<p>  </p> <p>The access of ring junction functionalized 5,6-hydrindanone systems has been elusive in the realm of synthetic methodology, and the functionalization of a pre-built ring system rarely explored. These 5,6-hydridanone systems are prevalent in a variety of terpenoid ring systems, especially that of steroidal molecules. Previous synthetic methods to reach these systems using a Diels-Alder cycloaddition proved to be difficult and lacked labile functional groups that would be useful for substitution after the cycloaddition. The design of the α-nitrile cyclopentenone dienophile allows for both post-cyclization adduct functionalization, as well as lowering the energy barrier of the cycloaddition itself. In this work, it is shown that the Lewis acid promoted Diels-Alder reaction with α-nitrile β-methyl cyclopentenone dienophile can be performed under standard temperatures and pressures unlike previously established methods.1 This reaction can generate four chiral centers in a single synthetic step when the starting materials are prochiral. After the generation of 5,6-hydrindanone systems, radical cleavage of the nitrile functionality also allowed for electrophile trapping at the ring junction. This radical cleavage and electrophile trapping pathway allows for functionalization of a quaternary carbon at the ring junction, a method that should be fruitful in the generation of difficult to synthesize steroidal and other terpenoid molecules.</p> <p>In the work on synthetic cell penetrating peptides, camptothecin whilst a notably effective topoisomerase I inhibitor, has never quite reached it’s potential as a therapeutic due to its poor solubility in living systems. Previously, cationic amphiphilic polyproline helices (CAPH) molecules from the Chmielewski lab have been hydrophobically functionalized through O-alkylation of hydroxyprolines at specific regions within the peptide to generate a hydrophobic face. The combination of the cationic faces and the hydrophobic face have made the CAPH molecules notably cell penetrant and tunable. With camptothecin’s notable insolubility in water, it may serve as valuable surrogate to the hydrophobic groups on CAPH molecules and allowing it to be delivered intracellularly. Using an endogenously cleavable linker, we have worked towards a CPP that acts as a drug delivery vehicle. Acting as a replacement of the hydrophobic residue of a CAPH molecule, camptothecin will be chaperoned into the cell and should be released through the action of intracellular esterases.</p>

<p>Total synthesis of massarinolin A, purpurlides B, D, E, 2,3-deoxypurpurolide C, phleghenrines A and B were finished. A halogen bond promoted michael addiation was discovered during mechanism study toward diamination of allenes. Computational chemsitry study conducted toward the selectivity of 2+2 reaction supported the proposed key reaction during total synthesis of gibberellic acid 18.</p>

<p> 2-Tetrazens are often used as high energy-density materials. Only a few synthetic methods  exist for making them. Further, their structure-property relationships remain largely unexplored.  Asphaltenes are usually a complex mixture found in the heaviest fraction of heavy crude oil. Their structural characterization and understanding have become a pertinent task for petroleum industry  around the world. Mass spectrometry is a powerful analytical tool for the detection and  characterization of unknown compounds even in complex mixtures. It features high sensitivity and  speed and can provide a variety of valuable information for different types of analytes. This thesis  focuses on the development of an effective synthetic method for 2-tetrazenes and the mass  spectrometry study of the ionized 2-tetrazenes. In addition, the mass spectrometric behavior of  ionized asphaltene model compounds are also discussed in this thesis. Chapter 2 describes the instrumentation and fundamental aspects of the mass spectrometers used in the research discussed in this thesis. Chapter3 introduces an effective synthetic method for  2-tetrazens based on iodine-mediated oxidative N-N coupling reaction of hydrazines. Chapter 4  presents the fragmentation behavior of ionized 2-tetrazenes in tandem mass spectrometry experiments. Upon collision-activated dissociation (CAD), ionized alkyl-substituted linear 2- tetrazenes underwent simpler fragmentation reactions than the ionized aromatic 2-tetrazenes or a  cyclic 2-tetrazene. The observations were rationalized by using quantum chemical calculations.  Chapter 5 presents the fragmentation behavior of ionized asphaltene model compounds under  medium-energy collision-activated dissociation (MCAD). The comparison between the different  behaviors of the molecular radical cations of these compounds provided useful information for the  identification of related unknown compound </p>

<p dir="ltr">Vinylidenes are highly reactive intermediates that undergo a variety of chemical reactions. Our group has pioneered the in-situ generation of vinylidenes from bench stable 1,1-dichloroalkenes using transition metal catalysts and an exogenous reductant.</p><p dir="ltr">Herein, we demonstrate the intramolecular insertion of vinylidenes into Si–H bonds for the synthesis of unsaturated silacycles of different ring sizes. It is well known that the replacement of carbon for silicon are of significant interest to medicinal chemists as a strategy for improving the potency or pharmacokinetic properties of biologically active compounds. This method provides convenient access to trisubstituted vinyl silanes which are synthesized intermolecularly, including those that can be used as nucleophilic partners in Hiyama cross-coupling reactions. Finally, deuterium isotope labelling experiments reveal interesting mechanistic features of the reaction.</p><p dir="ltr">The second chapter of the thesis further highlights the reactivity of vinylidenes through utilizing a cobalt catalyst. Vinylidene complexes can be added into an alkyne intramolecularly followed by a cobalt to zinc transmetalation step. The resulting organozinc intermediate can be trapped with various electrophiles. Further, by altering the reaction condition, the cobaltacycle intermediate can be accessed using π systems to form different cycloadducts.</p>

<p dir="ltr">Immunotherapy has revolutionized the field of oncology. While a lot of antibodies and small molecule inhibitors have been developed for this, a lot of targets remain undruggable in humans.</p><p dir="ltr">Targeted protein degradation has opened a new horizon in drug discovery where we can target these undruggable proteins. Proteolysis targeting chimeras using the ubiquitin-proteasomal system is one of the most popular TPD strategies that complement lysosomal degradation strategies to degrade intracellular proteins, typically using bifunctional small molecule degraders. Recently, large biomolecular and antibody conjugates have been developed for degrading membrane and extracellular proteins in cells, such as lysosomal targeting chimeras (LYTACs) and genetically encoded LYTACS, among several others. However, larger molecules have limitations in penetrating solid tumors. This dissertation work focused on the development of bifunctional small molecule degraders for programmed death-ligand 1 (PD-L1), a transmembrane protein ligand for the immune checkpoint programmed cell death 1 (PD-1). PD-L1 is highly expressed on several tumors, such as triple-negative breast cancer (TNBC), non-small cell lung carcinoma, and renal cancer, and is known to suppress cancer-killing immune cells via interaction with PD-1 on T-cells. In addition, PD-L1 is also present on macrophages in the tumor microenvironments leading to further immune suppression and acquired resistance to anti-PD-1 therapy is associated with the upregulation of alternative immune checkpoints, thereby reducing anti-tumor efficacy. We have designed and synthesized bifunctional small molecules as PD-L1 degraders with different recruiters and linkers guided by computational studies with known PD-1/PD-L1 structures to show both cell surface and total protein degradation in human TNBC cells. In a separate project, we also developed small molecule conjugates to degrade an intracellular integral membrane protein of the endoplasmic reticulum with an unknown 3D structure, namely Diglyceride acyltransferase 2 (DGAT2). Recently, our lab identified DGAT2 as a new target for combating Alzheimer’s disease. Specifically, DGAT2 catalyzes triacylglycerol (TAG) synthesis using diacylglycerol and fatty acyl CoA as substrates. The accumulation of TAGs, mechanistically linked to DGAT2, results in “fat” or lipid droplets (LDs) inside the cells. Our lab showed that microglial cells (resident immune cells in the brain) accumulate LDs in the postmortem brains of human patients and mouse models (5xFAD) of Alzheimer’s disease and that the LD accumulation is driven by amyloid-beta (Ab) – a hallmark of Alzheimer’s disease – via DGAT2 pathway. Further, these LD-laden microglia have phagocytic defects and are spared Aβ thereby affecting plaque accumulation and clearance. Inhibiting DGAT2 reduces the amount of TAG in the brain, which in turn reduces LDs and restores microglial ability to phagocytose Ab. However, commercially available DGAT2 inhibitors were unable to reduce LD load in older 5xFAD mice. Using AlphaFold’s models of DGAT2, we designed and identified sites to synthesize bifunctional DGAT2 degraders that resulted in reduced LDs in mouse primary microglial cells and enhanced phagocytosis of Aβ plaques in vivo in aged 5xFAD mice. Our approach shows a framework to develop bifunctional small molecule degraders for membrane proteins to potentially combat immune dysregulation in chronic diseases.</p>

No / The protein O6-alkylguanine-DNA alkyltransferase (Atase) is responsible for the repair of DNA lesions generated by several clinically important anti-cancer drugs; this is manifest as active resistance in those cancer cell lines proficient in Atase expression. Novel O6-substituted guanine analogues have been synthesized, bearing acidic, basic and hydrogen bonding functional groups. In contrast to existing O6-modified purine analogues, such as methyl or benzyl, the new compounds were found to resist repair by Atase even when tested at concentrations much higher than O6-benzylguanine, a well-established Atase substrate active both in vitro and in vivo. The inactivity of the new purines as covalent substrates for Atase indicates that agents to deliver these groups to DNA would represent a new class of DNA-modifying drug that circumvents Atase-mediated resistance.

The potentially most important challenges today are related to energy and the environment. New materials and methods are needed in order to, in a sustainable way, convert and store energy, reduce pollution, and clean the air and water from contaminations. In this, nanomaterials and nanocomposites play a key role, and hence knowledge about the relation between synthesis, structure, and properties of nanosystems is paramount. This thesis demonstrates that solution-chemical synthesis, using amine-modified acetates and nitrates, can be used to prepare widely different nanostructured films. By adjusting the synthesis parameters, metals, oxides, and metal–oxide or oxide–oxide nanocomposites were prepared for two systems based on Co and Zn:Fe, respectively, and the films were characterised using diffraction, spectroscopy, and microscopy techniques, and SQUID magnetometry. A variety of crystalline cobalt films—Co metal, CoO, Co3O4, and composites with different metal:oxide ratios—were synthesised. Heat-treatment parameters and control of the film thickness enabled tuning of the phase ratios. Random and layered Co–CoO composites were prepared by utilising different heating rates and gas flow rates together with a morphology effect associated with the furnace tube. The Co–CoO films exhibited exchange bias due to the ferromagnetic–antiferromagnetic interaction between the Co and CoO, whereas variations in e.g. coercivity and exchange bias field were attributed to differences in the structure and phase distribution. Ordered structures of wurtzite ZnO surrounded by amorphous ZnxFeyO were prepared through controlled phase segregation during the heating, which after multiple coating and heating cycles yielded ZnO–ZnxFeyO superlattices. The amorphous ZnxFeyO was a prerequisite for superlattice formation, and it profoundly affected the ZnO phase, inhibiting grain growth and texture, already from 1% Fe. In addition, ZnO–ZnxFeyO exhibited a photocatalytic activity for the oxidation of water that was higher than results reported for pure ZnO, and comparable to recent results reported for graphene-modified ZnO.

La réévaluation des impacts toxicologique et environnemental des répulsifs synthétiques conduit à reconsidérer les répulsifs d'origine naturelle pour la prévention des maladies transmises par les insectes (dengue, chikungunya, paludisme,…). Cette étude se rapporte aux structures de type bis(oxazolidine) envisagées comme prodrogues de répulsifs naturels par leur conversion avec le tris(hydroxyméthyl)aminométhane (TRIS). Différents protocoles et voies de synthèse ont été étudiés sur une série représentative d'aldéhydes pour définir l'étendue et les limites de l'approche permettant de concentrer deux unités d'un même principe actif au sein de bis(oxazolidines) symétriques et de reproduire un effet synergique avec deux unités différentes formant des bis(oxazolidines) dissymétriques. La fonctionnalisation des bis(oxazolidines) a été également envisagée pour moduler leur balance hydrophile-lipophile. L'étude de la réaction de cyclocondensation met en évidence l'influence des paramètres structuraux sur le procédé de synthèse des bis(oxazolidines), la stabilité des intermédiaires (monooxazolidines) et la stéréosélectivité de la réaction. L'interprétation des résultats est proposée sur la base des effets (stéréo)-électroniques. Cette étude démontre l'intérêt de cette approche chimique pour la production de prodrogues de répulsifs naturels qui peuvent constituer des atouts pour le développement durable. / The more sensitive human and environmental risk assessments of non natural repellents have encouraged the rehabilitation of botanical-based repellents for the prevention of insect-transmitted diseases (dengue, chikungunya, malaria…). This study is related to bis(oxazolidine) structures envisaged as prodrug derivatives of natural repellents by their conversion with tris(hydroxymethyl)aminomethane (TRIS). The scope and limitations of various procedures and pathways have been assessed with structurally diverse aldehydes to concentrate two identical units in the symmetrical structures and to reproduce a synergistic effect with two different units in the unsymmetrical ones. Subsequent functionalization of the heterocyclic derivatives has been achieved to modulate their hydrophilic-lipophilic balance. The study of the cyclocondensation reaction shows evidence for the influence of structural effects not only on the chemical process but also on the relative stability of the monocyclic intermediates and the stereochemical outcomes of the reaction. The results are discussed on the basis of (stereo)-electronic effects. Finally, this study confirms the feasibility of this chemical approach to produce prodrugs of natural repellents which could appear as a contributive effort to sustainable development.

[pt] Nanocompósitos de cobre com nanotubos de carbono (Cu-CNT) são considerados promissores para aplicações em materiais eletrônicos, trocadores de calor e como elementos estruturais. Espera-se que com a adição de CNTs, a matriz de cobre possa melhorar as propriedades mecânicas e de transporte. No presente estudo foram produzidos materiais nanocompósitos de matriz de cobre reforçados 0,5, 2 e 5,0 por cento em massa de MWCNT. O procedimento parte da funcionalização dos MWCNTS por método de oxidação convencional e microondas, e sua posterior incorporação na solução de nitrato de cobre, dispersão, dissociação e redução in-situ, com atmosfera de hidrogênio. Foram avaliadas soluções dispersantes como a água e THF no processo da síntese. Técnicas de compactação a frio com posterior sinterização convencional e Spark Plasma Sintering (SPS) foram usadas para produção de pastilhas. Os CNTs funcionalizados pelo método convencional se mostram efetivos para dispersão e decoração quando utilizado THF como solução dispersante. Análises por TEMEELS indicam a presença de cobre metálico na interface Cu-MWCNT. As pastilhas produzidas por sinterização convencional apresentaram tamanho de grão entre 50 nm e 4 um, com boa distribuição dos CNTs, assim como uma diminuição na resistividade elétrica em 98 por cento usando 5wt por cento MWCNT. Por outro lado, as pastilhas produzidas por SPS apresentaram tamanho de grão entre 50nm e 2 um, com alta segregação e modificação dos MWCNTs nos contornos de grão da matriz, assim como o aumento na resistividade elétrica. Aumento de 139 por cento na dureza e 65.5 por cento no módulo de elasticidade foi observado na amostra contendo 0.5 wt por cento MWCNTs produzida por SPS, enquanto valores similares ou inferiores foram observados nas outras frações em massa de MWCNTs. / [en] Copper- multiwall carbon nanotube nanocomposites (Cu-MWCNT) are been considered as a promising material for applications in electronic materials, heat exchanger and structural elements. It is expected that MWCNT addition in a copper matrix can improve the mechanical and transport properties. In this work Cu matrix nanocomposites reinforced with 0,5 wt percent; 2 wt percent; and 5,0 wt percent MWCNT were produced. The procedure starts from the MWCNTs functionalization by conventional oxidation and microwave methods and subsequent incorporation into the copper nitrate solution, dispersion, dissociation, and in-situ reduction in hydrogen atmosphere. Also, it was evaluated water and THF solutions for MWCNTs dispersants. Cold compaction follow by conventional sintering and Spark Plasma Sintering (SPS) techniques were used to produce pellets. CNTs functionalized by conventional method are shown effective for dispersing and decorating CNTs when THF was used as dispersant solution. TEM-EELS analyses indicate the presence of metallic copper in the Cu- MWCNT interface. Pellets produced by conventional sintering were in the 50nm - 4 um grain size, with good CNT distribution and decreasing in 98 per cent the electrical resistivity using 5wt percent MWCNT. Meanwhile, pellets produced by SPS were in the 50nm - 2um grain size with high segregation and modification of MWCNTs at the grain boundaries, as well as the increase in electrical resistivity. Increase of hardness 139 percent and 65.5 percent in elastic modulus were observed in the sample containing 0.5 wt percent MWCNTs produced by SPS, while similar or lower values were observed in the other MWCNTs fractions.

Les nanoparticules (NPs) de métaux nobles ont de nombreuses applications grâce à leurs propriétés optiques, chimiques et électriques extraordinaires. Les propriétés optiques résultent de plasmons localisés de surface, exaltant l’absorption et la diffusion de la lumière aux longueurs d’onde de résonance dans le domaine du visible. Les propriétés optiques, dépendantes de la taille et de la forme exacte de la NP, sont mises à profit dans l’objectif de créer un absorbant parfait en couche mince. Les applications de ces couches minces concernent, parmi d’autres, les photodétecteurs, le solaire thermique et les applications de furtivité.Les récents progrès accomplis dans le domaine des synthèses colloïdales de NPs nous permettent de synthétiser des nanosphères, nanocubes et nanoprismes d’Ag de différentes tailles. Ces NPs sont déposées aléatoirement dans une matrice hôte non-absorbante afin d’être caractérisées optiquement. Les résultats expérimentaux sont validés à l’aide de calculs numériques, permettant en outre de visualiser les phénomènes physiques à l’échelle de la NP.Cette thèse décrit les synthèses chimiques et les caractérisations optiques. Des mesures de spectroscopie ellipsométriques sont effectuées sur différentes couches minces. Un modèle optique simple, constitué d’une loi de Cauchy et d’une ou plusieurs lois de Gauss, est dérivé afin d’obtenir les indices optiques complexes de nos échantillons. La comparaison des coefficients d’extinction des différentes couches montre que les propriétés optiques de chaque NP sont additionnées en mélange et en empilement. Les calculs numériques relient ce résultat à la faible densité de nanoparticules en couche. / Noble metal nanoparticles (NPs) have a broad range of applications thanks to their extraordinary optical, chemical and electrical properties. The optical properties are driven by their ability to support localized surface plasmon resonances, which induce enhanced absorption and scattering at their resonance wavelengths in the visible spectrum. These size and shape dependent optical properties are taken advantage of in the search for a thin film layer perfect absorber in the visible wavelength band. The application for such thin film layers with engineered optical properties ranges from photodetectors, over thermal solar cells to stealth applications.Recent progress in colloidal NP synthesis makes the chemical wet synthesis of silver nanospheres, nanocubes and nanoprisms of various sizes easily feasible. The different NPs are then randomly deposited in a transparent and non-absorbing host matrix for optical characterizations. Computer simulations validate the experimental results and allow a visualization of the phenomena occurring at the nanoparticle scale.This PhD thesis reports the chemical synthesis of the different nanoparticles and their optical characterizations. Spectroscopic ellipsometry measurements are performed on single shape NPs, blends and multilayer stacks. A simple diffusion model, composed of a single Cauchy law and one or several Gauss laws, is chosen to determine the complex optical indices. The comparison of the extinction coefficients of the different layers shows that the optical properties of each NP are simply added in the blend and multilayer samples. Computer simulations relate this to the low density of nanoparticles.