-aryl-3-(alkynyl)-4-chloroquinolines were also transformed to the corresponding 2-aryl-4-(methylamino)-3-(alkynyl)quinoline derivatives using methylamine in ethanol under reflux. / Chemistry / M.Sc.

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 lymphomes à grandes cellules anaplasiques ou ALCL (Anaplastic Large-Cell Lymphoma) sont des cancers appartenant à la famille des lymphomes de type non-Hodgkin. La majorité des ALCL est issue d'une translocation t(2;5)(p23;q35) donnant lieu à la formation d'une protéine de fusion appelée NPM-ALK. A ce jour, peu d'inhibiteurs présentent de bonnes activités contre cette protéine chimérique. L'obésité représente un problème socio-médical d'envergure, à la fois pour ses effets directs et indirects ; le surpoids étant un facteur primaire dans de nombreuses maladies, tout particulièrement les diabètes, les accidents cardiovasculaires, le cancer, etc. A contrario, une restriction calorique (RC) est associée à des bénéfices importants en terme de santé. A l'issue de plusieurs criblages, un inhibiteur au motif 2-acylaminothiazole a montré une activité anticancéreuse sur ALK mais également la faculté de mimer la restriction calorique chez C. Elegans. Par conséquent, les travaux de recherche réalisés lors de cette thèse ont concerné la synthèse d'inhibiteurs comportant le squelette 2-acylaminothiazole. Les chromatographies d'affinité effectuées sur deux de nos inhibiteurs ont permis l'identification de cibles principales potentielles dans le cadre de la restriction calorique et des cibles secondaires possibles pour NPM-ALK. Ensuite, la présence d'un atome de brome sur le cycle aromatique a mené à la formation de liaisons C(sp2)-C(sp2), C(sp2)-C(sp) et C(sp2)- N, en utilisant les couplages catalysés par le palladium. Les différentes méthodes de modulation chimique ont conduit à mettre en place une librairie de 134 molécules. Certains d'entres eux et plus précisément ceux possédant un atome de silicium ont démontré une très bonne activité contre ALK et son mutant L1196M. Enfin, des résultats préliminaires ont également été obtenus sur le sujet de la restriction calorique avec quatre composés montrant une réduction du taux de lipides chez C. Elegans / Anaplastic Large-Cell Lymphoma (ALCL) is a type of cancer belonging to the non-Hodgkin family. The majority of ALCL arises from a translocation t(2;5) (p23;35) which leads to the formation of a fusion protein called NPM-ALK. Nowadays, few molecules are known to inhibit the activity of this chimeric protein. Obesity is a major socio-medical problem, for both direct and indirect effects, overweight is a primary factor in many diseases, especially diabetes, cardiovascular events, cancer, etc... In contrast, caloric restriction (CR) is associated with significant benefits in terms of health. After several screenings, one inhibitor based on a 2-acylaminothiazol scaffold showed anticancer activity on the protein ALK but also the ability to mimic caloric restriction in C. Elegans. The aim of this PhD was to develop the synthesis of new inhibitors including the 2-acylaminothiazol scaffold. The affinity chromatography performed on two of our inhibitors was used to identify potential major cellular targets in the process of caloric restriction and secondary cellular targets for NPM-ALK. Then, the presence of a bromo group on the aromatic ring allowed the formation of C(sp2)-C(sp2), C(sp2)- C(sp) and C(sp2)-N bonds, using palladium-catalyzed couplings. The different chemical methodologies afforded the synthesis of a library of 134 molecules. Some of them especially with a silicon atom demonstrated very good inhibitory activity and high selectivity against NPM-ALK and L1196M-NPM-ALK. Finally, preliminary results were also obtained on the subject of calorie restriction with four compounds showing a reduction of lipids in C. Elegans

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)

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)

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.

The known 2-aryl-6,8-dibromo-2,3-dihydroquinolin-4(1H)-ones 122 were dehydrogenated using thallium(III) p-tolylsulfonate in dimethoxyethane under reflux to afford the 2-aryl-6,8-dibromoquinolin-4(1H)-ones 136. Palladium-catalyzed Sonogashira cross-coupling of the 2-aryl-6,8-dibromo-2,3-dihydroquinolin-4(1H)-ones with terminal alkynes in the presence of PdCl2(PPh3)2-CuI (as homogeneous catalyst source) and 10% Pd/C-PPh3-CuI (as heterogeneous catalyst source) catalyst mixture and NEt3 as a base and co-solvent in ethanol under reflux afforded the corresponding 6,8-dialkynyl-2-aryl-2,3-dihydroquinolin-4(1H)-ones 138 and 8-alkynyl-2-aryl-6-bromo-2,3-dihydroquinolin-4(1H)-ones 137, respectively. PdCl2-catalyzed electrophilic cyclization of the 8-alkynyl-2-aryl-6-bromo-2,3-dihydroquinolin-4(1H)-ones in acetonitrile under reflux afforded the 4-aryl-8-bromo-2-phenyl-6H-pyrrolo[3,2,1-ij]quinolin-6-ones 139 or the 2-aryl-6-bromo-8-(4-hydroxybutanoyl)-2,3-dihydroquinolin-4(1H)-ones 140 from the 4-phenylethynyl-substituted or 4-alkylethynyl-substituted precursors, respectively. The 2-aryl-6,8-dibromoquinolin-4(1H)-ones 136 wturn, subjected to similar homogeneous and heterogeneous palladium catalyst sources using NEt3 as a base in DMF-water mixture under reflux and K2CO3 as a base in dioxane under reflux afforded 2,8-disubstituted 4-aryl-6-oxopyrrolo[3,2,1-ij]quinolines 143 and 2-substituted 4-aryl-8-bromo-6-oxopyrrolo[3,2,1-ij]quinolines 142, respectively. The monoalkynylated 4-aryl-8-bromo-2-phenyl-6H-pyrrolo[3,2,1-ij]quinolin-6-ones 139 and 2-substituted 4-aryl-8-bromo-6-oxopyrrolo[3,2,1-ij]quinolines 142 were subsequently transformed using palladium-catalyzed Suzuki-Miyaura cross-coupling with arylboronic acids in the presence of PdCl2(PPh3)2-PCy3 catalyst mixture and K2CO3 as a base in dioxane-water mixture to afford the corresponding novel 8-substituted 2-phenyl-6H-pyrrolo[3,2,1-ij]quinolin-6-ones 141 and 2,8-disubstituted 4-aryl-6-oxopyrrolo[3,2,1-ij]quinolines 144, respectively. All the new compounds were characterized using a combination of 1H NMR, 13C NMR, IR, mass spectroscopic techniques and X-ray crystallography. / Chemistry / D. Phil. (Chemistry)