- Novel bisubstrate uridine-peptide analogues bearing a pyrophosphate bioisostere as inhibitors of human O-GlcNAc transferase
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Protein O-linked β-D-N-acetylglucosamine (O-GlcNAc) modification (O-GlcNAcylation), an essential post-translational as well as cotranslational modification, is the attachment of β-D-N-acetylglucosamine to serine and threonine residues of nucleocytoplasmic proteins. An aberrant O-GlcNAc profile on certain proteins has been implicated in metabolic diseases such as diabetes and cancer. Inhibitors of O-GlcNAc transferase (OGT) are valuable tools to study the cell biology of protein O-GlcNAc modification. In this study we report novel uridine-peptide conjugate molecules composed of an acceptor peptide covalently linked to a catalytically inactive donor substrate analogue that bears a pyrophosphate bioisostere and explore their inhibitory activities against OGT by a radioactive hOGT assay. Further, we investigate the structural basis of their activities via molecular modelling, explaining their lack of potency towards OGT inhibition.
- Ryan, Philip,Shi, Yun,von Itzstein, Mark,Rudrawar, Santosh
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- 4'-HALOGEN CONTAINING NUCLEOTIDE AND NUCLEOSIDE THERAPEUTIC COMPOSITIONS AND USES RELATED THERETO
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Disclosed are halogen containing nucleotide and nucleoside therapeutic compositions and uses related thereto. In certain embodiments, the disclosure relates to the treatment or prophylaxis of viral infections. Such viral infections can include tongaviridae, bunyaviridae, arenaviridae, coronaviridae, flaviviridae, picornaviridae, Eastern, Western, and Venezuelan Equine Encephalitis (EEE, WEE and VEE, respectively), Chikungunya fever (CHIK), Ebola, Influenza, RSV, and Zika virus infections.
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- Tightly linked morpholino-nucleoside chimeras: new, compact cationic oligonucleotide analogues
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The polyanionic phosphodiester backbone of nucleic acids contributes to high nuclease sensitivity and low cellular uptake and is therefore a major obstacle to the biological application of native oligonucleotides. Backbone modifications, particularly charge alterations is a proven strategy to provide artificial oligonucleotides with improved properties. Here, we describe the synthesis of a new type of oligonucleotide analogues consisting of a morpholino and a ribo- or deoxyribonucleoside in which the 5′-amino group of the nucleoside unit provides the nitrogen of the morpholine ring. The synthetic protocol is compatible with trityl and dimethoxytrityl protecting groups and azido functionality, and was extended to the synthesis of higher oligomers. The chimeras are positively charged in aqueous medium, due to theN-alkylated tertiary amine structure of the morpholino unit.
- Batta, Gyula,Bege, Miklós,Bereczki, Ilona,Borbás, Anikó,Debreczeni, Nóra,Herczeg, Mihály,Herczegh, Pál
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p. 8711 - 8721
(2021/10/22)
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- Deploying Fluorescent Nucleoside Analogues for High-Throughput Inhibitor Screening
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High-throughput small-molecule screening in drug discovery processes commonly rely on fluorescence-based methods including fluorescent polarization and fluorescence/F?rster resonance energy transfer. These techniques use highly accessible instrumentation; however, they can suffer from high false-negative rates and background signals, or might involve complex schemes for the introduction of fluorophore pairs. Herein we present the synthesis and application of fluorescent nucleoside analogues as the foundation for directed approaches for competitive binding analyses. The general approach describes selective fluorescent environment-sensitive (ES) nucleoside analogues that are adaptable to diverse enzymes that act on nucleoside-based substrates. We demonstrate screening a set of uridine analogues and development of an assay for fragment-based lead discovery with the TcdB glycosyltransferase (GT), an enzyme associated with virulence in Clostridium difficile. The uridine-based probe used for this high-throughput screen has a KD value of 7.2 μm with the TcdB GT and shows a >30-fold increase in fluorescence intensity upon binding. The ES-based probe assay is benchmarked against two other screening approaches.
- Seebald, Leah,Madec, Ama?l G. E.,Imperiali, Barbara
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p. 108 - 112
(2019/12/12)
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- Propargylglycine-based antimicrobial compounds are targets of TolC-dependent efflux systems in Escherichia coli
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A library of novel L-propargylglycine-based compounds were designed and synthesized with the goal of inhibiting the growth of Gram-negative bacteria by targeting LpxC, a highly conserved Gram-negative enzyme which performs an essential step in the lipid A biosynthetic pathway. These compounds were designed with and without a nucleoside and had varying tail structures, which modulate their lipophilicity. The synthetic scheme was improved compared to previous methods: a methyl ester intermediate was converted to a hydroxamic acid, which obviated the need for a THP protecting group and improved the yields and purity of the final compounds. Antimicrobial activity was observed for non-nucleoside compounds containing a phenyl propargyl ether tail (5) or a biphenyl tail (6). An MIC of 16 μg/mL was achieved for 6 in Escherichia coli, but inhibition was only possible in the absence of TolC-mediated efflux. Compound 5 had an initial MIC >160 μg/mL in E. coli. Enhancing outer membrane permeability or eliminating efflux reduced the MIC modestly to 100 μg/mL and 80 μg/mL, respectively. These results highlight the importance of hydrophobicity of this class of compounds in developing LpxC inhibitors, as well as the design challenge of avoiding multidrug efflux activity.
- Roldan, Bec J.,Pajarillo, Andrea O.,Greenberg, Jacob D.,Karlinsey, Joyce E.,Cafiero, Mauricio,Frawley, Elaine R.,Peterson, Larryn W.
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- Efficient synthesis and antifungal investigation of nucleosides’ quaternary ammonium salt derivatives
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Quaternary ammonium salts are a group of compounds with diverse biological properties, the most important of which are their antiviral, antibacterial, and antifungal activities. The quaternization reactions of 5'-O-tosyl derivatives of uridine and thymidine with triethylamine, trimethylamine, 4-(N,N-dimethylamino)pyridine, 2-methylpyridine, and pyridine are described in this article. Two of the synthesized compounds are exceptional because they are first of this type that demonstrate concentration-dependent antifungal in vitro activity against two species of the genus Candida in minimal YNB-SG medium. The experimental results have been extended by adding full atom molecular dynamics simulations and substrates and products energies evaluation.
- Dmochowska, Barbara,Pellowska-Januszek, Lucyna,Samaszko-Fiertek, Justyna,Slusarz, Rafal,Wakiec, Roland,Madaj, Janusz
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p. 157 - 171
(2019/05/16)
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- 4'-HALOGEN CONTAINING NUCLEOTIDE AND NUCLEOSIDE THERAPEUTIC COMPOSITIONS AND USES RELATED THERETO
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Disclosed are halogen containing nucleotide and nucleoside therapeutic compositions and uses related thereto. In certain embodiments, the disclosure relates to the treatment or prophylaxis of viral infections. Such viral infections can include tongaviridae, bunyaviridae, arenaviridae, coronaviridae, flaviviridae, picornaviridae, Eastern, Western, and Venezuelan Equine Encephalitis (EEE, WEE and VEE, respectively), Chikungunya fever (CHIK), Ebola, Influenza, RSV, and Zika virus infections.
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- Inhibition of: O -GlcNAc transferase (OGT) by peptidic hybrids
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O-GlcNAc transferase (OGT) attaches a GlcNAc moiety on specific substrate proteins using UDP-GlcNAc as the sugar donor. This modification can alter protein function by regulating cellular signaling and transcription pathways in response to altered nutrient availability and stress. Specific inhibitors of OGT would be valuable tools for biological studies and lead structures for therapeutics. The existing OGT inhibitors are mainly derived from the sugar donor substrate, but poor cell permeability and off-target effects limit their use. Here, we describe our progress on OGT inhibition based on substrate peptides identified by array screening. Subsequently, bisubstrate inhibitors were prepared by conjugating these peptides to uridine in various ways. In parallel, an in silico fragment screening was conducted to obtain small molecules targeting the UDP binding pocket. After evaluation of the initial hits, one of these small molecules was elaborated into a novel OGT hybrid inhibitor, as the replacement of uridine. The novel compounds inhibit OGT activity with IC50 values in the micromolar range.
- Zhang, Hao,Toma?i?, Tihomir,Shi, Jie,Weiss, Matjaz,Ruijtenbeek, Rob,Anderluh, Marko,Pieters, Roland J.
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supporting information
p. 883 - 887
(2018/05/31)
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- Design, modeling & synthesis of 1,2,3-triazole-linked nucleoside-amino acid conjugates as potential antibacterial agents
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Copper-catalyzed azide-alkyne cycloadditions (CuAAC or click chemistry) are convenient methods to easily couple various pharmacophores or bioactive molecules. A new series of 1,2,3- Triazole-linked nucleoside-amino acid conjugates have been designed and synthesized in 57-76% yields using CuAAC. The azido group was introduced on the 50-position of uridine or the acyclic analogue using the tosyl-azide exchange method and alkylated serine or proparylglycine was the alkyne. Modeling studies of the conjugates in the active site of LpxC indicate they have promise as antibacterial agents.
- Malkowski, Sarah N.,Dishuck, Carolyn F.,Lamanilao, Gene G.,Embry, Carter P.,Grubb, Christopher S.,Cafiero, Mauricio,Peterson, Larryn W.
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- A low-temperature, photoinduced thiol-ene click reaction: A mild and efficient method for the synthesis of sugar-modified nucleosides
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Sugar-modified nucleosides are prime synthetic targets in anticancer and antiviral drug development. Radical mediated thiol-ene coupling was applied for the first time on nucleoside enofuranoside derivatives to produce a broad range of thio-substituted d-ribo, -arabino, -xylo and l-lyxo configured pyrimidine nucleosides. In contrast to the analogous reactions of simple sugar exomethylenes, surprisingly, hydrothiolation of nucleoside alkenes under the standard conditions of various initiation methods showed low to moderate yields and very low stereoselectivity. Optimizing the reaction conditions, we have found that cooling the reaction mixture has a significant beneficial effect on both the conversion and the stereoselectivity, and UV-light initiated hydrothiolation of C2′-, C3′- and C4′-exomethylene derivatives of nucleosides at -80 °C proceeded in good to high yields, and, in most cases, in excellent diastereoselectivity. Beyond the temperature, the solvent, the protecting groups on nucleosides and, in some cases, the configuration of the thiols also affected the stereochemical outcome of the additions. The anomalous l-lyxo diastereoselectivity observed upon the addition of 1-thio-β-d-gluco- and galactopyranose derivatives onto C4′,5′-unsaturated uridines is attributed to steric mismatch between the d-ribo C4′-radical intermediates and the β-configured 1-thiosugars.
- Bege, Miklós,Bereczki, Ilona,Herczeg, Mihály,Kicsák, Máté,Eszenyi, Dániel,Herczegh, Pál,Borbás, Anikó
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p. 9226 - 9233
(2017/11/14)
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- A Modular Approach to Phosphoglycosyltransferase Inhibitors Inspired by Nucleoside Antibiotics
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Phosphoglycosyltransferases (PGTs) represent "gatekeeper" enzymes in complex glycan assembly pathways by catalyzing transfer of a phosphosugar from an activated nucleotide diphosphosugar to a membrane-resident polyprenol phosphate. The unique structures of selected nucleoside antibiotics, such as tunicamycin and mureidomycin A, which are known to inhibit comparable biochemical transformations, are exploited as the foundation for the development of modular synthetic inhibitors of PGTs. Herein we present the design, synthesis, and biochemical evaluation of two readily manipulatable modular scaffolds as inhibitors of monotopic bacterial PGTs. Selected compounds show IC50 values down to the 40 μm range, thereby serving as lead compounds for future development of selective and effective inhibitors of diverse PGTs of biological and medicinal interest.
- Walvoort, Marthe T. C.,Lukose, Vinita,Imperiali, Barbara
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p. 3856 - 3864
(2016/03/08)
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- A procedure for the preparation and isolation of nucleoside-5′-diphosphates
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Tris[bis(triphenylphosphoranylidene)ammonium] pyrophosphate (PPN pyrophosphate) was used in the SN2 displacements of the tosylate ion from 5′-tosylnucleosides to afford nucleoside-5′-diphosphates. Selective precipitation permitted the direct isolation of nucleoside-5′-diphosphates from crude reaction mixtures.
- Korhonen, Heidi J.,Bolt, Hannah L.,Hodgson, David R. W.
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supporting information
p. 469 - 472
(2015/06/08)
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- Parallel solution-phase synthesis and general biological activity of a uridine antibiotic analog library
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A small library of ninety four uridine antibiotic analogs was synthesized, under the Pilot Scale Library (PSL) Program of the NIH Roadmap initiative, from amine 2 and carboxylic acids 33 and 77 in solution-phase fashion. Diverse aldehyde, sulfonyl chloride, and carboxylic acid reactant sets were condensed to 2, leading after acid-mediated hydrolysis, to the targeted compounds 3-32 in good yields and high purity. Similarly, treatment of 33 with diverse amines and sulfonamides gave 34-75. The coupling of the amino terminus of d-phenylalanine methyl ester to the free 5′-carboxylic acid moiety of 33 followed by sodium hydroxide treatment led to carboxylic acid analog 77. Hydrolysis of this material gave analog 78. The intermediate 77 served as the precursor for the preparation of novel dipeptidyl uridine analogs 79-99 through peptide coupling reactions to diverse amine reactants. None of the described compounds show significant anticancer or antimalarial acivity. A number of samples exhibited a variety of promising inhibitory, agonist, antagonist, or activator properties with enzymes and receptors in primary screens supplied and reported through the NIH MLPCN program.
- Moukha-Chafiq, Omar,Reynolds, Robert C.
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p. 232 - 237
(2014/06/09)
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- Nine enzymes are required for assembly of the pacidamycin group of peptidyl nucleoside antibiotics
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Pacidamycins are a family of uridyl peptide antibiotics that inhibit the translocase MraY, an essential enzyme in bacterial cell wall biosynthesis that to date has not been clinically targeted. The pacidamycin structural skeleton contains a doubly inverted peptidyl chain with a β-peptide and a ureido linkage as well as a 3′-deoxyuridine nucleoside attached to DABA 3 of the peptidyl chain via an enamide linkage. Although the biosynthetic gene cluster for pacidamycins was identified recently, the assembly line of this group of peptidyl nucleoside antibiotics remained poorly understood because of the highly dissociated nature of the encoded nonribosomal peptide synthetase (NRPS) domains and modules. This work has identified a minimum set of enzymes needed for generation of the pacidamycin scaffold from amino acid and nucleoside monomers, highlighting a freestanding thiolation (T) domain (PacH) as a key carrier component in the peptidyl chain assembly as well as a freestanding condensation (C) domain (PacI) catalyzing the release of the assembled peptide by a nucleoside moiety. On the basis of the substrate promiscuity of this enzymatic assembly line, several pacidamycin analogues were produced using in vitro total biosynthesis.
- Zhang, Wenjun,Ntai, Ioanna,Bolla, Megan L.,Malcolmson, Steven J.,Kahne, Daniel,Kelleher, Neil L.,Walsh, Christopher T.
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p. 5240 - 5243
(2011/06/17)
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- Biosynthetic origin and mechanism of formation of the aminoribosyl moiety of peptidyl nucleoside antibiotics
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Several peptidyl nucleoside antibiotics that inhibit bacterial translocase I involved in peptidoglycan cell wall biosynthesis contain an aminoribosyl moiety, an unusual sugar appendage in natural products. We present here the delineation of the biosynthetic pathway for this moiety upon in vitro characterization of four enzymes (LipM-P) that are functionally assigned as (i) LipO, an l-methionine:uridine-5′-aldehyde aminotransferase; (ii) LipP, a 5′-amino-5′-deoxyuridine phosphorylase; (iii) LipM, a UTP:5-amino-5-deoxy-α-d-ribose-1-phosphate uridylyltransferase; and (iv) LipN, a 5-amino-5-deoxyribosyltransferase. The cumulative results reveal a unique ribosylation pathway that is highlighted by, among other features, uridine-5′-monophosphate as the source of the sugar, a phosphorylase strategy to generate a sugar-1-phosphate, and a primary amine-requiring nucleotidylyltransferase that generates the NDP-sugar donor.
- Chi, Xiuling,Pahari, Pallab,Nonaka, Koichi,Van Lanen, Steven G.
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p. 14452 - 14459
(2011/11/04)
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- Biogenesis of the unique 4′,5′-dehydronucleoside of the uridyl peptide antibiotic pacidamycin
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The pacidamycins belong to a class of antimicrobial nucleoside antibiotics that act by inhibiting the clinically unexploited target translocase I, a key enzyme in peptidoglycan assembly. As with other nucleoside antibiotics, the pacidamycin 4′,5′-dehydronucleoside portion is an essential pharmacophore. Here we show that the biosynthesis of the pacidamycin nucleoside in Streptomyces coeruleorubidus proceeds through three steps from uridine. The transformations involve oxidation of the 5′-alcohol by Pac11, transamination of the resulting aldehyde by Pac5, and dehydration by the Cupin-domain protein Pac13.
- Ragab, Amany E.,Grueschow, Sabine,Tromans, Daniel R.,Goss, Rebecca J. M.
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p. 15288 - 15291
(2011/11/11)
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- Synthesis and biological activities of novel s-triazine bridged dinucleoside analogs
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A series of novel dinucleosides linked by s-triazine were synthesized via the nucleophilic substitution reaction of amino nucleoside and cyanuric chloride in THF/H2O. The biological activities of these novel dinucleoside analogs against HIV-RT, HeLa and A-549 cell lines in vitro were evaluated. Copyright
- Shen, Fengjuan,Li, Xiaoliu,Zhang, Xiaojuan,Qin, Zhanbin,Yin, Qingmei,Chen, Hua,Zhang, Jinchao
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p. 1205 - 1210
(2012/03/26)
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- Oligonucleotide analogues with integrated bases and backbones. Part 24: Synthesis, conformational analysis, and association of aminomethylene-linked self-complementary adenosine and uridine dinucleosides
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Inspection of Maruzen models and force-field calculations suggest that oligonucleotide analogues integrating backbone and bases (ONIBs) with an aminomethylene linker form similar cyclic duplexes as the analogous oxymethylene linked dinucleosides. The self
- Chiesa, Katja,Shvoryna, Alyena,Bernet, Bruno,Vasella, Andrea
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scheme or table
p. 668 - 691
(2010/07/07)
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- Inhibition of Escherichia coli glycosyltransferase MurG and Mycobacterium tuberculosis Gal transferase by uridine-linked transition state mimics
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Glycosyltransferase MurG catalyses the transfer of N-acetyl-d-glucosamine to lipid intermediate I on the bacterial peptidoglycan biosynthesis pathway, and is a target for development of new antibacterial agents. A transition state mimic was designed for MurG, containing a functionalised proline, linked through the α-carboxylic acid, via a spacer, to a uridine nucleoside. A set of 15 functionalised prolines were synthesised, using a convergent dipolar cycloaddition reaction, which were coupled via either a glycine, proline, sarcosine, or diester linkage to the 5′-position of uridine. The library of 18 final compounds were tested as inhibitors of Escherichia coli glycosyltransferase MurG. Ten compounds showed inhibition of MurG at 1 mM concentration, the most active with IC50 400 μM. The library was also tested against Mycobacterium tuberculosis galactosyltransferase GlfT2, and one compound showed effective inhibition at 1 mM concentration.
- Trunkfield, Amy E.,Gurcha, Sudagar S.,Besra, Gurdyal S.,Bugg, Timothy D.H.
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scheme or table
p. 2651 - 2663
(2010/06/16)
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- Probing replacement of pyrophosphate via click chemistry; synthesis of UDP-sugar analogues as potential glycosyl transferase inhibitors
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A series of potential UDP-sugar mimics were readily synthesised by copper(I) catalysed modified Huisgen cycloaddition of the corresponding α-propargyl glycosides with 5-azido uridine in aqueous solution. None of the compounds accessed displayed significant inhibitory activity at concentrations of up to 4.5 mM in an assay against bovine milk β-1,4-galactosyltransferase.
- Yeoh, Kar Kheng,Butters, Terry D.,Wilkinson, Brendan L.,Fairbanks, Antony J.
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scheme or table
p. 586 - 591
(2009/05/11)
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- Synthesis of 1-C-linked diphosphate analogues of UDP-N-Ac-glucosamine and UDP-N-Ac-muramic acid
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UDP-N-acetyl-glucosamine and UDP-N-acetyl-muramic acid are two important cytoplasmic precursors of bacterial peptidoglycan. The convergent synthesis of their analogues is reported. The α-1-C-linked-N-acetyl-glucosamine was synthesized using microwave-assisted Keck radical allylation. Oxidation of alkene derivatives to the corresponding carboxylic acids allowed attachment to O- and N-sulfamoyluridine giving stable diphosphate mimetics.
- Babi?, Andrej,Gobec, Stanislav,Gravier-Pelletier, Christine,Le Merrer, Yves,Pe?ar, Slavko
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p. 9093 - 9100
(2008/12/22)
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- Oligonucleotide analogues with integrated bases and backbone Part 17 1. Conformational analysis and association of ethylene-, oxymethylene-, and thiomethylene-linked self-complementary adenosine and uridine dimers
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The formation of cyclic duplexes (pairing) of known oxymethylene-linked self-complementary U*[o]A(*) dinucleosides contrasts with the absence of pairing of the ethylene-linked U*[ca]A(*) analogues. The origin of this difference, and the expected association of U*[x]A(*) and A*[x]U(*) dinucleosides with x=CH 2, O, or S was analysed. According to this analysis, pairing occurs via constitutionally isomeric Watson - Crick, reverse Watson - Crick, Hoogsteen, or reverse Hoogsteen H-bonded linear duplexes. Each one of them may give rise to three diastereoisomeric cyclic duplexes, and each one of them can adopt three main conformations. The relative stability of all conformers with x=CH 2, O, or S were analysed. U*[x]A(*) dinucleosides with x=CH2 do not form stable cyclic duplexes, dinucleosides with x=O may form cyclic duplexes with a gg-conformation about the C(4′)-C(5′) bond, and dinucleosides with x=S may form cyclic duplexes with a gt-conformation about this bond. The temperature dependence of the chemical shift of H-N(3) of the self-complementary, oxymethylene-linked U*[o]A(*) dinucleosides 1-6 in CDCl3 in the concentration range of 0.4-50 mM evidences equilibria between the monoplex, mainly linear duplexes, and higher associates for 3, between the monoplex and cyclic duplexes for 6, and between the monoplex, linear, and cyclic duplexes as well as higher associates for 1, 2, 4, and 5. The self-complementary, thiomethylene-linked U*[s]A(*) dinucleosides 27-32 and the sequence isomeric A*[s]U(*) analogues 33-38 were prepared by S-alkylation of the 6-(mesyloxymethyl)uridine 12 and the 8-(bromomethyl)adenosine 22. The required thiolates were prepared in situ from the C(5′)-acetylthio derivatives 9, 15, 19, and 25. The association in CHCl3 of the thiomethylene-linked dinucleoside analogues was studied by 1H-NMR and CD spectroscopy, and by vapour-pressure osmometric determination of the apparent molecular mass. The U*[s]A(*) alcohols 28, 30, and 31 form cyclic duplexes connected by Watson - Crick H-bonds, while the fully protected dimers 27 and 29 form mainly linear duplexes and higher associates. The diol 32 forms mainly cyclic duplexes in solution and corrugated ribbons in the solid state. The nucleobases of crystalline 32 form reverse Hoogsteen H-bonds, and the resulting ribbons are cross-linked by H-bonds between HOCH 2-C(8/I) and N(3/I). Among the A*[s]U(*) dimers, only the C(8/I)-hydroxymethylated 37 forms (mainly) a cyclic duplex, characterized by reverse Hoogsteen base pairing. The dimers 34-36 form mainly linear duplexes and higher associates. Dimers 34 and particularly 38 gelate CHCl3. Temperature-dependent CD spectra of 28, 30, 31, and 37 evidence π-stacking in the cyclic duplexes. Base stacking in the particularly strongly associating diol 32 in CHCl3 solution is evidenced by a melting temperature of ca. 2°.
- Ritter, Anne,Egli, Daniel,Bernet, Bruno,Vasella, Andrea
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experimental part
p. 673 - 714
(2009/02/07)
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- Novel chalcogenides of thymidine and uridine: synthesis, properties and applications
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A facile and efficient methodology has been developed for the synthesis of dithymidine and di-uridine derived disulfides using benzyltriethylammonium tetrathiomolybdate as a sulfur transfer reagent. However, a similar reaction of thymidine derivative with tetraethylammonium tetraselenotungstate as a selenium transfer reagent resulted in the formation of an unexpected cyclic diselenide. The disulfide derivatives of nucleosides have been used as precursors in a tandem disulfide cleavage-Michael addition/ring opening reactions to construct aminoacid and carbocyclic derivatives of nucleosides.
- Sivapriya, Kirubakaran,Suguna, Perumal,Shubashree,Sridhar, Perali Ramu,Chandrasekaran, Srinivasan
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p. 1151 - 1158
(2008/02/02)
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- A search for pyrophosphate mimics for the development of substrates and inhibitors of glycosyltransferases
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The design and synthesis of several β-1,4-galactosyltransferase inhibitors are reported. Mimics of the pyrophosphate-Mn2+ complex were the focus of the design. Malonic, tartaric, and monosaccharide moieties were used as replacements of the pyrophosphate moiety, and galactose or azasugars with potent galactosidase inhibitory activity were used as the 'donor' component. Compound 6, in which glucose was used as the pyrophosphate-Mn2+ complex mimic and galactose as the 'donor' component, showed the best inhibitory activity towards the transferase with a K(i) of 119.6 μM.
- Wang, Ruo,Steensma, Darryl H.,Takaoka, Yoshikazu,Yun, Joanne W.,Kajimoto, Tetsuya,Wong, Chi-Huey
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p. 661 - 672
(2007/10/03)
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