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Dr Mark Bagley 


 

  • Chemical intervention in accelerated ageing in Werner syndrome.
  • Microwave-assisted synthesis of nitrogen-containing heterocycles.
  • Synthesis and biological properties of heteroaromatic drugs and clinical candidates.
  • Heterocyclic chemistry and the synthesis of natural products, such as the thiopeptide antibiotics.
  • Synthesis of oxyphospholipids and deuterium-labelled disease biomarkers.
  • The development of new microwave flow reactors for the scale up of organic transformations.

Chemical Intervention in Accelerated Ageing

Werner’s Syndrome (WS) is a rare human genetic disease that shows accelerated ageing and an increased cancer incidence, and is studied for the insights that it might give into both processes. A key feature of WS is that cells from these individuals show a much reduced cellular lifespan in the laboratory as a consequence of replicative senescence. This project, which spans the chemistry-life sciences interface, seeks to investigate this phenomenon using different chemotypes prepared in our synthetic laboratories (Figure 1). This offers great potential for the development of clinical treatments for this disorder, in so doing understanding some of the fundamental mechanisms operating in telomere-independent cell senescence, cancer and human ageing and may lead to the first chemotherapeutic treatment for WS.

 

Figure 1a-d. P38 MAPK clinical candidates prepared in our laboratories for the study of Werner syndrome.

 

Synthesis of Thiopeptide Antibiotics

Infectious diseases have been estimated to kill almost 50,000 people every day and have emerged as the world’s leading cause of premature death. In this context, the search to discover, prepare and understand new antibiotics is an area of profound medical, social and political importance. The thiopeptide antibiotics represent promising candidates and leads for the development of new antibacterial agents effective against the so-called `superbugs’. As the search continues for new agents effective against resistant strains of bacteria, compounds that target the GTPase centre, such as the thiopeptide antibiotics, have been largely ignored by the pharmaceutical industry. We are developing new highly convergent synthetic approaches towards this family (Figure 2) to verify the structure of the natural products and understand the mode of action of new antibacterial agents inspired by nature.

Figure 2. Thiopeptide antibiotics and chemical derivatives thereof.