The modulatory effects of functionalised chalcones on protease-activated mediator release /Peng Kai Soh

Peng Kai Soh

Research output: ThesisDoctoral Thesis

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Abstract

[Truncated abstract] Inflammatory events that occur at, or involve the epithelium, are important and widely implicated in a variety of chronic airway diseases such as chronic obstructive pulmonary disease and asthma. During inflammation, the respiratory epithelium releases a wide array of pro-inflammatory mediators such as chemokines, cytokines and lipid mediators, and their modulation may have therapeutic implications. Proteases such as thrombin, and tryptase from mast cells, are often released in response to inflammatory stimuli in the lung and these are known to activate protease activated receptors (PARs) by cleaving the amino terminus of the receptors. Following PAR activation, a series of signalling transduction pathways are activated, and subsequently mediate the release of various pro-inflammatory mediators including interleukin (IL)-6 and IL-8 and prostaglandin (PG)E2. Mediator release can be modulated in various ways, and recent studies suggest that chalcones, organic compounds comprising the 1,3-diphenylprop-2-en-1-one framework may be useful. These naturally occurring compounds have been reported to possess a wide range of properties which include antiinflammatory, anti-tumour, antioxidant and antimicrobial activity. This thesis describes studies on the modulatory effects of several chalcone derivatives on protease- and PAR agonist peptide (AP)-mediated mediator release from the human respiratory epithelial A549 type II pneumocyte cell line, primary normal human bronchial epithelial (NHBE) cells and the prostate epithelial cell line (PC3), as well as their possible mode of action. Twenty six chalcone derivatives were synthesised and characterised by a co-worker using a base catalysed Claisen–Schmidt condensation reaction of an aryl methyl ketone and an aryl-aldehyde using polyethylene glycol (PEG) 300. Prior to testing their modulatory activity, solubility and cytotoxicity experiments were performed. All chalcones tested were soluble only in dimethyl sulphoxide (DMSO). Fourteen out of the twenty six compounds tested formed precipitates, while the remaining twelve were soluble in culture medium containing 1.5% (v/v) DMSO...
Original languageEnglish
QualificationDoctor of Philosophy
Publication statusUnpublished - 2010

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