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Browsing Chemistry publications by Author "Abell, A."
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Item Metadata only 1,2,3-triazoles in peptidomimetic chemistry(Wiley-V C H Verlag GMBH, 2011) Pedersen, D.; Abell, A.The ability to synthesise small peptidomimetics that mimic the secondary structure of proteins is an ever expanding area of research directed at sourcing new medicinal agents and biological probes. A significant current challenge is to mimic protein epitopes under physiological conditions using small peptidomimetics that are easy to prepare. The copper- and ruthenium-catalysed Huisgen cycloaddition reactions provide such a general synthetic method, with the resulting 1,2,3-triazoles being good peptide bond mimics. The ability to prepare both 1,4- and 1,5-substituted 1,2,3-triazoles under these chemically benign conditions provides both “linear” and “bent” peptidomimetics. Examples of the use of 1,2,3-triazoles to define the geometry and properties of a peptidomimetic abound. This review highlights such successes but also describes a number of failures in order to guide and inspire future efforts of chemists in this area.Item Metadata only 1,2,3-Triazolyl amino acids as AMPA receptor ligands(Pergamon-Elsevier Science Ltd, 2010) Stanley, N.; Pedersen, D.; Nielsen, B.; Kvist, T.; Mathiesen, J.; Brauner-Osborne, H.; Taylor, D.; Abell, A.The central nervous system glutamate receptors are an important target for drug discovery. Herein we report initial investigations into the synthesis and glutamate receptor activity of 1,2,3-triazolyl amino acids. Two compounds were found to be selective AMPA receptor ligands, which warrant further investigation.Item Open Access A controllable mechanistic transition of charge transfer in helical peptides: from hopping to superexchange(Royal Society of Chemistry, 2017) Yu, J.,; Horsley, J.; Abell, A.Understanding the electronic properties inherent to peptides is crucial for controlling charge transfer, and precursory to the design and fabrication of bio-inspired next generation electronic components. However, to achieve this objective one must first be able to predict and control the associated charge transfer mechanisms. Here we demonstrate for the first time a controllable mechanistic transition in peptides resulting directly from the introduction of a side-bridge. High level computational studies on two similar 3₁₀-helical hexapeptides, one further constrained into this geometry by linking the i to i + 3 residues with a lactam side-bridge, highlight the effects of the bridge on electron transfer parameters, i.e. thermodynamic driving forces, reorganization energies, and electronic coupling factors. The additional backbone rigidity imparted by the bridge significantly alters the molecular dynamics of the peptide to such an extent as to induce a mechanistic transition from hopping in the linear peptide, to superexchange in the constrained peptide. This exciting finding not only advances our fundamental knowledge of the mechanisms governing charge transfer in peptides, but also reveals novel approaches to design and develop new functional devices that are tailored for applications in molecular electronics.Item Metadata only A Convenient Method for the Synthesis of Dehydroquinic Acid(Marcel Dekker Inc, 2003) Le Sann, C.; Abell, C.; Abell, A.A convenient synthesis of dehydroquinic acid and its corresponding methyl ester are described. Protection of the trans diol of quinic acid, followed by PCC oxidation, gave fully protected dehydroquinic acid. This gave methyl dehydroquinate on mild acid catalyzed hydrolysis. Ester hydrolysis then gave potassium dehydroquinate which was treated with amberlite to afford dehydroquinic acid.Item Metadata only A diastereoselective synthesis of the tetrahydropyridazinone core of 2-oxo-1,6-diazobicyclo[4.3.0]nonane-9-carboxylate-based peptidomimetics starting from (S)-phenylalanine(Pergamon-Elsevier Science Ltd, 2003) Gardiner, J.; Abell, A.A diastereoseletvive synthesis of a peptidic tetrahydropyridazinone 10 from (S)-phenylalanine is reported. This derivative was then converted to the bicyclic peptidomimetic 11, an important class of β-strand mimetic. © 2003 Elsevier Science Ltd. All rights reserved.Item Metadata only A new metabotropic glutamate receptor agonist with in vivo anti-allodynic activity(Pergamon-Elsevier Science, 2010) Stanley, N.; Hutchinson, M.; Kvist, T.; Nielsen, B.; Mathiesen, J.; Brauner-Osborne, H.; Avery, T.; Tiekink, E.; Pedersen, D.; Irvine, R.; Abell, A.; Taylor, D.As part of the vital search towards improved therapeutic agents for the treatment of neuropathic pain, the central nervous system glutamate receptors have become a major focus of research. Outlined herein are the syntheses of two new biologically active 3'-cycloalkyl-substituted carboxycyclopropylglycines, utilizing novel synthetic chemistry. The reaction between substituted 1,2-dioxines and an aminophosphonate furnished the cyclopropane core in a single step with all required stereochemistry of pendant groups. In vitro binding assays at metabotropic glutamate receptors revealed selective activity. In vivo testing in a rodent model of neuropathic pain indicated one amino acid significantly and dose-dependently decreased mechanical allodynia.Item Metadata only A simple method for the preparation of 3-hydroxyiminodehydroquinate, a potent inhibitor of type II dehydroquinase(Royal Society of Chemistry, 2002) Le Sann, C.; Abell, C.; Abell, A.A number of routes to 3-hydroxyiminodehydroquinate 4, one of the most potent inhibitors of type II dehydroquinase that is currently known, have been investigated. Methods based on the existing literature synthesis, i.e. oxime formation of a suitably C-4 and C-5 protected methyl 3-dehydroquinate derivative were initially studied. Benzoyl protection as in 11 did give the desired product but in low overall yield. An alternative BBA protection strategy starting with 7 was successful in generating a C-4/C-5 analogue of the desired oxime 4 in high yield. Further investigation revealed that it was unnecessary to protect the dehydroquinate precursor, hence the potassium salt corresponding to oxime 4 was simply synthesised as a single isomer from methyl dehydroquinate 10.Item Metadata only A study on the diastereoselective synthesis of α-fluorinated β³-amino acids by α-fluorination(Wiley-V C H Verlag GMBH, 2012) Peddie, V.; Abell, A.AbstractThe treatment of a β3‐amino acid methyl ester with 2.2 equiv. of lithium diisopropylamide (LDA), followed by reaction with 5 equiv. of N‐fluorobenzenesulfonimide (NFSI) at −78° for 2.5 h and then 2 h at 0°, gives syn‐fluorination with high diastereoisomeric excess (de). The de and yield in these reactions are somewhat influenced by both the size of the amino acid side chain and the nature of the amine protecting group. In particular, fluorination of N‐Boc‐protected β3‐homophenylalanine, β3‐homoleucine, β3‐homovaline, and β3‐homoalanine methyl esters, 5 and 9–11, respectively, all proceeded with high de (>86% of the syn‐isomer). However, fluorination of N‐Boc‐protected β3‐homophenylglycine methyl ester (16) occurred with a significantly reduced de. The use of a Cbz or Bz amine‐protecting group (see 3 and 15) did not improve the de of fluorination. However, an N‐Ac protecting group (see 17) gave a reduced de of 26%. Thus, a large N‐protecting group should be employed in order to maximize selectivity for the syn‐isomer in these fluorination reactions.Item Metadata only An amino acid N-derivatising group that can be coloured on demand(Pergamon-Elsevier Science Ltd, 2002) Abell, A.; Martyn, D.; May, B.; Nabbs, B.A method is presented whereby an amino acid is reacted with 5-formyl-1H-pyrrole-2-carboxylic acid to give an N-derivatised tag that has a latent ability to be coloured. A characteristic red pyrrolizin-3-one (coloured tag) is then revealed on treatment with hydrocinnamoyl chloride. This sequence has been carried out on amino acids in solution, and on solid phase, and also on dipeptides. A method is presented whereby an amino acid is reacted with 5-formyl-1H-pyrrole-2-carboxylic acid to give an N-derivatised tag that has a latent ability to be coloured.Item Metadata only Azobenzene-containing photoswitchable proteasome inhibitors with selective activity and cellular toxicity(Elsevier, 2017) Blanco, B.; Palasis, K.; Adwal, A.; Callen, D.; Abell, A.Abstract not availableItem Metadata only Biosynthetically guided structure-activity relationship studies of Merochlorin A, an antibiotic marine natural product(Wiley, 2017) López-Pérez, B.; Pepper, H.; Ma, R.; Fawcett, B.; Pehere, A.; Wei, Q.; Ji, Z.; Polyak, S.; Dai, H.; Song, F.; Abell, A.; Zhang, L.; George, J.The onset of new multidrug-resistant strains of bacteria demands continuous development of antibacterial agents with new chemical scaffolds and mechanisms of action. We present the first structure-activity relationship (SAR) study of 16 derivatives of a structurally novel antibiotic merochlorin A that were designed using a biosynthetic blueprint. Our lead compounds are active against several Gram-positive bacteria such as Staphylococcus aureus (SA), methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus faecium (VRE) and Bacillus subtilis, inhibit intracellular growth of Mycobacterium bovis, and are relatively nontoxic to human cell lines. Furthermore, derivative 12 c {(±)-(3aR,4S,5R,10bS)-5-bromo-7,9-dimethoxy-4-methyl-4-(4-methylpent-3-en-1-yl)-2-(propan-2-ylidene)-1,2,3,3a,4,5-hexahydro-6H-5,10b-methanobenzo[e]azulene-6,11-dione} was found to inhibit the growth of Bacillus Calmette-Guérin (BCG)-infected cells at concentrations similar to rifampicin. These results outperform the natural product, underscoring the potential of merochlorin analogues as a new class of antibiotics.Item Metadata only Calpain inhibitors and compositions(2006) Abell, A.; Neffe, A.; Stuart, B.; Lee, H.; Morton, J.; Coxon, J.; Nikkel, J.; Robertson, L.; Jones, M.; Muir, M.; Bickerstaffe, R.; Miyamoto, S.; Aitken, S.Disclosed are compounds that inhibit calpains of formula I wherein X is NH, O or S and all other substituents are as described in the specification. The process for their production, and use in pharmaceutical compositions and in the treatment of prophylaxis of a disease or disorder resulting from excessive calpain activity is also disclosed.Item Metadata only Calpains: Attractive targets for the development of synthetic inhibitors(Bentham Science Publ Ltd, 2010) Pietsch, M.; Chua, K.; Abell, A.The physiological roles of calpains are discussed, as are the associated pathological disorders that result from their over-activation. We also present practical information for establishing functional inhibition assays and an overview of X-ray crystal structures of calpain-inhibitor complexes to aid inhibitor design. These structures reveal the expected extended β-strand conformation for the inhibitor backbone, a geometry that has been engineered into inhibitors with the introduction of either an N-terminal heterocycle or a macrocycle that links the P1 and P3 residues. The structure and function of all the main classes of inhibitors are reviewed, with most examples being classified according to the nature of the C-terminal reactive warhead group that reacts with the active site cysteine of calpains. These inhibitor classes include epoxysuccinate derivatives, aldehydes, aldehyde prodrugs (hemiacetals) and α-keto carbonyl compounds. Inhibitors derived from the endogenous inhibitor calpastatin and examples lacking a warhead, are now known and these are also discussed.Item Metadata only Compounds and compositions(2006) Abell, A.; Neffe, A.; Stuart, B.; Lee, H.; Morton, J.; Coxon, J.; Nikkel, J.; Duncan, J.; Robertson, L.; Jones, M.; Muir, M.; Klanchantra, M.; Bickerstaffe, R.; McNabb, S.; Aitken, S.Item Metadata only Conformationally constrained beta-amino acids(KENES INT, 2004) Anderson, K.; Gardiner, J.; Abell, A.; International Peptide Symposium & European Peptide Symposium (3rd & 28th : 2004 : Prague, Czech Republic); Flegel, M.; Fridkin, M.; Gilon, C.; Slaninova, J.Item Metadata only Cross metathesis of nitrogen-containing systems(Aldrich Chemical Co Inc, 2003) Vernall, A.; Abell, A.AbstractFor Abstract see ChemInform Abstract in Full Text.Item Metadata only Cross-metathesis and ring-closing metathesis reactions of amino acid-based substrates(Pergamon-Elsevier Science Ltd, 2008) Vernall, A.; Ballet, S.; Abell, A.Olefin tethers of variable length, introduced into a natural amino acid (side-chain of Ser, Cys; N-terminus of Arg; C-terminus of Phe and Tic; and in both the side-chain and either the N- or C-terminus of Ser, Cys and Tyr), undergo metathesis on treatment with Grubbs' second generation catalyst. Side-chain linked dimers of Ser, Cys and Tyr were obtained by cross-metathesis, while olefin installation at the N- and C-terminus led to dimers of Arg and Phe (or Tic), respectively. Ring-closing metathesis of the doubly alkenylated derivatives of Ser, Cys and Tyr gave 12-, 20- and 24-membered macrocycles. © 2008 Elsevier Ltd. All rights reserved.Item Metadata only Cross-metathesis coupling of sugars and fatty acids to lysine and cysteine(Royal Soc Chemistry, 2004) Vernall, A.; Abell, A.Attachment of an olefin tether to the side chain of either lysine or cysteine allows cross metathesis (CM) conjugation with olefin-containing sugar and fatty acid analogues.Item Metadata only Design and synthesis of a conformationally restricted trans peptide isostere based on the bioactive conformations of saquinavir and nelfinavir(Amer Chemical Soc, 2001) Edmonds, M.; Abell, A.The design and synthesis of a new peptide isostere which contains a trans alkene core is described. The key step involves a Wadsworth-Emmons reaction between chiral aldehyde (2S)-9a and chiral phosphonate 7 under base-sensitive conditions to give a chiral enone (2R)-24a which was reduced to afford the desired trans alkene isosteres (2R,5R)-6a and (2R,5S)-6b (Scheme 6). A potential application of this isostere in the synthesis of HIV protease inhibitors is also discussed.Item Metadata only Design and synthesis of aromatic inhibitors of anthranilate synthase(Royal Soc Chemistry, 2005) Payne, R.; Bulloch, E.; Abell, A.; Abell, C.Anthranilate synthase catalyses the conversion of chorismate to anthranilate, a key step in tryptophan biosynthesis. A series of 3-(1-carboxy-ethoxy) benzoic acids were synthesised as chorismate analogues, with varying functionality at C-4, the position of the departing hydroxyl group in chorismate. Most of the compounds were moderate inhibitors of anthranilate synthase, with inhibition constants between 20–30 μM. The exception was 3-(1-carboxy-ethoxy) benzoic acid, (C-4 = H), for which K₁ = 2.4 μM. These results suggest that a hydrogen bonding interaction with the active site general acid (Glu309) is less important than previously assumed for inhibition of the enzyme by these aromatic chorismate analogues.