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Title: Synthesis and biological evaluation of isoxazole derivatives as pre-mRNA splicing inhibitors
Author: Rashid, Srood
ISNI:       0000 0004 7965 2465
Awarding Body: University of Manchester
Current Institution: University of Manchester
Date of Award: 2017
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It is now known that eukaryotic pre-mRNA splicing is catalysed by complex molecular machinery called the spliceosome which consists of five U-type (snRNAs) and nearly 300 supplemental protein and non-protein snRNP groups. However, the exact mechanism by which the ends and branch point of introns of nuclear pre-mRNA are recognized and eliminated in order to produce complementary messenger RNA (mRNA) is as yet unknown. Tackling this complex issue is of immense importance as a number of inherited human diseases result from faults in pre-mRNA splicing. Prp8 is the largest and one of the essential spliceosomal proteins. This protein is implicated in splicing reactions although its exact biological role and structure remain largely undefined. That said it is known that pre-mRNA splicing is associated with chromatin modification and that chromatin modification can modulate spliceosome activity. Structural bioinformatics analysis has been used to gain additional insights into the molecular structure of Prp8. From these studies it has been concluded that the Prp8 N-terminal region contains a putative bromodomain. The bromodomain is an important chromosomal protein which is associated with chromatin modification, a hypothesis which should lend itself to practical investigation. Recent studies have shown that isoxazole derivatives have remarkable potency as inhibitors for bromodomains, an observation which may be reflected in the continued interest in the development of isoxazole-based structures as ethical pharmaceuticals. The outcomes of splicing assays indicate that isoxazole 183c shows complete inhibition for in vitro pre-mRNA splicing in both yeast and human cells at 250 μM with effects beginning at 100 μM. Hence, the existence of putative bromodomain or bromodomain-like structure in Prp8 N-terminal region have been confirmed by biochemical investigation. This was based on a comparative bioinformatics analysis which combined with X-ray crystallographic studies of bromodomain-isoxazole interactions. The current programme of research has investigated novel approaches to the synthesis of isoxazole derivatives. The use of a radical Truce-Smiles rearrangement reaction has been investigated for the synthesis of isoxazoles containing a bi-aryl axis. An indication of the rate of these rearrangement reactions has been gained from intramolecular and intermolecular radical trapping reactions.
Supervisor: Quayle, Peter Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Pre-mRNA splicing ; Isoxazoles ; Radical rearrangement reaction ; Bromodomains ; Antimicrobial agent