I. Efforts Toward the Synthesis of (–)-Tetracycline. A macrocyclic approach toward (–)-tetracycline is described. Traditional approaches towards the synthesis of tetracycline antibiotics employ the linear construction of the core structure starting with either the A- or D-rings. In contrast to this iterative annulation-based strategy, we have sought to employ a chiral macrocycle in our approach. Key to the success of our synthesis endeavor is the execution of two key steps: (1) a transannular Michael addition, which forms the A-ring and sets the C4a-stereogenic center; and (2) an isoxazole substitution reaction, which effects a ring contraction to produce both the B- and C-rings. This work describes our implementation of the strategy and focuses on the stereochemical interplay between the C4-, C4a-, C6-, and C12a-stereocenters within the context of the key steps. II. Analysis of the Peripheral Attack Model. The application of the peripheral attack model to 34 literature examples of intermolecular macrocyclic stereocontrol is described. While the peripheral attack model has been broadly applied in complex molecule synthesis, the validity of the model has not been subjected to analysis since being proposed in the early 1980’s. In order to assess the value of the model to organic chemists, we have developed a systematic method for probing the conformational profile of macrocycles. Using this tool, we then analyzed each of the 34 literature substrates and concluded whether the peripheral attack model predicts the correct stereochemical outcome in both a binary- and magnitude-based capacity. Analysis of both the bulk dataset and subsets of the dataset is included. / Chemistry and Chemical Biology

Reported in this thesis are the studies of micellar aggregates of four triblock copolymers and the unimolecular micelles of a triblock copolymer. The micelles were prepared from BCF and ACF copolymers. Here A, B, C, and F denote poly(acrylic acid), poly(tert-butyl acrylate), poly(2-cinnamoyloxylethyl methacrylate), and the liquid crystalline poly(perfluorooctylethyl methacrylate) block, respectively. At room temperature (21 oC) in solvents that were selective for the A or B blocks, three of the four copolymers formed exclusively cylindrical micelles regardless of their block ratios. Cylindrical micelles were formed because their geometries best accommodated the mesogen-ordering requirement of the core-forming F block, as supported by the results from wide angle X-ray scattering and differential scanning calorimetric studies. Mesogen-driven cylinder formation was further supported by the observation of ridges formed by collapsed coronal chains on the surfaces of dried cylinders. We also observed a morphological transformation from other micellar morphologies to cylindrical micelles at 70 oC, which is near the isotropic-to-smectic A phase transition temperature for the F blocks. This inter-conversion between the vesicular and cylindrical micelles of an ACF sample could be reversed repeatly by temperature cycling. These results provided additional evidence for the mesogen-driven micellization hypothesis. Unimolecular micelles were prepared from CDC triblock copolymers, where D and C denote poly(dimethylaminoethyl methacrylate) and poly(2-cinnamoyloxylethyl methacrylate), respectively. In selective solvents for the D block at high dilutions, the D chain formed a loop, and the terminal C blocks of the isolated unimer chain associated together as a globule, thus closing the loop and rendering a cyclic structure. Alternatively, the terminal C blocks formed individual globules, thus yielding a pompom-coil-pompom structure. To lock in these structures, the globules were photo-crosslinked. The D block chain was subsequently enlarged for AFM observation through a quaternization step, which increased the chain’s diameter and introduced cations to the chain. The semi-flexible thickened polymer chains and the globules were observed by AFM, confirming unambiguously the hypothesized architectures of the unimolecular micelles. The AFM images also allowed the quantification of the macrocyclic structures, and a correlation between the direct AFM results and determined from a traditional size exclusion chromatography technique. / Thesis (Ph.D, Chemistry) -- Queen's University, 2011-09-26 12:08:28.263

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Macrocycles (MCs) have become an increasing area of interest for drug design efforts, especially for classically “difficult” targets like protein-protein interactions (PPIs). And although there are many examples of successful MC drugs derived from natural products, there is little information about the characteristics of compounds with effective pharmacological and physicochemical properties. In this dissertation, I describe the development of design guidelines for new MC drugs based on a representative set of known inhibitor MCs and their target proteins. Analysis of both the individual MC structures and their interactions in the protein complex resulted in identification of several structural and physicochemical features likely to promote favorable binding and bioavailability. Additionally, investigation of the binding sites on the proteins suggest that MCs can bind targets conventionally considered “non-druggable,” strengthening the argument for exploring MC compounds to increase the druggable target space. Furthermore, this work includes the application of the proposed design guidelines to the development of synthetic MC libraries for a PPI target, the NEMO/IKKβ complex.

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Interest in macrocyclic monomers can be dated back to the 1960's. The recent surge of research activities in this area is prompted by two facts: the encouraging discovery of high yield synthesis and facile ring-opening polymerization of cyclic polycarbonate; the need for a technique to solve the tough processibility problem of high performance polymers. This work was intended to address the following aspects in the cyclic poly(ether ketone) or sulfone system. The first goal was to understand the structure-property relationship of this type of macrocycles. A large number of macrocycles were synthesized by nucleophilic aromatic substitution cyclization reactions under pseudo-high dilution conditions. Pure individual macrocycles as well as cyclic mixtures were characterized by NMR, HPLC, GPC, FABMS, MALDI-TOF-MS, DSC and TGA. Comparison study suggests that the cyclic distribution is kinetically controlled. Several factors determine the melting points of individual macrocycles. The first factor is the ring size. A series of cyclic monomers for poly(ether ether ketone)s were synthesized and isolated. The melting point decreases as ring size increases. Single crystal X-ray structural results suggest that this phenomenon is related to the increased flexibility of the larger sized macrocycles. The second factor is the functional groups of the macrocycles. X-ray structural and GPC experiments reveal that the sulfone group is more rigid than the ketone group, than ether group. The effect of functional groups on melting point is in the order sulfone>ketone>ether. A third factor is the symmetry of the macrocycles. Breaking the symmetry of macrocycle through comacrocyclization dramatically decreases the melting point of individual macrocycles as well as the cyclic mixture as a whole. Based on these findings, a novel two step method was developed to control the ring size distribution, which effectively reduced the amount of the small sized macrocycle and decreased the melting point. In addition to the nucleophilic aromatic substitution cyclization, it was also demonstrated in this work that macrocycles can be synthesized by Friedel-Crafts acylation cyclization. However, this method is limited by the solubility problem. The ring-opening polymerization of macrocyclic monomers was systematically studied. Several factors were considered in this study: the nature and amount of catalyst, temperature and time. CsF; metallic phenolate and Na2S are good initiators. Conversion to near 100 % is possible under the controlled polymerization conditions. It was found that crosslinking is an inherent phenomenon. The molecular weight of the soluble fraction near complete conversion is almost independent of initiator and polymerization temperature. It is limited by the crosslinking reaction. It is demonstrated for the first time that the macrocyclic monomer techniques can be applied to more valuable semicrystalline systems. Tough polymers such as high performance poly(ether ether ketone)s were produced through ring-opening polymerization. The last chapter is devoted to the challenging synthesis of monodisperse poly(ether ether ketone)s. A convergent strategy was devised. A monofluoroaryl compound was synthesized by Friedel-crafts acylation reaction. The final monodisperse linear oligomers were generated by reacting the monofunctional compound with a bisphenol through a quantitative reaction. / Ph. D.

L'apéline est le ligand endogène du récepteur APJ, un membre de la superfamille des récepteurs couplés aux protéines G. Le système apélinergique est apparu comme une cible prometteuse associée à plusieurs processus physiologiques. Notre intérêt s'est porté particulièrement sur les rôles liés au système cardiovasculaire et à la modulation de la douleur. Nous posons l'hypothèse que la synthèse d'analogues de l'apéline-13 nous permettrait d'identifier d'une part des composés plus stables et d'autre part les voies de signalisation impliquées dans la modulation de la douleur, les effets hypotenseurs et cardioprotecteurs de notre cible. Ces outils pharmacologiques contribueront ultimement à concevoir un agent thérapeutique pour le traitement de la douleur chronique et des maladies cardiovasculaires. Les données de relations structure-fonction de l'apéline-13 révèlent la présence de deux pharmacophores distants importants. Le fragment N-terminal Arg[indice supérieur 2]-Pro[indice supérieur 3]-Arg[indice supérieur 4]-Leu[indice supérieur 5] semble primordial pour l'affinité, alors que la Phe[indice supérieur 13] C-terminale serait cruciale pour l'internalisation du récepteur et les effets hypotenseurs. Afin de mieux comprendre les relations structure-fonction de l'apéline-13, nous avons synthétisé près d'une centaine d'analogues linéaires et macrocycliques. Les composés ont été évalués pour leurs capacités à lier APJ, à inhiber la formation d'AMPc, à recruter les β-arrestines et à activer les protéines Gα[indice inférieur i/o]. Une variété de modifications chimiques a été introduite en C-terminal, nous conduisant à la découverte de composés de haute affinité et puissance. Deux analogues, 1Nal[indice supérieur 13] et 2Nal[indice supérieur 13], se sont distingués pour leurs différences d'effets analgésiques dans un modèle in vivo de douleur tonique. Ces derniers présentent une intéressante divergence de sélectivité fonctionnelle suggérant que l'effet analgésique serait associé à un biais favorisant le recrutement des β-arrestines par rapport à l'inhibition de l'accumulation d'AMPc. Un autre volet du projet dédié à l'investigation de la stabilité plasmatique de l'apéline-13 nous a permis d'identifier son profil de dégradation protéolytique in vitro et in vivo. L'évaluation des demi-vies plasmatiques des analogues de l'apéline-13, modifiés à des positions clés, a révélé l'importance de l'acide aminé C-terminal dans la stabilité plasmatique. Enfin, une étude préliminaire de SAR par une approche macrocyclique novatrice du ligand endogène nous a conduit à un composé induisant un effet hypotenseur deux fois supérieur à celui de l'apéline-13. Un autre macrocycle a, quant à lui, démontré une sélectivité fonctionnelle inédite, n'activant pas la voie AMPc mais provoquant le recrutement de la β-arrestine2. Cette classe de molécules, potentiellement plus stables, a un grand potentiel pour nous aider à identifier les voies de signalisation liées aux effets physiologiques d'intérêts, et représente surtout un premier pas vers un futur agent thérapeutique.

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.