A. Supramolecular Chemistry and Nanotechnology
My interests focuss around the energy transduction properties of photosynthetic systems and the potential use of the principles involved to design and evaluate wholly synthetic systems that mimic all or part of this process for applications as molecular batteries, molecular logic, energy transduction devices and for solar energy conversion. Stable funding through the NCG Schemes since 2002 has allowed our independent research to flourish in the area of self-assembling multichromophoric systems. Figure 1 illustrates some examples of assemblies and arrays from my group which exploit the oxophilic nature of Sn(IV)porphyrins for light harvesting (see pubs: 30,34,35,36,53,63).
Figure 1. By developing methods to assemble porphyrin-based building blocks, the Langford group hope to gain more insight into how photosynthetic processes may be used in wholly synthetic systems. |
We have been interested in developing pragmatic molecular devices which employ visible light as an excitatory input and diagnostic output. One aspect of this approach has been to consider possible surfaces for adhesion of the porphyrin. Of those available, glass with its ubiquitous use in modern society holds as the surface of choice The structural integrity of the POSS scaffold, and in particular the T8 structure, which has been described as a model system for silica surfaces, was targeted to structurally model the tin(IV)porphyrin-siloxane architectures possible on macroscopic incorporation. We have recently discovered that Sn(IV) porphyrins have an affinity for silica (Pubs 61, 68) and have used this as a means of preparing nano-sized molecular architectures using POSS units. |
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Four further results obtained by my group illustrate the diversity of our research. The first involves the dyad shown in Figure 2. This example is part of a project that evaluates the role played by molecular recognition in the modulation of long-range electron transfer, leading to the design better artificial solar-energy converters and molecular electronic devices .Photophysical measurements on this complex carried out by Prof. Ghiggino's group (UMelb) have identified the formation of a microsecond charge separated state. The relevance here lies in the simplicity of the systems and the longevity is such that either useful chemical work, or charge storage can be investigated. This work has been recently submitted to J. Phys Chem. A following a preliminary account (pub 52).
The systems functions by taking advantage of intersystem crossing leading to the formation of a charge-separated triplet state, leading to the long-lived lifetime. |
Figure 2. Simple dyads such as the one displayed can form molecular batteries. |
Applying the concept of binary processing to the molecular level requires a system that can be reversibly interconverted between two or more states to produce outputs of 0 (off) or 1 (on). Complex operations such as addition and subtraction, require complex operators - in particular an XOR logic gate. By utilising the amphophilic nature of the inner periphery of 5,10,15,20-tetraphenylporphyrin (Figure 3) as well as changes in transmittance and emission at a particular wavelength we have been able to demonstrate the chemical equivalents of xor and inhibit logic gate, respectively. The ability to multiconfigure the system, i.e. detect transmittance and emission simultaneously led to this system being the first reported example of a molecular half-subtractor in the Journal of the American Chemical Society (pub 47). |
| We have designed, synthesised and characterised a family of novel fluorophores based on the substitution of 1,4,5,8-naphthalene diimides (NDIs) (Figure 4) for sensory and security applications within the packaging industry (CRC Smart Print). The fluorescent output of these NDIs (intensity, colour) can be modulated through substituent, solvent, exogenous anions and morphology of the solid-state. In vitro staining on myloma cells shows compartmentalisation. Chemical and electrochemical reduction of the NDIs yield anion radicals with hour lifetimes. The spectroscopic changes associated with these changes may prove useful in applying these compounds to optical device development. A number of publications have resulted (pubs: 28, 42, 43, 50, 51, 56). |
Figure 3. Changing the emission and absorption characterisitics of the porphyrin leads to a molecule that can subtract! |
Figure 4. Highly fluorescent molecules are being developed for a range of smart packaging applications. |
A bottom-up approach to the construction of discrete nanoscaled assemblies has important implications for a number of nanotechnologies. Multiporphyrin systems in which the porphyrin sub-units are interlinked via self-assembly or covalent means have produced an array of elegant and geometric nano-scaled structures designed to address aspects of photosynthetic mimicry, host-guest complexation or catalysis. We recently reported a strategy for preparing cubic porphyrin architectures based on the interplay of Sn(IV)-O and Ru(II)-N interactions (pub 53) and suggested that linking meso positions within the heptaporphyrin array would lead to novel supramolecular hosts. Inspired by the recent work of Kobuke using methathesis, we have embarked on detailed program to employ metathesis in the generation of multiporphyrin assemblies and arrays. One recent example is the synthesis of tetraporphyrinic macrocycles as a pseudo two-dimensional model to the more complicated cube structure, employing olefin metathesis and a coordinative template-directed strategy to achieve our goal.(Pub 65) |
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B. Medicinal Chemistry
An Investigation into the Versatility of Peptide Nucleic Acid Conjugates For Emerging Gene Technologies
The recent revolution in genomics and proteomics has led to the identification of specific genes (mutated or otherwise) which produce proteins that contribute to disease processes. In order to have an effective treatment, novel techniques are needed that will either switch off the production of the rogue proteins by blocking the production and translation of mRNA, or be employed for the early detection of genetic disorders by a sensitive diagnostic screen. My group is exploring both of these techniques using peptide nucleic acids (shown right), with motor neuron disease as the primary focus.
General Aims: (A) To advance the development of PNA hybrids for therapeutic use in MOTOR NEURON DISEASE (MND) and various CANCER conditions through either specific down-regulation or in a sensory role by each conditions early detection. (B) To improve our understanding of the potential PNAs have in the area of supramolecular chemistry. |
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PNA oligomers form a novel class of informational molecules that contain a neutral N-(2-aminoethyl)glycine backbone to which the four standard nucleic bases A, C, G, and T are attached by methylene carbonyl linkages. These design features allow the oligomer to hybridise to mRNA and DNA (above) with higher affinity and specificity than conventional oligonucleotides.10 PNAs have a number of general advantages that make them ideal for application as an antisense or antigene agent. The high thermal stability of PNA/DNA duplexes combined with the high level of sequence specificity in binding to complementary DNA in both duplex and triplex forms or mRNA, is advantageous for therapeutic and sensory applications.2 Such attributes have led to the design of smaller sequences (in terms of length) for application than would otherwise be necessary using more traditional means, which potentially leads to easier intercellular transport and lower therapeutic cost. Chemically, the resistance of PNAs to nucleases and proteases, greater stability over a wide pH range, their preparation by standard peptide synthetic techniques and their ability to bind independent of salt concentration bode well for their application in sensory and device technologies. |
| PNAs as Drug Candidates: Approximately 3 years ago the Langford and Cheema11 Groups began a collaboration directed towards the synthesis and evaluation of PNAs that target the specific mRNA sequences responsible for the differential expression of proteins (and hence cell death) in neurodegenerative diseases e.g. MND. This collaboration has been a multi-disciplinary effort involving the design and synthesis of novel PNA agents, evaluating them using in vitro neuronal assays and testing short-listed candidates for efficacy in whole animal models of neuronal disorder. Three targets p75NTR, GluR3 and SOD1G93A were identified and evaluated based on proteomic, histological and genetic information, respectively.6-8 A number of aspects are worth highlighting here. The AMPA receptor is a ligand-activated pentameric structure comprised of the four subunits GluR1-4 found in neurons.8,12 GluR2 is functionally dominant, controlling the permeability of extracellular Ca2+ into the cell through arginine (right (a)). Histology on spinal sections of a transgenic mouse model of MND (SOD1 G93A) suggested an up-regulation of GluR3, implying that the neurodegenerative condition may be caused by an over-stimulation of the AMPA receptor. In vitro analysis using a designer PNA showed down-regulation of the GluR3 subunit (left (b)). |
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In addition, the PNA was neuroprotective against (S)-5-fluorowillardiine - a potent AMPA receptor specific agonist. Armed with these data, we undertook an in vivo evaluation in the SOD1G93A transgenic mouse model through IP administration of the PNA.8 The prolonged survival of AS-PNA treated mice (ca. 20 days) was also correlated with later onset of paralysis (equating to a better quality of life) as determined by behavioural studies during treatment. In experiments directed against the mutated human SOD1 gene (SODG93A), we discovered that cellular uptake (and hence the efficacy of the PNA) is somewhat sequence dependant. To overcome this problem in vitro and to show the necessary down-regulation (labeled AS1 - below) a liposome vehicle was employed. Administration of AS1 in vivo (without aid) also led to an increase in survival, although not as pronounced as in the GluR3 study. |
Small Molecule, Dual-Action Therapeutics
The precise triggers and molecular cascades that drive the neurodegeneration associated with ischaemia, injury and neurodegenerative diseases are poorly understood. However, there is considerable evidence that excitotoxic pathways and oxidative stress are key mechanisms that kill neurons. To complement the antisense approach, my group has been investigating the conjoined use of free radical scavengers (FRS), such as vitamin E, and Ca2+ buffering agents for the treatment of neurodegenerative conditions (Figure 6). We have patented this approach (pub 39) and are developing it further in consultation with Neurosciences Victoria.
Figure 6. Dual action drugs are being developed to stop the harmful effects of free radicals and calcium excitotoxicity. |
Some of our most recent results on survival in a transgenic rat model SOD1G93A using an intrathecal infusion method are shown below. These are the best results obtained for this model. Future: Aqueous solubility and transport through the BBB are still ongoing issues that require attention. Use of compound in other neurodegenerative disease conditions and cataract are also targeted.
Figure 7. Kaplan-Meier plotting survival over time
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Insights into Malaria
In collaboration with Prof D. McNaughton and Dr B. Wood, I am investigating the structural and electronic properties of hemazoin and a synthetic analogue, which will hopefully lead to the early identification of malaria and help to design better drug candidates. This work has been published in journals with high impact factors (pubs: 48,54,58).
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