Dissertations / Theses on the topic 'Base pyrimidique'

O objetivo deste trabalho foi avaliar o efeito dos diferentes níveis de nucleotídeos sobre o desempenho de frangos de corte alimentados com probióticos. Para o trabalho, foi utilizado um delineamento inteiramente casualizado com cinco repetições dentro de cada tratamento. Foram utilizados 1050 frangos machos da linhagem Ross 308 totalizando trinta e cinco aves por boxe. As aves foram criadas até 42 dias de idade que receberam as rações experimentais a base de milho e farelo de soja contendo seis diferentes níveis de nucleotídeos (0; 100; 200; 300; 400 e 500 gramas por tonelada de ração). Os diferentes níveis de nucleotídeos foram utilizados na fase inicial (1 a 21 dias de idade) e crescimento (22 a 35 dias de idade). Durante a fase final (36 a 42 dias de idade) foi fornecido rações sem nucleotídeo para todos os tratamentos. Os resultados experimentais demonstraram que houve melhora linear no desempenho dos frangos de corte no período de 1 a 21 dias de idade, indicando que, quanto maior o nível de nucleotídeos na dieta de frangos de corte, maior foi o peso corporal das aves. A conversão alimentar também é melhorou linearmente no período de 1 a 21 dias de idade à medida que aumentou o nível de nucleotídeos na ração. O peso no período de 35 dias de idade, também teve um comportamento linear, semelhante ao período de 1 a 21 dias, indicando que, quanto maior o nível de nucleotídeos na dieta de frangos de corte, maior o desempenho das aves. Quanto aos níveis plasmáticos de ácido úrico, pôde-se observar efeito quadrático no período de 1 a 21 dias de idade, indicando o valor de 231,59 gramas de nucleotídeos por tonelada de ração, como o melhor, em níveis mínimos de ácido úrico, por outro lado, no período de 35 dias de idade, estima-se o nível de 208,99 g de nucleotídeos por tonelada de ração; como o melhor em níveis mínimos de ácido úrico no sangue. No período final (35 a 42 dias de idade) e período total (1 a 42 dias de idade) não foi possível o observar efeito dos contrastes testados em nenhum dos parâmetros avaliados.
The objective of this experiment was to evaluate the influence of different nucleotides levels in the rations of broilers containing probiotics on response of the birds and its influence on the performance. Birds were allocated in a randomized experimental design with five replications of each treatment. It was used 1,050 chicks of a day of age, males, distributed in 30 experimental boxes with 35 birds each. The chickens were reared from 1 to 42 days of age and the diets contained corn and soybean meal with one of six different nucleotídes levels (0; 100; 200; 300; 400 and 500 grams for ton of ration). The different nucleotides levels were used in the initial phase (1 to 21 days of age) and growth (22 to 35 days of age). During the final phase (36 to 42 days of age) it was supplied rations without nucleotides for all of the treatments. The experimental results demonstrated that there was improvement on broilers performance in the period from 1 to 21 days of age, demonstrating proportionality between nucleotides level in the diet of broilers and body weight of the birds. Feed conversion at 21 days of age was directly proportional to nucleotides level in the diet. Body weight at 35 days of age, also had a linear behavior, similar to the period from 1 to 21 days, indicating that, as higher the nucleotides level in the diet of broilers, higher the acting of the birds. Acid plasmatic uric levels, demonstrated quadratic effect at 21 days of age, indicating 231,59 grams of nucleotides for ton of ration, and at 35 days of age, it was considered the level of 208,99 g of nucleotides for ton of ration. In the final period (35 to 42 days of age) and total period (1 to 42 days of age) it was not demonstrated effect of the contrasts tested in none of the appraised parameters.

Au travers de ce manuscrit, nous décrivons la synthèse de moutardes à l’azote à motifs pyrimidiques, puriques ou triazoliques. Dans un premier temps, nous étudions la synthèse d’une moutarde à l’azote dérivée de l’uracile. L’étude de l’étape d’amidation directe a permis de généraliser cette méthode à diverses amines. Une e��tude de modélisation moléculaire a mis en évidence l’importance des interactions non liantes dans cette réaction. Dans une seconde partie, nous décrivons la synthèse de moutarde à l’azote à partir de bases puriques. Cette stratégie a conduit à la formation de composés tricycliques, dérivés de la purine. Dans une troisième partie, nous nous sommes intéressés à l’élaboration d’une nouvelle famille de moutardes à l’azote à motifs triazoliques. Grâce à l’utilisation de la réaction de CuAAC, nous avons synthétisé huit molécules aux structures innovantes. Cette dernière stratégie ouvre la voie à la synthèse d’une nouvelle famille de moutardes à l’azote aux motifs variés. Enfin, nous étudions l’activité biologique de certains des composés synthétisés par test de viabilité cellulaire, puis par cytométrie en flux. Deux composés obtenus ont présenté des résultats encourageants vis-à-vis de quatre lignées cancéreuses
The synthesis of pyrimidine, purine and triazole nitrogen mustards is described. First, we studied the synthesis of uracil-based nitrogen mustards. The amidation step was particularly studied and this method was extended to several amines. A series of DFT calculations highlighted the significance of non-bounding interactions in this amidation step. Second, the synthesis of several purine-based nitrogen mustards is described. This synthetic pathway led to the formation of tricyclic compounds, derive from purine. In a third part, we were interested in the elaboration of a new family of triazole nitrogen mustards. Thanks to the use of CuAAC reaction, we managed to synthesize 8 new nitrogen mustards. This latter strategy paves the way to the synthesis of a new family of nitrogen mustards, with an important structural variability. Furthermore, we studied the biological activity of synthesized compounds by testing their cytotoxicity and, then, by flow cytometry. Two of them showed encouraging results towards four cancer cells lines

Pyrimidine-based quartets and quadruplexes are unstable and thus are rarely encountered in nature. Uracil (U) and thymine (T) quartets in the solution state have only been found as part of pre-existing G-quadruplex scaffolds and the corresponding quadruplexes have not been reported. Studies on such systems might shed light on their role in nucleic acid topology and stability. This thesis describes the assembly and structural characterization of these motifs in vitro as a result of grafting the respective nucleosides onto resorcinol-based cavitands. These rigid macrocycles serve as molecular templates on which these motifs are preorganized. Reduction of entropic loss improves thermodynamic stability and promotes self-assembly. A convergent synthetic strategy was employed for accessing these cavitand-nucleoside conjugates. Cavitands and nucleosides were prepared separately using established literature methods, and the final coupling step of the two components entailed a copper (I)-catalyzed azide-alkyne cycloaddition, or a "click" reaction. NMR spectroscopy was used extensively in signal assignment, structure elucidation and oligomeric state analysis. CD spectroscopy was employed in some cases to provide further confirmation of defined structure. Findings indicated the spontaneous self-assembly of a U-quartet in CDCl3 at both 25 ºC and –20 ºC. In the presence of a metal cation (Sr²⁺), symmetric homodimerization of two U-quartets occurs at 25 ºC. The corresponding U-quadruplex unit was identified in DMSO-d₆ at 25 ºC. The T-quartet was shown to be nonexistent at 25 ºC, but assembles at a low temperature of –40 ºC. iii No evidence for metal cation uptake was found at 25 ºC. Assembly of the T-quadruplex was confirmed in DMSO-d₆ at 25 ºC. In all of these systems, stacking of the nucleobase and triazole linker rings was indicated suggesting π-stacking interactions to be a significant contributor to overall stability.
Science, Faculty of
Chemistry, Department of
Graduate

Nous décrivons la synthèse d’analogues d’oligonucléosides et de la chlorméthine à partir de bases pyrimidiques. Dans une première partie, la synthèse des analogues de dinucléosides reliés par une chaîne carbonée insaturée entre les positions 3’, 3 et 5’ à partir de la thymidine portant des groupements allyles est décrite. Un analogue de trinucléoside présentant la même chaîne carbonée entre les positions 3’ et 3 a également été synthétisé. L’étape clé de ces synthèses utilise la réaction de métathèse des oléfines. Une étude de cette réaction par activation micro-onde a été réalisée. Dans une seconde partie, nous présentons la synthèse d’agents alkylants à partir de bases pyrimidiques, suivie de leur évaluation biologique. L’étape clé de ces synthèses est la fixation d’une ou deux chaînes chloroéthyle sur la base pyrimidique, dont une optimisation a été réalisée par activation micro-onde. Certains analogues ont été glycosylés afin d’augmenter leur index thérapeutique. Tous les produits synthétisés ont été caractérisés par différentes méthodes spectroscopiques. L’activité anticancéreuse de plusieurs agents alkylants synthétisés donne des résultats préliminaires très encourageants
The synthesis of oligonucleoside and chlormethine analogues from pyrimidic bases is described. The first part presents the synthesis of dinucleoside analogues linked by an unsatured hydrocarbon chain between positions 3’, 3 and 5’ from thymidine with an allyle group. One trinucleoside analogue containing the same hydrocarbon chain between the positions 3’ and 3 is also synthesized. The key step of these syntheses is the use of olefin metathesis reaction. We performed a study of microwave-activated cross metathesis. In the second part, we present the synthesis and the biological activity of alkylating agents from pyrimidic bases. The key step of these syntheses is the fixation of one or two chloroethyle chains on pyrimidic base. An optimization of this step is obtained by microwave activation. Some analogues have been glycosylated to increase their therapeutic index. All synthesized products have been characterized by spectroscopic analyses. The antitumoral activity of several synthesized alkylating agents gave very interesting preliminary results

De nombreuses modifications des bases de l'adn peuvent etre generees par divers facteurs comme les agents oxydants ou cancerigenes, les rayonnements afin d'evaluer les consequences biologiques et physico-chimiques de ces dommages, il est necessaire de posseder des modeles plus complexes de ceux-ci qui peuvent etre obtenus par leur incorporation dans des oligonucleotides par voie chimique. Ce travail est consacre a la preparation de fragments d'adn contenant des derives de la 2'-desoxyuridine. Le premier volet de ce travail a consiste a preparer un synthon phosphoramidite de la 5-formyl-2'-desoxyuridine et a l'incorporer dans des oligonucleotides de synthese. La suite de ce travail concerne la mise en evidence et la caracterisation d'une nouvelle lesion, resultant de l'oxydation de la thymidine: la 5-carboxy-2'-desoxyuridine. Par ailleurs, la preparation d'oligonucleotides comportant cette lesion a ete realisee. La troisieme partie de ce travail correspond a l'incorporation d'un troisieme defaut dans des oligonucleotides: la 5,6-dihydro-2'-desoxyuridine (dhdu). Une etude plus complete sur les produits de degradation de cette lesion, susceptibles de se former en milieu alcalin, a ete ensuite menee avec le monomere et avec un trinucleotide, d(gdhdut). Dans une derniere partie, la recherche de conditions analytiques de separation de produits d'oxydation de la thymidine par electrophorese capillaire est presentee

Le but de cette etude etait d'ameliorer les connaissances concernant l'action de l'ozone sur les bases puriques et pyrimidiques. Des etudes cinetiques de l'ozonation de la purine, de la pyrimidine, et de leurs nucleobases correspondantes (adenine, guanine, cytosine, thymine et uracile) ont ete conduites dans differents types de reacteurs, en milieu aqueux tamponne et en presence d'ions hydrogenocarbonates comme pieges a radicaux. L'ordre global des reactions a ete determine, ainsi que les stoechiometries et les constantes de vitesse pour chaque compose. En outre, l'influence du ph et de la temperature a ete etudiee dans le cas de la reaction ozone-purine. Des experimentations en reacteur semi-batch ont permis de comparer la reactivite de certaines nucleobases, d'un nucleoside et d'un nucleotide dans ces conditions experimentales. La mineralisation de l'azote et du carbone organique a ete suivie en fonction du taux d'ozonation. Pour l'adenine et la thymine, certains sous-produits d'ozonation ont ete identifies

Divers facteurs comme des agents oxydants ou cancerigenes, les rayonnement ultraviolets et ionisants, peuvent engendrer des modifications des bases de l'adn. Afin d'evaluer les consequences biologiques et physico-chimiques de ces dommages, l'obtention de courts fragments d'adn (oligonucleotides), de sequence definie (20 a 50 bases de long) et comportant une ou plusieurs modifications en des sites bien precis est primordiale. La synthese oligonucleotidique est aujourd'hui la methode de choix pour preparer de tels composes modeles. Ce travail est consacre a la preparation de fragments d'adn synthetiques contenant des nucleosides modifies formes lors de la radiolyse ou de la photosensibilisation des acides nucleiques. La premiere partie de cette these concerne la preparation d'un synthon phosphoramidite de la 5-hydroxy-2-desoxycytidine et l'incorporation de ce dernier dans des oligonucleotides de synthese de 14 a 33 bases de long. La deuxieme partie (chapitres iii et iv) concerne la synthese et l'incorporation de lesions radio-induites originales : les cyclonucleosides. Les deux diastereoisomeres (5r)- et (5s)- des 5,8-cyclopurine-2-desoxyribonucleosides ont ete inseres separement dans differents oligonucleotides (3 a 22 bases de long) en utilisant la chimie phosphoramidite classique. L'incorporation de la (5s, 6s)-5,6-cyclo-5,6-dihydrothymidine a egalement ete effectuee. La structure particuliere de ce cyclonucleosides (perte du caractere aromatique de l'heterocycle azote) ainsi que sa faible reactivite (determinee au cours de nos experiences) nous ont contraint au developpement d'une strategie de synthese radicalement differente de celle utilisee pour les 5,8-cyclopurine-2-desoxyribonucleosides. La troisieme partie de ce travail est consacre a la preparation d'un synthon phosphoramidite pour la 4-hydroxy-8-oxo-7,8-dihydro-2-desoxyguanosine. Au cours de l'une des etapes de synthese de ce precurseur, nous avons pu facilement separer les deux diastereoisomeres (4r)- et (4s)- de ce nucleoside modifie. Ils ont ete incorpores separemment dans les fragments d'adn synthetiques; l'epimerisation de la position c-4 n'etant pas observee au cours de la synthese sur support solide et lors de l'etape de deprotection ammoniacale. La derniere partie de ce manuscrit concerne la preparation d'oligonucleotides (2 a 9 bases de long) contenant un nucleoside modifie precurseur du radical 5-(2-desoxyuridilyl)methyle : la 5-(phenylthiomethyl)-2-desoxyuridine. Ces substrats ont ete utilises dans des etudes mecanistiques ayant pour but de preciser la reactivite de cet intermediaire radicalaire. Pour chacun des dommages incorpores une attention toute particuliere a ete portee a l'integrite des oligonucleotides synthetises. L'utilisation de differentes methodes analytiques (spectrometrie de masse et analyses clhp et maldi-tof des digestions enzymatiques) a permis de demontrer la purete des produits obtenus.

Nous avons mesuré plusieurs modifications de bases dans l'ADN de monocytes, exposés au rayonnement y du 60Co, à la lumière UV LASER de haute intensité, ou soumis à un flux de particules de 12C6+. Nous avons eu recours à deux approches complémentaires. La première a impliqué les méthodes de chromatographie liquide haute performance ou gazeuse couplées à une détection par spectrométrie de masse (CLHP-SM/SM ou CG-SM) ou par électrochimie (CLHP-DE). Ces différentes techniques ont permis la mesure du niveau basal et du taux de formation de 7 lésions. La deuxième approche était basée sur l'utilisation de la méthode des comètes associée aux enzymes de réparation Fpg et endo III. La méthode, sous sa forme standard, permet de mettre en évidence les cassures simple et double brin ainsi que les sites alcali-labiles de l'ADN. Associée à Fpg et endo III, elle a permis de quantifier respectivement des purines et des pyrimidines modifiées. La confrontation des deux approches et le recours à d'autres agents oxydants comme le rayonnement UVA ou des photosensibilisateurs exogènes, a permis de calibrer la méthode afin d’estimer le niveau des différentes classes de lésions. Il ressort de ces travaux que l'approche indirecte, bien que moins spécifique est moins sujette aux problèmes d'oxydation des bases normales rencontrés lors de la préparation et de l'analyse des échantillons par les méthodes chromatographiques d 'analyse. Toutefois, lorsque ces problèmes d'oxydation sont pris en considération dans les mesures analytiques, les deux approches donnent approximativement les mêmes valeurs. Dans le cas contraire, des variations d 'un facteur 100 à 1000 peuvent être observées. Ainsi, il apparaît aujourd'hui que la plupart des travaux antérieurs concernant la mesure des bases modifiées de l'ADN par la méthode CG-SM doivent être reconsidérés
The main objective of the current project was to measure DNA base damage in the DNA of a monocytic cell line exposed to y-ray,UV LASER pulses orto 12C6+ particles. For this purpose, two approaches were developed. The first one consisted of chromatographie methods including high performance liquid or gas chromatography assay coupled with either an electrochemical (HPLC-EC) or a mass spectrometry detection (HPLC-MS/MS, GC-MS). After optimisation, the latter methods allowed the measurement of the level of 7 base lesions. An indirect approach based on the cornet assay associated to DNA N-glycosylases was also applied. The latter method, under its standard form, allowed the detection of single and double strand breaks together with alkali-labile sites. Associated to DNA repair enzymes such as Fpg and endo III, it allowed the measurement of modified purines and pyrimidines, respectively. Lt was possible to calibrate the modified cornet assay in order to evaluate the level of the previous classes of lesions. For this purpose, cells were also exposed to UVA and exogenous photosensitisers. Although the cornet assay associated to Fpg and endo III can suffer from a lack of specificity, it was shown to be less subject to the artefactual oxidation ofthe normal bases which occurs during the preparation of the samples prior to their analysis by HPLC-EC or GC-MS. However, when much attention is devoted to reduce these drawbacks, indirect and direct approaches give approximately the same values. These levels are at least 100 fold lower than those reported by many previous studies involving the use of GC-MS assay. Therefore, many results inferred from the latter method have today to be reconsidered

Nous décrivons la synthèse d'agents antiviraux et anticancéreux préparés à partir de bases pyrimidiques. La première partie de ce mémoire est consacrée à la synthèse d'acyclonucléosides et à l'évaluation de leurs propriétés antivirales (HIV-1). Ces synthèses utilisent une méthode originale conçue pour la débenzoylation sélective des hydroxyles secondaires de la partie glucidique du nucléoside. Dans la seconde partie, nous présentons la synthèse de nouveaux analogues du chlorambucil. La première étape de ces synthèses consiste dans l'alkylation de la thymine par activation micro-onde. Nous avons étudié l'influence de différents paramètres (longueur de la chaîne, mode d'activation, etc. . . ) sur le rendement et la sélectivité de la réaction. Ces nouvelles structures ont été caractérisées par RMN, spectrométrie de masse et spectroscopie IR
We describe the synthesis of antiviral and anti-cancer agents obtained from pyrimidine bases. The first part of this study is devoted to the syntheses of acyclonucleosides and an evaluation of their antiviral properties (Hiv-1). These syntheses make use of an original method designed for the selective debenzoylation of secondary hydroxyls of the glucidic part of nucleosides. In the second part, we present the synthesis of new analogues of chlorambucil. The first step of these syntheses consists in thymine alkylation by the means of micro-wave activation. We studied the influence of various parameters (length of the chain, mode of activation, etc. . . ) on both output and selectivity of the reaction. These new structures have been characterized by NMR, mass spectrometry and IR spectroscopy

The development of heterocyclic chemistry is important for various science areas and for the industry. The main task of this branch of chemistry is the search for the new, more effective synthetic methods for obtaining heterocyclic derivatives. That covers not only the formation of heterocycles, but also their functionalization, which leads to the creation of compounds having various chemical and physical properties. The accomplishments of this area are applied in biochemistry, pharmacochemistry, photophysics and other branches of science and industry. The creation of effective heterocycles synthesis methods, that may be applied for the formation of heterosystems based on pyrazolo[3,4-d]pyrimidine was the main aim in this work. During this work, three hitherto unknown peri-fused heterocyclic systems based on pyrazolo[3,4-d]pyrimidine scaffold were synthesized. The suitable conditions for the cyclization of 4-(2,2-diethoxyethyl)aminopyrimidines to 2,3-dihydroimidazo[1,2-c]pyrimidines were found. The influence of functional groups in pyrimidine moiety for the course of this reaction was investigated. It has been shown that functional groups including alkylthio, cyano, amino, formyl are tolerated in this type of reaction. The method for the replacement of ethoxy group with benzyl mercaptan in 3-ethoxy-2,3-dihydroimidazo[1,2-c]pyrazolo[4,3-e]pyrimidines has been found.
Heterociklų chemijos vystymasis turi didelę reikšmę įvairioms mokslo sritims ir pramonės raidai. Pagrindinis šios chemijos srities uždavinys – kurti naujus heterociklinių junginių sintezės metodus, leidžiančius paprasčiau, efektyviau gauti norimos struktūros junginius. Tai apima ne tik heterociklų formavimo būdus, bet ir jų funkcionalizavimą, leidžiantį sukurti įvairiomis cheminėmis ir fizikinėmis savybėmis pasižyminčių junginių įvairovę. Šios mokslo srities pasiekimai pritaikomi biochemijoje, farmacijoje, fotofizikoje ir kitose mokslo ir pramonės šakose. Šiame darbe buvo siekiama sukurti efektyvius heterosistemų sintezės būdus, kuriuos galima pritaikyti pirazolo[3,4-d]pirimidino fragmentą turinčių heterociklų formavimui. Šio darbo metu buvo susintetintos trys iki šiol neaprašytos heterociklinės sistemos atliekant peri-kondensuotų heterosistemų sintezę iš 3-amino-4-chlor-1-metil-6-metiltio-1H-pirazolo[3,4-d]pirimidino. Surastos tinkamos sąlygos 4-(2,2-dietoksietilmino)pirimidinų ciklizacijai į 3-etoksi-2,3-dihidroimidazo[1,2-c]pirimidinus. Ištirta pirimidino žiede esančių pakaitų įtaka šiai reakcijai. Parodyta, kad ši reakcija yra suderinama su tokiomis funkcinėmis grupėmis, kaip alkiltio-, cian-, amino-, formilgrupės. Surastas metodas 3-etoksi-2,3-dihidroimidazo[1,2-c]pirazolo[4,3-e]pirimidinų etoksigrupės pakeitimui benziltiogrupe.

[ES] La luz solar puede producir daños en el ADN por absorción directa de luz UVB, o por fotosensibilización tras la absorción de luz UVA por parte de fármacos, que pueden actuar como fotosensibilizadores (PS). La benzofenona (BP), presente en la estructura química de una amplia variedad de fármacos, tiene el potencial de fotosensibilizar daño al ADN, especialmente hacia la base de timina (Thy). Este daño puede dar lugar a dímeros de pirimidina de tipo ciclobutano (CPD) y a fotoproductos (6-4) pirimidina-pirimidona ((6-4)PPs), los cuales pueden causar mutaciones graves, melanomas o incluso la muerte celular. En algunos organismos, los (6-4)PPs pueden repararse de manera eficiente por las fotoliasas, en lo que se podría entender como una reacción Paternò-Büchi (PB) inversa a través de un intermedio de oxetano altamente inestable. Con el fin de profundizar en la fotorreactividad de los derivados BP-Thy y en la ruptura fotoinducida de oxetanos, se sintetizaron por primera vez una variedad de diadas en las que Thy y BP están covalentemente unidas por un espaciador lineal de diferente longitud y naturaleza. La fotorreactividad de los diferentes derivados se investigó por fotólisis de destello láser (LFP) y espectroscopía de absorción transitoria a escala de femtosegundo; además, se aislaron y caracterizaron los principales fotoproductos (PPs) derivados de la irradiación en estado estacionario. Los resultados mostraron un alto grado de quimioselectividad en la longitud y conformación del espaciador. En cuanto a la reactividad fotoquímica, se formaron PPs derivados de la PB y de la abstracción formal de hidrógeno; así, las diadas con el espaciador más largo dieron lugar a la formación de oxetanos y de PPs de abstracción de hidrógeno. Por el contrario, las diadas con espaciadores más cortos formaron un fotoproducto de abstracción formal de hidrógeno y/o polimerización. Por tanto, la fotorreactividad se vio influida por la longitud del espaciador, correlacionándose bien con los tiempos de 3BP*, observándose los tiempos más cortos para las diadas de espaciadores largos. En relación con la fotoapertura de oxetanos, la irradiación de los diferentes regio- y estereoisoméros condujo a la formación de la típica banda de absorción triplete-triplete de BP; por tanto, dicho proceso opera de forma adiabática. La fotólisis del oxetano que resulta de la irradiación de la diada con el espaciador más largo mostró una banda de absorción transitoria sobre 400 nm, atribuida a la formación del exciplejo triplete entre BP y Thy covalentemente unidos. Por otro lado, se investigó la reacción PB y la cicloreversión de oxetanos que surgen de la interacción entre Thy o derivados de uracilo (Ura) y BP. Así, se sintetizó una amplia gama de oxetanos Thy-BP y Ura-BP con diferentes sustituyentes en las posiciones 1 y 5 de la nucleobase, incluyéndose los regioisómeros cabeza-cabeza (HH) y cabeza-cola (HT). Los estudios espectroscópicos (absorción transitoria ultrarrápida y LFP), junto con el análisis teórico, coinciden en que la cicloreversión fotoinducida para los isómeros HH y HT implica la formación de un exciplejo en el estado excitado triplete antes de la ruptura. Generalmente, se observó que la reacción fue completamente adiabática para los regioisómeros HH. En el caso del oxetano HH que surge de la interacción entre 1,3-dimetiltimina (DMT) y BP, se observó la formación de una banda ~400 nm, que se atribuyó al exciplejo triplete 3[DMT···BP]*. Su formación fue altamente regioselectiva, siendo más rápida y eficiente para el isómero HH que para HT. Estos resultados fueron confirmados por análisis computacional. En general, se observó adiabaticidad en el proceso de fotorreversión para todos los oxetanos investigados, con un alto grado de regioselectividad y con la participación de exciplejos triplete.
[CA] La llum solar pot produir danys a l'ADN per absorció directa de llum UVB, o per fotosensibilització després de l'absorció de llum UVA per part de fàrmacs, que poden actuar com fotosensibilitzadors (PS). La benzofenona (BP), present en l'estructura química d'una àmplia varietat de fàrmacs, té el potencial de fotosensibilitzar dany a l'ADN, especialment a la base de timina (Thy). Aquest dany pot donar lloc a dímers de pirimidina de tipus ciclobutà (CPD) i a fotoproductes (6-4) pirimidina-pirimidona ((6-4)PPs), els quals poden causar mutacions greus, melanomes o fins i tot la mort cel·lular. En alguns organismes, els (6-4)PPs poden reparar-se de manera eficient per les fotoliases, en el que es podria entendre com una reacció Paternò-Büchi (PB) inversa a través d'un intermedi d'oxetà altament inestable. Amb la finalitat d'aprofundir en la fotoreactivitat dels derivats BP-Thy i en la ruptura fotoinduïda d'oxetans, es van sintetitzar per primera vegada una varietat de diades en les quals Thy i BP estan covalentment unides per un espaiador lineal de diferent longitud i naturalesa. La fotoreactivitat dels diferents derivats es va investigar per fotòlisi de centelleig làser (LFP) i espectroscopía d'absorció transitòria a escala de femtosegons; a més, es van aïllar i caracteritzar els principals fotoproductes (PPs) derivats de la irradiació en estat estacionari. Els resultats van mostrar un alt grau de quimioselectivitat en la longitud i conformació de l'espaiador. Quant a la reactivitat fotoquímica, es van formar PPs derivats de la PB i de l'abstracció formal d'hidrogen; així, les diades amb l'espaiador més llarg van donar lloc a la formació d'oxetans i de PPs d'abstracció d'hidrogen. Per contra, les diades amb espaiadors més curts van formar un fotoproducte d'abstracció formal d'hidrogen i/o polimerització. Per tant, la fotoreactivitat es va veure influïda per la longitud de l'espaiador, correlacionant-se bé amb els temps de 3BP*, observant-se els temps més curts per a les diades amb espaiadors llargs. En relació amb la fotoapertura d'oxetans, la irradiació dels diferents regi- i estereoisòmers va conduir a la formació de la típica banda d'absorció triplet-triplet de BP; per tant, aquest procés opera de manera adiabàtica. La fotòlisi de l'oxetà que resulta de la irradiació de la diada amb l'espaiador més llarg va mostrar una banda d'absorció transitòria sobre 400 nm, atribuïda a la formació de l'exciplex triplet entre BP i Thy covalentment units. D'altra banda, es va investigar la reacció PB i la cicloreversió d'oxetans que sorgeixen de la interacció entre Thy o derivats d'uracil (Ura) i BP. Així, es va sintetitzar una àmplia gamma d'oxetans Thy-BP i Ura-BP amb diferents substituents en les posicions 1 i 5 de la nucleobase, incloent-se els regioisòmers cap-cap (HH) i cap-cua (HT). Els estudis espectroscòpics (absorció transitòria ultraràpida i LFP), juntament amb l'anàlisi teòric, coincideixen en que la cicloreversió fotoinduïda per als isòmers HH i HT implica la formació d'un exciplex en l'estat excitat triplet abans de la ruptura. Generalment, es va observar que la reacció va ser completament adiabàtica per als regioisòmers HH. En el cas de l'oxetà HH que sorgeix de la interacció entre 1,3-dimetiltimina (DMT) i BP, es va observar la formació d'una banda ~400 nm, que es va atribuir a l'exciplex triplet 3[DMT···BP]*. La seua formació va ser altament regioselectiva, sent més ràpida i eficient per a l'isòmer HH que per a HT. Aquests resultats van ser confirmats per anàlisi computacional. En general, es va observar adiabaticitat en el procés de fotoreversió per a tots els oxetans investigats, amb un alt grau de regioselectivitat i amb la participació d'exciplexes triplet.
[EN] Sunlight light can produce damage to DNA through direct absorption of UVB or, more commonly, by photosensitization upon absorption of UVA light by drugs, that act as a photosensitizer (PS). Benzophenone (BP) as a building-block is present in a wide variety of drugs, and have the potential to photosensitize damage to DNA, specially towards the thymine (Thy) nucleobase. The resulting DNA damage can give rise to bulky dimers, i.e. cyclobutane pyrimidine dimers (CPDs) and pyrimidine-pyrimidone (6-4) photoproducts ((6-4)PPs), which can cause severe mutations, melanomas, or even be fatal for the cell. In some organisms, (6-4)PP can be efficiently repaired by photolyase enzymes, in what could be a reverse Paternò-Büchi (PB) reaction through an unstable oxetane intermediate. With the aim of getting deeper insight into the photoreactivity of BP-Thy derivatives and in the photoinduced cleavage of oxetanes, a variety of dyads where Thy and BP are covalently linked by a linear spacer of different lengths and nature were first synthesized. The photochemical reactivity and the photophysical properties of the different derivatives were investigated by means of laser flash photolysis (LFP) and femtosecond transient absorption spectroscopy; besides, the main photoproducts (PPs) arising from steady-state irradiation were also isolated and characterized. The results showed a high degree of chemoselectivity on the linking bridge length and conformation. Concerning the photochemical reactivity, PPs arising from the PB and from formal hydrogen abstraction were formed. In this context, the PB reaction took place for the dyads with the longest spacer with complete regio- and stereoselectivity, along with a hydrogen abstraction process. Finally, the dyads with shorter spacers gave rise to a formal hydrogen abstraction photoproduct and/or polymerization. Accordingly, the overall photoreactivity was proportional to the spacer length and was well correlated with the 3BP* lifetimes, the longer spacers giving rise to shorter lifetimes. In connection to the oxetane photocleavage, irradiation of the different regio- and stereoisomeric oxetanes led to the formation of the typical triplet-triplet absorption band of BP. Accordingly, the photoinduced cycloreversion also operates as an adiabatic process. Photolysis of the oxetane that results from irradiation of the dyad with the longest spacer showed a transient absorption at ~400 nm, which is ascribed to formation of the purported triplet exciplex between BP and Thy covalently linked. Additionally, the PB reaction and the cycloreversion of oxetanes arising from the interaction between Thy or uracil (Ura) derivatives and BP were also investigated. Thus, a wide range of Thy-BP and Ura-BP oxetanes with varying substituents at positions 1 and 5 of the nucleobase were synthesized, including both the head-to-head (HH) and head-to-tail (HT) regioisomers. Spectroscopic studies, including femtosecond transient absorption and LFP results, as well as theoretical multiconfigurational quantum chemistry analysis, agree that the photoinduced cycloreversion for the HH and HT isomers involved the formation of a triplet excited exciplex before the cleavage takes place. Generally, the photochemical reaction was fully adiabatic for the HH regioisomers. In the case of the HH-oxetane arising from the interaction between 1,3-dimethylthymine (DMT) and BP, an absorption band at ca. 400 nm was formed, and was attributed to the triplet exciplex 3[DMT···BP]*. Its formation was highly regioselective towards the HH regioisomer, being faster and more efficient than for the HT isomer. These results were confirmed by computational analysis. In general, adiabaticity was observed in the photoreversion process for all oxetanes, with a high degree of regioselectivity, which falls in line with the theory of the involvement of a triplet exciplex in the process.
Thanks to the Generalitat Valenciana for the finantial support through the Santiago Grisolía grant.
Blasco Brusola, A. (2021). Mechanistic Studies on the Photochemical Formation and Cleavage of Oxetanes Derived from Pyrimidine Bases [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/165256
TESIS

La synthèse de complexes de métaux de transition susceptibles d'avoir une activité antibiotique ou antitumorale semblable à celle de la bléomycine a été réalisée: ces complexes doivent être capable de s’associer à l'ADN et d’activer et d'activer l'oxygène moléculaire. Dans un premier temps nous avons préparé des bases de schiff dérivés de bases pyrimidiques: uracile; acide barbiturique et acide diméthyl-1,3 barbiturique. Nous en avons synthétisé les complexes de Cu(I) et de Co(II) qui ont montré des analogies avec·les complexes de type Cu Salen et Co Salen. Seuls les complexes de Co(II) dérivés de l'acide diméthyl-1,3 barbiturique sont capables d’activer l’oxygène moléculaire, mais aucun d’entre eux ne dégrade l'ADN. Nous avons ensuite effectué la synthèse d'une molécule comportant un noyau polyaromatique (acridine) sur lequel nous avons fixé un groupement chélatant de métaux comprenant une entité bipyridine-2. 2. Nous avons mis en évidence la dégradation de l'ADN de plasmide pBR 322 par ce composé en présence de fer et de réducteur.

Les oxydations sur les bases nucléiques constituent l'une des sources principale d'apparition de lésions sur l'ADN, qui peuvent être mutagènes ou létales pour les cellules en l'absence de réparation de l'ADN. La Formamidopyrimidine-ADN glycosylase (Fpg), une enzyme procaryote du système de réparation de l'ADN par excision de base (BER), initie la réparation d'un large panel de lésions de ce type via ses activités ADN glycosylase (excision de la base oxydée) et AP lyase (clivage du site abasique par β,δ-élimination). Nous avons réalisé des études fonctionnelles par des techniques biochimiques et structurales par cristallographie des rayons X afin de préciser la spécificité de substrat et le mécanisme catalytique de Fpg. Ainsi, nous avons pu mettre en évidence des déterminants structuraux permettant à cette enzyme d'accommoder des lésions de tailles très différentes dans son site actif, en l'occurrence des résidus 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapyG) substitués ou non en N7 par des adduits encombrants. D'autre part, nous avons caractérisé structuralement et fonctionnellement la reconnaissance et l'excision par Fpg d'une lésion pyrimidique, la 5-hydroxy-5-méthyle-hydantoïne (Hyd). Ainsi, nous avons montré que cette lésion appariée à une cytosine était un bon substrat pour l'enzyme, et nous avons précisé structuralement le mode de reconnaissance de l'Hyd par Fpg. D'autre part, nous avons mis en évidence un comportement inattendu de l'enzyme sur ce substrat. En l'occurrence, nous avons montré biochimiquement et structuralement qu'un pontage covalent se formait en quantités non négligeables entre Fpg et l'Hyd dans des conditions physiologiques. Mots clés : Réparation de l'ADN; Réparation par excision de base; Formamidopyrimidine-ADN glycosylase; 2,6- diamino-4-hydroxy-5-formamidopyrimidine; 7,8-dihydro-8-oxo-guanine; 5-hydroxy-5-méthyle-hydantoïne.

L'adequation de la spectroscopie vibrationnelle a l'etude de la flexibilite conformationnelle des acides nucleiques, est maintenant bien connue. Pour analyser les modes vibrationnels des fragments d'acides nucleiques : bases, nucleosides et nucleotides, nous avons entrepris une etude systematique. Sur le plan experimental nous avons montre que l'utilisation conjointe de la spectroscopie optique et la diffusion inelastique et incoherente de neutrons (diin) pouvaient permettre d'analyser aussi completement que possible, les spectres vibrationnels en phase condensee. Quant a l'interpretation de ces spectres experimentaux, nous avons opte pour des calculs quantiques de divers types, ab initio ou dft, en utilisant les fonctions de base double-zeta (6-31g et d95v) munies des orbitales de polarisation. Les donnees geometriques et le champ de forces moleculaire, sont determines a un stade theorique eleve (scf + mp2 et dft/b3lyp) prenant en compte de la correlation electronique. Ces donnees, bien qu'adaptees a l'interpretation des resultats theoriques obtenus en phase gazeuse, devaient etre corrigees pour etre employees dans l'analyse des resultats en phase condensee. -dans un premier temps, nous avons utilise les methodes de la remise a l'echelle du champ de forces. En ce qui concerne les modes provenant des elongations de liaisons et deformations angulaires, la remise a l'echelle se revele comme etant une methode tres adaptee. Alors que pour des modes de torsion et de balancement hors du plan, quelques problemes subsistent quant a leur interpretation. Il s'avere que les particularites de la phase solide, essentiellement caracterisees par des liaisons hydrogene intermoleculaires et dans une moindre mesure par des empilements moleculaires, sont a l'origine des desaccords entre les resultats experimentaux et ceux calcules pour une molecule isolee. -dans un second temps, nous avons montre, qu'en considerant des modeles dynamiques dans lesquels les liaisons hydrogene intermoleculaires sont explicites, ces problemes se trouvent, en grande partie, resolus. A cet effet, nous presentons les resultats theoriques obtenus a partir d'une supermolecule constituee par un uracile entouree par deux molecules d'eau. En fin, nous exposons ici les spectres diin obtenus a basse temperature sur les echantillons en phase solide des ribonucleosides et ribonucleotides, que nous accompagnons d'une breve discussion.

CARACTERISATION IN VITRO ET IN VIVO DE NOUVEAUX AGENTS PYRROLO-PYRIMIDINE CIBLANT LES MICROTUBULES POUR LE TRAITEMENT DES CANCERSEn dépit de l’émergence des thérapies ciblées et de l’immunothérapie, la chimiothérapie reste un gold-standard pour le traitement de nombreux cancers. Parmi les agents chimiothérapeutiques conventionnels, les poisons du fuseau interférant avec la dynamique des microtubules (taxanes, vinca-alcaloïdes) sont très largement utilisés. Cependant, leurs nombreux effets indésirables et l’émergence de chimiorésistance limitent leur efficacité et soulignent la nécessité d’identifier de nouveaux inhibiteurs de la tubuline.Notre équipe a réalisé un criblage cellulaire à haut-débit sur plus de 7500 molécules chimiques et identifié une famille de composés pyrrolo-pyrimidine, active sur les formes de cancer pulmonaire résistantes à l’apoptose et aux thérapies ciblées. Notre objectif était de caractériser in vitro et in vivo 15 molécules de cette famille afin d’identifier à terme un potentiel candidat-médicament pour le traitement des cancers résistants.Des essais préliminaires de cytotoxicité et d’apoptose sur différentes lignées cancéreuses pulmonaires ont permis de sélectionner, parmi les 15 composés pyrrolo-pyrimidine, 2 molécules prometteuses : PP-2 et PP-13. PP-2 et PP-13 ont des effets cytotoxiques sur de nombreuses lignées cancéreuses humaines, incluant les lignées résistantes aux thérapies ciblées. En perturbant l’organisation et la dynamique des microtubules, PP-2 et PP-13 induisent le blocage transitoire des cellules en prométaphase puis aboutissent aux phénomènes de catastrophe mitotique, de glissement mitotique ou de division asymétrique. Des études mécanistiques avancées montrent que PP-2 et PP-13 sont des agents poisons du fuseau et entrent en compétition avec la colchicine pour la liaison sur la tubuline. Contrairement aux antimitotiques conventionnels, PP-2 et PP-13 ne sont pas sensibles aux mécanismes de chimiorésistance par surexpression de pompes d’efflux. De plus, à l’IC50, ces 2 composés n’affectent pas le réseau microtubulaire des cellules à l’interphase suggérant un effet toxique (et principalement neurotoxique) moindre. La molécule PP-13 semble être la molécule anticancéreuse la plus prometteuse en raison de son IC50 10 fois inférieure à celle de PP-2 dans les différentes lignées cancéreuses étudiées et d’une affinité pour la tubuline 2 fois plus élevée. In vivo, PP-13 réduit significativement la croissance tumorale et étastatique. L’ensemble de ces résultats suggère que PP-13 pourrait être une alternative intéressante pour le traitement de nombreux cancers y compris des cancers chimiorésistants
CHARACTERIZATION OF NEW MICROTUBULE-TARGETING AGENTS WITH A PYRROLO-PYRIMIDINE STRUCTURE FOR THE TREATMENT OF CANCERSDespite the emergence of targeted therapies and immunotherapy, chemotherapy remains a gold-standard for the treatment of numerous malignancies. Spindle poisons that interfere with microtubule dynamics (taxanes, vinca alkaloids) are commonly used in chemotherapy drug combinations. However, their troublesome side effects and the emergence of resistance highlight the need for identifying alternative agents. Thanks to a high throughput cell-based assay, we screened agents able to restore apoptosis in apoptosis-resistant lung cancer cells. We selected 15 molecules belonging to the pyrrolopyrimidine family and investigated their anti-cancer effects in vitro and in vivo. Our aim was to identify a potential drug-candidate for the treatment of resistant cancers.From cytotoxicity and apoptosis preliminary assays, we selected the 2 most promising molecules (PP-2, PP-13) among the 15 pyrrolopyrimidine compounds. PP-2 and PP-13 exert cytotoxic effects on a large panel of human cancer cell lines, including targeted therapy-resistant cell lines. By interfering with mitotic spindle organization and microtubule dynamics, PP-2 and PP-13 impair the congression of the chromosomes, promote spindle assembly checkpoint-dependent mitotic blockade and finally lead to asymmetric division, mitotic slippage and direct apoptotic death. PP-2 and PP-13 directly target tubulin and compete with colchicine for the binding to tubulin. Unlike conventional antimitotic agents, PP-2 and PP-13 are not sensitive to chemoresistance mechanisms involving the overexpression of efflux pumps. Moreover, at IC50, these two compounds do not affect the microtubule network during interphase suggesting a less toxic (mainly neurotoxic) effect. Among these two compounds, the PP-13 molecule appears to be the most interesting anti-cancer molecule because of its IC50 10-fold lower than PP-2 and its 2-fold higher affinity for tubulin. In vivo, PP-13 significantly reduces tumor and metastasis growth. All these results suggest that PP-13 might be a potential alternative for the treatment of many cancers including chemoresistant cancers

Dans la première partie de cette thèse, les principes généraux de l’alkylation des bases pyrimidiques, xanthiques et puriques dans les conditions de la catalyse par transfert de phase (CTP) sans solvant sont présentés. Cette technique d’activation anionique nous a permis d’accéder à des molécules utilisées en thérapeutique. L’alkylation des bases puriques livre plusieurs produits>. La structure de ces composés est déterminée par RMN¹³C. Dans la deuxième partie, la CTP solide-liquide sans solvant est étendue à des réactions de MICHAEL dans le cas de systèmes peu réactifs dans les conditions classiques. Les résultats obtenus par cette méthode se comparent favorablement avec ceux de la littérature, en ce qui concerne les rendements, et permettent une simplification des conditions opératoires
In the first part, the general principles for the alkylation of pyrimidine, xanthine and purine by solid-liquid PTC are reported. This technique is exemplified by the preparation of drugs. In the second part, the method is applied to MICHAEL condensation in the case of hindered acceptors. This simplified process affords good yields and the work up is very easy?

Le 4(5)-nitroimidazole s'est revele etre un bon nucleophile dans les reactions de substitution nucleophile radicalaire en chaine (s#r#n1) avec les substrats gem-bromo-nitroalcanes simples ou fonctionnalises. Ces reactions conduisent a des derives 4-nitroimidazoles n-alcoyles. L'etude de reactivite de ces derniers, dans d'autres reactions de s#r#n1, retro henry, halogenation. . . A permis l'obtention d'une serie de 4-nitroimidazoliques par deux voies de synthese originale univoque. La synthese d'olefines n9-adeniliques, preparees anterieurement au laboratoire, a ete optimisee et generalisee. Ainsi, l'etude de la reactivite de ces olefines dans des reactions d'epoxydation a mene a de nouveaux analogues de nucleosides de type oxiraniques, par une voie de synthese originale. La cytosine s'est montree un nucleophile peu reactif vis-a-vis de gem-halogeno-alcanes dans des reactions de s#r#n1. Cependant, le choix judicieux des differents parametres a permis d'optimiser la reaction et d'acceder a des derives cytosiniques n1-alcoyles analogues d'acyclonucleosides. Par contre, l'uracile et ses derives (exception faite pour la thymine) se sont montres inertes vis-a-vis de ces substrats

By the use of model compounds such as pyrimidine bases, nucleosides and nucleotides in low-temperature aqueous glasses, the primary reduction product of gamma-irradiated frozen aqueous DNA has been examined using EPR spectroscopy. Ionisation of frozen aqueous solutions of lithium chloride, sodium chloride, methanol, ethylene glycol and sodium hydroxide generates positive 'holes' and mobile electrons. In the absence of suitable solutes, such as DNA bases, both species are trapped within the glass. In the presence of pyrimidine derivatives, however, the mobile electrons react to form n*-anions. For thymine and uracil derivatives the n*-anions, as monitored by EPR spectroscopy, give rise to anisotropic doublets in both H2O and D2O matrices (chapters 2 and 4 respectively). For cytosine derivatives, however, although doublets are observed in D2O, triplets are detected in H2O systems corresponding to an extra 12G splitting (chapter 3). This splitting is assigned to a proton attached to the exocyclic amino nitrogen atom (N4) and is taken as clear proof of heteroatom protonation of the radical anion of cytosine. No direct EPR evidence for the protonation states at 77K of either the thymine or uracil n*-anions is obtained in any of the glasses. On warming these systems, however, protonation of the n*-anions of both thymine and uracil at a carbon atom position (C6) is observed giving rise to C6 H-adduct radicals. No such species is detected for cytosine on annealing. Exposure of frozen aqueous DNA to 60Co gamma-rays at 77K gives electron-loss and -gain centres localised on the bases. The electron-gain centres are believed to be a mixture of pyrimidine n*-anions (Py-, i.e. C- + T-). This assumption is based on the fact that, on annealing, the Py-. doublet is only partially converted into the 5,6- dihydrothymine-5-yl radical TH, the resulting radical having a completely characteristic octet EPR spectrum. The results suggest that ca. 36% of the doublet is due to T-centres, the remainder (64%) being assigned to C-centres. It is argued that ejected electrons move through stacked bases, becoming trapped at cytosine or thymine depending upon the relative rates at which C- and T- are protonated to give C-(H+), protonated at N3 (not N4), and T-(H+), probably protonated on a carbonyl oxygen. For this to be correct then interconversion between C- and T on annealing is unlikely.

[EN] Bile acids are a family of amphiphilic steroids that play a pivotal role in physiological functions such as elimination of cholesterol or solubilization of lipids. Chemically, they share a steroidal skeleton with an unusual cis fusion between rings A and B, a short lateral chain ending in a carboxylic acid moiety and different number of hydroxyl groups on the alpha-face. Hence, bile acids offer a versatile architecture that can be used to investigate photophysical processes of interest such as hydrogen atom transfer, through-bond energy trasfer, through-bond exciplex formation and DNA photodamage-related reactions. First, unmodified bile acids have been used to evaluate hydrogen atom trasfer to benzophenone-like triplet carbonyls. Dehydrogenation of bile acids at positions C-3 and/or C-7 by a radical-mediated mechanism from the excited state of benzophenone has been demonstrated. Moreover, synthesized lithocholic acid derivatives including benzophenone or carbazole as donors and a naphthalene, biphenyl or thymine as acceptors have been employed to investigate through-bond energy transfer and exciplex formation processes. Thus, energy transfer from benzophenone to naphthalene or biphenyl and extended through-bond exciplex formation in benzophenone/naphthalene and benzophenone/biphenyl linked systems has been demostrated by laser flash photolysis. Finally, bile acid derivatives incorporating one benzophenone and two thymine units with different degrees of freedom have been prepared to investigate the photochemical formation of oxetanes or thymine dimers. Photosensitized formation of cyclobutane pyrimidine dimers through the generation of a delocalized triplet excited state has been demonstrated in intermolecular systems, while oxetane formation is observed when the degrees of freedom are reduced.
[ES] Los ácidos biliares son una familia de esteroides anfifílicos que juegan un papel clave en diferentes funciones fisiológicas tales como la eliminación del colesterol o la solubilización de lípidos. Su estructura química está constituida por un esqueleto esteroideo con una fusión cis poco común entre los anillos A y B, una cadena lateral corta que termina con una función ácida y un número variable de grupos hidroxilo en la cara alfa. Por tanto, los ácidos biliares ofrecen una estructura versátil que puede ser utilizada para investigar procesos fotofísicos de interés como abstracción de hidrógeno, transferencia de energía y formación de exciplejos a larga distancia o reacciones relacionadas con el daño fotoinducido al ADN. En esta Tesis, en primer lugar, los ácidos biliares naturales se han utilizado para evaluar la abstracción de hidrógeno a carbonilos triplete en compuestos derivados de la benzofenona, demostrándose la deshidrogenación de los ácidos biliares en las posiciones C-3 y/o C-7 por un mecanismo radicalario desde el mencionado triplete de la benzofenona. En segundo lugar, se han preparado derivados de ácido litocólico que incluyen los dadores benzofenona o carbazol y los aceptores naftaleno, bifenilo o timina, que a continuación se han utilizado para investigar los procesos de transferencia de energía y formación de exciplejo intramolecular a larga distancia. De hecho, en los sistemas benzofenona/naftaleno y benzofenona/bifenilo, se demostró por fotólisis de destello láser la transferencia de energía desde benzofenona a naftaleno o bifenilo y la formación de exciplejo a larga distancia. Por último, se han preparado derivados de ácidos bliares que incorporan una unidad de benzofenona y dos de timina en diferentes posiciones del esqueleto para investigar la influencia de los diferentes grados de libertad en la formación fotosensibilizada de oxetanos o dímeros de timina. Gracias a ellos, se ha demostrado la formación fotosensibilizada de dímeros ciclobutánicos pirimidínicos a través de la generación de estados excitados triplete deslocalizados en sistemas en los que la benzofenona es intermolecular, mientras que se observa formación de oxetanos cuando los grados de libertad se ven reducidos.
[CAT] Els àcids biliars són una família d'esteroides anfifílics que juguen un paper clau en funcions fisiològiques com l'eliminació del colesterol o la solubilització de lípids. La seua estructura química està constituïda per un esquelet esteroïdal amb una fusió cis entre els anells A i B poc comuna, una cadena lateral curta que acaba amb una funció àcida i un nombre diferent de grups hidroxil en la cara alfa. D'aquesta manera, els àcids biliars ofereixen una estructura versàtil que pot ser utilitzada per investigar processos fotofísics d'interès com abstracció d'hidrogen, transferència d'energia i formació de exciplexes a llarga distància o reaccions relacionades amb el dany a l'ADN induït per llum. En primer lloc, els àcids biliars naturals s'han utilitzat per avaluar la abstracció d'hidrogen a carbonils triplets derivats de la benzofenona, demostrant-se la deshidrogenació dels àcids biliars en les posicions C-3 i/o C-7 per un mecanisme radicalari des de l'estat excitat de la benzofenona. A més, derivats d'àcid litocòlic que inclouen els donadors benzofenona o carbazol i els acceptors naftalé, bifenil o timina s'han utilitzat per investigar els processos de transferència d'energia i formació de exciplexe a llarga distància. En els sistemes benzofenona /naftalé i benzofenona/bifenil la fotòlisis làser va demostrar la transferència d'energia des de benzofenona a naftalé o bifenil i la formació d'exciplexe a llarga distància. Finalment, per tal d'investigar la formació fotosensibilitzada d'oxetans o dímers de timina, s'han preparat derivats d'àcids bliars que incorporen una unitat de benzofenona i dues de timina amb diferents graus de llibertat. La formació fotosensibilitzada de dímers ciclobutànics pirimidínics mitjançant la generació d'estats excitats triplet deslocalitzats ha estat demostrada en sistemes intermoleculars, mentre que la formació d'oxetans s'observa quan els graus de llibertat es veuen reduïts.
Miró Richart, P. (2016). Hydrogen-Abstraction, Energy Transfer and Exciplex Formation in Photoactive Systems Based on Bile Acids [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/64084
TESIS

Dans ce travail, trois types de lésions des bases de l'ADN ont été étudiés d'un point de vue théorique à l'aide de méthodes de chimie quantique basées sur la théorie de la fonctionnelle de la densité : la désamination spontanée de la cytosine et de ses dérivés, la formation de lésions tandem induites par des radicaux hydroxyles en milieu anaérobie et la formation de dimères de bases pyrimidiques suite à une exposition à un rayonnement ultraviolet. L'utilisation complémentaire de méthodes quantitatives statiques permettant d'explorer en partie les surfaces d'énergie potentielle associées à une réaction chimique et de la « DFT conceptuelle » ont permis d'obtenir des renseignements quant aux mécanismes réactionnels mis en jeu et de rationaliser des différences de réactivité entre bases nucléiques vis-à-vis de la formation d'un même type de lésion.
Parallèlement à ces études, une réflexion a été menée concernant le concept de mécanisme concerté asynchrone, en particulier en termes de sens physique de l'état de transition, de respect du principe de dureté maximum, et de détermination du nombre de processus primitifs impliqués. Enfin, un nouvel indice de réactivité locale a été développé, pertinent pour décrire la réactivité de systèmes moléculaires dans un état excité.

Uracila (U), timina (T) e citosina (C) sÃo bases nitrogenadas do tipo pirimidÃnicas. Essas juntamente com as outras duas bases pÃricas adenina (A) e guanina (G), formam as bases essenciais da molÃcula do Ãcido ribonucleico (ARN) e Ãcido desoxirribonucleico (ADN), que contÃm as informaÃÃes genÃticas usadas pelas cÃlulas vivas. Os cristais de ADN e ARN apresentam caracterÃsticas semicondutoras bastantes atrativas na Ãrea de eletrÃnica orgÃnica, e por este motivo sÃo fortes candidatos na fabricaÃÃo de nanodispositivos moleculares. No entanto, os avanÃos nessa Ãrea ainda sÃo prematuros. Nesse trabalho sÃo apresentadas as propriedades estruturais, eletrÃnicas e Ãpticas dos cristais anidros das bases nucleotÃdicas pirimidÃnicas. Os resultados teÃricos foram obtidos apÃs cÃlculos baseados na teoria do funcional da densidade DFT, sob uma energia de corte de 830 eV, utilizando a aproximaÃÃes da densidade local (LDA) e do gradiente generalizado (GGA), nessa Ãltima foi incluindo correÃÃes empÃricas para interaÃÃes dispersivas (PBE+TS) disponÃveis no pacote CASTEP. Os resultados computacionais foram comparados entÃo com os experimentos de absorÃÃo Ãtica e de absorÃÃo UV para os cristais. Estudos teÃricos aplicados a cristais de citosina, timina, adenina e guanina jà estÃo disponÃveis na literatura. No entanto, faltava ainda uma descriÃÃo utilizando funcionais mais sofisticado como o adotado neste trabalho. Os valores de absorÃÃo apresentados para os cristais de uracila, timina e citosina mostra que estes possuem, respectivamente, gaps indireto, direto e indireto com valores obtidos de 4,03 eV, 3,80 eV e 4,20 eV. Como esperado, os resultados GGA+TS mostraram gaps de energia menores dos que os valores experimentais: 3,45 eV (U), 3,47 eV (C) e 3,50 eV (T). CÃlculos de massa efetiva confirmam os dados da literatura de que as bases, em geral, sÃo semicondutores de gaps largos. Por fim, os resultados obtidos por DFT sugerem um razoÃvel grau de anisotropia Ãptica para a absorÃÃo e funÃÃo dielÃtrica complexa, especialmente na uracila e timina
Uracil (U), thymine (T) and cytosine (C) are nitrogenous bases of the pyrimidine type. These along with the other two bases purines adenine (A) and guanine (G), form the essential basis of the ribonucleic acid molecule (RNA) and acid deoxyribonucleic (DNA), which contains the genetic information used by living cells. DNA and RNA crystals have enough attractive semiconductor characteristics in the field of organic electronics, and for this reason are strong candidates in the manufacture of molecular nanodevices. However, advancements in this area are still premature. This work presents the structural, electronic and optical of the anhydrous crystals of pyrimidine nucleotide bases. The theoretical results were obtained after calculations based on density functional theory (DFT), with an energy cut of 830 eV, using the approximations of local density (LDA) and generalized gradient (GGA), this last one including empirical corrections to dispersive interactions (PBE + TS) available at CASTEP package. The computational results were then compared with the crystals experiments of optical absorption and UV absorption. Theoretical studies applied to the crystals cytosine, thymine, adenine and guanine are already available in the literature. However, it is still missing a description using a more sophisticated functional as was used in this work. The absorption values obtained for the uracil, thymine and cytosine crystals shows that these have, respectively, indirect, direct and indirect gaps with values of 4.03 eV, 3.80 eV and 4.20 eV. As expected, the theoretical results exhibited energy gaps lower than the experimental values: 3.45 eV (U), 3.47 eV (C) and 3.50 eV (T). Effective mass calculations confirm literature data that the bases are generally wide gap semiconductor. Finally, the results obtained by DFT suggest a reasonable degree of optical anisotropy for the absorption and complex dielectric function, especially in uracil and thymine. As expected, the theoretical results exhibited energy gaps lower than the experimental values: 3.45 eV (U), 3.47 eV (C) and 3.50 eV. (T). Effective mass calculations confirm the literature data that the bases are semiconductor with wide gaps. Finally, the results obtained by DFT suggest a reasonable degree of optical anisotropy for the absorption and complex dielectric function, especially in the uracil and thymine cases.

SILVA, Mauricélio Bezerra da. Propriedades estruturais, eletrônicas e ópticas dos cristais anidros das bases pirimidínicas: simulações na teoria do funcional da densidade. 2016. 143 f. Dissertação (Mestrado em Física) - Programa de Pós-Graduação em Física, Departamento de Física, Centro de Ciências, Universidade Federal do Ceará, Fortaleza, 2016.
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Uracil (U), thymine (T) and cytosine (C) are nitrogenous bases of the pyrimidine type. These along with the other two bases purines adenine (A) and guanine (G), form the essential basis of the ribonucleic acid molecule (RNA) and acid deoxyribonucleic (DNA), which contains the genetic information used by living cells. DNA and RNA crystals have enough attractive semiconductor characteristics in the field of organic electronics, and for this reason are strong candidates in the manufacture of molecular nanodevices. However, advancements in this area are still premature. This work presents the structural, electronic and optical of the anhydrous crystals of pyrimidine nucleotide bases. The theoretical results were obtained after calculations based on density functional theory (DFT), with an energy cut of 830 eV, using the approximations of local density (LDA) and generalized gradient (GGA), this last one including empirical corrections to dispersive interactions (PBE + TS) available at CASTEP package. The computational results were then compared with the crystals experiments of optical absorption and UV absorption. Theoretical studies applied to the crystals cytosine, thymine, adenine and guanine are already available in the literature. However, it is still missing a description using a more sophisticated functional as was used in this work. The absorption values obtained for the uracil, thymine and cytosine crystals shows that these have, respectively, indirect, direct and indirect gaps with values of 4.03 eV, 3.80 eV and 4.20 eV. As expected, the theoretical results exhibited energy gaps lower than the experimental values: 3.45 eV (U), 3.47 eV (C) and 3.50 eV (T). Effective mass calculations confirm literature data that the bases are generally wide gap semiconductor. Finally, the results obtained by DFT suggest a reasonable degree of optical anisotropy for the absorption and complex dielectric function, especially in uracil and thymine. As expected, the theoretical results exhibited energy gaps lower than the experimental values: 3.45 eV (U), 3.47 eV (C) and 3.50 eV. (T). Effective mass calculations confirm the literature data that the bases are semiconductor with wide gaps. Finally, the results obtained by DFT suggest a reasonable degree of optical anisotropy for the absorption and complex dielectric function, especially in the uracil and thymine cases.
Uracila (U), timina (T) e citosina (C) são bases nitrogenadas do tipo pirimidínicas. Essas juntamente com as outras duas bases púricas adenina (A) e guanina (G), formam as bases essenciais da molécula do ácido ribonucleico (ARN) e ácido desoxirribonucleico (ADN), que contém as informações genéticas usadas pelas células vivas. Os cristais de ADN e ARN apresentam características semicondutoras bastantes atrativas na área de eletrônica orgânica, e por este motivo são fortes candidatos na fabricação de nanodispositivos moleculares. No entanto, os avanços nessa área ainda são prematuros. Nesse trabalho são apresentadas as propriedades estruturais, eletrônicas e ópticas dos cristais anidros das bases nucleotídicas pirimidínicas. Os resultados teóricos foram obtidos após cálculos baseados na teoria do funcional da densidade DFT, sob uma energia de corte de 830 eV, utilizando a aproximações da densidade local (LDA) e do gradiente generalizado (GGA), nessa última foi incluindo correções empíricas para interações dispersivas (PBE+TS) disponíveis no pacote CASTEP. Os resultados computacionais foram comparados então com os experimentos de absorção ótica e de absorção UV para os cristais. Estudos teóricos aplicados a cristais de citosina, timina, adenina e guanina já estão disponíveis na literatura. No entanto, faltava ainda uma descrição utilizando funcionais mais sofisticado como o adotado neste trabalho. Os valores de absorção apresentados para os cristais de uracila, timina e citosina mostra que estes possuem, respectivamente, gaps indireto, direto e indireto com valores obtidos de 4,03 eV, 3,80 eV e 4,20 eV. Como esperado, os resultados GGA+TS mostraram gaps de energia menores dos que os valores experimentais: 3,45 eV (U), 3,47 eV (C) e 3,50 eV (T). Cálculos de massa efetiva confirmam os dados da literatura de que as bases, em geral, são semicondutores de gaps largos. Por fim, os resultados obtidos por DFT sugerem um razoável grau de anisotropia óptica para a absorção e função dielétrica complexa, especialmente na uracila e timina.

碩士
國立中央大學
化學研究所
91
A series of novel bipolar light emitting materials containing pyrimidine core and different donor-acceptor groups were synthesized successfully via Sonogashira reaction and palladium catalyzed C-N coupling reaction. All the compounds were characterized by H1-NMR、Mass and Elemental Analysis. The thermal properties of these materials were investigated by TGA and DSC . The decomposition temperatures ( Td ) of the compounds range from 306 to 381℃. Compound pf1、pf2、pf3 and pk1 are amorphous with glass transition temperature ( Tg ), rangeing from 69 to 87℃. The optical properties of these materials were studied by UV/Vis and PL spectroscopic methods. All of these compounds exhibit the maxaimum absorption in the range of 355∼373 nm in dichloromathane. The compound pc1 emits greenish-yellow, all others emit in blue region. The maxium fluorescence wavelength lies within 467~522 nm in dichloromethane. Compounds are fluorescent with good quantum yield. HOMO and LUMO energies derived from cyclic voltametry ( CV ) data are in the range of 5.55∼5.62 eV and 2.58∼2.75 eV, respectively.

碩士
國立臺灣大學
化學研究所
90
Liquid crystalline base on Liquid crystal Display. Liquid crystal has the mesomorphic properties that become very hot investigated domain. Two types of liquid crystalline molecules have been investigated:(1) 2,4,6-triarylpyrimidine-based organic discotic liquid crystal. (2) Schiff’s base-derived rod-like liquid crystals. pyrimidine derivatives investigated result: Side chain length can made pyrimidine derivatives that has been 6 side chains and hexyloxyl side chain has liquid crystal properties. If alkoxy side chains was butyloxyl side chain, Pyrimidine add one methoxyl side chain that has liquid crystal properties The oxygen effect on the pyrimidine derivatives is different. The increase of oxygen atoms in the side chains causes inefficient molecular packing, which results in a change of molecular array from the Colhd phase to the Colrd phase.And might unfavorable for the formation of liquid crystalline phases. Schiff’s base-derived liquid crystals investigated result: Studies in this thesis focuses on the substituent effect on the mesomorphic properties of Schiff’s base-derived liquid crystalline molecules. Might be electron-withdrawing substituents group increase intermolecular attracting forces due to the induced dipole-dipole interactions. The copper complex or palladium complex that substituent nitro group, clearing point and increase the temperature range of mesophases.

碩士
國立中央大學
化學研究所
93
We have synthesized a new series of pyrimidine compounds. These compounds undergo cyclometalation with iridium trichloride to form iridium (III) complexes which exhibit strong phosphorescence. The photophysical and electrochemical properties of these compounds were investigated. Electroluminescent devices were fabricated from selected iridium complexes. The absorption wavelengths of the py ligands range from 290 to 313 nm, and their emission wavelengths remain in the ultraviolet region. The 1MLCT, 3MLCT and 3π – π transition bands of these iridium complexes have been resolved in the range of 360~500 nm of the absorption spectrum. The 3MLCT and 3π – π transition gain intensity by mixing with higher lying 1MLCT state through the spin-orbit coupling of iridium(III). These iridium complexes emit yellow-green to orange-red phosphorescence with wavelengths ranging from 522 to 558 nm . Also the strong spin-orbit coupling leads to good quantum yields in air-free solution at room temperature. The iridium complexes exhibit a reversible oxidation due to Ir(III)→Ir(IV), and the HOMO and LUMO energy levels for each complex can be obtained from the cyclic voltammogram and the UV-vis absorption edge. We also found that the photophysical and electrochemical properties can be correlated with the electronic characters and the relative locations of the substituents on the ligands.

碩士
中國文化大學
應用化學研究所
95
The aim of this study was to develop a self-assembly strategy for the preparation of metal-organic coordination polymers, using pyrimidine and carboxylate as ligands. Reaction of CuCl2•2H2O with 2,2´-bipyrimidine and biphenyl-4,4'-dicarboxylic acid under ambient temperature conditions gave a 2D coordination polymer [Cu2(bpdc)2(bpm)(H2O)2•5H2O]n ( 1 ). The structure of compound 1 was determined by a single-crystal X-ray diffraction analysis. Compound 1 adopts a 2D architecture. Hydrogen-bonding interactions play an important role in controlling the final topology of the structure. Compound [Cd(C10O6H8)(C12H8N2) •H2O]n ( 2 ) is a 2D polymer, was abtained by the reaction of Cd2+ ion with benzene-1,4-dioxydiacetic acid，1,10-phenanthroline under hydrothermal conditions. In ( 2 ), guest water molecules were found in channels due to hydrogen-bonding interation with the host.

碩士
國立臺北科技大學
化學工程系碩士班
92
A series of molecular rectangles and coordination polymers have been synthesized by using self-assembly strategy. Their structures have been characterized. The content of this thesis is described as follows. （I）Synthesis of Novel Rectangular Supramolecules In the first part of this thesis, the rational design and synthesis of self-assembled rhenium-based rectangle boxes have been performed. This complex has been characterized by IR, NMR, Mass and EA methods as well as X-ray diffraction analysis. The rational selection of fac-(CO)3Re as a corner, the judicial choice of a chelating three-electrons donor, 2,5-pyrazinedicarboxylic acid (2,5-prdca), and a two-electrons donor, 4,4’-bipyridyl (bpy) as a bridging ligand can fulfill the eighteen-electron configuration around the rhenium metal center. As a result, the self-assembly of a molecular rectangle [Re4(CO)12(2,5-prdca)2(bpy)2] (1) possessing a large cavity could be achieved instead of another two thermodynamically favored molecular squares. Alternatively, a dinuclear rhenium complex Re2(2,5-prdca)(bpy)2(toluene)2 (2) can also be synthesized under different reaction conditions. （II）Synthesis of Nanoporous Coordination Polymers Self-assembly of a series of nanometer-sized inorganic-organic hybrid materials has been achieved by treating transition metal ions, such as Cu2+, Ni2+, Zn2+, Co2+ and Mn2+ with organic ligands, such as 2,2''-bipyrimidine and 5,5''-bipyrimidine at room temperature. Their structures have been characterized by single-crystal X-ray diffraction analysis. The studies of their thermal stabilities and magnetic properties have also been carried out. The coordination solids of versatile network topologies have been described separately in five parts. First, treatment of 5,5''-bipyrimidine (5bpm) and 1,2,4,5-benzenetetracarboxylate (1,2,4,5-btec) with several metal ions, such as Cu2+ or Ni2+ or Zn2+ gave compounds 5bpm-(1,2,4,5-btec)-Cu (3), 5bpm-(1,2,4,5-btec)-Ni (4), and 5bpm-(1,2,4,5-btec)-Zn (5), respectively. In the second part, reaction of 5bpm and fumaric acid with Cu2+ afforded compounds 5bpm-fumarate-Cu2+ (6). Furthermore, interaction of 5bpm and 1,4-benzenedicarboxylate (1,4-bdc) with Cu2+, Co2+, Zn2+ produced 5bpm-(1,4-bdc)-Cu (7), 5bpm-(1,4-bdc)-Co (8), and 5bpm-(1,4-bdc)-Zn (9), respectively. In the third part, reaction of 2,2''-bipyrimidine (2bpm) and 1,3,5-benzenetricarboxylate (1,3,5-btc) with Mn2+, Zn2+ and Co2+ generated compounds 2bpm-(1,3,5-btc)-Mn (10), 2bpm-(1,3,5-btc)-Zn (11), and 2bpm-(1,3,5-btc)-Co (12), respectively. In the fourth part, treatment of 2bpm and fumaric acid with Mn2+, Co2+, Ni2+, Zn2+ yielded 2bpm-fumarate-Mn (13), 2bpm-fumarate-Co (14), 2bpm-fumarate-Ni (15), and 2bpm-fumarate-Zn (16), respectively. In the last part, reaction of 2bpm and 3,5-pyridinedicarboxylate (3,5-pdc), 2,3-pyridinedicarboxylate (2,3-pdc) and 2,6-pyridinedicarboxylate (2,6-pdc) with Co2+, Mn2+ and Cd2+ obtained 2bpm-(3,5-pdc)-Co (17), 2bpm-(2,3-pdc)-Mn (18), and 2bpm-(2,6-pdc)-Cd (19), respectively. The crystal structures of these compounds have been characterized by single-crystal X-ray diffraction analysis. The structures of compounds 8、9、14、15、16、17, and 19 exhibit the 1-D linear skeleton, which is further stacked into porous structures, while compounds 3、4、5、6、7、10、11、12、13, and 18 exhibit the 3-D net framework. Guest molecules trapped into the channels and pores have been studied. Furthermore, the thermal stabilities and magnetic properties of 3、10, and 17 have also been investigated.

碩士
國立臺灣大學
化學研究所
90
Abstract A series of conjugated light emitting materials based on 9,9-spirobifluorene as the core with different terminal substitutents were synthesized by a palladium-catalyzed Suzuki coupling reaction. For improving the electron accepting properties, we introduced pyrimidine into the conjugated backbone as the functional subunits. Optical properties: The photoluminescence (PL) spectra of F1~F4 in solution lay on blue-light range (392~443 nm), and exhibited good quantum yields. The effective conjugated length of F5 and F6 were shorter than F1~F4, the emission spectra of F5 and F6 were blue-shifted as compared to that of F1~F4. On the other hand, due to the lower symmetry, F5 and F6 performed lower PL efficiency in solution. The nearly identical absorption spectrum in solutions and in films suggests that there are minimal intermolecular interactions in ground state in thin films. These materials also exhibited very high PL quantum yields in thin film, the highest up to 95%. By inspecting the single-crystal X-ray diffraction data of F1 and F2, we found that the rigid structure of spirobifluorene core effectively suppresses intermolecular aggregation. Thermal analysis of these materials reveals high thermal stability with decomposition temperature around 460 oC. The glass-transition temperatures of these materials are higher than 124 oC. We applied F2 as emitter for light emitting diode. Device structure, ITO / PEDT/PSS (300A)/ NCB (450A) / F2 (300A) / Alq3(200A) / LiF / Al, EL lmax = 438（nm), Vturn-on = 4 (V), maximum brightness: 30000 (cd/m2), ΦEL= 2.3 (%). In doping F2 with 1wt.% perylene, the efficiencies had been improved, maximum brightness: 80000 (cd/m2), ΦEL= 4.0 (%).

Alzheimer’s disease (AD) is a highly complex and rapidly progressive neurodegenerative disorder characterized by the systemic collapse of cognitive function and formation of dense amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs). AD pathology is derived from the cholinergic, amyloid and tau hypotheses, respectively. Current pharmacotherapy with known anti-cholinesterases, such as Aricept ® and Exelon ®, only offer symptomatic relief without any disease-modifying effects (DMEs). It is now clear that in order to prevent the rapid progression of AD, new therapeutic treatments should target multiple AD pathways as opposed to the traditional “one drug, one target” approach. This research project employed medicinal chemistry tools to develop multifunctional small organic molecules against three key targets of AD pathology – the cholinesterases (AChE and BuChE), AChE-induced and self-induced Aβ1-40 aggregation and generation (β-secretase). A chemical library composed of 112 derivatives was generated to gather structure-activity relationship (SAR) data. The derivatives were based on a novel, non-fused, 2,4-disubstituted pyrimidine ring (2,4-DPR) template with substituents at the C-2 and C-4 position varying in size, steric and electronic properties. Molecular modeling was utilized to investigate their binding modes within the target enzymes and along with the acquired SAR, the chemical library was screened to identify lead multifunctional candidates.

碩士
國立臺灣大學
化學研究所
88
We have introduced the perfluorinated aliphatic side chains into several Schiff''s base-typed liquid crystalline complexes and investigated the effects of fluorination on the mesophases. In general, the melting points of the perfluorinated complexes are higher than the corresponding hydrocarbon analogues, and the difference increases as increasing the number of the difluorine methylene units. Moreover, it was found that the introduction of the perfluorinated side chains stabilizes the Smetic phase in the SBL-3A-R series, but it inhibits the formation of the Sc phase for the SBL-3B-R series, resulting in a direct transition from the SA to the I phase. In addition, several disc-shaped molecules derived from 2,4,6-triphenylpyrimidine have been synthesized. However, no liquid crystalline properties could be observed for those with three or six alkoxy side chains. Under the same reaction condition for the synthesis of the nine-side-chain analogue, we obtained a different product having the 2,4,6-tris(3'',4'',5''-trimethoxyphenyl)triazine core, which starts to display liquid crystalline properties when the carbon number of the side chains is as low as four. For longer side chains such as six, eight, and ten carbons, the mesomorphic phase exists even at the room temperature. The instrumentation of this work includes DSC, optical microscopy with polarized light, and X-ray diffraction.

碩士
中國文化大學
應用化學研究所
95
Abstract The purpose of this study was to develop a self-assembly strategy for the preparation of novel metal-organic coordination polymers using 2,2’-bipyrimidine (2bpm) as ligand. Treatment of 2bpm with CuCl2, MnCl2 or ZnCl2, using a metal-to-ligand ratio of 4 : 1, afforded blue crystal {Cu(C8H6N4)(C6H4O4S)(H2O)2}.3H2O (1), pale yellow crystal {Mn2(C8H6N4)(C6H4O4S)2(H2O)6} (2), and colorless crystal {Zn2(C8H6N4) (C6H4O4S)2(H2O)6} (3). Each of the three products is a discrete molecule. A solid-state packing diagram showed that molecule 1 formed a Z shape one-dimensional metal-organic Framework via hydrogen-bonding interactions. Compounds 2 and 3 are isostructures. Hydrogen bonding and π–π stacking interactions were key determinants of the final solid state topologies. Compounds {Cd(C8H6N4)(C10H10O6)•H2O}n (4) and {Cd(C10H10O6)(H2O)2}n (5) were obtained form the assembly reaction of 2bpm and CdCl2. For compound 4, coordination of Cd2+ with two bent benzene-1,4-dioxydiacetate (1,4-BDOA) molecules and chelating 2bpm led to the formation of a mill-wheel like 2-D polymer, in which guest water molecules formed strong hydrogen bonding with the host. The Cd2+ ion coordinated only with 1,4-BDOA in compound 5, forming a Z-shaped one-dimensional polymer with ladder topology. The reaction of ZnCl2 with 2bpm in the presence of p-phenylenediacrylic acid (p-PDA) or 4-carboxycinnamic acid (4-CCA) produced 2D polymers {Zn2(C8H6N4) (C12H10O4)2(H2O)2.CH3OH.3H2O}n (6) and {Zn2(C8H6N4)(C10H8O4)2(H2O)2.6H2O}n (7), respectively. Three-dimensional networks were observed in the packing diagram due to hydrogen bonding between ladders. In 6, guest water and methanol molecules are resided in channels due to hydrogen-bonding interactions. In 7, six guest water molecules also were found in channels as a result of hydrogen-bonding with the host.

博士
國立臺灣科技大學
高分子系
95
The disertation consists of two main themes: Firstiy, (1) 3,5-Di-(amino or methyl)-4-substituted-azoly-pyrazole and 3-amino-5- methyl-4-substituted-azoly-pyrazole have been synthesized via the cyclization from hydrazine hydrate with 2-substituted-azoly-malono- nitrile, 3-sub-stituted-azoly-pentane-2,4-dione and 3-imino-2-substitu- ted-azoly-butyronitrile, respectively; and (2) 5-amino-3-methyl-4-substi -tuted-azoly-pyrazole and 3-amino-4-substituted-azoly-5-pyrazolone were prepared by coupling reaction of aniline derivatives with 3-amino-5-pyrazolone and 5-amino-3-methylpyrazole, respectively. The effect of maximum absorption spectra on synthesized pyrazole monoazo dyes with different substituents and their different locations was also evaluated by UV-ray in acetone. After a series of analyses, we can realize that the substituent effect of maximum absorption spectra on the 5th position of pyrazole ring is more dominant than the 3rd position of that. Secondly, (1) 3,6-Diphenylazo pyrazole[1,5-a]pyrimidine disazo dyes were synthesized both by the cyclization of 2-(4-substituted- phenylazo)- malononitrile with 3,5-diamino-4-(4-substituted-phenyl- azo)-pyrazole; (2) 4-(Aryl or hetaryl)azo-3,5-diaminopyrazole com- pounds with arylazo- and hetarylazo- malononitriles were prepared by the cyclization to obtain the 3,6-di-(aryl or hetaryl)- azo-2,5,7-triamino- pyrazolo[1,5-a]pyrimidine heterocyclic disazo dyes; (3) 3,6-dihetaryl- azo-2,5,7-triamino-pyrazolo[1,5-a]pyrimidine heterocyclic disazo dyes have been synthesized via the cyclization from some substituted hetarylazomalononitrile precursors with various substituted hetarylazo- pyrazole compounds. The effect of maximum absorption spectra on these prepared hetercyclic disazo dyes with and various solvents was investigated by the UV-ray test. In addition, the effect due to different substituents and polarities was also evaluated.The solvatochromic behavior of these dyes in various solvents with different dielectric constants reveals bathochromic shifts as the solvent polarity is increased. Although, the substituents can be arylazo or hetarylazo by comparing with the synthesized hetarcyclic disazo dye, we can know the different effect of maximum absorption spectrum for pyrazole- [1,5-a]pyrimidind compounds. By the related analyses, the maximum absorption spectrum of dyes may have a trend of moving to long wavelength when the substituted on the 3,6th position of pyrazole- [1,5-a]pyrimidind ring changing to hetarylazo group. All synthesized compounds in this disertation were analyzed to recognize their chemical structures through spectrum identification of FT-IR, UV, and 1H-NMR and EA.

A Dissertation submitted to the Faculty of Science, University of the Witwatersrand, in fulfilment of the requirements of the Doctor of Philosophy Johannesburg, 2018
As part of our goal to identify heterocyclic-based analogues that could act as allosteric inhibitors of the HIV-1 reverse transcriptase (RT) enzyme, small libraries of novel molecules containing pyridine, pyrimidine and triazine central cores were designed and synthesized for a preliminary in vitro assay against the wild-type RT virus. To achieve this goal, in the first instance we explored a scaffold-hopping approach as a possible strategy for identifying promising molecules. This scaffold-hopping approach primarily involved the “dismantlement” of an imidazo[1,2-a]pyridine central core of a potent anti-HIV novel compound previously identified in our research laboratory to generate 2,6-disubstituted pyridines. As discussed in chapter 2, we utilized the 2,6-disubstituted pyridine core as a platform for accessing a more conformationally flexible set of analogues in which the central pyridine core was connected to the chloro-substituted aromatic ring via an amido, amino or sulfonamido hetero-linker to generate the pyridyl-benzamide, pyridyl-benzylamine and pyridyl-sulfonamides scaffolds, respectively. The scaffolds were cross-coupled with selected nitrogen-, oxygen- and sulfur-containing nucleophiles via a palladium-mediated methodology to generate a small library of novel analogues for testing against the wild-type virus. One novel pyridyl-benzamide, 2-chloro-N-(6-(piperidin-1-yl)pyridin-2-yl)benzamide, showing excellent antiviral activity (IC50=0.7μM), was identified from whole-cell antiviral screening. The second approach, which is covered in chapter 3, used molecular modelling in the design of potential heterocyclic NNRTI compounds that resembled a DAPY-type horse-shoe framework. The approach involved in silico docking of di-functionalized pyridine- and tri-functionalized pyridine-, pyrimidine-, and triazine-based virtual analogues into the allosteric site of the reverse transcriptase enzyme crystal structure (pdb: 3MEG RT). The tri-functionalized pyridine-core containing amides emerged as top modelling hits with superior ligand-receptor interaction energies. In addition, these analogues also displayed a favourable binding conformation that targeted key hydrophobic (Tyr181, Tyr188, Phe227, Trp229, Leu234, Pro236, Tyr318) and hydrophilic interactions in the allosteric site of the 3MEG RT crystal structure and were synthesized via our already developed palladium-catalyzed methodology as candidates for a primary screen against the wild-type HI virus. Moreover, biocatalysis was also successfully applied for the selective hydrolysis of a pyridyl nitrile group to access one of the top modelling hit compounds, 6-(4-chlorophenoxy)-2-((2-cyano-5-methylphenyl)amino)nicotinamide as a key target for the antiviral screening. The scaffold hopping approach proved more rewarding as it led to the identification of a novel pyridyl-benzamide novel compound with excellent antiviral activity against the wild-type RT virus. This is the first such compound to be identified as displaying activity against RT. As discussed in chapter 4, novel pyridyl-benzamide and pyridyl-sulfonamide compounds that displayed reasonable antimicrobial activity (39 μg/ml) against two gram-positive bacteria, S. aureus and B. cereus, were also identified from an antimicrobial screen.
MT 2018