Analytical & Biological Chemistry Research Facility - Journal Articles

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    Major structure-activity relationships of resolvins, protectins, maresins and their analogues
    (Future Science Ltd, 2022-11-30) Daly, Kevin; O'Sullivan, Killian; O'Sullivan, Timothy P.
    Resolvins, protectins and maresins are a series of polyunsaturated fatty acid-derived molecules which play important roles in the resolution of inflammation. They are termed specialized proresolving mediators and facilitate a return to homeostasis following an inflammatory response. These molecules are currently the focus of intensive investigation, primarily for their ability to suppress inflammation in chronic disease states. Researchers have employed different synthetic approaches to assess whether various structural modifications of these compounds could provide access to future therapeutics. This review summarizes the modifications made thus far and focuses on the key structure-activity relationships which have been uncovered for resolvins, protectins, maresins and their analogues.
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    Pharmaceutical salts of piroxicam and meloxicam with organic counterions
    (ACS Publications, 2022-10-21) Huang, Shan; Venables, Dean S.; Lawrence, Simon E.; Science Foundation Ireland
    Piroxicam (PRM) and meloxicam (MEL) are two nonsteroidal anti-inflammatory drugs, belonging to the Biopharmaceutics Classification System Class II drugs. In this study, six novel pharmaceutical salts of PRM and MEL with three basic organic counterions, that is, 4-aminopyridine (4AP), 4-dimethylaminopyridine (4DMP), and piperazine (PPZ), were prepared by both slurrying and slow evaporation. These salts were characterized by single-crystal and powder X-ray diffraction, thermal analysis, and Fourier transform infrared spectroscopy. All six salts, especially MEL-4DMP and MEL-4AP, showed a significantly improved apparent solubility and dissolution rate in sodium phosphate solution compared with the pure APIs. Notably, PRM-4AP and PRM-4DMP salts exhibited enhanced fluorescence, and the PRMPPZ salt showed weaker fluorescence compared with that of pure PRM due to different luminescence mechanisms.
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    Synthesis and reactivity of dihalofuranones
    (Bentham Science Publishers, 2022-08-01) Lyons, Thérèse A.; Gahan, Cormac G. M.; O'Sullivan, Timothy P.; Science Foundation Ireland
    Halogenated furanones have been found to act as potent quorum sensing inhibitors in several bacterial species. It is believed that dihalofuranones covalently bind to the LuxS enzyme, which is necessary for autoinducer-2 synthesis. In addition to their antimicrobial activity, halogen-ated furanones also possess anti-cancer, antioxidant, and depigmentation properties. However, traditional routes to these compounds are low-yielding and capricious. The aim of this study was to investigate higher-yielding preparations of gem-dihalofuranones and compare their reactivity using Suzuki chemistry. Ramirez dibromoolefination of maleic anhydride was optimised using a variety of conditions. A similar route was investigated for the preparation of bromofluorofuranones and dichlorofuranones. The conversion of a dichlorofuranone to the corresponding iodofuranone derivatives using microwave-assisted Finkelstein chemistry was also studied. Lastly, the reactivity of the different dihalofuranones was compared by Pd-mediated coupling with phenylboronic acid. A higher-yielding, concise synthesis of dibromofuranones was developed using a modified Ramirez reaction. Additionally, a telescoped preparation of dichlorofuranone was higher yielding than previous approaches. Bromine-and iodine-substituted dihalofuranones proved more reactive than their chlorine-substituted analogues. Higher yielding routes to bromine-, fluorine-, chlorine-and iodine-containing dihalofuranones were successfully developed. Suzuki couplings of gem-dihalofuranones were found to proceed with high stereoselectivity.
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    Genome mining and characterisation of a novel transaminase with remote stereoselectivity
    (Springer Nature Switzerland AG, 2019-12-30) Gavin, Declan P.; Reen, F. Jerry; Rocha-Martin, J.; Abreu-Castilla, I.; Woods, David F.; Foley, Aoife M.; Sanchez-Murcia, P. A.; Schwarz, Maria; O'Neill, P.; Maguire, Anita R.; O'Gara, Fergal; Enterprise Ireland; Health Research Board; Irish Thoracic Society; European Commission; Science Foundation Ireland; Irish Research Council for Science, Engineering and Technology; Cystic Fibrosis Foundation; Austrian Science Fund
    Microbial enzymes from pristine niches can potentially deliver disruptive opportunities in synthetic routes to Active Pharmaceutical Ingredients and intermediates in the Pharmaceutical Industry. Advances in green chemistry technologies and the importance of stereochemical control, further underscores the application of enzyme-based solutions in chemical synthesis. The rich tapestry of microbial diversity in the oceanic ecosystem encodes a capacity for novel biotransformations arising from the chemical complexity of this largely unexplored bioactive reservoir. Here we report a novel omega-transaminase discovered in a marine sponge Pseudovibrio sp. isolate. Remote stereoselection using a transaminase has been demonstrated for the first time using this novel protein. Application to the resolution of an intermediate in the synthesis of sertraline highlights the synthetic potential of this novel biocatalyst discovered through genomic mining. Integrated chemico-genomics revealed a unique substrate profile, while molecular modelling provided structural insights into this 'first in class' selectivity at a remote chiral centre.
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    Dirhodium carboxylate catalysts from 2-fenchyloxy or 2-menthyloxy arylacetic acids: enantioselective C-H insertion, aromatic addition and oxonium ylide formation/rearrangement
    (WILEY-VCH Verlag, 2021-10) Buckley, Aoife; Crowley, Daniel C; Brouder, Thomas A.; Ford, Alan; Khandavilli, Udaya Bhaskara Rao; Lawrence, Simon E.; Maguire, Anita R.; Irish Research Council; Science Foundation Ireland; European Regional Development Fund
    A new class of dirhodium carboxylate catalysts have been designed and synthesized from 2-fenchyloxy or 2-menthyloxy arylacetic acids which display excellent enantioselectivity across a range of transformations of alpha-diazocarbonyl compounds. The catalysts were successfully applied to enantioselective C-H insertion reactions of aryldiazoacetates and alpha-diazo-beta-oxosulfones affording the respective products in up to 93 % ee with excellent trans diastereoselectivity in most cases. Furthermore, efficient desymmetrization in an intramolecular C-H insertion was achieved. In addition, these catalysts prove highly enantioselective for intramolecular aromatic addition with up to 88% ee, and oxonium ylide formation and rearrangement with up to 74% ee.