Fluorine is a small element that packs a big punch.
When fluorine atoms are incorporated into organic molecules, they can have a dramatic impact on the substances' physical and chemical properties, and this leads to a wealth of applications in pharmaceuticals, agrochemicals, liquid crystals and polymers.
In the Hunter group we are particularly interested in developing new methods to synthesise organofluorine compounds, and in using fluorine atoms to control molecular conformation (a kind of "molecular origami").
The highly polarised C-F bond tends to align in very particular ways with adjacent functional groups, due to a variety of subtle stereoelectronic effects. In our lab, we harness these effects to produce novel bioactive molecules that are constrained into optimal 3D shapes, controlled by the precise positioning of fluorine atoms. The research is interdisciplinary in nature, and we collaborate extensively to analyse the biological properties of the molecules that we create.
Gamma-aminobutyric acid (GABA) is an important neurotransmitter molecule. It binds to several different receptors which are located on the surface of neuronal cells. These receptors are involved in a number of processes including memory, sleep, and ocular development; therefore, selective non-natural ligands of these receptors could be used as drugs to treat a variety of CNS disorders including epilepsy, schizophrenia and insomnia. GABA is a very flexible molecule, and crucially, it binds in different conformations to the different receptors. We are exploiting this shape-dependence by investigating fluorinated GABA analogues as shape-controlled selective GABA receptor ligands. We perform synthetic organic chemistry to create the fluorinated GABA analogues, then we use NMR and molecular modelling techniques to examine their conformations. Receptor binding is measured in patch-clamp assays with recombinant GABA receptors overexpressed in Xenopus oocytes.
Integrins are cell-surface receptors that mediate a variety of processes related to cell adhesion: for example, αIIbβ3 integrin mediates platelet aggregation and is therefore a target for the treatment of thrombosis, while αVβ3 integrin is involved in angiogenesis and is therefore a target for the treatment of solid tumors. Many different integrin receptors recognise the same tripeptide sequence: RGD (arginine-glycine-aspartate), which is commonly found in extracellular matrix proteins. Crucially, selectivity is determined by the ligand's 3D conformation. In this project, we are creating selective integrin ligands by synthesising RGD analogues in which the central glycine residue is replaced with a fluorinated amino acid. We use solid-phase peptide synthesis to create the peptides, then HPLC for purification. Subsequent integrin binding assays are performed in collaboration with GSK in England.
Unguisin A (below left) is a marine-derived cyclic peptide with promising antibacterial activity, including against Staphylococcus aureus. Pohlianin C (below right) is a plant-derived cyclic peptide with promising anti-malarial activity. Despite their potential pharmaceutical importance, neither of these natural products has previously been synthesised in the laboratory, and no structure-activity relationship studies or mechanism-of-action studies have been carried out. In the Hunter group we are synthesising both natural products, along with several fluorinated analogues that have been designed to identify and "lock in" the optimal bioactive conformations for maximal anti-microbial potency.
Creating organofluorine molecules is a challenge, particularly when installing fluorine atoms at stereogenic centres in a selective fashion. New methods are urgently required. In this project, we are investigating a new synthetic strategy designed to both create a heterocyclic ring and stereoselectively generate a C-F bond in the same step. The results will have broad applications in organic synthesis and drug development.
3. ARC Discovery Early Career Researcher Award (2012): $375K
2. University of New South Wales Science Faculty Research Grant (2012): $13K
1. University of Sydney Postdoctoral Research Fellowship (2009): $300K