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Walsh, Anthony. "Novel methods to access bioactive molecules." Thesis, University of Huddersfield, 2015. http://eprints.hud.ac.uk/id/eprint/26947/.
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This thesis is divided into two chapters detailing research on applying microwave methodology to access aminated nucleosides in significantly reduced time frames, and applying the Belluš-Claisen reaction to produce non-proteogenic dipeptides. 1. Amination of Nucleosides Using Microwave Methodology 2,2’-Anhydrouridine undergoes a ring opening reaction with aliphatic amines to give the corresponding aminated product. Under conventional heating reaction times are extremely lengthy, taking at least 3 to 4 days and up to a month in the case of very hindered amines. A modified procedure using microwave irradiation has proven to drastically reduce reaction time and has allowed access to novel nucleosides on gram scale. 2. Functionalised Amino Acids via the Belluš-Claisen Rearrangement The Belluš-Claisen reaction is a [3,3] sigmatropic rearrangement of allylic amines, ethers and thioethers to give the corresponding amide, ester of thioester. A modified procedure of the Belluš-Claisen rearrangement was used to prepare functionalised dipeptides by reaction of a ketene prepared from N-phthaloylglycyl chloride in situ with allylic amino acid derivatives in the presence of a Lewis Acid and diisopropylethylamine. Rearrangments were successfully carried out using N,N-diallyl alanine and N-allyl proline. A range of N-allyl proline derivatives are demonstrated. However, attempts to repeat the reaction with structurally more complex amino acids did not result in successful reactions.
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Odenthal, Katherine Jane Chemistry Faculty of Science UNSW. "Novel redox molecules for surface electrochemistry." Publisher:University of New South Wales. Chemistry, 2009. http://handle.unsw.edu.au/1959.4/43661.
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The research presented herein reports the development of two novel redox molecules for biosensing applications. Frequently electrochemical biosensors necessitate the use of strictly controlled conditions including the pH of the surrounding solution. Electrochemical biosensors that only operate under such conditions are not viable as portable sensors for in-field analysis. Consequently, a method for measuring the pH in conjunction with electrochemical biosensors would provide an opening for such sensors in in-field analysis. A novel redox molecule, JUGSH, has been prepared for this purpose. In a separate investigation, a ruthenium complex has been prepared which allows tuning of its formal potential by altering the structure of one ligand. This novel redox molecule is destined for use in multi-analyte arrays. By altering the formal potential of the redox molecule, a series of redox reporters can be prepared to allow differentiation between analytes. The novel redox molecule JUGSH consists of a hydroxy-naphthoquinone with an alkanethiol chain that allows formation of a self-assembled monolayer (SAM) of JUGSH on gold electrodes. X-ray spectroscopy analysis was employed for characterisation. The electrochemical properties of a JUGSH SAM were investigated along with the pH dependence of the formal potential. After further research into the pH dependence of the electron transfer rate coefficient, JUGSH was applied to the analysis of pH together with an electrochemical biosensor. Two peptide sensors for metal detection developed previously were employed to test the concept of measuring pH with JUGSH. The peptides employed were angiotensin I and Gly-Gly-His immobilised on a thioctic acid SAM and 3-mercaptopropionic acid SAM for lead and copper detection respectively. JUGSH was demonstrated to have the ability to measure the pH of the analyte solution allowing compensation of the sensor??s electrochemical response. The angiotensin I sensor was shown to have a viable working range from pH 3 to pH 7. A ruthenium complex containing two bipyridine ligands and a diketone ligand has been prepared that shows a shift in the formal potential upon alteration of the diketone ligand. Modification of the complex to include methylamine groups was attempted but non-ideal electrochemistry was indicated and no shift in the formal potential was observed after modifying the diketone ligand. Further work is required before attachment of the complex to a surface can be investigated.
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Strelko, Cheryl. "Novel Small Molecules and Tumor Cells." Thesis, Boston College, 2012. http://hdl.handle.net/2345/3778.
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Thesis advisor: Mary F. RobertsThesis advisor: Eranthie Weerapana
Small molecules are of interest both as metabolites in tumor cell biology and as potential therapeutics in the fight against cancer. In this work, small molecules in both roles have been examined. Modulation of tumor cell metabolism holds promise as a strategy to combat cancer, and both glucose and glutamine have been identified as critical fuels for tumor cell growth and proliferation. However, the reason for glutamine addiction is poorly understood. The differential metabolism of glutamine and glucose was therefore examined using ¹³C labeling and NMR-based metabolomics in the VM-M3 tumor cell line, which requires both glucose and glutamine for survival and proliferation. In the course of this study, a novel mammalian metabolite itaconic acid was identified. Itaconic acid was detected in extracts and tissue culture media from the murine macrophage-derived tumor cell lines VM-M3 and RAW 264.7 as well as in primary macrophages. Production and secretion of itaconic acid was increased upon stimulation. LC-MS and NMR based metabolomics studies show that this metabolite is synthesized by the decarboxylation of cis-aconitate from the TCA cycle, and provided evidence for a novel mammalian homologue of the enzyme cis-aconitic decarboxylase. D-3-deoxy diC₈PI is a small molecule of interest as a potential cancer therapeutic. This compound was designed to induce apoptosis in tumor cells by competitively binding to the Akt PH domain and preventing Akt translocation. However, high resolution ³¹P field-cycling studies show that both D-3-deoxy diC₈PI and an inactive analogue L-3,5-dideoxy diC₈PI bind to the same site on the PH domain, which is distinct from the binding site of the ligand diC₈PI(3,4,5)P₃. This makes the aforementioned mechanism of cytotoxicity unlikely. Aggregation of the PH domain in the presence of soluble headgroup IP₆ was also observed, which may be related to a physiological function of this protein and invalidates at least one other binding assay. Investigation into alterations in signaling pathways in the MCF-7 breast cancer cell line showed that D-3-deoxy diC₈PI activates the p38MAPK pathway which results in CREB hyperphosphorylation. However, activation of this pathway appears to be compensatory and unrelated to the mechanism of action. D-3-deoxy diC₈PI also decreases levels of cyclin D1 and cyclin D3, which regulate the progression of the cell cycle. These decreases appear to be occurring at the transcriptional level rather than due to increased proteasomal degradation. The loss of these two proteins does not cause apoptosis in MCF-7 cells, but siRNA knockdown of specifically cyclin D1 inhibits proliferation. This is consistent with the cell cycle arrest observed upon D-3-deoxy diC₈PI treatment in these cells. These findings do not conclusively elucidate the mechanism of cytotoxicity of D-3-deoxy diC₈PI, but provide a characterization of some of its effects in the MCF-7 cell line which may be useful for further studies
Thesis (PhD) — Boston College, 2012
Submitted to: Boston College. Graduate School of Arts and Sciences
Discipline: Chemistry
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Adamson, R. D. "Novel methods for large molecules in quantum chemistry." Thesis, University of Cambridge, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.595361.
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With the rapid increase in computing power Quantum Chemists are looking towards larger and larger molecules. This thesis presents new ways to reduce the expensive scaling of computational cost with system size, thus allowing the advances in computer science to be utilized. The first chapter is an introduction to Hartree-Fock theory and the traditional methods of calculating electron correlation. This is followed by an introduction to Density Functional Theory, concentrating on Kohn-Sham density functional theory. Chapter 3 presents a new way of assessing the accuracy of a density functional by partitioning the density and examining the energy of the component pieces. Chapter 4 describes a new density functional (EDF1), designed especially for small basis sets, thus making it ideal for large systems. The functional is formed from several other common functionals, grouped together in a way to minimize the error of the chemical energetics of a selection of molecules. Chapter 5 gives an introduction to modern two-electron integral theory and then describes a new method for efficiently calculating integrals arising from charges that are well separated. The new algorithm does not scale with the concentration of the basis set. The efficient algorithm of Chapter 5 is O(N2) overall, and therefore still too slow. To truly examine large molecules O(N) methods are required. Chapter 6 provides an introduction to these linear methods and also presents a new method, the CASE approximation, which neglects long-range interactions. How to implement this new method (in O(N) work) is described in Chapter 7. The method is extended to density functional theory in Chapter 8 by attenuating the Dirac functional. Chapter 9 presents a second way to reduce the magnitude (and speed) of the approximation, and also a correction for the main failure of the original approximation. Chapter 10 examines the accuracy of the approximation on a variety of chemical properties. The final chapter describes a way to improve the accuracy of CASE by correcting for the neglected terms in only O(N) work. This correction however is not without its own problems and work continues in this area.
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Smith, Euan Christopher. "Ultrafast third-order nonlinearities in novel zwitterionic molecules." Thesis, Heriot-Watt University, 1998. http://hdl.handle.net/10399/599.
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Drayna, Garrett Korda. "Novel Applications of Buffer-Gas Cooling to Cold Atoms, Diatomic Molecules, and Large Molecules." Thesis, Harvard University, 2016. http://nrs.harvard.edu/urn-3:HUL.InstRepos:26718757.
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Cold gases of atoms and molecules provide a system for the exploration of a diverse set of physical phenomena. For example, cold gasses of magnetically and electrically polar atoms and molecules are ideal systems for quantum simulation and quantum computation experiments, and cold gasses of large polar molecules allow for novel spectroscopic techniques. Buffer-gas cooling is a robust and widely applicable method for cooling atoms and molecules to temperatures of approximately 1 Kelvin. In this thesis, I present novel applications of buffer-gas cooling to obtaining gases of trapped, ultracold atoms and diatomic molecules, as well as the study of the cooling of large organic molecules. In the first experiment of this thesis, a buffer-gas beam source of atoms is used to directly load a magneto-optical trap. Due to the versatility of the buffer-gas beam source, we obtain trapped, sub-milliKelvin gases of four different lanthanide species using the same experimental apparatus. In the second experiment of this thesis, a buffer-gas beam is used as the initial stage of an experiment to directly laser cool and magneto-optically trap the diatomic molecule CaF. In the third experiment of this thesis, buffer-gas cooling is used to study the cooling of the conformational state of large organic molecules. We directly observe conformational relaxation of gas-phase 1,2-propanediol due to cold collisions with helium gas. Lastly, I present preliminary results on a variety of novel applications of buffer-gas cooling, such as mixture analysis, separation of chiral mixtures, the measurement of parity-violation in chiral molecules, and the cooling and spectroscopy of highly unstable reaction intermediates.Chemical Physics
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Tetteh, Kevin Kwaku Adjei. "Molecular characterisation of novel functionally important molecules of the model parasitic nematode, Toxocara canis." Thesis, University of Edinburgh, 1999. http://hdl.handle.net/1842/11455.
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The gastrointestinal parasite of dogs and their related species, Toxocara canis, is a prime example of a zoonotic parasite. It is the principal agent of visceral larva migrans and also a cause of ocular larval migrans. As a result of the close association that dogs have with man, the parasite enjoys a world-wide distribution. Infections can be contracted from contaminated soil and handling of infected dogs, and is particularly prevalent amongst professions that have a close association with dogs, such as hydatid control officers in New Zealand. Once inside the non-canid host, the parasite enters a state of arrested development, in which it neither grows nor differentiates. In this state the parasite releases up to 1% of its body weight in excretory/secretory antigens per day. Assuming that this high protein production was in some way linked to immune evasion, a modest EST project was undertaken using a cDNA library generated from infective larvae. The hypothesis behind this approach was that the high protein output demonstrated by these parasites would be mirrored at the mRNA level. In total 266 clones were sequenced, the majority of which were from the both the 5' and 3' ends of the transcripts. Homologues for these genes were sought by similarity searching against the GenBank protein and the dbEST nucleotide databases. Cluster analysis of the clones identified 129 distinct gene products, all but three of which represented new genes. The majority of the genes (96) were represented by single clones, although 8 transcripts were present at high frequencies, each composing >2% of all the clones sequenced. These high abundance transcripts include a mucin and a novel C-type lectin, which together comprise the two major excretory/secretory antigens released by the parasite. Four highly expressed novel transcripts were found, termed ant genes (abundant novel transcripts). Together these genes represented 18% of all the cDNA clones isolated, but no similar sequences occur in the C. elegans genome. While the coding regions of these genes are dissimilar, they exhibit a remarkable level of similarity in their 3' UTR at the nucleotide level. The discovery of these abundant parasite specific genes, of newly-identified lectins and mucins, as well as a range of conserved and novel proteins, provide defined candidates for future analysis of the molecular basis of immune evasion by Toxocara.
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Neri, Tommaso. "Novel organic semiconducting small molecules for X-ray detection." Master's thesis, Alma Mater Studiorum - Università di Bologna, 2017. http://amslaurea.unibo.it/14809/.
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L’elettronica organica ha trovato negli anni recenti diverse applicazioni, anche in dispositivi di uso quotidiano, come ad esempio gli schermi OLED (Organic Light Emitting Diode). I semiconduttori organici possono essere depositati con tecniche a basso costo, anche su scala industriale, e su grandi aree, fattore, quest’ultimo, che li rende particolarmente adatti alla fabbricazione di sensori di radiazioni ionizzanti. Il lavoro presentato riguarda la realizzazione di transistor organici a film sottile e la loro caratterizzazione, come transistor e come sensori di raggi X. In particolare, l’obiettivo di questo progetto sperimentale è il confronto delle sensibilità di due tipi di dispositivi fabbricati da soluzioni delle molecole diF-TES-ADT (5,11-bis(triethylsilylethynyl)anthradithiophene) e diF-TEG-ADT (5,11-bis(triethylgermylethynyl)anthradithiophene), appartenenti alla classe degli eteroaceni sostituiti. Nella prima molecola sono presenti due gruppi funzionali identici in cui è contenuto un atomo di silicio, mentre nell'altra essi contengono un atomo di germanio, caratterizzato da un numero atomico più alto. In questo lavoro viene dimostrato che il numero atomico più alto, grazie al maggiore coefficiente di assorbimento per la radiazione X, comporta una sensibilità più alta per il sensore di razioni ionizzanti, come confermato dai risultati ottenuti.
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Shen, Dong. "Syntheses and mesophase characterizations of novel bent core molecules." [S.l. : s.n.], 2000. http://deposit.ddb.de/cgi-bin/dokserv?idn=961481889.
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Dattani, Hema. "Novel Tripodal Receptors Designed to Recognize Anionic Guest Molecules." Thesis, University of Oxford, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.489428.
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The aim of this thesis is to develop novel tripodal receptors for the recognition of anionic guest species. Interaction between host and guest is analyzed by a variety of spectroscopic methods including ¹H NMR, UV-Visible, luminescence and electrochemical techniques.
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Fortuin, Elton E. "Novel aminoquinoline-polycyclic hybrid molecules as potential antimalarial agents." University of the Western Cape, 2014. http://hdl.handle.net/11394/4463.
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Magister Pharmaceuticae - MPharmPlasmodium falciparum malaria continues to be a worldwide health problem, especially in developing countries in Africa and is responsible for over a million fatalities per annum. Chloroquine (CQ) is low-cost, safe and was the mainstay aminoquinoline derived chemotherapeutic agent that has been used for many years against blood-stage malaria. However, today the control of malaria has been complicated by increased resistance of the malaria parasite to existing antimalarial agents such as CQ. The primary cause of resistance is mutation in a putative ATP-powered multidrug efflux pump known as the p-glycoprotein (pGP) pump, and point mutation in P. falciparum CQ resistance transporter (PfCRT) protein. These mutations are responsible for the reduced accumulation of CQ at its primary site of action, the acidic digestive food vacuole of the parasite.To overcome the challenges of CQ resistance in P. falciparum, chemosensitiser offer an attractive approach. Chemosensitisers or reversal agents are structurally diverse molecules that are known to reverse CQ resistance by inhibiting the pGP efflux pump and/or the PfCRT protein associated with CQ export from the digestive vacuole in CQ resistant parasites. Chemosensitisers include the well-studied calcium channel blocker verapamil and antihistaminic agent chlorpheniramine. These drugs have little or no inherent antimalarial activity but have shown to reverse CQ resistance in P. falciparum when co-administered with CQ. Because of the channel blocking abilities of pentacycloundecylamines (PCUs) such as NGP1-01, it is postulated that these agents may act as chemosensitisers and circumvent the resistance of the Plasmodium parasite against CQ. Therefore as a proof of concept we conducted an experiment using CQ co- administered with different concentrations of NGP1-01 to evaluate the ability of NGP1-01 to act as a chemosensitiser.Herein, we report the ability of NGP1-01, the prototype pentacycloundecylamine (PCU), to reverse CQ resistance (> 50 %) and act as a chemosensitiser. NGP1-01 alone exhibited very low intrinsic antimalarial activity against both the resistant and sensitive strain (> 2000 nM), with no toxicity to the parasite detected at 10 µM. A statistically significant (p < 0.05) dose dependent shift was seen in the CQ IC50 values at both 1 µM and 10 µM concentration of co-administeredNGP1-01 against the resistant strain. Based on this finding we set out to synthesise a series of novel agents comprising of a PCU moiety as the reversal agent (RA) conjugated to a CQ-like aminoquinoline (AM) molecule and evaluate the potential of these PCU-AM derivatives as antimalarial- and/or reversed CQ agents. As recently shown by Peyton et al., (2012), the conjugation of a CQ-like molecule with a RA such as the chemosensitiser imipramine and derivatives thereof is a viable strategy to reverse CQ resistance in multidrug-resistant P. falciparum. The novel compounds were obtained by amination and reductive amination reactions. The synthetic procedures involved the conjugation of the Cookson’s diketone with different tethered 4-aminoquinoline moieties to yield the respective carbinolamines and the subsequent imines. This was followed by a transannular cyclisation using sodium cyanoborohydride as reducing agent to yield the desired PCU-AM derivatives. The CQ-like AMderivatives were obtained using a novel microwave (MW) irradiation method. Structure elucidation was done by utilising 1H- and 13C NMR spectroscopy as well as IR absorption spectrophotometry and mass spectrometry. Five PCU-AM reversed CQ derivatives were successfully synthesised and showed significant in vitro antimalarial activity against the CQ sensitive strain (NF54). PCU-AM derivatives 1.1 – 1.4 showed antimalarial IC50 values in the ranges of 3.74 – 17.6 ng/mL and 27.6 – 253.5 ng/mL against the CQ-sensitive (NF54) and CQ-resistant strains (Dd2) of Plasmodium falciparum, respectively. Compound 1.1 presented with the highest antimalarial activity against both strains and was found to be 5 fold more active against the resistant strain than CQ. The reversed CQ approach resulted in improved resistance reversal and a significantly lower concentration PCU was required compared to NGP1-01 and CQ in combination. This may be attributed to the improved ability of compound 1.1 to actively block the pGP pump and/or the increased permeability thereof because of the lipophilic aza-PCU moiety. Compound 1.1 also showed the lowest RMI value confirming that this compound has the best potential to act as a reversed CQ agent in the series. Cytotoxicity IC50 values observed for compounds 1.1 – 1.4 were in the low micromolar concentrations (2.39 – 9.54 µM) indicating selectivity towards P. falciparum (SI = 149 – 2549) and low toxicity compared to the cytotoxic agent emetine (IC50 = 0.061 µM).These results indicate that PCU channel blockers and PCU-AM derived conjugates can be utilised as lead molecules for further optimisation and development to enhance their therapeuticpotential as reversal agents and reversed CQ compounds.
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Wheeler, Martyn David. "Two novel laser-based techniques for molecular spectroscopy." Thesis, University of Bristol, 1997. http://hdl.handle.net/1983/99fefda0-4274-4bb3-8f37-9506f028d011.
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Makha, Mohamed 1965. "Novel sulfonated extended arm calixarenes." Monash University, School of Chemistry, 2001. http://arrow.monash.edu.au/hdl/1959.1/8295.
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Sheldon, Alexander. "A novel desymmetrisation approach towards chiral molecules, using 'click' chemistry." Thesis, University of East Anglia, 2016. https://ueaeprints.uea.ac.uk/59616/.
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Typically, the popular click reaction between an alkyne and an azide forms a triazole in very high yield, but since this process does not produce a stereogenic centre, its use with chiral ligands has not been thoroughly investigated. Choosing a prochiral diyne as the starting material allows the click process to perform a desymmetrisation step. Desymmetrisation of prochiral molecules using click chemistry is a method that has had little attention in the past. Herein is described progress into a novel synthetic route to chiral molecules using this process. The first part of this thesis introduces the concept of chirality, why it is important, and how molecules with chirality are synthesised. Then, the importance of the click reaction and similar reactions are discussed. The second part of this thesis reports on the formation and characterisation of the bis-alkyne precursors, which are used in the key click chemistry step. Next, several azide compounds are discussed, as these are also required for the key step. The third part of this thesis is concerned with the main click chemistry step. There are sub-sections for the original racemic trial reactions, as well as a series of reactions assessing various ligands, culminating in a tuning of conditions for the best ligand. A general reaction scheme for the project is given below. Next follows the fourth part, which consists of some reactions performed in conjunction with a visiting project student. Whilst these are not key to my research, they are related to the main aim of a chiral click reaction. The final part of this thesis is the experimental section and the appendix.
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Ellis, Samantha. "Induction of the antigen presentation machinery using novel small molecules." Thesis, University of British Columbia, 2017. http://hdl.handle.net/2429/60473.
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Tinarelli, Alessandro <1975>. "Novel Methodologies for the Synthesis of Scaffolds for Bioactive Molecules." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2010. http://amsdottorato.unibo.it/2291/.
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Bateman, James. "Novel schemes for the optical manipulation of atoms and molecules." Thesis, University of Southampton, 2009. https://eprints.soton.ac.uk/66189/.
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The range of atoms which can be cooled by lasers is limited to those which have a closed two level structure. Several schemes have been proposed which aim to extend this range by using coherent control of the particle momenta, but none have yet been demonstrated. We hope to implement these and other coherent manipulation schemes, and we begin with a system which is well understood and over which we can exert precise control. This thesis covers the design and construction of an experiment to demonstrate coherent manipulation of cold rubidium atoms collected in a magneto-optical trap. The lower hyperfine levels of these cold atoms very closely mimic the ideal two-level atom, and we use carefully crafted laser pulses to prepare, manipulate, and read their quantum state. The hyperfine levels are coupled using two fields whose frequency difference is equal to the hyperfine splitting. The way in which these Raman coupled levels can be used to emulate a two-level atom is explored, and the experimental apparatus used to create and control the driving fields is described in detail. The amplitude, frequency and phase of these fields is programmable, and complex manipulation schemes can be implemented merely by programming a computer. We have observed Raman transitions in the cold rubidium atoms, and the experimental methods used to detect these features amidst large experimental noise are discussed. Although we have not yet seen Rabi oscillations, we are confident that we can now have sufficient control to begin to implement simple interferometric sequences. However, there remain significant challenges if we are to coherently manipulate the momentum, and the prospects for such manipulation are discussed.
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Rudge, James B. "An investigation into the synthesis of potentially chemiluminescent novel molecules." Thesis, Swansea University, 2004. https://cronfa.swan.ac.uk/Record/cronfa43129.
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Chemiluminescent compounds are essential tools as probes for the analysis of biological molecules. One such family, the Acridinium Esters, are safe to use and more sensitive than radio labels. The chemistry of the light-emitting reaction of the acridinium esters is a simple hydroperoxidation in basic conditions. However, like all chemiluminescent systems, the light-emitting reaction and chemical stability of these molecules can be vastly improved. Chapter Two explores the chemistry around synthesising a sulfonate ester derivative of the standard ester (i.e. a carboxylate). From molecular modelling studies, it was predicted that sulfonate esters would react more energetically during hydroperoxidation. However, synthesis of 9-substitued acridinium sulfonate esters was impossible to achieve. Methods for esterification resulted in substitution of the sulfonate for a nucleophile, such as HO- or Cl-. Moreover, the sulfonate anion was proven to be a very poor nucleophile, thus direct attack of the sulfonate ligand onto a nucleophile such as methyl iodide, was found to be unfavourable. Chapter Three explores the synthesis of a novel group potentially chemiluminescent molecules based on the original acridinium ester design but substituting the acridine ring for a pyridine ring. It was hoped through inter or intramolecular energy transfer to a bound fluor, that light of a desired wavelength could be selected based on choice of fluor. Finally, chapter four describes the synthesis of a family of molecules based on the parent molecule acridine-9-carboxylic acid pyridine-2-ylamide. Although classically, acridinium amides have proven to be too unreactive on hydroperoxidation, it was hoped that as the pyridine ring is electron withdrawing that it would improve said reactivity. However, when methylating these esters to potentially form an N-methyl acridinium, methylation preferentially occurred on the pyridine ring.
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Li, Mingxuan. "Self-Assemble of Novel Discotic Nano-Molecules Based on Polyhedraloligomericsilsesquioxanes." University of Akron / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=akron1399242960.
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Meyer, Amanda R. "Novel approaches for the chromatographic and electrophoretic separation of molecules." Diss., Manhattan, Kan. : Kansas State University, 2008. http://hdl.handle.net/2097/1031.
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Mollentze, Theodorus Bernardus. "Rabies virus emergence in novel hosts : from molecules to landscapes." Thesis, University of Glasgow, 2018. http://theses.gla.ac.uk/8935/.
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The invasion of novel host species by pathogens is one of the primary causes of pandemics and emerging diseases. Such host shifts are difficult to anticipate, in part because we lack an understanding of the barriers that prevent maintenance of pathogens by multiple species. Rabies virus provides an ideal model system in which to study these barriers, as well as the mechanisms used by host-shifting pathogens to overcome them. This virus appears to able to infect all mammals, but paradoxically is maintained in species-specific transmission cycles. These maintenance hosts are almost exclusively found within the Carnivora (carnivores) and Chiroptera (bats), and were established by numerous host shifts within and between these taxonomic orders. However, it remains unclear which – if any – adaptations are required when switching to a new host species, nor is it known why the virus is incapable of utilising multiple host species despite evidence of relatively frequent spill-overs between maintenance host species. This thesis describes investigations of the determinants of rabies virus host shifts across multiple scales of organisation, which aim to understand the host-specialisation of this virus. A meta-analysis of within- and cross-species infection studies shows evidence for a reduction in effective dose as the body temperature difference between the original and inoculated species increases. This affects the duration of the incubation period, suggesting adaptation of infectivity may be involved. Crucially, previous studies have linked temperature differences to infectivity differences in cell culture, and to the process of cell entry in particular. These data further show evidence for phylogenetic clustering of incubation period durations, which may be linked to clustering of sensitivity among inoculated host species. This in turn may help explain why only some carnivore and bat species are maintenance hosts of rabies virus. At the molecular level, whole genome sequencing of samples from a system in which rabies virus has made an unusual host shift to bovids suggests involvement of a single amino acid change in the acetylcholine receptor-binding site of the glycoprotein. Phylogenetic analyses involving these and other sequences shows evidence for distinct maintenance cycles in three host species in the same region, despite numerous spill-over infections between species. The involvement of the glycoprotein in this host shift further points to a role for infectivity changes in host adaptation. At the cellular level, the bovid-associated viruses show increased infectivity to a bovid cell line compared to canid-associated viruses. The bovid-associated viruses also show decreased infectivity to a canid cell line representing the original host species. Combined, these results point to a new model for the host adaptation of rabies virus. In this model, the infectivity of viruses is decreased at temperatures to which they are not adapted. This allows the emergence of genotypes with increased infectivity in the novel host species, which can be achieved through relatively minor genomic alterations. Because these adaptations are detrimental in the original host, they may combine with ecological differences between hosts to create the single-species maintenance cycles observed. Identifying the mechanisms constraining maintenance host range will allow better predictions of which host shifts are likely to be successful. In particular, the effect of body temperature difference found here is shown to explain a large part of the previously observed effect of phylogenetic distance between host species in reducing the frequency of rabies virus host shifts. The phylogenetic clustering of host sensitivity meanwhile, may explain how host shifts between very divergent hosts are possible.
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Warrier, Thulasi. "Novel small molecules targeting Ag85C, mycolyl transferase of Mycobacterium tuberculosis." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2010. http://dx.doi.org/10.18452/16160.
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Etwa ein Drittel der Weltbevölkerung ist mit Mycobacterium tuberculosis (Mtb), der Erreger der Tuberkulose (TB), infiziert. Daher ist es unbedingt notwendig vorhandenen Behandlungsstrategien weiter zu verbessern. Diese Study beschäftigt sich mit dem Mtb Protein Ag85C, einer Mycolyltransferase, als ein neues Ziel für die medikamentöse Behandlung der TB. Ag85C ist eines von drei verwandten Proteinen, Ag85A, B und C, welche zusammen an der Biogenese der Zellwand von Mtb beteiligt sind. Eine Gruppe von chemischen Molekülen mit den Namen Ag85C-1 bis -4 wurde als Inhibitoren von Ag85C getestet. Alle Verbindungen waren in der Lage das Wachstum von Mtb in Flüssigkulturen zu inhibieren, aber nur Ag85C-3 hatte ebenfalls einen Effekt auf intrazelluläre Bakterien, welches in einem Makrophagen-Infektions-System getestet wurde. Hervorzuheben ist, dass Ag85C-3 darüber hinaus auch das in vitro Überleben eines MDR Stammes inhibierte. Dies macht dieses Molekül zu einem interessanten Kandidaten für neue anti-mycobakterielle Therapieansätze. Desweiteren wurden detaillierte, funktionelle Charakterisierungen der Effekte von Ag85C-3 auf Mtb durchgeführt. Die Verbindung modifiziert die Lipide der mykolischen Säuren in der Zellwand durch die Blockierung der Ag85 Funktionen. Dieser Effekt führt dann zu einer Veränderung in der Durchlässigkeit der Außenhülle von Mtb. Mit Hilfe der microarray Analyse wurden die Regulierungen der Signalwege durch Ag85C-3 umfassend untersucht. Es konnte gezeigt werden, dass lebensnotwendige Siderophore durch das Molekül modifiziert werden, was auf mehrere Wirkungsmechanismen schließen lässt. Diese Erkenntnisse machen Ag85C, als Ziel, und Ag85C-3, als Inhibitor, zu vielversprechende Kandidaten für zukünftige Medikamentenforschung auf dem Gebiet der TB-Therapien. Diese Studie hebt zudem die zielbasierte Identifizierung von chemischen Inhibitoren als wichtigen und wertvollen Ansatz für die Medikamentenentwicklung hervor.Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB) infects about one-third of the world’s population. Therefore there is an urgent need to improve existing intervention strategies. This study evaluated the Mtb Ag85C protein, a mycolyl transferase, as a novel target for drug mediated intervention. Ag85C belongs to a family of three cognate proteins, Ag85A, B and C. They are involved in the final steps of Mtb cell envelope biogenesis. A panel of chemical molecules, Ag85C-1-4, which bind to Ag85C were utilized as inhibitors of Ag85C. All compounds inhibited growth of Mtb in vitro in liquid medium cultures but only Ag85C-3 had an effect on intracellular bacteria in macrophage infection system. Importantly, Ag85C-3 can inhibit in vitro survival of a MDR strain of Mtb making it a relevant molecule in the search for novel classes of anti-mycobacterial compounds. Furthermore a detailed functional characterization of Ag85C-3 effect on Mtb was performed. It modified the cell wall mycolic acid containing lipid amounts by blocking Ag85 function that led to changes in permeability of Mtb envelope. A comprehensive analysis of Mtb signalling pathways regulated by Ag85C-3 was investigated through microarray analysis. It showed modification of vital siderophore biosynthesis indicating multiple mechanisms of action. Thus the target, Ag85C and the inhibitor, Ag85C-3 are promising candidates for future TB drug research aimed at combating broad spectrum resistance development. This study also reinforces target based identification of chemical inhibitors as a valid and valuable approach in drug development.
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Muneer, Saiqa. "Novel nanoformulations and nanosensors for bioactive molecules of biomedical significance." Thesis, Queensland University of Technology, 2021. https://eprints.qut.edu.au/213224/1/Saiqa_Muneer_Thesis.pdf.
Full textAbstract:
This thesis demonstrates novel nanosensors and nanomaterials for the sensitive detection of bioactive molecules (antibody therapeutics and antibiotics) in complex biological matrices utilizing thiol chemistry for label-free SERS detection. In addition to biomedical analysis, formulation development of dry powder inhalers overcomes the issues of adverse effects associated with parenteral or oral route of drug administration. It is expected to accomplish the key requisites like aerosolization properties, physicochemical characteristics, biocompatibility, and biodegradation with minimal side effects. Therefore, this study provided a motivation to address current advancement of detection techniques and development of novel drug delivery systems for the bioactive molecules.
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Hermann, Keith R. "Novel Architectures in Cavitand Chemistry: Shaping Molecular Inner Space." The Ohio State University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=osu1406148569.
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Chang, Yuan-Pin. "Novel probes of angular momentum polarization." Thesis, University of Oxford, 2010. http://ora.ox.ac.uk/objects/uuid:d3880edf-436a-415e-8a74-6b1c0fd26e65.
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New dynamical applications of quantum beat spectroscopy (QBS) to molecular dynamics are employed to probe the angular momentum polarization effects in photodissociation and molecular collisions. The magnitude and the dynamical behaviour of angular momentum alignment and orientation, two types of polarization, can be measured via QBS technique on a shot-by-shot basis. The first part of this thesis describes the experimental studies of collisional angular momentum depolarization for the electronically excited state radicals in the presence of the collider partners. Depolarization accompanies both inelastic collisions, giving rise to rotational energy transfer (RET), and elastic collisions. Experimental results also have a fairly good agreement with the results of quasi-classical trajectory scattering calculations. Chapter 1 provides the brief theories about the application of the QBS technique and collisional depolarization. Chapter 2 describes the method and instrumentation employed in the experiments of this work. In Chapter 3, the QBS technique is used to measure the total elastic plus elastic depolarization rate constants under thermal conditions for NO(A,v=0) in the presence of He, Ar, N2, and O2. In the case of NO(A) with Ar, and particularly with He, collisional depolarization is significantly smaller than RET, reflecting the weak long-range forces in these systems. In the case of NO(A)+N2/O2, collisional depolarization and RET are comparable, reflecting the relatively strong long-range forces in these systems. In Chapter 4, the QBS technique is used to measure the elastic and inelastic depolarization and total RET rate constants for OH(A,v=0) under thermal conditions in the presence of He and Ar, as well as the total depolarization rate constants under superthermal conditions. In the case of OH(A)+He, elastic depolarization is sensitive to the N rotational state, and inelastic depolarization is strongly dependent on the collision energy. In the case of OH(A)+Ar, elastic depolarization is insensitive to N, and inelastic depolarization is less sensitive to the collision energy, reflecting that the relatively strong long-range force in OH(A)+Ar system. The second part of this thesis describes the experimental studies of photodissociation under thermal conditions. Chapter 5 provides a brief introduction about several polarization parameter formalisms used for photodissociation, and the incorporation of the QBS technique to measure these polarization parameters. In this thesis, most polarization parameters of the molecular photofragments are measured using the LIF method, and the QBS technique is used as a complementary tool to probe these polarization parameters. In Chapter 6, rotational orientation in the OH(X,v=0) photofragments from H2O2 photodissociation using circularly polarized light at 193 nm is observed. Although H2O2 can be excited to both the A and B electronic states by 193 nm, the observed orientation is only related to the A state dynamics. A proposed mechanism about the coupling between a polarized photon and the H2O2 parent rotation is simulated, and the good agreement between the experimental and simulation results further confirms the validity of this mechanism. In Chapter 7, rotational orientation in the NO(X,v) photofragments from NO2 photodissociation using circularly polarized light at 306 nm (v=0,1,2) and at 355 nm (v=0,1) is observed. Two possible mechanisms, the parent molecular rotation and the coherent effect between multiple electronic states, are discussed. NOCl is photodissociated using circularly polarized light at 306 nm, and NO(X,v) rotational distributions (v=0,1) and rotational orientation (v=0) are measured. For the case of NOCl, the generation of orientation is attributed to the coherent effect.
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Talló, Parra Marc 1992. "Circular RNAs : from host RNA molecules to novel broad-spectrum antivirals." Doctoral thesis, Universitat Pompeu Fabra, 2019. http://hdl.handle.net/10803/668309.
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La rellevància clínica dels virus transmesos per mosquits, com el virus del dengue (DENV), el virus del zika (ZIKV), el virus del chikungunya (CHIKV) i el virus del Nil Occidental (WNV), ha augmentat dràsticament durant els darrers anys, provocant un problema de salut global. Actualment, no hi ha cap tractament disponible ni cap vacuna efectiva per tractar aquestes infeccions. Tots aquests virus causen infeccions agudes que han de ser tractades ràpidament després de l’aparició dels símptomes inicials perquè els medicaments siguin efectius. Tot i això, el diagnòstic precoç continua sent un repte no resolt. Això evidencia la necessitat de descobrir noves interaccions essencials entre el virus i la cèl·lula que podrien ser utilitzades com a noves dianes terapèutiques; i la necessitat de desenvolupar teràpies antivirals d’ampli espectre, eficients, que puguin ser administrades abans que s’aconsegueixi un diagnòstic precís. En aquesta tesi hem abordat aquests dos grans problemes centrant-nos en els ARNs circulars (circRNAs).
Els circRNAs són una classe d’ARN generats a partir de progenitors lineals d'ARN mitjançant un mecanisme alternatiu de splicing anomenat back-splicing. En comparació amb els seus homòlegs lineals, els circRNAs són molt estables a causa de la seva resistència a les exonucleases. Actualment, s’ha descrit la implicació dels circRNAs en les infeccions virals, tanmateix, no es coneix el seu rol precís. El primer capítol de la tesi intenta respondre a aquest buit de coneixement utilitzant el virus de l’hepatitis C (HCV) com a sistema model i analitza l'efecte dels circRNAs identificats en altres virus de la mateixa família, en concret, els virus transmesos per mosquits. Mitjançant anàlisis de seqüenciació d’ARN, hem identificat 73 circRNAs cel·lulars induïts pel HCV. Aquest canvi en l’expressió dels circRNAs no pot ser explicat a través de canvis paral·lels en els ARNs lineals. A més a més, hem identificat que el silenciament de cinc d’aquests circRNAs provoca canvis en la infectivitat viral, actuant com a molècules pro- o anti- virals. Un d’aquests circRNAs, cPSD3, és clau per a la infectivitat del virus del dengue.
El segon capítol de la tesi se centra en desenvolupament d’una nova plataforma basada en circRNAs que sigui versàtil, dificulti l’aparició de mutants resistents i permeti desenvolupar antivirals d’ampli espectre. En contrast amb altres teràpies basades en ARN, els circRNAs són molècules altament estables, una característica que simplificarà el seu ús terapèutic. Els circRNAs sintètics dissenyats contenen seqüències llargues que s’hibriden a regions del genoma viral implicades en formar estructures d’RNA essencials per a la supervivència del virus. Com a prova de concepte, hem validat amb èxit circRNAs que inhibeixen el HCV, el DENV, el CHIKV o el WNV. A més, hem generat circRNAs amb capacitat antiviral d’ampli espectre i hem optimitzat la producció in vitro d’aquestes molècules per obtenir quantitats elevades a baix preu.
En conclusió, els nostres resultats (i) emfatitzen la complexitat de la interacció entre els circRNAs cel·lulars i els virus i (ii) descobreixen el gran potencial dels circRNAs artificials com a noves plataformes per al desenvolupament de fàrmacs.The clinical importance of the mosquito-borne viruses, such as dengue virus (DENV), zika virus (ZIKV) chikungunya virus (CHIKV) and West Nile virus (WNV), has dramatically increased over the last years, resulting in a global health problem. Currently, there are no available treatments or effective vaccines to treat these infections. All these viruses produce acute infections that require to be treated early after the onset of the symptoms for drugs to be effective. However, an early diagnosis remains still as an unsolved challenge. This brings to the spotlight the need to uncover novel fundamental virus-cell interactions that could be targeted and to develop efficient broad-spectrum antiviral therapies that could be administered before an accurate diagnosis is achieved. In this thesis we addressed these two major concerns with a focus in circular RNAs (circRNAs). CircRNAs are a class of RNAs generated from linear RNA progenitors by an alternative splicing mechanism termed back splicing. They are highly stable relative to their linear spliced counterparts due to exonuclease resistance. Currently, cellular circRNAs are described to be involved in viral infections. However, their precise role is mainly unknown. The first chapter of the thesis addresses this intriguing issue using HCV as a model system and analyzing the effect of the identified circRNAs in mosquito-borne viruses that belong to the same viral group. By RNA-Seq analyses we identified 73 HCV-differentially expressed circRNAs whose changes could not be explained by parallel changes in linear mRNAs. Silencing of five selected HCV-induced up-regulated circRNAs altered viral infectivity, acting either as anti-viral or pro-viral molecules. Further characterization of one of the selected circRNAs, cPSD3, show, that it also impaired DENV infections. The second chapter focuses on the generation of a novel circRNA-based platform that is versatile, hampers the emergence of resistant mutants, and allows developing broad-spectrum antivirals. In contrast to other RNA-based therapies, circRNAs are highly stable molecules, a trait that will simplify their therapeutic use. The designed synthetic circRNAs contain long sequences that hybridize to multiple target sequences in the viral RNA genome involved in forming RNA structures essential for virus survival. As a proof of concept, we have successfully validated circRNAs that inhibit HCV, DENV, CHIKV or WNV. Furthermore, we have generated circRNAs with broad-spectrum antiviral capacity and optimized the production in vitro of these molecules to obtain high amounts at low price. In conclusion, our results (i) emphasize the complexity of the interaction between cellular circRNAs and viruses and (ii) uncover the great potential of artificial circRNAs as novel platforms for drug development.
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Tennant, Ian. "Antibody-based strategies for identifying novel apoptotic-cell surface-associated molecules." Thesis, University of Edinburgh, 2005. http://hdl.handle.net/1842/29395.
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Defective clearance of apoptotic cells (ACs) is linked to autoimmune and inflammatory disease states such as systemic lupus erythematosus and cystic fibrosis. Relatively few markers exist for the ‘eat me’ signals displayed on the AC surface despite the great potential for such molecules as diagnostic or therapeutic reagents. In this work various antibody-based strategies were employed in an attempt to identify novel AC-specific epitopes. An initial strategy utilised a phage displayed antibody library containing a repertoire of ~108 antibody fragments encoded by human germline genes as an unbiased source of binding specificity. An alternative approach was based on the knowledge that receptors used by macrophages to recognise ACs also recognise pathogen-associated molecules. By looking for the ability of antibodies raised against pathogens to cross-react with ACs the hypothesis that cells undergoing apoptosis reveal molecular patterns that resemble those on pathogen related structures was tested. Screening of antibodies raised in vivo, that have previously been characterised as having specificity for pathogen-associated molecular patterns (PAMPs) revealed that some cross-react with cells undergoing apoptosis. One of these antibodies was found to bind an epitope found on the ubiquitously expressed ~40KDa precursor to Laminin-Binding-Protein (LBP/p40). These findings suggest that epitopes resembling PAMPs appear on the surface of mammalian cells as a result of apoptosis and that these epitopes can be found on endogenously expressed molecules which are normally excluded from the surface of viable cells. The ability of host receptors to cross-react with host and pathogen-associated epitopes in this way may lead to a greater understanding of the mechanisms of autoimmune reactions and allow design of approaches to stimulate the immune system for the treatment of cancer.
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Triana-Baltzer, Gallen B. "Nicotinic synapse formation between neurons novel roles for cell adhesion molecules /." Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2007. http://wwwlib.umi.com/cr/ucsd/fullcit?p3259623.
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Thesis (Ph. D.)--University of California, San Diego, 2007.Title from first page of PDF file (viewed June 21, 2007). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references.
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Cárdenas, Rafael. "Infrared studies on the spectra and structures of novel carbon molecules." Fort Worth, Tex. : Texas Christian University, 2007. http://etd.tcu.edu/etdfiles/available/etd-12062007-092327/unrestricted/Cardenas.pdf.
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Herrmann, Leonie. "Identification and characterization of novel candidate molecules for posttraumatic stress disorder." Diss., Ludwig-Maximilians-Universität München, 2012. http://nbn-resolving.de/urn:nbn:de:bvb:19-157327.
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Bell, I. S. "Novel phosphorus-bearing transient molecules studied by infrared diode laser spectroscopy." Thesis, University of Cambridge, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.596544.
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Studies of the reaction of white phosphorus vapour with oxygen are of considerable fundamental and practical interest. The reaction produces an intense chemiluminescence, although the identity of the emitting species has been controversial. In the experiments reported in this thesis, the phosphorus glow has been probed directly using infrared diode laser absorption spectroscopy to detect some of the transient intermediates present. The introductory chapter presents a review of the advantages of using lasers over conventional sources as spectroscopic tools. Lasers output light of a monochromatic nature, enabling extremely high resolution measurements to be made, whilst their high power engenders excellent sensitivity. The development of tunable infrared sources, especially the semiconductor diode laser, is also described. A review of previous spectroscopic measurements of transient phosphorus-bearing species is then presented, along with a discussion of some of the applications associated with their observation. A diode laser spectrometer equipped with a multi-pass (White) cell has been used to study such short-lived species in the experiments reported in this thesis, and is described in chapter 2. The transient species PO and PO2 have previously been observed in this laboratory. Chapter 3 presents the first reliable rotational assignment of P2O molecule, observed in the reaction of oxygen atoms with white phosphorus vapour. The addition of NO to this reaction mixture was then found to produce PNO, another analogue of N2O, as described in chapter 4. The upper state of the N=O stretching fundamental of the PNO molecule was found to be perturbed, enabling an absolute assignment of the infrared spectrum of this band to be made. This reaction opens the door to a range of novel species that may be produced in this system. The next two chapters describe the addition of halogen molecules to the phosphorus glow, producing the ClPO and BrPO molecules. Their infrared spectra have been assigned with the aid of a Loomis-Wood spectral display program.
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Ali, S. M. "Relaxation studies of various molecules using a novel modulated temperature technique." Thesis, University of Salford, 1985. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.353963.
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Andrews, Gracie L. "A novel role for cell adhesion molecules in nervous system development." abstract and full text PDF (free order & download UNR users only), 2008. http://0-gateway.proquest.com.innopac.library.unr.edu/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3307129.
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Karageorgis, George. "A novel evolutionary approach for the discovery of small bioactive molecules." Thesis, University of Leeds, 2015. http://etheses.whiterose.ac.uk/8343/.
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Current approaches for the discovery of bioactive molecules tend to treat all molecules in large collections with the same significance regardless of their ultimate biological activity. Furthermore, these approaches exploit a limited palette of reliable well-working reactions, that have been optimised for the preparation of individual compounds. This thesis describes the development of a new discovery approach –Activity-Directed Synthesis. The approach aims to merge the discovery of small bioactive molecules with the emergence of a synthetic route. In this regard Activity-Directed Synthesis may be analogous with the evolution of biosynthetic pathways as is observed in Nature. For the implementation of Activity-Directed Synthesis, a well-studied chemical toolbox – metal carbenoid chemistry – that has been underutilised in bioactive molecule discovery was used. The approach was demonstrated in the discovery of novel chemotypes of small bioactive molecules that agonise the Androgen Receptor. Both intra- and intermolecular reactions were exploited in sequential rounds of carbenoid reactions which had many alternative outcomes. Three iterative rounds of screening crude reaction mixtures and design of subsequent reaction arrays enabled the rapid discovery of reactions that yielded bioactive products. Hence small-molecule modulators of the Androgen Receptor, based on scaffolds with no previously annotated activity were discovered. A total of 272 microreactions was performed in the case of intramolecular reactions and a total of 326 microreactions was performed in the case of intermolecular reactions. In the case of the intramolecular chemistry, it was demonstrated retrospectively that the approach enabled the parallel optimisation of both the structure of bioactive molecules and the routes for their synthesis. In the case of the intermolecular chemistry, it was demonstrated that non-exhaustive reaction arrays could still lead to the discovery of sub-micromolar modulators of the Androgen Receptor, greatly improving the efficiency of Activity-Directed Synthesis.
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Foster, Michael Scott. "Design, synthesis, kinetic analysis, molecular modeling, and pharmacological evaluation of novel inhibitors of peptide amidation." Diss., Atlanta, Ga. : Georgia Institute of Technology, 2008. http://hdl.handle.net/1853/31816.
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Thesis (Ph.D)--Chemistry and Biochemistry, Georgia Institute of Technology, 2009.Committee Chair: Dr. Sheldon W. May; Committee Member: Dr. James C. Powers; Committee Member: Dr. Nicholas Hud; Committee Member: Dr. Niren Murthy; Committee Member: Dr. Stanley H. Pollock. Part of the SMARTech Electronic Thesis and Dissertation Collection.
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Jenkins, Jerry W. "Novel efficient simulation techniques for use in molecular modeling." Diss., Georgia Institute of Technology, 2000. http://hdl.handle.net/1853/11238.
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Dhillon, Jatinder Kaur. "Novel antibody based molecules for detection of the microbial pathogen Yersinia pestis." Thesis, University of Aberdeen, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.416572.
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The Gram negative bacterium Yersinia pestis is the aetiological agent of the plague, a disease which throughout history is believed to have caused death and social devastation on a scale unmatched by any other infectious disease. Plague is not an eradicated disease and is still prevalent today. Endemic within animal populations on nearly every continent it causes the death of approximately 2000 humans each year. The recent emergence of multi drug resistant strains along with a potential for illegitimate use as an agent of biological warfare, mean that plague still presents a significant threat to human health. The rapid and sensitive detection of microbial pathogens such as Y. pestis in the environment is essential for the successful implementation of effective countermeasures in order to minimise the outcome of a potential epidemic or biological agent attack. The research described herein investigated the efficacy of recombinant methodologies to generate antibody based molecules against Y. pestis, for employment as reagents in environmental monitoring systems designed to specifically detect and identify airborne pathogens. A total of twelve separate single chain antibody fragments (scAbs) were generated against three individual Y. pestis components, surface exposed or intracellular, either via the rescue and cloning of V genes from existing monoclonals or via the affinity selection of antigen specific antibody fragments from antibody phage display libraries. Of the twelve antibodies generated during this study a high majority (10/12) demonstrated an exceptionally high level of specificity and sensitivity for their particular antigen and initial results from preliminary binding analyses unequivocally established their significance as novel capture reagents within immuno-detection/diagnostic platforms.
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Moorthy, Ramkumar. "Novel Asymmetric Approaches for Construction of Small Molecules by Cyclization and Cycloaddition." Diss., North Dakota State University, 2015. http://hdl.handle.net/10365/25538.
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Development of novel asymmetric and catalytic methods for synthesizing small organic
molecules containing hindered quaternary and tertiary centers is a major challenge and a
dynamic area of investigation in synthetic organic chemistry. The incorporation of these chiral
centers into small molecules such as cyclopropanes, aziridines or isoxazolidines is important
because they are present in a large number of biologically active natural products as well as in
synthetically designed pharmaceutical agents. However, the synthesis of non-natural compounds
containing quaternary and tertiary centers that have potential as therapeutics are scarce due to the
limited number of readily available methods. We have successfully used 1-(benzyloxy)imidazole
as a new bidentate coordinating template for dipolar cycloaddition and cyclization reactions
using chiral Lewis acid as a promoter to access these highly functionalized small molecules in
high yields and selectivity.
Chapter 1. Review for Michael Initiated Ring Closure (MIRC) reaction. The chapter
provides different diastereo- and enantioselective strategies for the construction of chiral
cyclopropanes. Also, the chapter will provide the current methodologies developed for MIRC
reaction.
Chapter 2. Development of a novel chiral Lewis acid methodology for synthesizing
highly strained cyclopropanes with chiral quaternary and tertiary centers using Michael Initiated
Ring Closure (MIRC) reaction for β-substituted and β,β-disubstituted enones with N-benzyloxy
imidazole as an achiral template. Different types of nucleophiles such as sulfur ylides and
bromomalonate were successfully employed in the MIRC reaction.
Chapter 3. Development of a novel chiral Lewis acid methodology for synthesizing
highly strained chiral CF3-substituted aziridines using aza-Michael initiated ring closure reaction (aza-MIRC). The reaction involves β,β-disubstituted enones with N-benzyloxy imidazole as an
achiral template and N-nosyloxy carbamate as ‘nitrene’ source.
Chapter 4. Development of N-benzyloxy imidazole template as a chelating scaffold for
chiral Lewis acid catalyzed enantioselective nitrone cycloaddition of β,β-disubstituted enones for
the construction of isoxazolidines with trifluoromethyl group is described. The N-benzyloxy
imidazole in the cycloadduct was efficiently transformed into corresponding isoxazolidine ester,
which could be further converted into useful precursors such as β-hydroxycarbonyls, 1,3-diols,
β-aminoalcohols, β-aminoacids, β-lactams and other functionalized building blocks.
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Weightman, John S. "Spectroscopic and electrochemical sensing of anions and cations using novel receptor molecules." Thesis, Loughborough University, 1996. https://dspace.lboro.ac.uk/2134/13771.
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The aim of the project was to extend the field of molecular recognition of anions and cations of biochemical, medical, chemical and environmental importance. This was achieved by the use of a number of novel receptor molecules that are designed to bind anionic and cationic guests. The binding of the guest anions and cations was probed by various electrochemical, spectrochemical and IH NMR spectroscopy techniques. The receptor molecules studied included (i) ruthenium(II) trisbipyridyl complexes of acyclic, calix[4]arene and cyclic 2,2'-bipyridine ligands, (ii) the macrocycle Nphenylaza- 15-crown-5, and (iii) crown ether derivatives of diquat. These receptor molecules have been shown to sense anions and cations, such as chloride, bromide, dihydrogen phosphate, sodium, lithium and magnesium. Interestingly, one of diquat crown ether derivatives has been shown to complex both anions and cations at the same time. This is an important development, as the simultaneous molecular trapping of anions and cations in such systems is seen as a possible alternative to the use of ion exchange resins. With a view to producing spectrochemical and/or electrochemical sensor systems, work has been completed by the immobilisation of the novel receptor molecules. This has been achieved by the electropolymerisation of vinyl-substituted ruthenium(Il) trisbipyridyl complexes or the immobilisation of receptor molecules in a polyvinylchloride (PVC) matrix. The latter technique has been particularly successful and has led to the construction of a battery-powered fluorescence detector which has been used for anion sensing.
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Larcher, Leon Maria. "Development of novel oligonucleotide therapeutic molecules targeting microRNAs for tackling brain cancers." Thesis, Larcher, Leon Maria (2018) Development of novel oligonucleotide therapeutic molecules targeting microRNAs for tackling brain cancers. Honours thesis, Murdoch University, 2018. https://researchrepository.murdoch.edu.au/id/eprint/42397/.
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MicroRNAs are short non-coding RNA molecules ( ̴ 22 nucleotides) which are important in regulating numerous metabolic and cellular pathways responsible for cell proliferation, differentiation and survival. Due to the malignant nature of many cancer types, conventional treatment approaches face a number of challenges. In Glioblastoma Multiforme (GBM) localisation in the brain results in additional treatment challenges, such as, limited capacity for the brain to repair itself after treatment, ineffective drug delivery through the blood brain barrier, and neurotoxicity of chemotherapy. MicroRNA signature have been shown to be dysregulated in cancers. Interestingly, restoration of these dysregulated miRNA have been shown to abrogate and even reverse malignant phenotypes. In addition, it has been shown that miRNAs contribute to responses to drug therapy and are themselves modified by these drug therapies. There are a number of approaches targeting miRNAs that have shown great promise in cancer therapy. However, there are still key challenges that need to be overcome before the wide spread use of these technologies. In this project we develop the use of synthetic catalytic oligonucleotides (DNAzyme), which can bind and cleave target miRNAs. Following cleavage, the DNAzyme is free to continue their action, thus reducing the quantity of molecule needed to have a therapeutic effect. Two miRNA targets were selected in our study, namely, miR-21 and miR-494, which were selected following a comprehensive review of known miRNAs in GBM from the literature, miR-21 and miR-494 were selected due to their high overexpression and oncogenic roles (roles in growth, proliferation, invasion, and apoptosis) within GBM. In vitro cleavage analysis, revealed effective cleavage of the miRNA precursor (pre-miRNA) strands by three DNAzymes in a dose-dependent manner. In cell (U87MG, MDA-MB231) cleavage analysis revealed efficient knockdown of miR-21 using RNV541, however an increase in expression was observed when targeting miR-494 in cell (Huh-7) using RNV537 and RNV538. Concentration, structure, length, cell type and transfection reagent used can all influence transfection outcomes. Overall, the project showed that DNAzymes RNV541 efficiently cleaved miR-21 in vitro and inhibited the expression in cell. However cleavage of miR-494 was inducible only in vitro using both RNV537 and RNV538.
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Bubner, Timothy Paul. "Synthesis of novel sterically constrained aryl-alkyne type molecules for nonlinear optical studies /." Title page, table of contents and abstract only, 1996. http://web4.library.adelaide.edu.au/theses/09PH/09phb9173.pdf.
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Rodgers, Mark Andrew. "Using non-immunoglobulin proteins to develop novel impedimetric biosensors for small hydrophobic molecules." Thesis, University of Leeds, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.522978.
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Al, Suleimani Yousuf Mohammed. "An investigation into the actions of novel lipid signalling molecules in the vasculature." Thesis, University of Cambridge, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.610210.
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Eugster, Bickle Anne Caroline. "COP I domains required for coatomer integrity and novel interactions with regulatory molecules." Thesis, University of Cambridge, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.620984.
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Cameron, Joseph. "Small molecules based on novel electron-deficient acceptor units for organic electronic applications." Thesis, University of Strathclyde, 2016. http://oleg.lib.strath.ac.uk:80/R/?func=dbin-jump-full&object_id=26932.
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Demand for photovoltaic cells is ever-increasing due to the diminishing supply of oil-based fuels and the associated harmful environmental effects. Organic photovoltaic devices offer a light and flexible alternative to Si-based PVs. In addition to this, they can be processed using fabrication methods such as spin-coating and inkjet printing hence, such devices have potential to be produced cheaply on a large scale. Although they have been applied as donor materials with success, polymers often show end-group variation and are polydisperse so there can be batch-to-batch variation with respect to OPV performance. A solution to these problems is the use of small donor molecules which are monodisperse and have well-defined structures. However, the shorter conjugation of small molecules with respect to polymers requires measures to shorten the HOMO-LUMO gap. A common approach is the incorporation of electron-deficient acceptor units into the donor molecule, lowering the LUMO level and therefore the HOMO-LUMO gap. Chapter 1 reviews band theory, the development of organic semiconductors, including a summary of oligothiophene based materials and common electron-deficient acceptor units used, the principles behind OPV and OFET devices and how organic semiconductors can be optimised in order to produce the best working devices. The synthesis, physical properties and OPV performance of materials based on naphthyridine-2,6-dione acceptor unit are presented in chapter 2, focussing on the difference between compounds with Donor-Acceptor-Donor and Acceptor-Donor-Acceptor structures. Chapter 3 shows the novel naphthyridin-2-one moiety and the synthesis of materials containing the unit and how they have been used for different applications including ambipolar OFETs and both donor and acceptor materials for bulk heterojunction OPV devices. A study in improving the mobility of OFET devices is presented in chapter 4. Different inorganic nanoparticles were added to organic semiconductor solutions for and the effect of this simple process on the performance of the OFET devices is discussed. Chapter 5 introduces the thieno[3,2-b]thiophene-2,5-dione and novel furo[3,2-b]furan-2,5-dione acceptor units. The synthesis, optical and electrochemical properties, and OFET and OPV device optimisation of materials based on these moieties are presented and discussed. A summary of the work discussed is presented in chapter 6 whilst chapter 7 presents the experimental methods for electrochemistry, device work, and synthetic procedures for each compound presented in Chapters 2, 3, 4 and 5.
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Alqahtani, Hanan Dhafer S. "Studying the Mechanism of Ferroptosis Induced by a Novel Class of Small Molecules." University of Toledo / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1470398949.
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Xiao, Li. "Synthetic Apratoxin F and Novel Analogues - Molecules for Anticancer Mechanistic and Therapeutic Applications." The Ohio State University, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=osu1512083096370725.
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Mao, Yifan. "SYNTHESIS AND CHARACTERIZATION OF NOVEL p-CONJUGATED MOLECULES FOR ORGANIC REDOX-FLOW BATTERIES." University of Akron / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=akron1522333087480595.
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Hassanain, Waleed A. "Novel nanoscale platforms for the isolation and ultra-trace detection of bioactive molecules." Thesis, Queensland University of Technology, 2019. https://eprints.qut.edu.au/124159/1/Waleed_Hassanain_Thesis.pdf.
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This thesis demonstrates novel nanoscale analytical platforms for the selective and sensitive detection of biomolecules for pharmaceutical, environmental and biomedical applications. The new platforms comprised functionalized nanomaterials, disposable sensors and portable detectors for the combined Raman and electrochemical determination of biomolecules. The new nanosensing methodology utilizes the thiol chemistry of biomolecules for their label-free detection by SERS and DPV. Therefore, it can be applied to numerous biomolecules that have disulfide bonds structure. In terms of sensitivity, sample processing, analysis time and cost, the new methodology has significant advantages over the other current techniques such as chromatography and enzyme-linked immunosorbent assay.
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Al-Safadi, Sherin. "Mechanism of action of novel single arm alkylating "combi-molecules" and bi-functional "bis-combi-molecules"." Thesis, McGill University, 2008. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=112376.
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Overexpression of the epidermal growth factor receptor (EGFR), a member of the ErbB family, and its closest homologue HER2, have been associated with aggressive tumour progression and reduced sensitivity to DNA-damaging agents. In order to block the proliferation of refractory tumors overexpressing EGFR, a novel strategy has been developed that sought to design molecules capable of not only blocking EGFR-TK, but also damaging DNA. These molecules, termed combi-molecules (CMs), have been shown to degrade under physical conditions to release another inhibitor of EGFR, and to be potent against tumor cells of various origins including breast, prostate and carcinoma of the vulva. However, despite their potency, their growth inhibitory IC50 values were still in the high micromolar range. In order to augment the potency of the CMs, here they were re-designed to contain two quinazoline moieties and a central N,N-bis(2-aminoethyl)methylamine spacer which, following degradation, could yield higher concentrations of free inhibitors and a more cytotoxic bifunctional DNA damaging species. Here, we describe the mechanism of action of the first prototype of this approach, JDE52, which we now classify as a double-arm CM, in comparison with ZRBA1, its closest single-arm counterpart. The results indicated that JDE52 was capable of inducing significant blockade of EGFR, DNA single-strand breaks and inter-strand cross-links. ZRBA1, its single-arm counterpart, was capable of only forming DNA single-strand breaks. The fluorescent property of FD105, the secondary inhibitor that both JDE52 and ZRBA1 are capable of releasing, has permitted the analysis of its levels in tumor cells by UV flowcytometry. It was found that JDE52 was indeed capable of significantly releasing higher levels of fluorescence (p<0.05) in human tumor cells, compared with levels of fluorescence released by ZRBA1. More importantly, JDE52 induced higher levels of apoptosis and cell killing than ZRBA1. Apoptosis was triggered by JDE52 at a faster rate than ZRBA1. The results in toto suggest that the superior potency of JDE52, when compared with ZRBA1, may be imputed to mechanisms associated with the generation of higher levels of FD105 intracellularly, and the induction of DNA cross-links, which are known to be more cytotoxic. These combined mechanisms (blockade of EGFR-TK and formation of cross-links) contributed to an accelerated rate of apoptosis in cells treated with JDE52. This study conclusively demonstrated that designing molecules as prodrugs of high levels of quinazoline inhibitors of EGFR and bifunctional DNA cross-linking species is a valid strategy to enhance the potency of CMs against refractory tumors.