Research Network for Metals in Medicine

 

 

Associate Professor Margaret M Harding

BSc(Hons), PhD, FRACI

Position: Associate Professor in Chemistry, Deputy Head of School, Associate Dean (Postgraduate Research) Faculty of Science

Affiliation: School of Chemistry, University of Sydney

Postal Address:
School of Chemistry
University of Sydney, NSW 2006
AUSTRALIA

Phone: +61 (2) 9351 2745
Fax: +61 (2) 9351 6650
Email: harding@chem.usyd.edu.au
Webpage: http://www.usyd.edu.au/~harding

Research Profile

Margaret Harding research has been recognised by two major awards (i) 1993 Royal Australian Chemical Institute Rennie Medal (shared) (ii) 1995 Royal Australian Chemical Institute Biota Medal for Medicinal Chemistry. Margaret Harding has 82 publications in major international journals [1999 journal impact factor in brackets: JACS (5.537), JBC (7.666), J.Med.Chem. (4.079) Biochemistry (4.493), Chem. Commun (3.477), EJB (3.307), FEBS (3.72), Inorg Chem (2.843) Dalton (2.310)]. Margaret Harding has held a Rhone-Poulenc Exchange Fellowship (Strasbourg, Lehn, 1992), an Australian Academy of Science/Royal Society Exchange Fellowship in Warwick (Rodger, CD/LD drug/DNA interactions 1998), an Australian Acadmey of Science Fellowship at the University of Houston (Haymet, antfireeze proteins, 2002) and has presented invited research lectures at major centres in Europe including the Universities of Cambridge, Oxford, Warwick, Sheffield, Birmingham (UK), Universite Louis Pasteur, Rhone-Poulenc, Lyon (France), Geneva, Basel (Switzerland), Marburg (Germany). Margaret Harding has presented lectures at the XXth International Coordination Chemistry Conference (Vancouver 1999), ICBIC (Cairns, 2003) and plenary lectures in the Metals in Medicine Symposium (9th International Conference on Coordination Chemistry of Ge, Sn, Pb), the Gordon Conference on Inorganic Chemistry in 2002 (Rhode Island,USA), Antifreeze Proteins (California 2003) and Bioorganometallic Chemistry (Zurich 2004). Margaret Harding is an Editorial Advisory Board member for Mini-Reviews in Medicinal Chemistry and Molecular Engineering-Supramolecular Science and Technology.

Margaret Harding is recognised for research at the interface of chemistry and biochemistry with key contributions to the study of drug-DNA interactions and antifreeze proteins.

Drug-DNA Interactions: The interactions of established anticancer drugs with DNA and how these interactions are related to anticancer activity have provided insight into the mechanism of action of several clincially used drugs, and provided the basis for the rational design of new drugs. Key contributions include the preparation of the first water soluble derivatives of titanocene dichloride, currently in phase II clinical trials, and molecular level studies that have established the crucial features of metal-based drugs in this class. The significance of this work has been recognised by an invitation to speak on these drugs at the Gordon Conference on Inorganic Chemistry in 2002 and at the Bioorganometallic Chemistry Sympososium in Zurich in 2004. Independent studies on the DNA-binding properties on the antitumour antibiotic streptonigrin, anthracycline antitumour antibiotics and ellipticines have contributed to the understanding of the relationship between structure, reactivity and biological activity of these drugs.

Antifreeze Proteins: The design, synthesis and structural characterisation of antifreeze proteins by Margaret Harding, combined with the computational and physical chemistry expertise of collaborators, has allowed a novel, unique and innovative approach in the field (which is dominated by biologists, not chemists), which has resulted in the synthesis of new active mutants that disproved the widely accepted mechanism for type I antifreeze proteins. The significance of the results, and the impact to researchers in the field is demonstrated by high quality publications (JACS, FEBS, EJB, JBC), and citations of these publications.

Selected Publications

  1. M.M. Harding and G.V. Long, Interaction of the Antitumor Antibiotic Streptonigrin with Metal Ions and DNA, Current Medicinal Chemistry, 1997, 4, 405-420.
  2. G. Mokdsi and M.M. Harding, Water Soluble, Hydrolytically Stable Derivatives of the Antitumour Drug Titanocene Dichloride and Binding Studies with Nucleotides, J. Organometal. Chem., 1998, 565, 29-35.
  3. M.M. Harding , G. Mokdsi, J.P. Mackay, M. Prodigalidad and S. Wright Lucas, Interactions of the Antitumour Agent Molydocene Dichloride with Oligonucleotides, Inorg. Chem., 1998, 37, 2432-2437.
    4. G. Mokdsi and M.M. Harding, Antitumour Metallocenes : Effect of DMSO on the Stability of Cp2TiX2 and Implications for Anticancer Activity, Metal Based Drugs, 1998, 5, 207-215.
  4. G.V. Long, M.M. Harding and P. Turner, X-Ray Structure of the Zinc Complex of the Central Metal Chelation Site of the Antitumour Drug Streptonigrin, Polyhedron, 2000, 19, 1067-1071.
    5. M.M. Harding and G. Mokdsi, Antitumour Metallocenes: Structure-Activity Studies and Interactions with Biomolecules, Current Medicinal Chemistry, 2000, 7, 1289-1303.
  5. G. Mokdsi and M.M. Harding, Inhibition of Human Topoisomerase II by the Antitumor Metallocenes, J. Inorg. Biochem., 2001, 83, 205-209.
  6. G. Mokdsi and M M Harding A 1H NMR Study of the Interaction of Antitumour Metallocenes with Glutathione J. Inorg. Biochem. 2001, 86, 611-616.
  7. P. I. Anderberg and M. M. Harding The Role of Ring D in the Antitumor Antibiotic Streptonigrin. Metal Complexation, DNA Binding and Topoismerase II Inhibition of ABC Analogues of Streptonigrin. Anti-Cancer Drug Design, 2001, 16, 143-153.
  8. P. I. Anderberg, M. M. Harding, I. J. Luck and P. Turner Ruthenium Complexes of Analogues of the Antitumor Antibiotic Streptonigrin Inorganic Chemistry, 2002, 41, 1365-1371.
  9. P.I Anderberg, M.M. Harding and P. A. Lay The effect of Metal Ions on the Redox Potential of the Antitumour Antibiotic Streptonigrin J. Inorg. Biochem., 2003,in press.
  10. J. B. Waern and M.M. Harding Coordination Chemistry of the Antitumor Metallocene Molybdocene Dichloride with Biological Ligands Inorganic Chemistry 2004, 43, 206-213.


International Linkages

Dr Alison Rodger (University of Warwick, UK): CD and LD of drug-DNA interactions