Research Network for Metals in Medicine

 

 

Professor Sue Berners-Price

B.Sc. (Southampton) Ph.D. (London)

Position: Professor of Biological Chemistry

Affiliation: University of Western Australia, Department of Chemistry

Postal Address:
The University of Western Australia
Department of Chemistry
35 Stirling Highway
Crawley WA 6009
AUSTRALIA

Phone: +61 (08) 9380 3161
Email: ib@chem.uwa.edu.au
Webpage: http://www.chem.uwa.edu.au/people/academics/SueBernersPrice.html


Research Profile

Professor Sue Berners-Price was appointed to the newly established Chair in Biology Chemistry in 2001. Her teaching and research interests are in the field of bioinorganic chemistry with a particular interest in metal-based drugs and applications of NMR Spectroscopy. Research facilities in the department include recently installed and upgraded 600 and 500 MHz Bruker NMR spectrometers.

Current research projects are encompassed under two broad areas

Application of advanced NMR techniques to investigate the biological chemistry of platinum anticancer drugs
A major interest is the exploitation of multinuclear NMR methods for the study of the chemistry of metal-based drugs under biologically relevant conditions. In particular the development of [1H, 15N] NMR techniques over the past decade has provided important new insight into the kinetics and mechanism of binding of platinum drugs to DNA. Recent work in this area has focused on understanding the sequence specificity of the binding of cisplatin to DNA (a collaboration with Prof Trevor Hambley, University of Sydney). A current ARC Discovery project (in collaboration with Prof Nick Farrell, Virginia Commonwealth University, Richmond, USA) probes DNA binding interactions of di- and trinuclear Pt drugs related to the Phase II clinical candidate BBR3464 and are aimed at understanding the unique antitumour activity of this clinical candidate.

Design, synthesis and biological evaluation of novel metal phosphine antitumour agents
In early work in collaboration with Professor Peter Sadler (Edinburgh) a new class of metal phosphine antitumour agents were identified 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. As they are lipophilic cations it is possible that the selectivity depends on selective uptake into tumour cell mitochondria.

Current research is aimed at synthesising novel lipophilic cationic metal complexes of this type for evaluation as possible antitumour drugs. The mechanism of action is being investigated through studies of the effect of the compounds on mitochondria (in collaboration with Prof David Day, Biochemistry). An important component of the research is probing the structures of the compounds in the solid-state and solution, through a combination of NMR and crystallographic studies.



Selected Publications

  1. Kinetic analysis of the stepwise formation of a long-range DNA interstrand crosslink by a dinuclear platinum antitumour complex: Evidence for aquated intermediates and formation of both kinetically and thermodynamically controlled conformers. J.W. Cox, S. J. Berners-Price, M.S. Davies, Y. Qu and N. Farrell, J. Am. Chem. Soc. 123, 1316-1326 (2001).
  2. Role of lipophilicity in determining cellular uptake and antitumour activity of gold phosphine complexes. M.J. McKeage, S.J. Berners-Price, P. Galettis, R.J. Bowen, W. Brouwer, L. Ding, L. Zhuang, B.C. Baguley. Cancer Chemother. Pharmacol. 46, 343-350 (2000).
  3. Cisplatin aquation is slowed in the presence of DNA but not by phosphate: an improved understanding of the roles of monoaquated and diaquated species in the binding of cisplatin to DNA. M. S. Davies, S. J. Berners-Price and T.W. Hambley, Inorg. Chem. 39 , 5603-5613 (2000).
  4. Sequence-dependent Bending of DNA induced by Cisplatin: NMR Structures of an AT Rich 14-mer Duplex. J. A. Parkinson, Y. Chen, Z.Guo, S. J. Berners-Price, T. Brown and P. J. Sadler, Chem. Eur. J. 6, 3636-3644 (2000).
  5. Rates of Platination of -AG- and -GA- Containing Double Stranded Oligonucleotides: Effect of High Chloride Concentration. M.S. Davies, S.J. Berners-Price and T.W. Hambley, J. Inorg. Biochem. 79, 167-172 (2000).
  6. Equilibrium and Kinetic Studies of the Aquation of the Dinuclear Platinum Complex [{trans-PtCl(NH3)2}2( mu -NH2(CH2)6NH2)]2+: pKa Determinations of Aqua Ligands via [1H, 15N] NMR Spectroscopy . M. S. Davies, J. W. Cox, S. J. Berners-Price, W. Barklage, Y. Qu and N. Farrell, Inorg. Chem. 39, 1710-1715 (2000)
  7. The Chemistry of Cisplatin in Aqueous Solution S. J. Berners-Price and T.G. Appleton in "Platinum-Based Drugs in Cancer Therapy" (L.R. Kelland and N.P. Farrell eds). Humana Press. Totowa NJ, pp3-35 (2000).
  8. Structural and solution chemistry of gold(I) and silver(I) complexes of bidentate pyridyl phosphines: selective antitumour agents. S. J. Berners-Price, R. J. Bowen, P. Galettis, P. C. Healy and M.J. McKeage, Coord. Chem. Rev. 185-186 , 823-836 (1999).
  9. NMR and structural studies of gold(I)chloride adducts with bidentate 2-, 3- and 4-pyridyl phosphines. S.J. Berners-Price, R.J. Bowen, T.W. Hambley, P.C. Healy, J. Chem. Soc. Dalton Trans. 1337-1346 (1999).
  10. Reactions of cisplatin hydrolytes with methionine, cysteine and ultrafiltered plasma studied by a combination of HPLC and NMR techniques. M. El-Khateeb, T.G. Appleton, L.R. Gahan, B.G. Charles, S.J. Berners-Price and A-M Bolton. J. Inorg. Biochem. 77, 13-21 (1999).
  11. Rates of platination of double stranded AG and GA containing oligonucleotides: insights into why cisplatin binds to AG but not GA Sequences in DNA. M. S. Davies, S. J. Berners-Price and T. W. Hambley, J. Amer. Chem. Soc. 120 , 11380-11390 (1998).
  12. A new convenient synthetic route to monodentate and bidentate 3- and 4- pyridyl phosphines: useful water-soluble ligands. R.J. Bowen, C. Garner, S.J. Berners-Price and I.D. Jenkins, J. Organomet. Chem. 554, 181-184 (1998).
  13. Silver(I) nitrate adducts with bidentate 2-, 3- and 4-pyridyl phosphines. Solution 31P and [109Ag,31P] NMR studies of 1:2 complexes and the crystal structure of dimeric [(d2pype)Ag(mu2 -d2pype)]2(NO3)2?2CH2Cl2. S. J. Berners-Price, R. J. Bowen, P. J. Harvey, P. C. Healy and G. A. Koutsantonis, J. Chem. Soc. Dalton Trans. 1743-1750 (1998).