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Synthesis and Biological Evaluation of Tumour Targeting Analogues of Combretastatin A4


   School of Pharmacy (Medway Campus)


About the Project

The aim of this PhD project is to design, synthesise and evaluate novel CA4-PUFA conjugates to discover novel compounds with high selectivity for cancer cells.

Cancer is a global health issue and is currently the second leading cause of death globally (1). This means there is urgent need to develop new approaches to cancer treatment. Therefore, there is a need for improved chemotherapeutic treatments. Our work is currently focused on a natural product called the combretastatin A4 (CA4). CA4 has highly potent cytotoxic activity in several human solid tumours. This potent cytotoxic activity coupled with its anti-vascular effect, makes CA4 an excellent bullet against tumours and forms a good starting point for developing more selective and targeted CA4 based agents. Our main aim is to design and develop analogues of CA4 with improved selectivity for cancer cells.

Polyunsaturated fatty acids (PUFAs) are important nutritional constituents of dietary vegetable oils and cold water fish and therefore are considered to be safe. Studies have shown that there is a selective uptake of PUFAs into cancerous cells compared to healthy cells and that the incorporation of PUFAs into the lipid bilayer of the cancer cells disrupts their membrane structure and fluidity, which as a result modify their chemosensitivity (2). In the context of targeted therapies, conjugation of PUFAs to conventional cytotoxic drugs has been a promising strategy (3). Recently, we synthesised and evaluated four CA4-PUFA conjugates. The arachidonic acid conjugate displayed the highest in vitro activity and showed some concentration dependent potency similar to the natural product CA4 with an IC50 of 0.7 μM (4). We are currently conducting cancer cell selectivity studies on these analogues. The aim of this PhD project is to expand on this initial work to design, synthesise and evaluate novel CA4-PUFA conjugates to discover novel conjugates with high selectivity for cancer cells. The project will involve the synthesis and characterisation of novel CA4-PUFA conjugates, evaluation of cytotoxicity on normal and cancerous cells and a study of their binding to tubulin.

Entry requirements:

Applicants should have or expect to obtain a first or upper second class honours degree (or equivalent) in an appropriate subject and a Masters (at Merit or above) in Pharmaceutical Science or closely related subject.

How to Apply:

To apply please go to https://msp.ac.uk/postgraduate/?course_id=784&course_level=postgraduate

You will need to apply through the online application form on the main University website. Please note that you will be expected to provide personal details, education and employment history and supporting documentation (curriculum vitae, transcript of results, two academic references). You are not required to submit a research proposal.

We welcome applications from people with disabilities and Black, Asian and Minority Ethnic (BAME) backgrounds.

Funding Notes

This project is a self-funded opportunity available to both Home/EU and International students.

Applicant must have access to funding to cover tuition fees, living costs and any related project costs (i.e. bench fees).

References

1) https://gco.iarc.fr/today/data/factsheets/cancers/39-All-cancers-fact-sheet.pdf

2) Grammatikos et. al Br. J. Cancer 1994, 70, 219−227.

3) Bradley, M. O. et. al. Cancer Res. 2001, 7, 3229− 3238.

4) F. O. Ojike, N. Lavignac and M. A. Casely-Hayford, J. Nat. Prod. 2018, 81, 9, 2101-2105.

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