Helen M I Osborn

Publications (17)52.6 Total impact

• Article: Synthesis and glycosidase inhibitory profiles of functionalised morpholines and oxazepanes.

  Peter A Burland, Helen M I Osborn, Andrea Turkson
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  ABSTRACT: In this work libraries of morpholines and oxazepanes have been prepared via the reductive amination reaction between dialdehydes, derived from carbohydrates, and a range of amines. In this way, functionalised morpholines and oxazepanes have been prepared that include N-alkylated derivatives, disaccharide analogues, and ester containing derivatives. The abilities of these functionalised morpholines and oxazepanes to inhibit a broad panel of glycosidase enzymes, that are associated with a range of diseases, have been probed and in this way new inhibitors of a range of glycosidases, but particularly β-d-galactosidase derived from Bovine kidney, have been discovered. N-Alkyl morpholines demonstrated the best inhibition profiles for this enzyme and derivatives (15a)-(15d) acted as non-competitive inhibitors with IC(50) values of 55.1-88.6 μM. Within this study, some preliminary structure-activity relationships are proposed, and it is demonstrated that N-substituted morpholines display better inhibitory profiles for the enzymes analysed than any of the N-substituted oxazepanes.
  Bioorganic & medicinal chemistry 07/2011; 19(18):5679-92. · 2.82 Impact Factor
• Article: Synthesis and biological evaluation of a polyglutamic acid-dopamine conjugate: a new antiangiogenic agent.

  Cristina Fante, Anat Eldar-Boock, Ronit Satchi-Fainaro, Helen M I Osborn, Francesca Greco
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  ABSTRACT: Dopamine has previously been shown to inhibit angiogenesis in vitro and in vivo, but its clinical applications in this context are severely limited by its short half-life. Here we report the synthesis of a polyglutamic acid-dopamine conjugate and show that conjugation significantly extends (from 1 to 24 h) dopamine's antiangiogenic activity in vitro and in vivo. These findings form the basis for the development of a new class of agents for the treatment of angiogenesis-dependent diseases.
  Journal of Medicinal Chemistry 06/2011; 54(14):5255-9. · 4.80 Impact Factor
• Article: Rapid synthesis of carbohydrate derivatives, including mimetics of C-linked disaccharides and C-linked aza disaccharides, using the hetero-Diels-Alder reaction.

  Peter A Burland, David Coisson, Helen M I Osborn
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  ABSTRACT: In this work we demonstrate the value of performing a hetero-Diels-Alder reaction (HDAR) between Danishefsky's diene and a range of aldehydes or imines, under microwave irradiation. By using a range of aldehydes and imines, including those derived from carbohydrates, access to functionalized 2,3-dihydro-4H-pyran-4-ones or 2,3-dihydro-4-pyridinones in good to excellent synthetic yields is possible. A particular strength of the methodology is its ability to access mimetics of C-linked disaccharides and C-linked aza disaccharides, targets of current therapeutic interest, in a rapid, convenient, and diastereoselective manner. The effect of high pressure on the HDARs involving carbohydrate-derived aldehydes and imines is also explored, with enhancement in yields occurring for the aldehyde substrates. Finally, HDARs using carbohydrate derived ketones, enones, and enals are described under a range of conditions. Optimum results were obtained under high-pressure conditions, with highly functionalized carbohydrate derivatives being afforded, in good yields, in this way.
  The Journal of Organic Chemistry 10/2010; 75(21):7210-8. · 4.45 Impact Factor
• Article: Tyrosinase activated melanoma prodrugs.

  Samaila Jawaid, Tariq H Khan, Helen M I Osborn, Nana Aba O Williams
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  ABSTRACT: Metastatic malignant melanoma remains a highly aggressive form of skin cancer for which no reliable methods for treatment exist. Given the increasing incidence of this cancer, considerable attention has focused on the development of new and improved methods for tackling this disease. Within this article, methods for treating melanoma are reviewed and discussed with particular attention focusing on prodrugs that are activated by the tyrosinase enzyme. This enzyme is up-regulated and is of elevated activity within malignant melanomas compared with healthy melanocytes, providing an ideal in-situ tool for the activation of melanoma prodrugs. By way of background to the prodrug strategies discussed within this review, the causes of melanoma, the enzymology of tyrosinase, and the chemistry of the biosynthetic pathways associated with melanogenesis are presented. Aspects of the design, mode of action, and biological profiles of key prodrugs that are activated by tyrosinase, and that show potential for the treatment of melanoma, are then presented and compared.
  Anti-cancer agents in medicinal chemistry 11/2009; 9(7):717-27.
• Article: Alterations in receptor binding properties of recent human influenza H3N2 viruses are associated with reduced natural killer cell lysis of infected cells.

  Rachel E Owen, Eriko Yamada, Catherine I Thompson, Louisa J Phillipson, Clare Thompson, Elizabeth Taylor, Maria Zambon, Helen M I Osborn, Wendy S Barclay, Persephone Borrow
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  ABSTRACT: Natural killer (NK) cell recognition of influenza virus-infected cells involves hemagglutinin (HA) binding to sialic acid (SA) on activating NK receptors. SA also acts as a receptor for the binding of influenza virus to its target host cells. The SA binding properties of H3N2 influenza viruses have been observed to change during circulation in humans: recent isolates are unable to agglutinate chicken red blood cells and show reduced affinity for synthetic glycopolymers representing SA-alpha-2,3-lactose (3'SL-PAA) and SA-alpha-2,6-N-acetyl lactosamine (6'SLN-PAA) carbohydrates. Here, NK lysis of cells infected with human H3N2 influenza viruses isolated between 1969 and 2003 was analyzed. Cells infected with recent isolates (1999 to 2003) were found to be lysed less effectively than cells infected with older isolates (1969 to 1996). This change occurred concurrently with the acquisition of two new potential glycosylation site motifs in HA. Deletion of the potential glycosylation site motif at 133 to 135 in HA1 from a recent isolate partially restored the agglutination phenotype to a recombinant virus, indicating that the HA-SA interaction is inhibited by the glycosylation modification. Deletion of either of the recently acquired potential glycosylation sites from HA led to increased NK lysis of cells infected with recombinant viruses carrying modified HA. These results indicate that alterations in HA glycosylation may affect NK cell recognition of influenza virus-infected cells in addition to virus binding to host cells.
  Journal of Virology 11/2007; 81(20):11170-8. · 5.40 Impact Factor
• Article: Neoglycolipid probes prepared via oxime ligation for microarray analysis of oligosaccharide-protein interactions.

  Yan Liu, Ten Feizi, María A Campanero-Rhodes, Robert A Childs, Yibing Zhang, Barbara Mulloy, Philip G Evans, Helen M I Osborn, Diana Otto, Paul R Crocker, Wengang Chai
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  ABSTRACT: Neoglycolipid technology is the basis of a microarray platform for assigning oligosaccharide ligands for carbohydrate-binding proteins. The strategy for generating the neoglycolipid probes by reductive amination results in ring opening of the core monosaccharides. This often limits applicability to short-chain saccharides, although the majority of recognition motifs are satisfactorily presented with neoglycolipids of longer oligosaccharides. Here, we describe neoglycolipids prepared by oxime ligation. We provide evidence from NMR studies that a significant proportion of the oxime-linked core monosaccharide is in the ring-closed form, and this form selectively interacts with a carbohydrate-binding protein. By microarray analyses we demonstrate the effective presentation with oxime-linked neoglycolipids of (1) Lewis(x) trisaccharide to antibodies to Lewis(x), (2) sialyllactose analogs to the sialic acid-binding receptors, siglecs, and (3) N-glycans to a plant lectin that requires an intact N-acetylglucosamine core.
  Chemistry & Biology 08/2007; 14(7):847-59. · 5.83 Impact Factor
• Article: Probing the receptor interactions of an H5 avian influenza virus using a baculovirus expression system and functionalised poly(acrylic acid) ligands.

  Wendy S Barclay, Ian M Jones, Helen M I Osborn, Louisa Phillipson, Junyuan Ren, Guadalupe A Talevera, Catherine I Thompson
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  ABSTRACT: Influenza viruses attach to host cells by binding to terminal sialic acid (Neu5Ac) on glycoproteins or glycolipids. Both the linkage of Neu5Ac and the identity of other carbohydrates within the oligosaccharide are thought to play roles in restricting the host range of the virus. In this study, the receptor specificity of an H5 avian influenza virus haemagglutinin protein that has recently infected man (influenza strain A/Vietnam/1194/04) has been probed using carbohydrate functionalised poly(acrylic acid) polymers. A baculovirus expression system that allows facile and safe analysis of the Neu5Ac binding specificity of mutants of H5 HA engineered at sites that are predicted to effect a switch in host range has also been developed.
  Bioorganic & Medicinal Chemistry 07/2007; 15(12):4038-47. · 2.92 Impact Factor
• Article: Analysis of chain and blood group type and branching pattern of sialylated oligosaccharides by negative ion electrospray tandem mass spectrometry.

  Wengang Chai, Vladimir E Piskarev, Barbara Mulloy, Yan Liu, Philip G Evans, Helen M I Osborn, Alexander M Lawson
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  ABSTRACT: We previously reported sequence determination of neutral oligosaccharides by negative ion electrospray tandem mass spectrometry on a quadrupole-orthogonal time-of-flight instrument with high sensitivity and without the need of derivatization. In the present report, we extend our strategies to sialylated oligosaccharides for analysis of chain and blood group types together with branching patterns. A main feature in the negative ion mass spectrometry approach is the unique double glycosidic cleavage induced by 3-glycosidic substitution, producing characteristic D-type fragments which can be used to distinguish the type 1 and type 2 chains, the blood group related Lewis determinants, 3,6-disubstituted core branching patterns, and to assign the structural details of each of the branches. Twenty mono- and disialylated linear and branched oligosaccharides were used for the investigation, and the sensitivity achieved is in the femtomole range. To demonstrate the efficacy of the strategy, we have determined a novel complex disialylated and monofucosylated tridecasaccharide that is based on the lacto-N-decaose core. The structure and sequence assignment was corroborated by methylation analysis and 1H NMR spectroscopy.
  Analytical Chemistry 04/2006; 78(5):1581-92. · 5.86 Impact Factor
• Article: New prodrugs derived from 6-aminodopamine and 4-aminophenol as candidates for melanocyte-directed enzyme prodrug therapy (MDEPT).

  Sarah Knaggs, Hugh Malkin, Helen M I Osborn, Nana Aba O Williams, Parveen Yaqoob
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  ABSTRACT: Two novel tyrosinase mediated drug delivery pathways have been investigated for the selective delivery of cytotoxic units to melanocytes from urea and thiourea prodrugs. The synthesis of these prodrugs is reported, as well as oximetry data that illustrate that the targets are substrates for tyrosinase. The stability of each of the prodrugs in (i) phosphate buffer and (ii) bovine serum is discussed, and the urea prodrugs are identified as lead candidates for further studies. Finally, HPLC studies and preliminary cytotoxicity studies in a melanotic and an amelanotic cell line, that illustrate the feasibility of the approach, are presented.
  Organic & Biomolecular Chemistry 12/2005; 3(21):4002-10. · 3.70 Impact Factor
• Article: Development of tyrosinase labile protecting groups for amines.

  Helen M I Osborn, Nana Aba O Williams
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  ABSTRACT: [reaction: see text] The development of two novel protecting groups for amines is described. Thus, a range of amines have been converted to ureas, and the deprotection of these upon exposure to mushroom tyrosinase (E.C. 1.14.18.1) has been demonstrated.
  Organic Letters 10/2004; 6(18):3111-3. · 5.86 Impact Factor
• Article: Carbohydrate-based therapeutics.

  Helen M I Osborn, Philip G Evans, Natasha Gemmell, Sadie D Osborne
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  ABSTRACT: In recent years there has been a resurgence of interest in the biological roles of carbohydrates and as a result it is now known that carbohydrates are involved in a vast array of disease processes. This review summarises progress in the development of carbohydrate-based therapeutics that involve: inhibition of carbohydrate-lectin interactions; immunisation, using monoclonal antibodies for carbohydrate antigens; inhibition of enzymes that synthesise disease-associated carbohydrates; replacement of carbohydrate-processing enzymes; targeting of drugs to specific disease cells via carbohydrate-lectin interactions; carbohydrate based anti-thrombotic agents.
  Journal of Pharmacy and Pharmacology 07/2004; 56(6):691-702. · 2.17 Impact Factor
• Article: Stereoselective entry to beta-linked C-disaccharides using a carbon-Ferrier reaction.

  Natasha Gemmell, Paul Meo, Helen M I Osborn
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  ABSTRACT: [structure: see text] The synthesis of unsaturated beta-linked C-disaccharides by the Lewis acid-mediated reaction of 3-O-acetylated glycals with monosaccharide-derived alkenes is described. Deprotection and selective hydrogenation of an exocyclic carbon-carbon double, in the presence of an endocyclic double bond, for representative targets is also illustrated.
  Organic Letters 06/2003; 5(10):1649-52. · 5.86 Impact Factor
• Article: Synthesis and analysis of urea and carbamate prodrugs as candidates for melanocyte-directed enzyme prodrug therapy (MDEPT).

  Allan M Jordan, Tariq H Khan, Hugh Malkin, Helen M I Osborn
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  ABSTRACT: The suitability of 4-di(2-chloroethyl)aminoanilino-4-hydroxyphenethylaminomethanone 2 to act as a prodrug for melanocyte-directed enzyme prodrug therapy (MDEPT) is assessed. Thus its synthesis, ability to generate a cytotoxic agent upon exposure to tyrosinase, and stability within different sera are reported. A comparison is made to illustrate that the new urea prodrug 2 is a more suitable candidate for MDEPT than the corresponding carbamate prodrug 1.
  Bioorganic & Medicinal Chemistry 09/2002; 10(8):2625-33. · 2.92 Impact Factor
• Article: Melanocyte-directed enzyme prodrug therapy (MDEPT): development of a targeted treatment for malignant melanoma

  Allan M. Jordan, Tariq H. Khan, Helen M.I. Osborn, Andrew Photiou, Patrick A. Riley
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  ABSTRACT: A novel prodrug rationally designed to function as a tyrosinase substrate has been synthesised to allow targeted treatment of malignant melanoma. This agent has been evaluated for tyrosinase-mediated drug release, and has been shown to act in the desired manner. Furthermore, differential cytotoxicity has been demonstrated in cell lines which express tyrosinase and those which do not.
  Bioorganic & Medicinal Chemistry.
• Article: Tyrosinase activated melanoma prodrugs

  Samaila Jawaid, Tariq H Khan, Helen M I Osborn, Nana O. A. Williams
  [show abstract] [hide abstract]
  ABSTRACT: Metastatic malignant melanoma remains a highly aggressive form of skin cancer for which no reliable methods for treatment exist. Given the increasing incidence of this cancer, considerable attention has focused on the development of new and improved methods for tackling this disease. Within this article, methods for treating melanoma are reviewed and discussed with particular attention focusing on prodrugs that are activated by the tyrosinase enzyme. This enzyme is up-regulated and is of elevated activity within malignant melanomas compared with healthy melanocytes, providing an ideal in-situ tool for the activation of melanoma prodrugs. By way of background to the prodrug strategies discussed within this review, the causes of melanoma, the enzymology of tyrosinase, and the chemistry of the biosynthetic pathways associated with melanogenesis are presented. Aspects of the design, mode of action, and biological profiles of key prodrugs that are activated by tyrosinase, and that show potential for the treatment of melanoma, are then presented and compared.
• Article: Synthesis and NMR spectroscopic analysis of 3-nitro-pyranoside, 3-nitro-septanoside and 4-nitro-septanoside derivatives by condensation of the anion of nitromethane with glycoside

  Helen M I Osborn, Andrea Turkson
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  ABSTRACT: The utility of the nitroaldol reaction for accessing 3-nitro-pyranoside, 3-nitro-septanoside or 4-nitro-septanoside derivatives, by reaction of the anion of nitromethane with glycoside dialdehydes is demonstrated. Initially, the feasibility of using unprotected glucoside dialdehydes was probed for the synthesis of the septanoside products, but this affoided pyranoside rather than septanoside targets. Subsequent studies utilised protected glycoside dialdehydes within the methodology, which allowed entry into a range of 3-nitro or 4-nitro-septanosides in good yield NMR spectroscopic analysis allowed determination of the stereochemistry of each of the products thus afforded.
• Article: Recent developments in polymer supported syntheses of oligosaccharides and glycopeptides

  Helen M.I. Osborn, Tariq H. Khan
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  ABSTRACT: A review of methods available for the polymer supported syntheses of oligosaccharides and glycopeptides is presented. The range of polymers and linkers, oligosaccharide assembly strategies, and analytical techniques employed in recent syntheses are described.
  Tetrahedron.