The syntheses and characterization of a series of (NHC)Pd(II) complexes (NHC = N-heterocyclic carbene) are described. A variety of architectures and precursors have been employed to lead to numerous air- and moisture-stable complexes. The use of those complexes as pre-catalysts in cross-coupling (Suzuki- Miyaura, Buchwald-Hartwig) and related (catalytic dehalogenation, £-ketone arylation) reactions is also discussed. A comparison of the activity of a variety of (NHC)Pd complexes as pre-catalysts for cross-coupling reactions was carried out. The results indicate that the activation of those pre-catalysts, leading to the catalytically active [(NHC)Pd(0)] species, was key in assuring high catalytic performance under mild reaction conditions. For the first series of complexes described, (NHC)Pd(allyl)Cl complexes, a better understanding of the process leading to the catalytically active species has permitted us to introduce simple modifications (alkyl or aryl groups at the allyl moiety) that dramatically alter the performance of the complexes by facilitating their activation, decreasing reaction times, catalyst loadings and even allowing reactions to be conducted at room temperature. Catalyst loadings as low as 0.05 mol% can be used for the Suzuki-Miyaura crosscoupling of aryl chlorides and aryl boronic acids at room temperature, leading to the synthesis of poly-ortho-substituted biaryls in excellent yields. This catalyst loading is the lowest ever used for this purpose. The system also allows for the first examples of coupling between aryl chlorides and alkenyl boronic acids at room temperature. When the temperature is raised to 80 ¢ XC for these reactions, a catalyst loading as low as 50 ppm can be used to effectively carry out Suzuki-Miyaura cross-couplings in remarkably short reaction times. As an added advantage, these complexes are air- and moisture-stable and can be prepared in a facile one-pot, multigram scale synthesis from commercially available starting materials in very high yields. The second series of complexes described revolves around the (NHC)Pd(acac)n framework. These complexes are also air- and moisture-stable and can be prepared in a one-step synthesis in high yields from commercially available materials. These complexes were tested forƒn £-ketone arylation and Buchwald-Hartwig amination reactions affording high yields of the desired products, in short reaction times and mild reaction conditions.

Les ADN topoisomérases régulent la topologie de l’ADN lors des processus cellulaires tels que la réplication, la transcription ou la ségrégation des chromosomes au cours de la division cellulaire. Leur rôle crucial dans le maintien de l’intégrité du génome et dans la transmission des gènes en fait des cibles privilégiées pour le développement de molécules thérapeutiques. Cependant, les inhibiteurs utilisés actuellement comme agents anti-tumoraux contre les topoisomérases humaines sont peu spécifiques et entrainent de nombreux effets secondaires. De même, l’utilisation massive d’antibiotiques à large spectre contre les topoisomérases bactériennes entraine l’apparition de mutations et le développement de souches résistantes. L'amélioration des traitements dépend de notre compréhension du mécanisme catalytique, des fonctions cellulaires précises, des architectures tridimensionnelles et des processus d'inhibition de ces ADN topoisomérases. Nous nous sommes tout d’abord consacrés à l’étude structurale de l’interaction entre la Coumermycine-A1, un antibiotique de la famille des aminocoumarines, avec le domaine ATPase de l’ADN Gyrase, une topoisomérase 2A bactérienne. Les résultats obtenus ont révélé un mode d’inhibition inédit et ouvrent la voie à la conception de nouveaux dérivés de cet antibiotique, ciblant plus spécifiquement les ADN Gyrases de pathogènes. La seconde partie de la thèse a consisté en l’étude de l’architecture complète de l’ADN Gyrase et de l’isoforme alpha de la Topo II humaine par Cryo-microscopie électronique. Les données structurales obtenues révèlent pour la première fois l’architecture complète de ces topoisomérases à haute résolution. L’ensemble des résultats apporte de nouveaux éléments pour la compréhension des mouvements allostériques des topoisomérases 2A lors du cycle catalytique. Ces données, jusque-là inaccessibles par les méthodes structurales conventionnelles, sont essentielles pour le développement de nouvelles molécules inhibitrices pouvant cibler spécifiquement différents états catalytiques. / DNA topoisomerases regulate DNA topology during cellular processes such as replication, transcription or chromosome segregation. Their crucial role in maintaining the integrity of the genome and in genetic transmission makes them prime targets for the development of therapeutic molecules. However, the inhibitors currently used as anti-tumor agents against human topoisomerases are not very specific and cause many side effects. Similarly, the massive use of broad-spectrum antibiotics against bacterial topoisomerases leads to the appearance of mutations and the development of resistant strains. The optimization of current therapeutics depends on our understanding of the catalytic mechanism, the precise cellular functions, the complete three-dimensional architectures and the inhibition processes of these topoisomerases. This study first focused on the structural characterization of the interaction between Coumermycin-A1, an aminocoumarin antibiotic, with the ATPase domain of DNA Gyrase, a bacterial Type 2A topoisomerase. The results obtained revealed an unprecedented mode of inhibition and pave the way to the design of new variants of this antibiotic, specifically targeting pathogenic DNA Gyrases. The second part of the thesis consisted in the study of the complete architecture of the DNA Gyrase and the human Topo II alpha isoform by Cryo-electron microscopy. The structural data obtained reveal for the first time the complete architecture of these topoisomerases at high-resolution. The results shed light on the finely-tuned allosteric movements of topoisomerases 2A during the catalytic cycle. These information, until now out of reach using the conventional structural methods, are essential for the development of new inhibitory molecules that can specifically target different catalytic states.