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Dr Maxwell Casely-Hayford

Lecturer in Pharmaceutical Chemistry

Medway School of Pharmacy

 

Dr Casely-Hayford obtained his BSc with first class honours in Pharmaceutical Chemistry from Queen Mary, University of London in 2000. He then joined the School of Pharmacy, University of London to study for a PhD in Medicinal Chemistry under the supervision of Prof. Mark Searcey. His PhD focused on the chemical synthesis and biological evaluation of novel anti-cancer agents based on the azinomycins. Prior to joining Medway School of Pharmacy as a lecturer in Pharmaceutical Chemistry, he was a Post Doctoral Research Fellow at the London School of Pharmacy where he worked with Profs Laurence Patterson and Mark Searcey, focusing on methodology for the solid phase synthesis of anthraquinone-peptide conjugates as AP-1 inhibitors. His expertise is in solid and solution phase synthetic organic chemistry, natural product and peptide synthesis, organic medicinal chemistry and drug DNA interactions.

He teaches on the MPharm Degree Programme and is convener for the stage 1 chemistry and pharmaceutics course Medicines Design and Manufacture 1. back to top

Molecules isolated from natural sources such as plants, animals and microorganism (both of terrestrial and marine origin) play a very important role in modern drug discovery. A significant number of clinically employed anticancer drugs e.g. Taxol® and the topoisomerase inhibitor topotecan are of natural origin. Maxwell’s research focuses on solution-phase, solid phase synthesis, multi-component reactions and the development of methodologies applied to the synthesis of biologically interesting natural products and their analogues. Therapeutic areas of interest include cancer and malaria and as such natural product targets of current interest include combretastatin A4, artemisinin and cryptophycin .
The main focus of research is on:

  • The use of natural product molecular architecture as lead for the design and synthesis of structural analogues with improved biological activity and selectivity.
  • Biological evaluation of synthesised compounds.
  • Interrogation of the mechanism of action of novel synthesised compounds.

Research is carried out with the collaboration of Prof. Martin Michaelis (UoK, School of Biosciences), Dr Klaus Pors (Institute of Cancer Therapeutics, University of Bradford), Prof Mark Searcey’s group (UEA) and colleagues at the school.

Current Projects

Design, Synthesis and biological evaluation of novel combretastatin based antitumour agents.

Microtubules are polymeric filaments composed of α-tubulin and β-tubulin heterodimers.  They play several important roles in a variety of cellular functions including intracellular transport, maintenance of cell shape, polarity, cell signalling and cell division. Tubulin subunits are constantly attached or removed from the ends of the microtubules. The dynamics of this construction and degradation process vary during the cell cycle. Tubulin-binding agents that interfere with the microtubule dynamics belong to the most successful anti-cancer agents. This includes drugs that have been and continue to be the mainstay of anti-cancer therapies (e.g. the vinca alkaloids like vincristine or the taxanes like paclitaxel) as well as recently approved agents like the epothilone derivative ixabepilone or the vinca alkaloid vinflunine. The search for tubulin-binding agents showing improved cancer cell specificity, less neurotoxicity, and efficacy in chemo resistant cancer cells is on-going. The use of tubulin-binding agents (like that of other classes of anti-cancer agents) is limited by resistance development. Therefore, the development of novel therapeutics that is effective against drug-resistant cells is essential for the further improvement of anti-cancer therapies.

fig1Combretastatin A4 (CA-4) is a natural product isolated from the bark of the South African bush willow tree combretum caffrum. Combretastatin A4 is a biphenyl containing a cis-stilben motif as a key structural feature. It has potent cytotoxic activity in a variety of solid human tumours including cancers which have developed multidrug resistance. Mechanistically CA-4 is a strong inhibitor of microtubule polymerisation, binding to tubulin at the colchicine binding site thereby disrupting microtubule dynamics and formation. This results in cell cycle arrest in the M-Phase and subsequently leads to apoptotic cell death. In addition to their high potency on cancer cells CA-4 exerts highly selective effect on proliferating endothelial cells leading to a substantial antivascular activity on tumour blood vessels whilst causing much less damage to normal blood vessels.

The strong cytotoxic nature of CA-4 coupled with the antivascular effect makes it an excellent starting point for developing more selective and targeted anticancer agents.

The main aim of this project is:

  • Development of novel analogues and conjugates based on combretastatin as lead compound.
  • Systematic profiles of the action of these drugs on endothelial cells and on cancer cells, with a focus on a broad panel of cell lines adapted to tubulin-binding agents.

Artemisinin: A lead for the development of novel anticancer and antimalarial therapies.

fig2Artemisinin is a naturally occurring 1,2,4-trioxanesesquiterpene lactone with an endoperoxide bridge. It is extremely active against malaria including the deadly cerebral form and is currently used as the first line treatment for malaria including chloroquine resistant variants.

In addition to potent antimalarial activity, artemisinin derived compounds including the water soluble artesunate possess significant anticancer activity. Artemisinin and its derivatives exert their antimalarial and anticancer effect through the endoperoxide bridge. These compounds selectively target cells with high iron (II) content such as parasitic and cancer cells. In the presence of iron (II), artemisinin generates toxic carbon centred free radicals able to interact with bio-molecules and induce cell death.

Artemisinin-based Combination Therapy (ACT) is currently the first line of treatment for malaria. The drug and its derivatives are potent, well tolerated by patients and selective, but must be administered often due to a quick degradation in the bloodstream. Reports have also emerged on the development of resistance towards the artemisinins. Their nontoxic and selective nature makes the artemisinins an attractive lead compound for the development of both anticancer and antimalarial therapies.

The aim of this project is:

  • Design and synthesis of a diverse library of structurally related analogues.
  • Systematic evaluation of the action of synthesised analogues on drug sensitive and drug resistant malaria parasites and a broad panel of cancer cell lines.


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Selected Publications

  • Wahab A, Favretto ME, Onyeagor ND, Khan GM, Douroumis D, Casely-Hayford MA, Kallinteri P (2012). Development of poly(glycerol adipate) nanoparticles loaded with non-steroidal anti-inflammatory drugs. J. Microencapsulation (in press).

  • Casely-Hayford MA, Omobolaji TA (2010). Combretastatin A4 dimers: design, synthesis and biological evaluation. Journal of Pharmacy and Pharmacology; 62, SI:1363-1364.

  • Nsana LKMberi, Casely-Hayford MA (2010). Design and synthesis of artesunate-anthraquinone hybrids as potential antitumour agents. Journal of Pharmacy and Pharmacology, 62, SI:1366-1367.

  • Casely-Hayford MA, Nicholas SA and Sumbayev VV (2009). Azinomycin epoxide induces activation of apoptosis signal-regulating kinase 1 (ASK1) and caspase 3 in a HIF-1α-independent manner in human leukaemia myeloid macrophages. Eur. J. Pharmacol, 602; 262-267.

  • Coll A, Casely-Hayford MA (2009). DNA intercalators: effect of covalent binding sidechains on analogues of 9-chloroacridine-4-carboxylates.  Journal of Pharmacy and Pharmacology. 61, A100-A100.

  • David-Cordonier MH, Casely-Hayford M, Kouach M, Briand G, Patterson LH, Bailly C, and Searcy M (2006). Stereoselectivity, Sequence Specificity and Mechanism of Action of the Azinomycins Epoxide. ChemBioChem, 7; 1658-1661.

  • Casely-Hayford MA, Ortuzar Kerr N, Smith E, Gibbons S, Searcey M (2005). Antitumour nntibiotics with potent activity against Multidrug resistant staphylococcus aureus: A new approach to targeting resistant bacteria. Medicinal Chemistry, 1; 619-628.

  • Casely-Hayford MA, Pors K, Patterson LH, Hartley JA and Searcey M (2005). Design and synthesis of a DNA cross-linking analogue. Organic & Biomolecular Chemistry, 3; 3585-3589.

  • Casely-Hayford MA, Pors K, James CH, Patterson LH, Gerner C, Neidle S and Searcey M. (2005). Truncated azinomycin analogues intercalated into DNA. Bioorganic and Medicinal Chemistry Letters, 15; 653-656.

  • David-Cordonnier MH, Casely-Hayford M, Patterson LH Bailly C, Searcey M (2005). Influence of the stereoisomeric position of azinomycin epoxide on DNA binding and sequence selectivity. Clinical Cancer Research, 11, 9013S-9013S.

  • Casely-Hayford MA, Pors K, Patterson LH, Searcey M (2005). Design, synthesis and biological evaluation of potential anticancer agents based on the azinomycins. Abstracts of Papers of the American Chemical Society; 229, U183-U183.

Book Chapters

  • Casely-Hayford MA and Searcey M (2003). The azinomycins, Discovery, Synthesis, and DNA-binding Studies. In DNA and RNA binders – From small molecules to drugs. Eds. Demeunynck M, Bailly C and Wilson WD. 2: 676 – 696.

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Last Updated 02/11/2012