Research Guides

Our research interests are at the interface of chemistry and biology and focus on the use of synthetic organic chemistry to enable the study of biological problems. Key areas of activity include the synthesis of inositol-based probes to study intracellular calcium signalling, the synthesis of inositol-based compounds to probe pleckstrin homology domains and the use of photolabile protecting groups to develop light-activated molecular tools. We have collaborative interests in bacterial potassium channels and the molecular mechanisms involved in Alzheimer’s disease. Our interests also encompass the synthesis of “drug-like” molecules and we have recently reported an improved synthesis of hydantoins.

Inositol chemistry

Calcium signalling is involved in many fundamental processes within the body including fertilisation, behaviour, learning and memory. Calcium concentration in cells is usually low, until calcium release or influx is promoted by a chemical messenger. One such messenger is D-myo-inositol 1,4,5-trisphosphate (InsP₃), which is produced in response to the activation of G-protein-coupled receptors. InsP₃ exerts its biological action via activation of specific receptors (InsP₃Rs). We are interested in the synthesis of InsP₃ derivatives in order to develop selective tools to probe the InsP₃Rs.

Biological photochemistry – “caged” compounds

The use of light to selectively activate a biologically important molecule, once it is inside a cell, is a powerful technology. This technique allows spatial and temporal control over the release of the molecule and hence spatial and temporal control over the activation / inhibition of the biological target. We have synthesised a range of caged TRPV1 ligands and demonstrated that these compounds are photoreleased in vitro to activate their cellular target, TRPV1. We have also synthesised the first caged mitochondrial uncouplers and used these to prevent mitochondrial activity in spatially defined regions of cells.

Synthetic organic chemistry

Hydantoins are structural components of a number of important drugs and also serve as important precursors to amino acids. Hence new and improved methods of synthesising these compounds are useful to a wide range of chemists. We have recently reported a gallium (III) triflate-catalysed synthesis of hydantoins from aldehydes and ketones and demonstrated that this methodology is applicable to the synthesis of a wide range hydantoins

C. Cazares-Körner, I. M. Pires, I. D. Swallow, S. C. Grayer, L. O’Connor, M. M. Olcina, M. Christlieb, S. J. Conway, E. M. Hammond, CH-01 is a hypoxia-activated prodrug that sensitizes cells to hypoxia/reoxygenation through inhibition of Chk1 and Aurora A. ACS Chem. Biol., 2013, 8, 1451-1459.

D. S. Hewings, O. Fedorov, P. Filippakopoulos, S. Martin, S. Picaud, A. Tumber, C. Wells, M. M. Olcina, K. Freeman, A. Gill, A. J. Ritchie, D. W. Sheppard, A. J. Russell, E. M. Hammond, S. Knapp, P. E. Brennan, S. J. Conway, Optimization of 3,5-dimethylisoxazole derivatives as potent BET bromodomain ligands. J. Med. Chem., 2013, 56, 3217-3227.

M. N. Stanton-Humphreys, R. D. T. Taylor, C. McDougall, M. L. Hart, C. T. A. Brown, N. J. Emptage, S. J. Conway, Wavelength-orthogonal photolysis of neurotransmitters in vitro. Chem. Commun., 2012, 48, 657-659.

D. S. Hewings, M. Wang, M. Philpott, O. Fedorov, P. Filippakopoulos, S. Picaud, C. Vuppusetty, B. Marsden, S. Knapp, S. J. Conway, T. D. Heightman, 3,5-Dimethylisoxazoles act as acetyl-lysine-mimetic bromodomain ligands. J. Med. Chem., 2011, 54, 6761-6770.

N. S. Keddie, Y. Ye, T. Aslam, T. Luyten, D. Bello, C. Garnham, G. Bulynck, A. Galione, S. J. Conway, Development of inositol-based antagonists for the D-myo-inositol 1,4,5-trisphosphate receptor. Chem. Commun., 2011, 47, 242-244.