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Title: Application of pyridazinediones in the construction of self-immolative scaffolds for potential use in small molecule-drug conjugates
Author: Fernandez, Marcos
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2020
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Cancer constitutes one of the leading causes of death worldwide and research in this field is constantly aiming to discover and develop ever more efficient ways in which to treat and manage this disease. For much of the 20th century the leading strategy has been that of chemotherapy: a treatment invariably accompanied by undesirable side effects due to its lack of specificity. The field has therefore moved towards targeted-drug delivery, with antibody-drug conjugates (ADCs) having established themselves in this area with great success. Less work however has been undertaken on small molecule-drug conjugates (SMDCs) and this thesis describes the design of SMDC precursors based on the pyridazinedione (PD) molecule, as well as the development of a novel, sulfur-based self-immolative linker which could enable the attachment of drugs and fluorophores to such a construct. The first primary focus of this work centres around the PD core's thiol reactive centres, with the exploration of whether thioaryl- or thioalkyl-PDs fare better when subjected to human serum- and tumour cell-mimicking conditions. It was found that a bis-thioaryl PD performed best, and its aromatic thiol substituents were subsequently derivatised for the purpose of attaching a fluorophore via a novel, sulfur-based self-immolative linker. The release of the fluorophore seen by LC-MS and the turn-on fluorescence observed by fluorescence spectroscopy both confirmed the self-degradative mechanism of this linker. The second primary objective of this work was to then install groups that are relevant to an SMDC precursor onto the N-handles of the PD core, culminating in the successful isolation of di-bromo PEG azide and PEG alkyne PDs. The latters' bromine positions were then substituted with a derivatisable thiol to demonstrate that incorporating three distinct groups onto the same PD platform is possible, thus vindicating its versatility and modularity. Consequently, novel SMDC precursors have been synthesised whose functional groups have potential for future attachment of fluorophores, drugs and tumour-targeting ligands.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available