Williams Group Homepage
School of Chemistry
Bio21 Molecular Science and
Biotechnology Institute
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Office (rm 532): 61-3-8344-2422 Lab Phone: 8344 2409 Lab Office (rm 530): 8344 2418 Postdoc Office (rm 522): 8344
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Information for prospective PhD students and
postdoctoral fellows
We
are part of the
Our
area of expertise includes carbohydrate chemistry and medicinal chemistry. In
our research we are interested in the application of organic chemistry to the
study of biological systems. Our work requires the synthesis of carefully
designed molecules and their application in a variety of biological systems.
Specific research areas:
·
Carbohydrate metabolism in pathogenic
microorganisms
·
Sulfatases: Catalysis and inhibition
·
Medicinal
chemistry: Cardioprotective flavonoids for the treatment of cardiovascular
disease
·
Medicinal
chemistry: Novel antifibrotic agents
Williams
Group, May 2006
Carbohydrate metabolism in
pathogenic microorganisms
Our
laboratory has a strong and ongoing collaboration with the group of Prof
Malcolm McConville in the Department of Biochemistry and Molecular Biology.
Together we are interested in the study of mechanisms of microbial
pathogenesis. Recent achievements in the sequencing of genomes of pathogenic
microorganisms have revealed a wealth of new targets for the design of
next-generation therapeutics. However, the identification of new targets
represents only the first step in a long pathway to drug discovery and
development. In this program of research we are synthesizing substrates to
enable the development of assays for enzymes involved in the biosynthesis of
essential cell wall structures. With assays in hand we can then search for
novel inhibitors as lead compounds for drug development. We have also
synthesized combinatorial libraries of compounds using the newly reported
copper(I) catalyzed click chemistry reaction to screen against a series of
already validated targets in Mycobacterium
tuberculosis and Leishmania sp. Our work in Leishmania
is directed at understanding the biosynthesis of a novel b-1,2-mannan, and in Mycobacteria at studies of phosphatidylinositol mannosides.
a) Structure of a
phosphatidylinositol mannoside (PIM4) from Mycobacteria, and b) the cytosolic b-1,2-mannan of
Leishmania.
Use of click chemistry to define the substrate specificity of Leishmania b-1,2-mannosyltransferases
Sulfatases: Catalysis and
inhibition
In this project we are interested in generating a new set of chemical tools to enable the study of sulfatases, an important class of catabolic enzymes. Sulfatases are involved in nutrient cycling in the environment, in the progression of hormone dependent breast cancers, and in the remodelling of sulfated glycosaminoglycans in the developing embryo. This project aims to study the mechanism of these enzymes in detail through the synthesis of substrates, competitive inhibitors, and time-dependent inactivators. We then use these compounds to study enzyme mechanism using sulfatases that we express in-house.
The reaction catalyzed by sulfatases.
Estrone sulfamate and simple aryl sulfamates used
for biological and structural studies.
In
addition to these studies of sulfatase mechanism, we are also interested in
more fundamental aspects of sulfonyl group transfer. Using structure-reactivity
correlations, obtained from low temperature x-ray analysis of derivates of
varying reactivity, we have shown that the functionally disparate sulfate and
sulfamate groups proceed through essentially identical routes of unimolecular
decomposition. Moreover, through studies of low temperature x-ray crystal
structures we have identified key differences in the intrinsic reactivity
towards group transfer reactions of phosphate and sulfate monoesters, two of
the major inorganic esters found in biology.
Medicinal chemistry:
Cardioprotective flavonoids for the treatment of cardiovascular disease
As part
of a collaboration with the research group of A/Prof Owen Woodman in the
Department of Pharmacology, and NeuProtect Pty Ltd, we have been synthesizing
new flavonoids to optimize the cardioprotective actions of these naturally
occurring compounds. Flavonoids are polyphenolic compounds found in foodstuffs
including fruits and vegetables. In populations with a high dietary intake of
fruits and vegetables there is a lower incidence of coronary heart disease,
which has been linked to the beneficial action of flavonoids, including
flavones and flavonols. In particular, 3’,4’-dihydroxyflavonol is a
promising agent for the treatment of reperfusion injury following myocardial
infarct, but its further development is limited by its extremely poor water
solubility. Moreover, this flavonol and all other cardioprotective flavonols
possess two activities, vasorelaxant and antioxidant effects, which complicate
studies aimed at understanding their mechanism of cardioprotection. We have
been investigating structure-activity relationships of flavonols to understand
how the flavonol structure can be chemically modified. We have now synthesized
highly water soluble flavonol derivatives and have developed an understanding
of how to separate the antioxidant and vasorelaxant activities of flavonols.
a)
Structure of flavones and flavonols b) structure of modified derivatives of
quercetin.
Medicinal chemistry: Novel
antifibrotic agents
Pathological fibrosis has been
estimated to be an underlying pathology of 45% of deaths in the developed
world. As such there is a clear need for new antifibrotic agents to treat
diseases such as heart failure, idiopathic pulmonary fibrosis and diabetes
complications. As part of a collaboration with the
research group of A/Prof