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Abstract

Metformin (N, N-dimethylbiguanide) is the most widely used anti-diabetic drug to treat type II diabetes. Clinical studies have shown that metformin, and other biguanides (buformin and phenformin), have antineoplastic activity in different types of cancer. The purpose of this project was to devise a convenient synthetic route to produce pure metformin and, along with another biguanide called phenformin, to investigate their anticancer properties on high-grade brain tumour cells (glioblastoma multiforme).
The work presented in this study reports the synthesis and purification techniques of metformin. The methods by which metformin is synthesised commercially have been vague. In this work, metformin hydrochloride has been prepared by refluxing a reaction mixture of dimethylamine hydrochloride and dicyandiamide using different reaction conditions and purification techniques. Solid products were analysed using a range of techniques, such as melting points, Fourier Transform Infra-red spectroscopy, ¹H and ¹³C Nuclear Magnetic Resonance spectroscopy and High-Performance Liquid Chromatography. The conditions for the synthesis of pure metformin in good yield over 50 % were also identified. 

The cytotoxic role of metformin and phenformin was examined in a panel of a highgrade glioma cells to investigate the anticancer activity of both drugs. Metformin and phenformin exposure significantly reduced the cell viability. Cells were cultured in
high (25 mM) and low (5 mM) glucose level in the media and the IC50 of metformin and phenformin were assessed to examine the effect of glucose level on the efficacy of metformin and phenformin. The IC50 of metformin were lower in UP029 and SEBTA 74 when they were maintained in low (5 mM) glucose level 41mM and 2 mM respectively than when they were maintained in high (25 mM) glucose level 85 mM in both cell lines. While the IC50s of phenformin on UP029 showed that low glucose concentrations in the media has no effect on the IC50s of phenformin 29 mM compared to 13 mM when the cell was maintained in high (25 mM) glucose level.

Some of the cells showed different sensitivity to metformin and phenformin and this could be due to their genotype and mutation status. Apoptosis was investigated using an annexin V assay; no apoptotic cells were identified, but this is could have been due to the design of the experiment.

Course: Master of Philosophy - MPhil

Date Deposited: 2020-12-16

URI/permalink: https://library.port.ac.uk/dissert/dis13629.html