Dissertations / Theses on the topic 'Iodine fluorides'

A pulsed-beam fourier transform microwave spectrometer was used to measure the rotational spectra of iodine heptafluoride, iodine pentafluoride, and the weakly bound complex, HCl...NNO. For IF7, only five rotational transitions were observed, and no resolvable hyperfine structure was detected. Based on this data, the A, B, and C rotational constants were determined to be 1746(3) MHz, 1732.0(8) MHz, and 1553.0(2) MHz, respectively. The existence of a pure rotational spectrum confirms that this molecule undergoes polar distortions. Twenty-two hyperfine components of the IF5 spectrum were recorded. The B rotational constant for this molecule was determined to be 2727.421(3) MHz, and the quadrupole coupling constant was found to be 1069.35(13) MHz. Though the work is still in progress on HCl...NNO, nine transitions have been recorded. In addition, five transitions have been recorded for an apparent trimer species composed of HCl, NNO, and an as yet unidentified third species.

Etude de cette collision par la methode des faisceaux croises et grace a la transition (b <- x) intense, dans le visible, apres analyse de la saturation du processus d'excitation laser de cette transition de if forme. Deduction des populations des differents niveaux rovibrationnels de l'etat x. Etablissement d'une cartographie detaillee de la distribution rotationnelle des niveaux vibrationnels v = 8 a 20 de l'etat x de if: aspect bimodal qui implique la coexistence de deux chemins reactionnels differents. Attribution a un artefact de l'important signal observe anterieurement pour v = 0. Mesures preliminaires de la section efficace differentielle par effet doppler

Orientador: Alvimar Lima de Castro
Banca: Takeo Adhemar Furuse
Banca: Décio dos Santos Pinto
Banca: Norberto Perri Moraes
Banca: Izabel Yoko Ito
Resumo: A cárie dental, por ser uma doença cujo desenvolvimento depende basicamente da susceptibilidade dental, de microrganismos cariogênicos, e de um substrato fermentável que resulta na produção de ácidos, apresenta evolução que depende de fatores que favoreçam essas condições, como a radioterapia da região de cabeça e pescoço. Nesse sentido, o presente trabalho teve como objetivo comparar os efeitos do flúor, da clorexidina, e do iodeto de sódio, na prevenção das seqüelas como cárie de irradiação e/ou osteorradiomielite em pacientes portadores de câncer, tendo a radioterapia como um dos métodos terapêuticos utilizados. Foram utilizados 52 pacientes divididos em três grupos, que foram respectivamente tratados com gluconato de clorexidina a 0,12%, fluoreto de sódio a 0,5%, e solução de iodeto de sódio (2%)-H2O2 (10 volumes), após adequação do meio bucal e cicatrização das áreas de extrações dentárias, através de bochechos diários utilizando-se a substância referente ao grupo de estudo previamente estabelecido. Concluiu-se que o uso de fluoretos, clorexidina e solução de iodeto de sódio potencializaram os meios físicos de profilaxia, sendo a clorexidina a mais eficaz na redução de ufc de S. mutans. Considera-se, ainda, que a ocorrência de cárie e/ou osteorradionecrose nesses pacientes pode ser controlada, desde que sejam instituídos adequados meios de higiene bucal.
Abstract: The dental carie, for being a disease whose development depends basically of dental susceptibility, cariogenic microorganisms, and a fermentable substratum that results in the production of acids, it presents evolution that depends on factors that favor those conditions, as the radiotherapy of head and neck region. In that sense, the present work had as objective compares the effects of the fluorides, chlorhexidine, and sodium iodite, in the prevention of the sequels as radiation carie and/or osteoradionecrosis in oncology patients, tends the radiotherapy as a therapeutic method used. 52 patients were used divided in three groups, that they were treated respectively with chlorhexidine gluconate 0,12%, sodium fluoride 0,5%, and a combination of sodium iodite solution 2% and peroxide 10%, after dental assessment and cicatrization of the areas of dental extractions, through daily mouthfuls being used the substance regarding the previously established study group. It was concluded that the fluorides use, chlorhexidine and sodium iodites solution potentializing the physical methods of prophylaxis, being the chlorhexidine the most effective in the reduction of cfu of S. mutans. It's also considered that the occurrence of radiation carie and/or osteoradionecrosis in those patient can be controlled, since appropriate methods of buccal hygiene are instituted.
Doutor

Plant and animal wastes degrade in soils to form relatively stable humified compounds, which form ion complexes that affect the bioavailability of elements in the soil solution. Hydroponic studies with wheat and rice were conducted to characterize the effect of humic acid (HA) on phosphorus (P), iron (Fe), fluorine (F), and iodine (I) bioavailability. Ferrihydrite [Fe(OH)3] precipitation was greater on root surfaces without HA or synthetic chelates. Oxides such as ferrihydrite strongly adsorb P and provide exchange sites for metals. HA reduced this precipitate and increased P and Fe uptake. Humic acid had no effect on F toxicity in rice, where solution levels above 0.5 mM F inhibited growth. Data supported the hypothesis that in moderately acidic solutions (pH< 6), F uptake is primarily as HF rather than F. Doubling solution Ca caused a 10-fold increase in root surface CaF2 precipitates, but the additional Ca did not decrease F toxicity. Calcium levels above 1 mM caused HA to flocculate over time, but the addition of F reduced flocculation by competing with HA for Ca. The majority of shoot F was apparently associated with the middle lamella, suggesting that F may bind with phosphates and pectate-Ca. Organic matter promotes aqueous iodine (I2(aq)) reduction to I-, a less toxic species. HA reduced 12( aq) toxicity by 50%. In solutions without HA, 6.5 μM h(aq) was more toxic than 30 μM I-. Humic acid had no effect on I- uptake or toxicity, where I- and IO3- were toxic to rice at 10 and 100 μM, respectively. These data were used to model element cycling through plants in a regenerative human life support system for NASA 's Advanced Life Support program, where HA, P, Fe, F, and I from plant residues and human wastes are recycled to the crop production system.

Made available in DSpace on 2014-06-11T19:32:06Z (GMT). No. of bitstreams: 0 Previous issue date: 2001Bitstream added on 2014-06-13T19:21:15Z : No. of bitstreams: 1 tanimoto_hm_dr_araca.pdf: 452600 bytes, checksum: 35a6fdca100183a9bf9298314082cef6 (MD5)
A cárie dental, por ser uma doença cujo desenvolvimento depende basicamente da susceptibilidade dental, de microrganismos cariogênicos, e de um substrato fermentável que resulta na produção de ácidos, apresenta evolução que depende de fatores que favoreçam essas condições, como a radioterapia da região de cabeça e pescoço. Nesse sentido, o presente trabalho teve como objetivo comparar os efeitos do flúor, da clorexidina, e do iodeto de sódio, na prevenção das seqüelas como cárie de irradiação e/ou osteorradiomielite em pacientes portadores de câncer, tendo a radioterapia como um dos métodos terapêuticos utilizados. Foram utilizados 52 pacientes divididos em três grupos, que foram respectivamente tratados com gluconato de clorexidina a 0,12%, fluoreto de sódio a 0,5%, e solução de iodeto de sódio (2%)-H2O2 (10 volumes), após adequação do meio bucal e cicatrização das áreas de extrações dentárias, através de bochechos diários utilizando-se a substância referente ao grupo de estudo previamente estabelecido. Concluiu-se que o uso de fluoretos, clorexidina e solução de iodeto de sódio potencializaram os meios físicos de profilaxia, sendo a clorexidina a mais eficaz na redução de ufc de S. mutans. Considera-se, ainda, que a ocorrência de cárie e/ou osteorradionecrose nesses pacientes pode ser controlada, desde que sejam instituídos adequados meios de higiene bucal.
The dental carie, for being a disease whose development depends basically of dental susceptibility, cariogenic microorganisms, and a fermentable substratum that results in the production of acids, it presents evolution that depends on factors that favor those conditions, as the radiotherapy of head and neck region. In that sense, the present work had as objective compares the effects of the fluorides, chlorhexidine, and sodium iodite, in the prevention of the sequels as radiation carie and/or osteoradionecrosis in oncology patients, tends the radiotherapy as a therapeutic method used. 52 patients were used divided in three groups, that they were treated respectively with chlorhexidine gluconate 0,12%, sodium fluoride 0,5%, and a combination of sodium iodite solution 2% and peroxide 10%, after dental assessment and cicatrization of the areas of dental extractions, through daily mouthfuls being used the substance regarding the previously established study group. It was concluded that the fluorides use, chlorhexidine and sodium iodites solution potentializing the physical methods of prophylaxis, being the chlorhexidine the most effective in the reduction of cfu of S. mutans. It's also considered that the occurrence of radiation carie and/or osteoradionecrosis in those patient can be controlled, since appropriate methods of buccal hygiene are instituted.

Conception et synthèse de nouveaux Bambusurils pour des applications en biologie et en imagerie moléculaire. Les bambusurils, R₈BU[4] et R₁₂BU[6], sont des molécules cages synthétiques, constituées respectivement de 4 et 6 unités glycolurils. Ils diffèrent des cucurbiturils par la présence de glycolurils difonctionnalisés qui leur confèrent une topologie de type alternée et des propriétés supramoléculaires intéressantes. Les R₁₂BU[6] ont la capacité d’encapsuler un anion à l'intérieur de leur cavité avec une très grande affinité grâce à 12 liaisons hydrogènes. Au laboratoire, des bambusurils disposant de groupements allyles nommés Allyl₈BU[4] et Allyl₁₂BU[6] ont été synthétisés. Ils ont ensuite été fonctionnalisés par réactions de métathèse croisée et de thiol-ène click pour introduire facilement 8 à 12 thiols d'intérêts possédant des groupements esters, acides ou glycosides. Pour élargir la famille des bambusurils, de nouveaux bambusurils possédant des fonctions propargyliques ont été préparés. Ainsi, les Propargyl₈BU[4] et Propargyl₁₂BU[6] ont été obtenus avec de bons rendements. Ces bambusurils ont ensuite été post-fonctionnalisés avec différents azotures (esters, benzyl, glycosides, peptides) par réaction de chimie click pour conduire à de nouvelles plateformes multivalentes de valence 8 pour le BU[4] et 12 pour le BU[6]. Des glycoBUs fonctionnalisés par des dérivés du D-mannose ont été synthétisés pour la première fois, et leur activité antibactérienne a été évaluée. De plus, des iminosucres de la famille de la déoxynojirimycine azidoalkylée, ont également été greffés sur les PropargylBUs, pour conduire à de nouveaux inhibiteurs de glycosidases. Le squelette des bambusurils et la multivalence conduisent à des gains d'affinité importants par rapport aux analogues glycosides monovalents.L'affinité des R₁₂BU[6], hydrosolubles, a été évaluée pour les ions iodures par titration calorimétrique isotherme. Les résultats obtenus confirment la grande affinité des BU[6] pour cet anion dans l'eau (Ka ≃ 10⁵ M⁻¹).Une dernière application des bambusurils comme sonde d'imagerie a également été étudiée. Un nouveau bambusuril différemment substitué a été conçu et synthétisé pour permettre l'introduction d'une sonde bimodale TEP/Optique en dernière étape de synthèse. Cette sonde permettra la combinaison d'un double diagnostic médical par imagerie TEP et optique. Une preuve de concept a été réalisée avec l'introduction d'un groupement radiomarqué au ¹⁸F
Design and synthesis of new Bambusurils for biological applications and molecular imagingBambus[n]urils, R₈BU[4] and R₁₂BU[6], are synthetic cyclic macromolecules that belong to the cucurbit[n]urils families. They are composed of n-substituted glycoluril units connected via n-methylene bridges. The R₁₂BU[6], are able to bind anion inside their cavity with a good association constant through hydrogen bonds.In our laboratory, bambusurils bearing allyl functions, named Allyl₈BU[4] and Allyl₁₂BU[6], were efficiently prepared. These bambusurils were functionalized by ring-closing metathesis or thiol-ene click coupling to introduce 1 to 12 functions like ester, acids and glycosides.To develop the family of bambusurils, new bambusurils with propargyl functions were synthesized. The synthesis of the Propargyl₈BU[4] and Propargyl₁₂BU[6] were optimized. Theses BUs were functionalized by click chemistry with different azides like ester, benzyl and glycoside to dispose of new multivalent systems with a valency of 8 for the BU[4] and 12 for the BU[6]. For the first time, glycoBambusurils functionalized with D-mannose derivatives were prepared, and their antibacterial activities were assayed. Moreover, iminosugar from the family of the azido alkylated déoxynojirimycine, were grafted on the PropargylBUs to afford new inhibitors of glycosidases. These results show the importance of bambusuril scaffold and of the multivalence effect improve the affinity of the glycoBUs for the target.The association constants of R₁₂BU[6] functionalized, soluble in aqueous media for iodide were determined by isothermal titration calorimetry. The results show a good affinity of R12BU[6] for iodide (Ka ≃ 10⁵ M⁻¹).We studied as well an application of bambusuril for molecular imaging. A new bambusuril with biological ligands was designed and synthesized to introduce a bimodal probe PET/Optical in the last step. This probe will allow the combination of clinical diagnostic with PET and optical imaging. A proof of concept was realized with a function ¹⁸F labelled

Mineral supplementation of is a well-known factor contributing to productivity in sheep or cattle herds. However, little is known about mineral interactions in these species. The objective of the present work was to evaluate the inter-relation of iodine (I) and fluoride (F) in young ovine metabolism and the thyroid gland. Two experiments were conducted; first it was analyzed the dynamics of urinary I excretion in sheep. Five lambs were used in a repeated measurement protocol. After a 15-day adaptation period urine samples were collected (control group), then animals received 3 different 15-day treatments (0,05; 0,42; and 0,8 mg of I/kg DM) consecutively. Punctual (8 hour interval) and 24 hour total urine samples were collected. No differences in I excretion among treatments or collection time. Also, there were no differences in urinary creatinine levels among treatments or collection time, except between 16:00 and 24:00 hours in the medium dose. No significant correlation was found between urinary I and creatinine. In a second experiment, it was evaluated the effect of chronic fluoride administration in thyroid function and histology in sheep. Twelve ram lambs were allocated into 2 groups: Control which received 5g NaCl + 0,2 mg of I/Kg DM and treated group which received the same treatment plus sodium fluoride (4,7 mg F/ Kg BW) daily for 150 days. Blood samples were collected at 60, 90, 120, and 150 days for determination of F, I T3 and T4. At the same time points, total 24-hour urine production was collected for measurement of F and I. After euthanasia, at 150 days of treatment, thyroid gland was removed for histopathological and morphometrical analyses. No differences were found between or within groups for urinary I. Also no differences were found for T3 and T4 nor serum I between groups or among time points. No histological alterations were found in the thyroid. In conclusion, urinary I excretion is not a reliable parameter to access I status in animals with supplementation within the recommended levels. Additionally, data related to Iodine-fluoride interactions cannot be used across species, since the effect of fluoride on the thyroid appears to have specie dependant intensity
A suplementação mineral dos rebanhos é um fator que influi de forma relevante no índice de produtividade, porém, há carência de novos estudos relacionados à situação e interação dos elementos minerais nos rebanhos e nisso está alicerçado o objetivo do presente trabalho: avaliar a inter-relação do iodo (I) e do flúor (F) no metabolismo de ovinos jovens, através da avaliação do efeito do F sobre a glândula tireóide. Para tanto, foram realizados dois experimentos. O primeiro teve o objetivo de analisar a dinâmica da excreção urinária de I em ovinos. Assim, utilizaram-se cinco animais. Antes de iniciar o tratamento com I, coletou-se amostras de urina (grupo controle), posteriormente, os animais passaram a receber três diferentes tratamentos (0,05; 0,42 e 0,8 mg de iodo/kg de matéria seca), consecutivamente. Cada tratamento teve duração de 15 dias. Foram coletadas amostras de urina equivalente às 24 horas e amostras pontuais (intervalo de oito horas). Não houve diferença na excreção urinária de I entre tratamentos e entre horários de coleta. Os valores urinários de creatinina não diferiram entre os horários de coleta dentro de cada tratamento, exceto entre as 16:00 e às 24:00 horas, na dose média. A relação iodo/creatinina não demonstrou correlação. No segundo experimento, o objetivo foi avaliar o efeito da administração crônica de fluoreto de sódio na função e histologia da glândula tireóide de ovinos. Foram utilizados doze ovinos, os quais foram divididos em dois grupos: Controle, o qual recebeu somente sal iodado (5g NaCl/animal+0,2mg de iodo/kg MS) e o grupo Tratado, que recebeu sal iodado (5g NaCl/animal+0,2mg de iodo/kg MS) adicionado de fluoreto de sódio (4,7mg F/kg de peso corporal), durante um período de 150 dias. Amostras de sangue foram coletadas aos 60, 90, 120 e 150 dias de tratamento para análise sérica de I e F, Triiodotironina (T3) e Tetraiodotironina (T4). Ainda, nesse mesmo intervalo de tempo, coletou-se a urina, correspondente às 24 horas, para análise da excreção urinária de I e F. Após o sacrifício dos animais, a glândula tireóide foi removida para posterior exame histopatológico e morfométrico. Quanto ao I urinário, não foi observada diferença estatística entre os grupos controle e tratado e dentro de cada grupo, entre os períodos. As concentrações de T3 e T4 não diferiram estatisticamente entre ambos os grupos e dentro de cada grupo, nos diferentes tempos de tratamento. Assim como, também não houve diferença estatística nos teores de I sérico. Quanto à avaliação histopatológica da glândula tireóide, não foram observadas alterações. De um modo geral, é possível concluir que a excreção urinária de iodo, quando utilizada como estimativa do status nutricional deste elemento, deve ser considerada com parcimônia, principalmente se forem utilizadas doses dentro do intervalo de recomendação requerido para a espécie. Outrossim, conclui-se que dados referentes a inter-relação do iodo e flúor não podem ser aplicados de uma espécie para outra, pois o efeito do flúor sobre a glândula tireóide não ocorre na mesma forma e intensidade

Die Cyclin-abhängigen Kinasen 4 und 6 (Cdk4/6) wurden als essentielle Enzyme für die Regulation des Zellzyklus mit kritischem Beitrag zur gestörten Zellproliferation während der Kanzerogenese identifiziert. Als Konsequenz davon erwiesen sich die Cdk4/6 als attraktive Zielproteine für die Entwicklung neuer therapeutischer Konzepte zur pharmakologischen Tumorbehandlung. Verbindungen aus der Substanzklasse der Pyrido[2,3-d]pyrimidine zeigten vielversprechende inhibitorische Wirkungen auf die Aktivität der Cdk4/6 bei gleichzeitiger herausragender Selektivität gegenüber anderen Cdk. Anschließende Untersuchungen in vitro und in vivo verdeutlichten das Potential einiger Pyrido[2,3 d]pyrimidine zur Inhibierung des Tumorzellwachstums. Die Weiterentwicklung und Nutzung selektiver Cdk4/6-Inhibitoren zur funktionellen Charakterisierung der Cdk4/6 in Tumoren in vivo mit Hilfe der nicht-invasiven Bildgebungstechnik Positronen-Emissions-Tomographie (PET) ist ein neuer vielversprechender Forschungsansatz und von großem Interesse für die Evaluierung neuer Strategien zur Diagnose und Therapie maligner Erkrankungen. Das Ziel der vorliegenden Arbeit ist die biochemische und radiopharmakologische Charakterisierung neuer potentieller Cdk4/6-Inhibitoren aus der Verbindungsklasse der Pyrido[2,3-d]pyrimidine und deren Bewertung hinsichtlich ihrer therapeutischen Wirksamkeit zur gezielten Cdk4/6-Inhibierung in ausgewählten Tumorzelllinien sowie ihres Potentials zur funktionellen Bildgebung der Cdk4/6 in Tumoren mittels PET am Tiermodell. Die biochemische Charakterisierung der Pyrido[2,3 d]pyrimidine CKIA, CKIB, CKIC, CKID und CKIE hinsichtlich ihrer zellulären und molekularen Wirkung erfolgte in den kontinuierlich proliferierenden humanen Tumorzelllinien HT-29, FaDu und THP 1 und in differenzierten THP-1-Makrophagen. Die Zweckmäßigkeit der untersuchten Zelllinien zur Charakterisierung potentieller Cdk4/6-Inhibitoren wurde anhand von Studien zur mRNA-Expression und Proteinbiosynthese der Kinasen Cdk4/6 nachgewiesen. Des Weiteren wurde das Vorkommen der Cdk4/6 in den humanen Xenograft-Tumoren HT-29 und FaDu, sowie in ausgewählten Organen und Geweben von nu/nu-NMRI-Mäusen charakterisiert. In vitro wurden für alle untersuchten Pyrido[2,3-d]pyrimidine signifikante, konzentrations- und zeitabhängige inhibitorische Effekte auf die Tumorzellproliferation beobachtet. Durchflusszytometrische Zellzyklusanalysen 24 Stunden nach Inkubation mit den Pyrido[2,3 d]pyrimidinen zeigten eine konzentrationsabhängige Zunahme des Anteils der HT-29-, FaDu- und THP-1-Zellen in der G1-Phase bis auf 90%. Für die nicht-proliferierenden THP 1-Makrophagen wurden bei Inkubation mit den Pyrido[2,3 d]pyrimidinen geringe Veränderungen ihrer Zellzahl und Zellzyklusphasen-verteilung detektiert. Die zellulären Studien identifizierten deutliche qualitative und quantitative Unterschiede der untersuchten Pyrido[2,3 d]pyrimidin-Derivate. Nanomolare Konzentrationen von CKIA, CKIB bzw. CKIE erzielten bereits 24 Stunden nach Inkubation deutliche Effekte, während für CKIC und CKID die 10- bis 100-fache Konzentration eingesetzt werden musste, um eine ähnliche Wirkung zu erhalten. Die molekularen Ursachen der Wachstumshemmung und des Zellzyklusarrests wurden durch Untersuchungen zur Pyrido[2,3 d]pyrimidin-abhängigen Beeinflussung des Cdk4/6-Cyclin D-Retinoblastom-E2F-Signalwegs geklärt. In allen Zelllinien wurde eine deutliche Inhibierung der Cdk4/6-spezifischen Phosphorylierung der Aminosäure Serin-780 des Retinoblastom-Proteins (pRb) beobachtet. Als Konsequenz dieser Inhibierung wurde für CKIA, CKIB und CKIE die signifikante konzentrationsabhängige Unterbrechung der Genexpression von E2F-1 und PCNA nachgewiesen. Die Radiomarkierung der Cdk4/6-Inhibitoren CKIA und CKIB mit 124I bzw. von CKIE mit 18F ermöglichte erstmals die Charakterisierung von in vivo-Interaktionen und des Metabolismus im Blut zirkulierender Pyrido[2,3 d]pyrimidin-Derivate. Die radiopharmako-logischen Eigenschaften von [124I]CKIA, [124I]CKIB und [18F]CKIE wurden in Untersuchungen zur zellulären Radiotracer-Aufnahme, der metabolischen Stabilität und der Bioverteilung bei Ratten sowie abschließend in Kleintier-PET-Untersuchungen bei FaDu-Tumor-tragenden nu/nu-NMRI-Mäusen analysiert. In vitro-Experimente mit [124I]CKIA, [124I]CKIB und [18F]CKIE verdeutlichten eine hohe Stabilität und schnelle Aufnahme der Radiotracer in humane Tumorzellen bei 37°C. Allerdings deutet die Zelltyp-unabhängige Anreicherung auf eine geringe Abhängigkeit der Pyrido[2,3 d]pyrimidin-Akkumulation vom Cdk4/6-Status der Zellen hin. Die signifikant geringeren Aufnahmewerte aller untersuchten Pyrido[2,3-d]pyrimidine bei 4°C und die Blockierung der Aufnahme von [18F]CKIE mit nichtradioaktivem CKIE unterstützen die Vermutung spezifischer Transportmechanismen für die Aufnahme der Pyrido[2,3 d]pyrimidine. Untersuchungen von [124I]CKIA, [124I]CKIB und [18F]CKIE in vivo identifizierten eine schnelle, innerhalb weniger Minuten stattfindende Eliminierung aus dem Blut und die primäre Aufnahme in die Leber als grundlegende Stoffwechseleigenschaft aller drei Radiotracer. Aus den PET-Untersuchungen mit [124I]CKIA und [124I]CKIB bei FaDu-Tumor-tragenden Mäusen wurden nur marginale Anreicherungen der radioaktiven Substanzen im Bereich des Tumors festgestellt. Für [18F]CKIE wurde eine Akkumulation im proliferierenden Randbereich des Tumors beobachtet. Die schnelle Metabolisierung von [18F]CKIE im Blut sowie das konstante, geringe Verhältnis der Aktivität im Tumor zur Aktivität im Skelettmuskel wiesen allerdings auf eine unspezifische Anreicherung hin. Schlussfolgernd aus den Ergebnissen der vorliegenden Arbeit wurde die Effektivität der Pyrido[2,3 d]pyrimidine CKIA, CKIB und CKIE hinsichtlich der Inhibierung der Cdk4/6-vermittelten Zellzyklusprogression gezeigt. Die antiproliferative Aktivität der Substanzen unterstützt eine weiterführende Evaluierung dieser Cdk4/6-Inhibitoren zur pharmakologischen Tumortherapie. Auf der Basis der erhaltenen radiopharmakologischen Ergebnisse werden die kurze biologische Halbwertszeit und unspezifische Tumoranreicherung von [124I]CKIA, [124I]CKIB und [18F]CKIE als limitierende Faktoren für die Eignung dieser Verbindungen als Radiotracer zur nicht-invasiven Bildgebung der Cdk4/6 im Zielgewebe mittels PET angesehen. Es bleibt zu klären, ob eine längere Verweildauer und höhere Stabilität radiomarkierter Pyrido[2,3-d]pyrimidine im Blut die Chance der Cdk4/6-spezifischen Gewebeanreicherung erhöhen oder Transport-mechanistische Effekte allein ausschlaggebend für die Anreicherung in Zellen und Geweben sind. Die Untersuchung optimierter Cdk4/6-selektiver Inhibitoren für die Charakterisierung und Therapie von Tumoren bleibt weiterhin ein interessanter Aspekt in der Tumorforschung.

Krebserkrankungen stellen in Deutschland die zweithäufigste Todesursache dar und die Anzahl der Neuerkrankungen nimmt stetig zu. Frühzeitige Diagnosen und Therapiemöglichkeiten sind daher dringend erforderlich. Cyklinabhängige Proteinkinasen (Cdk) spielen eine entscheidende Rolle bei der Regulation des Zellzyklus. Viele Tumore zeigen eine deregulierte Cdk4‑Aktivität und/oder ‑Expression. Insgesamt zeigen ca. 80% aller Tumore eine Fehlregulation der für den Zellzyklus zentralen Cdk4/CykD1/INK4/pRb/E2F Signalkaskade. Somit besitzen Cdks ein enormes therapeutisches Potential im Kampf gegen Krebs. Die spezifische Inhibierung der Cdks verhindert die Zellproliferation und damit das Tumorwachstum. In den letzten Jahren wurden verschiedenste Strukturklassen vorgestellt, die als Cdk4-Inhibitor wirken. Im Rahmen der Promotion sollen die Möglichkeiten einer funktionellen Tumordiagnose mittels cyklinabhängiger Kinasen untersucht werden. Die Entwicklung von radioaktiv markierten Inhibitoren der Cdk4/6 als Radiotracer und ihre radiopharmakologische Charakterisierung stellt dabei einen neuen Ansatz dar. Um die Rolle der Cdk4/6 im Zellzyklus von gesunden und deregulierten (z.B. Tumor-) Zellen aufzuklären, sollten mit Iod-124 und Fluor-18 markierte Inhibitoren eingesetzt werden, die hochselektiv diese Cdks blockieren. Zunächst wurden verschiedene Inhibitoren der Cdk4/6 und deren Vorstufen für die Radiomarkierung dargestellt. Die bereits aus den Vorarbeiten von VanderWel et al., 2005 und Toogood et al., 2001 bekannten Syntheserouten mussten dazu optimiert werden und für neue Verbindungen, wie die fluorethylierten Substanzen, wurden neue Reaktionswege gefunden. Die dargestellten Referenzverbindungen CKIA-E wurden anschließend mittels Durchflusszytometrie an den Zelllinien HT-29 und FaDu auf ihre inhibitorischen Wirkung untersucht. Die Untersuchungen der Verbindungen CKIA/B/E zeigte, dass ein Zellzyklusarrest unter Einwirkung der Inhibitoren erreichbar ist. Die weiteren Untersuchungen zur Radiomarkierbarkeit sowie die radiopharmakologische Evaluation sollten daher an den Verbindungen CKIA, CKIB und CKIE stattfinden. Die Darstellung der Verbindungen [124I]CKIA und [124I]CKIB erfolgte in zwei Schritten über die elektrophile Substitution durch regioselektive Destannylierung mit anschließender Entschützung der Seitenkette. Die Darstellung der fluorethylierten Verbindung erfolgte ebenfalls über eine Zweischrittsynthese beginnend mit der Synthese der prosthetischen Gruppe [18F]BFE aus der Tosylmarkierungsvorstufe. Die zur Markierung des sekundären Amins zur Auswahl stehenden prosthetischen Gruppen [18F]Fluorethyltosylat ([18F]FETos) und [18F]Bromfluorethan ([18F]BFE) wurden auf ihre Eignung untersucht, ebenso wie die Auswahl einer geeigneten Markierungsvorstufe für die Darstellung der prosthetischen Gruppe. Die optimierten Syntheserouten ermöglichten die Isolierung von ausreichenden Mengen an Produktaktivität für die radiopharmakologischen Untersuchungen. Es fanden, neben der Bestimmung der spezifischen Aktivität und der Lipophilie der Verbindungen, Zellaufnahmeuntersuchungen und Bestimmungen zur Stabilität der Verbindungen in vitro, ex vivo und in vivo statt. Die radioiodierten Verbindungen konnten des Weiteren zur Untersuchungen der Bioverteilung in normalen männlichen Wistar-Ratten eingesetzt werden. Für alle drei Verbindungen konnte eine sehr hohe in vitro-Stabilität festgestellt werden. Die Zellaufnahmeuntersuchungen zeigten vor allem für die Verbindungen [124I]CKIA und [124I]CKIB eine beträchtliche Zellaufnahme von über 1000% ID/mg Protein nach 2 h. Die Zellaufnahme der Verbindung CKIE ist geringer, sollte allerdings für eine in vivo-Anwendung ausreichend sein. Die Untersuchung der in vivo‑Stabilität der Verbindungen [124I]CKIA, [124I]CKIB und [18F]CKIE im Blut von Wistar Ratten ergab allerdings, dass alle Verbindungen schnell metabolisiert werden. Die Untersuchung der Bioverteilung der radioiodierten Verbindungen belegen eine in vivo Radiodeiodierung sowie eine hohe hepatobliliäre Auscheidungsrate. Im Hinblick auf eine Anwendung als Radiotracer konnten im Rahmen dieser Arbeit neue Erkenntnisse gewonnen werden. Die dargestellten Inhibitoren sind in der Lage am Zellmodell den Zellzyklusarrest in der G1-Phase zu induzieren. Eine Radiomarkierung der ausgewählten Strukturen liefert das Produkt mit reproduzierbarer Ausbeute in hoher radiochemischer Reinheit und ausreichender spezifischer Aktivität, allerdings ist eine Herstellung der fluorethylierten Verbindung unter GMP-Bedingungen nur schwer realisierbar. Die radiomarkierten Verbindungen zeigen eine hohe in vitro-Stabilität und werden energieabhängig in die Zelle aufgenommen. Anhand der Stabilitätsuntersuchungen in vivo wurde gezeigt, dass alle drei Verbindungen in vivo instabil sind und sehr schnell hepatobiliär eliminiert.

L'action d'aldéhydes aromatiques sur des pivalolaminopyridines ortho lithiées a donné des alcools secondaires qui ont été oxydés en cétones. Ceci permettant une synthèse en 4 étapes des amino-2 pyridyl-3, amino-3 pyridyl-4 et amino-4 pyridyl-3 arylméthanones. De la même façon, la fluoro-4 lithio-3 pyridine conduit à l'amino-4 pyridyl-3 phénylméthanone. Pour montrer l'intérêt de la méthode, des pyridopyrimidinones et des benzonaphtyridines ont été synthétisées. Par ailleurs, la fluoro-2 pyridine métallée, réagit avec l'iode pour donner des iodo-3 pyridines diversement substituées en 2. Une synthèse en 2 étapes des ortho iodo aminopyridines a été développée à partir des trois monoaminopyridines. La substitution de l'iode par des énolates dans les conditions de la SNR1 conduit après cyclisation acide aux aza-5, -6 et -7 indoles substitués en 2. Enfin, des aza-5 indoles disubstitués en -2, -3 ont été obtenus par action d'alphaméthoxycétones sur la lithio-3 pivalamido-4 pyridine et cyclisation acide

碩士
國立屏東科技大學
環境工程與科學系所
99
Photocatalysts have been widely used on the studies of solar energy conversion and environmental applications. However, the modified titanium dioxide (TiO2) has become an important topic to increase the usage of visible light absorption region. Fluoride (F), iodine (I) and Nitrogen (N) were added to modify TiO2 to reduce the usage of precious metals and improve to absorption of visible light. In this study, sol-gel method was applied using TiO2 and a small amount of different elements (F, I, N) in order to compare the effects of TiO2, F-TiO2, I-TiO2, FN-TiO2, IN-TiO2, FNI-TiO2 and INF-TiO2 catalysts Methylene blue degradation and mineralization rate were investigated. The results showed that doping F, I and N could effectively enhance the visible light absorption on titanium dioxide. The X-ray diffraction analyzer (XRD) also showed further confirmation of the catalyst used in this study with higher photocatalytic activity of anatase. Scanning electron microscopy (SEM) results showed that F, I and N increased the surface area and the particle size analyzed by BET. In addition, the UV radiationof the xenon lamp was cut off using a filter glass. The percent degradation for methylene blue and pentachlorophenol were 98 % and 70 %, respectively. The toxicity and the concentration of chloride ion of samples decreased with the increase of exposure time. The increase of illumination time, while the relative concentration of PCP decreased with increasing illumination time may be due to the effects of F, I and N atoms. Due to the high temperature calcination of titanium dioxide into the lattice, the atoms of F, I and N replaced the oxygen atoms, and thus reduce the energy level making the absorption intensity of visible light increased. When the F, I and N were doped on titanium dioxide, the modified photocatalysts could be a useful system with natural sunlight to remediate the organic polluted water.

Abstract: Poly (vinylidene fluoride) (PVDF), thanks to its versatile properties, finds many applications ranging from water purification membranes (thermal and chemical stability) to electronic devices (piezoelectric, pyroelectric and ferroelectric properties). Block copolymers of PVDF with other polymers further expand its properties and, consequently, its applications. Toward this line, my thesis investigates the synthesis, molecular characterization and properties of novel PVDF-based copolymers mainly with poly(tert-butyl acrylate) (PtBuA), poly(methyl methacrylate) (PMMA) and polystyrene (PSt). To prepare the block copolymers a living polymerization is needed, which is compatible with the VDF and the comonomer (tBuA, MMA, St). For this purpose, we used iodine transfer polymerization (ITP) with the difunctional chain transfer agent (CTA) C4F8I2. Difunctional macroinitiator (I-PVDF-I) was first obtained by ITP of VDF monomer with C4F8I2, followed by addition of the comonomer tBuA, MMA or St to afford the triblock copolymers poly(tert-butyl acrylate)-block-poly(vinylidene fluoride)-block-poly(tert-butyl acrylate) (PtBuA-b-PVDF-b-PtBuA), poly(methyl methacrylate)-block-poly(vinylidene fluoride)-block-poly(methyl methacrylate) (PMMA-b-PVDF-b-PMMA) and polystyrene-block-poly(vinylidene fluoride)-block-polystyrene (PSt-b-PVDF-b-PSt). The structure of all intermediates and final products were characterized by Nuclear Magnetic Resonance (NMR) and Gel Permeation Chromatography (GPC). The microstructure and polymorphism of all triblock copolymers, characterized by XRD, shown that the PVDF in the first two copolymers exhibits the electroactive β-phase, while in the third copolymer there is the coexistence of α- and γ-phases. Linear PVDF homopolymers, using the free radical and IT polymerizations, were prepared for comparison purposes. All linear polymers possess the α-phase. The thesis is divided into the following five chapters: 1. Introduction, where the scope of this thesis is given with a brief background on PVDF; 2. Literature Review, where a summary of previously published works on PVDF synthesis and polymorphism is presented; 3. Experimental Section, where detailed procedures and characterization methods are given; 4. Results and Discussion, where outcomes of successful experiments are discussed; and 5. Conclusion and Perspective, where the outcomes of this work are summarized and perspective are discussed.

博士
國立陽明大學
生物醫學影像暨放射科學系暨研究所
98
Alzheimer’s disease (AD) is one of the epidemic neurodegeneration disease-affecting millions in elders. In AD, much number of dystrophic neuritis has been shown to correlate with the clinical severity of dementia, and neuronal dystrophy is associated with synaptic loss in cortical cultures exposed to fibrillar A? (??amyloid). As senile plaques (SPs) and neurofibrillay tangles (NFTs) are hallmarks in AD. Histological dye analogs, like Thioflavin-S, had many kinds of biomarker for mapping A?? [18F]FDDNP (2-(1-{6-[(2-[18F]fluoroethyl)(methyl)amino]-2-naphthyl} ethylidene)malononitrile) and [123I]IMPY (6-iodo-2-(4?S-dimethylamino)phenylimidazo [1,2-a]-pyridine), also showed the superiority characteristics in binding with SPs and NFTs. In the article, we modified the protocol on an auto-synthesizer and used these radiopharmaceuticals in vitro, in vivo and ex vivo study for identification. In the first, modification of the protocol on an auto-synthesizer (by [18F]FDG and [123I]ADAM) and wish to use the high purity radiopharmaceuticals in the future study. In radio-synthesis, higher quality product by in-house-labeling [18F]FDDNP. (95%, identified by radioHPLC, yield about the 30%) and in [123I]IMPY (98%, identified by radioTLC, yield about the 30%). Identify the lipophilic by the partition coefficient test, and the result values were 1.93 and 1.82, respectively. It means higher lipophilic could had ability to penetrate the blood brain barrier (BBB). Second, in in vitro assays by the competitive assay showed that [18F]FDDNP high selectivity and specificity in Tg2576 brain region (selectivity between hippocampus and frontal cortex were 2.10 ± 0.34 and 1.90 ± 0.17, respectively (compare with cerebellum), specificity between hippocampus and frontal cortex were 4.62 ± 1.58 and 7.27 ± 5.53, respectively (compare with cold FDDNP)). And in [123I]IMPY, hippocampus of transgenic mice compared with controls showed 2.04 ?b 0.37 times accumulated, while the frontal cortex showed 2.12 ?b 0.47 times. In addition of the competitive assay for the IMPY: the hippocampus of Tg2576 transgenic mice showed 1.16 ?b 0.34 times than controls while the cortical cortex in transgenic mice showed 1.22 ?b 0.40 times of controls. Third, in ex vivo assay, [18F]FDDNP and [123I]IMPY in post-injected 30min in frontal cortex and hippocampus in transgenic mice compare to control mice had 4.39 and 2.19 folds (in frontal cortex) and 3.09 and 2.40 folds (in hippocampus), in FDDNP and IMPY. Fourth, in in vivo assay, microPET or microSPECT showed that Tg2576 brain section/reference (cerebellum or muscle) ratio lager than control mice. In microPET the ratio was about 0.83 to 1.00 in Tg2576 mice compare with muscle, and in control mice the ratio between muscle only had 0.05 to 0.19 in different brain region (like cortex, stratum, thalamus, and cerebellum) by [18F]FDDNP. In microSPECT the Tg2576 mice had 2.8 and 2.9 fold between frontal cortex and thalamus to cerebellum, and in control group only had 1.5 and 1.4 fold by [123I]IMPY. All of those results, synthesize of [18F]FDDNP and [123I]IMPY were success. Higher quality product and in those experiments were showed the superiority results. In vitro competitive assay and ex vivo assay showed that [18F]FDDNP and [123I]IMPY is available for tracing A? in AD research. In the past, researcher less the imaging report by transgenic mice. But in my in vivo imaging study had encourage result by this kind of radiopharmaceuticals, and wish to exploitative the preclinical platform for early diagnosis on AD patients.