Metals in MedicineResearch Network - Queensland Regional Meeting
(Brisbane, 20/1/04)
Present: Alastair McEwan, David Fairlie, Graeme Hanson, Trevor Appleton, Paul
Bernhardt, Mark Riley, Ian Brereton (UQ); Peter Healey, Michael Williams
(Griffith U); Murray Davies (JCU), Jack Ng (NRCET); Greg Anderson (QIMR)
Summary of the Meeting
The ARC Research Network presentation of Peter Lay was presented by Alastair
McEwan and this followed by a series of talks which described the particular
focus of groups and institutions in the Metals in Medicine area.
David Fairlie (IMB, UQ) discussed his longstanding interest in inorganic
pharmacology, particularly Zn complexes as antivirals and anti-inflammatories
(one compound is in man). He also discussed Zn proteases and Ca
phospholipases in the context of metalloproteins as drug targets and his work on
computer-based drug design leading to clinical candidates. The potential to link
with the Protease Network was highlighted. Metals as drug targets were also
discussed for ARC research on metals in neurodegenerative diseases, a series
of his papers showing possible relevance of Cu to Alzheimers disease, the effect
of chelating ligands, and evidence for Cu-induced peptide radicals.
Michael Williams (Griffith) described the work that he and Peter Healey have
been engaged in the area of synthesis of metal-phosphines and metallocenes.
Their potential as anti-cancer agents was discussed and a number of results of
cytotoxicity tests were reported. These were carried out in collaboration with
Peter Parsons (QIMR) and it was suggested that he might be linked to the Metals
in Medicine Network.
Murray Davies (JCU) and described his work on Pt oligomer and cancer, Rudimers as well as recent developments with Richard Keane in the area of
diagnostic kits. He also gave an overview of recent developments in Pharmacy
and Molecular Sciences at JCU and it was agreed that recent investment in a
medical genomics facility might be of use to the network in the area of production
of transgenic mice with specific mutations.
Graeme Hanson (Centre for Magnetic Resonance, UQ) described the EPR
facility at UQ including the pulsed EPR instrument purchased via ARC LIEF
funds. He showed how the recent improvements in EPR instrumentation as well
as improved computational methods are making EPR a much more powerful tool
for the determination of the geometric and electronic structure of metal centres.
UQ’s strength in NMR was also highlighted and the particular utility of a widebore 750 MHz instrument, expected to be purchased in 2004, in animal studies
was considered. Graeme also described the emerging Magnetic Circular
Dichroism facility at UQ that is being developed by Mark Riley with equipment
also funded by an ARC LIEF grant.
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Greg Anderson (QIMR) described QIMR’s longstanding and extensive research
interest in iron metabolism and disease. He showed how recent genetic work
was identified key proteins in the trafficking of iron from the intestine to the blood
but commented that the molecular characterization of these components was at
an early stage. The regulation of iron metabolism by novel hepatic polypeptides
was also discussed. Greg also commented on the value of linking studies in
humans to results from model systems (yeast, C. elegens etc).
Alastair McEwan (UQ) described the Centre for Metals in Biology at UQ and its
expertise in molecular microbiology, protein electrochemistry, biocatalysis and
spectroscopy (covered by Graeme Hanson). He focused on the Metals in
Bacterial Pathogenicity research programme, currently funded by an NH & MRC
Program grant and discussed ways in which genomic analysis of microbes can
be linked via phenotypic characterization to identification of new metalloprotein
antimicrobial targets. The work of Trevor Appleton in the area of Pt drugs as antitumor agents and Paul Bernhardt in Fe chelation in cytotoxicity and treatment of
iron overload was also presented.
Jack Ng (NRCET) gave an overview of EnTox in terms of its current role and
funding. He described the analytical facilities available at EnTox and highlighted
their expertise in risk assessment as well as their developments in the area of
toxicity testing. He also presented his work on Metalloid (arsenic) toxicity.
Steve Bottle (QUT) discussed nitroxide radicals as reactive oxygen species
quenchers, how these radicals interact with metal ions and how they can be used
to report anti-oxidant activity or oxidative stress. He also described fluorescent
derivatives that have importance in imaging.
Discussion

It was agreed that the Metals in Medicine Network should now be
considered in terms of at least 3 complementary themes.
Metal Drugs As Medicines Fairlie : Inorganic pharmacology, enzyme Inhibitors,
Zn complexes as antivirals/antiinflammatories.
Williams/Healy : Metal-phosphines, metallocenes, structures, antitumour
cytotoxicities.
Davies/Keene : Pt-oligomers and cancer, Ru-dimers and DNA, diagnostic kits
(ligands for metals). Bernhardt/Appleton : Fe/Pt complexes as antitumour agents.
Metalloproteins as Drug Targets
McEwan and centre : Metals in bacterial pathogenesis, Mn/Fe as potential
targets for antibiotics?
Hanson : Magnetic EPR/NMR spectroscopies for characterising metals and
metalloproteins.
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Bernhardt : Metalloprotein electrochemistry.
Fairlie : Calcium enzymes and antiinflammatories (ischemia-reperfuion, arthritis),
Zn proteases and inhibitors, metallopeptide inhibitors of proteins.
Riley : computing network capabilities?
Metals As Drug Targets
Anderson
:
Fe
overload,
absorption/metabolism,
genetics,
mitochondrial/hepatic/systemic Fe.
Bottle : Nitroxide spin traps and fluorescent assay for detection of metal-induced
radicals.
Ng : Arsenic as a "metalloid", metals in indigenous health (Cd), inorganic
toxicology, risk assessment.
Bernhardt : Chelating agents for Fe.
Fairlie : Metals in Neurodegenerative diseases (Cu, Fe, Al), Cu in Alzheimer's
disease, metal deficiency/overload.
McEwan : metals & pathogens.

The need to increase links with clinicians was discussed as well as
the importance of getting support from key researchers. It was
suggested that a letter of support from Lawrie Powell (Research
Director, Royal Brisbane Hospital) and an eminent researcher is
hepatology and iron metabolism would be valuable.

It was agreed that it was important to document the existing
Preclinical/Clinical Capabilities in Queensland, provided by QIMR,
IMB, RBH, EnTox and others.
Comment was made of the number of clinical/preclinical centres now
available for drug testing, even in Australia (e.g. RBH, QIMR, QPharm (Qld);
IDT (Vic); Firefly (NSW); C-scan? (SA). Is it a worthwhile exercise for the
Network to establish another one, since no unique expertise is needed for
most preclinical/clinical testing of metal complexes?
 Possible QLD Contribution To National Capabilities :
(1) EPR/NMR spectroscopy (unique EPRs and 700 MHz wide bore NMR -soon).
(2) Testing capabilities (enzymes, cells, rodents, preclinical and clinical)
(a) enzyme assays and cellular receptor assays - robotic and fluorescent
assay equipment bid (IMB)
(b) anti-viral and anti-nflammatory assays, including 20 animal assays for
latter (IMB)
(c) antitumour, antimalarial, antiparasitic testing (QIMR)
(d) antibiotic testing (McEwan et al)
(e) PC2 & PC3 (multiple Qld sites), PC4 (EnTox)
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(3) IMB can offer computer-assisted drug design for national use. It has a strong
and expert capacity in that area.
Maximising the utility of the network and leveraging ARC funds
The importance of institutional commitment to the network was also
discussed and it was agreed that this might work best if 0.5 salaries of 2-3
people funded by network and rest by Unis would be the best way to see
tangible and continuing network involvement close at hand as well as make
national facilities/expertise more widely available.
 Other Discussions/Suggestions :
Enlist Peter Parsons (QIMR) – cytotoxicity testing , James Paton (Adelaide) –
microbial pathogens,
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