Synthesis and evaluation of tetramethoxy stilbenes related to combretastatin A-4 as potential anticancer agents

Adegbulugbe, B 2022, Synthesis and evaluation of tetramethoxy stilbenes related to combretastatin A-4 as potential anticancer agents , MSc by research thesis, University of Salford.

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Abstract

It has been found that in many cases, the current drugs used for cancer treatment result in reoccurrence of the tumour and severe side effects. Drugs from natural sources display less toxicity (Ali et al., 2012). Combretastatins are known to have cytotoxic activity against cancer cells with minimal side effects (Kretzschmann & Fürst, 2013). Derivatives with improved activity and less detrimental side effects are required. The different activities of different combretastatins and their derivatives is due to differences in the binding of the compounds to the Colchicine binding site (CBS) in the protein tubulin (Jin et al., 2011). It was thought to investigate whether addition of a further methoxy group to the A ring improved the binding of combretastatin derivatives to the CBS Studies of the structure- activity relationship of combretastatins suggest that methoxy groups on the A ring are essential for activity against cancer cells. The purpose of this project was to synthesize a range of combretastatins, via Wittig reactions, with a tetramethoxy unit instead of a trimethoxy unit as the A ring, and to test these for activity against cancer cell lines. The activity of these compounds was found and compared to that of the anti-cancer drug Cisplatin, that of combretastatin A4 and the activities of corresponding trimethoxy CA4 analogues. The combretastatin structure is relatively simple and easily manipulated and it has been found that making changes to the double bond and or substituents on the rings changes the activities and properties of compounds, hence the investigation into the effects of having a tetramethoxy A ring unit. Combretastains are easily synthesized using the Wittig reaction, in this case using water as the solvent. In this project, a range of 10 benzaldehydes with different substituents were each reacted with a tetramethoxy phosphonium salt. The phosphonium salt was synthesized via a sequence of synthetic steps, starting from commercially available materials. Very few tetramethoxy combretastatins have been synthesized and even fewer have been tested for their cytotoxic activity. Synthesis of the combretastatins resulted in formation of both E and Z isomers for each compound. It was attempted to separate the isomers in each case and to purify the compounds using flash column chromatography. Separation of the isomers proved to be very difficult but separation of the product from leftover starting materials and impurity products was possible. The cytotoxicities of the synthesized stilbenes against two human cancer cell lines were obtained using an MTT assay. Not much testing has been done with modifications to the trimethoxy motif of CA-4 (Bukhari, Kumar, Revankar & Qin, 2017). In this project it was found in all cases, where the activities of both trimethoxy and tetramethoxy combretastatin derivatives against the same cell line were known, that tetramethoxy analogues are less active than trimethoxy analogues and that some of the compounds synthesized were more active than Cisplatin.

Item Type: Thesis (MSc by research)
Schools: Schools > School of Environment and Life Sciences
Depositing User: Babatunde Adegbulugbe
Date Deposited: 06 Apr 2022 11:57
Last Modified: 12 Apr 2022 15:41
URI: http://usir.salford.ac.uk/id/eprint/63185

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