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dc.contributor.advisorFerrante, Antonio-
dc.contributor.advisorPoulos, Alf-
dc.contributor.authorYeh, Mei-Chun-
dc.description.abstractThe anti-malarial chloroquine (CQ) and derivatives are useful anti-inflammatory agents which have been useful in treating patients with rheumatoid arthritis and systemic lupus erythromytosus. Nevertheless derivatives of CQ, such as hydroxychloroquine (HCQ) have been made to reduce the toxicity and increase the potency of the drug. We have approached this challenge by synthesizing 13 quinoline based compounds bearing a saturated or un-saturated fatty acid side chain (carbon chain length of 3 to 20). Examination of their immunomodulatory properties in vitro at concentrations up to 50μM showed these compounds to have no effect on phytohaemagglutinin- and antigen, tetanus toxoid- induced human lymphocyte proliferation and interferon-γ, interleukin(IL)-2, IL-10 and lymphotoxin production. Similarly, there was no effect on the responses induced by the B cell mitogen, Staphylococcus aureus. In contrast, at the same concentrations, CQ significantly inhibited lymphoproliferation and cytokine production induced by these agents. Using bacterial lipopolyssacharide (LPS) as a stimulus for monocytes in the peripheral blood mononuclear fraction, we found that cytokine production, tumour necrosis factor alpha (TNFα), IL-1β and IL-6 was inhibited by CQ but not the NT compounds. In contrast the data demonstrated that a number of the NT compounds were effective in inhibiting human neutrophil adherence induced by TNF. However, this activity was not related to either the carbon chain length or their saturated versus un-saturated state of the fatty acid side chain. In comparison, both CQ and HCQ had no effect on this response. The compound NT8 which had lauric acid on the side chain of the quinoline structure was the most active. Further studies with this compound revealed that it was particularly effective in inhibiting TNF-induced neutrophil cytokine (IL-1β and IL-8) production but not TNF-induced neutrophil migration inhibition or TNF-induced respiratory burst. CQ and HCQ had no effect on all of these responses. At the lower concentrations of NT8 which significantly inhibited neutrophil adherence and cytokine production, the compound had no effect on adherence induced by phorbol 12-myristate 13-acetate (PMA) and calcium ionophore (A23187). These agents are known to by-pass the surface receptors and act on protein kinase C and cause an increase in intracellular calcium levels respectively, suggesting that the effects of NT8 are upstream in the signalling cascade. Interestingly we found that NT8 caused a significant decrease in surface expression of TNF receptor II (TNFRII) but not TNFRI. This selective effect of NT8 on neutrophil functions such as adherence was lost with an increase in concentration, where the neutrophil responses to the agonists, complement fragment C5a, IL-8, granulocyte macrophage-colony stimulating factor, formyl-Met-Leu-Phe, PMA, A23187 and arachidonic acid were also inhibited. A similar selectivity was seen for neutrophil responses to leukotriene B4. The anti-inflammatory effects of NT8 were confirmed in vivo in a mouse model of LPS-induced peritonitis, where both TNF and neutrophils play an important role. The research in this thesis has enabled the development and characterization of a new class of quinoline based compounds with anti-inflammation properties distinguishable from those of CQ and HCQ, thus, providing a new avenue for the development of anti-inflammatory agents.en
dc.titleSynthesis of quinoline-fatty acid conjugates and characterization of their immunomodulatory propertiesen
dc.contributor.schoolAdelaide Medical Schoolen
dc.provenanceThis electronic version is made publicly available by the University of Adelaide in accordance with its open access policy for student theses. Copyright in this thesis remains with the author. This thesis may incorporate third party material which has been used by the author pursuant to Fair Dealing exceptions. If you are the owner of any included third party copyright material you wish to be removed from this electronic version, please complete the take down form located at:
dc.description.dissertationThesis (Ph.D.) -- University of Adelaide, Adelaide Medical School, 2010en
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