Key Research Interests and Expertise

Targeting DNA

One of the main focuses of the laboratory is the targeting of DNA as a potential route to therapeutically useful molecules. Many clinically used antitumour agents depend on the disruption of nucleic acid associated processes to exert their effects. In the future, new agents that have lower side effects and are more focussed on single targets (either genes or structures) will be required and this is a subject of investigation. 

We are interested in both synthetic molecules and natural products and combine studies of synthesis, biophysical and biochemical properties. In 2006, in collaboration with Christine Cardin at Reading University, we disclosed the first structure of a molecule binding to the four-way Holliday junction through a novel mode of action.[1] In 2011, we followed this with the first molecule that can promote the assembly of the junction at room temperature.[2] This compound was derived from a click chemistry approach that led to a series of compounds that could bind to various DNA structures, from duplexes to G-quadruplexes via junctions.[3] 

Molecules that bind to double stranded DNA still have potential as antitumour agents. Almost 10 years ago, with Laurence Patterson of the Bradford Institute for Cancer Therapeutics, Searcey proposed that the duocarmycins, ultrapotent antitumour natural products, could be redesigned to become prodrugs that were activated by bio-oxidative processes in cancer cells.[4] Working with the Bradford team, we have demonstrated that this is indeed the case [5] and have shown that the prodrugs have antitumour activity in cells expressing cytochrome P450 enzymes [6].

References

[1] Angew. Chem. Int. Ed. Eng. 2007, 46, 3850-3854; [2] Chem. Commun. 2011, 47, 8262-8264; [3] ChemMedChem, 2012, 7, 792-804; [4] Current Medicinal Chemistry - Anticancer Agents 2004 4, 457-460; [5] Chem. Commun. 2011, 47, 12062-12064; [6] J. Med. Chem. 2013, 56, 6273-6277.

Targeting protein-protein interactions

Signalling pathways in cellular systems are excellent targets for drug design. The plethora of projects focussed on designing kinase inhibitors comes from this recognition and the progression of imatinib into the marketplace. Whereas kinases have a defined binding site, signalling can also take place through two protein surfaces coming together, a daunting prospect for the design of inhibitors but one which is coming to the fore in the design of new agents. In 2003, we described the first synthesis of the peptide structure of chlorofusin, a natural product that has been shown to inhibit the interaction between p53 and mdm2.[7] The peptide lacked inhibitory activity, as did a series of analogues [8] and later work showed that the full structure of the natural product is required for activity, although the stereochemistry of the azaphilone was relatively unimportant.[9] 

More recently, we have begun a collaboration with the O’Connell group at UEA to study the Nrf2/Keap1 interaction. Inhibition of this interaction has potential in cancer chemoprevention and in inflammation and in 2013, we disclosed the first cell penetrating peptide to activate Nrf2 through binding to Keap1.[10] We are currently investigating small molecules that may also have an effect. We have developed a number of in vitro and cell culture assays in house in order to do this. Ironically, Nrf2 upregulation may also be a problem in cancer and we are also investigating Nrf2 as a target for inhibition.

References

[7] Org. Lett. 2003, 5, 5051-5054; [8] J. Org. Chem. 2007, 72, 5146-5151; [9] Tetrahedron Lett. 2009 50, 3151-3153 (50th Anniversary issue.); [10] ACS Med. Chem. Lett. 2012, 3, 407-410.

Synthesis and natural products

At the centre of all of our projects is organic synthesis. We use both solid and solution phase methodologies to generate the structures that are of interest to us. Often, this may involve the development of routes to natural products in order to study structure-activity relationships. In 2005, following on from our successful solid phase synthesis of the chlorofusin peptide, we synthesised the triostin A analogue TANDEM via a route that also allowed us to generate water soluble analogues [11][12]. We are applying solid phase methodology to the synthesis of other natural products.

Heterocyclic chemistry sits at the heart of most of our DNA targeting, with routes to acridines and analogues via, amongst others, classical [3] and benzyne [13] click chemistry, well established. We are currently investigating DNA gyrase inhibitors via the development of flexible routes to coumarins and analogues.

References

[11] J. Org. Chem. 2005, 70, 7654-7661; [12] Biochemistry, 2008, 47, 7900-7906; [13] Bioorg. Med. Chem. Lett. 2009, 19, 5880-5883.

 

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