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Title: Oxazolomycin : a natural product lead structure for novel antibiotics
Author: Bagwell, Claire Lucy
Awarding Body: Oxford University
Current Institution: University of Oxford
Date of Award: 2010
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Abstract:
This thesis is concerned with studies towards the design, synthesis and biological evaluation of analogues of the oxazolomycins, a class of structurally complex natural products with potent antibiotic, antiviral and in vivo antitumour activity. Initial investigations focused towards a flexible synthetic route to the left-hand triene system, utilising a series of stereoselective Wittig olefinations. This resulted in the synthesis of truncated inthomycin C analogue (±)-209, which displayed antibacterial activity against S. aureus, E. coli and S. pneumoniae. Methodology was also developed which gave rapid access to the central c.c-dimethyl-Ii-hydroxy amide fragment via ring- opening of substituted p-Iactones, derived from the corresponding aldehydes by a tandem aldol-cyclisation reaction, with primary amines. Installation of the amide functionality at this position had posed difficulties in previous syntheses as a result of the steric hindrance imposed by the neighbouring gem-dimethyl groups. Molecular modelling of oxazolomycin B and a related structure was employed to determine their lowest energy conformations and revealed that the u.o-dimethyl-Bchydroxy amide moiety is likely to control the conformational preferences of the natural products. A library of simplified amide analogues based on this motif was synthesised and their biological activity evaluated, which showed that this subunit can display intrinsic antibacterial activity when appropriately substituted. This investigation was extended to synthesis of a series of c.o-dimethyl-Bchydroxy esters, which exhibited similar J~vels of antibacterial activity to their amide congeners. The structures and conformational preferences of the synthesised amides and esters were studied using X-ray crystallography and IH NMR spectroscopy. Coupling of the u.o-dimethyl-Bchydroxy amide fragment with analogues of the right-hand pyroglutamate core, to give simplified "hybrid" analogues of the oxazolomycins, was explored using a variety of linking strategies. The most successful of these exploited the "Click" 1,3-dipolar cycloaddition of azides and nitrile oxides with terminal alkynes, yielding "hybrid" oxazolomycin mimics featuring triazole and isoxazole linking groups respectively. This approach lead to the development of several novel conjugates exhibiting potent anti-infective bioactivity not shown by either of the constituent components alone; of particular note was derivative 330, which was found to possess an MIC value of 2 ug/rnl. against H influenzae. Such routes to structurally unusual templates based upon the oxazolomycins by lactam and amide subunit conjugation may be amenable to convenient library generation for the purpose of optimisation against different bacterial targets.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.558208  DOI: Not available
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