|
Royal Society Florey Fellow, (Sydney) 1987-1988
NHMRC Douglas Wright Fellow (Griffith University, Brisbane)
1992-1995
Lecturer, Senior Lecturer, Assoc. Professor (Griffith University,
Brisbane) 1990-2000
Research Interests
Professor Sue Berners-Price was appointed to the newly
established Chair in Biological Chemistry at UWA in 2001. Her
teaching and research interests are in the field of Bioinorganic
Chemistry and more specifically in the field of Medicinal
Inorganic Chemistry. Research at the interface between inorganic
chemistry, biology and medicine is providing exciting new insight
into biological processes as well as novel ideas for the design
of therapeutic agents involving both novel targets and novel
mechanisms. Our research is directed towards the design and
mechanism of action of metal-based anticancer agents. All
projects involve strong interdisciplinary and some international
collaboration.
Current research projects are encompassed under two broad
areas funded by grants from the Australian Research Council.
Application of advanced NMR
techniques to investigate the biological chemistry of platinum
anticancer drugs
A major contribution of our work
has been the exploitation of multinuclear NMR methods for the
study the chemistry of platinum anticancer drugs under conditions
of biological relevance including a pioneering study of the
reaction of cisplatin with glutathione inside cells. Over the
past decade [1H,15N] NMR methods (developed
in collaboration with Prof. Peter Sadler, Edinburgh) have
provided unique insight into the molecular mechanism of action of
platinum drugs including investigations of simple aquation
reactions, protein binding and the kinetics and sequence
selectivity of DNA binding interactions. Our current projects in
this area focus on new platinum drugs under investigation.
A major current research effort
focuses on the use of [1H,15N] NMR
spectroscopy to probe, in detail, the DNA binding profiles of
polynuclear platinum compounds related to BBR3464 (collaboration
with Prof. Nick Farrell, Richmond, Virginia, USA). This
trinuclear platinum compound, developed by Farrell has been
evaluated in clinical trials as a new type of platinum anticancer
drug with a different profile of activity to cisplatin. Our
recent studies have provided important new insight into the
mechanism of BBR3464. In particular, we are able to follow the
stepwise formation of long-range DNA interstrand cross-links and
derive kinetic parameters for each step in the pathway. A current
ARC funded project addresses specific aspects of the DNA binding,
metabolism and cellular uptake of both BBR3464 and
second-generation analogues.
Design, synthesis and biological
evaluation of gold antimitochondrial antitumour agents
In early work we identified a new
class of metal phosphine antitumour agents including the Au(I)
complex [Au(dppe)2]+. Clinical development of these
compounds was abandoned when unacceptable levels of toxicity were
identified in pre-clinical trials. However, more recent work (in
collaboration with Dr. Mark McKeage, and Prof. Bruce Baguely,
University of Auckland) has demonstrated that by fine-tuning the
hydrophilic/hydrophobic balance of these types of compounds it is
possible to eliminate the toxicity and achieve selectivity for
tumour cells over normal cells. These metal-based (Au(I), Ag(I)
and Cu(I)) compounds appear to act by a mechanism of action that
is different to all anticancer agents currently in clinical
use.
Current research efforts are
directed at understanding the mechanism of action of compounds of
this class, which are thought to target tumour cell mitochondria.
An ARC funded project also investigates Au(I) complexes of
N-heterocyclic carbenes (NHCs) as analogs of different classes of
Au(I) phosphine complexes that have shown antimitochondrial
activity. Several different classes of Au(I) NHC compounds are
under investigation (a collaboration with Assoc. Prof. Murray
Baker, UWA). A variety of different complexes have shown the
ability to induce mitochondrial membrane permeabilization
indicating that phosphine ligands are not essential for
antimitochondrial activity. Dinuclear Au(I) NHC complexes are of
particular interest as the inherent luminescent arising from the
short Au-Au distances allows the investigation of the
intracellular distribution in single living cancer cells using
confocal fluorescence microscopy.
Recent Publications
P. J. Barnard,
L. E. Wedlock, M. V. Baker, S. J. Berners-Price, D. A. Joyce, B.
W. Skelton, J. H. Steer. Luminescence Studies of the
Intracellular Distribution of a Dinuclear Gold(I) N-Heterocyclic
Carbene Complex. Angew. Chem., Int. Ed.
45, 5966-5970 (2006).
S. J. Berners-Price, L. Ronconi, P. J.
Sadler. Insights into the mechanism of action of platinum
anticancer drugs from multinuclear NMR spectroscopy. Prog. Nucl. Magn. Reson. Spectrosc. 49, 65-98
(2006).
M. V. Baker, P. J. Barnard, S. J.
Berners-Price, S. K. Brayshaw, J. L. Hickey, B. W. Skelton, A. H.
White. Cationic, linear Au(I) N-heterocyclic carbene
complexes: synthesis, structure and anti-mitochondrial activity.
Dalton Trans. 3708-3715 (2006).
M. V. Baker, P. J. Barnard, S. J.
Berners-Price, S. K. Brayshaw, J. L. Hickey, B. W. Skelton, A. H.
White. Synthesis and structural characterization of linear
Au(I) N-heterocyclic carbene complexes: New analogues of the
Au(I) phosphine drug Auranofin. J. Organomet.
Chem. 690, 5625-5635 (2005).
J. Zhang, D. S. Thomas, M. S. Davies, S. J.
Berners-Price, N. Farrell. Effects of geometric isomerism
in dinuclear platinum antitumor complexes on aquation reactions
in the presence of perchlorate, acetate and phosphate.
J. Biol. Inorg. Chem. 10, 652-666
(2005).
S. J. Berners-Price, R. J. Bowen, M. A.
Fernandes, M. Layh, W. J. Lesueur, S. Mahepal, M. M. Mtotywa, R.
E. Sue, C. E. J. van Rensburg. Gold(I) and silver(I)
complexes of 2,3-bis(diphenylphosphino)maleic acid: Structural
studies and antitumour activity. Inorg. Chim.
Acta 358, 4237-4246 (2005).
P. J. Barnard, M. V. Baker, S. J.
Berners-Price, D. A. Day. Mitochondrial permeability
transition induced by dinuclear gold(I)-carbene complexes:
potential new antimitochondrial antitumour agents. J. Inorg. Biochem. 98, 1642-1647 (2004).
P. J. Barnard, M. V. Baker, S. J.
Berners-Price, B. W. Skelton, A. H. White. Dinuclear
gold(I) complexes of bridging bidentate carbene ligands:
synthesis, structure and spectroscopic characterisation.
Dalton Trans. 1038-1047 (2004).
S. J. Berners-Price. Targeting the
mitochondrial cell death pathway with gold complexes.
Chem. in Aus. 71, 10-12 (2004).
A. Hegmans, S. J. Berners-Price, M. S.
Davies, D. S. Thomas, A. S. Humphreys, N. Farrell. Long
Range 1,4 and 1,6-Interstrand Cross-Links Formed by a Trinuclear
Platinum Complex. Minor Groove Preassociation Affects Kinetics
and Mechanism of Cross-Link Formation as Well as Adduct
Structure. J. Am. Chem. Soc. 126,
2166-2180 (2004).
M. S. Davies, S. J. Berners-Price, J. W.
Cox, N. Farrell. The nature of the DNA template (single-
versus double-stranded) affects the rate of aquation of a
dinuclear Pt anticancer drug. Chem.
Commun. 122-123 (2003).
S. J. Berners-Price, M. S. Davies, J. W.
Cox, D. S. Thomas, N. Farrell. Competitive reactions of
interstrand and intrastrand DNA-Pt adducts: A dinuclear-platinum
complex preferentially forms a 1,4-interstrand cross-link rather
than a 1,2 intrastrand cross-link on binding to a GG 14-mer
duplex. Chem. Eur. J. 9, 713-725 (2003).
M. J. McKeage, L. Maharaj, S. J.
Berners-Price. Mechanisms of cytotoxicity and antitumor
activity of gold(I) phosphine complexes: the possible role of
mitochondria. Coord. Chem. Rev. 232,
127-135 (2002).
M. S. Davies, D. S. Thomas, A. Hegmans, S.
J. Berners-Price, N. Farrell. Kinetic and Equilibria
Studies of the Aquation of the Trinuclear Platinum Phase II
Anticancer Agent
[{trans-PtCl(NH3)2}2{μ-trans-Pt(NH3)2(NH2(CH2)6NH2)2}]4+
(BBR3464). Inorg. Chem. 41, 1101-1109
(2002).
J. W. Cox, S. J. Berners-Price, M. S.
Davies, Y. Qu, N. Farrell. Kinetic analysis of the
stepwise formation of a long-range DNA interstrand cross-link by
a dinuclear platinum antitumor complex: evidence for aquated
intermediates and formation of both Kinetically and
thermodynamically controlled conformers. J. Am.
Chem. Soc. 123, 1316-1326 (2001).
M. J. McKeage, S. J. Berners-Price, P.
Galettis, R. J. Bowen, W. Brouwer, L. Ding, L. Zhuang, B. C.
Baguley. Role of lipophilicity in determining cellular
uptake and antitumour activity of gold phosphine complexes.
Cancer Chemother. Pharmacol. 46, 343-350
(2000).
M. S. Davies, S. J. Berners-Price, T. W.
Hambley. Slowing of Cisplatin Aquation in the Presence of
DNA but Not in the Presence of Phosphate: Improved Understanding
of Sequence Selectivity and the Roles of Monoaquated and
Diaquated Species in the Binding of Cisplatin to DNA.
Inorg. Chem. 39, 5603-5613 (2000).
Y. Chen, J. A. Parkinson, P. Del Socorro
Murdoch, Z. Guo, S. J. Berners-Price, T. Brown, P. J.
Sadler. Sequence-dependent bending of DNA induced by
cisplatin: NMR structures of an AT-rich 14-mer duplex.
Chem. Eur. J. 6, 3636-3644 (2000).
M. S. Davies, S. J. Berners-Price, T. W.
Hambley. Rates of platination of -AG- and -GA- containing
double-stranded oligonucleotides: effect of chloride
concentration. J. Inorg. Biochem. 79,
167-172 (2000).
M. S. Davies, J. W. Cox, S. J.
Berners-Price, W. Barklage, Y. Qu, N. Farrell. Equilibrium
and Kinetic Studies of the Aquation of the Dinuclear Platinum
Complex
[{trans-PtCl(NH3)2}2(μ-NH2(CH2)6NH2)]2+:
pKa Determinations of Aqua Ligands via
[1H,15N] NMR Spectroscopy. Inorg. Chem. 39, 1710-1715 (2000).
Selected Publications prior to 2000
M. S. Davies,
S. J. Berners-Price, T. W. Hambley. Rates of Platination
of AG and GA Containing Double-Stranded Oligonucleotides:
Insights into Why Cisplatin Binds to GG and AG but Not GA
Sequences in DNA. J. Am. Chem. Soc. 120,
11380-11390 (1998).
S. J. Berners-Price, P. J. Sadler.
Coordination chemistry of metallodrugs: insights into biological
speciation from NMR spectroscopy. Coord. Chem.
Rev. 151, 1-40 (1996).
K. J. Barnham, S. J. Berners-Price, A.
Corazza, P. J. Sadler. Pathways of DNA platination
reactions: detection of aqua-chloro intermediates. J. Inorg. Biochem. 59, 171 (1995).
S. J. Berners-Price, T. A. Frenkiel, U.
Frey, J. D. Ranford, P. J. Sadler. Hydrolysis products of
cisplatin: pKa determinations via
[1H,15N] NMR spectroscopy. J. Chem. Soc., Chem. Commun. 789-791 (1992).
S. J. Berners-Price, P. W. Kuchel.
Reaction of cis- and
trans-[PtCl2(NH3)2] (cisplatin)
with reduced glutathione inside human red blood cells, studied by
proton and nitrogen-15-{proton} DEPT NMR. J.
Inorg. Biochem. 38, 327-345 (1990).
S. J. Berners-Price, P. J. Sadler.
Phosphines and metal phosphine complexes: relationship of
chemistry to anticancer and other biological activity.
Structure and Bonding (Berlin, Germany)
70, 27-102 (1988).
S. J. Berners-Price, C. K. Mirabelli, R. K.
Johnson, M. R. Mattern, F. L. McCabe, L. F. Faucette, C. M. Sung,
S. M. Mong, P. J. Sadler, S. T. Crooke. In vivo antitumor
activity and in vitro cytotoxic properties of
bis[1,2-bis(diphenylphosphino)ethane]gold(I) chloride.
Cancer Res. 46, 5486-5493 (1986).
S. J. Berners-Price, P. J. Sadler.
Gold(I) complexes with bidentate tertiary phosphine ligands:
formation of annular vs. tetrahedral chelated complexes.
Inorg. Chem. 25, 3822-3827
(1986).
|
