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Abstract
This thesis describes the development of two bioactive small molecule scaffolds to investigate how and why they target their respective biological systems. Chapter 1 provides an introduction to the valuable use and development of small molecules in accessing effective therapeutics, and as chemical probes, to explore protein targets and biochemical pathways.
Chapter 2 explores O-benzyl AAL(S) as a lead compound for the development of selective CerS1 inhibitors. Synthetic protocols utilising (S)-Schöllkopf’s reagent were used to access 39 analogues with variation of the benzyl tail and amino-alcohol head group. By conducting relevant biological investigations, it was found that variation to the head group was not tolerated, while addition of substituents onto the tail provided non-cytotoxic compounds with nanomolar potency. Importantly, compounds identified are the first ever reported to be selective towards a single CerS isoform. To have a more directed approach to analogue design, a photoactive O-benzyl AAL(S) probe was developed that will be used to identify the binding mode of the O-benzyl AAL(S) scaffold to CerS1.
Chapter 3 investigates effects of the FTY720 and deoxy AAL(S) scaffolds towards PP2A, an enzyme that is repressed in leukaemia cells. An effective synthetic route was developed to access derivatives of these scaffolds that could be used as chemical probes. These compounds contained a terminal alkyne group within the deoxy tail. Additionally, head-group analogues were synthesised in efforts to activate PP2A. Multiple cell based biological investigations were conducted and identified that these compounds upregulate PP2A, and have a range of cytotoxic effects.
Chapter 4 examines a 2’,6’-disubstituted imidazopyridine scaffold for the upregulation of βIII-tubulin, a protein that contributes to tumour cell growth. Analogue libraries exploring variations of the 6’-amide group, the core moiety and the 2’ aryl ring provided 38 analogues with up to a 9.9-fold increase in TUBB3 mRNA expression. Additionally, affinity pull down assays were performed using two developed small molecule probes. These assays successfully identified the endogenous protein binding partners of the imidazopyridine scaffold.
A summary of the work described and future directions for the projects are given in Chapter 5. Full experimental procedures have been reported in Chapter 6.