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1
Waterfield, P. C. "Novel C-organostannyl heterocycles." Thesis, University of Bath, 1988. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.384138.
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Balanta, Castillo Angelica. "Novel molecular and colloidal catalysts for c-c bond formation processes." Doctoral thesis, Universitat Rovira i Virgili, 2011. http://hdl.handle.net/10803/66243.
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Esta tesis doctoral se centró en la síntesis y la caracterización de nanopartículas metálicas (Pd, Ni, Pt) estabilizadas por varios tipos de ligandos y el uso de estas nanopartículas en reacciones de formación de nuevos C-C o C-heteroatomo: a) Reacción de substitución alílica catalizadas por Pd; b) Reacción de acoplamiento asimétrico de Suzuki-Miyaura; c) Reacción de acoplamiento de Suzuki-Miyaura; d) reacción de adición 1,4 de ácidos borónicos a cetonas. En cada una de estas reacciones se llevó a cabo la síntesis y caracterización de nanoparticulas metálica y complejos moleculares usando muchos tipos de ligandos en los sistemas moleculares y los sistemas análogos cataliazados por nanopartículas. Excelentes actividades y enatioselectividades fueron obtenidas en la reacción de alquilación y aminación alílica. Además, estos sistemas fueron reciclados usando líquidos iónicos. También, nuevos y selectivas nanoparticulas fueron sintetizadas y caracterizadas. Estas nanopartículas fueron usadas exitosamente en varias reacciones de formación de nuevos enlaces C-C.This doctoral thesis focuses on the synthesis and characterization of metal nanoparticles (Pd, Ni, Pt) stabilized by several types of ligands and the used of these nanoparticles in new C-C or C-heteroatom bond formation reactions: a) Pd-catalysed asymmetric allylic substitution reactions; b) Pd-catalysed asymmetric Suzuki-Miyaura coupling reactions; c) Ni-catalysed Suzuki-Miyaura coupling reactions; d) Pt-catalysed 1,4-addition of phenylboronic acid to 2-cyclohexen-1-one reaction. For each reaction, the synthesis and characterization of metal nanoparticles and molecular complexes using several types of ligands were performed and both types of catalytic systems were tested in the appropriate reactions. Remarkably, excellent enantioselectivities using Pd/phosphite ligand were obtained in allylic substitution reaction. An efficient recovery of the catalytic system was carried out using ionic liquids as reaction medium. New active and selective nanoparticles were synthesized and characterized. These nanoparticles were applied successfully in various C-C bond formation reactions.
3
Redpath, P. "A novel and versatile approach to C- and C-AZA-nucleosides." Thesis, Queen's University Belfast, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.517040.
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Edwards, Michael Gareth. "Borrowing hydrogen : a novel concept for C-C bond formation with alcohols." Thesis, University of Bath, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.397556.
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Ferguson, William James. "The nitrile oxide/isoxazoline route to novel C-glycosides and C-disaccharides." Thesis, University of Edinburgh, 1996. http://hdl.handle.net/1842/13815.
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A convergent route, based on nitrile oxide/isoxazoline chemistry to carbon-linked disaccharides (C-disaccharides) and C-glycosides with functionalised linkages has been investigated. The sequence involves three steps. Firstly, the cycloaddition of a sugar-derived nitrile oxide to a terminal alkene provides a 3,5-disubstituted 2-isoxazoline. Next, the substituents attached to the isoxazoline may be modified, and finally the heterocycle subjected to either hydrogenolysis or reductive cleavage to afford a C-glycoside with a carbonyl or an amino functionalised linkage. Four terminal alkenes were selected; two ω-unsaturated monosaccharide derivatives, methyl 5, 6-dideoxy-2,3-0-isopropylidene-α-D-lyxo-hex-5-enofuranoside (93) and 3-O-benzyl-5, 6-dideoxy-2, 3-O-isopropylidene-α-D-xylo-hex-5-enofuranose (84), and two non-carbohydrate model alkenes, methylenecyclohexane and styrene. The in situ Mukaiyama dehydration of the peracetylated 2,6-anhydro-1-deoxy-1-nitroalditol derivatives from nitromethane and D-xylose, D-galactose and D-mannose provided the source of nitrile oxides (79), (89) and (90) respectively. Cycloadditions of the xylopyranosyl and galactopyranosyl nitrile oxides (79) and (89) to alkenes (93) and (84) proceeded regiospecifically and with a high degree of π-facial selectivity (40-64% d.e.). In each case the major adduct was found to possess R-configuration at the newly formed chiral centre C-5, corresponding to an erythro relationship between it and the adjacent C-4 position of the attached furanose unit. The structure of the isoxazoline formed from xylopyranosyl nitrile oxide (79) and D-mannose derived alkene (93) was established by X-ray crystallography. The observed selectivies may be rationalised in terms of the "inside alkoxy effect" proposed by Houk and the "homoallylic" modification of De Micheli et al.
6
Gonzalez, De Castro Angela. "Novel iron-pybisulidine catalysts for the selective aerobic oxidation and C-O/C-C cleavage of organic substrates." Thesis, University of Liverpool, 2014. http://livrepository.liverpool.ac.uk/19373/.
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The selective oxidation of organic compounds is one of the most attractive transformations for both, industry and academia. Industrial interest stems from the potential application of such oxidation methodologies in the economic, greener synthesis of valuable products, whereas academic research is challenged by the difficulties in achieving specific, direct functionalisation of the “inert” CH bonds in complex molecules. In this Ph. D. thesis, our contribution to the selective oxidation of organic substrates using a novel class of iron catalysts is presented. A general introduction covering the major challenges in the area of iron-catalysed selective oxidation of organic compounds is described in Chapter 1. Chapter 2 covers the design, synthesis and coordination properties of the novel PyBisulidine type ligands, which we have conceived for their potential use in selective oxidation, attempting to overcome some of the limitations of current methods. The efficiency of such PyBisulidine ligands is demonstrated in Chapter 3, where iron-PyBisulidine complexes are used for catalysing the aerobic α-oxidation of functionalised ethers. High catalytic efficiency, very good mass balance and excellent functional group tolerance were achieved with these catalysts under mild conditions. Such advantages stem from an unconventional reaction mechanism, involving the dehydrogenative oxygenation of the ether substrate to give a peroxobisether, followed by the cleavage of the peroxy bond to form two ester molecules. Unlike metalloenzymes and biomimetic iron complexes, H2 is released as the sole byproduct during the catalytic cycle. The oxidation mechanism is discussed in Chapter 4. Like natural dioxygenases, iron-PyBisulidine catalysts were found capable of promoting the aerobic cleavage of aliphatic C-C and C-O bonds. Even though biomimetic complexes are often seen as simplified models to study enzymatic processes, a more synthetic perspective of the selective aerobic cleavage of ethereal C-C and C-O bonds is described in Chapter 5.The great potential of such cleavages in organic synthesis is well exemplified in the iron-PyBisulidine catalysed direct conversion of natural isochromans into biologically active isochromanones with excellent selectivity. The ability of the iron-PyBisulidine complexes in catalysing aerobic C-C cleavages is further expanded in Chapter 6, where the oxidative cleavage of olefinic C=C bonds to carbonyl compounds is demonstrated. The catalytic reactions proceeded efficiently, showing a broad scope and a mechanism that involves the formation of dioxetane intermediates is postulated. Chapter 7 is an extension of Chapter 6, in which iron-PyBisulidine complexes were found to catalyse α-methylstyrene linear dimerisation under an inert atmosphere. Moreover, control in the regioselectivity of the double bond in the dimers can be achieved by modifications in the PyBisulidine ligands. Final conclusions and a perspective of the research covered in this Ph.D. thesis are provided in Chapter 8.
7
Zhou, Yixing Harden T. Kendall. "Cloning and characterization of a novel phospholipase C enzyme, human phospholipase C eta2." Chapel Hill, N.C. : University of North Carolina at Chapel Hill, 2007. http://dc.lib.unc.edu/u?/etd,1271.
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Thesis (Ph. D.)--University of North Carolina at Chapel Hill, 2007.Title from electronic title page (viewed Mar. 26, 2008). "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Pharmacology." Discipline: Pharmacology; Department/School: Medicine.
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Niblock, Helen Sarah. "Synthesis of the C(1)-C(9) fragment of disorazole C1 and novel heterocyclic analogues." Thesis, University of Edinburgh, 2012. http://hdl.handle.net/1842/6251.
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A highly convergent strategy for the synthesis of the antitubulin polyketide disorazole C1 is proposed based around the alkyne precursor I, featuring a novel Evans-Tishchenko/ring closing alkyne metathesis approach. Due to the inherent symmetry of the molecule this retrosynthesis leads to two fragments: a β- hydroxyketone II and the oxazole C(1)-(9) fragment III. A review of previous syntheses of disorazole C1 and established structure activity relationships (SARs) highlights a gap in current knowledge relating to the role of the oxazole in tubulin binding. Therefore, the focus of this research has been towards developing new routes for the synthesis of the C(1)-C(9) fragment that can be adapted to the synthesis of heterocyclic analogues to further establish the SAR of disorazole C1. Chapter 2 focuses on a disconnection at the C(5)-C(6) bond and a novel synthesis of the racemic C(1)-C(9) fragment has been achieved via a lithiation of methyl 2- methyl-1,3-oxazole-4-carboxylate and coupling to aldehyde V. First generation asymmetric routes to the C(1)-C(9) fragment centred on i. a biomimetic amino acid condensation route via an oxazoline intermediate based on the precedent of Meyers et al. and ii. a C(4)-C(5) disconnection approach based around the epoxide VII; are discussed in chapter 3. A second generation C(4)-C(5) disconnection centred on the novel tosylate VIII is discussed in chapter 4. Attempts to synthesise the parent C(1)- C(9) oxazole fragment using the tosylate VIII via i. a palladium catalysed C-H activation of ethyl 4-oxazole carboxylate and ii. lithiation of oxazole are reported. Coupling of fragment VIII (X = OTs) with ethyl 1H-pyrazole-4-carboxylate and a CuAAC coupling of the azide derived from tosylate VIII with methyl propiolate has allowed the successful completion of the synthesis of pyrazole and triazole analogues of this fragment.
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Rogers, Joshua Peter. "Photoelectron spectroscopy of (C₆F₆)-ₙ and C₆F₆ · I-clusters in a novel instrument." Thesis, Durham University, 2017. http://etheses.dur.ac.uk/12364/.
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The capabilities of a new photoelectron spectrometer are characterised in the study of (C6F6)n– and (C6F6)I– clusters. The photoelectron spectrometer consists of a series of vacuum chambers that facilitate a molecular beam of gas-phase anions. These anions and clusters are generated at the point of intersection between an electron beam and the supersonic expansion produced by a high temperature Even-Lavie pulsed valve. The anions are extracted orthogonally and mass-separated in a Wiley-McLaren time-of-flight mass spectrometer. The analyte is addressed by a laser pulse produced by either a tuneable nanosecond OPO for one-photon frequency-resolved measurements or a femtosecond pump-probe regime for two-photon time-resolved measurements. The kinetic energy of the resulting photoelectrons are measured in a velocity-map imaging spectrometer. C6F6- is of interest due to the prediction that it ought to host a meta-stable binding mode of the excess electron known as a correlation-bound state (CBS). Similar to other non-valence binding modes, such as the dipole-bound state, this CBS is thought to act as a doorway state in the mechanism of low energy electron capture. The CBS is characterised by a large and diffuse orbital in which the excess electron is bound primarily through charge:induced-dipole interactions with the molecule’s valence orbital system. In the CBS, C6F6- is predicted to adopt a planar geometry like that of the neutral species, in contrast to the buckled geometry adopted when the excess electron occupies a valence orbital. Frequency- and time-resolved measurements of the anion were made in an effort to generate and observe the CBS. Initially, frequency resolved measurements of (C6F6)n– revealed a vertical detachment energy of 1.60 ± 0.07 eV for n = 1, increasing by 200 meV per additional cluster unit up to n = 5. The broad shape of the direct detachment peak confirms the disparity in geometry between the anion and neutral species. However, no evidence of the CBS was evident in these data. In subsequent explorations, an in-situ electron donor was employed to mimic the electron impact process. An I– ion was introduced to the neutral C6F6 molecule to produce clusters of (C6F6)I–. Frequency-resolved measurements of this cluster revealed a mechanism for electron loss below the threshold for the single-photon direct detachment process. This suggested the presence of a charge-transfer channel centred around hv = 3.3 eV. Time-resolved measurements of (C6F6)I– confirmed the presence of the charge-transfer state and revealed an instantaneous and coherent transfer of the electron onwards into the valence orbital system of the C6F6 molecule. This transfer of charge causes the molecule to vibrate as its geometry changes from planar to buckled. The oscillations observed in the photoelectron spectra are coherent and sinusoidal and have a frequency of 121 ± 2 cm−1. This compares very favourably to the frequency of 122 cm−1 calculated by time-dependent density functional theory for the bending mode of C6F6 along the coordinate between the planar and buckled geometries. I argue that this charge-transfer state exhibits the predicted characteristics of a CBS.
10
Godage, Himali Yasmin. "Novel approaches to the synthesis of C-glycosides." Thesis, University of Oxford, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.401067.
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Haji, Dheere Abdul Karim. "Novel [¹¹C]CO₂ radiolabelling methodologies for PET neuroimaging." Thesis, King's College London (University of London), 2015. http://kclpure.kcl.ac.uk/portal/en/theses/novel-11cco2-radiolabelling-methodologies-for-pet-neuroimaging(a28f9e70-d697-4d69-afec-a8c3c34f1e93).html.
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PET is a non-invasive molecular imaging technique that is increasingly being used for medical imaging and drug development. Carbon-11 (11C; half-life 20.4 min) is one of the most commonly used radionuclides for PET molecular imaging. 11C is usually produced in the form of [11C]CO2 and converted into more reactive secondary precursors such as [11C]methyl iodide and [11C]carbon monoxide for radiolabelling. Although such secondary precursors are undoubtedly useful, given the short half-life of 11C, it would be advantageous to use [11C]CO2 directly from the cyclotron without additional time-consuming processing. Therefore, the development of radiochemical methods to efficiently radiolabel compounds directly with [11C]CO2 for applications in PET neuroimaging is an important goal and is the focus of this thesis. This work includes the development of novel radiolabelling methodology utilising [11C]CO2 for the radiolabelling of molecules based on urea and carbamate scaffolds. These functional groups are found in a plethora of biologically active molecules and pharmaceuticals. As proof of concept, the utility of the developed radiochemistry methods were applied to the synthesis of novel GABA and glutamate radiotracers. GABA and glutamate are major excitatory and inhibitory neurotransmitters in the brain. Although implicated in many diseases, the in vivo function of these neurotransmitter system is poorly understood. Their dysfunction are implicated in pathologies such as addiction, Alzheimer’s disease, Parkinson’s disease and autism. Monitoring the expression of the receptors in vivo and in vitro would enable better understanding of these diseases, their progression and treatment. The research described in this thesis unveils new methods to radiolabel novel molecules for these targets with 11C thereby enabling more opportunities to study them in vitro using autoradiography and in vivo using PET molecular imaging.
12
Hamza, Daniel. "Novel solid and solution phase intermolecular radical reactions." Thesis, University of Sussex, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.247970.
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Reich, Blair Jesse Ellyn. "Cyanide-catalyzed C-C bond formation: synthesis of novel compounds, materials and ligands for homogeneous catalysis." Texas A&M University, 2005. http://hdl.handle.net/1969.1/4987.
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Cyanide-catalyzed aldimine coupling was employed to synthesize compounds
with 1,2-ene-diamine and ñ-imine-amine structural motifs: 1,2,N,N'-
tetraphenyletheylene-1,2-diamine (13) and (+/-)-2,3-di-(2-hydroxyphenyl)-1,2-
dihydroquinoxaline (17), respectively. Single crystal X-ray diffraction provided solidstate
structures and density functional theory calculations were used to probe isomeric
preferences within this and the related hydroxy-ketone/ene-diol system. The enediamine
and imine-amine core structures were calculated to be essentially identical in
energy. However, additional effects-such as ÃÂ conjugation-in 13 render an enediamine
structure that is slightly more stable than the imine-amine tautomer (14). In
contrast, the intramolecular hydrogen bonding present in 17 significantly favors the
imine-amine isomer over the ene-diamine tautomer (18).
Aldimine coupling (AIC) is the nitrogen analogue of the benzoin condensation
and has been applied to dialdimines, providing the first examples of cyclizations effected
by cyanide-catalyzed AIC. Sodium cyanide promoted the facile, intramolecular
cyclization of several dialdimines in N,N-dimethylformamide, methanol, or
dichloromethane/water (phase-transfer conditions) yielding a variety of six-membered
heterocycles. Under aerobic conditions, an oxidative cyclization occurs to provide the
diimine heterocycle.
Cyanide-catalyzed aldimine coupling was employed as a new synthetic method
for oligomerization. Nine rigidly spaced dialdimines were oxidatively coupled under
aerobic conditions to yield conjugated oligoketimines and polyketimines with
unprecedented structure and molecular weight (DP = 2 - 23, ~700 -8200 g/mol). The ñ- diimine linkage was established based on IR spectroscopy, NMR spectroscopy, size
exclusion chromatography, and X-ray crystallographic characterization of the model
oxidized dimer of N-benzylidene-(p-phenoxy)-aniline. Cyclic voltammetry indicates ptype
electrical conductivity, suggesting they are promising candidates for plastic
electronic devices.
The cyanide-catalyzed benzoin condensation reaction of 4-substituted
benzaldehydes followed by oxidation to the diketone, and the Schiff Base condensation
of two equivalents of o-aminophenol provides 2,3-(4-X-phenyl)2-1,4-(2-
hydroxyphenyl)2-1,4-diazabutadiene. The ligand is given the moniker X-dabphol.
These ligands are readily metallated to form M-X-dabphol complexes. The copper
complexes catalytically fix CO2 with propylene oxide to yield propylene carbonate. DFT
studies along with a comparison with Hammet parameters help validate and elaborate on
the catalytic cycle and the catalytic results obtained. The nickel complex is competent
for olefin epoxidation. Synthesis, characterization, X-ray structure, DFT analysis, and
catalytic activity of the parent nickel dabphol complex are reported.
14
Svensson, Peter J. "Resistance to activated protein c a novel risk factor for venous thrombosis /." Lund : Dept. for Coagulation Disorders, Malmö University Hospital, Lund University, 1997. http://catalog.hathitrust.org/api/volumes/oclc/68945075.html.
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Ors, Aslihan. "Identification of novel APC/C regulators in fission yeast." Thesis, Institute of Cancer Research (University Of London), 2009. http://publications.icr.ac.uk/10297/.
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Sequential degradation of cell cycle proteins is a major regulatory mechanism for proper cell proliferation. Turnover of these proteins is performed by the ubiquitin/proteasome pathway, which poly-ubiquitylates and subsequently degrades the target proteins. The anaphase-promoting complex/cyclosome (APC/C) is a multi subunit E3 ubiquitin ligase that provides substrate specificity and regulation of the ubiquitin pathway. Two of the most important substrates are Cut2/securin and Cdc13/cyclin B, enabling chromosome segregation and exit from mitosis, respectively. Since APC/C function is very important for the cell cycle progression, its activity is strictly regulated. The aim of this study is to understand the regulation of APC/C and how its subunits contribute to this regulation. For this purpose, we have focused on the two least understood subunits: Apc1/Cut4 and Apc5. Conditionally lethal temperature sensitive mutants of these two subunits were created in fission yeast and the used for suppressor screening. We identified atf1+ as a multicopy suppressor of apc5-1, a mutation causing mitotic arrest. Fission yeast Atf1, which is homologous to human ATF2/CRE-BP1, is a bZIP domain mutant of Atf1, which has lost its transcription activation function, was still able to suppress the ts phenotype of apc5-1. The atf1+-dependent rescue was specific to the apc5-1 allele, rather than rescuing other APC/C subunit mutants and deletion of atf1+ increased the mitotic defects of the mutant. Interestingly, Atf1 physically binds to the APC/C in vivo. Furthermore, in vitro studies proved that Atf1 stimulates ubiquitylation activity of the APC/C. Finally; this interaction was shown to contribute to conjugation/mating efficiency of S. pombe cells upon nitrogen starvation and G1 arrest. Altogether, these results reveal a novel role for Atf1 in regulating the APC/C ubiquitin ligase, besides its transcription factor activity.
16
Turner, Susan Margaret. "Characterisation of novel cytochrome c lipoproteins in Niesseria gonorrhoeae." Thesis, University of Birmingham, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.403008.
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Simoneti, Marco. "Novel approaches for Ru-promoted C-H arylation methods." Thesis, Queen Mary, University of London, 2016. http://qmro.qmul.ac.uk/xmlui/handle/123456789/24249.
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The development of new procedures for the production of biologically and industrially relevant compounds still remains a big challenge in chemistry. The biaryl motif is ubiquitous among a wide range of compounds of industrial importance. For example, the biaryl skeleton is found in molecular switches and motors, agrochemicals or medicines such as antifungal, anticancer, antibiotics, anti-inflammatory treatments. These properties make the biaryl functionality a highly desirable synthetic target, for both commercial and research purposes. In this context, C-H arylation has been acknowledged as a useful alternative to traditional cross-couplings, replacing the organometallic coupling partner by a non-prefunctionalised substrate in the reaction with a haloarene. Approaches for the development of Ru-catalysed C-H arylation methodologies are presented herein. The introduction provides a general overview about different strategies employed in metalcatalysed direct C-H arylation methods. The rational behind selectivity and reactivity are also thoroughly discussed. The second chapter describes studies on the C-H activation of perfluorinated arenes by Ru(II)-species. The synthesis of unprecedented aryl rutyhenium complexes and mechanistic considerations on the metalation of the arene are presented. In the last part of the second chapter the development of a bis-cationic rutehium(II) complex able to catalyse direct C-H arylation of electron-poor arenes with bromoarenes in the absence of any directing group is described. A complete mechanistic analysis, along with the scope of the methodology, is therefore given.
18
Poletti, Marco. "Concepts for C++: analysis of established and novel features." Master's thesis, Alma Mater Studiorum - Università di Bologna, 2013. http://amslaurea.unibo.it/5092/.
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Giroult, André. "Novel carboazidation reactions and applications." Bordeaux 1, 2007. http://www.theses.fr/2007BOR13342.
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Cette thèse est axée sur le développement de la réaction de carboazidation radicalaire d'oléfines. Cette réaction permet la création de deux nouvelles liaisons C-C et C-N via un mécanisme radicalaire en chaîne. La propagation de la chaîne radicalaire requière toutefois l'emploi de dérivés toxiques de l'étain. De plus, l'isolement du produit final est difficile. Notre premier objectif a été d'améliorer cette réaction en développant la synthèse d'un nouveau iodoacétate supporté sur polystyrène conduisant à des réactions plus propres et à des produits purifiables par simple précipitation. Dans un deuxième temps, nous avons développé une nouvelle version en solution sans étain basée sur l'utilisation de l'acétate d'azidosulfonyl d'éthyle, conduisant à des produits beaucoup plus aisément purifiables. Notre deuxième objectif a été d'utiliser la réaction de carboazidation pour la synthèse de nouvelles fonctions. Nous avons ainsi développé la synthèse de tétrazoles substitués en 1,5 par des chaînes alkyls, en une seule opéation par carboazidation radicalaire d'alcènes en présence de S-cyanomethyl O-ethyl carbonodithioate. Ce processus en cascade a conduit à l'obtention des tétrazoles attendus avec des rendements satisfaisants.
20
East, Lucy. "Functional characterisation of Endo180, a novel transmembrane C-type lectin." Thesis, Institute of Cancer Research (University Of London), 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.405017.
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Dooley, Johnathon Daniel. "Developments in C-H functionalization : novel metal-catalysed oxidative annulations." Thesis, University of Edinburgh, 2016. http://hdl.handle.net/1842/23673.
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Catalyst-Controlled Divergent C–H Functionalization of Unsymmetrical 2-Aryl Cyclic 1,3-Dicarbonyl Compounds with Alkynes and Alkenes A problem faced within the area of C–H functionalization is achieving siteselectivity when several similar C–H bonds are present within a given compound. One solution to this problem is the development of reactions that employ different catalytic systems to control the required selectivity. Herein, it is shown that such catalyst-controlled selectivity could be achieved on 2-aryl cyclic 1,3-dicarbonyl compounds where there exist two potential, non-adjacent sites for C–H functionalization. Examples demonstrate the palladium- and ruthenium-catalysed oxidative annulations of the 2-aryl cyclic 1,3-dicarbonyl substrates with alkynes, as well as with alkenes, where initial C–H bond cleavage occurs at one of two potential sites, depending on the catalyst used, which give unique products. 1,4-Rhodium(III) Migration in the One-Carbon Oxidative Annulations of 2-Arylphenols, Benzamides, and Benzoic Acids with 1,3-Enynes Oxidative annulations of 2-arylphenols, benzamides, and benzoic acids with alkynes and enynes are precedented and provide a range of heterocyclic products. However, in these examples, either the alkyne or enyne acts as a two-carbon annulation partner, reacting only across the alkynyl moiety. Herein, a more expansive scope of a previously published process in which 1,3-enynes, possessing allylic hydrogen atoms cis to the alkyne, undergo oxidative annulations with the three aforementioned classes of substrates as a one-carbon annulation partner is described. Proposed to occur via the 1,4-migration of a rhodium(III) species, annulated products were formed from a range of 1,3-enynes and substrates possessing a variety of functional groups.
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Sedgwick, Garry Gray. "Identification and functional characterisation of novel APC/C interacting proteins." Thesis, University of Birmingham, 2010. http://etheses.bham.ac.uk//id/eprint/1090/.
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The anaphase promoting complex /cyclosome (APC/C) is a multi-protein E3 ubiquitin ligase complex that regulates cellular proliferation through its ability to target essential cell cycle regulators such as cyclin A, cyclin B, securin and S-phase kinase-associated protein 2 (SKP2) for proteasomal-dependent degradation. APC/C substrates and coactivators are aberrantly expressed in many cancers. It is thought that the APC/C can also regulate cellular proliferation by controlling p21 and cell division cycle 6 homologue (CDC6) transcription. It is therefore of great interest to study other cellular proteins that interact with the APC/C as these proteins may also be important in cell cycle regulation and hence may enhance our understanding of the molecular basis of cancer. Therefore, the aim of my study was to identify novel APC/C interacting proteins through mass spectrometric analysis of APC/C subunit 7 (APC7) immunoprecipitates and go on to examine the functional significance of these interactions. I identified six novel APC7 interacting proteins, and decided to focus on two of these interactions. Initially I examined the interaction between APC7 and transcriptional intermediary factor 1\(\gamma\) (TIF1\(\gamma\)), a transcriptional repressor previously reported to be aberrantly expressed in cancer. Data presented in this study demonstrate that the APC/C and TIF1\(\gamma\) cooperate to regulate mitotic progression. Notably TIF1\(\gamma\) displays in vivo interactions with APC/C subunits 1-8, the APC/C‟s mitotic coactivator CDC20 and mitotic substrate cyclin A. Moreover, TIF1\(\gamma\) depletion by RNAi arrests cells in a metaphase-like state characterised by elevated levels of APC/C substrates, cyclin A, cyclin B and CDC20. In support of a role for TIF1\(\gamma\) in regulating mitotic progression by directly targeting the APC/C, cells treated with TIF1\(\gamma\)-specific siRNA exhibit reduced APC/C E3 ubiquitin ligase activity. This work defines TIF1\(\gamma\) as a novel mitotic regulatory protein essential for APC/C function and suggests that loss of TIF1\(\gamma\) may compromise genomic integrity by allowing the mis-segregation of chromosomes. I also investigated the functional relationship between APC7 and the nuclear factor 90/45 heterodimer (NF90/NF45), given that all of these proteins function as transcription factors. Results obtained demonstrate that APC5 and APC7 bind directly to NF90 in vitro and also form complexes with NF90 in vivo. It appears that APC/C interaction with NF90 is important in the regulation of interleukin-2 (IL-2) and tumour neucrosis factor (TNF) transcription, as exogenous APC5 and APC7 cooperate with NF90/NF45 to transactivate IL-2 and TNF promoter constructs. Lastly endogenous APC5 and APC7 bind to the IL-2 promoter in vivo while endogenous APC5 represses TNF transcription in vivo. Given that TNF and IL-2 stimulate cellular proliferation data presented here suggests that the APC/C might control cellular proliferation by regulating TNF and IL-2 transcription.
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Li, Bor-Ran. "Functional studies on a novel cytochrome c from Rhodobacter sphaeroides." Thesis, University of Edinburgh, 2009. http://hdl.handle.net/1842/3936.
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SHP (Sphaeroides Heme Protein) is a monoheme cytochrome c of unknown function. In general, ligands cannot bind to ferric SHP, but some diatomic molecules, such as O2 or NO, can bind to ferrous SHP. The gene encoding SHP and genes encoding a diheme cytochrome c (DHC) and a b-type cytochrome (Cyt-b) are found in the same chromosome region in different species. In the case of Shewanella oneidensis MR-1, mRNA levels for SHP, DHC, and Cyt-b are up-regulated by nearly 10-fold when grown under anaerobic conditions using nitrate as the electron acceptor. Thus it is possible that the physiological role of SHP may be in nitrate metabolism. However, nitrate is too big to be a candidate substrate for SHP, and some nitrification steps need more than one electron transfer (SHP is a monoheme cytochrome). Therefore, we will focus on the nitrite reductase, nitric oxide reductase and nitric oxide dioxygenase activities of SHP. In this thesis it is shown that SHP can catalyse the reaction between oxygen and nitric oxide to give a nitrate ion as the final product. Thus a possible aerobic function for SHP as a nitric oxide dioxygenase is proposed. Aerobically, SHP is proposed to be a nitric oxide dioxygenase which utilizes the same mechanism as other NO dioxygenases, flavohemoglobin (HMP) and neuroglobin (Ngb). This mechanism is proposed to proceed via an oxy-ferrous complex (SHP2+-O2) which reacts with nitric oxide. A mechanism for the catalytic reaction with ferrous-NO complex is described. SHP2+-NO can be quickly converted back to ferrous SHP by reacting with superoxide liberated by SHP2+-O2 or from another source. In addition it is also found that Shewanella MR-1 wild type reveals a higher NO tolerance than the SHP knockout strain in aerobic conditions. The catalytic mechanism of NO dioxygenase is oxygen-dependent, but the SHP mRNA up-regulation in Shewanella oneidensis MR-1 grown with nitrate under anaerobic conditions indicates that SHP may also perform some anaerobic function and may possibly be involved in nitrate metabolism. This work found that SHP reveals anaerobic nitrite reductase activity. However, the catalytic efficiency of SHP is considerably lower than other nitrite reductases. This infers that although SHP can reduce nitrite in vitro, it is unlikely to function as a nitrite reductase in vivo. Ferrous SHP binds NO with a Kd of less than 1 μM, and does not auto-oxidise. Therefore, under anaerobic conditions SHP2+-NO must be processed by some other mechanism. In addition, biochemical results reveal that the SHP/DHC complex has NO reductase activity under anaerobic conditions. Unfortunately, this function was not proved in vivo. SHP was initially isolated from Rhodobacter sphaeroides and its structure was reported in 2000. Based upon this structure, SHP is clearly a class I cytochrome c with one axial histidine ligand to the heme iron. Unusually, however, it has an asparagine residue as the other axial heme ligand, and as such is unique among cytochromes c. For this reason it may be assumed that the asparagine plays a special role. This study reveals several potential reasons why SHP utilises asparagine as a heme ligand. Firstly, in the ferric form, asparagine 88 binds to the heme iron to prevent small molecules binding. Secondly, in the ferrous form it moves to allow oxygen to bind and form the oxy-ferrous complex, using hydrogen bonding for stability. Thirdly, using asparagine as a heme ligand creates a suitable redox potential for reduction by DHC, thus allowing NO dioxygenation.
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de, Jesus Tristan J. "Novel Mechanisms of Immune Regulation by NF-kappaB c-Rel." Case Western Reserve University School of Graduate Studies / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=case1576176282590614.
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Smith, Jennifer. "Novel iridicycles for the asymmetric reduction of C=N bonds." Thesis, University of Liverpool, 2015. http://livrepository.liverpool.ac.uk/2049619/.
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The asymmetric reduction of imino bonds is a well known and utilised method of chiral amine synthesis. Chapter 1 gives an insight into the published methods for a range of substrates via hydrogenation and transfer hydrogention systems. This thesis presents a range of novel iridicycles, all of which contain chiral oxazoline and imidazoline ligands. The synthesised complexes demonstrate a variety of electronic and steric properties. Their activities are presented in the latter chapters for the asymmetric reduction of C=N bonds. Chapter 3 demonstrates the activity of the 4,5,6-trimethoxyimidazoline iridium complex for direct asymmetric reductive amination. High activity, yielding up to quantitative product is reported, under unusually mild conditions, in both aqueous and organic solvent systems. The enantioselectivites achieved were moderate to high for the substrates screened. The use of a bulky 2,4,6-tri-iso-propyloxazoline iridium complex is reported for the asymmetric reduction of quinolines, via transfer hydrogenation conditions. The tetrahydroquinolines were produced in high yields and moderate enantioselectivities. The addition of co-solvents to the aqueous system yielded improved enantioselectivies and conversions. For the reduction of pyridinium salts a bromo-dioxole imidazoline iridium complex presented high activity. This presents unprecedentedly mild conditions via a transfer hydrogenation system, producing high yields of N-benzyl piperidines. The enantioselectivites determined were high, although some could not be measured by the available means. The 2,4,6-tri-iso-propyloxazoline iridium complex further demonstrates high activity and enantioselectivity for the asymmetric hydrogenation of acyclic imines. An NMR and mechanistic study revealed the in-situ formation of a new iridium species present only in TFE.
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Jerhaoui, Soufyan. "Sulfoxydes : novel strategy for the asymmetric C(sp3)-H activation." Thesis, Strasbourg, 2018. http://www.theses.fr/2018STRAF025/document.
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Pendant de nombreuses années, les liaisons C-H aliphatiques ont été considérées comme dormantes, difficilement exploitables dans le contexte de la chimie organique. Le défi le plus important est de sélectionner une liaison C-H parmi toutes celles que contient une molécule. L’approche la plus utilisée à ce jour est l’utilisation d’un groupement directeur qui permet, en se liant à un métal, de diriger l’activation d’une liaison C-H en particulier. Suite au développement des groupements bicoordinants, nous avons développé notre propre groupement bicoordinant chiral. Cet auxiliaire nous a permis de réaliser de nombreuses transformations diastéréosélectives sur des carbones aliphatiques telles que l'arylation et l'oléfination. Nous l’avons également utilisé pour développer une méthodologie innovante pour la synthèse de produits naturels. Suite à ces travaux, nous avons développé un nouveau ligand chiral qui a été utilisé dans l’arylation et l’alkynylation énantiosélectives de cycloalcanesOver the decades, non-activated C-H bonds have been considered as dormant functionalities, hardly exploitable in the context of multistep synthesis of complex scaffolds. The main challenge is to select one C-H bond among all contained in one molecule. To answer to this problem bicoordinating directing groups allowing directed C(sp3)-H activation have been developed. Following the work of Daugulis and Babu, we developed our own chiral bicoordinating directing group, (S)-2-(p-tolylsulfinyl)aniline. This chiral auxiliary allowed us to realise various diastereoselective transformations on aliphatic chains such as arylation, olefination oracetoxylation. We also used it to develop a brand-new methodology for the total synthesis ofcyclopropane-bearing natural products. Moreover we developed a new chiral sulfinyl ligand, N-((S)-1-(4-(tert-butyl)phenyl)-2-((R)-p-tolylsulfinyl)ethyl)acetamide, that has been used for the enantioselective arylation and alkynylation of cycloalkanes
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Saito, Hidehiko, Shigeru Shirakawa, Katsumi Deguchi, Hideo Wada, Eiichi Iwasaki, Junki Takamatsu, Isamu Sugiura, Tadashi Matsushita, and Koji Yamamoto. "Homozygous protein C deficiency: identification of a novel missense mutation that causes impaired secretion of the mutant protein C." Thesis, Elsevier, 1992. http://hdl.handle.net/2237/16344.
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Hamdi, Anis. "Novel Chromatographic methodology for virus particles purification." Master's thesis, Universidade Nova de Lisboa, Instituto de Tecnologia Química e Biológica António Xavier, 2016. http://hdl.handle.net/10362/64186.
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"Virus based biopharmaceuticals are considered the most dynamic adopted tools in modern therapeutic medicine. Their use is increasing in the fields of vaccination and gene therapy. Membrane chromatography is becoming an attractive alternative t ool that can be used for virus purification due to its scalability, potential for optimization and economical features, allowing higher productivities with lower DSP costs. (…)"N/A
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Gibeau, Craig R. "First total synthesis of the novel brominated polyacetylenic diol (+)-diplyne a and (+)-diplyne c." Connect to this document online, 2005. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=miami1122997578.
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Thesis (M.S.)--Miami University, Dept. of Chemistry and Biochemistry, 2005.Title from first page of PDF document. Document formatted into pages; contains [1], ix, 112 p. : ill. Includes bibliographical references (p. 35-37).
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Marais, Saberi. "XvVHA-c``1- a novel stress responsive V-ATPase subunit c`` homologue isolated from the resurrection plant Xerophyta viscosa Baker." Master's thesis, University of Cape Town, 2004. http://hdl.handle.net/11427/4291.
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Liang, Yong. "Novel Approaches for the Synthesis of C-5 Modified Pyrimidine Nucleosides." FIU Digital Commons, 2014. http://digitalcommons.fiu.edu/etd/1591.
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The antiviral or anticancer activities of C-5 modified pyrimidine nucleoside analogues validate the need for the development of their syntheses. In the first half of this dissertation, I explore the Pd-catalyzed cross-coupling reaction of allylphenylgermanes with aryl halides in the presence of SbF5/TBAF to give various biaryls by transferring multiple phenyl groups, which has also been applied to the 5-halo pyrimidine nucleosides for the synthesis of 5-aryl derivatives. To avoid the use of organometallic reagents, I developed Pd-catalyzed direct arylation of 5-halo pyrimidine nucleosides. It was discovered that 5-aryl pyrimidine nucleosides could be synthesized by Pd-catalyzed direct arylation of N3-free 5-halo uracil and uracil nucleosides with simple arenes or heteroaromatics in the presence of TBAF within 1 h. Both N3-protected and N3-free uracil and uracil nucleosides could undergo base-promoted Pd-catalyzed direct arylation, but only with electron rich heteroaromatics.
In the second half of this dissertation, 5-acetylenic uracil and uracil nucleosides have been employed to investigate the hydrogermylation, hydrosulfonylation as well as hydroazidation for the synthesis of various functionalized 5-vinyl pyrimidine nucleosides. Hydrogermylation of 5-alkynyl uracil analogues with trialkylgermane or tris(trimethylsilyl)germane hydride gave the corresponding vinyl trialkylgermane, or tris(trimethylsilyl)germane uracil derivatives. During the hydrogermylation with triphenylgermane, besides the vinyl triphenylgermane uracil derivatives, 5-[2-(triphenylgermyl)acetyl]uracil was also isolated and characterized and the origin of the acetyl oxygen was clarified. Tris(trimethylsilyl)germane uracil derivatives were coupled to aryl halides but with decent yield. Iron-mediated regio- and stereoselective hydrosulfonylation of the 5-ethynyl pyrimidine analogues with sulfonyl chloride or sulfonyl hydrazine to give 5-(1-halo-2-tosyl)vinyluracil nucleoside derivatives has been developed. Nucleophilic substitution of the 5-(β-halovinyl)sulfonyl nucleosides with various nucleophiles have been performed to give highly functionalized 5-vinyl pyrimidine nucleosides via the addition-elimination mechanism. The 5-(β-keto)sulfonyluracil derivative has also been synthesized via the aerobic difunctionalization of 5-ethynyluracil analogue with sulfinic acid in the presence of catalytic amount of pyridine. Silver catalyzed hydroazidation of protected 2'-deoxy-5-ethynyluridine with TMSN3 in the presence of catalytic amount of water to give 5-(α-azidovinyl)uracil nucleoside derivatives was developed. Strain promoted Click reaction of the 5-(α-azidovinyl)uracil with cyclooctyne provide the corresponding fully conjugated triazole product.
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Guthrie, Kelly. "Vitamin C and Glycoalkaloids in Organically Grown Potatoes of Novel Varieties." Fogler Library, University of Maine, 2006. http://www.library.umaine.edu/theses/pdf/GuthrieKX2006.pdf.
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Marshall, Andrew. "The characterisation of a novel C-type lectin-like receptor MICL." Thesis, University of Oxford, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.409114.
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Gordon, Euan H. J. "The physiological role of a novel flavocytochrome c from Shewanella putrefaciens." Thesis, University of Edinburgh, 1996. http://hdl.handle.net/1842/14921.
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Flavocytochrome c (Fcc) is a novel, soluble periplasmic fumarate reductase from the Gram-negative bacterium Shewanella putrefaciens. A null mutant (Δfcc) which lacked the gene coding for the Fcc was constructed. The resultant strain was devoid of fumarate reductase activity and could not grow on fumarate as the sole terminal electron acceptor. Complementation of this mutation with recombinant Fcc restored the ability to grow anaerobically with fumarate. No other phenotype could be found for the Δfcc strain. This work demonstrates that flavocytochrome c is essential for fumarate respiration and furthermore is the sole terminal reductase for fumarate respiration. The fcc null mutant also allowed the expression of recombinant forms of fcc coding for the individual domains of the protein. The in vivo interaction between the haem and flavin domains of Fcc was investigated by expressing recombinant forms of the genes coding for these domains in the same cell. This indicated that the tether between the two domains, while not absolutely essential, was important for wild-type enzyme function. Studies using lacZ reporter genes fused to the fcc promoter demonstrated that the fcc gene is regulated primarily at the level of transcription and is regulated hierarchically in response to the redox potential of terminal electron acceptors. Regions of the fcc promoter sequence important to regulation of the fcc gene were identified by deletion analysis. The succinate dehydrogenase operon from S. putrefaciens was sequenced. The inferred amino acid sequences of the flavoprotein, and iron/sulphur subunits showed high sequence identity (77%) with the corresponding subunits from Escherichia coli succinate dehydrogenase.
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Huysamen, Cristal. "The characterization of a novel C-type lectin-like receptor, CLEC9A." Doctoral thesis, University of Cape Town, 2008. http://hdl.handle.net/11427/3060.
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Montgomery, Michelle. "Novel strategies for the site-selective C-H functionalisation of arenes." Thesis, University of Bristol, 2015. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.690758.
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Substituted arenes are ubiquitous frameworks within the pharmaceutical, agrochemical and materials science industry. These valuable motifs have traditionally been prepared by electrophilic or radical substitution reactions, e.g. Friedel-Crafts acylation, however, their synthesis has been revolutionised through the development of transition metal catalysed C-H functionalisatipn reactions. The palladium-catalysed direct arylation of estrone has been achieved using a carbamate directing group to create a modest library of 2-aryl-3-diethylcarbamate estrones. Cleavage of the carbamate directing group with lithium aluminium hydride affords the corresponding 2- arylestradiol.
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Copeland, Jeffrey Michael Deshaies Raymond Joseph. "Identification of novel cell death regulators in C. elegans and Drosophila /." Diss., Pasadena, Calif. : California Institute of Technology, 2005. http://resolver.caltech.edu/CaltechETD:etd-06012005-114127.
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Kelly, Patrick A. "C₁ symmetric ansa-metallocenes via a novel 2-(Phenylsulfonyl)indane route /." For electronic version search Digital dissertations database. Restricted to UC campuses. Access is free to UC campus dissertations, 2002. http://uclibs.org/PID/11984.
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Röckl, Johannes Ludwig [Verfasser]. "Novel Concepts in Direct Electrochemical C-H Functionalization / Johannes Ludwig Röckl." Mainz : Universitätsbibliothek der Johannes Gutenberg-Universität Mainz, 2020. http://d-nb.info/1224896343/34.
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Barajas, Solano José Ignacio. "Novel active magnetic bearings for direct drive C-Gen linear generator." Thesis, University of Edinburgh, 2017. http://hdl.handle.net/1842/28900.
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This document presents a novel active magnetic levitation system. In the pursued of this endeavour different topics related with wave energy were explore. Climate change and energy security are the main motivation to pursued new options for non-fossil fuels energy generation. An overview of renewable energy and specifically of wave energy was presented. The potential for wave energy in The United Kingdom turn out to be 75 TWh/year from wave energy, 3 times more of what wind energy has produced in 2013. This means a massive impact on the energy market and emission reduction. In order to achieve this, improvements on wave energy devices have to be done. An overview of wave energy converters was covered selecting the C-Gen as the generator topology this document will base its studies. Linear generator bearings are desired to have long lifespan with long maintenance intervals. The objective is to come with an active magnetic levitation design that can replace traditional bearings augmenting the reliability of the system. Therefore magnetic bearings option have been reviewed and simulation experimentations has resulted in a novel active magnetic levitation system using an air-cored coils Halbach array acting over a levitation track. The configuration would generate bi directional repulsion forces with respect of the levitating body. Different software were used to analyse the magnetic field and forces generation. Additionally a prototype was built and tested to corroborate the results. As part of the modelling a mathematical model was explored and robust control implementation was also realised. Finally a scalability study of the device as well as a reliability analysis was done. Although the reliability studies shows an increase of ten times of the mean time to failure, the concept is not able to endure the loads acting on the generator unless the magnetic bearings became bigger than the generator and therefore economically unfeasible.
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Marfil, Vives Vanessa. "Characterization of novel Hhex partners: SOX13 and c-Myc. New mechanism for the regulation of Wnt/TCF and c-Myc pathways." Doctoral thesis, Universitat Pompeu Fabra, 2010. http://hdl.handle.net/10803/22701.
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Hhex transcription factor is expressed in multiple endoderm-derived tissues, like the liver, where it is essential for proper development. The pleiotropic effect of Hhex in the embryo and its dual role as a transcriptional repressor/activator suggest the presence of different interaction partners capable of modulating its activity and function. In the current study we identified two new Hhex protein interactors: SOX13 and c-Myc.
We show that Hhex interacts directly with SOX13. By doing so, Hhex sequesters SOX13 from the SOX13•TCF1 complex, overturning SOX13-dependent repression of the Wnt pathway. On the other hand, Hhex induces proliferation of non-tumorigenic human fibroblast through a Myc-dependent mechanism. Hhex and c-Myc interact directly upregulating Cyclin D1, a c-Myc target gene involved in cell cycle progression and proliferation. Elevation of Cyclin D1 might be the final effector of Hhex capacity to regulate cell proliferation.
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Tian, Qizhi Verfasser], Sorin A. [Akademischer Betreuer] [Huss, and Ray C. C. [Akademischer Betreuer] Cheung. "Novel Power Trace Processing Methods for Side-Channel Analysis of Cryptosystems / Qizhi Tian. Betreuer: Sorin A. Huss ; Ray C. C. Cheung." Darmstadt : Universitäts- und Landesbibliothek Darmstadt, 2013. http://d-nb.info/1107770734/34.
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Kerry, Mark Anthony. "The design and synthesis of novel topoisomerase I poisons." Thesis, University of Sunderland, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.245780.
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Arbesú, Andrés Miguel. "A novel regulatory unit in the N-terminal region of c-Src." Doctoral thesis, Universitat de Barcelona, 2018. http://hdl.handle.net/10803/543572.
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c-Src is a central player in several cellular signaling pathways. It controls impor- tant cellular processes like cellular proliferation, survival or motility. Therefore, a number of tumoral diseases have been related to abnormal c-Src activity. Among them, colorectal cancer stands out, as c-Src deregulation correlates with tumor progression and clinical outcome.
This tyrosine kinase is part of a larger group of functionally and structurally related proteins termed Src Family Kinases. These proteins share the same domain architecture: a cassette formed by a catalytic domain (SH1), two reg- ulatory domains, SH2 and SH3, and a variable intrinsically disordered region (the Unique domain) that ultimately anchors to the inner face of the cellular membrane via the N-terminal SH4 domain, also disordered. The sequence and structure of the cassette are highly conserved, and thus unsurprisingly Src Family Kinases perform closely related and often overlapping functions. However, the role of intrinsically disordered regions has remained unclear, although they are known to be functionally relevant.
In this work, the structural and functional relationship between the intrinsically disordered SH4 and Unique domains with the neighboring folded SH3 domain in c-Src is explored. Interactions between disordered and ordered proteins are often characterized by the formation of complexes that are specific and functional but structurally heterogeneous. Moreover, conformational plasticity is a fundamental feature for function. These assemblies are known as fuzzy complexes. Here this theoretical framework, usually applied to isolated partners, is extended to the intramolecular interface between covalently bound domains instead of isolated pairs. The concept of fuzzy binding is also used in order to describe interactions based on sets of dynamic, transient, and promiscuous contacts between ill-defined sets of interactors.
In order to characterize the system, an integrative strategy using short and long range Nuclear Magnetic Resonance techniques and Small Angle X-ray Scattering is applied to several constructs containing different combinations of bound or isolated domains. It is demonstrated that the folded SH3 domain acts as a scaffold for the disordered region, which interacts in a specific manner with its partner. Both disordered domains, SH4 and Unique, are involved in the process albeit they contribute differently. Additionally, it is shown that the Unique domain is not a random coil, but contains a significant degree of pre-arrangement that is independent of the scaffold.
Sequence determinants are then searched by comparison of the sequences of different Src Family Kinases. Four conserved phenylalanine residues are found and their implication in Unique domain pre-organization and Unique:SH3 domain interaction tested. All these amino acids are found to favor compaction of the intrinsically disordered region, and at the same time to perturb close contact with the scaffold. In addition, mutations in the interacting zones of the SH3 domain are also studied to test reciprocity. In all, the fuzzy complex model is proven for the SH4:Unique:SH3 system.
Then, the results are extrapolated to the full-length c-Src to test its biological relevance. A co evolutionary analysis suggests that the fuzzy model may be a general feature for the whole Src Family, so the closest member of the family, Yes, is also tested experimentally. The initial results on long-range contacts suggests a similar arrangement between the scaffold and the disordered region.
In all, it is suggested that plastic, fuzzy interfaces between ordered and disordered domains may be a relevant mode for the transmission of functional information within multidomain proteins.
Finally, a first approach for a structural study of the c-Src fuzzy complex in a native-like lipid environment, including natural co-translational modifications, is presented. A protocol for sample preparation is developed and Dynamic Nuclear Polarization solid state NMR is shown to be an adequate tool for further analysis.c-Src es una tirosina quinasa clave en múltiples rutas de señalización celulares. Su desregulación ha sido asociada a diversos procesos tumorales, entre los que destaca el cáncer de cólon. Una actividad anómala de c-Src se correlaciona con el desarrollo tumoral y pronóstico clínico desfavorable. c-Src forma parte de un grupo de proteínas relacionadas estructural y funcional- mente, la Familia de Quinasas Src. Todas ellas comparten la misma arquitectura modular, que incluye un dominio catalítico (SH1), dos dominios regulatorios, SH2 y SH3, y a continuación una región variable intrínsecamente desordenada que incluye los dominios Único y SH4. Mientras que el segmento ordenado está bien caracterizado, el papel de la región desordenada no está claro, aunque es funcionalmente relevante. En este trabajo se explora la relación estructural y funcional entre la región desordenada y el dominio ordenado adyacente SH3. Dado que este tipo de interacciones implican un grado significativo de heterogeneidad estructural, se ha aplicado el concepto de unión difusa para caracterizar este sistema. Este marco teórico permite modelar interacciones basadas en contactos dinámicos y transitorios entre múltiples interactores vagamente definidos, que sin embargo son específicos y funcionales. Para ello, se ha usado una estrategia que implica el uso combinado de técnicas de Resonancia Magnética Nuclear de largo y corto alcance, así como Dispersión de rayos X a Bajo Ángulo. Se demuestra así que el dominio plegado SH3 actúa como armazón para la región desordenada, que a su vez contiene un grado significativo de pre-organización estructural. Se han identificado cuatro fenilalaninas en el dominio Único responsables de esta pre-formación que también afectan a la interacción entre la región desordenada y el armazón. Los resultados demuestran que el conjunto de dominios SH4, Único y SH3 forman una unidad funcional que puede ser definida como un complejo difuso. Además, datos teóricos y experimentales de otros miembros de la familia sugieren que el modelo difuso es una característica común de todos ellos. Finalmente, se ha demostrado que la Resonancia Magnética de estado sólido con Polarización Dinámica Nuclear es una técnica adecuada para el estudio estructural de c-Src unida a una matriz lipídica similar a la natural.
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García, de la Concepción María Belén. "Novel Halogen(I) Reagents in the C-sp3- and Csp3-Bond Functionalization." Doctoral thesis, Universitat Rovira i Virgili, 2018. http://hdl.handle.net/10803/663299.
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En el treball presentat en aquesta tesi es mostren els desenvolupaments importants realitzats sobre l’ús de reactius d'halogen(I), específicament en la funcionalització d’enllaços C(sp2)-H i C(sp3)-H mitjançant reactius de iode(I) i brom(I).
El present manuscrit està dividit en tres apartats principals:
1-Reactius de iode(I) per la difuncionalització d’alquens.
2- Aminació oxidativa d'enllaços C-(sp3)-H de tetrahidrocarbazoles.
3-Aplicació de reactius de iode(I) o catàlisi de brom en la síntesi formal de (±)-aspidospermidina.
En la primera secció sobre la difuncionalització d'alquens, hem presentat la síntesi general, aïllament i caracterització de nous reactius de iode(I) amb fórmula R4N[I(O2CAr)2]. Aquests compostos posseeixen alta estabilitat davant l’exposició a l'aire i la humitat. El nostre interès radica en l'exploració de reaccions promogudes per iode electrofílic cap a una iodooxigenació de derivats d’estirè.
En la segona secció, s'ha dut a terme una exploració sobre l'ús del reactiu de Varvoglis PhI(NPhth)2. Aquest es va utilitzar per a la síntesi de reactius de iode(I) i brom(I) amb lligands de ftalimida. Com l’aminació de tetrahidrocarbazoles en la posició 4 no s’ha explorat fins al moment, desenvolupem una metodologia innovadora per dur a terme l’aminación oxidativa en C(sp3)-H de derivats de tetrahidrocarbazol, utilitzant reactiu de iode(I) o catàlisi de brom.
Finalment, en el tercer capítol volíem demostrar la versatilitat i el rendiment dels reactius d'halògens descrits en el capítol anterior per a la síntesi de (±)-aspidospermidina.El trabajo presentado en esta tesis representa algunos desarrollos importantes en reactivos de halógeno(I), concretamente hacia la funcionalización de los enlaces C(sp2)-H y C(sp3)-H a través de reactivos de yodo(I) y bromo(I). El presente manuscrito está dividido en tres partes principales: 1- Reactivos de yodo(I) para la difuncionalización del alquenos. 2- Aminación oxidativa de enlaces C-(sp3)-H de tetrahidrocarbazoles 3- Aplicación de reactivos de yodo(I) o catálisis de bromo hacía la síntesis formal de (±)-aspidospermidina. En la primera sección sobre la difuncionalización de alquenos, hemos presentado una síntesis general, aislamiento y caracterización de varios reactivos de yodo(I) con la fórmula R4N[I(O2CAr)2]. Estos compuestos poseen alta estabilidad ante el aire y la humedad. Nuestro interés radica en la exploración de reacciones promovidas por yodo electrófilo hacia la yodooxigenación con derivados de estireno. En la segunda sección, se ha llevado a cabo una exploración del uso del reactivo de Varvoglis PhI(NPhth)2. Este reactivo se usó para la síntesis de reactivos de yodo(I) y bromo(I) con ligandos de ftalimida. Como la aminación de tetrahidrocarbazolas en la posición 4 no se ha sido explorada hasta el momento, se. llevó a cabo el desarrollo de una metodología innovadora para dar lugar a una aminación oxidativa en C(sp3) con derivados de tetrahidrocarbazol, usando reactivo de yodo(I) o catálisis de bromo. Finalmente, en el tercer capítulo queríamos demostrar la versatilidad y el rendimiento de los reactivos de halógenos descritos en el capítulo anterior para dar lugar a la síntesis de un compuesto natural, tal como (±)-aspidospermidina.
The work presented in this thesis represents some major developments in halogen(I) reagents, specifically towards the functionalization of C(sp2)-H and C(sp3)-H bonds through iodine(I)- and bromine(I)-reagents. The present manuscript is divided into three principal parts: 1- Iodine(I) reagents for vicinal alkene difunctionalization 2- Oxidative amination of C-(sp3)-H bonds of tetrahydrocarbazoles 3- Application of iodine(I) reagent or bromine catalysis to the formal synthesis of (±)-aspidospermidine. In the first section on alkene difunctionalization, we have presented a general synthesis, isolation and characterization of several novel iodine(I) reagents with the formula R4N[I(O2CAr)2]. These compounds exhibit high air and moisture stability. We were interested in the exploration of reactions promoted by electro-philic iodine towards a vicinal iodooxy-genation of styrene derivatives. In the second section an exploration of the use of Varvoglis reagent PhI(NPhth)2 has been carried out. This reagent was used to the synthesis of iodine(I) and bromine(I) reagents with phthalimide ligands to stabilize the electrophilic halogen center. As oxidative amination of tetrahydrocarbazoles in position 4 has not been explored so far, we developed an innovative methodology to carryout the C(sp3) oxidative amination of tetrahydrocarbazole derivatives using iodi-ne(I) reagent or bromine catalysis. Finally, in the third chapter we wanted to demonstrate the versatility and performance of halogen reagents described in the previous chapter, which were used in the synthesis of (±)-aspidospermidine.
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Weraarpachai, Woranontee. "Identification and characterization of novel genes involved in cytochrome c oxidase deficiencies." Thesis, McGill University, 2012. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=107626.
Full textAbstract:
In mitochondria, ATP is generated by oxidative phosphorylation (OXPHOS), a process that requires five multimeric enzyme complexes. Electrons are passed along the first four enzyme complexes (complex I-IV) that make up the mitochondria respiratory chain, releasing energy that is stored in the form of a proton gradient across the mitochondrial inner membrane, and is subsequently used by the ATP synthase (complex V) to produce ATP. Complex IV or cytochrome c oxidase (COX) is the terminal enzyme in the mitochondrial respiratory chain, catalyzing the oxidation of cytochrome c by molecular oxygen. It contains 13 structural subunits in mammals, 3 of which are encoded by mitochondrial DNA. Cytochrome c oxidase deficiencies can be caused by mutations in either mitochondrial or nuclear DNA. COX deficiency can result from mutations in the structural subunits or factors necessary for the assembly of the enzyme complex. In this thesis, two novel genes mutated in two subjects with COX deficiency have been identified. First, we identified a specific defect in the synthesis of the mtDNA-encoded COX subunit 1 (COX I) in a pedigree segregating late-onset Leigh Syndrome and COX deficiency. We mapped the defect to chromosome 17q by microcell-mediated chromosome transfer and identified a homozygous single base pair insertion causing a premature stop in CCDC44, renamed TACO1 for translational activator of COX I. TACO1 is a member of a large family of hypothetical proteins containing a conserved DUF28 domain that localizes to the mitochondrial matrix. Expression of the wild-type cDNA restored TACO1 protein and rescued the translation defect. TACO1 is the first specific mitochondrial translational activator identified in mammals. Respiratory competence, mitochondrial translation and COX activity were normal in yeast strain deleted for the orthologue YGR021w, suggesting that TACO1 has evolved a novel function in mammalian mitochondrial translation. Secondly, we studied a family in which the subject presented with severe congenital lactic acidosis and dysmorphic features associated with a COX assembly defect and a specific decrease in the synthesis of COX I. Using a combination of microcell mediated chromosome transfer, homozygosity mapping, and transcript profiling we mapped the gene defect to chromosome 12, and identified a homozygous missense mutation causing an amino acid change from methionine to isoleucine in C12orf62, a gene apparently restricted to the vertebrate lineage. Expression of the wild-type cDNA restored C12orf62 protein levels, and rescued the COX I synthesis and COX assembly defect. C12orf62 is a very small (6 kDa), uncharacterized, single transmembrane protein that localizes to mitochondria. COX I, II and IV subunits co-immunoprecipitated with an epitope-tagged version of C12orf62, and 2D BN-PAGE analysis of newly synthesized mitochondrial COX subunits in subject fibroblasts showed that COX assembly was impaired, and the nascent enzyme complex unstable. We conclude that C12orf62 is required for coordinating the early steps of COX assembly with the synthesis of COX I.Dans les mitochondries, l'ATP est généré par la phosphorylation oxydative (PHOSOX), un processus qui nécessite cinq complexes enzymatiques multimériques. Le transport des électrons le long des quatre premiers complexes enzymatiques (complexes I-IV) libère l'énergie qui est stockée sous la forme d'un gradient de protons à travers la membrane interne mitochondriale et est ensuite utilisée par l'ATP synthétase (complexe V) pour produire de l'ATP. Le complexe IV ou cytochrome C oxydase (COX) est l'enzyme terminale de la chaîne respiratoire mitochondriale, catalysant l'oxydation du cytochrome c par l'oxygène moléculaire. Il contient 13 sous-unités structurelles chez les mammifères, dont 3 sont codées par l'ADN mitochondriale. Les déficiences en cytochrome C oxydase peuvent être causées par des mutations dans l'ADN mitochondriale ou l'ADN nucléaire. Les carences en COX peuvent être liées à des mutations dans les sous-unités structurelles ou à des mutations dans des facteurs nécessaires à l'assemblage du complexe enzymatique. Dans cette thèse, deux nouveaux gènes mutés ont été identifiés et caractérisés dans deux patients présentant un déficit en COX. Premièrement, nous avons identifié un défaut spécifique dans la synthèse de la sous-unité COX 1 de l'ADN mitochondriale (COX I) dans un pedigree présentant une apparition tardive du syndrome de Leigh et une carence en COX. Nous avons cartographié le défaut génétique au chromosome 17q par la technique de transfert de chromosomes à médiation microcellulaire. Nous avons, par la suite, identifié une mutation homozygote, une insertion d'une base causant l'apparition prématurée d'un codon stop qui entraîne l'arrêt de la synthèse de la protéine CCDC44, renommé TACO1 pour activateur de la traduction de la COX I. TACO1 est membre d'une famille de protéines contenant un domaine conservé à fonction inconnue, nommé DUF28, qui se localise à la matrice mitochondriale. L'expression de l'ADN complémentaire de type sauvage de TACO1 compense le défaut de traduction de COX I. TACO1 est le premier activateur spécifique de la traduction mitochondriale à être identifié chez les mammifères. Il a été observé que l'absence (knock-down) du gène codant l'orthologue de TACO1 chez la levure, le YGR021w, ne perturbait pas la compétence des voies respiratoires, la traduction mitochondriale, ni l'activité de COX. Ceci suggère que TACO1 a évolué et a acquérit une nouvelle fonction dans la traduction mitochondriale chez les mammifères. Deuxièmement, nous avons étudié une famille dans laquelle le sujet présentait une acidose lactique congénitale et dysmorphie associée à un défaut d'assemblage et une diminution de l'activité enzymatique de la COX due à un défaut spécifique dans la traduction de COX I. En utilisant une combinaison de techniques dont le transfert de chromosomes à médiation microcellulaire, la cartographie d'homozygotie et le profilage de transcription, nous avons cartographié le gène défectueux sur le chromosome 12. Nous avons identifié une mutation faux sens à l'état homozygote provoquant un changement d'acide aminé de méthionine en isoleucine dans le gène C12orf62, un gène qui semble restreint à la lignée des vertébrés. L'expression de l'ADN complémentaire de type sauvage de C12orf62 a restauré la synthèse de COX I et le défaut d'assemblage de la COX. C12orf62 est une très petite protéine transmembranaire (6 kDa), non caractérisée, qui se localise aux mitochondries. Les sous-unités COX I, II et IV co-immunoprécipitent avec un épitope marqué de la protéine C12orf62. Les analyses de bleu d'électrophorèse sur gel de polyacrylamide natif (BN-PAGE) en deux dimensions pour les sous-unités nouvellement synthétisées de la COX mitochondriale ont démontré que la COX assemblée est altérée et que le complexe enzymatique naissant est instable dans les fibroblastes du patient atteint. Nous concluons que C12orf62 est nécessaire pour coordonner les étapes précoces de l'assemblage de la COX et de la synthèse de COX I.
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Quan, Ton-Yee. "Cloning and characterization of a novel «gpa-16» mutant in «C. elegans»." Thesis, McGill University, 2010. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=86846.
Full textAbstract:
Meiosis is a specialized cell division, producing unique daughter cells containing half the chromosome number of the parental cell. In the hermaphroditic nematode C. elegans, meiotic mutants can be recognized by embryonic lethality (Emb) and high incidence of males (Him) phenotypes due to chromosome missegregation. In search of new meiotic mutants, we isolated vv33 in an EMS-based "Green eggs and Him" screen (Kelly et al. 2000; Tom Nolis, unpublished data). DAPI stainings of vv33 mutant gonads reveal unusually large nuclei and micronuclei throughout the germline. Characterization suggests that defects in cell division and chromosome segregation in mitotic germ cells are transmitted through the meiotic cell cycle, resulting in 80% Emb and 7% Him. Cloning of vv33 identified it as a novel allele of gpa-16, a Gα protein with known functions in mitosis in the early embryo (Gonczy 2002). Based on our observations, we hypothesize that there is a germline-specific requirement for GPA-16.La méiose est une division cellulaire spécialisée qui produit des cellules filles haploides à partir de cellules parentales diploides. Chez le nématode hermaphrodite C. elegans, des anomalies de ségrégation des chromosomes lors de la méiose donnent lieu à des phénotypes de létalité embryonnaire (Emb) et d'augmentation du nombre de males (Him). Lors d'un crible génétique basé sur la recherche de nouveaux mutants him (Tom Nolis, non publié), nous avons isolé l'allèle vv33. Une analyse cytologique par coloration DAPI des gonades du mutant vv33 à révélé la présence de noyaux de tailles irrégulières. De plus, des études ont mis en évidence des défauts de ségrégation des chromosomes dans les cellules mitotiques de la lignée germinale. Les anomalies chromosomiques sont ensuite héritées par les cellules méiotiques et génèrent 80% de létalité embryonnaire. Le clonage de vv33 à permit d'identifier une mutation dans le gene gpa-16, qui code une sous-unité alpha d'une protéine G précédemment décrite pour son rôle dans la mitose embryonnaire (Gonczy 2002). Nos résultats nous permettent donc d'envisager une nouvelle fonction spécifique pour GPA-16 dans la lignée germinale.
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Sankey, Rosalind Fay. "Beyond C-H activation : the preparation of novel heterocycles using catalytic dearomatisation." Thesis, University of Bristol, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.559388.
Full textAbstract:
The continuous drive for efficient bond forming reactions has led to the emergence of C-H activation methodologies. More specifically, direct arylation reactions are commonly employed in the synthesis of a range of heteroaromatic products. The latter make up a considerable proportion of medicinally important compounds and therefore their rapid and efficient synthesis is paramount. The preparation of carbazoles has been extensively developed within the Bedford group. The expansion of this palladium-catalysed intramolecular direct arylation methodology has been explored with the aim of producing interesting heterocycles, namely acridans and acridines. Interestingly, instead of the expected C-H activation reaction, an unprecedented catalytic dearomatisation reaction took place. This was developed into a more general methodology to produce a range of novel heterocycles, including 4a-alkyl-4aH- carbazoles and dihydroindolo[2,3-b]indoles. Due to their instability these heterocycles undergo a range of interesting transformations, including dimerisation, dealkylation and hydro lysis reactions. Furthermore, it was proposed that typical direct arylation reactions could be occurring via a catalytic dearomatisation mechanism rather than one of the more generally accepted C-H activation mechanisms. A detailed kinetic study has been carried out. Although evidence to support a dearomatisation mechanism could not be obtained, the turnover-limiting step for two substrates could be proposed and a number of interesting observations made.
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Woodward, Hannah Louise. "Novel approaches to the synthesis of C-glycosides and mucin type oligosaccharides." Thesis, University of Bristol, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.508095.
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Efthymiou, Maria A. "Activated protein C and severe sepsis : Generation and characterisation of novel variants." Thesis, Imperial College London, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.534976.
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