Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / This work describes, at first, the synthesis of 4,6,6-trimethoxy-1,1,1-trifluorohex-3-en-2-one by the acylation reaction of 1,1,3,3-tetramethoxybutane, in 65% yields. Afterwards, the synthesis of a new series of 4,5-dihydro-1H-pyrazoles, which contain a ketal-protected aldehyde function as substituent, is described. These compounds are obtained by the reaction of 4,6,6-trimethoxy-1,1,1-trifluorohex-3-en-2-one with hydrazines (NH2NHR, R= 2-furoyl, C6F5, COOMe, COMe, Nicotinoyl), in 90-97% yields. In a subsequent step, dehydration reactions of 4,5-dihydro-1H-pyrazoles are reported, leading to 1H-pyrazoles. In addition, this work proposes a fluorination methodology of the ketal substituent of the 4,5-diidro-1H-pyrazoles and 1H-pyrazoles using diethylaminosulfur trifluoride (DAST). Finally, this work reports the desprotection of the ketal substituent to obtain the respective carbonyl compound and the subsequent fluorination reaction leading to the difluorinated analogues, in 55-60% yields. The compounds were characterized by 1H and 13C NMR experiments and by Mass Spectrometry, and their purity was confirmed by elemental analysis. / A presente dissertação descreve, inicialmente, a síntese de 4,6,6-trimetoxi-1,1,1-trifluorhex-3-en-2-ona através da reação de acilação do acetal 1,1,3,3-tetrametoxibutano, com rendimento de 65%. Subsequentemente é descrita a síntese de uma nova série de 4,5-diidro-1H-pirazóis, que possuem como substituinte uma função aldeído protegida sob a forma de acetal, obtidos a partir da reação de 4,6,6-trimetoxi-1,1,1-trifluorhex-3-en-2-ona com hidrazinas (NH2NHR, R= 2-furanoil, C6F5, COOMe, COMe, Nicotinoil), com rendimentos de 90-97%. Numa etapa posterior, são descritas as reações de desidratação dos 4,5-diidro-1Hpirazóis, as quais levaram ao isolamento dos respectivos 1H-pirazóis. Além disso, são propostas neste trabalho metodologias para a fluoração do substituinte acetal dos 4,5-diidro-1H-pirazóis e 1H-pirazóis, utilizando Dietilamino Trifluoreto de Enxofre (DAST). Finalmente, é descrito neste trabalho a etapa de desproteção do substituinte acetal para obtenção do composto carbonílico correspondente e posterior reação de fluoração levando ao isolamento dos análogos difluorados com rendimentos de 55-60%. Os compostos foram caracterizados por experimentos de RMN de 1H, RMN de 13C {1H} e por Espectrometria de Massas, e sua pureza comprovada por Análise Elementar.

Dans le premier chapitre de cette thèse, nous nous sommes intéressés aux virus de l'immunodéficience humaine et des hépatites B et C ainsi qu'aux thérapies utilisées dans le traitement de ces affections. Nous avons introduit l'importance des nucléosides fluorés, et nous avons donné quelques exemples de nucléosides fluorés utilisés en chimiothérapie antivirale et antitumorale. Dans le second chapitre, nous avons présenté une synthèse rapide de 2',3'-didésoxy-3'-fluoro-beta-D-thréo-nucléosides portant les bases pyrimidiques naturelles et substituées en position N3 par un groupement nitro ou amino. Les composés obtenus ont été évaluées contre divers virus à ADN et ARN (y compris le VIH) dans des expériences de culture cellulaire. Dans le troisième chapitre, nous nous somme intéressés à la synthèse de différents 2',3'-didésoxy-2'-fluoro-3'-(N-hydroxyimino), (N-methoxyimino) and (hydroxyl-amino) nucléosides en série pyrimidine. Les composés obtenus ont été évaluées contre divers virus à ADN et ARN dans des expériences de culture cellulaire. / In the first chapter, we presented the human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV), as well as the therapies used to treat these diseases. In a second part, we discussed about the importance of the incorporation of fluorine atom into nucleoside analogues, and in a third part of this chapter, we presented the recent literature sources of the synthesis and biological activity of fluorinated nucleosides. In the second chapter, we designed and synthesized a series of 2',3'-dideoxy-3'-fluoro-threo-pyrimidine nucleosides by direct and rapid methodology and evaluated them for their inhibitory effects on a number of RNA and DNA viruses in cell culture experiments. None of these nucleoside derivatives showed any antiretroviral activity nor cytotoxicity. In the third chapter of this manuscript, we synthesized a new series of 2',3'-dideoxy-2'-fluoro-3'-(N-hydroxyimino),(N-methoxyimino) and (hydroxylamino)pyrim idine nucleosides and also evaluated for their inhibitory effects on a number of RNA and DNA viruses, without finding any activity or cytotoxicity.

Les prolinols peuvent être tranformés en 3-hydroxypipéridines par une réaction stéréospécifique d'agrandissement de cycle initiée par l'anhydride trifluoroacétique. Ce réarrangement peut être expliqué par la formation d'un intermédiaire aziridinium. Cette réaction a été mise à profit dans la synthèse formelle du composé Ro 67-8867 qui a été réalisée à partir de la (R)-(+)-α-méthylbenzylamine en utilisant comme étape-clé une réaction de cyclisation d'énolate de zinc et la réaction d'agrandissement de cycle. Deux synthèses formelles de la (-)-swainsonine ont également été développées à partir de la L-proline en utilisant une addition diastéréosélective d'organomagnésien sur un prolinal, une réaction de métathèse cyclisante, une dihydroxylation diastéréosélective et un agrandissement de cycle de prolinols. Par analogie avec le réarrangement précédent, l'expansion de cycle de prolinols en présence de DAST a été étudiée: dans le cas général, un mélange de 3-fluoropipéridines et de fluorométhylpyrrolidines est obtenu. Dans certains cas, un réarrangement sélectif a pu être observé. Des cas de réarrangements très sélectifs ont été observés lorsque les prolinols sont substitués par un groupement encombrant soit en C4 (éther silylé), soit en C2 (centre quaternaire) soit sur l'azote (Tr).

Wetterfester Baustahl zeichnet sich im Vergleich zu unlegiertem Baustahl durch einen höheren Widerstand gegen atmosphärische Korrosion aus. Bei gleichen mechanischen Werkstoffeigenschaften ermöglicht der unbeschichtete Einsatz des wetterfesten Baustahls aufgrund der korrosionshemmenden Deckschicht wesentliche ökologische und wirtschaftliche Vorteile gegenüber unlegiertem Baustahl mit einer zusätzlichen Korrosionsschutzbeschichtung. Gleichwohl sind für den dauerhaften Einsatz neben geeigneten Umgebungsbedingungen vor allem korrosionsschutzgerechte Konstruktionsregeln zu beachten, die auf Basis neuer Forschungserkenntnisse zu einer Aktualisierung der DASt-Richt linie 007 geführt haben.

Broken Access Control is the most serious web application security risk as published by Open Worldwide Application Security Project (OWASP). This category has highly complex vulnerabilities such as Broken Object Level Authorization (BOLA) and Exposure of Sensitive Information. Finding such critical vulnerabilities in large software systems requires intelligent and automated tools. State-of-the-art (SOTA) research including hybrid application security testing tools, algorithmic brute forcers, and artificial intelligence has shown great promise in detection. Nevertheless, there exists a gap in research for reliably identifying logical and context-dependant Broken Access Control vulnerabilities. We modeled the problem as text classification and proposed KARTAL, a novel method for web application vulnerability detection using a Large Language Model (LLM). It consists of 3 components: Fuzzer, Prompter, and Detector. The Fuzzer is responsible for methodically collecting application behavior. The Prompter processes the data from the Fuzzer and formulates a prompt. Finally, the Detector uses an LLM which we have finetuned for detecting vulnerabilities. In the study, we investigate the performance, key factors, and limitations of the proposed method. Our research reveals the need for a labeled Broken Access Control vulnerability dataset in the cybersecurity field. Thus, we custom-generate our own dataset using an auto-regressive LLM with SOTA few-shot prompting techniques. We experiment with finetuning 3 types of decoder-only pre-trained transformers for detecting 2 sophisticated vulnerabilities. Our best model attained an accuracy of 87.19%, with an F1 score of 0.82. By using hardware acceleration on a consumer-grade laptop, our fastest model can make up to 539 predictions per second. The experiments on varying the training sample size demonstrated the great learning capabilities of our model. Every 400 samples added to training resulted in an average MCC score improvement of 19.58%. Furthermore, the dynamic properties of KARTAL enable inferencetime adaption to the application domain, resulting in reduced false positives. / Brutet åtkomstkontroll är den allvarligaste säkerhetsrisken för webbapplikationer enligt Open Worldwide Application Security Project (OWASP). Denna kategori har mycket komplexa sårbarheter såsom Brutet behörighetskontroll på objektnivå (BOLA) och exponering av känslig information. Att hitta sådana kritiska sårbarheter i stora programvarusystem kräver intelligenta och automatiserade verktyg. Senaste tekniken (SOTA)-forskning, inklusive hybridverktyg för säkerhetstestning av applikationer, algoritmiska bruteforcers och artificiell intelligens, har visat stor potential för upptäckt. Trots detta finns det en lucka i forskningen när det gäller tillförlitlig identifiering av logiska och kontextberoende sårbarheter relaterade till Brutet åtkomstkontroll. Vi modellerade problemet som textklassificering och föreslog KARTAL, en ny metod för att upptäcka sårbarheter i webbapplikationer med hjälp av en stor språkmodell (LLM). Den består av 3 komponenter: Fuzzer, Prompter och Detector. Fuzzer ansvarar för att systematiskt samla in applikationsbeteende. Prompter bearbetar data från Fuzzer och formulerar en förfrågan. Slutligen använder Detector en LLM som vi har finjusterat för att upptäcka sårbarheter. I studien undersöker vi prestanda, nyckelfaktorer och begränsningar hos den föreslagna metoden. Vår forskning visar behovet av en märkt dataset för sårbarheter relaterade till Brutet åtkomstkontroll inom cybersäkerhetsområdet. Därför genererar vi anpassade dataset med hjälp av en auto-regressiv LLM med SOTA few-shot-prompting-tekniker. Vi experimenterar med att finjustera 3 typer av endast avkodare transformers som är förtränade för att upptäcka 2 sofistikerade sårbarheter. Vår bästa modell uppnådde en noggrannhet på 87.19% med en F1-poäng på 0.82. Genom att använda hårdvaruacceleration på en bärbar dator för konsumenter kan vår snabbaste modell göra upp till 539 förutsägelser per sekund. Experimenten med varierande storlek på träningsprovet visade på vår modells stora förmåga att lära sig. Varje 400 prover som lades till träningen resulterade i en genomsnittlig förbättring av MCC-poängen med 19.58%. Dessutom möjliggör de dynamiska egenskaperna hos KARTAL anpassning vid inferringstid till applikationsdomänen, vilket resulterar i färre falska positiva resultat.

Abuse of prescription and over-the-counter substances other than alcohol is becoming a prevalent issue; therefore, it is important to identify factors that may help predict risk for this abuse. Some demographic and situational factors have been identified for traditional 4-year college students. However, less is known about community college students, who enter college less academically prepared and may be still enmeshed with family and peer groups from high school. In this correlational study, predictors of substance abuse other than alcohol were explored among a convenience sample of 118 students from an American community college. The research question was developed based on previous research such as Bandura's social learning theory and Arnett's theory of emerging adults. The question explored how well gender (male, female, other) and 2 dimensions from the Ryff scale of psychological well-being (sense of autonomy and positive relationships with others) predict substance use among the community college sample. Use of substances other than alcohol was measured using the Drug Abuse Screening Test-10. A multiple linear regression analysis was used to test the research hypotheses. Although gender was not related to substance use, higher autonomy and more positive relationships scores were statistically significant predictors of higher use of substances other than alcohol among this sample. These findings were consistent with characteristics of emerging adulthood that may present risk factors for this group of college students. Findings support positive social change as they may be considered by stakeholders when considering possible prevention or intervention activities to address substance use issues on community college campuses.

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