Browsing by Author "Avgenikos, Moscos"

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    Synthesis of small molecule bioactive compounds with potential anti–cancer activity
    (Stellenbosch : Stellenbosch University, 2020-03) Avgenikos, Moscos; Van Otterlo, Willem A. L.; Kaschula, Catherine H.; Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.
    ENGLISH ABSTRACT: Cancer is a major burden on human health and infrastructure as a leading cause of death worldwide. A collective name for a group of diseases characterised by uncontrolled cellular growth; cancer can be caused by a variety of factors including genetic factors and lifestyle choices. The approach to managing these diseases can be summarised into two broad categories, prevention and treatment. The pool of natural products (broadly chemicals derived from natural sources) has long been drawn upon for healing effect and a starting point for the development of pharmaceuticals. Humans have passed down knowledge of the healing properties of certain species plants, for example, for many generations. The paths to maximise the positive effect natural products have to offer against cancer, within the context of the studies herein, are twofold. Achieving a biological understanding of how these products gain their effect paving the way for new treatments and preventions to be developed; and improving access to, and quality of, the active compounds we have at our disposal already. This study is composed of three parts. Firstly, an investigation into the nutraceutical compounds of Flavokawain A and Fisetin, naturally occurring in the Kava plant of Fijian origin and strawberries respectively. These agents display prophylactic properties, and are proposed to reduce the occurrence of certain cancers in the populations that consume the plants these compounds occur in. The mechanism by which these compounds achieve their properties is not well understood. Fluorescent analogues of these compounds were achieved synthetically and imaged via confocal microscopy. Both compounds were found to collect in the endoplasmic reticulum of A549 lung cancer cells as well as displaying low micromolar toxicities to these cells. The second study arose as a short-term collaboration with researchers from Leipzig University, Germany. The researchers have developed synthetic strategies useful for forming 1-4 dihydroquinoline-3 carboxylate derivatives enantioselectively. This scaffold is similar to those of 4–aza–podophyllotoxins, a synthetic analogue to the natural product podophyllotoxin. Previous research reveals that a single enantiomer is responsible for the low nanomolar efficiencies this compound class displays. Thus, our study attempted to achieve an enantioselective synthesis of 4–aza–podophyllotoxin and succeeded in achieving enantioenriched samples using binaphthol phosphoric acid catalysts. Lastly, an investigation into the synthesis of a modified lung cancer drug combatting resistant, mutant epidermal growth factor receptor (EGFR) lung cancer was attempted. Within the investigation a synthetic scaffold was achieved based on WZ 4002 – an irreversible inhibitor currently undergoing clinical trials for resistant lung cancers. EGFR mediated resistance rejects the covalent modifiers currently in use; within this study sulfonyl fluorides have been proposed as replacements. Demonstrated within the study is a viable copper mediated triazole formation strategy which tolerates the sulfonyl fluoride electrophile. The scaffold is primed to achieve a variety of triazole linked probes containing sulfonyl fluorides which we proposed to investigate the chemical space around the EGFR binding site to combat resistance.