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The effect of thiazinoquinones and poly (para-phenylene ethynylene) (PPE), poly (para-phenylene vinylene) (PPV) and poly[(2-(methacryloyloxy)ethyl) trimethylammonium chloride] (PMETAC) graft copolymers as anti-cancer or antimicrobial agents for drug repurposing.

McBrearty, Jordan (2018) The effect of thiazinoquinones and poly (para-phenylene ethynylene) (PPE), poly (para-phenylene vinylene) (PPV) and poly[(2-(methacryloyloxy)ethyl) trimethylammonium chloride] (PMETAC) graft copolymers as anti-cancer or antimicrobial agents for drug repurposing. Masters thesis (MSc), Manchester Metropolitan University.

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Abstract

The expensive nature of drug development and growth of antimicrobial resistance is resulting in the need for novel anti-cancer and antimicrobial treatments. While it is important to develop novel compounds, drug repurposing is also becoming an appealing option in finding new treatment. Two types of novel compounds, thiazinoquinones and poly (para-phenylene ethynylene) (PPE), poly (para-phenylene vinylene) (PPV) and poly[(2-(methacryloyloxy)ethyl) trimethylammonium chloride] (PMETAC) graft copolymers were evaluated as both anti-cancer drugs and antimicrobials. MTS proliferation assays and Annexin V/ propidium iodide assays were used to evaluate anti-cancer activity of both sets of the compounds. The antimicrobial activity of the PPE/PPV copolymers was evaluated by performing zones of inhibition, minimum inhibitory concentration and minimum bactericidal concentration assays. In addition, Galleria mellonella toxicity models were used to investigate the cytotoxicity of one of the PPE/PPV copolymers. Overall the thiazinoquinones did significantly reduce the survival rate of the cell population at the highest concentration in which, the sub category MC4 displayed more efficacy than the others. Thiazinoquinone MC4-176-1 decreased the surviving cell population to 0.2% at 100 μM. The MC4 sub category remained the most active in which MC4-176-2 reduced the viable population the most to 9.51%. In contrast to this, MC4-176-1 and MC8-28-1 had the highest early apoptotic population percentage. Overall the thiazinoquinones tested were prominently inducers of apoptosis in Jurkat cells. As the apoptotic pathways and the prevention of apoptosis is significant in the development of cancers, further investigation should be done into the mode of action of these compounds. The PPE/PPV copolymers were collectively ineffective at reducing the survival rate of the Jurkat cells below normal population levels so would not need to be investigated further however, they were found to be effective antimicrobials against a range of bacteria including Escherichia coli, Methicillin Resistant Staphylococcus aureus and Enterococcus faecium. The antimicrobial activity ranged in efficacy with each compound and bacteria; The zones of inhibition indicated a high efficacy of compound 003 and 033 against L.monocytogenes at 41.67mm and 51.67mm respectively. In addition compound 043 was overall a more effective inhibitory and bactericidal antimicrobial against the range of bacteria in a planktonic state. Compound 043 was most effective at inhibiting the growth of E. coli, MRSA and E. faecium at concentrations of 19.5μg/ml, 83μg/ml and 78.1μg/ml respectively. The most bactericidal concentration of 043 was 39.1μg/ml against E.coli. Their lack of anti-cancer abilities suggests they may make a suitable topical antimicrobial as they do not cause cell damage and mode of action should be investigated. The galleria models indicated the compounds were not toxic at the highest level tested i.e. 50mg and should be taken through to use in a full infection model.

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