Please use this identifier to cite or link to this item: http://theses.ncl.ac.uk/jspui/handle/10443/5478
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dc.contributor.authorHunter, James Henry-
dc.date.accessioned2022-06-30T09:25:10Z-
dc.date.available2022-06-30T09:25:10Z-
dc.date.issued2021-
dc.identifier.urihttp://hdl.handle.net/10443/5478-
dc.descriptionPhD Thesisen_US
dc.description.abstractThe discovery of potential lead like molecules is a crucial phase for any drug discovery program. Current methods to identify lead molecules are often resource intensive, often requiring millions of compounds to be screened in biological assays. Reducing the time and cost taken to generate, store and screen large compound libraries would have a positive impact on academia and small pharmaceutical companies. DNA encoded libraries (DELs) aim to improve upon this by screening an entire library in a single vessel against a target and utilising the DNA tag to identify potential inhibitors. Current methods of preparing DELs are limited to chemistry that is compatible with DNA. These chemical methods are often limited to simple chemical reactions, such as cross-couplings and amide bond formation, which are used combinatoriality to generate vast libraries. As analogous chemical reactions are used, current libraries are often populated with compounds with similar physical properties and have limited structural diversity. The reactions used to generate DELs are often low yielding, or are limited in substrate scope, further reducing the diversity of potential libraries. Development of new approaches with DEL synthesis will increase the ability to synthesise libraries with greater chemical diversity and improved physical property profiles. Products produced from the encoded transformation paradigm. A new paradigm termed “encoded transformations” was introduced. This technique involves encoding a specific chemical transformation of a reactive core molecule instead of coding the addition of a building block. This would lead to a potential library of compounds with reduced overall molecular weight and more lead-like physical properties. A common reactive 2-oxobetenamide core was used and several chemical transformations have been successfully employed. These chemical transformations were developed off-DNA and provide a means to prepare libraries with significant scaffold diversity using DNA compatible chemistry. Micellar solvents have been shown to improve normal phase organic chemical reactions. Applying this technique to on-DNA synthesis vastly improved the scope and diversity of the reactants used. Both amide couplings and Suzuki-Miyaura reactions were successfully optimised utilising micellar media as a solvent. Optimisation was carried out in both examples by factorial experimental design (FED), which revealed second order relationships between variables tested that would not likely be discovered using conventional techniques. Products produced from novel micellar promoted Suzuki-Miyaura and amide reactions. These novel reactions were used to synthesise a prototype 6x6 library, which was PCR amplified and sequenced proving that reactions in micellar media do not cause DNA damage. The reverse amide coupling was then used to create a 99,405-member library, including compounds designed to specifically target the SARs-CoV-2 main protease (Mpro) binding site, using an array of both covalent and non-covalent inhibitors.en_US
dc.description.sponsorshipAstraZenecaen_US
dc.language.isoenen_US
dc.publisherNewcastle Universityen_US
dc.titleExpanding the scope of DNA compatible chemistry for the application within DNA encoded librariesen_US
dc.typeThesisen_US
Appears in Collections:Northern Institute for Cancer Research

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