Density functional (DFT) methods are first used to study 22 of the most stable solution-phase UN4O12 isomers containing uranyl nitrate, UO2(NO3)2. Based on relative free energy calculations, 4 solution (a6, a5, a8, and a1) and 5 gas-phase isomers (a1, a2, a3, b1, and b2) are identified as the strongest candidates to exist and possibly predominate within their respective environments. DFT is then applied to a new form of binucleating Schiff–base polypyrrolic macrocycles containing actinyl ions [AnO2]n+ (An = U, Np, Pu; n = 1, 2) and 3d transition metals (TM): Mn, Fe, Co, and Zn. Formal bond order evidence is provided for 24 TM to actinyl–endo–oxygen partial bond formations. Special structural cases are discussed. Redox potentials for AnVIO21/AnVO21– couples closely follow the Np > Pu > U trend seen for AnO2(H2O)52+/1+. Predictions of –1.10, 0.25, and 0.01 eV are made for U, Np, and Pu redox potentials.

Density functional (DFT) methods are first used to study 22 of the most stable solution-phase UN4O12 isomers containing uranyl nitrate, UO2(NO3)2. Based on relative free energy calculations, 4 solution (a6, a5, a8, and a1) and 5 gas-phase isomers (a1, a2, a3, b1, and b2) are identified as the strongest candidates to exist and possibly predominate within their respective environments. DFT is then applied to a new form of binucleating Schiff–base polypyrrolic macrocycles containing actinyl ions [AnO2]n+ (An = U, Np, Pu; n = 1, 2) and 3d transition metals (TM): Mn, Fe, Co, and Zn. Formal bond order evidence is provided for 24 TM to actinyl–endo–oxygen partial bond formations. Special structural cases are discussed. Redox potentials for AnVIO21/AnVO21– couples closely follow the Np > Pu > U trend seen for AnO2(H2O)52+/1+. Predictions of –1.10, 0.25, and 0.01 eV are made for U, Np, and Pu redox potentials.

The utility of fluorophores for sensing applications in the current state of the art of biological imaging hardly needs to be stated. The use of fluorophores in exploring and determining the internal structure and active dynamics of cellular processes has been pivotal, allowing us to explore areas of study inaccessible through other means. A simple search of fluorophores in Scifinder© demonstrates their popularity, as the number of hits increases year after year, until the year of 2015 when there were 1400+ journal articles published with the phrase. Fluorophore applications range far and wide, from sensing applications related to environmental concerns, to public health, to clinical usage. Fluorophores have been developed to detect explosive residues, to monitor environmental pollutants, and even to detect illicit substances. In cellular applications, a fluorophore needs to be well suited to examining the relevant processes, including participating in the cellular milieu and actively signifying the phenomena that are desired. Chapter I examines the usage of alkynes in fluorescent sensing scaffolds and gives a survey of their applicability in the field. Chapter II demonstrates the utility of disulfide-based macrocyclic scaffolds in the design of supramolecular hosts for chloride anions and their use as solid-state sensors for these anions. Chapter III explores the synthesis and application of an alkyne-based scaffold in the reversible detection of dithiol/disulfide redox flux and a new mode of quantification of dithiol-disulfide redox couples, a classically difficult area of study. Chapter IV focuses on methods utilized to improve the disulfide-based redox sensing capabilities. Chapters V and VI explore the properties of a new fluorophore scaffold discovered during research into another sensing scaffold, demonstrating a new reaction which yields a heretofore underexplored heterocycle with novel photophysical and supramolecular behaviors. This dissertation contains both previously published and unpublished co-authored material.

Le développement de médicaments de nature peptidique est principalement limité par une faible biodisponibilité orale. La macrocyclisation a été identifiée comme une solution possible à certains problèmes de métabolisme, mais une basse perméabilité constitue souvent le facteur limitant. Pourtant, certains macrocycles, dont la cyclosporine, parviennent à traverser les membranes. À l’heure actuelle, alors que la perméabilité de grands macrocycles peptidiques fait l’objet de nombreuses études, celle des macrocycles semi-peptidiques demeure peu explorée. Afin de mieux comprendre la relation structure perméabilité des macrocycles peptidiques et semi peptidiques, une librairie de 36 composés a été synthétisée en incorporant de façon systématique deux modifications structurales ciblant l’aspect conformationnel : 1) le remplacement de résidus peptidiques par des résidus peptoïdiques et 2) l’utilisation de différents chaînons chiraux. Ces composés ont été testés dans des essais de perméabilité et les résultats obtenus couvrent une grande plage de valeurs. Une de ces modifications a apporté une hausse importante de la perméabilité dans la majorité des cas.

The aim of this thesis is to synthesize new kind of macrocyclic ligands for complexation of Zr4+ . Zirconium(IV) complexes have potential as contrast agents in immuno-PET. Three macrocyclic ligands L1, L2 and L3 with dif- ferent pendant arms (HOPO, maltol, hydroxamate) were designed. Despite numerous attempts syntheses of L1 and L2 were unsuccessful. Ligand L3 was synthesized and the protonation constants were determined by poten- tiometric titration. Complexes [Zr4+ (L3)] were studied too. Catechol ligand L4 was prepared and complexes with cations Zn2+ , Ga3+ and Zr4+ were investigated. 1

No description available.

Protein-protein interactions (PPI) mediate numerous biological processes, but inhibiting these interactions with small molecules has been difficult to achieve in drug discovery. A small number of successes have shown that some PPIs are amenable to inhibition. Computational algorithms designed to measure the druggability of PPIs have been developed based on these successes. These algorithms have identified the interaction between the NF-κB essential modulator (NEMO) and I𝜅B kinase β (IKKβ) as a candidate for inhibition. Furthermore, in vivo peptide-based inhibition of the NEMO-IKKβ interface has shown benefits in attenuating the NF-𝜅B response in cellular and animal models. In addition to its intrinsic interest as a drug target, developing inhibitors against the NEMO/IKKβ interaction may help in the development of improved methods for PPI inhibition. In this thesis, the production of full-length, recombinant forms of soluble NEMO is described. This protein was used in a variety of biochemical assays to advance our understanding of NEMO structure and function. Furthermore, a fluorescence anisotropy (FA) assay was developed to screen for compounds inhibiting the NEMO/IKKβ PPI. Hits from the FA assay were tested by several methods to confirm true inhibition. Additionally, the FA assay was used to accurately measure the affinity of NEMO for IKKβ and to assess the degree of cooperativity in IKKβ binding. The oligomeric state of NEMO has been characterized through the development of a panel of NEMO cysteine to alanine mutants, using polyacrylamide gel electrophoresis analysis, analytical ultracentrifugation, and fluorescence anisotropy. These data represent the first comprehensive characterization of full-length human NEMO, and may provide a path toward development of drug-like inhibitors of the NEMO/IKKβ interaction.

No description available.

Ce travail décrit la synthèse et l'étude structurale de 1:1-[alpha/alpha-Nalpha-Bn-hydrazino]mères linéaires et cycliques. Après avoir mis au point une méthode générale de synthèse en solution des alpha-Nalpha-hydrazinoesters diversement substitués sur l'azote alpha, ces derniers ont été engagés dans l'élaboration de 1:1-[alpha/alpha-Nalpha-Bn-hydrazino]mères linéaires et cycliques de taille variable. Des études conformationnelles utilisant la RMN, l'IR et les RX ont permis de montrer que la présence de l'azote supplémentaire dans le squelette permettait l'établissement de liaisons hydrogène intramoléculaires conduisant à la formation d'hydrazinoturn. Ainsi l'alternance d'acides alpha-aminés naturels et d'alpha-hydrazinoacides conduit à une auto-structuration des oligomères linéaires par formation de y-turn et d'hydrazinoturn, identique en série hétéro- comme homochirale. En série cyclique, une analyse par RX a permis de mettre en évidence, à l'état solide, la formation de nanotubes due à l'empilement des cyclotétramères hétérochiraux. Cette conformation existe dans le toluène et le dodécane et conduit à la formation d'un gel. Bien que n'ayant pas de preuves de sa structure à l'état solide, le gel formé par le cyclohexamère hétérochiral dans le cyclohexane nous conforte dans l'idée d'une auto-structuration comparable. Les analyses RMN et IR en variation de concentration et température ont quant à elles mis en évidence la dynamique de formation des nanotubes. L'étude sur le cyclotétramère homochiral a cependant montré qu'il ne formait pas de gel. Le gel étant révélateur d'une auto-structuration, ceci nous conduit à nous interroger sur la versatilité du squelette macrocyclique 1:1-[alpha/alpha-Nalpha-Bn-hydrazino] pour l'établissement de nanotubes / This work describes the synthesis and the structural study of linear and cyclic 1:1-[alpha/alpha-Nalpha-Bn-hydrazino]mers. After having designed a general method to synthesize alpha-Nalpha-hydrazinoesters with various surrogates on the alpha nitrogen in solution, these were used to build linear and cyclic 1:1-[alpha/alpha-Nalpha-Bn-hydrazino]mers of varied length. Conformational studies resorting to NMR, IR and X-ray crystallography have shown that the presence of a supplementary nitrogen within the backbone enables to form intramolecular hydrogen bonds, leading to the formation of hydrazinoturns. Thus, the alternation of natural alpha-aminoacids and alpha-hydrazinoacids leads to the autostructuration of the linear oligomers through the formation of y-turns and hydrazinoturns, both in the hetero and homochiral series. In the cyclic series, an X-ray crystallography analysis revealed the formation of nanotubes in the solid state, through the stacking of heterochiral cyclotetramers. This conformation exists in toluene and dodecane and leads to the formation of a gel. Despite having no proof of its structure in the solid state, the gel formed by the heterochiral cyclohexamer in cyclohexane confirms a comparable auto-structuration. Finally, concentration- and temperature-dependant NMR and IR studies have revealed the dynamics of the formation of nanotubes. The study of the homochiral cyclotetramer has however shown that it was not able to form a gel. As the gel is indicative of an auto-structuration, this has led us to question the versatility of the macrocyclic 1:1-[alpha/alpha-Nalpha-Bn-hydrazino] backbone towards the formation of nanotubes

La synthèse organique contrôlée de nanobagues de carbone est un challenge scientifique de longue date. Ces composés polycycliques aromatiques cylindriques peuvent être définis comme des sections de nanotubes de carbone plus larges qu’épaisses ; et la courbure de leur système pi pourrait leur conférer des propriétés électroniques intéressantes.Depuis quelques années, notre équipe développe une approche générale de synthèse de composés aromatiques polycycliques fonctionnalisés par des fonctions carboxyliques. Cette approche repose sur la réaction de Perkin entre des acides aryle-acétiques et des acides aryle-glyoxyliques, qui va permettre l’assemblage de ces briques élémentaires en longs précurseurs flexibles mais conjugués. Une dernière étape de cyclisation intramoléculaire, ou « graphitisation », pourra alors conjuguer complètement et donc rigidifier la molécule finale. Cette approche a permis la synthèse de plusieurs nouveaux composés aromatiques polycycliques linéaires.L’objectif de cette thèse est l’adaptation de l’approche de Perkin à la formation de nanobagues aromatiques. Un premier défi a été efficacement remporté avec l’obtention et la caractérisation complète de plusieurs macrocycles flexibles mais conjugués. Certains de ces macrocycles ont même été formés avec d’excellents rendements grâce à la mise en place d’une technique de haute dilution. Plusieurs tentatives de graphitisation ont été menées sur ces composés, impliquant différentes techniques de synthèse telles que la photochimie ou la catalyse au palladium, mais ne permirent malheureusement pas la formation des nanobagues aromatiques désirées. Néanmoins, en modifiant la structure initiale de certaines briques élémentaires nous avons pu obtenir d’autres macrocycles conjugués plus flexibles qui, après photocyclisation, ont abouti à la formation d’autres macrocycles conjugués présentant des structures rigides mais atypiques car non planes. / The controlled organic synthesis of carbon nanobelts has been scientific challenge for a long time. Such cylindrical polycyclic aromatic compounds can be defined as sections of carbon nanotubes that are larger than wide. Interesting electronic properties could result from the curvature of their pi system.These last years, our team has developed a general synthetic approach for the formation of carboxy-functionalised polycyclic aromatic compounds. This approach involves the Perkin reaction of arylacetic acids with arylglyoxylic acids, in order to form conjugated and flexible elongated precursors. The last step is an intramolecular cyclisation, or “graphitisation”, which rigidifies the precursor and yields a fully conjugated final molecule. Applying this approach, our team has synthesised several new linear polycyclic aromatic compounds.The aim of this thesis is to adapt the Perkin reaction for the formation of aromatic nanobelts. A first challenge has been solved by synthesising and fully characterising several flexible and conjugated macrocycles. Some of those macrocyclic compounds have been obtained with unexpectedly good yields using a high dilution addition technique. Graphitisations have been tried on some of those macrocycles by different synthetic methods, i.e. photochemistry and palladium catalysis, but none of them led to the formation of the desired aromatic nanobelt. However, by modifying the initial structure of some of the building blocks, we obtained more flexible conjugated macrocycles, which then reacted, by photocyclisation, to form conjugated and non-planar rigid macrocycles with atypical structures.