Analytical & Biological Chemistry Research Facility

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Qualitative and quantitative comparison of the cytotoxic and apoptotic potential of phytosterol oxidation products with their corresponding cholesterol oxidation products
(Cambridge University Press, 2005-01) Ryan, Eileen; Chopra, Jay; McCarthy, Florence O.; Maguire, Anita R.; O'Brien, Nora M.; Enterprise Ireland
Phytosterols contain an unsaturated ring structure and therefore are susceptible to oxidation under certain conditions. Whilst the cytotoxicity of the analogous cholesterol oxidation products (COP) has been well documented, the biological effects of phytosterol oxidation products (POP)have not yet been fully ascertained. The objective of the present study was to examine the cytotoxicity of β-sitosterol oxides and their corresponding COP in a human monocytic cell line (U937), a colonic adenocarcinoma cell line (CaCo-2) and a hepatoma liver cell line (HepG2). 7β-Hydroxysitosterol, 7-ketositosterol, sitosterol-3β,5α,6β-triol and a sitosterol-5α,6α-epoxide sitosterol-5β,6β-epoxide (6:1) mixture were found to be cytotoxic to all three cell lines employed; the mode of cell death was by apoptosis in the U937 cell line and necrosis in the CaCo-2 and HepG2 cells. 7β-Hydroxysitosterol was the only β-sitosterol oxide to cause depletion in glutathione, indicating that POP-induced apoptosis may not be dependent on the generation of an oxidative stress. A further objective of this study was to assess the ability of the antioxidants α-tocopherol, γ-tocopherol and β-carotene to modulate POP-induced cytotoxicity in U937 cells. Whilst α/γ-tocopherol protected against 7β-hydroxycholesterol-induced apoptosis, they did not confer protection against 7β-hydroxysitosterol-or 7-ketositosterol-induced toxicity, indicating that perhaps COP provoke different apoptotic pathways than POP. β-Carotene did not protect against COP- or POP-induced toxicity. In general, results indicate that POP have qualitatively similar toxic effects to COP. However, higher concentrations of POP are required to elicit comparable levels of toxicity.
Effect of 1-deoxy-D-lactose upon the crystallization of D-lactose
(American Chemical Society, 2008-01) Guiry, Kevin P.; Coles, Simon J.; Moynihan, Humphrey A.; Lawrence, Simon E.
The synthesis and crystal structure of 1-deoxy-d-lactose is described, as is its use as an additive in the crystallization of d-lactose. This has resulted in the formation of αβ-d-lactose for the first time at room temperature. Single-crystal analysis shows differences between this analysis and the structure previously obtained from powder data, particularly in the hydrogen-bonding patterns.
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.
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).
Crystal polymorphs and transformations of 2-iodo-4-nitroaniline
(American Chemical Society, 2010) Kelly, Dawn M.; Eccles, Kevin S.; Elcoate, Curtis J.; Lawrence, Simon E.; Moynihan, Humphrey A.; Irish Research Council for Science Engineering and Technology; Science Foundation Ireland
Full crystal structural characterization of three crystal polymorphs of 2-iodo-4-nitroaniline was carried out: the triclinic, orthorhombic, and a new monoclinic form. Powder X-ray diffraction, differential scanning calorimetry, and infrared data on the three of these are reported. Solvent-mediated transformations were observed on the basis of changes in crystal morphology and data from an in situ laser probe. Transformation to the monoclinic form was observed in all cases. [Published as part of a virtual special issue of selected papers presented in celebration of the 40th Anniversary Conference of the British Association for Crystal Growth (BACG), which was held at Wills Hall, Bristol, UK, September 6-8, 2009]
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.
Direction of copper phthalocyanine crystallization using in situ generated tethered phthalocyanines
(The Royal Society of Chemistry, 2010-05) Moynihan, Humphrey A.; Claudon, Geraldine; Enterprise Ireland; European Commission
Copper phthalocyanine in the metastable α crystal polymorph can be obtained directly from phthalonitrile or from phthalodiimide, which would normally give the more stable β crystal form, by the inclusion of 3% or greater of the sulfide 2 or the diimide 3. The resulting α form material does not revert to the β form upon treatment in boiling xylene, unlike conventionally prepared α copper phthalocyanine.
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.
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.
Evaluation of the Bruker SMART X2S: crystallography for the nonspecialist?
(International Union of Crystallography, 2011-02) Eccles, Kevin S.; Stokes, Stephen P.; Daly, Carla A.; Barry, Nicola M.; McSweeney, Sharon P.; O'Neill, Damian J.; Kelly, Dawn M.; Jennings, W. Brian; Ní Dhubhghaill, Orla M.; Moynihan, Humphrey A.; Maguire, Anita R.; Lawrence, Simon E.; Kaysser-Pyzalla, Anke R.; Science Foundation Ireland; Higher Education Authority; Irish Research Council for Science Engineering and Technology
An evaluation of the Bruker SMART X2S for the collection of crystallographic diffraction data, structure solution and refinement is carried out with a variety of materials with different electron densities, presenting some of the successes and challenges of automation in chemical crystallography.

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