| Lipid A, the glycolipid component of Gram-negative bacterial lipopolysaccharide has been shown to engage the Toll-like receptor 4 (TLR4) signalling pathway. While this signalling cascade results in cellular mediators which serve to activate the immune system and eliminate the invading organism, the associated toxicity is potentially harmful to the host. With an ever increasing molecular understanding of TLR4 mediated signalling, synthetic analogs of the natural Lipid A structure and the structure-activity relationship information they provide have emerged as a potential method of harnessing the desired immunomodulating effects from the undesired toxicity. As such, the therapeutic potential of TLR4 signalling is becoming an increasing possibility.;*Please refer to dissertation for diagrams.;Two novel synthetic frameworks have been designed and synthesized to potentially mimic the natural Lipid A structure. A dimeric monosaccharide framework was obtained, however, attempts at functionalization (R = Lipid) to generate a series of analogs were generally unsuccessful due to unforeseen circumstances. A revised synthetic strategy has thereby been undertaken to allow more facile functionalization of this framework. A monosaccharide framework in which diethanolamine is employed as an acyclic scaffold replacing one of the sugar groups common to the natural disaccharide Lipid A structure has also been obtained. Functionalization (R = Lipid) has been successfully achieved, with further functionalization of this framework through the acyclic hydroxyl moiety intended. Ultimately, biological evaluation will determine the potential of these frameworks as being ligands for TLR4.*... |
