Crystallographic evidence for the action of potassium, thallium, and lithium ions on fructose-1,6-bisphosphatase.

Fructose-1,6-bisphosphatase (Fru-1,6-Pase; D-fructose-1,6-bisphosphate 1-phosphohydrolase, EC 3.1.3.11) requires two divalent metal ions to hydrolyze alpha-D-fructose 1,6-bisphosphate. Although not required for catalysis, monovalent cations modify the enzyme activity; K+ and Tl+ ions are activators, whereas Li+ ions are inhibitors. Their mechanisms of action are still unknown. We report here crystallographic structures of pig kidney Fru-1,6-Pase complexed with K+, Tl+, or both Tl+ and Li+. In the T form Fru-1,6-Pase complexed with the substrate analogue 2,5-anhydro-D-glucitol 1,6-bisphosphate (AhG-1,6-P2) and Tl+ or K+ ions, three Tl+ or K+ binding sites are found. Site 1 is defined by Glu-97, Asp-118, Asp-121, Glu-280, and a 1-phosphate oxygen of AhG-1,6-P2; site 2 is defined by Glu-97, Glu-98, Asp-118, and Leu-120. Finally, site 3 is defined by Arg-276, Glu-280, and the 1-phosphate group of AhG-1,6-P2. The Tl+ or K+ ions at sites 1 and 2 are very close to the positions previously identified for the divalent metal ions. Site 3 is specific to K+ or Tl+. In the divalent metal ion complexes, site 3 is occupied by the guanidinium group of Arg-276. These observations suggest that Tl+ or K+ ions can substitute for Arg-276 in the active site and polarize the 1-phosphate group, thus facilitating nucleophilic attack on the phosphorus center. In the T form complexed with both Tl+ and Li+ ions, Li+ replaces Tl+ at metal site 1. Inhibition by lithium very likely occurs as it binds to this site, thus retarding turnover or phosphate release. The present study provides a structural basis for a similar mechanism of inhibition for inositol monophosphatase, one of the potential targets of lithium ions in the treatment of manic depression.

Photoconductivity and Electro-Optical Properties of Wide Band Gap Metal Oxides

The PhD activity described in this Thesis was focused on the study of metal-oxide wide-bandgap materials, aiming at fabricating new optoelectronic devices such as solar-blind UV photodetectors, high power electronics, and gas sensors. Photocurrent spectroscopy and DC photocurrent time evolution were used to investigate the performance of prototypes under different atmospheres, temperatures and excitation wavelengths (or dark conditions). Cathodoluminescence, absorption spectroscopy, XRD and SEM were used to assess structural, morphologic, electrical and optical properties of materials. This thesis is divided into two main sections, each describing the work done on a different metal-oxide semiconductor. 1) MOVPE-grown Ga2O3 thin films for UV solar-blind photodetectors and high power devices The semiconducting oxides, among them Ga2O3, have been employed for several decades as transparent conducting oxide (TCO) electrodes for fabrication of solar cells, displays, electronic, and opto-electronic devices. The interest was mainly confined to such applications, as these materials tend to grow intrinsically n-type, and attempts to get an effective p-type doping has consistently failed. The key requirements of TCO electrodes are indeed high electrical conductivity and good transparency, while crystallographic perfection is a minor issue. Furthermore, for a long period no high-quality substrates and epi-layers were available, which in turn impeded the development of a truly full-oxide electronics. Recently, Ga2O3 has attracted renewed interest, as large single crystals and high-quality homo- and hetero-epitaxial layers became available, which paved the way to novel application areas. Our research group spent the last two years in developing a low temperature (500-700°C) MOVPE growth procedure to obtain thin films of Ga2O3 on different substrates (Dept. of Physics and IMEM-CNR at UNIPR). We obtained a significant result growing on oriented sapphire epitaxial films of high crystalline, undoped, pure phase -Ga2O3 (hexagonal). The crystallographic properties of this phase were investigated by XRD, in order to clarify the lattice parameters of the hexagonal cell. First design and development of solar blind UV photodetectors based on -phase was carried out and the optoelectronic performance is evaluated by means of photocurrent spectroscopy. The UV-response is adequately fast and reliable to render this unusual phase a subject of great interest for future applications. The availability of a hexagonal phase of Ga2O3 stable up to 700°C, belonging to the same space group of gallium nitride, with high crystallinity and tunable electrical properties, is intriguing in view of the development of nitride-based devices, by taking advantage of the more favorable symmetry and epitaxial relationships with respect to the monoclinic β-phase. In addition, annealing at temperatures higher than 700°C demonstrate that the hexagonal phase converts totally in the monoclinic one. 2) ZnO nano-tetrapods: charge transport mechanisms and time-response in optoelectronic devices and sensors Size and morphology of ZnO at the nanometer scale play a key role in tailoring its physical and chemical properties. Thanks to the possibility of growing zinc oxide in a variety of different nanostructures, there is a great variety of applications, among which gas sensors, light emitting diodes, transparent conducting oxides, solar cells. Even if the operation of ZnO nanostructure-based devices has been recently demonstrated, the mechanisms of charge transport in these assembly is still under debate. The candidate performed an accurate investigation by photocurrent spectroscopy and DC-photocurrent time evolution of electrical response of both single-tetrapod and tetrapod-assembly devices. During the research done for this thesis, a thermal activation energy enables the performance of samples at high temperatures (above about 300°C). The energy barrier is related to the leg-to-leg interconnection in the assembly of nanotetrapods. Percolation mechanisms are responsible for both the very slow photo-response (minutes to hours or days) and the significant persistent photocurrent. Below the bandgap energy, electronic states were investigated but their contribution to the photocurrent are two-three order of magnitude lower than the band edge. Such devices are suitable for employ in photodetectors as well as in gas sensors, provided that the mechanism by which the photo-current is generated and gas adsorption on the surface modify the conductivity of the material are known.

Polímeros de coordenação à base de cobalto(II) e N,N'-bis(4-piridil)-1,4,5,8-naftaleno diimida como ligante e suas propriedade estruturais, espectroscópicas e fotoelétricas

Polímeros de coordenação têm atraído a atenção de pesquisadores na última década por conta de sua incrível versatilidade e virtualmente infinito número de possibilidades de combinação de ligantes orgânicos e centros metálicos. Estes compostos normalmente herdam as características magnéticas, eletrônicas e espectroscópicas de seus componentes base. Entretanto, apesar do crescente número de trabalhos na área, ainda são raros os polímeros de coordenação que apresentem condutividade elétrica. Para este fim, utilizou-se a N,N\'-bis(4-piridil)-1,4,5,8-naftaleno diimida, ou NDI-py, que pertence a uma classe de compostos rígidos, planares, quimicamente e termicamente estáveis e que já foram extensamente estudados por suas propriedades fotoeletroquímicas e semicondução do tipo n. O primeiro polímero de coordenação sintetizado, MOF-CoNDI-py-1, indicou ser um polímero linear, de estrutura 1D. O segundo, MOF-CoNDI-py-2, que conta com ácido tereftálico como ligante suporte, é um sólido cristalino com cela unitária monoclínica pertencente ao grupo espacial C2/c, determinado por difração de raios-X de monocristal. A rede apresenta um arranjo trinuclear de íons Co(II) alto spin com coordenados em uma geometria de octaedro distorcido, enquanto os ligantes NDI-py se encontram em um arranjo paralelo na estrutura, em distâncias apropriadas para transferência eletrônica. Com o auxílio de cálculo teóricos a nível de DFT, foi realizado um estudo aprofundado dos espectros eletrônicos e vibracionais, com atribuição das transições observadas, tanto para o MOF-CoNDI-py-2 quanto para o ligante NDI-py livre. A rede de coordenação absorve em toda a região do espectro eletrônico analisada, de 200 nm a 2500 nm, além de apresentar luminescência com característica do ligante. Dispositivos eletrônicos fabricados com um cristal do MOF-CoNDI-py-2 revelaram condutividades da ordem de 7,9 10-3 S cm -1, a maior já observada para um MOF. Além de elevada, a condutividade elétrica dos cristais demonstrou-se altamente anisotrópica, sendo significativamente menos condutor em algumas direções. Os perfis de corrente versus voltagem foram analisados em termos de mecanismos de condutividade, sendo melhores descritos por um mecanismo limitado pelo eletrodo to tipo Space-Charge Limited Current, concordando com a proposta de condutividade através dos planos de NDI-py na rede. A condutividade dos cristais também é fortemente dependente de luz, apresentando fotocondução quando irradiado por um laser vermelho, de 632 nm, enquanto apresenta um comportamento fotorresistivo frente a uma fonte de luz branca. Estes resultados, combinados, trazem um MOF em uma estrutura incomum e com elevada condutividade elétrica, modulada por luz, em medidas diretas de corrente. Não existem exemplos conhecidos de MOFs na literatura com estas características.

Estudo e desenvolvimento de catalisadores para células a combustível visando o aumento de escala e avaliação da distribuição de corrente

O trabalho visa o desenvolvimento do sistema para medidas de distribuição de corrente e ampliação de escala (50 cm²) buscando aperfeiçoar as condições de preparação do conjunto eletrodo membrana (MEA) quanto às condições de operação da célula e avaliar a melhor geometria. Foram realizados estudos de síntese de catalisadores de Pt-M e avaliação do desempenho desses materias e das rotas de síntese utilizadas com objetivo de aplicar estes materias em sistemas de maior escala. A insuficiência do desempenho e estabilidade dos catalisadores são fatores que ainda inviabilizam o uso em larga escala das células a combustível de eletrólito polimérico sólido, destacando-se as perdas associadas ao desempenho do cátodo. Os catalisadores preparados foram nanopartículas bimetálicas PtM/C (M = Fe, Co e Ni) suportadas em carbono de elevada área superficial, por duas rotas sintéticas. Foram utilizadas as rotas: ácido fórmico e etilenoglicol modificado (EG). Em ambas as rotas se buscou catalisadores com alto grau de incorporação do segundo metal, tamanho de partícula pequeno e bom desempenho catalítico do cátodo. Observou-se que pela rota do ácido fórmico com modificações no processo de síntese é possível obter a incorporação nominal do segundo metal no catalisador, porém há desvantagem de o tamanho de partícula ser elevado. Pela rota do EG obteve-se catalisadores com pequeno tamanho de partícula, porém a incorporação do segundo metal mostrou-se ineficiente. Os estudos de ampliação de escala foram realizados em células de 50 cm2 variando-se as condições de operação; i) diferentes placas de distribuição de gás, e ii) diferentes valores de fluxo dos gases reagentes. Foi observado que a baixos fluxos de gases a quantidade de reagente é insuficiente para ser difundida por todo eletrodo, o que ocasiona reação apenas na região de entrada de gases no sistema, ocasionando uma rápida limitação em obter-se densidades de corrente alta. Pode-se observar que a diferença de desempenho entre as placas é pequena, porém a placa serpentina 6 apresentou melhor desempenho. O desempenho dos cátodos preparados com catalisadores comerciais e os sintetizados no laboratório nas células de 50 cm² mostrou sofrer bastante influência das condições de operação comparada com as células de 4,6 cm².

Oxide Semiconductors For Organic Opto-electronic Devices

Development of transparent oxide semiconductors (TOS) from Earth-abundant materials is of great interest for cost-effective thin film device applications, such as solar cells, light emitting diodes (LEDs), touch-sensitive displays, electronic paper, and transparent thin film transistors. The need of inexpensive or high performance electrode might be even greater for organic photovoltaic (OPV), with the goal to harvest renewable energy with inexpensive, lightweight, and cost competitive materials. The natural abundance of zinc and the wide bandgap ($sim$3.3 eV) of its oxide make it an ideal candidate. In this dissertation, I have introduced various concepts on the modulations of various surface, interface and bulk opto-electronic properties of ZnO based semiconductor for charge transport, charge selectivity and optimal device performance. I have categorized transparent semiconductors into two sub groups depending upon their role in a device. Electrodes, usually 200 to 500 nm thick, optimized for good transparency and transporting the charges to the external circuit. Here, the electrical conductivity in parallel direction to thin film, i.e bulk conductivity is important. And contacts, usually 5 to 50 nm thick, are optimized in case of solar cells for providing charge selectivity and asymmetry to manipulate the built in field inside the device for charge separation and collection. Whereas in Organic LEDs (OLEDs), contacts provide optimum energy level alignment at organic oxide interface for improved charge injections. For an optimal solar cell performance, transparent electrodes are designed with maximum transparency in the region of interest to maximize the light to pass through to the absorber layer for photo-generation, plus they are designed for minimum sheet resistance for efficient charge collection and transport. As such there is need for material with high conductivity and transparency. Doping ZnO with some common elements such as B, Al, Ga, In, Ge, Si, and F result in n-type doping with increase in carriers resulting in high conductivity electrode, with better or comparable opto-electronic properties compared to current industry-standard indium tin oxide (ITO). Furthermore, improvement in mobility due to improvement on crystallographic structure also provide alternative path for high conductivity ZnO TCOs. Implementing these two aspects, various studies were done on gallium doped zinc oxide (GZO) transparent electrode, a very promising indium free electrode. The dynamics of the superimposed RF and DC power sputtering was utilized to improve the microstructure during the thin films growth, resulting in GZO electrode with conductivity greater than 4000 S/cm and transparency greater than 90 %. Similarly, various studies on research and development of Indium Zinc Tin Oxide and Indium Zinc Oxide thin films which can be applied to flexible substrates for next generation solar cells application is presented. In these new TCO systems, understanding the role of crystallographic structure ranging from poly-crystalline to amorphous phase and the influence on the charge transport and optical transparency as well as important surface passivation and surface charge transport properties. Implementation of these electrode based on ZnO on opto-electronics devices such as OLED and OPV is complicated due to chemical interaction over time with the organic layer or with ambient. The problem of inefficient charge collection/injection due to poor understanding of interface and/or bulk property of oxide electrode exists at several oxide-organic interfaces. The surface conductivity, the work function, the formation of dipoles and the band-bending at the interfacial sites can positively or negatively impact the device performance. Detailed characterization of the surface composition both before and after various chemicals treatment of various oxide electrode can therefore provide insight into optimization of device performance. Some of the work related to controlling the interfacial chemistry associated with charge transport of transparent electrodes are discussed. Thus, the role of various pre-treatment on poly-crystalline GZO electrode and amorphous indium zinc oxide (IZO) electrode is compared and contrasted. From the study, we have found that removal of defects and self passivating defects caused by accumulation of hydroxides in the surface of both poly-crystalline GZO and amorphous IZO, are critical for improving the surface conductivity and charge transport. Further insight on how these insulating and self-passivating defects cause charge accumulation and recombination in an device is discussed. With recent rapid development of bulk-heterojunction organic photovoltaics active materials, devices employing ZnO and ZnO based electrode provide air stable and cost-competitive alternatives to traditional inorganic photovoltaics. The organic light emitting diodes (OLEDs) have already been commercialized, thus to follow in the footsteps of this technology, OPV devices need further improvement in power conversion efficiency and stable materials resulting in long device lifetimes. Use of low work function metals such as Ca/Al in standard geometry do provide good electrode for electron collection, but serious problems using low work-function metal electrodes originates from the formation of non-conductive metal oxide due to oxidation resulting in rapid device failure. Hence, using low work-function, air stable, conductive metal oxides such as ZnO as electrons collecting electrode and high work-function, air stable metals such as silver for harvesting holes, has been on the rise. Devices with degenerately doped ZnO functioning as transparent conductive electrode, or as charge selective layer in a polymer/fullerene based heterojunction, present useful device structures for investigating the functional mechanisms within OPV devices and a possible pathway towards improved air-stable high efficiency devices. Furthermore, analysis of the physical properties of the ZnO layers with varying thickness, crystallographic structure, surface chemistry and grain size deposited via various techniques such as atomic layer deposition, sputtering and solution-processed ZnO with their respective OPV device performance is discussed. We find similarity and differences in electrode property for good charge injection in OLEDs and good charge collection in OPV devices very insightful in understanding physics behind device failures and successes. In general, self-passivating surface of amorphous TCOs IZO, ZTO and IZTO forms insulating layer that hinders the charge collection. Similarly, we find modulation of the carrier concentration and the mobility in electron transport layer, namely zinc oxide thin films, very important for optimizing device performance.

Electrocatalytic hydrogenation of acetophenone using a Polymer Electrolyte Membrane Electrochemical Reactor

The use of a solid polymeric electrolyte, spe, is not commonly found in organic electrosynthesis despite its inherent advantages such as the possible elimination of the electrolyte entailing simpler purification processes, a smaller sized reactor and lower energetic costs. In order to test if it were possible to use a spe in industrial organic electrosynthesis, we studied the synthesis of 1-phenylethanol through the electrochemical hydrogenation of acetophenone using Pd/C 30 wt% with different loadings as cathode and a hydrogen gas diffusion anode. A Polymer Electrolyte Membrane Electrochemical Reactor, PEMER, with a fuel cell structure was chosen to carry out electrochemical reduction with a view to simplifying an industrial scale-up of the electrochemical process. We studied the influence of current density and cathode catalyst loading on this electroorganic synthesis. Selectivity for 1-phenylethanol was around 90% with only ethylbenzene and hydrogen detected as by-products.

From community approaches to single-cell genomics: the discovery of ubiquitous hyperhalophilic Bacteroidetes generalists

The microbiota of multi-pond solar salterns around the world has been analyzed using a variety of culture-dependent and molecular techniques. However, studies addressing the dynamic nature of these systems are very scarce. Here we have characterized the temporal variation during 1 year of the microbiota of five ponds with increasing salinity (from 18% to >40%), by means of CARD-FISH and DGGE. Microbial community structure was statistically correlated with several environmental parameters, including ionic composition and meteorological factors, indicating that the microbial community was dynamic as specific phylotypes appeared only at certain times of the year. In addition to total salinity, microbial composition was strongly influenced by temperature and specific ionic composition. Remarkably, DGGE analyses unveiled the presence of most phylotypes previously detected in hypersaline systems using metagenomics and other molecular techniques, such as the very abundant Haloquadratum and Salinibacter representatives or the recently described low GC Actinobacteria and Nanohaloarchaeota. In addition, an uncultured group of Bacteroidetes was present along the whole range of salinity. Database searches indicated a previously unrecognized widespread distribution of this phylotype. Single-cell genome analysis of five members of this group suggested a set of metabolic characteristics that could provide competitive advantages in hypersaline environments, such as polymer degradation capabilities, the presence of retinal-binding light-activated proton pumps and arsenate reduction potential. In addition, the fairly high metagenomic fragment recruitment obtained for these single cells in both the intermediate and hypersaline ponds further confirm the DGGE data and point to the generalist lifestyle of this new Bacteroidetes group.

Electrocatalytic reduction of CO2 to formate using particulate Sn electrodes: Effect of metal loading and particle size

The development of electrochemical processes for the conversion of CO2 into value-added products allows innovative carbon capture & utilization (CCU) instead of carbon capture & storage (CCS). In addition, coupling this conversion with renewable energy sources would make it possible to chemically store electricity from these intermittent renewable sources. The electroreduction of CO2 to formate in aqueous solution has been performed using Sn particles deposited over a carbon support. The effect of the particle size and Sn metal loading has been evaluated using cyclic voltammetry and chronoamperometry. The selected electrode has been tested on an experimental filter-press type cell system for continuous and single pass CO2 electroreduction to obtain formate as main product at ambient pressure and temperature. Experimental results show that using electrodes with 0.75 mg Sn cm−2, 150 nm Sn particles, and working at a current density of 90 mA cm−2, it is possible to achieve rates of formate production over 3.2 mmol m−2 s−1 and faradaic efficiencies around 70% for 90 min of continuous operation. These experimental conditions allow formate concentrations of about 1.5 g L−1 to be obtained on a continuous mode and with a single pass of catholyte through the cell.

Large spin splitting in the conduction band of transition metal dichalcogenide monolayers

We study the conduction band spin splitting that arises in transition metal dichalcogenide (TMD) semiconductor monolayers such as MoS2, MoSe2, WS2, and WSe2 due to the combination of spin-orbit coupling and lack of inversion symmetry. Two types of calculation are done. First, density functional theory (DFT) calculations based on plane waves that yield large splittings, between 3 and 30 meV. Second, we derive a tight-binding model that permits to address the atomic origin of the splitting. The basis set of the model is provided by the maximally localized Wannier orbitals, obtained from the DFT calculation, and formed by 11 atomiclike orbitals corresponding to d and p orbitals of the transition metal (W, Mo) and chalcogenide (S, Se) atoms respectively. In the resulting Hamiltonian, we can independently change the atomic spin-orbit coupling constant of the two atomic species at the unit cell, which permits to analyze their contribution to the spin splitting at the high symmetry points. We find that—in contrast to the valence band—both atoms give comparable contributions to the conduction band splittings. Given that these materials are most often n-doped, our findings are important for developments in TMD spintronics.

Design and synthesis of constrained azacyclic pyrrolidine analogues of FTY720 as anticancer agents & metal coordination-controlled and bifunctional catalysis toward tertiary β-Ketols

Cette thèse se compose en deux parties: Première Partie: La conception et la synthèse d’analogues pyrrolidiniques, utilisés comme agents anticancéreux, dérivés du FTY720. FTY720 est actuellement commercialisé comme médicament (GilenyaTM) pour le traitement de la sclérose en plaques rémittente-récurrente. Il agit comme immunosuppresseur en raison de son effet sur les récepteurs de la sphingosine-1-phosphate. A fortes doses, FTY720 présente un effet antinéoplasique. Cependant, à de telles doses, un des effets secondaires observé est la bradycardie dû à l’activation des récepteurs S1P1 et S1P3. Ceci limite son potentiel d’utilisation lors de chimiothérapie. Nos précédentes études ont montré que des analogues pyrrolidiniques dérivés du FTY720 présentaient une activité anticancéreuse mais aucune sur les récepteurs S1P1 et S1P3. Nous avons soumis l’idée qu’une étude relation structure-activité (SARs) pourrait nous conduire à la découverte de nouveaux agents anti tumoraux. Ainsi, deux séries de composés pyrrolidiniques (O-arylmethyl substitué et C-arylmethyl substitué) ont pu être envisagés et synthétisés (Chapitre 1). Ces analogues ont montré d’excellentes activités cytotoxiques contre diverses cellules cancéreuses humaines (prostate, colon, sein, pancréas et leucémie), plus particulièrement les analogues actifs qui ne peuvent pas être phosphorylés par SphK, présentent un plus grand potentiel pour le traitement du cancer sans effet secondaire comme la bradycardie. Les études mécanistiques suggèrent que ces analogues de déclencheurs de régulation négative sur les transporteurs de nutriments induisent une crise bioénergétique en affamant les cellules cancéreuses. Afin d’approfondir nos connaissances sur les récepteurs cibles, nous avons conçu et synthétisé des sondes diazirine basées sur le marquage d’affinité aux photons (méthode PAL: Photo-Affinity Labeling) (Chapitre 2). En s’appuyant sur la méthode PAL, il est possible de récolter des informations sur les récepteurs cibles à travers l’analyse LC/MS/MS de la protéine. Ces tests sont en cours et les résultats sont prometteurs. Deuxième partie: Coordination métallique et catalyse di fonctionnelle de dérivés β-hydroxy cétones tertiaires. Les réactions de Barbier et de Grignard sont des méthodes classiques pour former des liaisons carbone-carbone, et généralement utilisées pour la préparation d’alcools secondaires et tertiaires. En vue d’améliorer la réaction de Grignard avec le 1-iodobutane dans les conditions « one-pot » de Barbier, nous avons obtenu comme produit majoritaire la β-hydroxy cétone provenant de l’auto aldolisation de la 5-hexen-2-one, plutôt que le produit attendu d’addition de l’alcool (Chapitre 3). La formation inattendue de la β-hydroxy cétone a également été observée en utilisant d’autres dérivés méthyl cétone. Étonnement dans la réaction intramoléculaire d’une tricétone, connue pour former la cétone Hajos-Parrish, le produit majoritaire est rarement la β-hydroxy cétone présentant la fonction alcool en position axiale. Intrigué par ces résultats et après l’étude systématique des conditions de réaction, nous avons développé deux nouvelles méthodes à travers la synthèse sélective et catalytique de β-hydroxy cétones spécifiques par cyclisation intramoléculaire avec des rendements élevés (Chapitre 4). La réaction peut être catalysée soit par une base adaptée et du bromure de lithium comme additif en passant par un état de transition coordonné au lithium, ou bien soit à l’aide d’un catalyseur TBD di fonctionnel, via un état de transition médiée par une coordination bidenté au TBD. Les mécanismes proposés ont été corroborés par calcul DFT. Ces réactions catalytiques ont également été appliquées à d’autres substrats comme les tricétones et les dicétones. Bien que les efforts préliminaires afin d’obtenir une enantioselectivité se sont révélés sans succès, la synthèse et la recherche de nouveaux catalyseurs chiraux sont en cours.

Design and synthesis of constrained azacyclic pyrrolidine analogues of FTY720 as anticancer agents & metal coordination-controlled and bifunctional catalysis toward tertiary β-Ketols

Cette thèse se compose en deux parties: Première Partie: La conception et la synthèse d’analogues pyrrolidiniques, utilisés comme agents anticancéreux, dérivés du FTY720. FTY720 est actuellement commercialisé comme médicament (GilenyaTM) pour le traitement de la sclérose en plaques rémittente-récurrente. Il agit comme immunosuppresseur en raison de son effet sur les récepteurs de la sphingosine-1-phosphate. A fortes doses, FTY720 présente un effet antinéoplasique. Cependant, à de telles doses, un des effets secondaires observé est la bradycardie dû à l’activation des récepteurs S1P1 et S1P3. Ceci limite son potentiel d’utilisation lors de chimiothérapie. Nos précédentes études ont montré que des analogues pyrrolidiniques dérivés du FTY720 présentaient une activité anticancéreuse mais aucune sur les récepteurs S1P1 et S1P3. Nous avons soumis l’idée qu’une étude relation structure-activité (SARs) pourrait nous conduire à la découverte de nouveaux agents anti tumoraux. Ainsi, deux séries de composés pyrrolidiniques (O-arylmethyl substitué et C-arylmethyl substitué) ont pu être envisagés et synthétisés (Chapitre 1). Ces analogues ont montré d’excellentes activités cytotoxiques contre diverses cellules cancéreuses humaines (prostate, colon, sein, pancréas et leucémie), plus particulièrement les analogues actifs qui ne peuvent pas être phosphorylés par SphK, présentent un plus grand potentiel pour le traitement du cancer sans effet secondaire comme la bradycardie. Les études mécanistiques suggèrent que ces analogues de déclencheurs de régulation négative sur les transporteurs de nutriments induisent une crise bioénergétique en affamant les cellules cancéreuses. Afin d’approfondir nos connaissances sur les récepteurs cibles, nous avons conçu et synthétisé des sondes diazirine basées sur le marquage d’affinité aux photons (méthode PAL: Photo-Affinity Labeling) (Chapitre 2). En s’appuyant sur la méthode PAL, il est possible de récolter des informations sur les récepteurs cibles à travers l’analyse LC/MS/MS de la protéine. Ces tests sont en cours et les résultats sont prometteurs. Deuxième partie: Coordination métallique et catalyse di fonctionnelle de dérivés β-hydroxy cétones tertiaires. Les réactions de Barbier et de Grignard sont des méthodes classiques pour former des liaisons carbone-carbone, et généralement utilisées pour la préparation d’alcools secondaires et tertiaires. En vue d’améliorer la réaction de Grignard avec le 1-iodobutane dans les conditions « one-pot » de Barbier, nous avons obtenu comme produit majoritaire la β-hydroxy cétone provenant de l’auto aldolisation de la 5-hexen-2-one, plutôt que le produit attendu d’addition de l’alcool (Chapitre 3). La formation inattendue de la β-hydroxy cétone a également été observée en utilisant d’autres dérivés méthyl cétone. Étonnement dans la réaction intramoléculaire d’une tricétone, connue pour former la cétone Hajos-Parrish, le produit majoritaire est rarement la β-hydroxy cétone présentant la fonction alcool en position axiale. Intrigué par ces résultats et après l’étude systématique des conditions de réaction, nous avons développé deux nouvelles méthodes à travers la synthèse sélective et catalytique de β-hydroxy cétones spécifiques par cyclisation intramoléculaire avec des rendements élevés (Chapitre 4). La réaction peut être catalysée soit par une base adaptée et du bromure de lithium comme additif en passant par un état de transition coordonné au lithium, ou bien soit à l’aide d’un catalyseur TBD di fonctionnel, via un état de transition médiée par une coordination bidenté au TBD. Les mécanismes proposés ont été corroborés par calcul DFT. Ces réactions catalytiques ont également été appliquées à d’autres substrats comme les tricétones et les dicétones. Bien que les efforts préliminaires afin d’obtenir une enantioselectivité se sont révélés sans succès, la synthèse et la recherche de nouveaux catalyseurs chiraux sont en cours.

Quarterly technical progress and schedule report "high resolution, low cost solar cell contact development" : for the quarter ending 24 August 1979 /

"21 September 1979."

Preliminary test on axial spindle expansion of nuber 739 Ex-Cell-O numerical tape control machine /

"U.S. Atomic Energy Commission Contract AT(29-1)-1106."

Development of liquid metal level probes /

"Contract AT(30-1)-2789."