Professor Donal O'Shea
Current Research Projects
New class of light activated anti-cancer and anti-microbial agents
Photodynamic therapy (PDT) is a unique treatment modality for a range of disease classes, both cancerous and non-cancerous, which uses low energy light in conjunction with a photosensitizer to effect specific cell death. My research has developed a totally new class of PDT agent, the BF2 chelated dibromo-tetraarylazadipyrromethenes. Optimised synthetic procedures have been developed to facilitate the generation of an array of specifically substituted derivatives to demonstrate how control of key therapeutic parameters such as wavelength of maximum absorbance and singlet oxygen generation can be achieved. Our lead compounds display nano-molar EC50 values across a broad spectrum of human cancer cell lines and excellent levels of tumour clearance in a pre-clinical in vivo efficacy study of human tumour bearing nude mice. In addition a new approach to achieving selectivity for photodynamic therapy based upon the reversible off/on switching of the key therapeutic property (singlet oxygen generation) of a supramolecular photonic therapeutic agent in response to an external microenvironment stimulus has been developed. Further work into this unique selectivity approach is on-going.
Key publications
(a) Frimannsson, D.O.; Grossi, M.; Murtagh, J.; Paradisi, F.; O’Shea, D.F. J. Med. Chem. 2010, 53, 7337.
(b) Byrne, A.T.; O’Connor, A.; Hall, M.; Murtagh, J.; O’Neill, K.; Curran, K.; Mongrain, K.; Rousseau, J.A.; Lecomte, R.; McGee, S.; Callanan, S.; O’Shea, D.F.; Gallagher, W.M. British J. Cancer , 2009 , 101 , 1565.
(c) McDonnell, S.O.; Hall, M.J.; Allen, L.T.; Byrne, A.; Gallagher, W.M.; O’Shea, D.F. J. Am. Chem. Soc . 2005, 127, 16360.
(d) Gorman, A.; Killoran, J.; O’Shea, C.; Kenna, T.; Gallagher, W.M.; O’Shea, D.F. J. Am. Chem. Soc. 2004, 126, 10619.
New class of near-infrared (NIR) fluorescent imaging agents and nanoparticles
The use of in vitro and in vivo fluorescence imaging has become an increasingly common tool for gaining an understanding of the functioning of biological systems at a molecular level. Most of the existing fluorescent agents have operational light input/output wavelengths in the 300-650 nm wavelength range. These spectral regions suffer from strong interference due to background absorbance and auto-fluorescence from endogenous chromophores. The use of longer wavelength near-infrared (beyond 720 nm) light circumvents these problems, allowing for better resolution, greater penetration of biological tissue and a reduction of light induced cellular damage. We have recently described the synthesis of a series of visible red and near-infrared fluorescent probes based upon the BF2 chelated tetraarylazadipyrromethene structure, which have the potential to act as analyte-activated fluorescent imaging agents. On-going research is focused on tailoring of this class of imaging agent for the generation of analyte responsive NIR fluorescent bio-conjugates, which would allow for targeted real-time in vivo imaging. In addition, synthetically controlled functionalization of nanoparticles with our fluorophore class has allowed us to develop the first cellular activated off to on responsive nanoparticle which switches fluorescence on only when taken up into cells.
Key publications
(a) Tasior, M.; O’Shea, D.F. Bioconjugate Chem., 2010, 21, 1130.
(b) Murtagh, J.; Frimannsson, D.O.; O’Shea, D.F. Org. Lett., 2009, 11, 5386.
(c) Palma, A.; Tasior, M.; Vu, T.T.; Méallet-Renault, R.; O’Shea, D.F. Org. Lett., 2009, 11, 3638.
Enantioselective carbolithiations and mixed Li/K amides as effective synthetic tools
Enantioselective cascade reaction sequences are very powerful synthetic protocols for the assembly of complex organic architectures. The goal is to devise systems in which a facile transformation triggers the conversion of prochiral starting materials to chiral intermediates of high synthetic potential that can subsequently be converted in situ into products of increasing complexity. Our current approach is to exploit a chiral amine controlled enantioselective carbolithiation of ortho-substituted b-methylstyrenes. The chiral centre, formed in good enantiomeric excess in the carbolithiation step, can be carried through different reaction sequences thereby generating a collection of products. As the chiral centre generated during the carbolithiation step is carried through the subsequent reaction sequences to the final products, selectivity is solely dependent upon achieving an enantioselective alkyllithium addition. In addition, we have recently published the first direct vinyl-lithiation of cis-stilbenes and are currently establishing the scope of this novel methodology for other direct C-H bond activation transformations utilising novel mixed Li/K amide reagents. The future goal is to continue to expand the scope of these methodologies for the synthesis of specific structural targets for on-going medicinal chemistry projects.
Key publications
(a) Fleming, P.; O’Shea, D.F. J. Am. Chem. Soc. 2011, 133, 1698.
(b) Tricotet, T.; Fleming, P.; Cotter, J.; Hogan, A.M.L.; Strohmann, C.; Gessner, V.H.; O’Shea, D.F. J. Am. Chem. Soc. 2009, 131, 3142.
(c) Hogan, A.-M.L.; O’Shea, D.F. J. Am. Chem. Soc. 2006, 128, 10360.
(d) Coleman, C.M.; O'Shea, D.F. J. Am. Chem. Soc. 2003, 125, 4054.
Library generation with automated flow micro-reactors and parallel microwave-assisted synthesis
The ability of microwave heating to funnel a spectrum of chemical reactivity found in a combinatorial library into a very short time span has the potential to become a new practical tool for high-throughput synthesis. My research has given rise to a new methodology that can overcome the technical problems associated with parallel microwave parallel synthesis. As a proof of concept we have developed a diversity tolerant multi-component route to sulfanyl-imidazoles and have shown that a comparable microwave generated library can be achieved with a dramatic reduction in library generation time. More recently continuous flow chemistry has emerged as a productive technology for synthetic chemists. It offers the chemist a new tool to speed discovery and development as it provides reliable control of reaction conditions, such as time, temperature, equivalents of reagents and mixing, and allows exothermic reactions to be performed without the need for cryogenics. In addition, by pressurising the system, reactions can be superheated to give reaction rates significantly faster than in reflux. This gives microwave-like rate enhancement without the problems associated with microwave-based reactions. On-going research involves the application of fully automated flow micro-reactor systems to combinatorial library formation.
Key publications
(a) Tricotet, T.; O’Shea, D.F. Chem. Eur. J. 2010, 16, 6678.
(b) Le Bas, M.-D.H.; O’Shea, D.F. J. Comb. Chem., 2005, 7, 947 .
(c) Coleman, C.M.; MacElroy, J.M.D.; Gallagher, J.F.; O'Shea, D.F. J. Comb. Chem., 2002, 4, 87.
Publication List
The list of publications is available below in PDF format.
Laboratory
