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1
Ibrahim, Mohamed M. "Pyrimidine Metabolism in Rhizobium: Physiological Aspects of Pyrimidine Salvage". Thesis, University of North Texas, 1989. https://digital.library.unt.edu/ark:/67531/metadc330907/.
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The objective of this research was to study the pyrimidine salvage pathways of Rhizobium. Three approaches were used to define the pyrimidine salvage pathways operative in two species of Rhizobium, R. meliloti and R. leguminosarum . The first approach was to ascertain the pyrimidine bases and nucleosides that could satisfy the pyrimidine requirement of pyrimidine auxotrophs. Uracil, cytosine, uridine or cytidine all satisfied the absolute pyrimidine requirement. The second approach was to select for mutants resistant to 5-fluoropyrimidine analogues which block known steps in the interconversion of the pyrimidine bases and nucleosides. Mutants resistant to 5-fluorouracil lacked the enzyme uracil phosphoribosyltransferase (upp ) and could no longer use uracil to satisfy their pyrimidine requirement. Mutants resistant to 5-fluorocytosine, while remaining sensitive to 5- fluorouracil, lacked cytosine deaminase (cod) and thus could no longer use cytosine to satisfy their pyrimidine auxotrophy. The third approach used a reversed phase HPLC column to identify the products that accumulated when cytidine, uridine or cytosine was incubated with cell extracts of wild type and analogue resistant mutants of Rhizobium. When cytidine was incubated with cell extracts of Rhizobium wild type, uridine, uracil and cytosine were produced. This Indicated that Rhizobium had an active cytidine deaminase (cdd) and either uridine phosphorylase or uridine hydrolase. By dialyzing the extract and reincubating it with cytidine, uridine and uracil still appeared. This proved that it was a hydrolase ( nuh ) rather than a phosphorylase that degraded the nucleoside. Thus, Rhizobium was found to contain an active cytidine deaminase and cytosine deaminase with no uridine phosphorylase present. The nucleoside hydrolase was active with cytidine, uridine and to a far lesser extent with purines, adenosine and inosine. When high concentrations of cytidine were added to mutants devoid of hydrolase, cytosine was produced from cytidine - 5-monophosphate by the sequential action of uridine ( cytidine ) kinase and nucleoside monophosphate glycosylase. Both ft meliloti and ft leguminosarum had identical salvage pathways.
2
Beck, Debrah A. (Debrah Ann). "Pyrimidine Salvage Enzymes in Microorganisms: Labyrinths of Enzymatic Diversity". Thesis, University of North Texas, 1995. https://digital.library.unt.edu/ark:/67531/metadc278204/.
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Pyrimidine salvage pathways are essential to all cells. They provide a balance of RNA synthesis with the biosynthetic pathway in pyrimidine prototrophs and supply all the pyrimidine requirements in auxotrophs. While the pyrimidine biosynthetic pathway is found in almost all organisms and is nearly identical throughout nature, the salvage pathway often differs from species to species, with aspects of salvage seen in every organism. Thus significant taxonomic value may be ascribed to the salvage pathway. The pyrimidine salvage pathways were studied in 55 microorganisms. Nine different salvage motifs, grouped I-IX, were identified in this study based on the presence of different combinations of the following enzymes: cytidine deaminase (Cdd), cytosine deaminase (Cod), uridine phosphorylase (Udp), uracil phosphoribosyltransferase (Upp), uridine hydrolase (Udh), nucleoside hydrolase (Nuh), uridine/cytidine kinase (Udk), 5'-nucleotidase and CMP kinase (Cmk).
3
Roush, Wendy A. "Pyrimidine Genes in Pseudomonas Species". Thesis, University of North Texas, 2003. https://digital.library.unt.edu/ark:/67531/metadc4395/.
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This thesis is a comparative study of gene arrangements in Pseudomonas species, and is organized into three major sections. The first section compares gene arrangements for different pathways in Pseudomonas aeruginosa PAO1 to determine if the gene arrangements are similar to previous studies. It also serves as a reference for pyrimidine gene arrangements in P. aeruginosa. The second part compares the physical, and genetic maps of P. aeruginosa PAO1 with the genome sequence. The final section compares pyrimidine gene arrangements in three species of Pseudomonas. Pyrimidine biosynthesis and salvage genes will be aligned for P. aeruginosa PAO1, P. putida KT2440, and P. syringae DC3000. The whole study will gives insight into gene patterns in Pseudomonas, with a focus on pyrimidine genes.
4
Mélo, Sébastiao José de. "Synthèse, réactivité et propriétés pharmacologiques des fluoro-5 (3H) pyrimidinones-4". Université Joseph Fourier (Grenoble), 1989. http://www.theses.fr/1989GRE18003.
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Hughes, Lee E. (Lee Everette). "Pyrimidine Metabolism in Streptomyces griseus". Thesis, University of North Texas, 1994. https://digital.library.unt.edu/ark:/67531/metadc278710/.
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Salvage of pyrimidine nucleosides and bases by S. griseus and the regulation of aspartate transcarbamoylase (ATCase) were studied. The velocity-substrate curve for S. griseus ATCase was hyperbolic for both aspartate and carbamoylphosphate. The enzyme activity was diminished in the presence of ATP, CTP, or UTP. The synthesis of ATCase was repressed in cells grown in the presence of exogenous uracil. The specific activity of cells grown with uracil was 43 percent of that for cells grown in minimal medium only. Maximal ATCase and dihydroorotase activities were found in the same column fraction after size-exclusion chromatography, suggesting that both activities could reside in the same polypeptide. The pyrimidine salvage enzymes cytosine deaminase and uridine phosphorylase were identified in S. griseus using HPLC reversed-phase chromatography.
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Hughes, Lee E. (Lee Everette). "Pyrimidine Biosynthesis in the Genus Streptomyces : Characterization of Aspartate Transcarbamoylase and Its Interaction with Other Pyrimidine Enzymes". Thesis, University of North Texas, 1998. https://digital.library.unt.edu/ark:/67531/metadc278797/.
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Asfour, Hani. "Regulation of pyrimidine biosynthesis and virulence factor production in wild type, Pyr- and Crc- mutants in Pseudomonas aeruginosa". Thesis, University of North Texas, 2006. https://digital.library.unt.edu/ark:/67531/metadc5297/.
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Previous research in our laboratory established that pyrB, pyrC or pyrD knock-out mutants in Pseudomonas aeruginosa required pyrimidines for growth. Each mutant was also discovered to be defective in the production of virulence factors. Moreover, the addition of exogenous uracil did not restore the mutant to wild type virulence levels. In an earlier study using non-pathogenic P. putida, mutants blocked in one of the first three enzymes of the pyrimidine pathway produced no pyoverdine pigment while mutants blocked in the fourth, fifth or sixth steps produced copious quantities of pigment, just like wild type P. putida. The present study explored the correlation between pyrimidine auxotrophy and pigment production in P. aeruginosa. Since the pigment pyoverdine is a siderophore it may also be considered a virulence factor. Other virulence factors tested included casein protease, elastase, hemolysin, swimming, swarming and twitching motilities, and iron binding capacity. In all cases, these virulence factors were significantly decreased in the pyrB, pyrC or pyrD mutants and even in the presence of uracil did not attain wild type levels. In order to complete this comprehensive study, pyrimidine mutants blocked in the fifth (pyrE) and sixth (pyrF) steps of the biosynthetic pathway were examined in P. aeruginosa. A third mutant, crc, was also studied because of its location within 80 base pairs of the pyrE gene on the P. aeruginosa chromosome and because of its importance for carbon source utilization. Production of the virulence factors listed above showed a significant decrease in the three mutant strains used in this study when compared with the wild type. This finding may be exploited for novel chemotherapy strategies for ameliorating P. aeruginosa infections in cystic fibrosis patients.
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Patel, Monal V. "The regulatory roles of PyrR and Crc in pyrimidine metabolism in Pseudomonas aeruginosa". Thesis, University of North Texas, 2001. https://digital.library.unt.edu/ark:/67531/metadc2875/.
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The regulatory gene for pyrimidine biosynthesis has been identified and designated pyrR. The pyrR gene product was purified to homogeneity and found to have a monomeric molecular mass of 19 kDa. The pyrR gene is located directly upstream of the pyrBC' genes in the pyrRBC' operon. Insertional mutagenesis of pyrR led to a 50- 70% decrease in the expression of pyrBC', pyrD, pyrE and pyrF while pyrC was unchanged. This suggests that PyrR is a positive activator. The upstream regions of the pyrD, pyrE and pyrF genes contain a common conserved 9 bp sequence to which the purified PyrR protein is proposed to bind. This consensus sequence is absent in pyrC but is present, as an imperfect inverted repeat separated by 11 bp, within the promoter region of pyrR. Gel retardation assays using upstream DNA fragments proved PyrR binds to the DNA of pyrD, pyrE, pyrF as well as pyrR. This suggests that expression of pyrR is autoregulated; moreover, a stable stem-loop structure was determined in the pyrR promoter region such that the SD sequence and the translation start codon for pyrR is sequestered. β-galactosidase activity from transcriptional pyrR::lacZ fusion assays, showed a two-fold in increase when expressed in a pyrR- strain compared to the isogenic pyrR+ strain. Thus, pyrR is negatively regulated while the other pyr genes (except pyrC) are positively activated by PyrR. That no regulation was seen for pyrC is in keeping with the recent discovery of a second functional pyrC that is not regulated in P. aeruginosa. Gel filtration chromatography shows the PyrR protein exists in a dynamic equilibrium, and it is proposed that PyrR functions as a monomer in activating pyrD, pyrE and pyrF and as a dimeric repressor for pyrR by binding to the inverted repeat. A related study discovered that the catabolite repression control (Crc) protein was indirectly involved in pyr gene regulation, and shown to negatively regulate expression of PyrR at the posttranscriptional level.
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Griffin, Roger J. "Novel biological roles for pyrimidines". Thesis, Aston University, 1986. http://publications.aston.ac.uk/12540/.
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The development of classical and lipophilic inhibitors of dihydrofolate reductase (DHFR) as antitumour agents is reviewed and the advantages and problems associated with each class are discussed. The antitumour activity, pharmacokinetics and metabolism of m-azido-pyrimethamine (MZP), a novel lipophilic inhibitor, are considered and compared with metoprine, the prototype lipophilic antifolate. Evidence for a folate-independent target for lipophilic DHFR inhibitors is presented. Synthetic studies centred on three principal objectives. Firstly a series of structural analogues of MZP were prepared encompassing alkoxy, chloro and alkylamino substituents and evaluated, as the ethanesulphonate salts, for activity against mammalian DHFR. Inhibitory constant (KI) determinations were conducted by a Zone B analysis, the corresponding 4'-azido isomer of MZP proving more potent than the parent compound. Secondly, to facilitate metabolism and stability studies on MZP, a range of possible reference compounds were synthesised and characterised. Finally, a series of diaminopyrimidine derivatives were synthesised embracing structural features incompatible with DHFR inhibitory activity, in order that such compounds may serve as biochemical probes for the unidentified folate-independent target for lipophilic diaminopyrimidines discussed previously. Inactivity against DHFR was achieved via introduction of an ionic or basic group into a normally hydrophobic region of the molecule and compounds were screened against a mammalian DHFR and thymidylate synthase to confirm the abolition of activity. Several derivatives surprisingly proved potent inhibitors of DHFR exhibiting KI values comparable to that of methotrexate. Analogues were screened for antitumour activity in vitro and in vivo against murine leukaemia cell lines in order to identify potential lead compounds. Several derivatives virtually inactive against DHFR exhibited a disparate cytotoxicity and further biochemical studies are warranted. The nobreak hitherto unreported debenzylation of 2,4-diamino-5-(N-alkyl-benzylaminophenyl) pyrimidines was discovered during the course of the synthetic studies, treatment of these compounds with nitrous acid affording the corresponding benzotriazoles.
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Lee, Jeong-Hwan. "Synthesis of pyrrolo[2,3-d]pyrimidines and pyrazino[2,3-d]pyrimidines and their biological activities". Thesis, University of Strathclyde, 2010. http://oleg.lib.strath.ac.uk:80/R/?func=dbin-jump-full&object_id=14350.
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Chang, Mingren. "Characterization of Pyrimidine Biosynthesis in Pseudomonas putida Using Mutant and Wild Type Strains". Thesis, University of North Texas, 1991. https://digital.library.unt.edu/ark:/67531/metadc500647/.
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The biosynthesis of pyrimidines in Pseudomonas putida was investigated. In this study, pyrimidine requiring mutants were isolated by conventional mutagenesis and enrichment. The strains required exogenously supplied pyrimidines for growth and were found by enzyme assays to be deficient for the product of the pyrB gene encoding the enzyme aspartate transcarbamoylase. None of the intermediates of the pathway could supply the auxotrophic requirement of the strain; only preformed pyrimidines, metabolized via salvage pathways could suffice. Pyrimidine limitation in the mutant caused a slight but significant fifty per cent increase in expression of all the de novo biosynthetic enzymes. Pyrimidine starvation's effect on nucleotide pool levels was examined in the mutant and caused a marked swelling of the purine nucleotide pools.
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Clain, Jérôme. "Inhibiteurs de la biosynthèse des pyrimidines chez Plasmodium falciparum : mode d'action et mécanisme de résistance". Paris 5, 1998. http://www.theses.fr/1998PA05P100.
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Nicolle, Edwige. "Nouvelles thiazolidino [3,2-a] pyrimidines : synthèse, étude structurale et pharmacologique". Université Joseph Fourier (Grenoble), 1990. http://www.theses.fr/1990GRE18007.
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Brichta, Dayna Michelle. "Construction of a Pseudomonas aeruginosa Dihydroorotase Mutant and the Discovery of a Novel Link between Pyrimidine Biosynthetic Intermediates and the Ability to Produce Virulence Factors". Thesis, University of North Texas, 2003. https://digital.library.unt.edu/ark:/67531/metadc4344/.
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The ability to synthesize pyrimidine nucleotides is essential for most organisms. Pyrimidines are required for RNA and DNA synthesis, as well as cell wall synthesis and the metabolism of certain carbohydrates. Recent findings, however, indicate that the pyrimidine biosynthetic pathway and its intermediates maybe more important for bacterial metabolism than originally thought. Maksimova et al., 1994, reported that a P. putida M, pyrimidine auxotroph in the third step of the pathway, dihydroorotase (DHOase), failed to produce the siderophore pyoverdin. We created a PAO1 DHOase pyrimidine auxotroph to determine if this was also true for P. aeruginosa. Creation of this mutant was a two-step process, as P. aeruginosa has two pyrC genes (pyrC and pyrC2), both of which encode active DHOase enzymes. The pyrC gene was inactivated by gene replacement with a truncated form of the gene. Next, the pyrC2 gene was insertionally inactivated with the aacC1 gentamicin resistance gene, isolated from pCGMW. The resulting pyrimidine auxotroph produced significantly less pyoverdin than did the wild type. In addition, the mutant produced 40% less of the phenazine antibiotic, pyocyanin, than did the wild type. As both of these compounds have been reported to be vital to the virulence response of P. aeruginosa, we decided to test the ability of the DHOase mutant strain to produce other virulence factors as well. Here we report that a block in the conversion of carbamoyl aspartate (CAA) to dihydroorotate significantly impairs the ability of P. aeruginosa to affect virulence. We believe that the accumulation of CAA in the cell is the root cause of this observed defect. This research demonstrates a potential role for pyrimidine intermediates in the virulence response of P. aeruginosa and may lead to novel targets for chemotherapy against P. aeruginosa infections.
15
Langlet, Abraham. "Nitration of oxo-pyrimidines and oxo-imidazoles /". Stockholm, 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-601.
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Parks, Emma Louise. "Polyfunctionalised pyrimidines and pyrazines from perhalogenated precursors". Thesis, Durham University, 2008. http://etheses.dur.ac.uk/2551/.
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Chapter 1 introduces the modem pharmaceutical industry in terms of the drug discovery process leading into a discussion of the relevance of heterocyclic compounds with particular focus on the synthesis of multifunctional pyrimidines and pyrazines. An introduction into organofluorine chemistry is included followed by a review of the literature on 5-chloro-trifluoropyrimidine, tetrafluoropyrimidine and tetrafluoropyrazine. Chapter 2 describes a study of the reactivity of 5-chlorotrifluoropyrimidine with mono- and difunctional-nucleophiles. This research demonstrates the former are not selective and in the latter the 5-position chlorine atom is inert to nucleophilic aromatic substitution and cross-coupling methodologies. Chapter 3 explores the reactivity of tetrafluoropyrimidine with nitrogen, sulphur and oxygen containing nucleophiles and describes the development of a methodology for the synthesis of multisubstituted pyrimidines by establishing the regioselectivities of such processes. Chapter 4 investigates the reactivity of tetrafluoropyrimidine with difunctional nucleophiles. This study indicated it was not possible to synthesise [5,6]-ring fused systems and that in some cases dimers were formed owing to the 5-position fluorine atom being inactive substitution. Chapter 5 discusses the use of tetrafluoropyrazine in the syntheses of [5,6] ring-fused systems. The reactivity of the system towards MiV-dinucleophiles and C,0-dinucleophiles was investigated. Further functionalisations by nucleophilic aromatic substitution of the remaining fluorine atoms with nitrogen and oxygen nucleophiles are also discussed. Chapter 6 contains the experimental data for Chapters 2 to 5.
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Swetnam, S. P. "N.M.R. studies of the protonation of pyrimidines". Thesis, Keele University, 1985. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.372826.
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Prieur, Vanessa. "Pyrrolo[2,3-d]pyrimidines : conception, synthèse, fonctionnalisation". Thesis, Orléans, 2015. http://www.theses.fr/2015ORLE2072/document.
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Les pyrrolo[2,3-d]pyrimidines, également connues sous le nom de 7-déazapurines, sont une classe importante d’hétérocycliques aromatiques, de par leurs potentiels biologiques (antitumoral, antiinflammatoire, antibactérien, etc.). C’est pourquoi ce squelette a été une source d’intérêt pour les chimistes organiciens. Outre leurs atouts biologiques, ces molécules présentent également de remarquables propriétés physico-chimiques (fluorescence UV), ce qui permet de nouvelles applications en électronique. Bien que ces dernières années, un bon nombre de recherche ont été mises en oeuvre en vue de synthétiser ces molécules, il n’existe encore que peu de méthodes générales pour obtenir des pyrrolo[2,3-d]pyrimidines hautement substituées. Le but de ces travaux de thèse est de développer différentes stratégies régiosélectives et chimiosélectives de synthèse pour accéder à des pyrrolo[2,3-d]pyrimidines diversement substituées et ce, en un minimum d’étapes. Dans un premier temps, il a été synthétisé une famille de 7-méthylpyrrolo[2,3-d]pyrimidines 4,5,6 triarylées notamment via l’utilisation de deux réactions de Suzuki-Miyaura. Pour faire suite, nous avons envisagé la préparation d’une série de pyrrolopyrimidines 2,4,6-triarylées où le motif aromatique de la position 2 est introduit suivant les conditions de Liebeskind-Srogl. Enfin la préparation de pyrrolo[2,3-d]pyrimidines 4-aminées à partir d’alkynylpyrimidines a été mise au point et divers composés de cette famille ont été élaborésThe pyrrolo [2,3-d]pyrimidines, also known as 7-deazapurines, are an important class of aromatic heterocycles by their biological potencial (antitumor, anti-inflammatory, antibacterial, etc.). Therefore, this skeleton is a source of interest for the organic chemists. A part of the biological activity, these compounds present also outstanding physicochemical properties (UV-fluorescence); enabling new applications in electronics. The last few years, a great number of researches have been put in execution with a view to synthesizing these molecules, where still few general methods exist to obtain pyrrolo [2,3-d] pyrimidines highly substituted. The aim of these works of thesis is to develop different regioselective and chemoselective synthetic strategies to accede to pyrrolo [2,3-d]pyrimidines diversely substituted and furthemore in a reduced number of steps. First has been synthesized a family of 4,5,6-triarylated-7-methylpyrrolo[2,3-d]pyrimidines including the use of two Suzuki-Miyaura's reactions. Also we contemplated the preparation of a series of 2,4,6-triarylated pyrrolopyrimidines where the aryl group at the position 2 has been introduced under Liebeskind-Srogl reaction conditions. Finally the preparation of 4-aminated pyrrolo [2,3-d] pyrimidines from alkynylpyrimidines has been fine-tuned and diverse derivative compounds have been synthesized
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Barnes, Samuel. "Synthesis of 2, 4-distributed pyrimidines of possible biological interest". unrestricted, 2008. http://etd.gsu.edu/theses/available/etd-05012008-164917/.
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Thesis (M.S.)--Georgia State University, 2008.Title from file title page. Lucjan Strekowski, committee chair; A.L. Baumstark, Jerry Smith, committee members. Electronic text (83 p. : ill.) : digital, PDF file. Description based on contents viewed August 8, 2008. Includes bibliographical references (p. 44-46).
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Ratelle, Guillaume. "Incorporation spécifique d'une pyrimidine oxydée dans l'ADN cellulaire". Sherbrooke : Université de Sherbrooke, 2001.
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PERIGNON, JEAN-LOUIS. "Metabolisme des pyrimidines dans les cellules lymphoides humaines". Paris 6, 1987. http://www.theses.fr/1987PA066799.
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Afin d'estimer le role du metabolisme intermediaire des pyrimidines dans la reponse immunitaire, la fonction immunitaire de deux malades ayant un deficit enzymatique hereditaire portant sur la voie de synthese de novo des pyrimidines (oroticurie) est etudie. Le metabolisme intermediaire des nucleosides pyrimidiques dans des lymphocytes et lymphoblastes humains fait l'objet d'une deuxieme etude
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Kumar, Alan P. "Structure-Function Studies on Aspartate Transcarbamoylase and Regulation of Pyrimidine Biosynthesis by a Positive Activator Protein, PyrR in Pseudomonas putida". Thesis, University of North Texas, 2003. https://digital.library.unt.edu/ark:/67531/metadc4362/.
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The regulation of pyrimidine biosynthesis was studied in Pseudomonas putida. The biosynthetic and salvage pathways provide pyrimidine nucleotides for RNA, DNA, cell membrane and cell wall biosynthesis. Pyrimidine metabolism is intensely studied because many of its enzymes are targets for chemotheraphy. Four aspects of pyrimidine regulation are described in this dissertation. Chapter I compares the salvage pathways of Escherichia coli and P. putida. Surprisingly, P. putida lacks several salvage enzymes including nucleoside kinases, uridine phosphorylase and cytidine deaminase. Without a functional nucleoside kinase, it was impossible to feed exogenous uridine to P. putida. To obviate this problem, uridine kinase was transferred to P. putida from E. coli and shown to function in this heterologous host. Chapter II details the enzymology of Pseudomonas aspartate transcarbamoylase (ATCase), its allosteric regulation and how it is assembled. The E. coli ATCase is a dodecamer of two different polypeptides, encoded by pyrBI. Six regulatory (PyrI) and six catalytic (PyrB) polypeptides assemble from two preformed trimers (B3) and three preformed regulatory dimers (I2) in the conserved 2B3:3I2 molecular structure. The Pseudomonas ATCase also assembles from two different polypeptides encoded by pyrBC'. However, a PyrB polypeptide combines with a PyrC. polypeptide to form a PyrB:PyrC. protomer; six of these assemble into a dodecamer of structure 2B3:3C'2. pyrC' encodes an inactive dihydroorotase with pyrB and pyrC' overlapping by 4 bp. Chapter III explores how catabolite repression affects pyrimidine metabolism. The global catabolite repression control protein, Crc, has been shown to affect pyrimidine metabolism in a number of ways. This includes orotate transport for use as pyrimidine, carbon and nitrogen sources. Orotate is important because it interacts with PyrR in repressing the pyr genes. Chapter IV describes PyrR, the positive activator of the pyrimidine pathway. As with other positive activator proteins, when pyrimidine nucleotides are depleted, PyrR binds to DNA thereby enhancing expression of pyrD, pyrE and pyrF genes. When pyrimidine nucleotides are in excess, the PyrR apoprotein binds to orotate, its co-repressor, to shut down all the pyrimidine genes. Like many positive activators, PyrR is subject to autoregulation and has catalytic activity for uracil phosphoribosyltransferase inducible by orotate.
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Tkacz, Victoria. "Synthesis of thieno[2,3]-pyrimidines as candidate antileishmanial agents". Connect to resource, 2006. http://hdl.handle.net/1811/6636.
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Thesis (Honors)--Ohio State University, 2006.Title from first page of PDF file. Document formatted into pages: contains 14 p.; also includes graphics. Includes bibliographical references (p. 8). Available online via Ohio State University's Knowledge Bank.
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Barnes, Samuel. "Synthesis of 2,4-Disubstituted Pyrimidines of Possible Biological Interest". Digital Archive @ GSU, 2008. http://digitalarchive.gsu.edu/chemistry_theses/10.
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The synthesis of 2,4-disubstituted pyrimidine derivatives is described. The synthetic route involved the addition reaction of lithiated intermediates, mostly heterocycles, to position 4 of 2-chloropyrimidine to give a dihydropyrimidine intermediate which was oxidized back to a pyrimidine. This was followed by nucleophilic aromatic substitution with various amines of the chlorine in the position 2. A number of compounds were prepared which showed binding towards various serotonin receptors in preliminary biological evaluation.
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Pouliquen, Laure. "Deazaguanines (pyrrolo(2,3-d)pyrimidines) as potential antiparastic drugs". Thesis, University of Strathclyde, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.502340.
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Malaria, Leishmania and Tiypanasomia are parasitic diseases which are very severe in number of countries, essentially tropical. Due to the massive proliferation of these diseases and the increase of resistance against drugs usually used, current treatments are no more efficient and expose the patient to very severe side effects, which can cause death in the most severe cases.
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Wessner, Rachael Ann. "Theoretical Estimation of pKa’s of Pyrimidines and Related Heterocycles". Wright State University / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=wright1469798346.
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Entezampour, Mohammad. "Quantitation of Endogenous Nucleotide Pools in Pseudomonas aeruginosa". Thesis, University of North Texas, 1988. https://digital.library.unt.edu/ark:/67531/metadc500491/.
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Nucleotide pools were extracted and quantified from Pyr^+ and Pyr^- strains of P. aerucjinosa. Strains were grown in succinate minimal medium with and without pyrimidines, and nucleotides were extracted using trichloracetic acid (TCA; 6% w/v). The pyrimidine requirement was satisfied by uracil, uridine, cytosine or cytidine. Pyr^- mutants were starved for pyrimidines for two hours before nucleotide levels were measured. This starvation depleted the nucleotide pools which were restored to wild type levels by the addition of pyrimidines to the medium. When the pyrimidine analogue, 6-azauracil, known to inhibit OMP decarboxylase, was added to cultures of the wild type strain, the uridine and cytidine nucleotides were depleted to near zero. Thus, the nucleotide pool levels of Pseudomonas strains can be manipulated.
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Simkovsky, Nadja Melitta. "Synthesis of some potential IKK inhibitors based around a pyrimidine scaffold". Thesis, University of Liverpool, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.367619.
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Brom, Jacques. "Squelettes pyrimidohétérocycliques dérivés d'amino- et d'hydrazino- uraciles". Mulhouse, 1991. http://www.theses.fr/1991MULH0205.
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Les 6-amino-, 6-hydrazino- et 6-(azavinyl) pyrimidinediones riches en électrons réagissent par leur carbone 5 avec différents électrophiles (l’O-tosylisonitrosomalodinitrile (OTMD), le tétracyanoéthylène (TCNE), l'acétylènedicarboxylate de diméthyle (DMAD), et le diméthylacétal du diméthylformamide (DMFDMA) pour conduire après cyclisation à toute une série d'hétérocycles polycycliques. La 6-amino-1,3-diméthylpyrimidine-2,4(1H, 3H)-dione fournit ainsi, avec l'OTMD, une lumazine précurseur de pyrimido [5,4-g] ptéridines, et avec le TCNE, une pyrido [2,3-d] pyrimidine. Une isomérisation du squelette carboné est mise en évidence dans le cas de la réaction entre la 6-hydrazino-1,3-diméthylpyrimidine-2,4(1H, 3H) dione et le TCNE. Des réactions analogues sur carbone sont également observées dans les séries naphtaléniques et anthracéniques
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Simon, Gaëlle. "Analogues et dérivés des méridianines : Synthèse et Étude structure-activité biologique". Brest, 2004. http://www.theses.fr/2004BRES2011.
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Le milieu marin est une source de molécules bioactives originales. Les méridianines, indoles substitués en position 3 par un reste pyrimidine, font partie de ces molécules découvertes récemment qui présentent une activité inhibitrice des kinases cycline-dépendantes. Afin de compléter les premiers tests biologiques sur ces indolopyrimidines, nous rapportons dans un premier temps la synthèse d'analogues NH des méridianines par deux voies : un couplage de Suzuki entre des acides indolylboroniques et une 2-amino-4-chloropyrimidine et, la formation d'un cycle 2-aminopyrimidine par condensation de la guanidine sur des ènaminones obtenues par réaction du DMF-DMA sur des 3-acétylindoles. Nous avons, dans un deuxième temps, préparé selon cette même synthèse linéaire des dérivés N-alkylés des méridianines, la formation de l'ènaminone nécessitant, cette fois, la présence de pyrrolidine. Enfin, les synthèses de divers dérivés ont été réalisées en remplaçant l'indole par le cycle 1,2,3,9-tetrahydro-4H-carbazol-4-one ou par variations autour du cycle 2-aminopyrimidine. Une partie de ces molécules a ensuite été testée, dans le cadre de la recherche contre le cancer, sur des kinases cycline-dépendantes (GSK-3 et CDK1) et sur des lignées cellulaires (RAJI, DAUDI, K562). Une série de tests a également été réalisée sur la fixation des larves de balanes afin de préciser les propriétés antifouling de ces nouvelles moléculesThe marine environment constitues a very promising source for novel and bioactive molecules, and meridianins have been identified among those recently discovered. These indoles with a 2-aminopyrimidine at C-3 can inhibit cyclin-dependent kinases. In order to conduct additionnal biological tests about these 3-(2-aminopyrimidine)indoles, we first synthesised NH meridianin-analogues through two routes: (i) a Miyaura-Suzuki coupling of indol-3-ylboronic acids to 2-amino-4-chloropyrimidine, and (ii) the formation of a 2-amino-pyrimidine by guanidine condensation with enaminones issued from the reaction of N,N-dimethylformamide dimethylacetal (DMF-DMA) with 3-acetylindoles. Then, in a second stage we prepared N-alkyled derivatives of meridianins by applying the same linear synthesis, using pyrrolidine for the formation of enaminones. At last, various derivatives were prepared by replacing the indole with the 1,2,3,9-tetrahydro-4H-carbazol-4-one cycle or using various pyrimidines. Some of these molecules were finally tested against cyclin-dependent kinases (GSK-3 and CDK1) and cell lines (RAJI, DAUDI and K562) as part of cancer-related researches. Other tests about the fixation of barnacle larvae were also performed to investigate the antifouling properties of these new molecules
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Black, Duncan Arthur. "Aspects of purine and pyrimidine metabolism". Doctoral thesis, University of Cape Town, 1989. http://hdl.handle.net/11427/26590.
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In Chapter 1 a review of the literature concerning aspects of erythrocyte membrane transport and metabolism, and purine and pyrimidine metabolism is presented. The effects of pH, pO₂ and inorganic phosphate (Pi) on the uptake and metabolism of hypoxanthine by erythrocytes has been studied in Chapter 2. Uptake of hypoxanthine and accumulation of inosine 5'-monophosphate (IMP) were markedly increased at acid pH, high external phosphate concentrations, and low pO₂. Release of accumulated IMP as hypoxanthine occurred at alkaline pH values and low external phosphate concentrations. Conditions favouring IMP accumulation gave rise, in the absence of hypoxanthine, to a corresponding increase in 5'-phosphoribosyl-1-pyrophosphate (PRPP). Intracellular phosphate concentrations were markedly pH dependent and a model is presented whereby hypoxanthine uptake and release are controlled by intracellular concentrations of inorganic phosphate and 2,3- bisphosphoglycerate (2,3-DPG). These allosteric effectors influence, in opposing ways, two enzymes governing IMP accumulation, namely PRPP synthetase and 5'-nucleotidase. These metabolic properties suggest that the erythrocyte could play a role in the removal of hypoxanthine from anoxic tissue. In Chapter 3 the kinetics and mechanism of transport of orotate across the human erythrocyte membrane and the effect of pH and inorganic phosphate on its metabolism (in the erythrocyte) have been studied. It has been shown that orotate enters erythrocytes with non-saturable kinetics and with a capacity of 190 μmoles/1 packed cells/min at a concentration of 4-6 mmolar. The presence of competition for transport by a number of anions and the lack of competition by uridine is indicative of transport by a general anion transporter, with the ability for concentrative uptake in the absence of other external anions being compatible with transport via a ping-pong mechanism. Inhibition of transport by the specific band 3 inhibitors DIDS and CHCA confirm that transport is via the band 3 anion transporter. This explains the lack of significant uptake of orotate by most differentiated tissues which lack the intact band 3 protein. However, the demonstration of band 3 in rat hepatocytes (Cheng and Levy, 1980) provides a mechanism for the orotate transport which has been observed in liver (Handschumacher and Coleridge, 1979). Changes in pH and inorganic phosphate (Pi) concentrations have been shown to have marked effects on the relative quantities of metabolic products produced by the erythrocyte from orotate. There was an increase in orotate metabolised with increasing Pi, an effect augmented by lowering the pH, and most easily explained by the allosteric activation of PRPP synthetase by Pi. The increase in UTP levels with decreasing pH may be the consequence of both increased PRPP availability for the formation of uridine nucleotide from orotate, and decreased conversion of UMP to uridine by pyrimidine 5'-nucleotidase, which is known to be inhibited by phosphate. The accumulation of UDP sugars is optimal at a phosphate concentration of 10 mmolar, which is unexplained but would be compatible with an inhibitory effect of Pi on CTP synthetase. A PRPP wasting cycle at alkaline pH values is proposed to explain the apparent paradox where no PRPP was observed to accumulate in erythrocytes (Chapter 2) at pH values of 7.6 and above in the presence of 10 mmolar phosphate and no added hypoxanthine, yet the metabolism of orotate, which is a PRPP utilising reaction, at alkaline pH values was readily demonstrable here. This (apparent paradox) can be resolved if one assumes that even in the absence of added hypoxanthine and demonstrable intracellular IMP there are sufficient quantities of hypoxanthine and/or IMP to maintain a PRPP wasting cycle at alkaline pH values. The cycle is interrupted at acidic pH values as phosphate levels rise and inhibit 5'-nucleotidase, an effect augmented by the decreasing levels of 2,3-DPG which accompany decreasing pH. This wasting cycle has recently been confirmed by P. Berman (unpublished). The kinetics of orotate uptake by erythrocytes and its eventual release as uridine provides a role for the erythrocyte in the transport and distribution of pyrimidines to peripheral tissues. A model is proposed and involves the de novo production of orotate in the liver. In the next step erythrocytes take up the orotate secreted by the liver into the circulation, convert it into an intermediate buffer store of uridine nucleotides, whose distribution is a function of pH and phosphate concentration, and eventually release it as uridine, which is a readily available form of pyrimidine for utilisation by peripheral nucleated cells. The enhancement of uptake of labelled orotate into nucleic acids of cultured cells is demonstrated here. The degradative half of the cycle proposes that uracil and palanine are the predominant degradative forms of pyrimidines produced by peripheral cells, and their ultimate metabolic fate is complete catabolism in the liver to CO₂ and water. In the final chapter the possible role of the human erythrocyte in the prevention of reperfusion injury has been investigated. The development of a model of renal ischaemia in the rat is described. The ability of human erythrocytes, "primed" by preincubating in acid medium of high Pi concentration and low pO₂, to take up hypoxanthine in a concentrative manner when perfused through ischaemic rat kidney is demonstrated. Attempts to demonstrate improved survival and renal function in rats with "primed" human erythrocytes prior to reperfusion were, however, unsuccessful. It is further demonstrated that "unprimed" human erythrocytes, resident in ischaemic rat kidney for 3 hours, take up hypoxanthine and convert it to IMP. that erythrocytes could play a physiological prevention of reperfusion injury.
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Scott, Allelia Worrall. "Pyrimidine Nucleoside Metabolism in Pseudomonads and Enteric Bacteria". Thesis, University of North Texas, 1991. https://digital.library.unt.edu/ark:/67531/metadc500941/.
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Metabolic differences in the strategies used for pyrimidine base and nucleoside salvage were studied in the pseudomonads and enteric bacteria. Fluoro--analogs were used to select mutant strains of E. coli, S. typhimurium, P. putida, and P. aeruginosa blocked in one or more of the uracil and uridine salvage enzymes. HPLC analysis of cell-free extracts from wild-type and mutant strains examined the effectiveness of the selections. Evidence was found for cytidine kinase in Pseudomonas and for an activity that converted uracil compounds to cytosine compounds. Using media supplemented with 150 μg of orotic acid per ml, P. putida SOC 1, a Pyr, upp mutant which utilizes orotic acid as a pyrimidine source was isolated for the first time in any study.
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Hou, Geneviève. "Synthèse de pyrido et de thiénopyrimidin-4(3H)-ones et de leurs produits de réduction : intérêt potentiel de ces composés dans le traitement de la thrombose". Bordeaux 2, 1997. http://www.theses.fr/1997BOR2E001.
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Gayon, Eric. "Stratégies pour l'accès rapide à des hétérocycles azotés à partir d'alcools propargyliques". Thesis, Montpellier, Ecole nationale supérieure de chimie, 2012. http://www.theses.fr/2012ENCM0017/document.
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La partie principale de ce manuscrit traite du développement de nouvelles méthodologies utilisant la substitution propargylique catalysée par des sels de fer(III), pour la formation de divers hétérocycles azotés (∆4-isoxazolines, isoxazoles, cis-acylaziridines et pyrimidines). En premier lieu, de nouvelles synthèses monotopes de ∆4-isoxazolines et d'isoxazoles diversement substitués impliquant des réactions de cyclisation catalysées par diverses espèces carbophiles ([Au], [Pd], [I+]) ont été développées. La fragilité de la liaison N-O des ∆4-isoxazolines a pu être ensuite exploitée pour conduire à la formation de cis-acylaziridines. De nouvelles voies d'accès aux (Z)-β-énaminones et aux pyrimidines trisubstituées ont été également développéesThe main part of this manuscript deals with the development of new methodologies using iron(III)-catalyzed propargylic substitution, for the synthesis of various nitrogen-containing heterocycles (Δ4-isoxazolines, isoxazoles, cis-acylaziridines and pyrimidines). Firstly, new one-pot syntheses of variously substituted Δ4-isoxazolines and isoxazoles involving cyclization reactions promoted by various carbophilic species ([Au], [Pd], [I+]) have been developed. The weakness of the Δ4-isoxazoline N-O bond has been then exploited, leading to the formation of cis-acylaziridines. New pathways to (Z)-β-enaminones and trisubstituted pyrimidines have also been developed
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Do, Khoa Quang. "Design, Synthesis and Binding Studies of Trisubstitutedpyrazolo[3,4-d]pyrimidines". Thesis, Griffith University, 2006. http://hdl.handle.net/10072/367533.
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Pyrazolo[3,4-d]pyrimidines were known as adenosine antagonists at the rat A1 and A2A adenosine receptors based on our previous studies. In this study, 245 pyrazolo[3,4-d]pyrimidines derivatives with various benzyl substitutents at N-1 and various hydrophobic side chains at C-4 and C-6 were synthesized and screened at the human A1, A2A and A3 adenosine receptors. 14 out of 245 compounds were resynthesized and purified to determine the Ki values of these compounds at the human A1 adenosine receptor. Chapter 1 of the thesis is a literature review of adenosine research. It describes the physiology of adenosine and the discovery and characterization of all adenosine receptors namely A1, A2A, A2B and A3. It also looks at the medical application of adenosine, adenosine analogs, adenosine agonists and adenosine antagonists. The final part of the chapter discusses the discovery and development of adenosine agonists and antagonists. Chapter 2 of the thesis describes the rational design of the pyrazolo[3,4-d]pyrimidines template using ligand-based molecular modelling technique and describes the synthesis of the template.
Chapter 3 and chapter 4 describe the application of silicon chemistry and attempts to synthesise a series of pyrazolo[3,4-d]pyrimidines heterocycle by solid phase synthesis. Chapter 5 and chapter 6 describe the synthesis of a series of pyrazolo[3,4-d]pyrimidines heterocycle using the solution phase parallel synthesis and the binding studies of a library of 245 compounds and the resynthesis of 14 target compounds. Chapter 7 describes the cell culture and membrane preparation of the human A1, A2A, A2B and A3 adenosine receptors and radioligands binding assays.Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Science
Full Text
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Lee, Yick-Shun. "Pyrimidine Metabolism in Bacteria: Physiological Properties of Nucleoside Hydrolase and Uridine Kinase". Thesis, University of North Texas, 1991. https://digital.library.unt.edu/ark:/67531/metadc798309/.
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Ralli, Pooja. "Impaired virulence factor production in a dihydroorotate dehydrogenase mutant (pyrD) of Pseudomonas aeruginosa". Thesis, University of North Texas, 2005. https://digital.library.unt.edu/ark:/67531/metadc4940/.
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Previous research in our laboratory showed that when knockout mutations were created in the pyrB and pyrC genes of the pyrimidine pathway in Pseudomonas aeruginosa, not only were the resultant mutants auxotrophic for pyrimidines but they were also impaired in virulence factor production. Such a correlation had not been previously reported for P. aeruginosa, a ubiquitous opportunistic pathogen in humans. In an earlier study it was reported that mutants blocked in one of the first three enzymes of the pyrimidine pathway in the non-pathogenic strain P. putida M produced no pyoverdin pigment while mutants blocked in the later steps produced copious amounts of pigment, just like the wild type. This study probed for the same connection between pyrimidine auxotrophy and pigment production applied in P. aeruginosa. To that end a knockout mutation was created in pyrD, the fourth step in the pyrimidine pathway which encodes dihydroorotate dehydrogenase. The resulting mutant required pyrimidines for growth but produced wild type pigment levels. Since the pigment pyoverdin is a siderophore it may also be considered a virulence factor, other virulence factors were quantified in the mutant. These included casein protease, hemolysin, elastase, swimming, swarming and twitching motility, and iron binding capacity. In all cases these virulence factors were significantly decreased in the mutant. Even supplementing with uracil did not attain wild type levels. Starvation of the pyrimidine mutant for uracil caused increased specific activity of the pyrimidine enzymes, suggesting that regulation of the pyrimidine pathway occurred at the level of transcription. This effect has also been reported for P. oleovorans. The present research consolidates the idea that pyrimidine auxotrophs cause decreased pathogenicity in P. aeruginosa. Such a finding may open the search for chemotherapy targets in cystic fibrosis and burn victims where P. aeruginosa is an infecting agent.
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Majumdar, Papiya. "Nitrosative guanosine deamination pyrimidine ring opening implications of effects in homogeneous solution as well as ansiotropic environments /". Diss., Columbia, Mo. : University of Missouri-Columbia, 2007. http://hdl.handle.net/10355/5967.
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Thesis (Ph. D.)--University of Missouri-Columbia, 2007.The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Title from title screen of research.pdf file (viewed Oct. 16, 2007). Vita. Includes bibliographical references.
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Farajallah, Azizeh M. "Focused chemical libraries targeting pyrimidine metabolism in Plasmodium falciparum /". Thesis, Connect to this title online; UW restricted, 2007. http://hdl.handle.net/1773/8652.
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Mainguet, Samuel. "Caractérisation moléculaire et fonctionnelle du recyclage de l'uracile par l'uracile-phosphoribosyltransférase d'Arabidopsis thaliana". Paris 11, 2009. http://www.theses.fr/2009PA112278.
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L’UMP est le précurseur de toutes les pyrimidines, lesquelles sont requises pour la synthèse des acides nucléiques, des glycérolipides, et des glycoprotéines. Il peut être formé par la voie de novo, coûteuse en énergie, ou par le recyclage de nucléobases ou nucléosides. Jusqu'alors, les Uracile PhosphoRibosylTransferases, qui recyclent l’uracile en UMP, étaient décrites comme non-essentielles, mais aucun mutant pour cette voie n’était étudié chez les plantes. L’étude de la famille de gènes annotés comme UPRT chez Arabidopsis a permis d’identifier un gène unique (UPP) codant pour une protéine plastidiale et responsable de la quasi-totalité de l’activité UPRT de la plante. Les mutants KO upp présentent un phénotype drastique photo-dépendant de retard développemental et dé-pigmentation. L’analyse de leur transcriptome précoce révèle un phénotype moléculaire de stress oxydatif. Nous montrons aussi une corrélation positive entre l’activité UPRT et l’accumulation d’amidon chez les mutants upp et des lignées 35S :UPP. De plus, les 35S :UPP sont plus résistants au stress salin. Des lignées amiRNA ont été crées pour étudier la mutation d’UPP à des stades plus tardifs. La protéine UPP a été purifiée chez E. Coli pour des analyses à venir. L’UPP-like du riz a été clonée et validée par complémentation chez un mutant d’E. Coli. Des lignées amiRNA et sur-expresseur d’OsUPP ont été générées pour étudier l’importance d’UPP chez cette espèce qui stocke de l’amidon. Nous proposons que le coût énergétique de la synthèse d’UMP puisse affecter le pool d’UDP-glucose chez les plantes, lequel est d’importance dans le métabolisme glucidique et la glycosylation de métabolites secondaires impliquées dans la réponse aux stressUridine is the precursor for all pyrimidines, which are required for nucleic acids, polysaccharides, glycerolipids, and glycoproteins synthesis. They can be formed either by the energy-consuming de novo synthesis or by the energy-saving recycling of nucleobases. Lately, Uracil PhosphoRibosylTransferases, which form UMP from uracil in the salvage pathway, were described as unessential enzymes but no mutant of this pathway were studied in plants. A phylogenetic study of the UPRT annotated gene family shows that a single member (UPP) was conserved with the cyanobacteria gene ancestor. Accordingly, it was the only gene validated by complementation in E. Coli and in planta enzymatic activity measurement. We showed that UPP is targeted to plastids. The KO upp mutants displayed a light-dependent drastic pale-green phenotype and their transcriptomic analysis revealed a strong oxidative stress molecular phenotype. We showed a positive correlation between uracil recycling and starch accumulation in upp mutants and 35S:UPP lines. In addition, overexpressors are more tolerant to salt stresses. AmiRNA plants have been designed to silence UPP at later stages. The UPP protein has been expressed and purified in E. Coli for further studies. The UPP-like gene of rice has been cloned, and validated by complementation in E. Coli. OsUPP overexpressing, and amiRNA silenced Oryza lines are generated to study the importance of UPP in this starch storing species. We hypothesize that the energetic cost of uridine synthesis may directly affect the stock of UDP-glucose in plants, required for carbohydrate metabolism and the glycosylation of secondary metabolites involved in oxidative stress response
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Sullivan, Shannon M. "Synthesis of 2,4-disubstituted pyrimidine derivatives as potential 5-HT7 receptor antagonist". unrestricted, 2008. http://etd.gsu.edu/theses/available/etd-05052008-153400/.
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Thesis (M.S.)--Georgia State University, 2008.Title from file title page. Lucjan Strekowski, committee chair; A.L. Baumstark, Gabor Patonay, Doyle Barrow , committee members. Electronic text (68 p. : ill.) : digital, PDF file. Description based on contents viewed June 23, 2008. Includes bibliographical references (p. 42-430.
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Scammells, Peter J., i n/a. "Pyrazolo(3,4-d)Pyrimidines and adenosine receptors: a structure/activity study". Griffith University. Division of Science and Technology, 1990. http://www4.gu.edu.au:8080/adt-root/public/adt-QGU20050826.141630.
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Pyrazolopyrimidines are a general class of compounds which exhibit Aj adenosine receptor affmity. A number of pyrazolo(3,4-d)pyrimidine analogues of isoguanosine and i-methylisoguanosine has been synthesised. All compounds were tested forAi adenosine receptor affinity using a (311) R-PIA competitive binding assay. The N-i and N-5 positions were substituted with a number of different ailcyl and aryi groups. 3-Chiorophenyl substitution of the N-i position and butyl substitution of the N-5 position greatly enhanced the overall adenosine receptor affinity. Substitution by a methyl group at the N-7 position fixed the C-4 position in the imino tautomeric form. This resulted in a marked reduction in activity. The substitution of the N-2 position with a phenyl group produced an analogue with a similar structure to i,3-dipropyl-8-(2-amino-4-chlorophenyl)xanthine (PACPX). A 2-phenyl substituent was favourable for interaction with the adenosine receptor. A number of pyrazolo(3,4-d)pyrirnidine analogues of 4,6-bis-a-carbamoylethylthio-i-phenylthiopyrazolo(3,4-d)pyrinhidine (DJB-KK) has also been synthesised and tested for Aj adenosine receptor affinity. 4,6-Bis-alkylthio-1-phenylpyrazolo(3,4-d)pyrimidines with a-carbamoylethyl and u-carbamoylpropyi groups were compared. The additional methyiene of the a-carbamoylpropyl group produced increased adenosine receptor affinity. 6-a-Carbamoylethylthio-4-mercapto-1-phenylpyrazolo(3,4-d)pyrimidine and 4-cc-carbamoylethylthio- i-phenylpyrazolo(3,4-dlpyrimidine were compared. Substitution of the C-6 position maintained activity, while substitution of the C-4 reduced activity.
43
Doise, Muriel. "Synthèse d'oxazolo et d'imidazo(m, n-x)pyridines, pyrimidines et pyrazines". Lille 1, 1991. http://www.theses.fr/1991LIL10129.
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Ce travail décrit la synthèse et l'étude structurale de nouveaux composés hétérocycliques condensés dérivés d'orthohydroxyaminoazines. La première partie est consacrée à la synthèse de deux nouveaux hétérocycles fondamentaux isostères de la purine: l'oxazolo(4,5-b)pyridine et de l'oxazolo(4,5-d) pyrimidine ainsi que celle de leurs dérivés substitués en -2; cette seconde série était jusqu'alors inconnue. La seconde partie décrit la synthèse de nouveaux phénols susceptibles de présenter des propriétés complexantes en série imidazo(1,2-a)pyridine et pyrazine par condensation de glyoxals avec la benzyloxy-3 amino-2 pyridine ou la méthoxy-3 amino-2 pyrazine. Après clivage de la fonction éther on aboutit aux dihydroxy-3,8 méthyl-2 (ou phényl-2) imidazo(1,2-a)pyridines et pyrazines. L'étude spectroscopique en IR, UV et RMN montre l'existence de tautomères zwitterioniques et, dans la seconde série, de formes oxo. La troisième partie est consacrée à l'ouverture en milieu HClO4/MeOH d'hydroxy-3 imidazo(1,2-a)pyridines, ou à l'action de ce même milieu sur un mélange de glyoxals et d'amino-2 pyridines diversement substitués, qui conduisent à des N-(pyridyl-2) amino-2 esters et acides dérivés de la glycine, de l'alanine et de la phénylalanine dans lesquels le cycle pyridine est substitué par un groupe 3-OH, 3-NO2 ou 5-NO2. Tous les composés étudiés ont été caractérisés par étude spectroscopique en IR, UV et RMN (1H et 13C) ainsi que par spectrométrie de masse
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Léger, Dominique. "L'aspartate transcarbamylase, enzyme clef de la regulation du metabolisme des pyrimidines". Paris 6, 1987. http://www.theses.fr/1987PA066181.
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Scammells, Peter. "Pyrazolo(3,4-d)Pyrimidines and adenosine receptors: a structure/activity study". Thesis, Griffith University, 1990. http://hdl.handle.net/10072/365214.
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Pyrazolopyrimidines are a general class of compounds which exhibit Aj adenosine receptor affmity. A number of pyrazolo(3,4-d)pyrimidine analogues of isoguanosine and i-methylisoguanosine has been synthesised. All compounds were tested forAi adenosine receptor affinity using a (311) R-PIA competitive binding assay. The N-i and N-5 positions were substituted with a number of different ailcyl and aryi groups. 3-Chiorophenyl substitution of the N-i position and butyl substitution of the N-5 position greatly enhanced the overall adenosine receptor affinity. Substitution by a methyl group at the N-7 position fixed the C-4 position in the imino tautomeric form. This resulted in a marked reduction in activity. The substitution of the N-2 position with a phenyl group produced an analogue with a similar structure to i,3-dipropyl-8-(2-amino-4-chlorophenyl)xanthine (PACPX). A 2-phenyl substituent was favourable for interaction with the adenosine receptor. A number of pyrazolo(3,4-d)pyrirnidine analogues of 4,6-bis-a-carbamoylethylthio-i-phenylthiopyrazolo(3,4-d)pyrinhidine (DJB-KK) has also been synthesised and tested for Aj adenosine receptor affinity. 4,6-Bis-alkylthio-1-phenylpyrazolo(3,4-d)pyrimidines with a-carbamoylethyl and u-carbamoylpropyi groups were compared. The additional methyiene of the a-carbamoylpropyl group produced increased adenosine receptor affinity. 6-a-Carbamoylethylthio-4-mercapto-1-phenylpyrazolo(3,4-d)pyrimidine and 4-cc-carbamoylethylthio- i-phenylpyrazolo(3,4-dlpyrimidine were compared. Substitution of the C-6 position maintained activity, while substitution of the C-4 reduced activity.Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
Division of Science and Technology
Full Text
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Poulsen, Sally-Ann, i n/a. "Pyrazolo(3,4-d)pyrimidines: Synthesis and Structure-Activity Relationships for Binding to Adenosine Receptors". Griffith University. School of Science, 1996. http://www4.gu.edu.au:8080/adt-root/public/adt-QGU20050901.161632.
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Chapter 1 of thesis is a literature review of adenosine research. The central importance of the contributions of both classical pharmacology and, more recently, molecular biology to adenosine research is demonstrated. These disciplines have enabled the classification and characterisation of adenosine receptors and as well an understanding of the physiological significance of endogenous adenosine. The significant benefits of developing therapeutics for regulation of the diverse physiological functions of adenosine, by regulation of adenosine receptors, is outlined. For this therapeutic potential to be realised both high affinity and subtype selective adenosine agonists and antagonists are required. The structure-activity relationships for agonists and xanthine antagonists are discussed. The assimilation of these structure-activity relationships have guided the development of ligand based models of the adenosine receptor pharmacophore. The 'flipped', 'N6-C8' and 'three binding domain' models were described. These models aim to direct the future design of high affinity and selective ligands for adenosine receptors. The development of receptor based models by modelling of the receptor-ligand complex is also presented. The main body of this thesis presents a study of the structure-activity relationships for pyrazolo(3,4-d) pyrimidines binding to adenosine Ai and A2a receptors. Prior to this study few non-xanthine adenosine antagonists had been well defined or optimised in terms of structure-activity relationships. However, the value of such ligands is immense, facilitating further definition of structural requirements for high affinity and selective adenosine receptor binding. These ligands should complement existing agonists and xanthine antagonists in developing an understanding of adenosine receptor binding. The experimental approach to development of the lead compound of this study, a-(6-(l'-carbamoylethylthio)- l-phenylpyrazolo(3,4-d)pyrimidin-4-ylthio)propanamide (5), is outlined in Chapter 2 of this thesis. 5 is substituted at C-4, C-6 and N-i of the pyrazolo(3,4-d)pyrimidine heterocycle. The experimental approach to optiniising 5 was approached in a rational manner, requiring an iterative approach i.e. design of generation I target compounds --synthesis -- biological evaluation -- structure-activity relationships -- design of generation II target compounds, etc. Chapters 3, 4 and 5 of this thesis describe this experimental approach as it relates to optimising the lead compound, 5, for adenosine receptor affinity and subtype selectivity. The importance of receptor interactions with multiple ligand domains, to achieve both potency and selectivity, was recognised so that optimisation of the C-4, C-6 and N-i substituents of the lead compound was targeted and achieved. Previous structure-activity studies with agonists and xanthine antagonists have concentrated on modifying a single ligand domain. Chapter 3 presents twelve generation I target compounds to examine C-4 and C-6 substituent structure-activity relationships. Chapter 4 presents twelve generation II target compounds to further examine C-4 and C-6 substituent structure-activity relationships. Chapter 5 presents sixteen generation ifi target compounds to examine N-I substituent structure-activity relationships. A major outcome from the research presented in these chapters was the development of highly potent and highly selective ligands for the adenosine A1 receptor subtype. a(4-Methylamino- I -phenylpyrazolo(3,4-d)pyrimidin-6-ylthio)hexanamide (29) was the most potent ligand at the Ai receptor identified in this study, and is one of the most potent Ai selective antagonists ever reported. 29 has an A1 K1 value of 0.745±0.045 nM and is 332-fold selective for the A1 receptor over the A2a receptor. a-(1-Phenyl-4-propylthiopyrazolo(3,4-d)pyrimidin-6-ylthio)butanainide (27) was the most selective ligand of this study. It is four orders of magnitude selective for the A1 receptor (up to 16900-fold), and one of the most selective antagonists ever reported. This high selectivity has been achieved with the maintenance of good A1 affinity (A1 K1 = 29.5±6.6 nM). These results prove the value of modifying multiple substituents of adenosine receptor ligands, generating ligands which bind with high potency and selectivity to adenosine Al receptors compared to adenosine A2a receptors.
47
McIntyre, Neil A. "Synthesis of ring-constrained thiazolylpyrimidines : inhibitors of cyclin-dependent kinases /". St Andrews, 2007. http://hdl.handle.net/10023/353.
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48
Zhang, Min. "Study on selective carbon-carbon, carbon-nitrogen, and carbon-oxygen bonds formation starting from alkynes". Rennes 1, 2009. http://www.theses.fr/2009REN1S036.
Pełny tekst źródłaStreszczenie:
The thesis is composed of two parts. Part I presents catalytic C-C, C-N, C-O bond formation: a series of dienylethers, 2,5-disubstituted furans, allylketones, γ-functionalized ketones, multisubstituted quinolines were made starting from terminal alkynes with the initial help of a ruthenium catalyst. Part II presents C-C, C-N, C-O bond formation reactions: a variety of tetrahydropyrimidines, and 1,3-oxazines were synthesized starting from electron-deficient alkynes via multiple component reactionsLa thèse est composée de deux parties. La partie I présente la formation catalytique de liaisons C-C, C-N et C-O : une série d’ethers, de diényle, furanes 2,5-disubstitués, cétones allyliques et γ-fonctionalisées et quinolines polysubstituées ont été préparées à partir d’alcynes avec l’aide initiale d’un catalyseur de ruthenium. La partie II présente la formation de liaisons C-C, C-N, C-O: une variété de tetrahydropyridines, et de 1,3-oxazines ont été synthétisées à partir d’alcynes electrophiles via des réactions à composants multiples
49
Moldovan, Salomia-Oana. "Ingénierie des systèmes conjugués A-π-D diaziniques et évaluation de leurs propriétés opto-électroniques. Mélamines spirodendritiques à partir des amino-1,3-dioxanes sérinoliques enantiopures. Design, synthèse et analyse structurale". Rouen, 2012. http://www.theses.fr/2012ROUES023.
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Our work described in this Ph. D Thesis comprises two parts entitled as Chapters. The research reported in Chapter1 concerns the synthesis and photophysical properties of new fluorophore A-π-D using diazine moiety as π-acceptor. The research reported in Chapter 2 concerns the design, synthesis and structural analysis of some new spiro-dendritic chiral melamines with peripheral units of type serinol / serinol-aminoacetal. The first Chapter presents the synthesis of a new A-π-D fluorophore using Sonogashira cross coupling reaction and copper-catalyzed Huisgen 1,3-dipolar cycloaddition. The target compounds consist of diazines as electron acceptor group A, N,N-dmethylaniline as electron-donating group D and fluorene as a π-conjugated central transmitter. All compounds have been fluorescent. Generally, good quantum yields were obtained, up to 72%, broad Stokes shifts and two-photon absorption cross-section values up to 367 GM. The second Chapter describes the preparation and stereochemistry of new G-0, -1 small dendrimers, seen as "model compounds" for the next investigated iterative syntheses of G-1, -2 target dendrimers. These structures contain, for the first time in the dendritic chemistry, the 7,11,18,21-tetraoxa-3,15-diazatrispiro[5. 2. 2. 5. 2. 2]heneicosan-3,15-diyl chiral skeleton as internal or central linker. The target dendrimers contained C-2 substituted 2-aminopropane-1,3-diols (Serinols, "open-chain" motif) and enantiopures amino-1,3-dioxanes ["closed-chain" motif, derivatives of (1S,2S)-2-amino-1-(4-nitrophenyl)-propane-1,3-diol] as peripheral units. The stereochemistry of rotational phenomena occurring about the C(s-triazine)-N(exocyclic) partial double bonds involving the peripheral units is discussed by means several methods and parameters : NH Gradient Temperatures (GT, from 1H NMR), rotational barriers ΔG* (from VT 1H NMR), hydrodynamic diameteres dH (from 2D-1H DOSY NMR), spatial (dipolar) interactions (from 2D-1H, 1H-NOESY and QC 13C NMR) and optical rotations [α]D20 (polarimetry).
50
Poulsen, Sally-Ann. "Pyrazolo(3,4-d)pyrimidines: Synthesis and Structure-Activity Relationships for Binding to Adenosine Receptors". Thesis, Griffith University, 1996. http://hdl.handle.net/10072/365893.
Pełny tekst źródłaStreszczenie:
Chapter 1 of thesis is a literature review of adenosine research. The central importance of the contributions of both classical pharmacology and, more recently, molecular biology to adenosine research is demonstrated. These disciplines have enabled the classification and characterisation of adenosine receptors and as well an understanding of the physiological significance of endogenous adenosine. The significant benefits of developing therapeutics for regulation of the diverse physiological functions of adenosine, by regulation of adenosine receptors, is outlined. For this therapeutic potential to be realised both high affinity and subtype selective adenosine agonists and antagonists are required. The structure-activity relationships for agonists and xanthine antagonists are discussed. The assimilation of these structure-activity relationships have guided the development of ligand based models of the adenosine receptor pharmacophore. The 'flipped', 'N6-C8' and 'three binding domain' models were described. These models aim to direct the future design of high affinity and selective ligands for adenosine receptors. The development of receptor based models by modelling of the receptor-ligand complex is also presented. The main body of this thesis presents a study of the structure-activity relationships for pyrazolo(3,4-d) pyrimidines binding to adenosine Ai and A2a receptors. Prior to this study few non-xanthine adenosine antagonists had been well defined or optimised in terms of structure-activity relationships. However, the value of such ligands is immense, facilitating further definition of structural requirements for high affinity and selective adenosine receptor binding. These ligands should complement existing agonists and xanthine antagonists in developing an understanding of adenosine receptor binding. The experimental approach to development of the lead compound of this study, a-(6-(l'-carbamoylethylthio)- l-phenylpyrazolo(3,4-d)pyrimidin-4-ylthio)propanamide (5), is outlined in Chapter 2 of this thesis. 5 is substituted at C-4, C-6 and N-i of the pyrazolo(3,4-d)pyrimidine heterocycle. The experimental approach to optiniising 5 was approached in a rational manner, requiring an iterative approach i.e. design of generation I target compounds --synthesis -- biological evaluation -- structure-activity relationships -- design of generation II target compounds, etc. Chapters 3, 4 and 5 of this thesis describe this experimental approach as it relates to optimising the lead compound, 5, for adenosine receptor affinity and subtype selectivity. The importance of receptor interactions with multiple ligand domains, to achieve both potency and selectivity, was recognised so that optimisation of the C-4, C-6 and N-i substituents of the lead compound was targeted and achieved. Previous structure-activity studies with agonists and xanthine antagonists have concentrated on modifying a single ligand domain. Chapter 3 presents twelve generation I target compounds to examine C-4 and C-6 substituent structure-activity relationships. Chapter 4 presents twelve generation II target compounds to further examine C-4 and C-6 substituent structure-activity relationships. Chapter 5 presents sixteen generation ifi target compounds to examine N-I substituent structure-activity relationships. A major outcome from the research presented in these chapters was the development of highly potent and highly selective ligands for the adenosine A1 receptor subtype. a(4-Methylamino- I -phenylpyrazolo(3,4-d)pyrimidin-6-ylthio)hexanamide (29) was the most potent ligand at the Ai receptor identified in this study, and is one of the most potent Ai selective antagonists ever reported. 29 has an A1 K1 value of 0.745±0.045 nM and is 332-fold selective for the A1 receptor over the A2a receptor. a-(1-Phenyl-4-propylthiopyrazolo(3,4-d)pyrimidin-6-ylthio)butanainide (27) was the most selective ligand of this study. It is four orders of magnitude selective for the A1 receptor (up to 16900-fold), and one of the most selective antagonists ever reported. This high selectivity has been achieved with the maintenance of good A1 affinity (A1 K1 = 29.5±6.6 nM). These results prove the value of modifying multiple substituents of adenosine receptor ligands, generating ligands which bind with high potency and selectivity to adenosine Al receptors compared to adenosine A2a receptors.Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Science
Science, Environment, Engineering and Technology
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