Purcell, Ian Charles (2007) Bacterial Autoinducer Derived 4-Quinolones as Novel Immune Modulators. PhD thesis, University of Nottingham.
Immunological disorders, including those of an autoimmune nature, cause chronic morbidity and disability. These conditions are not well controlled with current therapies and issues, including the lack of specificity of action, lead to a number of adverse drug effects. Thus the search for alternative immune modulating agents is a well sought after objective.
Recently, the quorum sensing signal molecules, N-(3-oxododecanoyl)-L-homoserine lactone (OdDHL) and 2-n-heptyl-3-hydroxy-4(1H)-quinolone (PQS), isolated from Pseudomonas aeruginosa, were found to possess the ability to modulate the immune response. The immune modulatory activity of PQS suggests that an evaluation of its synthetic analogues may provide better understanding of the structural components that influence its activity and may lead to the development of novel therapeutic agents. Additionally, to allow an effective SAR study to be attempted with PQS a more efficient synthetic route has to be developed.
To address these issues, the research in this thesis firstly investigates a number of synthetic routes towards the preparation of PQS and its synthetic analogues. The successful synthetic routes yielded analogues with alterations to the main structural components of PQS, namely the alkyl side chain, N-substitution, 3-hydroxyl group and substitution on, and in, the carbocyclic ring.
All analogues were characterised for identity and purity, then their immune modulatory activity assessed in a concanavalin A mitogen stimulated murine cell proliferation assay and their cytotoxicity using a dye exclusion assay. Bioactivity was shown to be dependent on the length of the 2-akyl side chain, with extensions to the chain more tolerated than a reduction. The nature of the substitution at the 3-position has an influence on activity, whereas a proton on the nitrogen is not essential. The less polar and more lipophilic molecules displayed increased bioactivity. The core quinolone structure can tolerate insertion of extra heteroatoms the heterocyclic ring and substitution of chlorine on the carbocyclic ring, while retaining an acceptable level of activity. A similar trend was observed in the quinazolinone derivatives.
|Item Type:||Thesis (PhD)|
|Uncontrolled Keywords:||quorum sensing, PQS, pseudomonas quinolone signal, immune modulation, structure activity relationship, SAR|
|Faculties/Schools:||UK Campuses > Faculty of Science > School of Pharmacy|
|Deposited By:||Ian Charles Purcell|
|Deposited On:||20 Mar 2008|
|Last Modified:||06 Feb 2009 14:43|
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