Group leader
Research interests
Our research interests centre on the redox chemistry and mechanistic aspects underlying
free radical damage to biomolecules, including DNA and proteins. While such radical
reactions are deleterious to normal cells in the body, they can offer a means to
attack certain diseases such as cancer. Radical reactions occur very quickly, often
on the millionth of a second timescale, requiring fast-detection techniques for
their study.
The FRR Group uses short (nanosecond) pulses of high energy electrons from a 4MV
linear accelerator to initiate radical reaction (pulse radiolysis)
combined with fast spectrophotometry and conductivity detection for observations to be made in
real time. Radical intermediates can also be identified using radical trapping agents
followed by electron paramagnetic resonance to obtain finger print spectra. Steady-state
radiolysis is used to produce products from radical reactions for analysis. The
Pulse Radiolysis Facility is a regional resource supporting health-related research
by both NZ and Australian scientists under the AINSE program.
Current areas of research
Electron transfer in DNA
Understanding the properties of DNA radicals is fundamental to the design of drugs
aimed to counter the deleterious effects of such lesions. The fast chemical repair
of these lesions by antioxidants is under study, in particular with
Associate Professor Roger Martin of the Peter MacCallum
Cancer institute on DNA-targeted ligands, which are designed to protect certain
normal tissues in radiotherapy.
Associate Professor Roger Martin
Bioreductive drug development
The FRR Group collaborates closely with both the Medicinal
Chemistry Group and the Experimental Therapeutics
Group
on a variety of projects with the common aim to develop improved therapeutic drugs
against disease, based on an in depth understanding of the underlying chemical mechanisms.
Medicinal
Chemistry Group
Experimental Therapeutics
Group
The controlling parameters by which different classes of bioreductive prodrugs are selectively activated to anti-cancer cytotoxins under hypoxia and not in normoxia
are studied with Associate
Professor Michael Hay and
Dr Jeff Smaill. Also, redox aspects which are important in the activation of certain anti-tuberculosis drugs are under study with
Associate Professor Brian Palmer.
Associate
Professor Michael Hay
Dr Jeff Smaill
Associate Professor Brian Palmer
Superoxide dismutase mimetics
Superoxide, a by-product of cellular metabolism where
oxygen gains an electron,
is normally kept at low levels by the superoxide dismutase (SOD) proteins. Its over
production is linked to several inflammatory diseases and therapeutics are presently
being sought to act as adjuncts to the overwhelmed natural detoxifying systems.
The mechanism and kinetic parameters of the manganese-based SOD mimetics, as well
as mitochondria-targeted antioxidants, are under study in a collaboration with
Professor Robin Smith of Otago University. Possible future
application is in their co-administration with bioreductive drugs (above) to help
minimize superoxide formation in normal tissues through futile redox cycling.
Professor Robin Smith
Group members
Recent publications
2009. Shinde, S.S., Maroz, A., Hay, M.P. and Anderson, R.F. One-electron reduction potential
of the neutral guanyl radical in the GC base pair of duplex DNA. J. Am. Chem. Soc.,
131, 5203-5207.
2009. Thompson, A.M., Blaser, A., Anderson, R.F., Shinde, S.S., Franzblau, S.G., Ma, Z.,
Denny, W.A. and Palmer, B.D. Synthesis, reduction potentials and anti-tubercular
activity of ring A/B analogues of the bioreductive drug (6S)-2-nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine
(PA-824). J. Med. Chem., 52, 637-645.
2009. Maroz, A., Anderson, R.F., Smith, R.A.J. and Murphy, M.P. Reactivity of ubiquinone
and ubiquinol with superoxide and hydroperoxyl radical: implications for in vivo
antioxidant activity. Free Rad. Biol. Med., 46, 105-109.
2008. Hay, M.P., Pchalek, K., Lee, H.H., Hicks, K.O., Blaser, A., Pruijn, F.B., Siim,
B.G., Anderson, R.F., Shinde, S.S., Wilson, W.R. and Denny, W.A. Tricyclic [1,2,4]triazine
1,4-dioxided as hypoxia selective cytotoxins. J. Med. Chem., 51, 6853-6865.
2008. Anderson, R.F., Shinde, S.S., Maroz, A., Palmer, B.D., Boyd, M. and Denny, W.A.
Intermediates in the reduction of the antituberculosis drug PA-824, (6S)-2-nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}
-6,7-dihydro-5H-imidazo[2,1-b][1.3]oxazine, in aqueous solution. Org. Biomol. Chem.,
6, 1973-1980.
2008. Maroz, A., Kelso, G.F., Smith, R.A.J., Ware, D.C. and Anderson, R.F. Pulse radiolysis
investigation on the mechanism of the catalytic action of Mn(II)-pentaazamacrocycle
compounds as superoxide dismutase mimetics. J. Phys. Chem. A., 112, 4929-4935.
