Donnelly RESEARCH GROUP

Bio21 Institute
School of Chemistry, the University of Melbourne, Victoria 3010, Australia
Tel: +61-3-8344-2399; Email:

 

 

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Research

The research of the Donnelly Group focuses on the application of synthetic inorganic/organic chemistry to biology and materials science. In particular, I am interested in the application of coordination chemistry to metal-based drugs and the study of metal ions in biological systems.

Our multidisciplinary research involves inorganic/organic synthesis and the application of a wide range of analytical techniques including: multinuclear NMR, mass spectrometry, electronic and fluorescent spectroscopy, EPR, electrochemical techniques and X-ray crystallography.

The research group is based in new ‘state of art’ laboratories in the $100 million Bio21 Institute of Molecular Science and Biotechnology building that opened in 2005. This exciting development provides state-of-the-art facilities for researchers in a dynamic interdisciplinary environment.

Research Area

1. Radiopharmaceuticals and Imaging Agents

a) Copper and Rhenium Chemistry

Copper has several isotopes that are of clinical interest for both imaging and therapy. Rhenium has two isotopes, Re-186 and Re-188, which are beta emitters that can be used for radiotherapy. For both imaging and therapeutic applications it is essential that the radionuclide be delivered selectively to the target site in the body. For metal isotopes such as copper and rhenium this can be achieved by the formation of coordination complexes where the biodistribution is determined by several factors such as charge, shape, lipophilicity and redox chemistry. The attachment of certain biologically active molecules to the complex can provide further selectivity. We are interested in the design and synthesis of new copper (Figure 1) and rhenium complexes that have potential application as radiopharmaceuticals.

Figure 1. Representations of structures of two new copper complexes designed as radiopharmaceuticals.

b) Technetium Imaging Agents

Technetium-99m is the most commonly used radioisotope for diagnostic imaging. In collaboration with researchers and clinicians at the Nuclear Medicine Department of the Austin Hospital, Melbourne (Dr. Uwe Ackermann) we are investigating new coordination complexes of technetium designed to aid in the diagnosis of hypoxia. Hypoxia (low oxygen concentrations in tissue) is associated with cancer and stroke.

c) Fluorescent Imaging

We are also interested in the synthesis of metal-based anti-cancer agents, their cell uptake and intracellular distribution. A microscope image of an ovarian cancer cell and the fluorescence image after the cell was treated with a fluorescent metal complex are shown in Figure 2. The fluorescence imaging shows significant uptake of the drug in the area of the cell nucleolus that allows interaction with DNA.

Figure 2. A representation of the X-ray structure of a biologically active zinc bis(thiosemicarbazonato) complex (left), a microscope image of an IGROV ovarian cancer cell (middle) and the fluorescence image of the same cell after exposure to the zinc bis(thiosemicarbazonato) complex (right).

Collaborations: Professor Jonathan Dilworth (University of Oxford), Nuclear Medicine Dept. Austin Hospital, Melbourne.

Selected References

  1. Therapeutic Rhenium Radiopharmaceuticals. J. R. Dilworth and P. S. Donnelly. In Metallotherapeutics – The Use of Metal-Based Drugs in Medicine, Eds, Marcel Gielen and Edward Tiekink, Wiley, Chichester, 2005, p. 463
  2. New Bimetallic Compounds Based on the Bis(thiosemicarbazonato) Motif. M. Christlieb, A. R. Cowley, J. R. Dilworth, P. S. Donnelly, B. M. Paterson, H. S. R. Struthers and Jonathan M. White. Dalton Trans., 2007, 327.
  3. Bifunctional chelators for copper radiopharmaceuticals: The synthesis of [Cu(ATSM)-amino acid] and [Cu(ATSM)-octreotide] conjugates. A. R. Cowley, J. R. Dilworth, P. S. Donnelly, J. M. Heslop, and S. J. Ratcliffe. Dalton Trans., 2007, 209.

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2. Metal Complexes of Macrocyclic Ligands and New Materials

a) Applications in Radiopharmaceuticals

Macrocyclic cage amine ligands are known to form very stable complexes (Figure 3) with a variety of metal ions. As a consequence the ligands offer considerable potential in the design of copper-based biological imaging agents (PET tracers). To image cancer the imaging agent (copper complex) needs to be “targeted” to the tumour. This can be achieved by tethering the cage complex to biologically active molecules that localise in tumour tissue. This project would synthesise copper cage complexes with functional groups to allow incorporation into peptides that bind to tumours.
Figure 3. A copper cage complex functionalised with the amino acid, glycine and a space filling representation showing the tight fit of the ligand around the metal atom

b) New Materials

Electroactive and luminescent metal complexes have the potential to be used in a variety of new materials or devices. The bimetallic ‘coordination polymer’ shown below (Figure 4) consists of linear chains of electro-active metal complexes linked via coordination of pendant groups to a second metal atom.
Figure 4. A bimetallic Co/Zn “coordination polymer”.4

c) New Luminescent Metal Complexes

Another project in collaboration with Dr. Scott Watkins (CSIRO) aims to prepare new luminescent metal complexes for application in organic light emitting diodes (OLED) and new light emitting devices.

Selected References

  1. Chirality in Coordination Polymers: Homo-vs. Hetero-chiral Strand Construction. P. S. Donnelly, J. M. Harrowfield, B. W. Skelton and A. H. White. J. Chem. Soc., Dalton Trans., 2001, 3078.
  2. Carboxymethylation of Cage Amines: Control of Alkylation by Metal Ion Coordination. P. S. Donnelly, J. M. Harrowfield, B. W. Skelton and A. H. White. Inorg. Chem., 2000, 39, 5817-5830.
  3. Synthesis with Coordinated Ligands: Biomolecule Attachment to Cage Amines. P. S. Donnelly and J. M. Harrowfield. J. Chem. Soc., Dalton Trans., 2002, 906.

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3. Metal Ions and Alzheimer’s Disease

a) Metal-based Drugs for the Treatment of Alzheimer’s Disease

In collaboration with A/Prof. Kevin Barnham and Dr. Tony White (both Dept. of Pathology) we are investigating metal-based drugs for the treatment of Alzheimer’s disease. The disease is associated with the precipitation of insoluble aggregates of a peptide (called Aβ) that form plaques in the brain (Figure 5). These plaques are toxic and are thought to cause some of the symptoms of the disease. We are investigating copper and zinc complexes that are capable of breaking down the peptide and offer possibilities as new therapeutics.

b) Imaging Agents for the Diagnosis of Alzheimer’s Disease

Another project aims to develop and synthesise copper and zinc complexes suitable for PET (radiopharmaceuticals) or fluorescent imaging of Aβ plaques to allow effective diagnosis of the disease (Figure 5b). The newly synthesised compounds are be characterised by standard techniques such as NMR, MS and electrochemistry. The new agents are tested in a range of biological assays.

a)

b)
Figure 5. a) The Aβ peptide that forms plaques in Alzheimer’s disease patients. b) A PET scan of a patient with Alzheimer’s disease. The plaques are “stained” (red sections) with a radiopharmaceutical. (PET image courtesy of Dr Villemagne, Austin Hospital).

Selected References

  1. Copper and Alzheimer’s Disease. Paul S. Donnelly, Zhiguang Xiao and Anthony G. Wedd. Curr. Opin. Chem. Biol., 2007, 11, 128.

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4. Interaction of Metal-based Drugs with Proteins

Metal ions are essential for the function of certain enzymes. The acquisition and regulation of metal ions in cells is governed by a sophisticated array of “transport proteins” or “chaperone proteins” (Figure 6).

In collaboration with Prof. Tony Wedd and Dr. Zhiguang Xiao in the Bio21 Institute we are investigating the interactions of these transport proteins with metal-based drugs. In particular we are interested in the interactions of the anti-cancer drug cis-platin and copper radiopharmaceuticals.

Our aim is to gain insight into the molecular nature of these important biochemical interactions and this may help to design drugs with fewer side effects.

The molecular probes needed are provided by techniques such as NMR, ESR, MS, fluorescence, X-ray crystallography and electrochemistry.
Figure 6. A copper transport protein.

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First created:25/05/07 - Last updated: 28/05/07.
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