Analytical & Biological Chemistry Research Facility - Doctoral Theses
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Item Multifaceted computational modelling in pharmaceutical research and development(University College Cork, 2023) Vinay Kumar Reddy, Cheemarla; Tiana, Davide; Lawrence, Simon; Swiss Forum for International Agricultural Research; National Institute of Neurological Disorders and StrokeDrug development is a multi-step process and takes around 12 to 15 years for a new drug to get approved. In the current scenario, to accelerate the drug development process and to reduce the time frame, most pharmaceutical companies have in-house developed workflows comprised of a hybrid use of computational and experimental approaches. This thesis was focused on employing state-of-the-art molecular modelling methods in three significant areas of pharmaceutical research and development. This thesis comprises an introductory part (chapter 1) and a productive part (chapter 3 to chapter 5). The first chapter of this thesis is the literature review, outlining the foundational studies and research framework used in chapters 3 to 5. The second chapter describes the thesis structure and objectives of the other three chapters. The third chapter explores the hit identification process, utilising docking to screen a small database of phytopharmaceuticals against sclerostin protein followed by an investigation of the stability of the protein-ligand complexes through standard molecular dynamics and funnel meta dynamics. The fourth chapter involves the modelling of adsorption and diffusion of doxorubicin, paclitaxel, carboplatin, and gemcitabine anticancer drugs and also drug combinations such as doxorubicin with carboplatin, paclitaxel with gemcitabine and carboplatin employing NUIG-4 metal-organic framework as drug delivery agents. In this chapter, the comprehensive understanding of molecular interactions governing drug adsorption and diffusion was studied using Grand Canonical Monte Carlo (GCMC) and Molecular Dynamics (MD) simulations. The fifth chapter focuses on investigating the mechanism of chiral Bronsted acid catalysed asymmetric synthesis of homoallyl alcohols from ortho vinyl benzaldehydes and allyl boron pinacol ester using density functional theory methods (DFT), QTAIM, and NCI analysis. Furthermore, a comparative analysis of transition structures of Ortho vinyl and ortho alkynyl benzaldehyde substrates was studied.Item Studies in synthesis using CO2 and H2 gases(University College Cork, 2023) Lowry, Amy; Mcglacken, Gerard P.; Byrne, Peter; Irish Research Council; Higher Education AuthorityThis thesis is split into two parts based on two different areas of research. Part 1 Part 1 is sub-divided into four chapters. Chapter 1 involves a review of the existing research conducted in this area. Chapter 2 provides details on the research carried out in this project on the development of a Wittig CO2 utilisation methodology for the synthesis of α,β unsaturated carboxylic acids. Chapter 3 involves discussion on the development of protocols for purification of the α,β-unsaturated carboxylic acids synthesised. The Conclusions and Future Work section relating to this area of research is found at the end of Chapter 3. Chapter 4 outlines the experimental work for Part 1. CO2 utilisation continues to capture the attention of chemists due to the ever-increasing levels of CO2 and the negative effects of global warming. CO2 is an inexpensive and environmentally friendly C1 building block, which can be used in the synthesis of value-added chemicals. Many medicinally important compounds and natural products contain the elements of CO2 within their structure, including carboxylic acids, enoates, and carbamates. In particular, α,β unsaturated carboxyl compounds are typically accessed by metal-catalysed transformations or condensation reactions, which often require hydrolysis of the ester product to furnish the corresponding acid. In this project, a telescoped process was developed, that not only achieves CO2 activation, but exploits a novel application of the Wittig reaction, enabling direct installation of the carboxyl group by two successive carbon-carbon bond forming events. Reaction optimisation and purification studies were carried out and 34 α,β-unsaturated carboxylic acids were synthesised using the method, containing a wide range of functional groups, as well as a number of pharmaceutical precursors, in moderate to excellent yields. As part of this work, a novel method for purification of α,β-unsaturated carboxylic acids was developed. Part 2 Part 2 is sub-divided into three chapters. Chapter 5 involves a discussion on the background of the project and a review of the existing research conducted in the area. Chapter 6 involves a discussion of the research carried out in this project on the dearomatisation of benzofuroquinolines by a Pd-catalysed hydrogenation reaction. The Conclusions and Future Work section relating to this part of the thesis is found at the end of Chapter 6. Chapter 7 outlines the experimental work for Part 2. Within the McGlacken group, development of C-H activation methodologies has been a large area of research, and, in particular, benzofuroquinolines have been synthesised via direct intramolecular arylation of 4-phenoxyquinolines. The quinoline nucleus is one of the most frequently occurring ring systems in approved drugs, and hydrogenation of the quinoline nucleus and the selectivity thereof, has been reported in the literature. In addition, increasing interest in the concept of ‘escaping flatland’, whereby the saturation of compounds is increased, allowing for the exploration of more architecturally complex molecules that will potentially give rise to enhanced biological activities. In this part of the thesis, a range of differently substituted benzofuroquinolines were hydrogenated to generate 18 selectively dearomatised benzofuroquinolines. Investigations were carried out into different reaction conditions tolerated by the reaction, and the fate of halogen substituents in the reaction. In addition, a double reduction product side-product was identified and characterised, opening up the methodology to the formation of a new class of novel compounds.Item The powerful combination of novel organosulfur methodology and continuous flow technology(University College Cork, 2023) Kearney, Aoife M.; Maguire, Anita; Collins, Stuart; Irish Research Council; Higher Education AuthorityThe work described in this thesis focuses on the use of novel methodologies in the form of continuous flow technology, FlowNMR, and FlowIR, as well as traditional batch techniques, to deliver powerful transformations based on organosulfur chemistry. The main objective of this work was the synthesis of key building-blocks for biologically relevant compounds coupled with the use of Process Analytical Technologies (PAT), to gain critical mechanistic insight and understanding, not previously accessible, to further add to the knowledge in the field, and deliver more efficient processes. Chapter 1 is a literature overview of the use of Process Analytical Technologies in continuous flow systems, with specific attention on the positive impacts of PAT in enabling the telescoping of multi-step sequences, both in industry and academia. Chapter 2 describes the synthesis of α-sulfenyl-β-chloroenones through a NCS chlorination transformation, and their subsequent use in a Stille cross-coupling reaction to form chalcone derivatives. Key mechanistic insight into the formation of the α-sulfenyl-β-chloroenones was provided through use of reaction monitoring via a combined FlowNMR and FlowIR study. This technology expanded our understanding of the mechanistic pathway to these substrates, showing for the first time the formation of the E-isomer as the kinetically favoured product, with isomerisation leading to the thermodynamically more favoured Z-isomer. Significantly, while exploring the reactivity of these compounds, through alteration of the synthetic steps in the sequence, complimentary routes to either the Z- or E-sulfoxide chalcone derivatives were designed; this provided access to the Z-sulfoxide chalcones for the first time. Chapter 3 details the successful extension of the NCS-mediated chlorination reaction to include lactam derivatives, synthesising a number of novel α-sulfenyl-β-chloro-enelactams. Once again, the mechanistic route to these derivatives was confirmed through use of FlowNMR as a reaction monitoring tool. Continuous flow technology was incorporated into the synthesis of the α-sulfenyl lactam core, leading to a three-step telescoped reaction sequence involving in situ sulfonyl azide formation, followed by diazo transfer and a rhodium-catalysed S– H insertion, with real-time monitoring provided by FlowIR spectroscopy. The effect of ring size and substituents on the NCS-mediated transformation was investigated with 5-membered, 6-membered, and a fused ring derivative prepared during this work. Notably, this work demonstrated for the first time that the NCS chlorination sequence is effective in lactams, in addition to the acyclic systems, despite the increased conformational constraints in a cyclic system. A number of five-membered β-chloroenelactams exhibited cytotoxic properties against specific cancer cell lines when screened for biological activity in The National Cancer Institute, Maryland, US. Chapter 5 outlines the successful optimisation of a three-step synthesis towards E-α-sulfenyl-β-hydroxyacrylamides in batch, without handling or isolation of any reaction intermediates, and the development, for the first time, of a three-step telescoped continuous flow reaction sequence. The use of continuous flow technology improved the synthetic route, providing the product in a high degree of purity in a fraction of the time required for the same process in batch, with clear potential for scale-up. An investigation into the feasibility of conducting the three-step sequence using an advanced CSTR was undertaken, for comparison with batch and continuous flow processing. Insight into the transformation was gained by both a high-field (600 MHz) and low-field (80 MHz) FlowNMR study, revealing for the first time, the appearance of the Z-isomer of β-hydroxyacrylamide in the aqueous acetonitrile reaction medium, in contrast to the E-isomer typically isolated from batch reactions. Chapter 6 describes the synthesis of a series of amino-tetralin and amino-indane derivatives for use in a transaminase-mediated kinetic resolution biotransformation. Full experimental details and spectroscopic characterisation of the compounds synthesised in the work are provided in Chapters 4, 5, and 6. Lastly, Chapter 7 contains the overall conclusions of the thesis.Item Development of an electrochemical immunosensor for environmental monitoring of polychlorinated biphenyls (PCBs) in soil environment(University College Cork, 2023) Alsefri, Samia; Moore, Eric; Ministry of Education – Kingdom of Saudi ArabiPolychlorinated biphenyls, PCBs are a type of chemical contaminant known as persistent organic pollutants (POPs). They consist of biphenyl molecules covalently bonded with one to ten chlorine atoms. PCBs pose a threat to ecosystems and food safety due to their high toxicity, long-term stability, poor degradation, and bioaccumulation. The current methods, although sensitive, have their limitations, for example, time-consuming, laborious, and costly. Further, the instrumentation cannot be used for on-site analysis. The aim of this research is to develop a novel electrochemical method that will be capable of providing a direct, portable, cost-effective, and easy method for analysing and monitoring PCBs in the environment. For the first time, a self-assembled monolayer was used to modify an electrode as a method for fabricating a transducer for detection of PCBs by using a gold electrode, it was modified with 11-mercaptoundecanoic acid (11-MUA), and the activation of the carboxylic acid terminal was performed by cross-linking 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) and N-hyrodsuccinmide (NHS). The electrochemical behaviour of the electrode was investigated by CV (Cyclic Voltammetry), LSV (Linear Sweep Voltammetry) and EIS (Electrochemical Impedance Spectroscopy) using a ferrocyanide/ferricyanide redox pair. It was found that the indirect competitive assay showed the best performance for Aroclor1254 detection, with a commercial Polyclonal chicken antibody (IgY) specific to PCB was used as primary antibody. The limit of detection was found at 0.20 ng/ml using bare gold electrode. However, the sensitivity of the sensor was increased after the electrode surface modification was found at 0.09 ng/ml. A novel electrochemical immunosensor method showed a good performance with a 3-fold decrease in sensitivity achieved after the surface modification. The electrode coated with coating conjugate was found stable for more than 25 days at 4 ˚C. In conclusion, this Ph.D. thesis demonstrates that the integration of electrochemical techniques with immunoassay methods can achieve detection limits as low as required for in-situ and real-time analysis of soil samples. It was found that the electrochemical immunosensor method showed better results compared to ELISA and that was verified with GC-MS. The usage of this a novel electrochemical immunosensor as a complement to the electrochemical studies not only enhanced the quality of the research but also contributed to the construction and improvement of immunosensors. As a result, they represent an accurate and a new robust method that can be applied to microsensors and microfluidic systems for the effective control and prevention of PCBs in the environment.Item Studies in the synthesis and impurity profiling of pharmacologically active benzodifurans(University College Cork, 2022) O'Connor, Richard Eric; Keating, J J; Higher Education AuthoritySubstituted 2,3-dihydrobenzofuran derivatives as well as their benzofuran and benzodifuranyl analogues are versatile heterocycles that are increasing in prominence as key building blocks in organic chemistry. In particular, benzodifuran-containing structures are gaining significant interest in medicinal chemistry as pharmacophores and in industrial chemistry as scaffolds for organic electroluminescent devices, organic field-effect transistors, solar cell sensitizers and semiconducting polymers. The synthesis of pharmacologically active benzodifurans are complex multi-step processes and each individual step has the potential for considerable side-product/impurity formation. This project focused on synthetic strategies to benzofuran and benzodifuran derivatives in addition to their hydrogenated and substituted analogues. The chosen synthetic routes to target molecules further focused on the propensity of synthetic steps to produce impurities, modifiable variables to modulate impurity formation and the impurity profile of each synthetic route explored. Organic process impurities identified were isolated and fully characterised where possible, in addition to intended products.