bioinorganic medicinal chemistry
Our research group has a strong interest in the medicinal chemistry of boron and gadolinium. We have made considerable advances in the development of new drug classes and also medicinal agents with neutron and X-ray photon applications.
We are heavily involved in the development of new boron and gadolinium agents for an exciting cancer treatment known as neutron capture therapy (NCT). To date, we have discovered several new classes of DNA-, mitochondrial- and tumour-targeted compounds and we are currently exploring their use as potential BNCT and GdNCT agents. We are also interested in the use of boron clusters, in particular the carboranes, as unique classes of pharmacophore in drug design. Perhaps boron really is the new carbon!
Our research is funded by organizations including the Australian Research Council, The Prostate Cancer Foundation of Australia, Cure Cancer Australia Foundation and The National Breast Cancer Foundation.
The Honours projects outlined below would ideally suit those students who enjoy synthetic inorganic and organic chemistry, and no organoboron or lanthanide chemistry experience is assumed. Our group website has further details of all projects (http://sydney.edu.au/science/chemistry/~lmrgroup).
Boronated phosphonium salts as novel tumour targeting agents for BNCT
Boron neutron capture therapy (BNCT) utilizes a combination of low-energy neutrons and 10B-containing compounds to destroy cancer cells as a result of the tremendous amount of energy which is liberated upon the capture of a neutron by the non-radioactive 10B nucleus. Lipophilic cations with delocalised charges such as the phosphonium salt [PPh3Me]+ accumulate in the mitochondria of most tumour cells more rapidly than in normal cells, and also have the capacity to accumulate significantly in brain tumours. In this project, we will investigate whether boronated analogues of phosphonium salts have the capacity to target tumour cells and deliver boron to the mitochondria for BNCT. Biological studies may also be incorporated into the project, depending upon the student’s own interests and background.
Carboranes as unique pharmacophores in medicinal chemistry
Boron-based drugs are increasingly being investigated in many disease categories, with numerous pharmaceutical companies (e.g. GSK, Anacor, and Takeda) dramatically expanding their boron research programs in recent years in the quest for novel drug candidates, e.g. Velcade® (bortezomib) which is used in the treatment of multiple myeloma. Almost all boron drugs investigated to date, however, are based upon boronic acids and boronate esters. In contrast, polyhedral boron clusters known as carboranes have rarely been exploited as pharmacophores in medicinal chemistry, and their use as enzyme inhibitors or receptor antagonists is largely underdeveloped. We are currently investigating the use of carboranes as unique pharmacophores for the diagnosis and treatment of CNS diseases (in collaboration with Prof. M. Kassiou) and cancer. Biological studies may also be incorporated into the project, depending upon the student’s own interests and background.
Gadolinium complexes as a new class of agents for neutron capture therapy
The non-radioactive 157Gd possesses the largest effective nuclear capture cross-section of all the naturally-occurring elements. In this project, we will incorporate Gd3+ ions into DNA- and mitochondrial-targeting agents in order to localise the neutron capture reaction near critical cellular components which will ultimately lead to substantial tumour cell destruction. We have already shown that Gd3+ can be delivered selectively to the nuclei and mitochondria of lung and brain tumour cells. Biological studies may also be incorporated into the project, depending upon the student’s own interests and background. The use of Gd agents to target chromosomal DNA or mitochondria would open up new vistas in NCT, with additional applications in tumour radiotherapy and also MRI.
New boron-based epigenetic inhibitors for the treatment of malignant cancers
Epigenetics (and the so-called “epigenetic code”) will undoubtedly play an important role in future drug design and, indeed, several drug companies are now actively searching for small molecule epigenetic inhibitors for diseases such as cancer. These drugs can block critical pathways associated with, for example, DNA methylation and histone modification such as acetylation. A small number of epigenetic inhibitors have recently been approved for use in humans for the treatment of selected cancers including cutaneous T-cell lymphoma (CTCL). In this project, we will exploit carboranes as new pharmacophores in the design of small molecules that can inhibit histone deacetylase (HDAC) for the treatment of intractable cancers such as malignant glioma.
For further information, please contact:
School of Chemistry
University of Sydney NSW 2006
Phone: +61 2 9351 4781