Os radicais livres são espécies químicas que reagem rapidamente com diversos compostos e alvos celulares, por possuírem tempo de meia vida muito curto e serem espécies altamente instáveis. A formação destes compostos constitui uma ação contínua e fisiológica, cumprindo funções biológicas essenciais as quais ocorrem pela perda ou adição de um único elétron a um composto não radicalar. Estas reações podem ocorrer em processos bioquímicos do sistema imune ou químicos, causando prejuízo às células através da destruição de componentes, como proteínas, lipídios, açúcares e nucleotídeos. Sabe-se que existem compostos que são efetivos contra tais espécies, prevenindo os danos provocados pelo estresse oxidativo. O objetivo deste trabalho foi estudar compostos heterocíclicos que possuam nitrogênio em sua estrutura (azóis), que figuram na literatura como moléculas exemplares de compostos de aplicação farmacológica de amplo espectro. Dentre estes compostos foram analisados os derivados de pirazóis (26 compostos), tiazóis (7 compostos) e 1 isoxazol (3,5-dimetilisoxazol). Estes 34 compostos foram avaliados pela metodologia ORAC (Capacidade de Absorção de Radicais Oxigênio) a fim de determinar e/ou de avaliar seu potencial antioxidante. A escolha do método ORAC se deu pelo fato das moléculas estudadas apresentarem características hidrofílicas e lipofílicas, além de ser um método validado pela literatura, disponível e de ampla aplicação. O método ORAC avalia a capacidade antioxidante da amostra, medindo sua habilidade de proteger a fluoresceína (FL) da oxidação pelo AAPH no meio reacional. O AAPH é um gerador de radicais livres que a 37°C retira hidrogênio do meio, promovendo a redução da fluorescência da fluoresceína em λ medido pelo tempo. Seis compostos apresentaram atividade antioxidante de boa à moderada: 3,5-dimetil-1H-pirazol (2.382 µmol eq.Trolox/g); 3-fenil-5-(4-fluorfenil)-1-tiocarbamoil-4,5-diidro-1H-pirazol (6.354 µmol eq.Trolox/g); 3-fenil-5-(2-metoxifenil)-1-tiocarbamoil-4,5-diidro-1H-pirazol (8.739 µmol eq.Trolox/g); 5-(2,4-diclorofenil)-3-fenil-1-tiocarbamoil-4,5-diidro-1H-pirazol (6.022,226 µmol eq.Trolox/g); 2-[5-(4-metoxifenil)-3-fenil-4,5-diidro-1H-pirazol-1-il]-4-feniltiazol (3.135 µmol eq.Trolox/g); e finalmente 2-[5-(3-nitrofenil)-3-fenil-4,5-diidro-1H-pirazol-1-il]-4-feniltiazol (2.700 µmol eq.Trolox/g). Os experimentos com o método ORAC para os azóis estudados apresentaram reprodutibilidade na execução experimental e demonstraram ser uma alternativa viável para estudos de moléculas sintéticas de potencial antioxidante. / Free radicals are chemical species that react rapidly with various compounds and target cells, as they have a very short half life and are highly unstable. The formation of these compounds consists of a continuous, physiological action, which includes essential biological functions and occurs through the loss or addition of a single electron to a non-radical compound. These reactions may occur in biochemical processes of the immune system, or by chemical reactions, causing damage to the cells through the destruction of components such as proteins, lipids, sugars and nucleotides. It is known that compounds exist which are effective against these species, preventing damage caused by oxidative stress. The object of this work was to study heterocyclic compounds that have nitrogen in their structure (azoles), which appear in the literature as exemplary molecules of compounds with a wide spectrum of pharmacological applications. Of these compounds, derivatives of pyrazoles (26 compounds), thiazoles (7 compounds) and 1 isoxazole (3,5-dimethylisoxazole) were analyzed. These 34 compounds were evaluated by the ORAC (Oxygen Radicals Absorption Capacity) in order to determine and/or evaluate its antioxidant potential. The choice of ORAC method is based on the fact that the molecules studied have hydrophilic and lipophilic characteristics, as well as a method validated by the literature, which is available and widely used. The ORAC method evaluates the antioxidant capacity of the sample, measuring its ability to protect the fluorescence (FL) of the oxidation by the AAPH in the reaction medium. AAPH is a generator of free radicals which, at 37°C, removes hydrogen from the medium, promoting the reduction of fluorescence from fluorescein in λ measured by time. Six compounds present good to moderate antioxidant activity: 3,5-dimethyl-1H-pyrazole (2.382 µmol eq.Trolox/g); 3-phenyl-5-(4-fluorphenyl)-1-thiocarbamoyl-4,5-dihydro-1H-pyrazole (6.354 µmol eq.Trolox/g); 3-phenyl-5-(2-methoxyphenyl)-1-thiocarbamoyl-4,5-dihydro-1H-pyrazole (8.739 µmol eq.Trolox/g); 5-(2,4-diclorophenyl)-3-phenyl-1-thiocarbamoyl-4,5-dihydro-1H-pyrazole (6.022,226 µmol eq.Trolox/g); 2-[5-(4-methoxyphenyl)-3-phenyl-4,5-dihydro-1H-pyrazole-1-il]-4-phenylthiazole (3.135 µmol eq.Trolox/g); and finally, 2-[5-(3-nitrophenyl)-3-phenyl-4,5-dihydro-1H-pyrazole-1-il]- 4-phenylthiazole (2.700 µmol eq.Trolox/g). Experiments with the ORAC method for the azoles studied present reproducibility in the experimental execution, and have proven to be a viable alternative for studies of synthetic molecules with antioxidant potential.

Nous avons réalisé la synthèse de thiazoles, sélénazoles, thiéno[2,3-d]thiazoles et thiéno[2,3-d][1,3]sélénazoles, ce dernier étant préparé facilement à partir de cyanamide et de sulfure de carbone. Nous avons de cette manière pu synthétiser des 4-amino-1,3-thiazoles et 1,3-sélénazoles substitués en position 2 et 5 en deux étapes. Appliqué ces hétérocycles, les 4-halogéno-1,3-thiazoles et 1,3-sélénazoles ont été synthétisés par la méthode de Doyle. La labilité des halogènes dans les dérivés précédents a permis de préparer de nouveaux thiéno[2,3-d]thiazoles et [1,3]sélénazoles. La détermination du potentiel antiprolifératif de ces composés a permis de mettre en évidence deux composés, présentant des IC50 de l’ordre du micromolaire sur les lignées cellulaires cancéreuses : MCF-7, PC-3, Hs683, U373, SKMEL-28 et A549. Un composé surtout a montré une activité d’inhibition de Na+/K+-ATPase et de l'oncogène Ras. Par ailleurs dans un second sujet, nous nous sommes intéressés à la mise au point d’une synthèse des deux isomères (alpha et bêta) de 4-butoxylvinyl-coumarines, -thiocoumarine et -2-quinolones par couplage de Heck. Nous avons ainsi pu montrer que suivant le substituant présent en position 4 des hétérocycles le couplage était régiosélectif. Ces dérivés butoxyvinyliques se caractérisaient par leur caractère diénique et nous avons étudié leur réactivité, stéréoséléctivité et régiosélectivité avec différents diénophiles dans des réactions de cycloaddition de Diels-Alder. Parmi tous les composés polyhétérocycliques ainsi préparés, nous avons identifié des composés tétracycliques à noyau quinonique qui présentent un potentiel anticancéreux par des valeurs d’IC50 sur l’inhibition des phosphatases CDC25 et sur plusieurs lignées de cellules tumorales / We performed the synthesis of thiazoles, selenazoles, thieno[2,3-d]thiazoles and thieno[2,3-d][1,3] selenazoles which are easily prepared from cyanamide and carbon disulfide. By this way, we have synthesized 4-amino-1,3-thiazoles et 1,3-selenazoles substituted in position 2 and 5 in two steps. Used these heterocycles, 4-halogeno-1,3-thiazoles et 1,3-selenazoles were synthesized by Doyle’s method. Lability of halogens in previous derivatives allowed to prepare new thieno[2,3-d]thiazoles and [1,3]selenazoles. Determination of the antiproliferative activity of these compounds has brought out two compounds, showing IC50 values in micromolar range on investigated cancer cell lines: MCF-7, PC-3, Hs683, U373, SKMEL-28, and A549. One particular compound showed a high activity of anti-Na+/K+-ATPase and anti-ROS. In addition in the second subject, we were interested in the development of the synthesis of two isomers (alpha and beta) of 4-butoxylvinyl-coumarins, -thiocoumarin and -2-quinolones by Heck coupling. We showed that, depending on the substituent in the position 4 of the heterocycle, the coupling was regioselective. These butoxyvinylic derivatives, characterized by dienic character, were studied for their reactivity, stereoselectivity and regioselectivity with several dienophiles in Diels-Alder cycloaddition. Among all the polyheterocyclic compounds prepared, we have identified the tetracyclic compounds with quinonic ring which have potential anticancer activity by inhibition of CDC25 phosphatase and on several tumor cell lines

Background. Both basal-like subtype and BRCA1-related breast cancers tend to have a poor overall prognosis and lack of effective treatments. Given that the lung cancer drug gefitinib and the leukemia drug dasatinib inhibit proteins also belonging to the molecular signature of this subtype, we and others hypothesized that they might be useful therapies for those two breast cancer subgroups. / Methods. Eight breast cancer cell lines were characterized by immunohistochemistry and western blotting and were treated with both drugs. Response was measured by using the sulphorhodamine B (SRB) assay. / Results. Two out of six basal-like cell lines were sensitive to gefitinib and five of six to dasatinib. BRCA1-related breast cancers were also responsive to dasatinib (three out of four). Moreover, EGFR and caveolin-1 act as markers for dasatinib sensitivity, but do not appear to be the primary targets of this drug. The presence of SRC but not ABL is necessary to achieve a response to dasatinib. / Conclusion. Dasatinib is more effective in the treatment of basal-like breast cancers than gefitinib and acts by inhibiting SRC and other molecules that are yet to be determined.

[Truncated abstract] In recent years a better understanding of the biology of PPAR , a nuclear transcription factor, has emerged, leading to a resurgence in targeting PPAR for chemotherapy. The family of synthetic PPAR agonists, the thiazolidinediones (TZDs), and non-steroidal anti-inflammatory drugs (NSAIDs) have been implicated in the inhibition of cell proliferation, apoptosis and cell cycle arrest of androgen-sensitive (LNCaP) and androgen-independent (PC-3 and DU145) prostate cancer cells generating much interest in their use for potential curative cancer therapies. In light of the potential use of TZDs and NSAIDs in prostate cancer prevention and their ability to induce inhibitory effects in vitro and in vivo, the first aim of this project was to undertake a comprehensive study of the effects of ciglitazone (TZD) and indomethacin (NSAID) on the androgen-independent prostate cancer cell line DU145, using standardised concentrations and time-points to compare the effects of TZDs and NSAIDs on cell proliferation, cell cycle and apoptosis. Treating the cells with either 10 µM ciglitazone or 10 µM indomethacin resulted in a time-dependent decrease in DU145 cell proliferation. The anti-proliferative effects were found to be in-part attributed to the slowing of cell progression through the G1/S-phase checkpoint of the cell cycle, and in the case of ciglitazone, apoptosis also played a role in its anti-proliferative effects in this cell line. Interestingly, although indomethacin failed to induce apoptosis, its antiproliferative effects were more potent than ciglitazone. The second aim of this project was to further investigate the underlying mechanisms responsible for the anti-proliferative effects of ciglitazone and indomethacin by evaluating their ability to modulate PPAR mRNA and protein expression, and to induce PPAR transcriptional activity. ... In addition, ligandinduced regulation of secreted frizzled related protein 4 (sFRP4) expression, a Wnt/ - catenin antagonists, was investigated. It was demonstrated that both ciglitazone and indomethacin attenuated Wnt/ -catenin signalling via the down-regulation of total - catenin levels within the cells, inhibition or slowing of the translocation of cytoplasmic -catenin into the nucleus and inhibition of cyclin–D1 expression An inverse relationship between PPAR and -catenin protein levels was also detected, suggesting that PPAR may directly bind to -catenin itself. sFRP4 expression was transiently upregulated by ciglitazone and indomethacin-treatment, suggesting that the antiproliferative effects of the ligands may be mediated in part through regulation of sFRP4 mRNA and protein levels. In summary, the anti-proliferative effects of ciglitazone and indomethacin on the androgen-independent prostate cancer cell line, DU145, described in this thesis are progressive steps in characterising the role of PPAR in prostate cancer cell proliferation. The identification of indomethacin as a more potent PPAR agonist than ciglitazone represents a novel target for the development of preventative strategies for advanced disease, and the relationship between PPAR and the Wnt/ -catenin signalling pathway provide an insight into the mechanisms involved in the anti-proliferative effects of ciglitazone and indomethacin. Further studies into this relationship would advance help identify novel preventative and curative therapeutic strategies for advanced prostate cancer.

Glyphosate (N-phosphonomethylglycine) is an organophosphate compound which was developed by the Monsanto Company in 1971 and is the active ingredient found in several herbicide formulations. The use of glyphosate-based herbicides in South Africa for the control of alien invasive plants and weeds is well established, extensive and currently unregulated, which vastly increases the likelihood of glyphosate contamination in environmental water systems. Although the use of glyphosate-based herbicides is required for economic enhancement in industries such as agriculture, the presence of this compound in natural water systems presents a potential risk to human health. Glyphosate and glyphosate formulations were previously considered safe, however their toxicity has become a major focal point of research over recent years. The lack of monitoring protocols for pesticides in South Africa is primarily due to limited financial capacity and the lack of analytical techniques.

This thesis, largely describing diverse studies in organic synthesis, is divided into three parts. Part I, titled ‘Heterocycles’, describes in two chapters studies directed towards elaborating certain thiazole and oxazole derivatives as useful synthons. Part II, titled ‘Hydride transfers’, describes in two chapters synthetic and some mechanistic studies involving the Cannizzaro and Tishchenko reactions, apart from work with chirally-modified alumino and borohydride reagents. Finally, Part III, titled ‘Miscellaneous studies’, describes structural studies on cyclic carbonates. (For structural formula see the abstract.pdf file.)

No description available.

Dissertation (Ph.D.)--University of South Florida, 2009. / Includes vita. Includes bibliographical references. Also available online.

Dissertation (Ph.D.)--University of South Florida, 2009. / Title from PDF of title page. Document formatted into pages; contains 149 pages. Includes vita. Includes bibliographical references.

Gas-phase thermolysis is a long-known and well established method for the preparation of reactive species. It is, however, limited to relatively volatile substances, which are easily vaporised. In the present work, the solution-spray technique for preparative scale was developed. With this technique, it is possible to subject low-volatile substances, which hardly vaporise even under high-vacuum conditions, to gas-phase thermolysis. By utilising oil nozzles used in heating and burner systems, it was possible to integrate a stable solution-spray into the existing flash-vacuum-pyrolysis system. The influence of several variables, such as flow-rate, pressure, temperature and solvent was determined. The solution-spray technique was applied in [3,3]-sigmatropic rearrangements of certain propargyl thiocyanates to the corresponding allenyl isothiocyanates. Furthermore, the parent compound propa-1,2-dienyl isothiocyanate was reacted with various sterically demanding primary and secondary amines to form 2-amino-1,3-thiazoles in moderate to excellent yields. Based on this, a catalyst-free four-center three-component reaction was developed. 2-Amino-1,3-thiazoles with complex substituents in 5-position at the heterocyclic ring are formed. Reaction mechanisms are discussed to explain the occurance of a highly substituted 1,3-thiazine structure. The influence of reaction temperature, concentrations and solvent were determined and are also discussed. It was shown that 2-amino-5-methyl-1,3-thiazoles are the apparently first aromatic substance class, that readily undergoes Prins-type 1,3-dioxane ring-formation. / Die Gasphasenthermolyse ist eine lang bekannte und etablierte Methodik zur Synthese reaktiver Spezies. Sie ist allerdings auf flüchtige Substanzen mit einer guten Verdampfbarkeit beschränkt. Für schwerflüchtige Verbindungen, welche sich selbst im Hochvakuum nur mäßig oder gar nicht in die Gasphase bringen lassen, wurde in der vorliegenden Arbeit die Solution-Spray-Technik für die Anwendung im präparativen Maßstab entwickelt. Unter Verwendung von Ölzerstäuberdüsen, wie sie in der Heizungs- und Brennertechnik Anwendung finden, wurde die Erzeugung eines stabilen Lösungs-Sprays in die vorhandene Blitzvakuumpyrolyse-Technik integriert. Der Einfluss verschiedener Variablen, wie Flussrate, Druck, Temperatur und Lösungsmittel wurde untersucht. Die Solution-Spray-Technik wurde für die [3,3]-sigmatrope Umlagerung bestimmter Propargylthiocyanate zu Allenyl-isothiocyanaten angewendet. Des Weiteren wurde Propa-1,2-dienylisothiocyanat – das einfachste Allenylisothiocyanat – mit diversen sterisch anspruchsvollen primären und sekundären Aminen in mäßigen bis exzellenten Ausbeuten zu 2-Amino-1,3-thiazolen umgesetzt. Darauf aufbauend konnte eine Vier-Zentren-drei-Komponenten-Reaktion entwickelt werden. Es entstehen in hohen Ausbeuten 2-Amino-1,3-thiazole mit komplexen Substituenten an der 5-Position des Heterocyclus. Reaktionsmechanismen werden diskutiert um die alternative Bildung einer hochsubstituierten 1,3-Thiazinstruktur zu erklären. Der Einfluss von Reaktionstemperatur, Konzentration und Lösungsmittel auf das Produktverhältnis wurde ebenfalls untersucht und wird diskutiert. Es konnte gezeigt werden, dass 2-Amino-5-methyl-1,3-thiazole als offenbar erste aromatische Substanzklasse sehr gute Substrate für die Bildung von 1,3-Dioxanen nach Prins darstellen.