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 Synthesis and anticancer evaluation of novel, functionalised bisindolylmaleimides and indolocarbazoles(University College Cork, 2022-10-07) Cooney, Louise; McCarthy, Florence; Irish Research CouncilBisindolylmaleimides (BIMs) and indolocarbazoles (ICZs) have been reported for their potent anticancer activity. These molecules elicit their antiproliferative effects through one of the molecular mechanisms; protein kinase inhibition or interference of topoisomerase I activity. This project focuses on exploring the gaps in knowledge surrounding the BIM and ICZ scaffolds by exploring the target’s horizontal and vertical binding space through structural modifications. This was achieved through the incorporation of rationally designed and selected aromatic units. One indole-type unit of the indolylmaleimide framework was retained to generate a steric probe through N-functionalisation. The hydrogen bonding maleimide headgroup, characteristic to BIM and ICZ, was significantly developed to investigate its importance in biological activity on a molecular level. The NCI-60 human cancer cell line screen was the primary screening method for this project. This in vitro evaluation allowed us to identify lead compounds from the diverse panel of compounds. Initially, 5,6-substituted benzofuran components were incorporated into the BIM and ICZ frame to generate a panel of 55 novel benzofuranylindolylmaleimides (BfIMs) and benzofuranopyrrolocarbazoles (BPCs). Significant anticancer activity was reported for the BfIM series in the one dose screen, with one candidate advancing to five dose screening and having a reported GI50 value of 0.407 µM. Other collaborative studies with the University of Nantes and Ohio added important dimensions to the project by investigating BfIMs that showed no anticancer effects and screening them against fungal and adipocyte PKC-β. These supplementary studies resulted in the identification of compounds as potent kinase inhibitors. A total of 6 BPC candidates progressed to five dose anticancer screening and demonstrated remarkable inhibition. A further 53 novel derivatives were prepared when naphthalene was incorporated to develop naphthylindolylmaleimides (NIMs) and naphthopyrrolocarbazoles (NPCs). Significant antiproliferative effects were exhibited by the NPC panel of compounds compared to the ring-open NIMs with 8 compounds advancing to five dose anticancer screening. In fact, it was the F-ring modified NPCs which were identified as lead candidates. It was noted that many of the BPC and NPC five dose anticancer candidates had strong correlations with known topoisomerase I inhibitors on the COMPARE analysis database.Item Studies in the synthesis and analysis of novel heterocyclic synthetic cannabinoid receptor agonists(University College Cork, 2022-03-08) Alam, Ryan; Keating, J J; Eli Lilly and CompanyOver the past decade, synthetic cannabinoid receptor agonists (SCRA) have come to represent a diverse category of new psychoactive substance (NPS). However, from a chemical perspective, little is known about the clandestine chemical syntheses of SCRAs. To contextualise the latter paucity of information, this thesis introduces the pharmacological significance of the endocannabinoid system and describes the subsequent advances that have been made to develop synthetic cannabinoid-based therapeutics. The repurposing of cannabinoids that were developed as a part of legitimate drug discovery programmes, for recreational use as illicit NPS, is then discussed with a particular focus on the structural diversity, toxicological adverse effects, legislative control, and chemical characterisation of newly emerging SCRA ligands. Following the assembly of the key heterocyclic building block in the synthesis of indazole-type SCRA ligands, 1H-indazole-3-carboxylic acid, this work describes the development and application of a protocol for the regioselective (>99%) N-1 alkylation of the indazole scaffold to generate a wide range of structurally diverse N-1 substituted indazole derivatives in excellent yield (up to 99%). Additionally, the latter optimised N-alkylation protocol is also shown to regioselectively (> 99%) afford N-2 substituted indazoles. Through the variation of “tail” and “head” group motifs inspired by structural trends observed in newly emerging cannabimimetic SCRA NPS, we have generated a prophetic library of novel 1,3-disubstituted indazole-3-carboxamide derivatives. The subsequent discussion of notable spectroscopic features of these heterocyclic SCRA analogues provides further information of forensic interest. Finally, the development and optimisation of a methodology for an expedient approach to analogous, novel, 1,3-disubstituted pyrazolo[3,4-b]pyridine-3- carboxamide SCRA derivatives in high yield (up to 99%), via palladium-catalysed aminocarbonylation is described. This aminocarbonylation protocol is applied to the synthesis of isomeric 4-, 5-, 6-, and 7-azaindazole analogues of the known illicit indazole SCRA ligand, MDMB-PINACA, to facilitate their unambiguous spectroscopic differentiation and structural confirmation. The latter work provides a robust and convenient methodology for the synthesis of pyrazolopyridine-3-carboxamides and presents the first reported spectroscopic discussion of azaindazole-type SCRA NPS.