Organometallic Chemistry - Development of cross coupling and bond activation methodology using first row transition metals, novel phosphine & carbene ligands, and new substrates for oxidative addition allowing extension of cross coupling methodology to new compound types.
Synthetic Chemistry - development of tandem activating/protecting groups for regioselective glycosidation reactions.
Physical Organic Chemistry - development of rate-equilibrium relationships & quantitaitve Lewis acidity & basicity scales. Rationalisation of regioselectivity in reactions of enolates. The mechanism of the Wittig reaction.
Stuart's research is focused mainly in the area of natural product synthesis and organic synthetic methodology with a particular emphasis on continuous processing and flow chemistry. The synthesis of small organic molecules that show biological activity against specific targets such as cancer, leukaemia, HIV etc. is a key overall theme of the group. All of his research students and visiting students are doing research in the area of natural product synthesis with a view to synthesizing potential drug molecules for cancer, HIV and leukemia therapy; or organic synthetic methodology.
The active research projects in his group at the moment are:
The synthesis and reactivity of 2-thio-3-chloroacrylamides (beta-chloroacrylamides).
New insights into the synthesis of novel alpha-diazocarbonyl compounds and applications to the synthesis of beta-lactone natural products.
Studies towards the synthesis of lanostane-type natural products.
Synthesis and reactivity of novel alpha-diazosulfoxides: Formation of alpha-oxo sulfines as reactive intermediates.
Synthesis of neolamellarin analogues as antitumor agents.
Synthesis of glycoalkaloid natural products isolated from potato peel.
Synthesis of furanolipids as possible antitumor agents.
The use of aryne chemistry in natural product synthesis.
Application of flow chemistry to processing involving hazardous intermediates.
Development of tunable and scalable API processes through Advanced Process Control.
Dr. Keating's current main research interest is the impurity profiling of amphetamine-type drugs of abuse.
Impurity profiling of drugs of abuse is an tool widely used by forensic scientists in the on-going fight against illegal drug trafficking and abuse. His main focus concerns the impurity profiling of newly emerging hallucinogenic amphetamines which have been reported in Europe. While the impurity profiles of many drugs of abuse, including cocaine and heroin, have been well documented in the literature, newer amphetamine derivatives are constantly emerging on the European market. Recent examples include MBDB, 4-MTA, DOB and BromoDragonfly.
Characterisation and impurity profiling of seized amphetamines are used in conjunction with investigative work:
To establish chemical links between batches of related drugs.
To help identify new clandestine drug manufacturing laboratories and to monitor synthetic routes widely used in the synthesis of illicit amphetamines.
To determine the toxicity, if any, of impurities which arise from the synthesis of amphetamines employing various different routes.
Prof. Maguire's research team, the Organic and Pharmaceutical Synthesis Research Team, is focussed on both synthetic and mechanistic aspects of organic chemistry (including asymmetric synthesis and development of novel synthetic methodology), medicinal chemistry and synthesis of bioactive compounds, and crystal engineering.
In relation to their synthetic research activities, the programmes in the area of synthetic and mechanistic aspects of organic chemistry cover a wide range of areas and have led, for example, to significant advances in our understanding of asymmetric sulfur oxidation, and the C-H insertion and aromatic addition reacton of diazoketones, including recent reports of highly enantioselective catalysis employing copper catalysts in these transformations with up to >98%ee.
One of the early contributions from their team was the first synthesis of diazosulfoxides; synthesis of these novel derivatives with significant potential in stereoselective synthesis had been attempted without success by many leading research teams in the field; our report in 1998 created significant interest as they had successfully designed the first stable isolable diazosulfoxides. Other areas of activity include biocatalysis in asymmetric synthesis using both wild type and `designer enzymes', and new synthetic methodology employing organosulfur chemistry.
Dr. Florence McCarthy leads a team of researchers in medicinal and pharmaceutical chemistry investigating the synthesis and evaluation of diverse bioactive molecules from steroids to complex heterocycles. their objective is the development of novel molecules for the treatment of diseases such as cancer and HIV and to this end, lead compounds are devised and synthesised to address a particular receptor in the body.
Once the synthesised molecules have been validated these are taken forward (both in-house and in collaboration) toward biological evaluation. This drug discovery approach has so far yielded many highly cited publications concerning the synthesis of novel heterocycles and the relationship of these compounds to biological phenomena. The current focus of the group centres on the following: Indole and carbazole chemistry and their heterocyclic variants. Identification of new molecular templates for drug discovery.
The Irish Chemical Industry exported 44.17 billion euro worth of pharmaceuticals in 2009. It remains one of the strongest performing industries and has been largely recession-proof. Ireland is moving away from Process Chemistry, up the value chain towards Research and Discovery. Key skills acquired during a PhD term withib his group will equip researchers with the essentials to progress into this sector.
Area 1 | Asymmetric Synthesis
The synthesis of chiral α-substituted ketones.
The synthesis of chiral amino acids.
Area 2 | Organometallic transformations
The abundance of the biaryl structural motif in natural products, biologically active molecules and in materials chemistry has positioned aryl-aryl (Ar-Ar) bond formation high on the agenda of synthetic chemists. For decades well-known reactions such as the Mizoroki-Heck and Suzuki-Miyaura have been the methods of choice to furnish biaryls. More recently however, alternative methods, most notably direct arylation via C-H activation, have become the focus of many research groups including ours. Compared to traditional methods, direct arylation affords ArAr compounds in fewer steps by removing the need for pre-functionalisation. Furthermore, given that either one or two hydrogens are targeted, less waste and good atom economy are features of this methodology. We use C-H activation in biologically important synthons.
Area 3 | Synthesis of non-traditional antibiotics and biomarker detection
Bacteria produce small-molecule signals to help coordinate their behaviour. This communication system serves many purposes, including cooperative tasks such as the formation of protective biofilms. These protective sheets greatly impair the effectiveness of antibiotics. This, added to the growing resistance to antibiotics, necessitates an alternative look at treating bacteria infections. We prepare analogues of bacteria communication molecules to interrupt their communication systems and prevent biofilm formation. In this non-biocidal approach, developed resistance is avoided. In parallel, early detection of these molecules allows for early medical intervention.
Crystallisation and crystal chemistry of organic compounds.
Most pharmaceuticals, foodstuffs and fine chemicals are crystalline solids in their pure forms. Crystallization provides a method of isolating pure compounds in a convenient physical form. Many compounds crystallize in more than one form, i.e. crystal polymorphs and solvates. Crystals can also differ in their shape (morphology, habit), size and size distribution. Controlling crystal form and morphology is very important for pharmaceuticals, foods, pigments and many other high-value fine chemicals.
Dr. Moynihan's research into crystallisation and crystal chemistry of organic includes crystal engineering, crystallisation method development and crystal nucleation studies. The research is often in collaboration with Dr. Simon Lawrence and Prof. Anita Maguire.
Synthesis of Natural Products and Medicinal Compounds Our research is focused on developing new methods and strategies for the synthesis of bioactive, natural products. The underlying goal in this work is to improve upon existing techniques and to discover novel methods for assembling complex molecular targets. Ultimately, we aim to apply this knowledge to the development of more potent analogues of existing compounds, with a view to producing pharmaceutically relevant therapeutic agents.
New Drugs for Chagas Disease The infectious agent of Chagas disease is Trypanosoma cruzi, which is closely related to the parasites which cause African sleeping sickness and leishmaniasis. The parasite usually enters the bloodstream of mammals through blood-sucking insects e.g. assassin bugs. Between 8 to 11 million people in Mexico, Central America, and South America are estimated to have Chagas disease, most of whom do not know they are infected. If untreated, infection is lifelong and can be life threatening.
Signalling Molecules - Disrupting Biofilm Formation in Cystic Fibrosis Lung Cystic Fibrosis (CF) is an inherited disease which affects about 1,500 Irish people. CF causes the body to produce an abnormally sticky fluid in the lungs which makes CF patients susceptible to serious bacterial infection. CF patients are faced with frequent stays in hospital as they are prone to infection by antibiotic-resistant bacteria. Approximately 60% CF patients have a chronic respiratory infection co-infected with multiple bacteria that settle into the thick mucus trapped in the airways.
Novel Anti-viral Therapies There is a huge demand for new anti-retroviral drugs to increase patients treatment options, especially for drugs with enhanced safety profiles that display reduced side-effects and which are competitively priced. Given that NRTIs (Nucleotide Reverse Transcriptase Inhibitors) are currently used in first-line treatment in combination therapies, we are investigating their mode of action at a molecular level with the aim discovering more potent NRTIs.