School of Physical, Environmental & Mathematical Sciences Research

Biological Chemistry

This research primarily focuses on the interactions between transition metal complexes and DNA. This work aims at understanding the principles of DNA recognition, with the ultimate goal of being able to design compounds that can control gene expression - the next great target now that most of the human genome has been sequenced. We study the interactions of inert dinuclear ruthenium complexes with DNA and RNA. Dinuclear ruthenium complexes, rather than the more often studied mononuclear complexes, offer many advantages. Dinuclear complexes bind selectively at DNA and RNA non-duplex sites, e.g. bulges and hairpin-loops, where shape, size, functionality and charge govern selectivity and affinity. In addition, we are also involved in the development of a new, and very promising, class of anti-cancer drug – multinuclear platinum complexes. We design and synthesise new complexes, determine their biological activity and examine their binding to DNA by NMR spectroscopy. In addition, we are exploring the possibility of reducing the toxicity and degradation by plasma proteins of multinuclear platinum complexes by encapsulating them in cucurbituril, an open-ended barrel shaped host molecule.

Members of the Biological Chemistry Research Group:

Academic Staff:

Assoc. Prof. Grant Collins (g.collins@adfa.edu.au) BSc, PhD ANU , MRACI, CChem

Research Assistant:

Dr Damian Buck (d.buck@adfa.edu.au) BSc, PhD ANU

Research Students:

Khaleda Ferdous - Research Topic - Iridium complexes as biological agents

Fanfei Li - Research Topic - Dinuclear ruthenium complexes as therapeutic agents. Fanfei Li is jointly supervised by A. Day (Molecular Design and Reaction Mechanisms) and G. Collins

Vijaybabu Mandadapu - Research Topic -Combined delivery methodologies that can increase the effecctiveness of existing drugs

Mallesh Pandrala - Research Topic -Inert polypyridyliridium(III) complexes as anti-microbial agents

Recent Graduate Students:

Adnan, Najia, 2010, Analysis of the DNA binding of Pixantrone, School of Physical, Environmental & Mathematical Sciences, Australian Defence Force Academy, UNSW, Masters Thesis, Available at: http://handle.unsw.edu.au/1959.4/45607.

Pisani, Michelle, 2011, Inert dinuclear Polypyridylruthenium(II) complexes as anticancer drugs, PhD Thesis, School of Physical, Environmental & Mathematical Sciences, Australian Defence Force Academy, UNSW.

Yunjie Zhao, 2009, Cucurbit[n]uril- a delivery host for anti-cancer drugs, School of Physical, Environmental & Mathematical Sciences, Australian Defence Force Academy, UNSW, PhD Thesis, Access to this thesis is restricted for 12 months, http://handle.unsw.edu.au/1959.4/44380.

Research Collaborators:

Prof. Richard Keene (James Cook University, Townsville)
Assoc. Prof. Janice Aldrich-Wright (University of Western Sydney)

Research Degrees - Apply

Scholarships - Apply

PhD Opportunities and Scholarships:

There are PhD and Masters opportunities in all the research areas described. Further information is available from:

Assoc. Prof. Grant Collins (g.collins@adfa.edu.au)

Recent Research in the Biological Chemistry Group

Assoc. Prof. Grant Collins

Over the last decade there has been considerable interest in DNA secondary structures that deviate from the well-known double helix. One example is a bulge structure in which there are regions of the duplex possessing one or more unpaired bases. These structural motifs are often associated with important biological functions: DNA bulge sites can be created during recombination between imperfectly homologous sequences, and are thought to play an important role in frame-shift mutagenesis. More recently, bulge sites have been shown to bind some DNA-repair proteins more tightly than duplex DNA and consequently are potential binding sites for therapeutic agents. Given their biological importance and potential as a target for novel drugs, there has been considerable research aimed at developing small molecules that can selectively target DNA bulge sites.

In collaboration with Prof. R. Keene (JCU) we have shown that non-intercalating, rigid, dinuclear ruthenium complexes associate weakly with the minor groove of duplex DNA; importantly however, these complexes demonstrate a much greater affinity for more open and/or flexible secondary structures such as bulge sites.

Multinuclear platinum complexes , developed by Farrell and coworkers, have shown considerable promise as anti-cancer agents. Unlike cisplatin, di- and trinuclear platinum complexes, where two or three platinum coordination centres are linked by diamine chains, form flexible long-range interstrand DNA adducts. It is from this novel DNA binding mode that multinuclear platinum complexes are thought to derive a different cytotoxic profile to cisplatin. Pre-clinical studies demonstrated that the multinuclear platinum complexes were considerably more active than cisplatin in a range of cell lines, and more importantly, maintained their activity in the corresponding cisplatin resistant cell lines. While multinuclear platinum complexes are highly cytotoxic, they have a relatively narrow therapeutic index. Phase I clinical trials indicated that the Maximum Tolerated Dose (MTD) for the trinuclear complex BBR3464 was much lower than platinum drugs already in the clinic. Furthermore, most of the platinum drug binds thiol containing plasma proteins in the bloodstream, and is subsequently degraded to nonactive metabolites. Consequently, methods that can reduce the toxicity and/or decrease the binding of thiol containing proteins could improve the clinical utility of multinuclear platinum drugs. We have demonstrated that encapsulation of the multinuclear platinum complexes within the cavity of a cucurbituril overcomes the problems associated with plasma protein binding, and hence, may represent a new drug delivery technique for this class of anti-cancer compound.

Student Research in the Biological Chemistry Group

Analysis of DNA binding of Pixantrone
Najia Adnan (n.adnan@adfa.edu.au) Masters
Field of Study: Biological Chemistry

The reversible DNA-binding of pixantrone and its activated reactive form should be identical, as the binding is due to the intercalculation of the non-reactive planar polycyclic aromatic part of the drug. Consequently, we propose to examine the binding of pixantrone to a range of small segments of DNA (oligonucleotides) by nuclear magnetic resonance (NMR) spectroscopy. In order to compare the DNA-binding of pixantrone to other anthracyclines, initial NMR experiments will utilize a particular well-characterised oligonucleotide. Then, in conjunction with molecular modelling, a detailed picture of the reversible binding will be developed. In the second phase of the research, the reversible binding of pixantrone will be screened against a wide range of oligonucleotides that contain different base sequences and structures (such as base-bulges), using fluorescence intercalator displacement assays. Those sequences or structures that show the strongest pixantrone binding will then be used in subsequent NMR experiments.

Dinuclear ruthenium complexes as therapeutic agents
**Fangfei Li (fangfei.li@student.adfa.edu.au) PhD
Field of Study: Biological Chemistry**

Li, F., Mulyana, Y., Feterl, M., Warner, J., Collins, J.G. & Keene, F.R., 2011, The antimicrobial activity of inert oligonuclear polypyridylruthenium(ii) complexes against pathogenic bacteria, including MRSA, Dalton Transactions, 40(18), 5032-5038. http://dx.doi.org/10.1039/c1dt10250h

Cucurbit[n]uril- a delivery host for anti-cancer drugs
Yunjie Zhao (y.zhao@student.adfa.edu.au) PhD
Field of Study: Biological Chemistry

Multinuclear platinum complexes and the organic drug albendazole offer real potential for the treatment of cancer. However, and as with many other anti-cancer agents, their clinical use is limited by pharmacological problems. The potential of a relatively new class of macrocyclic host molecules, called cucurbit[n]uril (Q[n]), to act as a delivery system for these drugs and overcome the clinical drawbacks has been investigated. In order to examine particular aspects of the cucubit[n]uril binding of the drugs, new multinuclear platinum complexes and benzimidazole carbamate derivatives have been synthesized, and their biological activity compared to the parent compounds.

PhD student Yunjie Zhao operating a flurometer, PEMS, UNSW@ADFA

PhD student Yunjie Zhao operating a flurometer, PEMS, UNSW@ADFA. After completing her thesis in 2009 Yunjie received a Research Publication Fellowship for a period of 3 months. She was a winner of the Ria de Groot Prize for 2009 (best female postgraduate research student graduating from UNSW@ADFA) [Photo credit: K. Badek].

Inert dinuclear Polypyridylruthenium(II) complexes as anticancer drugs
**Michelle Pisani (m.pisani@adfa.edu.au) PhD
Field of Study: Biological Chemistry**

Pisani, M., Wheate, N.J., Keene, F.R., Aldrich-Wright, J.R., & Collins, J.G., 2009, Anionic PAMAM dendrimers as drug delivery vehicles for transition metal-based anticancer drugs, Journal of Inorganic Biochemistry, 103(3), 373-380, doi:10.1016/j.jinorgbio.2008.11.014 .

Buck, D.P., Paul, J.A., Pisani, M., Collins, J.G.& Keene, F.R., 2010, Binding of a flexibly-linked dinuclear Ruthenium(II), Australian Journal of Chemistry, 63(9) 1365–1375.

Pisani, M., Weber, D.K., Heimann, K., Collins, J.G. & Keene, F.R., 2010, Selective mitochondrial accumulation of cytotoxic dinuclear polypyridyl rutheniunm(II) complexes, Metallomics, 2 , 393-396.

Pisani, M.J., Zhao, Y., Wallace, L., Woodward, C.E., Keene, F.R., Day, A.I. & Collins, J.G., 2010, Cucurbit[10]uril binding of dinuclear platinum(II) and ruthenium(II) complexes: Association/dissociation rates from seconds to hours, Dalton Transactions, 39, 2078-2086, doi:10.1039/B921172A.

Pisani, M., Fromm, P., Mulyana, Y., Clarke, R.A., Korner, H., Heimann, K., Collins, J.G. & Keene, F.R. 2011, Mechanism of cytotoxicity and cellular uptake of lipophilic inert dinuclear polypyridylruthenium(II) complexes, ChemMedChem, 6(5), 848-858, doi:10.1002/cmdc.201100053.