1,721,052 research outputs found
Synthesis of N-heterocycles as anti-asthma drugs and compounds with antimycobacterial properties
Get PDFPart A: Synthesis of N-heterocycles with dual pharmacology for the treatment of asthma The most common and effective anti-inflammatory asthma treatment is carried out through use of steroids but these can have significant side effects. An alternative non-steroidal oral treatment is montelukast which targets the leukotriene inflammatory pathway, but is less effective at controlling asthma symptoms. The asthma inflammation pathway is complex involving many inflammatory mediators, and it was anticipated that a compound with dual pharmacology which impacted both leukotriene and prostaglandin pathways simultaneously would yield compounds with an enhanced ability to treat asthma. An attractive novel dual target strategy was the inhibition of the 5-lipoxygenase activating protein (FLAP) and antagonism of the prostaglandin D2 receptor CRTh2. A combination of GlaxoSmithKline and literature SAR studies were elaborated in the design of the target compounds, incorporating known pharmacophores for FLAP inhibitors and CRTh2 antagonists. Synthetic routes towards the target compounds were developed and their biological activity against the intended targets determined. Part B: Synthesis of tetrahydroisoquinolines, tetrahydrobenzazepines and profens and their antimycobacterial properties Tuberculosis (TB) is an infectious disease caused by the Mycobacterium tuberculosis pathogen. The increasing prevalence of drug resistant strains of M. tuberculosis means there is an urgent need to develop new anti-TB drugs with novel modes of action. Aporphine alkaloid natural products and synthetic tetrahydroisoquinolines have demonstrated a specific antimycobacterial effect, as well as M. tuberculosis MurE inhibitory activity. The tetrahydroisoquinoline skeleton therefore provides a unique template for the development of new anti-TB drugs. Recently we developed biomimetic reaction conditions for the Pictet-Spengler condensation of aldehydes and amines into tetrahydroisoquinolines. The reaction is mediated by phosphate and proceeds under mild reaction conditions. The scope of the phosphate mediated Pictet-Spengler reaction was investigated in order to access novel alkaloid structures and identify new leads for mycobacterial growth inhibitors. Studies into asymmetric versions of the reaction using chiral phosphates and extending the reaction for the construction of larger ring sizes were explored. Another interesting class of compounds recently identified as active against mycobacterial growth were non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen. Analogues of profen compounds were synthesised for evaluation as mycobacterial growth inhibitors
Design and Development of Tuneable Cationic Lipopolyplexes as Vectors in Gene Therapy
No full textGene therapy is a promising technique that offers great potential for the treatment of inherited and acquired disorders. However, one of the major obstacles is identifying suitable vectors with high targeting and transfection efficiency. A literature review on gene therapy and studies on the developments of vectors in gene therapy is presented in Chapter 1. The results and discussion for the development of novel targeting peptides is outlined in Chapter 2. Biophysical analyses of the peptides were performed in PD (peptide-DNA) and LPD (lipid-peptide-DNA) formulations, and found to be stable over time. The protection and release of DNA within the PD and LPD complexes was studied by using gel assays. The DNA binding affinity and transfection efficiencies are presented and discussed. Chapter 3 outlines the synthetic procedures to generate novel glycerol-based cationic lipids. The cationic headgroup was shielded with n-(ethylene glycol) (nEG) chains attached through non degradable and biodegradable linkers. It was noted that the transfection efficiency of formulations of lipid-nEG conjugate with DOPE was increasing with time. Further investigations using mass spectroscopy indicated the transacylation of an oleoyl group from DOPE to the terminal hydroxyl group of lipid-nEG conjugate, resulting in the formation of a new product compromised of three acyl chains (tri-chain lipids). This finding led to the synthesis of several series of novel tri-chain lipids. It was noted that most tri-chained analogues offered an enhanced transfection efficiency and DNA packaging compared to their original di-chained analogues. The synthetic routes towards the formation of novel glycerol-based lipids bearing a disulfide linker are given in Chapter 4. An overall summary and possible areas of future research are discussed in Chapter 5. A formal description of the experimental methods and procedures is presented in Chapter 6
Biocatalysis using plant and metagenomic enzymes for organic synthesis
Get PDFBiocatalysts provide an excellent alternative to traditional organic chemistry strategies, with advantages such as mild reaction conditions and high enantio- and stereoselectivities. The use of metagenomics has enabled new enzymes to be sourced with high sequence diversity. At UCL a metagenomics strategy has been developed for enzyme discovery, in which the library generated is annotated and searched for desired enzyme sequences. In this PhD, a metagenomic approach was used to retrieve 37 short chain reductase/dehydrogenases (SDRs) from an oral environment metagenome. Eight enzymes displayed activity towards cyclohexanone and their substrate selectivities were investigated. Four of the SDRs displayed activity to the Wieland-Miescher ketone (WMK), a motif found in several pharmaceutically relevant compounds. SDR-17 displayed high conversions and stereoselectivities and was co-expressed with the co-factor recycling enzyme glucose-6-phosphate dehydrogenase. This system was then successfully used to reduce (R)-WMK on a preparative scale reaction in 89% isolated yield and >99% e.e.. In further studies using reductases, the substrate specificities of two ketoreductases known as tropinone reductase I and II (TRI and TRII respectively) from the plant D. stramonium and MecgoR from E. coca were investigated. These studies expanded on reported substrate activities with these enzymes in the literature. A selection of symmetric and asymmetric tropinone analogues were synthesised, towards which MecgoR and TRI showed high activities, providing a strategy to access novel alcohols. Furthermore, sixteen ketoreductases were selected from a drain metagenome based on their sequence similarity of over 24% to MecgoR. They were annotated as aldo/keto reductases (ARKs) and five were successfully expressed in E. coli. Interestingly, the novel enzyme AKR-3 displayed activities toward aromatic ketones and aldehydes such as 2-indanone, phenylacetaldehyde and benzaldehyde. Transaminases (TAms) from the enzyme library toolbox at UCL were also tested with tropinone analogues and related cyclic compounds, several of which showed good activities
Sustainable Approaches to the Synthesis of Aromatic Compounds and α-Hydroxyketones
Get PDFThe unifying theme of this thesis is a sustainable approach to synthetic chemistry, focussing on two areas; the synthesis of aromatic compounds from biomass-derived furfural derivatives using environmentally friendly methodology, and the synthesis of α-hydroxyketones by expanding the substrate scope of transketolase enzymes by medium throughput mutant screening. Chapter I gives an overview of the principles and importance of sustainability in synthetic chemistry and presents a broad discussion of biomass sources and uses, the use of water as a solvent, and enzymatic catalysis in organic synthesis. Chapter II discusses the production of furfural derivatives from biomass, including the potential role of sugar beet pulp as a feedstock, and an overview of furfurals in synthesis. A new route to substituted benzene rings from furfurals via a three-step, one-pot cascade in water is then described, its scope explored, and an intramolecular variant developed. A ‘Design of Experiment’ optimisation of a furfural Michael addition is also presented. Chapter III concerns the reactivity and potential uses of the phthalimide hydrazones produced by the methodology introduced in Chapter II, presenting an overview of potential downstream products, a broad investigation of functional group manipulation, and a new synthetic route to a poly(ADP-ribose) ribose polymerase inhibitor and substituted phthalocyanines. Chapter IV explores the use of transketolase enzymes in the synthesis of α-hydroxyketones, investigating the role of enzyme variants in enhancing the acceptance of previously unreported non-natural keto-acid donor substrates. The development of a medium throughput methodology and its application in enzyme mutant screening is described. Chapter V gives a summary of the research carried out, presents some general conclusions, and describes future work, and Chapter VI contains the details of experimental procedures and compound characterisation for the results discussed in Chapters II-IV
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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