Targeted proteomics and phosphoinositides that control intracellular signalling

A synthetic programme has been developed to prepare phosphatidylinositol polyphosphates (e.g. PI-3,4,5-P3 1), attach them to affinity matrices and in collaboration with biological colleagues identify the proteins that bind to the beads. We now wish to understand how these proteins control signalling in a variety of important processes such as diabetes and cancer.

Reference: Dove, S. K.; Piper, R. C.; McEwen, R. K.; Yu, J. W.; King, M. C.; Hughes, D. C.; Thuring, J.; Holmes, A. B.; Cooke, F. T.; Michell, R. H.; Parker, P. J.; Lemmon, M. A. EMBO J. 2004, 23, 1922-1933.

Poison arrow frog venom alkaloids

We have developed the synthesis of histrionicotoxins 2 isolated from poison arrow frog skin secretions. We want to know how these molecules control the function of the acetylcholine nicotinic receptor.

Reference: Horsley, H. T.; Holmes, A. B.; Davies, J. E.; Goodman, J. M.; Silva, M. A.; Pascu, S. I.; Collins, I. Org. Biomol. Chem. 2004, 2, 1258-1265.

Medium ring ethers as cytotoxic (anticancer) agents

A variety of biologically active medium ring ethers such as the eunicellins 3 and eleutherobins 4 have been isolated from marine sources and shown to exhibit microtubule stabilising properties similar to taxol. Our programme is to synthesise these molecules and simple analogues for cytotoxicity studies. Another target is the nine-membered ether fish antifeedant, obtusenyne 5.

Reference: Davidson, J. E. P.; Gilmour, R.; Ducki, S.; Davies, J. E.; Green, R.;
Holmes, A. B. Synlett 2004, 8, 1434-1436.

Polymeric organic semiconducting materials

Among the most exciting discoveries in materials science has been the observation that organic conjugated materials can show semiconductor properties. We were part of the team that discovered light emitting polymers which have potential applications as the emissive layer in flat panel TV screens. A typical example is the polyfluorene 6. Organic semiconductors are also being actively researched in field effect transistors and solar cells. Projects in this area have potential for exploitation in collaboration with spinout companies.

Reference: Sandee, A. J.; Williams, C. K.; Evans, N. R.; Davies, J. E.; Boothby, C. E.; Köhler, A.; Friend, R. H.; Holmes, A. B. J. Am. Chem. Soc., 2004, 126, 7041-7048.

Supercritical carbon dioxide as an environmentally benign solvent

Supercritical carbon dioxide is a gas-like fluid with liquid-like solvent densities. It can be used to carry out C-C bond forming reactions, polymer synthesis and formation of monolayers on surfaces. We even use it to deposit polymers on patterned surfaces, and expect these properties to make it a popular solvent in the 21st century.

Reference: Smith, C. J.; Early, T. R.; Holmes, A. B.; Shute, R. E. Chem. Commun. 2004, 1976-1977.