Current research projects are in the area of organic synthesis and its application to Chemical Biology and Green Chemistry. These projects cover many areas including the synthesis of biologically active molecules and the development of new synthetic methods. Projects are multi-disciplinary involving contemporary organic synthetic and spectroscopic techniques as well as mechanistic chemistry.
Novel CNS Agonists-Epibatidine Analogues
Novel CNS agonists are potential drugs for the relief of pain and the treatment of neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease. In this regard we are interested in the synthesis and biological activity of novel analogues of the natural product epibatidine that are potent and subtype selective N-acetylcholine receptor (nAChR) agonists. We have reported our results with one such compound - isoepibatidine and current studies are investigating the synthesis of fluorinated analogues.
Glycosidae Enzyme Inhibitors
We are interested in the synthesis and biological activity of novel glycosidase inhibitors based on azasugars and have reported the asymmetric synthesis of a series of 3-aminopyrollidines. We are also exploring the attachment of a second aglycone-mimicking unit to generate aza-disaccharides. In related studies we have already synthesised a number of novel O - and N -linked aza-disaccharides employing complementary pinacol and ring closing metathesis (RCM) – dihydroxylation strategies. Our interest in glycosidase inhibitors also extends into the synthesis of novel calystegines.
Enzyme Mechanisms of Tryptophan Oxidation
We have been working with Professor Raven’s group to investigate the catalytic mechanism of heme peroxidase and dioxygenase enzymes. Current focus is on the enzymes involved in the degradation of L-tryptophan to N-formylkynurenine, namely tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO). In this regard we have synthesised a number of potential intermediates on the degradation pathway for use in both turnover studies and as confirmation of their occurrence in the natural reaction. The current focus is on application of our free-radical chemistry knowledge to design mechanism based inhibitors for both these enzymes.
Mechanistic Free-radical Chemistry
During the course of our synthetic projects we sometimes discover unusual or unexpected results that can lead to an intriguing insight into the mechanism of a particular reaction. We are always keen to fully investigate these findings to shed some light on our observations. Thus we have recently reported the use of cyclopropyl ketones to investigate the mechanism and rate of SmI2-mediated pinacol reactions. We have also investigated novel free-radical mediated biomimetic 1,2-imino migrations.