Bradford Scholars
Bradford Scholars is the University of Bradford online research archive. Access is free to anyone interested in research being conducted at Bradford. In the repository you will find a range of materials from journal articles and conference papers to research reports and theses.
Contact the repository team via openaccess@bradford.ac.uk with any queries about Open Access or how to deposit your research papers.
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Publication Modulating Bone morphogenetic protein (BMP) and Transforming growth factor-beta (TGF-β) signalling with green tea catechins in mammalian cellsFamilial cases of pulmonary arterial hypertension (PAH) are often caused by germline mutations, the most common being a loss of characteristic mutation in the BMPR2 gene, a member of the TGFβ Superfamily. In this study, it was hypothesised that these green tea catechin compounds might inhibit TGFβ signalling while promoting BMP signalling. This study demonstrates that these green tea catechin compounds inhibit TGFβR-II and TGFβ1-induced SMAD-dependent by reducing reporter activity, reduce the phosphorylation of SMAD3 proteins, and decrease the expression of pai-1 transcript. These green tea catechin compounds also decreased the BMP4-induced phosphorylation of p38 mitogen-activated protein kinase proteins and promoted BMP4-induced SMAD-dependent by increasing the phosphorylation of BMP4-induced SMAD1/5 protein expressions. Also, these catechin compounds increased id1 target gene expression in the presence and absence of BMP type-II-receptors. The data of this study demonstrated that catechin compounds might exert an inhibitory effect on TGFβ signalling and promote BMP signalling. Finally, in this research, elevated expression of CALM1, DYRK2, and MPP1 genes have been observed in the nucleus as revealed by their induction of pai-1 and id1-specific target gene expression, also modulating the regulation of specific ligand-induced phosphorylation of SMAD3 and SMAD1/5 proteins respectively. Therefore, CALM1, DYRK2, and MPP1 may have a nuclear function in modulating TGFβ and BMP signalling pathways respectively. These results obtained from this research have experimental and clinical potentials for identifying a novel treatment for PAH.Publication Synthesis, Spectrometry, Spectroscopy and Chromatography of Aromatic CompoundsReactive ambient mass spectrometry has been combined with competition experiments to develop a novel methodology for investigating the mechanisms and relative rates of organic synthesis. This approach has been applied to intermolecular reactions in the generation of quinoxalines and has confirmed that the mechanism operating under reactive ESI conditions is the same as that operating in the classical bulk synthesis: the phenylenediamine acts as a nucleophile and the benzil as an electrophile. The Hammett equation has also been applied to the quinoxaline system to develop a novel understanding of the effect of substitution on the rate of reaction in both the phenylenediamine and benzil components in accelerated microdroplet synthesis. Competition experiments have also been applied to intramolecular reactions of isolated ions within a mass spectrometer. Useful mechanistic information has been obtained in the fragmentations of four classes of ionised compounds, benzophenones, dibenzylideneacetones, benzanilides and cinnamamides. This new approach has given high quality, reproducible data in all cases, and provided valuable insights into the mechanisms of these ionised compounds. In summary, mass spectrometry has been used in a novel way in conjunction with competition experiments to probe in greater depth the mechanisms by which neutral and ionised species react.Publication Sustainable Supply Chain Management in an Uncertain Business Environment: Investigating the Resilience of Upstream oil supply in LibyaThis research investigates the factors influencing the resilience and sustainability of the upstream oil and gas supply chain in an uncertain environment, with a focus on Sustainable Supply Chain Risk Management (SSCRM) through dynamic capabilities. The study is uniquely conducted in the turbulent context of the Libyan oil and gas sector, contrasting with studies in more stable environments. It employs a novel approach, utilising dynamic capabilities as a lens to examine SSCRM. The research aims to identify the dynamic capabilities that contributed to the resilience of the Libyan oil and gas industry amidst economic downturns and conflicts. By analysing this exemplary case, the study seeks to pinpoint the specific dynamic capabilities that positively impacted the industry's resilience and sustainability in chaotic circumstances. The study employs a quantitative methodology based on a conceptual model integrating key dynamic capabilities (DCs) from existing literature. An online questionnaire was crafted to gauge the perceived impact of these DCs on the resilience and sustainability of the organisation's supply chains. The survey targeted key employees with expertise in supply chain management, and 277 responses were collected. Structured Equation Modelling (SEM) was utilised for data analysis. The results indicate that, except for one sensing DC, namely risk identification, the other capabilities, (risk assessment, mitigation, and control) were found to have significantly influenced the organisation’s resilience and the sustainability of its supply chains. The study provides a tentative explanation for the exceptional case and anticipates that these findings will have positive implications for organisations navigating uncertain economic landscapes.Publication Advances in medicinal inorganic chemistry: Exploiting the biological activity of metal arene complexesHalf-sandwich complexes containing transition metals offer a wide range of applications owing to their interactions with a variety of targets/molecules that are not accessible for some organic scaffolds. The use of such complexes is therefore a way to provide new mechanisms of action. In this thesis, a series of metal complexes containing ruthenium, osmium, cobalt, rhodium, and iridium are explored for different biological applications, such as antibacterial and anticancer activities. Herein, the ability of some of these complexes to act as biocatalysts to reduce the coenzyme NAD+ in presence of sodium formate is reported, alongside in-depth studies on their chemistry in solution, and their mode of action within the cell. The metal ion (Ru, Os, Rh, Ir) can strongly alter the reactivity of the complexes in solution, and therefore, their biological activity. This work gives insights into our understanding of this class of compounds and paves the way for finding better chemotherapeutic agents to palliate the side effects and the resistance of current treatments. On a related note, preliminary data on some complexes containing the biocompatible metal cobalt are also reported. This data demonstrates the potential of these complexes to be explored more in detail and be considered as a promising alternative to its heavier congeners rhodium and iridium. This thesis highlights the significance of organometallic chemistry and brings to light a bright future for this class of complexes, as their versatility and adaptability make them a cornerstone of modern chemistry.Publication Synthesis and Biological Evaluation of Novel GlycomimeticsCarbohydrate molecules play important roles in the biology of the cell as sources of energy and as a constituent of glycoproteins. In many diseases, such as cancer, energy production and biosynthesis of glycoproteins are dysregulated. This thesis explores two methods for the synthesis of molecules that interfere with these processes and, therefore, can be potential starting points in a drug discovery programme. The first method is to change the main skeleton core of the sugar by synthesising a carbasugar, using the cycloaddition of a novel 2H-pyran-2-one. The second method is changing the groups that decorate the sugar molecule by preparing two novel classes of glucose derivatives. In the first chapter, recent methodologies for synthesising carbasugars are described. The second chapter explored using pyrone cycloaddition to synthesise pseudodisaccharides as potential Golgi α-mannosidase II inhibitors. The synthesis is performed over seven steps. Further optimisation is needed to increase the overall yield. Also, an enzyme assay has to be performed to confirm the biological activity of the synthesised compound. The third chapter describes the synthesis of glucose-6-phosphoramidic acid and glucose-6-triazole derivatives as inhibitors of HK II and the biological evaluation of the synthesised compounds on cancer cells. The triazoloderivatives are synthesised in fewer steps and have shown comparable inhibitory activity against cancer cells to the phosphoramidic acid derivatives. An enzyme assay has to be performed to confirm the mode of action of the synthesised compound against HKII. The last chapter explored the experimental procedures, characterisation of chemical compounds, and details of biological evaluations.