Paul V. Murphy

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Organization: National University of Ireland Galway , Ireland

Department: School of Chemistry

Title: Professor(PhD)

TOPICS

Organic Chemistry

Chemicals
References

Stereoselective Epimerizations of Glycosyl Thiols

Co-reporter:Lisa M. Doyle, Shane O’Sullivan, Claudia Di Salvo, Michelle McKinney, Patrick McArdle, and Paul V. Murphy

Organic Letters November 3, 2017 Volume 19(Issue 21) pp:5802-5802

Publication Date(Web):October 17, 2017

DOI:10.1021/acs.orglett.7b02760

Glycosyl thiols are widely used in stereoselective S-glycoside synthesis. Their epimerization from 1,2-trans to 1,2-cis thiols (e.g., equatorial to axial epimerization in thioglucopyranose) was attained using TiCl4, while SnCl4 promoted their axial-to-equatorial epimerization. The method included application for stereoselective β-d-manno- and β-l-rhamnopyranosyl thiol formation. Complex formation explains the equatorial preference when using SnCl4, whereas TiCl4 can shift the equilibrium toward the 1,2-cis thiol via 1,3-oxathiolane formation.

Lewis Acid Induced Anomerization of Se-Glycosides. Application to Synthesis of α-Se-GalCer

Co-reporter:Anthony W. McDonagh, Mary F. Mahon, and Paul V. Murphy

Organic Letters 2016 Volume 18(Issue 3) pp:552-555

Publication Date(Web):January 22, 2016

DOI:10.1021/acs.orglett.5b03591

The TiCl4 induced anomerization of selenium glycosides of galacturonic acid derivatives is reported. The reaction was successful for galacturonic acid when various alkyl, alkenyl, alkynyl, saccharide, steroid, and lipid groups were attached to the anomeric Se atom. An increased amount of TiCl4 and/or higher temperature were needed to ensure completion of the reaction in some cases. Yields were higher for reactions carried out at higher dilution. The reaction was applied to the synthesis of Se-based mimics of the potent immunostimulant α-GalCer (KRN7000).

Coiled coil type neoglycoproteins presenting three lactose residues

Co-reporter:Sinclair M. Sweeney, Gemma A. Bullen, Richard B. Gillis, Gary G. Adams, Arthur J. Rowe, Stephen E. Harding, James H.R. Tucker, Anna F.A. Peacock, Paul V. Murphy

Tetrahedron Letters 2016 Volume 57(Issue 13) pp:1414-1417

Publication Date(Web):30 March 2016

DOI:10.1016/j.tetlet.2016.02.005

Scaffold design, synthesis and application are relevant for biomedical research. For example, multivalent interactions, such as those between cell surface glycoproteins and lectins can influence the potency and duration of signalling. The spacing between carbohydrates on their native protein scaffold could be important. Herein, the coiled coil design principle is used to generate synthetic coiled coil type glycoproteins, where three lactose residues are grafted to the coil via N-linkages to asparagine. Molecular modelling indicates that the distance between the galactose anomeric carbon atoms on the neoglycoproteins is ∼30 Å. The inclusion of lactose was accommodated in both the final heptad towards the N-terminus, or more centrally in the penultimate heptad. In either case, neither the helicity nor the assembly to the trimeric form was unduly altered by the presence of the disaccharide.

Allylic Azide Rearrangement in Tandem with Huisgen Cycloaddition for Stereoselective Annulation: Synthesis of C-Glycosyl Iminosugars

Co-reporter:Lorna Moynihan, Rekha Chadda, Patrick McArdle, and Paul V. Murphy

Organic Letters 2015 Volume 17(Issue 24) pp:6226-6229

Publication Date(Web):December 9, 2015

DOI:10.1021/acs.orglett.5b03209

Allylic azide rearrangement is used in tandem with intramolecular azide–alkene cycloaddition to give a triazoline that when subsequently decomposed in the presence of a nucleophile gives piperidines. The tandem reaction gives two stereocenters that are generated with high control. The formation of the piperidines required the presence of innate conformational constraint. The applicability of the annulation reaction is demonstrated by the synthesis of iminosugars. A proposal is included to account for the observed stereoselectivity, which is influenced by the precursor structure.

Decorated Macrocycles via Ring-Closing Double-Reductive Amination. Identification of an Apoptosis Inducer of Leukemic Cells That at Least Partially Antagonizes a 5-HT2 Receptor

Co-reporter:Jian Zhou, Mairead Reidy, Ciaran O’Reilly, Dilip V. Jarikote, Arvind Negi, Afshin Samali, Eva Szegezdi, and Paul V. Murphy

Organic Letters 2015 Volume 17(Issue 7) pp:1672-1675

Publication Date(Web):March 16, 2015

DOI:10.1021/acs.orglett.5b00404

A build–couple–pair strategy, including double-reductive amination macrocyclization, has been used to generate decorated macrocycles (eannaphanes) with an embedded triazole and monosaccharide. Biological screening led to the identification of an inducer of apoptosis in leukemic cells, which acts at least partially as a 5-HT2 antagonist.

Bi- to tetravalent glycoclusters presenting GlcNAc/GalNAc as inhibitors: from plant agglutinins to human macrophage galactose-type lectin (CD301) and galectins

Co-reporter:Sabine André, Shane O'Sullivan, Christiane Koller, Paul V. Murphy and Hans-Joachim Gabius

Organic & Biomolecular Chemistry 2015 vol. 13(Issue 14) pp:4190-4203

Publication Date(Web):17 Feb 2015

DOI:10.1039/C5OB00048C

Emerging insights into the functional spectrum of tissue lectins leads to identification of new targets for the custom-made design of potent inhibitors, providing a challenge for synthetic chemistry. The affinity and selectivity of a carbohydrate ligand for a lectin may immensely be increased by a number of approaches, which includes varying geometrical or topological features. This perspective leads to the design and synthesis of glycoclusters and their testing using assays of physiological relevance. Herein, hydroquinone, resorcinol, benzene-1,3,5-triol and tetra(4-hydroxyphenyl)ethene have been employed as scaffolds and propargyl derivatives obtained. The triazole-containing linker to the α/β-O/S-glycosides of GlcNAc/GalNAc presented on these scaffolds was generated by copper-catalysed azide–alkyne cycloaddition. This strategy was used to give a panel of nine glycoclusters with bi-, tri- and tetravalency. Maintained activity for lectin binding after conjugation was ascertained for both sugars in solid-phase assays with the plant agglutinins WGA (GlcNAc) and DBA (GalNAc). Absence of cross-reactivity excluded any carbohydrate-independent reactivity of the bivalent compounds, allowing us to proceed to further testing with a biomedically relevant lectin specific for GalNAc. Macrophage galactose(-binding C)-type lectin, involved in immune defence by dendritic cells and in virus uptake, was produced as a soluble protein without/with its α-helical coiled-coil stalk region. Binding to ligands presented on a matrix and on cell surfaces was highly susceptible to the presence of the tetravalent inhibitor derived from the tetraphenylethene-containing scaffold, and presentation of GalNAc with an α-thioglycosidic linkage proved favorable. Cross-reactivity of this glycocluster to human galectins-3 and -4, which interact with Tn-antigen-presenting mucins, was rather small. Evidently, the valency and spatial display of α-GalNAc residues is a key factor to design potent and selective inhibitors for this lectin.

Cover Picture: Synthesis of Migrastatin Analogues as Inhibitors of Tumour Cell Migration: Exploring Structural Change in and on the Macrocyclic Ring (Chem. Eur. J. 50/2015)

Co-reporter:Dr. Daniele LoRe;Dr. Ying Zhou;Dr. Joanna Mucha;Dr. Leigh F. Jones;Lorraine Leahy; Corrado Santocanale; Magdalena Krol; Paul V. Murphy

Chemistry - A European Journal 2015 Volume 21( Issue 50) pp:

Publication Date(Web):

DOI:10.1002/chem.201585001

Synthesis of Migrastatin Analogues as Inhibitors of Tumour Cell Migration: Exploring Structural Change in and on the Macrocyclic Ring

Co-reporter:Daniele LoRe;Ying Zhou;Joanna Mucha;Leigh F. Jones;Lorraine Leahy;Corrado Santocanale;Magdalena Krol

Chemistry - A European Journal 2015 Volume 21( Issue 50) pp:

Publication Date(Web):

DOI:10.1002/chem.201504167

Abstract

Invited for the cover of this issue are Paul V. Murphy and co-workers at the National University of Ireland Galway (NUI Galway) and Warsaw University. The image depicts MGSTA-6 giving a stop signal to tumour cells that are on the move. Read the full text of the article at 10.1002/chem.201502861.

Synthesis of Migrastatin Analogues as Inhibitors of Tumour Cell Migration: Exploring Structural Change in and on the Macrocyclic Ring

Co-reporter:Dr. Daniele LoRe;Dr. Ying Zhou;Dr. Joanna Mucha;Dr. Leigh F. Jones;Lorraine Leahy; Corrado Santocanale; Magdalena Krol; Paul V. Murphy

Chemistry - A European Journal 2015 Volume 21( Issue 50) pp:18109-18121

Publication Date(Web):

DOI:10.1002/chem.201502861

Abstract

Migrastatin and isomigrastatin analogues have been synthesised in order to contribute to structure–activity studies on tumour cell migration inhibitors. These include macrocycles varying in ring size, functionality and alkene stereochemistry, as well as glucuronides. The synthesis work included application of the Saegusa–Ito reaction for regio- and stereoselective unsaturated macroketone formation, diastereoselective Brown allylation to generate 9-methylmigrastatin analogues and chelation-induced anomerisation to vary glucuronide configuration. Compounds were tested in vitro against both breast and pancreatic cancer cell lines and inhibition of tumour cell migration was observed in both wound-healing (scratch) and Boyden chamber assays. One unsaturated macroketone showed low affinity for a range of secondary drug targets, indicating it is at low risk of displaying adverse side effects.

Glycoclusters as lectin inhibitors: comparative analysis on two plant agglutinins with different folding as a step towards rules for selectivity

Co-reporter:Sabine André, Shane O'Sullivan, Hans-Joachim Gabius, Paul V. Murphy

Tetrahedron 2015 Volume 71(Issue 38) pp:6867-6880

Publication Date(Web):23 September 2015

DOI:10.1016/j.tet.2015.07.020

The emerging physiological significance of carbohydrate (glycan)–protein (lectin) recognition engenders the interest to design synthetic inhibitors with a high level of selectivity among natural sugar receptors. Plant agglutinins are common models to determine structure–activity relationships. Focussing on the contribution of valency towards selectivity, copper-catalysed azide (sugar derivative)–alkyne (scaffold) cycloaddition yielded a panel of 10 bi- to tetravalent glycoclusters with N-acetylglucosamine as the bioactive headgroup. They were introduced into assays using (neo)glycoproteins and cell surfaces as platforms to study carbohydrate-dependent lectin binding. The ability of the bivalent compounds, which exhibit a distance profile of the sugar headgroups of about 16–21 Å, for intramolecular bridging of two contact sites from the eight hevein domains of wheat germ agglutinin led to comparatively high enhancements of inhibitory potency relative to a tetrameric leguminous lectin (distance profile of 50–70 Å between sugar-specific sites), especially for a β-S-glycoside. The extent of inhibition at fixed concentrations of the sugar depended on the type of matrix used for the assay. Increases to tri- and tetravalency played a less important role than the anomeric position to keep cross-reactivity low, these tested topologies enabling cross-linking for both lectins. The potential for cis-interactions (intramolecular interactions), with glycoclusters serving as molecular rulers, is suggested to help designing selective blocking reagents.

Synthesis of iminosugar derivatives presenting naphthyl and alkyl amine interacting groups and binding to somatostatin receptors

Co-reporter:Stephen Barron and Paul V. Murphy

MedChemComm 2014 vol. 5(Issue 8) pp:1150-1158

Publication Date(Web):20 Mar 2014

DOI:10.1039/C4MD00074A

The synthesis of 1-deoxynojirimycin (DNJ) derivatives presenting a 2-naphthylmethyl and an alkyl amino side chain from L-sorbose is described. The synthetic derivatives were tested for their ability to inhibit the binding of somatostatin-14 to human recombinant somatostatin receptors (hSSTRs). One DNJ derivative showed selective binding for hSSTR5 over hSSTR4. The presence of benzyl groups and acetates on the oxygen atoms of the iminosugar scaffold led to increased affinity for both hSSTR5 and hSSTR4. Ligand-lipophilicity efficiencies (LLEs) are calculated for the iminosugar derivatives. The LLE values are significantly higher for iminosugar derivatives where hydroxyl groups are not protected, as compared to where they are benzylated. This indicates that leaving hydroxyl groups free or avoiding the use of multiple benzyl groups could be important for drug discovery research based on sugar scaffolds.

Combining glycocluster synthesis with protein engineering: an approach to probe into the significance of linker length in a tandem-repeat-type lectin (galectin-4)

Co-reporter:Sabine André, Guan-Nan Wang, Hans-Joachim Gabius, Paul V. Murphy

Carbohydrate Research 2014 Volume 389() pp:25-38

Publication Date(Web):7 May 2014

DOI:10.1016/j.carres.2013.12.024

•Synthesis of glycoclusters presenting lactose and 2′-fucosyl lactose on different scaffolds.•Engineering of galectin-4 mutants to probe structure–activity relationships with glycoclusters.•The impact of structural alterations by combining application of glycoclusters and mutants.Complementarity in lectin–glycan interactions in situ is assumed to involve spatial features in both the lectin and the glycan, giving a functional meaning to structural aspects of the lectin beyond its carbohydrate-binding site. In combining protein engineering with glycocluster synthesis, it is shown that the natural linker length of a tandem-repeat-type human lectin (galectin-4) determines binding properties in two binding assays (using surface-presented glycoprotein and cell surface assays). The types of glycocluster tested included bivalent lactosides based on tertiary amides of terephthalic, isophthalic, 2,6-naphthalic and oxalic acids as well as bivalent H(type 2) trisaccharides grafted on secondary/tertiary terephthalamides and two triazole-linker-containing cores. The presented data reveal a marked change in susceptibility to the test compounds when turning the tandem-repeat-type to a proto-type-like display. The testing of glycoclusters is suggested as a general strategy to help to delineate the significance of distinct structural features of lectins beyond their contact sites to the glycan.Graphical abstract

Synthesis of Migrastatin and its Macroketone Analogue and In Vivo FRAP Analysis of the Macroketone on E-Cadherin Dynamics

Co-reporter:Dr. Daniele Lo Re;Dr. Ying Zhou;Max Nobis; Kurt I. Anderson; Paul V. Murphy

ChemBioChem 2014 Volume 15( Issue 10) pp:1459-1464

Publication Date(Web):

DOI:10.1002/cbic.201402061

Abstract

An efficient and scalable synthesis of a key acyclic intermediate used for the preparation of migrastatin and its macroketone analogue is described; Brown alkoxyallylation is the key step for this synthesis. The macroketone was prepared on 100 mg scale by this route. Treatment of invasive pancreatic cancer cells grown on a cell-derived matrix or as subcutaneous tumours in nude mice with the macroketone inhibited E-cadherin dynamics in a manner consistent with increased cell adhesion and reduced invasive potential.

Synthesis of α-galactosyl ceramide analogues with an α-triazole at the anomeric carbon

Co-reporter:Anthony W. McDonagh, Paul V. Murphy

Tetrahedron 2014 70(19) pp: 3191-3196

Publication Date(Web):

DOI:10.1016/j.tet.2014.03.029

Regiospecific Anomerisation of Acylated Glycosyl Azides and Benzoylated Disaccharides by Using TiCl4

Co-reporter:Mark Farrell;Dr. Jian Zhou ;Dr. Paul V. Murphy

Chemistry - A European Journal 2013 Volume 19( Issue 44) pp:14836-14851

Publication Date(Web):

DOI:10.1002/chem.201302572

Abstract

Chelation induced anomerisation is promoted when Lewis acids, such as TiCl₄ or SnCl₄, coordinate to the pyranose ring oxygen atom and another site, giving rise to endocyclic cleavage and isomerisation to the more stable anomer. In this research regiospecific site-directed anomerisation is demonstrated. TiCl₄ (2.5 equiv) was employed to induce anomerisation of 15 glycosyl azide and disaccharide substrates of low reactivity, and high yields (>75 %) and stereoselectivies (α/β>9:1) were achieved. The examples included glucopyranuronate, galactopyranuronate and mannopyranuronate as well as N-acetylated glucopyranuronate and galactopyranuronate derivatives. A disaccharide with the α14 linkage found in polygalacturonan was included. The use of benzoylated saccharides was found to be important in disaccharide anomerisation as attempts to isomerise related acetyl protected and 2,3-carbonate protected derivatives were not successful.

Bi- to tetravalent glycoclusters: synthesis, structure–activity profiles as lectin inhibitors and impact of combining both valency and headgroup tailoring on selectivity

Co-reporter:Guan-Nan Wang, Sabine André, Hans-Joachim Gabius and Paul V. Murphy

Organic & Biomolecular Chemistry 2012 vol. 10(Issue 34) pp:6893-6907

Publication Date(Web):29 Jun 2012

DOI:10.1039/C2OB25870F

The emerging functional versatility of cellular glycans makes research on the design of synthetic inhibitors a timely topic. In detail, the combination of ligand (or headgroup or contact site) structure with spatial parameters that depend on topological and geometrical factors underlies the physiological selectivity of glycan-protein (lectin) recognition. We herein tested a panel of bi-, tri- and tetravalent compounds against two plant agglutinins and adhesion/growth-regulatory lectins (galectins). In addition, we examined the impact of headgroup tailoring (converting lactose to 2′-fucosyllactose) in combination with valency increase in two assay types of increasing biorelevance (from solid-phase binding to cell binding). Compounds were prepared using copper-catalysed azide alkyne cycloaddition from peracetylated lactosyl or 2′-fucosyllactosyl azides. Significant inhibition was achieved for the plant toxin with a tetravalent compound. Different levels of sensitivity were noted for the three groups of the galectin family. The headgroup extension to 2′-fucosyllactose led to a selectivity gain, especially for the chimera-type galectin-3. Valency increase established discrimination against the homodimeric proteins, whereas the combination of valency with the headgroup extension led to discrimination against the tandem-repeat-type galectin-8 for chicken galectins but not human galectins-3 and -4. Thus, detailed structure–activity profiling of glycoclusters combined with suitably modifying the contact site for the targeted lectin will help minimize cross-reactivity among this class of closely related proteins.

Synthesis of bivalent lactosides and their activity as sensors for differences between lectins in inter- and intrafamily comparisons

Co-reporter:Sabine André, Dilip V. Jarikote, Dandan Yan, Lisa Vincenz, Guan-Nan Wang, Herbert Kaltner, Paul V. Murphy, Hans-Joachim Gabius

Bioorganic & Medicinal Chemistry Letters 2012 Volume 22(Issue 1) pp:313-318

Publication Date(Web):1 January 2012

DOI:10.1016/j.bmcl.2011.11.010

The synthesis of nine bivalent lactosides (based on ditriazoles, diamides, a glycocyclophane and an acyclic analogue of the glycocyclophane) and one monovalent lactosyl triazole facilitated the assessment of the sensitivity of plant/animal lectins to this type of ligand display. The inhibitory potency of the compounds was determined in two assays of increasing biorelevance. These were solid-phase and cell binding set-ups. Hereby, the ability of the compounds to inhibit the binding of two plant agglutinins and the entire set of adhesion/growth-regulatory galectins from one organism (chicken) to a glycoprotein or to cell surfaces was systematically evaluated. Differential sensitivities were detected between plant and animal lectins and also between distinct galectin forms within the chicken series. Two of the bivalent probes can be considered as sensors for interlectin differences. Most pronounced were the selectivities of N-glycosyl 1,2,3-triazole derivatives for the chimera-type galectin and its proteolytically truncated version.Synthesis of bivalent lactosides generates selective tools to interfere with cell binding of adhesion/growth-regulatory lectins, with the compound shown being the most potent.

Synthesis of bivalent glycoclusters containing GlcNAc as hexasaccharide mimetics. Bactericidal activity against Helicobacter pylori

Co-reporter:Dandan Yan, Julie Naughton, Marguerite Clyne, Paul V. Murphy

Carbohydrate Research 2012 360() pp: 1-7

Publication Date(Web):

DOI:10.1016/j.carres.2012.07.011

Synthesis, kinase activity and molecular modeling of a resorcylic acid lactone incorporating an amide and a trans-enone in the macrocycle

Co-reporter:Carmela Napolitano, Viraja R. Palwai, Leif A. Eriksson, Paul V. Murphy

Tetrahedron 2012 68(27–28) pp: 5533-5540

Publication Date(Web):

DOI:10.1016/j.tet.2012.04.082

Towards echinomycin mimetics by grafting quinoxaline residues on glycophane scaffolds

Co-reporter:Dilip V. Jarikote, Wei Li, Tao Jiang, Leif A. Eriksson, Paul V. Murphy

Bioorganic & Medicinal Chemistry 2011 Volume 19(Issue 2) pp:826-835

Publication Date(Web):15 January 2011

DOI:10.1016/j.bmc.2010.12.009

Echinomycin is a natural depsipeptide, which is a bisintercalator, inserting quinoxaline units preferentially adjacent to CG base pairs of DNA. Herein the design and synthesis of echinomycin mimetics based on grafting of two quinoxaline residues onto a macrocyclic scaffold (glycophane) is addressed. Binding of the compounds to calf-thymus DNA was studied using UV–vis and steady state fluorescence spectroscopy, as well as thermal denaturation. An interesting observation was enhancement of fluorescence emission for the peptidomimetics on binding to DNA, which contrasted with observations for echinomycin. Molecular dynamics simulations were exploited to explore in more detail if bis-intercalation to DNA was possible for one of the glycophanes. Bis-intercalating echinomycin complexes with DNA were found to be stable during 20 ns simulations at 298 K. However, the MD simulations of a glycophane complexed with a DNA octamer displayed very different behaviour to echinomycin and its quinoxaline units were found to rapidly migrate out from the intercalation site. Release of bis-intercalation strain occurred with only one of the quinoxaline chromophores remaining intercalated throughout the simulation. The distance between the quinoxaline residues in the glycophane at the end of the MD simulation was 7.3–7.5 Å, whereas in echinomycin, the distance between the residues was ∼11 Å, suggesting that longer glycophane scaffolds would be required to generate bis-intercalating echinomycin mimetics.

Isosteric replacement of the Z-enone with haloethyl ketone and E-enone in a resorcylic acid lactone series and biological evaluation

Co-reporter:Carmela Napolitano, Alessandro Natoni, Corrado Santocanale, Lasse Evensen, James B. Lorens, Paul V. Murphy

Bioorganic & Medicinal Chemistry Letters 2011 Volume 21(Issue 4) pp:1167-1170

Publication Date(Web):15 February 2011

DOI:10.1016/j.bmcl.2010.12.100

The synthesis of a small library of resorcylic acid lactones and evaluation of their biological properties as kinase inhibitors is described. Within the series E-enones were found more active than corresponding Z-enones as inhibitors of a subset of kinases containing a conserved cysteine. Replacement of the enone moiety with a β-haloketone group led to compounds with an interesting kinase selectivity profile and also antiproliferative activity against Jurkat cells. An E-enone derivative also showed activity against capillary tube formation based on a co-culture of primary human umbilical cord endothelial cells (HUVECs) and vascular smooth muscle cells (vSMCs).

Biological study of a somatostatin mimetic based on the 1-deoxynojrimycin scaffold

Co-reporter:Yunxue Zhao, Min Liu, Vincent Chagnault, Juying Wang, Xiumei Zhang, Paul V. Murphy

Bioorganic & Medicinal Chemistry Letters 2011 Volume 21(Issue 2) pp:824-828

Publication Date(Web):15 January 2011

DOI:10.1016/j.bmcl.2010.11.088

Previously the synthesis of novel somatostatin mimetic from 1-deoxynojirimycin (DNJ) led to identification of a compound with affinity for human somatostatin receptor subtypes 4 and 5 (hSSTR4 and hSSTR5). Here we examined the properties of this peptidomimetic in a human umbilical vein endothelial cell (HUVEC) based assays. The peptidomimetic prevented capillary tube formation based on HUVECs. It also inhibited HUVEC proliferation by inducing G1 phase cell cycle arrest and apoptosis. Stress fiber assembly and cell migration in HUVECs was markedly suppressed by the somatostatin receptor ligand.

Biological study of the Angiogenesis Inhibitor N-(8-(3-ethynylphenoxy)octyl-1-deoxynojirimycin

Co-reporter:Yunxue Zhao;Ying Zhou;Kathy M. O’ Boyle

Chemical Biology & Drug Design 2010 Volume 75( Issue 6) pp:570-577

Publication Date(Web):

DOI:10.1111/j.1747-0285.2010.00968.x

The α-glucosidase inhibitors N-methyl-1-deoxynojirimycin (MDNJ) and castanospermine have been shown to inhibit angiogenesis. A hybrid of 1-deoxynojirimycin (DNJ) and an aryl-1,2,3-triazole, which inhibits both an α-glucosidase and methionine aminopeptidase-2 (MetAP2), displayed properties associated with inhibition of angiogenesis (Bioorg. Med. Chem., 16, 2008, 6333–7). The biological evaluation of a structural analogue N-(8-(3-ethynylphenoxy)octyl-1-deoxynojirimycin is described herein. Although this alkyne derivative did not inhibit MetAP2, it inhibited a bacterial α-glucosidase, altered bovine aortic endothelial cell (BAEC) surface oligosaccharide expression and inhibited BAEC proliferation by inducing G1 phase cell cycle arrest. Experiments showed G1 arrest was attributable to the α-glucosidase inhibitor inducing an increase in p27^Kip1 expression and high phosphorylation of ERK1/2 without a reduction in cyclin D1. The DNJ derivative (0.1 mm) prevented capillary tube formation from bovine aortic endothelial cells, whereas DNJ or other analogues were unable to inhibit tube formation at the same concentration. Stress fiber assembly in bovine aortic endothelial cells was abolished, and BAEC migration was inhibited indicating the inhibition of tube formation by this derivative is partially a result of a reduction in cell motility. The agent also caused a reduction in secretion of MMP-2 from bovine aortic endothelial cells. Therefore, the new α-glucosidase inhibitor has a different mechanism by which it inhibits angiogenesis in vitro when compared with deoxynojirimycin, the deoxynojirimycin -triazole hybrid, N-methyl-1-deoxynojirimycin and castanospermine.

Metathesis and Macrocycles with Embedded Carbohydrates

Co-reporter:Dilip Venkatrao Jarikote

European Journal of Organic Chemistry 2010 Volume 2010( Issue 26) pp:4959-4970

Publication Date(Web):

DOI:10.1002/ejoc.201000491

Abstract

Macrocycles containing embedded carbohydrates are found in nature. Tricholorin A and G, woodrosin, sophorolipid lactone, cycloviracin B1, glucolipsin A and ipomoeassins A–F are natural products with interesting biological properties. They have inspired synthesis of non-natural macrocyclic structures which contain embedded carbohydrates. Glycophanes (hybrids of carbohydrates and cyclophanes) were prepared which show potential in host-guest chemistry and which have been applied as rigid scaffolds for the synthesis of bivalent inhibitors of lectin binding to tumour cells. Macrocyclic neoglycoconjugates have also been prepared. These include macrocyclic neooligoaminodeoxysaccharides which bind to RNA regions containing either asymmetric internal loop or hairpin loop-stem junctions, and vaccine candidates. Non-natural macrolides having antibacterial and antifungal activity have been synthesised. Metathesis using Grubbs and Hoyveda-Grubbs catalysts has been key to the successful generation of these compounds. Herein we review the recent application of metathesis to the synthesis of ipomoeassins A, B and F, glycophanes, neooligoaminodeoxysaccharides,macrolides and other macrocycles with embedded carbohydrates.

Synthesis of congeners of migrastatin and dorrigocin A from d-xylose

Co-reporter:Ying Zhou, Paul V. Murphy

Tetrahedron Letters 2010 Volume 51(Issue 40) pp:5262-5264

Publication Date(Web):6 October 2010

DOI:10.1016/j.tetlet.2010.07.141

Ultrasound-assisted synthesis of C-glycosides

Co-reporter:Dilip V. Jarikote, Ciaran O’Reilly, Paul V. Murphy

Tetrahedron Letters 2010 Volume 51(Issue 51) pp:6776-6778

Publication Date(Web):22 December 2010

DOI:10.1016/j.tetlet.2010.10.113

A significant rate enhancement was observed in the preparation of allyl and allenyl-C-glycosides from glycosyl acetate or methyl O-glycoside precursors when ultrasound irradiation was employed as an energy source. The C-glycosides were obtained in 77–96% yields in <20 min using TMSOTf as promoter. These results show that sonication provides rapid and efficient access to useful C-glycoside-based building blocks.

SnCl4- and TiCl4-Catalyzed Anomerization of Acylated O- and S-Glycosides: Analysis of Factors That Lead to Higher α:β Anomer Ratios and Reaction Rates

Co-reporter:Wayne Pilgrim and Paul V. Murphy

The Journal of Organic Chemistry 2010 Volume 75(Issue 20) pp:6747-6755

Publication Date(Web):September 13, 2010

DOI:10.1021/jo101090f

The quantification of factors that influence both rates and stereoselectivity of anomerization reactions catalyzed by SnCl4 and TiCl4 and how this has informed the synthesis of α-O- and α-S-glycolipids is discussed. The SnCl4-catalyzed anomerization reactions of β-S- and β-O-glycosides of 18 substrates followed first order equilibrium kinetics and kf + kr values were obtained, where kf is the rate constant for the forward reaction (β → α) and kr is the rate constant for the reverse reaction (α → β). Comparison of the kf + kr values showed that reactions of glucuronic acid or galacturonic acid derivatives were ∼10 to 3000 times faster than those of related glucoside and galactopyranoside counterparts and α:β ratios were generally also higher. Stereoelectronic effects contributed from galacto-configured compounds were up to 2-fold faster than those of corresponding glucosides. The introduction of groups, including protecting groups, which are increasingly electron releasing generally led to rate enhancements. The anomerization of S-glycosides was consistently faster than that of corresponding O-glycosides. Reactions were generally faster for reactions with TiCl4 than those with SnCl4. Anomeric ratios depended on the Lewis acid, the number equivalents of the Lewis acid, temperature, and substrate. Very high ratios of α-products for both O- and S-glucuronides were observed for reactions promoted by TiCl4; for these substrates TiCl4 was superior to SnCl4. Anomeric ratios from anomerization of S-glucosides were higher with SnCl4 than with TiCl4. The dependence of equilibrium ratio on Lewis acid and the number of equivalents of Lewis acid indicated that the equilibrium ratio is determined by a complex of the saccharide residue bound to the Lewis acid and not the free glycoside. The high α:β ratios observed for anomerization of both O- and S-glycuronic acids can be explained by coordination of the C-1 heteroatom and C-6 carbonyl group of the product to the Lewis acid, which would enhance the anomeric effect by increasing the electron-withdrawing ability of the anomeric substituent and lead to an increase in the proportion of the α-anomer. Such an observation would argue against the existence of a reverse anomeric effect. Support for a chelation-induced endocyclic cleavage mechanism for the anomerization is provided by the trapping of a key intermediate. The data herein will help predict the tendency of β-glycosides to undergo anomerization; this includes cases where 1,2-trans glycosides are initial products of glycosidation reactions catalyzed by TiCl4 or SnCl4.

Phenylenediamine-based bivalent glycocyclophanes: synthesis and analysis of the influence of scaffold rigidity and ligand spacing on lectin binding in cell systems with different glycomic profiles

Co-reporter:Sabine André, Trinidad Velasco-Torrijos, Rosaria Leyden, Sebastien Gouin, Manuela Tosin, Paul V. Murphy and Hans-Joachim Gabius

Organic & Biomolecular Chemistry 2009 vol. 7(Issue 22) pp:4715-4725

Publication Date(Web):23 Sep 2009

DOI:10.1039/B913010A

The conjugation of carbohydrates to synthetic scaffolds has the goal of preparing potent inhibitors of lectin binding. We herein report the synthesis of a panel of bivalent compounds (cyclophane and terephthalamide-derivatives) then used to establish the influence of scaffold flexibility on respective inhibitory potency in a medically relevant test system. Synthetic routes to two phenylenediamine-based glycocyclophanes involving Ugi reactions of glucuronic acid derivatives and subsequent ring closing metathesis are described, as are improvements for producing terephthalamide-based carbohydrate carriers. Assays were performed with human tumour cells measuring quantitatively the influence of the test compounds on fluorescent surface staining by labelled lectins. Biological evaluation using two different lines of cancer cells as well as cells with known alterations in the glycomic profile (cells treated with an inhibitor of glycan processing and a glycosylation mutant) reduced the risk of generating premature generalizations regarding inhibitor potency. Bioactivity relative to free mannose was invariably determined for the synthetic compounds. A clear trend for enhanced inhibitory properties for macrocyclic compounds compared to non-macrocyclic derivatives was discerned for one type of glycocyclophane. Herein we also document the impact of altering the spacing between the mannose residues, altering cell surface ligand density and cell-type reactivity. The applied strategy for the cell assays is proposed to be of general importance in the quest to identify medically relevant lectin inhibitors.

Synthesis of a constrained polyfunctional bicyclic iminocyclitol scaffold from l-sorbose via a tandem sequence including stereoselective intramolecular Huisgen cycloaddition

Co-reporter:Ciaran O’Reilly, Colin O’Brien, Paul V. Murphy

Tetrahedron Letters 2009 50(31) pp: 4427-4429

Publication Date(Web):

DOI:10.1016/j.tetlet.2009.05.060

Bi- to tetravalent glycoclusters presenting GlcNAc/GalNAc as inhibitors: from plant agglutinins to human macrophage galactose-type lectin (CD301) and galectins

Co-reporter:Sabine André, Shane O'Sullivan, Christiane Koller, Paul V. Murphy and Hans-Joachim Gabius

Organic & Biomolecular Chemistry 2015 - vol. 13(Issue 14) pp:NaN4203-4203

Publication Date(Web):2015/02/17

DOI:10.1039/C5OB00048C

Bi- to tetravalent glycoclusters: synthesis, structure–activity profiles as lectin inhibitors and impact of combining both valency and headgroup tailoring on selectivity

Co-reporter:Guan-Nan Wang, Sabine André, Hans-Joachim Gabius and Paul V. Murphy