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Title: Activity-directed fragment-based ligand discovery
Author: Liver, Samuel James
ISNI:       0000 0004 7970 2194
Awarding Body: University of Leeds
Current Institution: University of Leeds
Date of Award: 2019
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Biologically active small molecules are typically discovered in designsynthesis-purify-test cycles. These workflows are underpinned by a remarkably narrow toolkit of robust and reliable chemical transformations and place equal resources on all molecules regardless of their biological function. Activity-directed synthesis harnesses the potential of chemical reactions that can form more than one possible product and allows resources to be focussed on small molecules with biological activity. The discovery of small molecules through activity-directed synthesis emerge in parallel to their associated synthetic routes. A feedback mechanism can serve to optimise the range of bioactive products, analogous to the emergence of natural products through the evolution of biosynthetic pathways found in nature. The implementation of fragments as substrates in activity-directed synthesis has the potential to enable their optimisation into lead-like compounds without the target molecule being predefined, contrasting starkly to typical structureguided fragment-to-lead studies. A range of C-H functionalisation chemistry was configured in microscale parallel reaction array format, for its implementation as a fragment elaboration strategy in activity-directed synthesis. This chemistry, along with the previously established metalcatalysed carbenoid chemistry, was assessed for its potential to elaborate Hsp90 fragments. To ensure a streamlined workflow for activity-directed synthesis a series of protocols, for scavenging of metal catalysts and electrophiles and removal of fragment protecting groups, was established for use in parallel reaction array format. To enable the elaboration of Hsp90 fragments with the chosen chemistries in activity-directed synthesis, a set of fragments designed for biological activity against Hsp90 was prepared. The fragments were screened in the established high-throughput assay and led to the discovery of analogues of Hsp90 fragments with previously unreported activity. The use of the high-throughput assay and LC-MS enabled the biological activity and success rate of the crude reaction mixtures from the arrays to be rapidly assessed. The study highlighted the poor functional group tolerance of modern chemical methodologies and the need for robust and reliable chemical transformations in medicinal chemistry workflows.
Supervisor: Nelson, Adam ; Warriner, Stuart Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available