Pharmacy - Journal Articles

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Model studies toward the synthesis of the bioactive diterpenoid, harringtonolide
(Royal Society of Chemistry, 2007-06-19) O'Sullivan, Timothy P.; Zhang, Hongbin; Mander, Lewis N.
In model studies towards the synthesis of harringtonolide, the construction of the tropone moiety via arene cyclopropanation was investigated. The installation of the lactone ring was accomplished by way of a Diels-Alder cycloaddition of various indenones and 𝛼-pyones. The incorporation of the key bridge methyl group and subsequent control of its stereochemistry is also outlined.
Investigation of the chemoselective and enantioselective oxidation of α-thio-β-chloroacrylamides
(Elsevier, 2008-05-30) Kissane, Marie; Lynch, Denis; Chopra, Jay; Lawrence, Simon E.; Maguire, Anita R.; Irish Research Council for Science Engineering and Technology; Enterprise Ireland; BioResearch Ireland; Forbairt; University College Cork
Investigation of the chemoselective and enantioselective oxidation of α-thio-β-chloroacrylamides is described. The α-thio-β-chloroacrylamides can be selectively oxidized to either the racemic sulfoxide or the sulfone very efficiently. The asymmetric sulfur oxidation of α-thio-β-chloroacrylamides is also discussed, with sulfoxide enantioselectivites of up to 52% ee achieved using the Kagan oxidation, and up to 71% ee when the Bolm oxidation is employed. While the enantioselectivities achieved are modest, these are among the most highly functionalised sulfides investigated in catalytic asymmetric oxidation, and the resulting enantioenriched sulfoxides have significant synthetic potential.
Development of multiple strain competitive index assays for Listeria monocytogenes using pIMC; a new site-specific integrative vector
(BioMed Central, 2008-06) Monk, Ian R.; Casey, Pat G.; Cronin, Michael S.; Gahan, Cormac G.; Hill, Colin; Irish Research Council for Science, Engineering and Technology
The foodborne, gram-positive pathogen, Listeria monocytogenes, is capable of causing lethal infections in compromised individuals. In the post genomic era of L. monocytogenes research, techniques are required to identify and validate genes involved in the pathogenicity and environmental biology of the organism. The aim here was to develop a widely applicable method to tag L. monocytogenes strains, with a particular emphasis on the development of multiple strain competitive index assays.
Nisin inducible production of listeriolysin O in Lactococcus lactis NZ9000
(BioMed Central, 2008-07) Bahey-El-Din, Mohammed; Griffin, Brendan T.; Gahan, Cormac G.; Science Foundation Ireland
Background: Listeria monocytogenes is a well-characterized food-borne pathogen that infects pregnant women and immunocompromised individuals. Listeriolysin O (LLO) is the major virulence factor of the pathogen and is often used as a diagnostic marker for detection of L. monocytogenes. In addition, LLO represents a potent antigen driving T cell-mediated immunity during infection. In the present work, Lactococcus lactis NZ9000 was used as an expression host to hyper-produce LLO under inducible conditions using the NICE (NIsin Controlled Expression) system. We created a modified pNZ8048 vector encoding a six-His-tagged LLO downstream of the strong inducible PnisA promoter. Results: The constructed vector (pNZPnisA:CYTO-LLO) was expressed in L. lactis NZ9000 and was best induced at mid-log phase with 0.2% v/v nisin for 4 h statically at 30°C. Purification of the His-tagged LLO was accomplished by Ni-NTA affinity chromatography and functionality was confirmed through haemolytic assays. Total LLO yield (measured as total protein content) was 4.43–5.9 mg per litre culture and the haemolytic activity was still detectable after 8 months of storage at 4°C. Conclusion: The LLO production method described in this work provides an approach to efficient LLO production in the Gram-positive Lactococcus bacterium to yield a significant source of the protein for research and diagnostic applications. Expression of LLO in L. lactis has a number of benefits over E. coli which may facilitate both in vivo and in vitro applications of this system.
Investigation of the reaction of α-Thioamides, α-esters and α–nitriles with N-halosuccinimides
(Elsevier, 2008-08-04) Kissane, Marie; Murphy, Maureen; Lynch, Denis; Ford, Alan; Maguire, Anita R.; Irish Research Council for Science Engineering and Technology; BioResearch Ireland; Forbairt; University College Cork
Investigation of the reaction of α-thioamides, α-esters and α-nitriles with NBS and NCS is described. The scope of this stereoselective oxidative transformation to the β- haloacrylamides, β-acrylates and β–acrylonitriles has been determined. A mechanistic rationale to explain the observed differences in reactivity between the amide, ester and nitrile series is proposed.
Asymmetric 1,3-dipolar cycloadditions of acrylamides
(RSC Publishing, 2009) Kissane, Marie; Maguire, Anita R.
This critical review, which is relevant to researchers in synthetic organic chemistry, focuses on asymmetric 1,3-dipolar cycloadditions with acrylamides. The use of chiral acrylamides as dipolarophiles leads to high levels of stereocontrol, due to conformational constraint in the acrylamides. Employment of chiral tertiary acrylamides containing nitrogen heterocycles is particularly effective in controlling the stereoselectivity. Following a general overview of 1,3-dipolar cycloadditions, the main body of the review focuses on asymmetric 1,3-dipolar cycloadditions of acrylamides with nitrile oxides, nitrones, diazoalkanes and azomethine ylides, with particular emphasis on the rationale for the observed stereocontrol (215 references).
Therapeutic targeting in the silent era: advances in non-viral siRNA delivery
(Royal Society of Chemistry, 2010-04) Guo, Jianfeng; Fisher, Karen A.; Darcy, Raphael; Cryan, John F.; O'Driscoll, Caitríona M.; Science Foundation Ireland; Irish Research Council for Science Engineering and Technology
Gene silencing using RNA-interference, first described in mammalian systems almost a decade ago, is revolutionizing therapeutic target validation efforts both in vitro and in vivo. Moreover, the potential for using short interfering RNA (siRNA) as a therapy in its own right is also progressing at a significant pace. However, the widespread use of such approaches is contingent on having appropriate systems to achieve clinically appropriate, safe, and efficient delivery of siRNA. There are many physicochemical and biological barriers to such delivery, and a growing emphasis on the design and characterisation of non-viral technologies that will overcome these barriers and expedite targeted delivery. This review discusses the considerations and challenges associated with use of siRNA-based therapeutics, including stability and off-target effects. Speculation is made on the properties of an ideal delivery system and the non-viral delivery approaches used to date, both in vitro and in vivo, are classified and discussed. Moreover, the ability of cyclodextrin-based delivery vectors to fulfil many of the criteria of an ideal delivery construct is also elaborated.
Diastereoselective sulfur oxidation of 2-thio-3-chloroacrylamides
(Elsevier, 2010-04-21) Kissane, Marie; Lawrence, Simon E.; Maguire, Anita R.; Irish Research Council for Science Engineering and Technology; University College Cork
Diastereoselective sulfur oxidation in 2-thio-3-chloroacrylamides is described. A range of chiral amine auxiliaries were incorporated in the β-chloroacrylamide, and the efficiency with which the stereochemistry was relayed to the sulfur centre during sulfoxidation was investigated. Diastereomeric ratios of up to 3.3:1 were achieved.
1,3-Dipolar cycloadditions of 2-thio-3-chloroacrylamides with nitrile oxides and nitrones
(Elsevier, 2010-06-19) Kissane, Marie; Lawrence, Simon E.; Maguire, Anita R.; Irish Research Council for Science Engineering and Technology
1,3-Dipolar cycloadditions of 2-thio-3-chloroacrylamides with nitrile oxides and nitrones is described. A series of novel isoxazolines are isolated from the nitrile oxide cycloadditions, whilst the isoxazolines generated from the nitrone cycloadditions undergo further ring opening to yield piperidines.
1,3-Dipolar cycloadditions of 2-thio-3-chloroacrylamides with diazoalkanes
(RSC Publishing, 2010-06-21) Kissane, Marie; Lawrence, Simon E.; Maguire, Anita R.; Irish Research Council for Science Engineering and Technology
2-Thio-3-chloroacrylamides undergo 1,3-dipolar cycloadditions with diazoalkanes leading to a series of novel pyrazolines and pyrazoles. The mechanistic and synthetic features of the cycloadditions to the 2-thio-3-chloroacrylamides at both the sulfide and sulfoxide levels of oxidation are rationalised on the basis of the nature of the substituents.
Convenient and robust one-pot synthesis of symmetrical and unsymmetrical benzyl thioethers from benzyl halides using thiourea
(ARKAT USA, 2010-07-07) Eccles, Kevin S.; Elcoate, Curtis J.; Lawrence, Simon E.; Maguire, Anita R.; Science Foundation Ireland
A series of symmetrical and unsymmetrical benzyl thioethers have been synthesised using a one-pot reaction from benzyl halides and thiourea. This procedure avoids the isolation or handling of malodorous thiols and generates high yields of benzyl thioethers in excellent purity.
Catalytic asymmetric C-H insertion reactions of α-diazocarbonyl compounds
(Elsevier, 2010-08-21) Slattery, Catherine N.; Ford, Alan; Maguire, Anita R.; Irish Research Council for Science Engineering and Technology; Eli Lilly and Company, United States
The purpose of this review is to provide an overview of the development of asymmetric catalysts for C-H insertion reactions over the past two decades, focusing on the application of these catalysts in the decomposition of α-diazocarbonyl compounds. Given the rapid pace of development in the field of enantioselective C-H insertion chemistry, an up-to-date review of this type is warranted. While recent reviews22,23 have dissected their content into intramolecular and intermolecular processes, this article is differentiated in extending this division to include classification of C-H insertion reactions according to product type. Thus, catalytic methods for the asymmetric synthesis of carbocyclic compounds, oxygen-containing heterocycles, nitrogen-containing heterocycles and sulfur-containing heterocycles are readily identifiable. Due to the diversity of compounds resulting from intermolecular C-H insertion processes, classification of reactions by product type was not attempted in this section of the review.
Sulfoxides: potent co-crystal formers
(American Chemical Society, 2010-10) Eccles, Kevin S.; Elcoate, Curtis J.; Stokes, Stephen P.; Maguire, Anita R.; Lawrence, Simon E.; Science Foundation Ireland
The design of co-crystals requires knowledge of robust supramol. synthons. The sulfoxide is a potent H bond acceptor and was used as a co-crystal former with a range of NH functional groups, via N-H···O=S H bonds. The NH functional group retains favorable H bond motifs from its own structure in all cases where this is possible, with the sulfoxide interacting in a discrete, capping fashion in four cases and in a bifurcated, bridging fashion in the three other cases presented here. Crystallog. data are given for 7 co-formers, dibenzyl sulfoxide and cyclohexanecarbothioamide.
The influence of reaction conditions on the Diels-Alder cycloadditions of 2-thio-3-chloroacrylamides; investigation of thermal, catalytic and microwave conditions
(RSC Publishing, 2010-10-07) Kissane, Marie; Lynch, Denis; Chopra, Jay; Lawrence, Simon E.; Maguire, Anita R.; Irish Research Council for Science Engineering and Technology; Forbairt; University College Cork
The Diels-Alder cycloadditions of cyclopentadiene and 2,3-dimethyl-1,3-butadiene to a range of 2-thio-3-chloroacrylamides under thermal, catalytic and microwave conditions is described. The influence of reaction conditions on the outcome of the cycloadditions, in particular the stereoselectivity and reaction efficiency, is discussed. While the cycloadditions have been attempted at the sulfide, sulfoxide and sulfone levels of oxidation, use of the sulfoxide derivatives is clearly beneficial for stereoselective construction of Diels-Alder cycloadducts.
Synthesis and stereoselective oxidation of α-Thio-β- chloropropenyloxazolidin-2-ones
(Elsevier, 2010-11-08) Kissane, Marie; Murphy, Maureen; Lawrence, Simon E.; Maguire, Anita R.; Irish Research Council for Science Engineering and Technology; University College Cork
Investigation of the stereoselective reaction of α-thiopropanoyloxazolidin-2-ones with NCS to yield α-thio-β-chloropropenyloxazolidin-2-ones is described. Diastereoselective sulfur oxidation of the resulting α-thio-β-chloropropenyloxazolidin-2-ones is also discussed, with modest diastereocontrol achieved. However, through a combination of diastereoselective oxidation and subsequent kinetic resolution in the sulfoxide oxidation, diastereoselectivities of up to 94% de are achieved.
Development of stabilized vaccines with needle-free devices for targeted skin immunization
(Russell Publishing Limited, 2010-12) Moore, Anne C.; Crean, Abina M.; O'Mahony, Conor; Difford, Helen
Vaccination represents the primary public health measure to combat infectious diseases. However, limitations of cold-chain storage, vaccine wastage, hazardous sharps-waste and the requirements for trained personnel add significant and unsustainable financial and logistic costs to immunisation programmes. Developments of needle-free methods should aim to overcome these logistics issues from the very start of the vaccine production process. Dermal vaccine administration using microneedle-based devices promises to be one such needle-free method that addresses all of these issues. Methods of stabilisation of vaccines onto or incorporated into microneedles should be developed to permit seamless transition and cost-effectiveness from vaccine bulk-up to final product. This review examines recent developments in microneedle technology and highlights the current challenges to translate this technology into practice.
Unzipping the dimer in primary amides by cocrystallization with sulfoxides
(American Chemical Society, 2011-01) Eccles, Kevin S.; Elcoate, Curtis J.; Maguire, Anita R.; Lawrence, Simon E.; Science Foundation Ireland
A systematic crystal engineering study was undertaken to investigate how different electronic substituents on the aromatic ring of primary aromatic amides impact on the ability of the amide to cocrystallize with dibenzyl sulfoxide. Amides which cocrystallize with dibenzyl sulfoxide form 1:1 cocrystals containing a discrete N-H•••O=S supramolecular synthon as well as the well-known C(4) amide chain. The combination of these two synthons give rise to linear chains of amide molecules, with each amide molecule capped by one sulfoxide molecule. Thus, the R 2(over)2 (8) dimer typically seen for primary amides is no longer present in these cocrystals. The influence of the amide due to electronic effects is similar to that observed for acids in cocrystals.
Cocrystals of fenamic acids with nicotinamide
(American Chemical Society, 2011-01) Fábián, László; Hamill, Noel; Eccles, Kevin S.; Moynihan, Humphrey A.; Maguire, Anita R.; McCausland, Linda; Lawrence, Simon E.; Science Foundation Ireland
Cocrystal formation between nicotinamide and five fenamic acid derivative drugs (flufenamic acid, niflumic tolfenamic acid, mefenamic acid and meclofenamic acid) was investigated using solution-based and solid-state preparation methods. It was anticipated that the well-known acid-aromatic nitrogen heterosynthon would provide a sufficient driving force for cocrystallization. The experiments yielded cocrystals with four of the five acids. Although the structures of these molecules are similar, they showed marked differences in both the stability and the stoichiometry of the cocrystals. A detailed analysis of the structures and properties of both the starting materials and the cocrystals allows a tentative explanation of these differences, but it also shows that even though all four cocrystals utilize one of the most predictable supramolecular synthons (COOH center dot center dot center dot N), their structures and properties remain elusive to design.
The use of co-crystals for the determination of absolute stereochemistry: an alternative to salt formation
(American Chemical Society, 2011-01) Eccles, Kevin S.; Deasy, Rebecca E.; Fábián, László; Maguire, Anita R.; Lawrence, Simon E.; Science Foundation Ireland; Irish Research Council for Science Engineering and Technology; Eli Lilly and Company, United States
Absolute stereochemistry of oils and viscous liquids can be difficult to determine. Co-crystallization involves generating a crystalline material consisting of more than one neutral compound. The combination of cocrystallization with both X-ray diffraction and chiral HPLC was particularly powerful in overcoming these difficulties for a series of chiral 3-arylbutanoic acids. Cocrystallization offers advantages over salt formation because co-crystals dissociate in solution, meaning identical HPLC conditions can be used for both the materials of interest and their co-crystals.
Expanding the crystal landscape of isonicotinamide: concomitant polymorphism and co-crystallisation
(Royal Society of Chemistry, 2011-01) Eccles, Kevin S.; Deasy, Rebecca E.; Fábián, László; Braun, Doris E.; Maguire, Anita R.; Lawrence, Simon E.; Science Foundation Ireland; Irish Research Council for Science Engineering and Technology; Eli Lilly and Company, United States
Attempts to co-crystallise 3-arylbutanoic acid derivatives with isonicotinamide have led to co-crystals and novel polymorphs of the isonicotinamide co-former appearing under similar crystallisation conditions.

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