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Murphy, Cormac D.
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Murphy, Cormac D.
Official Name
Murphy, Cormac D.
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Now showing 1 - 10 of 40
- PublicationBiosynthesis of pyrrolylpolyenes in Auxarthron umbrinumThe biosynthesis of the pyrrolylpolyene rumbrin (1) in the fungus Auxarthron umbrinum was elucidated using feeding studies with labelled precursors. Incorporation of stable isotopes from [15N]-proline, [13C]-methionine and [13C]-acetate confirmed that these were the precursors of the pyrrole moiety, methyl groups, and backbone of rumbrin, respectively. Label-dilution experiments with pyrrole-2-carboxylate confirmed it was a direct precursor in the biosynthesis of rumbrin. Both 3- and 4-chloropyrrolecarboxylates were also accepted as precursors in polyene production.
631Scopus© Citations 18 - PublicationFactors influencing 4-fluorobenzoate degradation in biofilm cultures of Pseudomonas knackmussii B13Membrane aerated biofilm reactors (MABRs) have potential in wastewater treatment as they permit simultaneous COD minimisation, nitrification and denitrification. Here we report on the application of the MABR to the removal of fluorinated xenobiotics from wastewater, employing a Pseudomonas knackmussii monoculture to degrade the model compound 4-fluorobenzoate. Growth of biofilm in the MABR using the fluorinated compound as the sole carbon source occurred in two distinct phases, with early rapid growth (up to 0.007 h−1) followed by ten-fold slower growth after 200 h operation. Furthermore, the specific 4-fluorobenzoate degradation rate decreased from 1.2 g g−1 h−1 to 0.2 g g−1 h−1, indicating a diminishing effectiveness of the biofilm as thickness increased. In planktonic cultures stoichiometric conversion of substrate to the fluoride ion was observed, however in the MABR, approximately 85% of the fluorine added was recovered as fluoride, suggesting accumulation of ‘fluorine’ in the biofilm might account for the decreasing efficiency. This was investigated by culturing the bacterium in a tubular biofilm reactor (TBR), revealing that there was significant fluoride accumulation within the biofilm (0.25 M), which might be responsible for inhibition of 4-fluorobenzoate degradation. This contention was supported by the observation of the inhibition of biofilm accumulation on glass cover slips in the presence of 40 mM fluoride. These experiments highlight the importance of fluoride ion accumulation on biofilm performance when applied to organofluorine remediation.
1070Scopus© Citations 33 - PublicationA convenient chemical-microbial method for developing fluorinated pharmaceuticals(Royal Society of Chemistry, 2013)
; ; ; ; ; A significant proportion of pharmaceuticals are fluorinated and selecting the site of fluorine incorporation can be an important beneficial part a drug development process. Here we describe initial experiments aimed at the development of a general method of selecting optimum sites on pro - drug molecules for fluorination, so that metabolic stability may be improved. Several model biphenyl derivatives were transformed by the fungus Cunninghamella elegans and the bacterium Streptomyces griseus, both of which contain cytochromes P450 that mimic oxidation processes in vivo, so that the site of oxidation could be determined. Subsequently, fluorinated biphenyl derivatives were synthesised using appropriate Suzuki - Miyaura coupling reactions, positioning the fluorine atom at the pre - determined site of microbial oxidation; the fluorinated biphenyl derivatives were incubated with the microorganisms and the degree of oxidation assessed. Biphenyl-4-carboxylic acid was transformed completely to 4' - hydroxybiphenyl - 4 - carboxylic acid by C. elegans but, in contrast, the 4' fluoro - analogue remained untransformed exemplifying the microbial oxidation – chemical fluorination concept. 2' - Fluoro-and 3' - fluoro - biphenyl - 4 - carboxylic acid were also transformed, but more slowly than the non - fluorinated biphenyl carboxylic acid derivative. Thus, it is possible to design compounds in an iterative fashion with a longer metabolic half - life by identifying the sites that are most easily oxidised by in vitro methods and subsequent fluorination without recourse to extensive animal studies.437Scopus© Citations 39 - PublicationSimultaneous removal of malachite green and hexavalent chromium by Cunninghamella elegans biofilm in a semi-continuous systemThe present study was conducted to evaluate the potential of the fungus Cunninghamella elegans for simultaneous decolourisation of a triphenylmethane dye malachite green (MG) and hexavalent chromium [Cr(VI)] in the same media. This fungus can degrade MG through its reduction into leucomalachite green and then demethylation followed by oxidative cleavage. Along with MG degradation, C. elegans biofilm could effectively and repeatedly remove Cr(VI) from the liquid cultures even in the presence of high concentrations (40 g L−1) of NaCl and various other metal ions. C. elegans biofilm was also found to adsorb different dyes (reactive black-5, acid orange 7, direct red 81 and brilliant blue G) concurrently with Cr(VI). Based on its potential for simultaneous removal of dyes and Cr(VI) as well as reusability, C. elegans biofilm is envisaged as an efficient bioresource to devise strategies for treatment of wastewaters loaded with multiple pollutants.
46Scopus© Citations 36 - PublicationAlternative mild route to the synthesis of 4-methylenecyclohex-2-enone, a key moiety of the anticancer compounds ottelione A and B(Taylor & Francis, 2012-02-27)
; ; ; Rare 4-methylenecyclohex-2-enone is prepared from a Diels-Alder methanesulfonate adduct and sodium iodide in acetone in up to 70% yield under mild conditions. This procedure is envisaged to be relevant to the synthesis of 4-methylenecyclo hex-2-enone analogues, structurally similar to the key functionality of cytotoxic otteliones and with potentially significant bioactivity.545Scopus© Citations 3 - PublicationTargeted Fluorination of a Non-steroidal Anti-inflammatory Drug to Prolong Metabolic Half-life(Wiley, 2014-04)
; ; ; ; ; In drug design, one way of improving metabolic stability is to introduce fluorine at a metabolically labile site. In the early stages of drug design, identification of such sites is challenging, and a rapid method of assessing the effect of fluorination on a putative drug’s metabolic stability would be of clear benefit. One approach to this is to employ micro-organisms that are established as models of drug metabolism in parallel with the synthesis of fluorinated drug analogues. In this study, we have used the filamentous fungus Cunninghamella elegans to identify the metabolically labile site of the nonsteroidal anti-inflammatory drug flurbiprofen, to aid in the design of fluorinated derivatives that were subsequently synthesised. The effect of the additional fluorine substitution on cytochrome P450-catalysed oxidation was then determined via incubation with the fungus, and demonstrated that fluorine substitution at the 4′-position rendered the drug inactive to oxidative transformation, whereas substitution of fluorine at either 2' or 3' resulted in slower oxidation compared to the original drug. This approach to modulating the metabolic stability of a drug-like compound is widely applicable and can be used to address metabolic issues of otherwise good lead compounds in drug development.382Scopus© Citations 20 - PublicationExploiting the genome sequence of Streptomyces nodosus for enhanced antibiotic productionThe genome of the amphotericin producer Streptomyces nodosus was sequenced. A single scaffold of 7,714,110 bp was obtained. Biosynthetic genes were identified for several natural products including polyketides, peptides, siderophores and terpenes. The majority of these clusters specified known compounds. Most were silent or expressed at low levels and unlikely to compete with amphotericin production. Biosynthesis of a skyllamycin analogue was activated by introducing expression plasmids containing either a gene for a LuxR transcriptional regulator or genes for synthesis of the acyl moiety of the lipopeptide. In an attempt to boost amphotericin production, genes for acyl CoA carboxylases, a phosphopantetheinyl transferase and the AmphRIV transcriptional activator were overexpressed, and the effects on yields were investigated. This study provides the groundwork for metabolic engineering of S. nodosus strains to produce high yields of amphotericin analogues.
741Scopus© Citations 21 - PublicationBiotransformation of flurbiprofen by Cunninghamella species(American Society for Microbiology, 2010-09)
; ; The biotransformation of the fluorinated anti-inflammatory drug flurbiprofen was investigated in Cunninghamella spp. Mono- and di-hydroxylated metabolites were detected using gas chromatography-mass spectrometry and fluorine-19 nuclear magnetic resonance spectroscopy, and the major metabolite 4’-hydroxyflurbiprofen was isolated by preparative HPLC. C. elegans DSM 1908 and C. blakesleeana DSM 1906 also produced a phase II (conjugated) metabolite, which was identified as the sulfated drug via deconjugation experiments.515Scopus© Citations 42 - PublicationDrug metabolism in microorganismsSeveral wild type and recombinant microorganisms can transform drugs to the equivalent human metabolites. Fungi, such as Cunninghamella spp., and Streptomyces bacteria express cytochrome P450 (CYP) enzymes that enable analogous phase I (oxidative) reactions with a wide range of drugs. The gene encoding the bifunctional CYP102A1 in Bacillus megaterium can be expressed easily in E. coli, and extensive mutagenesis experiments have generated numerous variants that can produce human drug metabolites. Additionally, human CYP isoforms have been expressed in various hosts. The application of microbial CYPs to the production of human drug metabolites is reviewed, and additional applications in the field of drug development are considered.
444Scopus© Citations 46 - PublicationRecent advances in fluorination techniques and their anticipated impact on drug metabolism and toxicityIntroduction: Fluorine’s unique physicochemical properties make it a key element for incorporation into pharmacologically active compounds. Its presence in a drug can alter a number of characteristics that affect ADME-Tox, which has prompted efforts at improving synthetic fluorination procedures. Areas covered: This review describes the influence of fluorine on attributes such as potency, lipophilicity, metabolic stability and bioavailablility and how the effects observed are related to the physicochemical characteristics of the element. Examples of more recently used larger scale synthetic methods for introduction of fluorine into drug leads are detailed and the potential for using biological systems for fluorinated drug production is discussed. Expert opinion: The synthetic procedures for carbon-fluorine bond formation largely still rely on decades-old technology for the manufacturing scale and new reagents and methods are required to meet the demands for the preparation of structurally more complex drugs. The improvement of in vitro and computational methods should make fluorinated drug design more efficient and place less emphasis on approaches such as fluorine scanning and animal studies. The introduction of new fluorinated drugs, and in particular those that have novel fluorinated functional groups, should be accompanied by rigorous environmental assessment to determine the nature of transformation products that may cause ecological damage.
722Scopus© Citations 63