Dr Kellie L Tuck

Research Projects

1. Alternate Routes to the Synthesis of Core Mycolactone
2. Towards the Synthesis of Novel Natural Products
3. Alternate Assay Methods for Pantothenate Synthetase

1. Alternate Routes to the Synthesis of Core Mycolactone

In collaboration with Dr Tim Stinear and Dr Grant Jenkin (Department of Microbiology)

The macrolide polyketide mycolactone is an exotoxin of Mycobacterium ulcerans, the bacterium that causes Buruli ulcer (BU). BU is an emerging disease endemic to certain regions of Australia and major health problem in West Africa. Mycolactone has significant immunosupressive and cytotoxic activity. The first total synthesis of mycolactone A/B (Fig. 1) confirmed its relative and absolute stereochemistry.1 However, further research into its biological properties has been hindered by the lack of a viable synthetic route. This project will explore alternate routes for formation of the mycolactone core.

Reference
1. F. Song, S. Fidanze, A.B. Benowitz, Y. Kishi. Total synthesis of Mycolactones A and B. Tetrahedron, 2007, 63, 5739.

2. Towards the Synthesis of Novel Natural Products

Recently a class of potent cytotoxic brominated diterpenes, called prevezols, was isolated from the secondary metabolites of the red algae, Laurencia obtusa.2 They are an exciting class of compounds as they contain two new carbon skeletons that are unprecedented in the literature. Structures of three of the diterpenes are shown below. The synthesis of the prevezols as well as simpler analogues will allow their cytotoxic properties to be investigated.

2. D. Iliopoulou, N. Mihopoulos, C Vagias, P. Papazafiri, V. Roussis, Novel Cytotoxic Brominated Diterpenes from the Red Alga Laurencia obtusa. J. Org. Chem., 2003, 68, 7667.

3. Alternate Assay Methods for Pantothenate Synthetase

(Collaboration with Peter Duggan, CSIRO)

Pantothenate (otherwise known as Vitamin B5) is necessary for cell growth and is involved in essential biosynthetic pathways. Pantothenate is not biosynthesised in mammals and must be obtained from the diet, consequently inhibition of its biosynthesis represents an exciting target for the development of novel antibiotics. Pantothenate synthetase is an ATP-dependant ligase, which forms the amide bond of pantothenate from pantoate and ß-alanine. The current assay for pantothenate synthetase is a coupled assay which uses three coupling enzymes. Whilst an assay does exist, the goal of producing a rapid and robust applicable assay for monitoring the activity of pantothenate synthetase and other ATP-utilizing enzymes in real-time has yet to be attained. A more efficient assay would be to use a fluorescent probe (chemosensor) to detect the presence of an enzymatic product.

This project will investigate a completely new approach to monitoring the activity of ATP utilizing enzymes, we will address the problems associated with the current assay method, and devise a chemosensor that will be more amenable to the high-throughput screening of potential enzyme inhibitors