Au cours de ce travail, nous nous sommes intéressés à la synthèse d'un analogue de Milnacipran, une molécule commercialisée sous le nom d'Ixel pour son activité anti-dépresseur. Il s'agit d'un cyclobutane trisubstitué portant deux centres stéréogènes contigus. L'objectif est de développer une voie de synthèse efficace et transposable à la version énantiosélective.Nous avons également travaillé sur la formulation nanométrique d'épiPodophyllotoxines, un produit naturel biologiquement active. Nous avons imaginé une architecture moléculaire permettant à la molécule de s'auto-assembler en micelle, ainsi elle peut être transportée de manière efficace au tumeur cancéreux. Les études in vitro et in vivo ont apporté des résultats prometteurs vis-à-vis du potentiel thérapeutique de notre nano-objet. Enfin nous avons étudié au cours de cette thèse deux méthodologies: la réactivité des époxydes en milieu alcalin fort et les dérivés d'organobismuth pour les réactions d'oxydation. Ces derniers ont été exploités afin d'oxyder des hydroxylamines en nitrone dans des conditions douces, permettant de réaliser le tandem oxydation/cycloaddition 1,3 dipolaire in situ avec des alcynes tendus. / My PhD thesis mainly involves the enantioselective synthesis of the Milnacipran's analog, a trisubstituted cyclobutane bearing two contiguous stereogenic centers. We have devised a conventional approach which consists of an intramolecular SN2 cyclization. After an acidic treatment, the key intermediate lactone was isolated with an ee > 99%, which was converted to the Milnacarre with no erosion of the ee value. We have also interested in the nanometric formulation of Podophyllotoxine derivatives. The natural product was designed to bear a hydrophilic and hydrophobic side chain. Its micellar solution was evaluated in vitro, in vivo and the obtained resuls were shown to be promising.We have also studied two methodologies: the reactivity of glycidyl ether toward alkyllithium reagents and oxydation of hydroxylamines to nitrone using triphenylbismuth carbonate. We observed in the former case an original rearrangement of the substrate to a vicinal diol, while in the latter case we have developped a mild condition to perform an tandem oxydation/1,3-dipolar cycloaddition in situ with a strained alkyne.

No description available.

<p>U radu je ostvarena totalna sinteza novih acikličnih&nbsp;tiazolnih C-nukleozide sa dvostrukom &nbsp;vezom i&nbsp;2&prime;,3&prime;-dideoksi funkcijom u &scaron;ećernoj komponenti.&nbsp;Ostvarena vi&scaron;efazna sinteza &nbsp;pomenutih acikličnih&nbsp;analoga tiazofurina zasnovana je na D-arabinozi&nbsp;kao hiralnom prekursoru. Ispitana je in vitro&nbsp;citotoksična&nbsp;aktivnost&nbsp;novosintetizovanih&nbsp;nukleozida prema ćelijskim linijama K562, HL-60,&nbsp;HT-29, MCF-7, MDA-MB-231, HeLa, Raji, PC3,&nbsp;Jurkat, Hs 294T i MRC-5, kao i provera ćelijskih&nbsp;mehanizama koji su u osnovi &nbsp;uočenog&nbsp;citotoksičnog potencijala novosintetisanih analoga&nbsp;u odnosu na tiazofurin kao referentno jedinjenje.</p> / <p>A total synthesis of new acyclic thiazole C-nucleozides&nbsp;bearing a double bond or 2&prime;,3&prime;-dideoxy functionality in&nbsp;the sugar moiety was achieved in this work. The multi-step synthesis of the mentioned thiazofurin analogues is&nbsp;based on&nbsp; D-arabinose as a chiral precursor. In vitro&nbsp;cytotoxic activity of newly synthesized compounds was&nbsp;evaluated against the following cell lines: K562, HL-60,&nbsp;HT-29, MCF-7, MDA-MB-231, HeLa, Raji, PC3, Jurkat,&nbsp;Hs 294T and MRC-5. A study of cell mechanisms&nbsp;underlaying the significant cytotoxic potential of these&nbsp;molecules was caried out and the results were compared&nbsp;to thiazofurin that servad as a referent compound in all&nbsp;biological testings.</p>

De par leur grande diversité chimique et leur implication dans de nombreux mécanismes biologiques, les molécules phosphorées font l'objet de nombreuses recherches scientifiques. Depuis près de 30 ans, plusieurs composés phosphorés ont été développés et utilisés pour leurs propriétés médicinales ou phytosanitaires. Les dérivés de type phosphinates ou phosphonates se sont révélés être des composés de choix, grâce à leur grande stabilité chimique et enzymatique. Par ailleurs, les sucres et leurs analogues ont largement démontré leur potentiel biologique en raison de leur implication dans de nombreux processus biologiques. Dans ce contexte, il a été envisagé de développer des analogues de sucres phosphorés possédant un atome de phosphore endocyclique. Il s'agit de structures totalement inédites obtenues à partir de précurseurs phosphorés simples et par des réactions de type : P-alkylation, Pudovik, ouverture d'époxyde, cyclisation par transacétalisation ou transestérification. Grâce à des synthèses en 4 à 7 étapes, deux familles de phosphinosucres ont été préparées ainsi qu'une famille de phosphonosucres en tant qu'analogues de sucre. En parallèle, la synthèse d'analogues de nucléosides phosphorés a également été étudiée par introduction de nucléobases sur les analogues de sucres phosphorés précédemment cités. Ces travaux ont mis en jeu des réactions issues à la fois de la chimie de nucléosides mais également de la chimie du phosphore, permettant d'accéder à des analogues de nucléosides totalement inédits dont l'activité antivirale a pu être évaluée. Enfin, une nouvelle famille de phosphonates nucléosidiques acycliques a été synthétisée en 6 ou 7 étapes en série pyrimidique. Deux prodrogues dérivées de la cytosine et de l'uracile ont également été préparées avec des groupements enzymolabiles de type Bis-(S-acyl-2-thioéthyle). L'ensemble des analogues de nucléotides synthétisés ont été évalués pour leurs propriétés antivirales contre les virus de l'hépatite C et du SIDA. Ainsi, à travers ce projet, trois grandes familles de nouvelles molécules phosphorées ont été développées : les hétérocycles phosphorés oxygénés en tant qu'analogues de sucres, des analogues de nucléosides phosphorés, une nouvelle classe de phosphonates nucléosidiques acycliques. / According to their wide chemical diversity and their implication in many biological processes, phosphorus compounds are intensively studied by organic chemists. Since 30 years, many phosphorus molecules have been developed and used for their biological properties in medicine or agrochemistry. Chemically and enzymatically stable compounds, phosphonates and phosphoninates are potential derivatives for drug design. Besides, sugars are an important biological family involved in numerous biological pathways which have widely revealed a high therapeutic potential. In this context, the first objective of these works was to develop sugar analogues with an endocyclic phosphorus atom (phosphasugars) to synthesize unpublished families of phosphinosugars and phosphonosugars. Their synthesis were carried out in 4 to 7 steps, using as key reactions : P-alkylation, Pudovik, epoxyde ring-opening reaction, cyclisation by transacetalisation or transesterification. Moreover, these phosphasugars were extended to the synthesis of new nucleoside analogues by introducing nucleobase on phosphasugar moiety. The antiviral activity of these new compounds was evaluated. Finally, a new class of acyclic nucleoside phosphonates was prepared in pyrimidinyl series. Different nucleotide analogues and prodrugs were synthesized in 6-7 steps with uracil, thymine and cytosine and evaluated against HCV and HIV.

Tato disertační práce se zabývá analýzou stability a konvergence klasických numerických metod pro řešení obyčejných diferenciálních rovnic. Jsou představeny klasické jednokrokové metody, jako je Eulerova metoda, Runge-Kuttovy metody a nepříliš známá, ale rychlá a přesná metoda Taylorovy řady. V práci uvažujeme zobecnění jednokrokových metod do vícekrokových metod, jako jsou Adamsovy metody, a jejich implementaci ve dvojicích prediktor-korektor. Dále uvádíme generalizaci do vícekrokových metod vyšších derivací, jako jsou např. Obreshkovovy metody. Dvojice prediktor-korektor jsou často implementovány v kombinacích modů, v práci uvažujeme tzv. módy PEC a PECE. Hlavním cílem a přínosem této práce je nová metoda čtvrtého řádu, která se skládá z dvoukrokového prediktoru a jednokrokového korektoru, jejichž formule využívají druhých derivací. V práci je diskutována Nordsieckova reprezentace, algoritmus pro výběr proměnlivého integračního kroku nebo odhad lokálních a globálních chyb. Navržený přístup je vhodně upraven pro použití proměnlivého integračního kroku s přístupe vyšších derivací. Uvádíme srovnání s klasickými metodami a provedené experimenty pro lineární a nelineární problémy.

Trifluoromethylierung von Mischungen hoeherer Fullerene mit CF3I wurde in Ampullen bei 400-420 Grad Celsius und 500-600 Grad Celsius durchgefuehrt. Die Produktmischungen wurden mittels mehrstufiger HPLC getrennt. In mehreren Versuchen konnten aus den isolierten HPLC-Fraktionen Kristalle fuer die Roentgenstrukturanalyse gewonnen werden. Die folgenden Strukturen der CF3-Derivate der Fullerene C84, C86 und C88 wurden bestimmt: 1 Isomer von C84(4)(CF3)12, C84(11)(CF3)10, C84(11)(CF3)12, C84(11)(CF3)16, C84(16)(CF3)8, C84(16)(CF3)14, C84(18)(CF3)10, C84(18)(CF3)12, C84(22)(CF3)20, C84(23)(CF3)8, C84(22)(CF3)10, C84(22)(CF3)12, C84(22)(CF3)18, C86(17)(CF3)10, C86(17)(CF3)16, C88(33)(CF3)16, C88(33)(CF3)18 und C88(33)(CF3)20. 2 Isomere von C84(22)(CF3)12, C84(22)(CF3)14 und C84(23)(CF3)14. 3 Isomere von C84(11)(CF3)14. 4 Isomere von C84(22)(CF3)16. Die Additionsmuster der Strukturen wurden diskutiert. Die experimentell nachgewiesenen Strukturen wurden mit berechneten Modellstrukturen verglichen. Dabei wurde auch die Stabilitaet der experimentellen Strukturen vorausgesagt. Zusaetzlich wurden die moeglichen Reaktionspfade fuer die Bildung hoeherer Derivate ausgehend von niedrigen Derivaten diskutiert. Sie zeigen, dass die Regioselektivitaet der Addition vom Kaefigisomer abhaengig ist. Die Reaktionspfade von vier Fullerenkaefigen werden in dieser Arbeit vorgestellt. C84(11)(CF3)10 --> C84(11)(CF3)16 C84(22)(CF3)2 --> C84(22)(CF3)20 C84(23)(CF3)10 --> C84(23)(CF3)18 C86(17)(CF3)10 --> C86(17)(CF3)16 / Trifluoromethylation of higher fullerene mixtures with CF3I was performed in ampoules at 400 to 420 degree Celsius and 500 to 600 degree Celsius. The obtained product mixtures were separated by multistep HPLC. Subsequent crystal growth and X-ray diffraction measurements allowed for structural characterization of the CF3 derivatives of fullerenes C84, C86 and C88 listed as the following. 1 isomer of C84(4)(CF3)12, C84(11)(CF3)10, C84(11)(CF3)12, C84(11)(CF3)16, C84(16)(CF3)8, C84(16)(CF3)14, C84(18)(CF3)10, C84(18)(CF3)12, C84(22)(CF3)20, C84(23)(CF3)8, C84(22)(CF3)10, C84(22)(CF3)12, C84(22)(CF3)18, C86(17)(CF3)10, C86(17)(CF3)16, C88(33)(CF3)16, C88(33)(CF3)18 and C88(33)(CF3)20. 2 isomers of C84(22)(CF3)12, C84(22)(CF3)14 and C84(23)(CF3)14. 3 isomers of C84(11)(CF3)14. 4 isomers of C84(22)(CF3)16. The molecular structures of isolated isomers were discussed in terms of their addition patterns and relative formation energies. DFT calculations were used to predict stable molecular structures of the CF3 derivatives. Calculated model structures have been compared with the experimental ones. In addition, the reaction pathways from the lower derivatives to higher ones of selected compounds were predicted. The pathways indicate the regioselectivity of additions depending on the fullerene cage isomer. Reaction pathways are presented for four fullerene cages in this work. C84(11)(CF3)10 --> C84(11)(CF3)16 C84(22)(CF3)2 --> C84(22)(CF3)20 C84(23)(CF3)10 --> C84(23)(CF3)18 C86(17)(CF3)10 --> C86(17)(CF3)16

[pt] Estudos empíricos na área de séries temporais indicam que combinar modelos preditivos, originados a partir de diferentes técnicas de modelagem, levam a previsões consensuais superiores, em termos de acurácia, às previsões individuais dos modelos envolvidos na combinação. No presente trabalho é apresentada uma metodologia de combinação convexa de modelos estatísticos de previsão, cujo sucesso depende da forma como os pesos de combinação de cada modelo são estimados. Uma Rede Neural Artificial Perceptron Multi-camada (Multilayer Perceptron - MLP) é utilizada para gerar dinamicamente vetores de pesos ao longo do horizonte de previsão, sendo estes dependentes da contribuição individual de cada previsor observada nos dados históricos da série. O ajuste dos parâmetros da rede MLP é efetuado através de um algoritmo de treinamento híbrido, que integra técnicas de busca global, baseadas em computação evolucionária, junto com o algoritmo de busca local backpropagation, de modo a otimizar de forma simultânea tanto os pesos quanto a arquitetura da rede, visando, assim, a gerar de forma automática um modelo de ponderação dinâmica de previsores de alto desempenho. O modelo proposto, batizado de Neural Expert Weighting - Genetic Algorithm (NEW-GA), foi avaliado em diversos experimentos comparativos com outros modelos de ponderação de previsores, assim como também com os modelos individuais envolvidos na combinação, contemplando 15 séries temporais divididas em dois estudos de casos: séries de derivados de petróleo e séries da versão reduzida da competição NN3, uma competição entre metodologias de previsão, com maior ênfase nos modelos baseados em Redes Neurais. Os resultados demonstraram o potencial do NEWGA em fornecer modelos acurados de previsão de séries temporais. / [en] Empirical studies on time series indicate that the combination of forecasting models, generated from different modeling techniques, leads to higher consen+sus forecasts, in terms of accuracy, than the forecasts of individual models involved in the combination scheme. In this work, we present a methodology for convex combination of statistical forecasting models, whose success depends on how the combination weights of each model are estimated. An Artificial Neural Network Multilayer Perceptron (MLP) is used to generate dynamically weighting vectors over the forecast horizon, being dependent on the individual contribution of each forecaster observed over historical data series. The MLP network parameters are adjusted via a hybrid training algorithm that integrates global search techniques, based on evolutionary computation, along with the local search algorithm backpropagation, in order to optimize simultaneously both weights and network architecture. This approach aims to automatically generate a dynamic weighted forecast aggregation model with high performance. The proposed model, called Neural Expert Weighting - Genetic Algorithm (NEW-GA), was com- pared with other forecaster combination models, as well as with the individual models involved in the combination scheme, comprising 15 time series divided into two case studies: Petroleum Products and the reduced set of NN3 forecasting competition, a competition between forecasting methodologies, with greater emphasis on models based on neural networks. The results obtained demonstrated the potential of NEW-GA in providing accurate models for time series forecasting.

Es sollte untersucht werden, ob Ganzkörper-Hyperthermie (GKH) plus Chemotherapie im Rahmen systemischer Krebs-Mehrschritt-Therapie (sKMT) eine wiederholt anwendbare und verträgliche Therapieoption für Patienten mit fortgeschrittenen, metastasierten Tumorerkrankungen darstellt. Im klinischen Zusammenhang sollten funktionelle Veränderungen verschiedener Organsysteme und toxische Reaktionen unter GKH/sKMT aufgezeigt werden sowie das anästhesiologische Management hinsichtlich der Anwendung verschiedener Monitoringverfahren beurteilt werden. Bei 26 Patienten erfolgten in Allgemeinanästhesie Messungen von Hämodynamik, Gasaustausch, O2-Transport und Metabolismus sowie klinische, laborchemische und immunologische Analysen während und nach 63 GKH/sKMT-Behandlungen. Die GKH mit einer Plateauphase von einer Stunde bei 41,8°C wurde durch Infrarotstrahlung induziert. Das anästhesiologische Monitoring der Patienten beinhaltete Pulmonalarterienkatheter, Doppelindikator-Dilutionsverfahren, invasive und nicht-invasive Blutdruckmessung sowie Dopplersonografie. Es konnte gezeigt werden, dass heute eine GKH/sKMT in Allgemeinanästhesie und mit sorgfältiger Auswahl der Patienten ein verträgliches und sicheres Verfahren darstellt. Alterationen der gemessenen Parameter zeigten am Ende der Behandlung meistens eine deutliche Tendenz in Richtung der Initialwerte. Toxische Reaktionen konnten in einem akzeptablen Ausmaß gehalten und lang anhaltende Organschäden vermieden werden. Ein adäquates Monitoring beinhaltet eine invasive arterielle und zentralvenöse Druckmessung. Das hämodynamische Management sollte sich am mittleren arteriellen Blutdruck orientieren. Somit erscheint derzeit eine weitere Evaluierung dieser Therapie im Rahmen von multimodalen onkologischen Behandlungskonzepten sinnvoll. / This investigation was performed to investigate the safety of whole body hyperthermia (WBH) within the context of systemic Cancer Multistep Therapy (sCMT) in patients with disseminated malignancies. Furthermore, alterations in various organ functions and toxicities during WBH/sCMT as well as an appropriate anesthesiological management should be evaluated. 63 WBH/sCMT treatments in 26 patients were carried out under general anesthesia and measurements of hemodynamics, pulmonary gas exchange and metabolism as well as clinical, laboratory and immunological investigations were performed. WBH with a plateau phase of one hour at 41.8°C was induced by infrared radiation. Anesthesiological monitoring included pulmonary artery catheter, transpulmonary double indicator dilution technique, invasive and non-invasive blood pressure measurement and Doppler ultrasonography. By careful selection of patients WBH/sCMT can be performed safely using general anesthesia. Most parameters showed a clear tendency towards the pretreatment levels at the end of therapy. Toxicities stayed in an acceptable range and persistent organ dysfunctions could be avoided. An appropriate anesthesiological monitoring includes invasive arterial and central venous pressure measurements. Hemodynamic management during WBH should be guided by the mean arterial pressure. This enables further evaluation of WBH in multimodal treatment concepts.

This dissertation contains three essays in international macroeconomics and financial time series forecasting. In the first essay, I show, numerically, that a two-country New-Keynesian Sticky Prices model, driven by monetary and productivity shocks, is capable of explaining the highly positive correlation across the industrialized countries' inflation even though their cross-country correlation in money growth rate is negligible. The structure of this model generates cross-country correlations of inflation, output and consumption that appear to closely correspond to the data. Additionally, this model can explain the internal correlation between inflation and output observed in the data. The second essay presents two important results. First, gains from monetary policy cooperation are different from zero when the elasticity of substitution between domestic and imported goods consumption is different from one. Second, when monetary policy is endogenous in a two-country model, the only Nash equilibria supported by this model are those that are symmetrical. That is, all exporting firms in both countries choose to price in their own currency, or all exporting firms in both countries choose to price in the importer's currency. The last essay provides both conditional and unconditional predictive ability evaluations of the aluminum futures contracts prices, by using five different econometric models, in forecasting the aluminum spot price monthly return 3, 15, and 27-months ahead for the sample period 1989.01-2010.10. From these evaluations, the best model in forecasting the aluminum spot price monthly return 3 and 15 months ahead is followed by a (VAR) model whose variables are aluminum futures contracts price, aluminum spot price and risk free interest rate, whereas for the aluminum spot price monthly return 27 months ahead is a single equation model in which the aluminum spot price today is explained by the aluminum futures price 27 months earlier. Finally, it shows that iterated multiperiod-ahead time series forecasts have a better conditional out-of-sample forecasting performance of the aluminum spot price monthly return when an estimated (VAR) model is used as a forecasting tool.

Made available in DSpace on 2014-06-11T19:26:56Z (GMT). No. of bitstreams: 0 Previous issue date: 2005-02-25Bitstream added on 2014-06-13T19:47:24Z : No. of bitstreams: 1 santos_ca_me_sjrp.pdf: 757765 bytes, checksum: bd1f77ee4f0f4cdebfc0a29af4d9bc39 (MD5) / Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) / O objetivo deste trabalho þe aplicar Mþetodos Numþericos de ordem de precisão mais alta ao problema de Retoque Digital, visando melhorar a qualidade da aproximação quando comparada com o Método de Euler, que þe geralmente utilizado para esse tipo de problema. Para testar a eficiência de tais métodos, utilizamos três modelos de Retoque Digital: o modelo proposto por Bertalmþýo, Sapiro, Ballester e Caselles (BSBC), o modelo de Rudin, Osher e Fatemi conhecido como Variacional Total (TV) e o modelo de Chan e Shen, chamado de Difusão Guiada pela Curvatura (CDD). / The purpose of this work is to apply Numerical Methods of higher order to the problem of Digital Inpainting, aiming to improve the quality of the approach when compared with the Euler s Method which is generally used for this kind of problem. To test the e ciency of these methods we use three models of Digital Inpainting: the model considered by Bertalmþýo, Sapiro, Ballester and Caselles (BSBC), the model of Rudin, Osher and Fatemi known as Total Variation (TV) and the model of Chan and Shen, named Curvature Driven Di usion (CDD)