Publications by authors named "Alan Hennessy"

20 Publications

  • Page 1 of 1

Iron-mediated oxidative C-H coupling of arenes and alkenes directed by sulfur: an expedient route to dihydrobenzofurans.

Org Biomol Chem 2016 Jun 20;14(23):5286-92. Epub 2016 May 20.

School of Chemistry, University of Manchester, Oxford Road, Manchester, M13 9PL, UK.

A novel route to medicinally-relevant dihydrobenzofurans utilises a sulfur-directed C-H ortho-coupling of arenes and unactivated terminal alkenes mediated by iron, and a palladium-catalysed deallylation/heterocyclisation sequence. The iron-mediated coupling affords linear products of alkene chloroarylation in good yield and with complete regioselectivity. The coupling likely proceeds by redox-activation of the arene partner by iron(iii) and alkene addition to the resultant radical cation.
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http://dx.doi.org/10.1039/c6ob00883fDOI Listing
June 2016

Novel tricyclics (e.g., GSK945237) as potent inhibitors of bacterial type IIA topoisomerases.

Bioorg Med Chem Lett 2016 05 31;26(10):2464-2469. Epub 2016 Mar 31.

Infectious Diseases CEDD, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA.

During the course of our research on the lead optimisation of the NBTI (Novel Bacterial Type II Topoisomerase Inhibitors) class of antibacterials, we discovered a series of tricyclic compounds that showed good Gram-positive and Gram-negative potency. Herein we will discuss the various subunits that were investigated in this series and report advanced studies on compound 1 (GSK945237) which demonstrates good PK and in vivo efficacy properties.
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http://dx.doi.org/10.1016/j.bmcl.2016.03.106DOI Listing
May 2016

Sources and Bioactive Properties of Conjugated Dietary Fatty Acids.

Lipids 2016 Apr 11;51(4):377-97. Epub 2016 Mar 11.

Teagasc Food Research Centre, Moorepark, Fermoy, Co. Cork, Ireland.

The group of conjugated fatty acids known as conjugated linoleic acid (CLA) isomers have been extensively studied with regard to their bioactive potential in treating some of the most prominent human health malignancies. However, CLA isomers are not the only group of potentially bioactive conjugated fatty acids currently undergoing study. In this regard, isomers of conjugated α-linolenic acid, conjugated nonadecadienoic acid and conjugated eicosapentaenoic acid, to name but a few, have undergone experimental assessment. These studies have indicated many of these conjugated fatty acid isomers commonly possess anti-carcinogenic, anti-adipogenic, anti-inflammatory and immune modulating properties, a number of which will be discussed in this review. The mechanisms through which these bioactivities are mediated have not yet been fully elucidated. However, existing evidence indicates that these fatty acids may play a role in modulating the expression of several oncogenes, cell cycle regulators, and genes associated with energy metabolism. Despite such bioactive potential, interest in these conjugated fatty acids has remained low relative to the CLA isomers. This may be partly attributed to the relatively recent emergence of these fatty acids as bioactives, but also due to a lack of awareness regarding sources from which they can be produced. In this review, we will also highlight the common sources of these conjugated fatty acids, including plants, algae, microbes and chemosynthesis.
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http://dx.doi.org/10.1007/s11745-016-4135-zDOI Listing
April 2016

Iron-mediated C-H coupling of arenes and unactivated terminal alkenes directed by sulfur.

Chem Commun (Camb) 2015 Jun;51(45):9272-5

School of Chemistry, University of Manchester, Oxford Road, Manchester, M13 9PL, UK.

A sulfur-directed Fe(iii)-mediated ortho C-H coupling of arenes with unactivated terminal alkenes gives products of regioselective alkene chloroarylation. The novel mechanism involves redox-activation of the arene partner and alkene addition to the resultant aryl radical cation.
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http://dx.doi.org/10.1039/c5cc02676hDOI Listing
June 2015

Role of the gut in modulating lipoprotein metabolism.

Curr Cardiol Rep 2014 Aug;16(8):515

Teagasc Food Research Centre, Moorepark, Fermoy, Co. Cork, Ireland,

The intestinal production of lipoproteins is one of the key processes by which the body prepares dietary lipid for dissemination to locations throughout the body where they are required. Paramount to this is the relationship between dietary lipid and the enterocytes that line the gut, along with the processes which prepare this lipid for efficient uptake by these cells. These include those which occur in the mouth and stomach along with those which occur within the intestinal lumen itself. Additionally, the interplay between digested lipid, dual avenues for lipid uptake by enterocytes (passive and lipid transporter proteins), a system of intercellular lipid resynthesis and transport, and a complex system of lipoprotein synthesis yield a system open to significant modulation. In this review, we will attempt to outline the processes of lipid digestion, lipoprotein synthesis and the exogenous and endogenous factors which exert their influence.
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http://dx.doi.org/10.1007/s11886-014-0515-2DOI Listing
August 2014

DABSO-based, three-component, one-pot sulfone synthesis.

Org Lett 2014 Jan 5;16(1):150-3. Epub 2013 Dec 5.

Department of Chemistry, University of Oxford, Chemistry Research Laboratory , Mansfield Road, Oxford OX1 3TA, United Kingdom.

The addition of Grignard reagents or organolithium reagents to the SO2-surrogate DABSO generates a diverse set of metal sulfinates, suitable for direct conversion to sulfone products. The metal sulfinates can be trapped in situ with a wide range of C-electrophiles, including alkyl, allyl, and benzyl halides, epoxides, and (hetero)aryliodoniums.
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http://dx.doi.org/10.1021/ol403122aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3883144PMC
January 2014

Novel hydroxyl tricyclics (e.g., GSK966587) as potent inhibitors of bacterial type IIA topoisomerases.

Bioorg Med Chem Lett 2013 Oct 17;23(19):5437-41. Epub 2013 Jul 17.

Diseases of the Developing World CEDD, GlaxoSmithKline, Madrid, Spain.

During the course of our research to find novel mode of action antibacterials, we discovered a series of hydroxyl tricyclic compounds that showed good potency against Gram-positive and Gram-negative pathogens. These compounds inhibit bacterial type IIA topoisomerases. Herein we will discuss structure-activity relationships in this series and report advanced studies on compound 1 (GSK966587) which demonstrates good PK and in vivo efficacy properties. X-ray crystallographic studies were used to provide insight into the structural basis for the difference in antibacterial potency between enantiomers.
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http://dx.doi.org/10.1016/j.bmcl.2013.07.013DOI Listing
October 2013

β-Lactoglobulin-linoleate complexes: In vitro digestion and the role of protein in fatty acid uptake.

J Dairy Sci 2013 Jul 16;96(7):4258-68. Epub 2013 May 16.

INRA, UMR1253 STLO, 65 rue de Saint Brieuc, F-35042 Rennes, France.

The dairy protein β-lactoglobulin (BLG) is known to bind fatty acids such as the salt of the essential longchain fatty acid linoleic acid (cis,cis-9,12-octadecadienoic acid, n-6, 18:2). The aim of the current study was to investigate how bovine BLG-linoleate complexes, of various stoichiometry, affect the enzymatic digestion of BLG and the intracellular transport of linoleate into enterocyte-like monolayers. Duodenal and gastric digestions of the complexes indicated that BLG was hydrolyzed more rapidly when complexed with linoleate. Digested as well as undigested BLG-linoleate complexes reduced intracellular linoleate transport as compared with free linoleate. To investigate whether enteroendocrine cells perceive linoleate differently when part of a complex, the ability of linoleate to increase production or secretion of the enteroendocrine satiety hormone, cholecystokinin, was measured. Cholecystokinin mRNA levels were different when linoleate was presented to the cells alone or as part of a protein complex. In conclusion, understanding interactions between linoleate and BLG could help to formulate foods with targeted fatty acid bioaccessibility and, therefore, aid in the development of food matrices with optimal bioactive efficacy.
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http://dx.doi.org/10.3168/jds.2013-6682DOI Listing
July 2013

Gold-catalysed cascade rearrangements of ynamide propargyl esters.

Chem Commun (Camb) 2013 Mar;49(23):2314-6

Department of Chemistry, University of Bath, Claverton Down, UK BA2 7AY.

The Au(I)-catalysed rearrangement of propargylic esters formed from an ynamide has been studied. The reaction is facile, and when conducted in the presence of a reactive indole nucleophile, leads to a cascade process whereby γ-indolyl α-acyloxyenamides are formed in good yield and excellent E-stereoselectivity.
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http://dx.doi.org/10.1039/c3cc00273jDOI Listing
March 2013

Feed allowance and maternal backfat levels during gestation influence maternal cortisol levels, milk fat composition and offspring growth.

J Nutr Sci 2013 10;2:e1. Epub 2013 Jan 10.

Teagasc, Pig Development Department , Animal and Grassland Research and Innovation Centre , Moorepark, Fermoy, Co. Cork , Republic of Ireland.

The fetal and early postnatal environment can have a long-term influence on offspring growth. Using a pig model, we investigated the effects of maternal body condition (thin or fat) and maternal gestation feeding level (restricted, control or high) on maternal stress, milk composition, litter size, piglet birth weight and pre-weaning growth. A total of sixty-eight thin (backfat depth about 8 mm) and seventy-two fat (backfat depth about 12 mm) gilts were selected at about 22 weeks. This backfat difference was then accentuated nutritionally up to service at about 32 weeks. During gestation, individual gilts from within each group were randomly allocated to a gestation diet at the following feed allowances: 1·8 kg/d (restricted); 2·5 kg/d (control) and 3·5 kg/d (high) until day 90 of gestation. During gestation restricted gilts had higher levels of cortisol than high and control fed animals. Piglets born to fat gilts had higher average daily gain during the lactation period and higher weaning weights at day 28 than piglets born to thin gilts. Gilts on a high feed level had heavier piglets than those provided with restricted and control allocations. Fat gilts had less saturated fat in their milk at day 21 of lactation and higher unsaturated fat levels. No differences were found in the n-6:n-3 PUFA ratio in the milk between thin and fat gilts. In conclusion, maternal body condition influenced the daily weight gain of offspring up to weaning (day 28) and milk fat composition. Furthermore, maternal feed level during gestation alters maternal cortisol levels and milk fat composition.
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http://dx.doi.org/10.1017/jns.2012.20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4153285PMC
September 2014

The production of conjugated α-linolenic, γ-linolenic and stearidonic acids by strains of bifidobacteria and propionibacteria.

Lipids 2012 Mar 10;47(3):313-27. Epub 2011 Dec 10.

Teagasc Food Research Centre, Moorepark, Fermoy, Co., Cork, Ireland.

Conjugated fatty acids are regularly found in nature and have a history of biogenic activity in animals and humans. A number of these conjugated fatty acids are microbially produced and have been associated with potent anti-carcinogenic, anti-adipogenic, anti-atherosclerotic and anti-diabetogenic activities. Therefore, the identification of novel conjugated fatty acids is highly desirable. In this study, strains of bifidobacteria and propionibacteria previously shown by us and others to display linoleic acid isomerase activity were assessed for their ability to conjugate a range of other unsaturated fatty acids during fermentation. Only four, linoleic, α-linolenic, γ-linolenic and stearidonic acids, were converted to their respective conjugated isomers, conjugated linoleic acid (CLA), conjugated α-linolenic acid (CLNA), conjugated γ-linolenic acid (CGLA) and conjugated stearidonic acid (CSA), each of which contained a conjugated double bond at the 9,11 position. Of the strains assayed, Bifidobacterium breve DPC6330 proved the most effective conjugated fatty acid producer, bio-converting 70% of the linoleic acid to CLA, 90% of the α-linolenic acid to CLNA, 17% of the γ-linolenic acid to CGLA, and 28% of the stearidonic acid to CSA at a substrate concentration of 0.3 mg mL⁻¹. In conclusion, strains of bifidobacteria and propionibacteria can bio-convert linoleic, α-linolenic, γ-linolenic and stearidonic acids to their conjugated isomers via the activity of the enzyme linoleic acid isomerase. These conjugated fatty acids may offer the combined health promoting properties of conjugated fatty acids such as CLA and CLNA, along with those of the unsaturated fatty acids from which they are formed.
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http://dx.doi.org/10.1007/s11745-011-3636-zDOI Listing
March 2012

Novel amino-piperidines as potent antibacterials targeting bacterial type IIA topoisomerases.

Bioorg Med Chem Lett 2011 Dec 10;21(24):7489-95. Epub 2011 Oct 10.

Diseases of the Developing World CEDD, GlaxoSmithKline, Calle Severo Ochoa 2, 28760, Tres Cantos, Madrid, Spain.

We have identified a series of amino-piperidine antibacterials with a good broad spectrum potency. We report the investigation of various subunits in this series and advanced studies on compound 8. Compound 8 possesses good pharmacokinetics, broad spectrum antibacterial activity and demonstrates oral efficacy in a rat lung infection model.
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http://dx.doi.org/10.1016/j.bmcl.2011.09.117DOI Listing
December 2011

Novel cyclohexyl-amides as potent antibacterials targeting bacterial type IIA topoisomerases.

Bioorg Med Chem Lett 2011 Dec 10;21(24):7483-8. Epub 2011 Oct 10.

Diseases of the Developing World CEDD, GlaxoSmithKline, Calle Severo Ochoa, 2, 28760, Tres Cantos, Madrid, Spain.

As part of our wider efforts to exploit novel mode of action antibacterials, we have discovered a series of cyclohexyl-amide compounds that has good Gram positive and Gram negative potency. The mechanism of action is via inhibition of bacterial topoisomerases II and IV. We have investigated various subunits in this series and report advanced studies on compound 7 which demonstrates good PK and in vivo efficacy properties.
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http://dx.doi.org/10.1016/j.bmcl.2011.09.114DOI Listing
December 2011

The health promoting properties of the conjugated isomers of α-linolenic acid.

Lipids 2011 Feb 15;46(2):105-19. Epub 2010 Dec 15.

TEAGASC, Moorepark Food Research Centre, Fermoy, Co. Cork, Ireland.

The bioactive properties of the conjugated linoleic acid (CLA) isomers have long been recognised and are the subject of a number of excellent reviews. However, despite this prominence the CLA isomers are not the only group of naturally occurring dietary conjugated fatty acids which have shown potent bioactivity. In a large number of in vitro and in vivo studies, conjugated α-linolenic acid (CLNA) isomers have displayed potent anti-inflammatory, immunomodulatory, anti-obese and anti-carcinogenic activity, along with the ability to improve biomarkers of cardio-vascular health. CLNA isomers are naturally present in high concentrations in a large variety of seed oils but can also be produced in vitro by strains of lactobacilli and bifidobactena through the activity of the enzyme linoleic acid isomerase on α-linolenic acid. In this review, we will address the possible therapeutic roles that CLNA may play in a number of conditions afflicting Western society and the mechanisms through which this activity is mediated.
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http://dx.doi.org/10.1007/s11745-010-3501-5DOI Listing
February 2011

Type IIA topoisomerase inhibition by a new class of antibacterial agents.

Nature 2010 Aug 4;466(7309):935-40. Epub 2010 Aug 4.

Molecular Discovery Research, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK.

Despite the success of genomics in identifying new essential bacterial genes, there is a lack of sustainable leads in antibacterial drug discovery to address increasing multidrug resistance. Type IIA topoisomerases cleave and religate DNA to regulate DNA topology and are a major class of antibacterial and anticancer drug targets, yet there is no well developed structural basis for understanding drug action. Here we report the 2.1 A crystal structure of a potent, new class, broad-spectrum antibacterial agent in complex with Staphylococcus aureus DNA gyrase and DNA, showing a new mode of inhibition that circumvents fluoroquinolone resistance in this clinically important drug target. The inhibitor 'bridges' the DNA and a transient non-catalytic pocket on the two-fold axis at the GyrA dimer interface, and is close to the active sites and fluoroquinolone binding sites. In the inhibitor complex the active site seems poised to cleave the DNA, with a single metal ion observed between the TOPRIM (topoisomerase/primase) domain and the scissile phosphate. This work provides new insights into the mechanism of topoisomerase action and a platform for structure-based drug design of a new class of antibacterial agents against a clinically proven, but conformationally flexible, enzyme class.
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http://dx.doi.org/10.1038/nature09197DOI Listing
August 2010

Target-directed synthesis of antibacterial drug candidate GSK966587.

Org Lett 2010 Aug;12(15):3422-5

GlaxoSmithKline, Synthetic Chemistry Department, 709 Swedeland Road, P.O. Box 1539, King of Prussia, Pennsylvania 19406, USA.

An efficient enantioselective total synthesis of the potent antibiotic GSK966587 was accomplished. Highlights of the synthesis include two innovative Heck reactions, a highly selective zincate base directed ortho-metalation, Sharpless asymmetric epoxidation, and a fully convergent final step fragment coupling.
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http://dx.doi.org/10.1021/ol101235fDOI Listing
August 2010

Marked elevations in pro-inflammatory polyunsaturated fatty acid metabolites in females with irritable bowel syndrome.

J Lipid Res 2010 May 11;51(5):1186-92. Epub 2009 Nov 11.

Department of Psychiatry, University College Cork, Cork, Ireland.

Irritable bowel syndrome (IBS) is the most common functional gastrointestinal disorder referred to gastroenterologists. Although the pathophysiology remains unclear, accumulating evidence points to the presence of low-level immune activation both in the gut and systemically. Circulating polyunsaturated fatty acids (PUFA) have recently attracted attention as being altered in a variety of disease states. Arachidonic acid (AA), in particular, has been implicated in the development of a pro-inflammatory profile in a number of immune-related disorders. AA is the precursor of a number of important immunomodulatory eicosanoids, including prostaglandin E(2) (PGE(2)) and leukotriene B(4) (LTB(4)). We investigated the hypothesis that elevated plasma AA concentrations in plasma contribute to the proposed pro-inflammatory profile in IBS. Plasma AA and related PUFA were quantified by gas chromatography analysis in IBS patients and controls. Both PGE(2) and LTB(4) were measured in serum using commercially available ELISA assays. AA concentrations were elevated in our patient cohort compared with healthy controls. Moreover, we demonstrated that this disturbance in plasma AA concentrations leads to downstream elevations in eicosanoids. Together, our data identifies a novel proinflammatory mechanism in irritable bowel syndrome and also suggests that elevated arachidonic acid levels in plasma may serve as putative biological markers in this condition.
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http://dx.doi.org/10.1194/jlr.P000695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2853445PMC
May 2010

Chain reactions: early-life stress alters the metabolic profile of plasma polyunsaturated fatty acids in adulthood.

Behav Brain Res 2009 Dec 16;205(1):319-21. Epub 2009 Jul 16.

Department of Psychiatry, University College Cork, Cork, Ireland; Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland.

The rat maternal separation paradigm can be used to examine the biological consequences of early-life stress. Immunomodulatory polyunsaturated fatty acids (PUFAs) have recently attracted attention in the study of stress-related disorders. We established the plasma PUFA profile of maternally separated rodents compared to controls. Our results identify a proinflammatory PUFA profile as a persistent consequence of early-life stress and suggest new avenues of investigation in stress-related disorders.
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http://dx.doi.org/10.1016/j.bbr.2009.07.008DOI Listing
December 2009

Synthesis of diverse macrocyclic peptidomimetics utilizing ring-closing metathesis and solid-phase synthesis.

J Org Chem 2004 Feb;69(4):1028-37

Department of Chemistry, Imperial College London, South Kensington, UK.

The synthesis of a range of highly functionalized peptidomimetic macrocycles has been accomplished using ring-closing metathesis and enyne tandem cross-metathesis-ring-closing metathesis reactions. This approach gives access to rigidified macrocycles modeled on the structures of cyclic peptides and designed to be biologically stable. The potential for peripheral functionalization of these templates has been demonstrated using Diels-Alder reactions, palladium(0) coupling reactions, and amide formation both in the solution phase and using polymer-supported syntheses.
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http://dx.doi.org/10.1021/jo0352629DOI Listing
February 2004