- 5',6'-Nucleoside phosphonate analogues architecture: Synthesis and comparative evaluation towards metabolic enzymes
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Nucleoside phosphonates have been designed as stable 5'-mononucleotide mimics and are nowadays considered a potent class of antiviral agents. Within cells, they must be metabolised to the corresponding diphosphate to exert their biological activity. In this process, the first phosphorylation step, catalysed by nucleoside monophosphate kinases (NMP kinases), has been proposed as a bottleneck. Herein, we report the synthesis of a series of ribonucleoside phosphonate derivatives isosteric to 5'-mononucleotides, with different degrees of flexibility within the 5',6'-C-C bond, as well as different polarities, through the introduction of hydroxy groups. The influence of these modifications on the capacity of the compounds to act as substrates for appropriate human NMP kinases, involved in nucleic acids metabolism, has been investigated. Low flexibility, as well as an absence of hydroxy groups within the ribose-phosphorus architecture, is critical for efficient phosphotransfer. Among the series of pyrimidine analogues, one derivative was shown to be phosphorylated by human UMP-CMP kinase, with rates similar to those of dUMP and even better than dCMP. Mimicking nature: A series of ribonucleoside phosphonate analogues were synthesized, and among them, a pyrimidine derivative was shown to be phosphorylated by hUMP-CMP kinase, with rates similar to those of dUMP and even better than dCMP. Furthermore, one purine derivative was found to be phosphorylated by hAMP kinases1 and2 with improved efficiency over tenofovir.
- Gallier, Franck,Alexandre, Julie A. C.,ElAmri, Chahrazade,Deville-Bonne, Dominique,Peyrottes, Suzanne,Perigaud, Christian
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- Synthesis and utility of novel C-meso-glycosylated metalloporphyrins
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Novel hybrid porphyrins bearing two and four suitably protected glycosidic units appended at the meso positions of the central macrocycle through robust carbon-carbon bonds have been constructed and characterized. Metallation of these constructs with certain bivalent metal ions then produced a series of porphyrinato entities which had all the sugar protecting groups removed to arrive at the corresponding water soluble porphyrin-sugar hybrid species. It is noteworthy that two palladium derivatives, compounds 6 and 10, proved to be efficient reagents for the selective cleavage of double strand DNA into form II nicked circular DNA upon exposure to visible light at room temperature in aqueous media. (C) 2000 Elsevier Science Ltd.
- Cornia, Mara,Menozzi, Monica,Ragg, Enzio,Mazzini, Stefania,Scarafoni, Alessio,Zanardi, Franca,Casiraghi, Giovanni
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- Flexible nucleobase receptor - Effect of self-preorganization of artificial receptor
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A new type flexible receptor which has two uracil moieties connected with a long alkyl chain was synthesized and its molecular recognition ability toward adenine derivatives was investigated. The present receptor shows equilibrium between two states, open and close forms. In contrast to the open form, the closed form exhibits enthalpically less favorable but entropically more favorable molecular recognition toward adenine derivatives. This observation is rationally explained by the effect of self-preorganization of the present receptor.
- Kuroda, Yasuhisa,Lintuluoto, Juha M.,Ogoshi, Hisanobu
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- 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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- Rapid Synthesis of a Natural Product-Inspired Uridine Containing Library
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The preparation of natural product-inspired nucleoside analogs using solution-phase parallel synthesis is described. The key intermediates containing alkyne and N-protected amino moieties were developed to allow for further skeleton and substituent diversity using click chemistry and urea or amide bond formation. Rapid purification was accomplished using solid-phase extraction. The obtained library comprised 80 molecules incorporating two diversity positions and one chiral center, each of which was efficiently prepared in good purity and acceptable overall yield. A bacterial morphology study was also performed.
- Chen, Wei-An,Cheng, Wei-Chieh,Hu, Kung-Hsiang,Lin, Yan-Ting,Liu, Wan-Ju,Lo, Lee-Chiang,Tan, Yee-Ling
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- A Simple Conversion of 5-Cyanouridine into Uridine
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2',3'-O-Isopropylideneuridine (4) was prepared in high yield from 5-cyano-2',3'-O-isopropylideneuridine (2) by the action of sodium dithionite in aqueous sodium hydrogen carbonate.
- Mincher, David J.,Shaw, Gordon
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- Effect of uridine protecting groups on the diastereoselectivity of uridine-derived aldehyde 5’-alkynylation
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The 5′-alkynylation of uridine-derived aldehydes is described. The addition of alkynyl Grignard reagents on the carbonyl group is significantly influenced by the 2′,3′-di-O-protecting groups (R1): O-alkyl groups led to modest diastereoselectivities (65:35) in favor of the 5′R-isomer, whereas O-silyl groups promoted higher diastereoselectivities (up to 99:1) in favor of the 5′S-isomer. A study related to this protecting group effect on the diastereoselectivity is reported.
- Othman, Raja Ben,Fer, Micka?l J.,Le Corre, Laurent,Calvet-Vitale, Sandrine,Gravier-Pelletier, Christine
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- Synthesis and antibacterial activity of 5′-tetrachlorophthalimido and 5′-azido 5′-deoxyribonucleosides
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Reported is an efficient synthesis of adenyl and uridyl 5′-tetrachlorophthalimido-5′-deoxyribonucleosides, and guanylyl 5′-azido-5′-deoxyribonucleosides, which are useful in solid-phase synthesis of phosphoramidate and ribonucleic guanidine oligonucleotides. Replacement of 5′-hydroxyl with tetrachlorophthalimido group was performed via Mitsunobu reaction for adenosine and uridine. An alternative method was applied for guanosine which replaced the 5′-hydroxyl with an azido group. The resulting compounds were converted to 5′-amino-5′-deoxyribonucleosides for oligonucleotide synthesis. Synthetic intermediates were tested as antimicrobials against six bacterial strains. All analogs containing the 2′,3′-O-isopropylidine protecting group demonstrated antibacterial activity against Neisseria meningitidis, and among those analogs with 5′-tetrachlorophthalimido and 5′-azido demonstrated increased antibacterial effect.
- Van Ostrand, Robert,Jacobsen, Casey,Delahunty, Alicia,Stringer, Carley,Noorbehesht, Ryan,Ahmed, Haidi,Awad, Ahmed M.
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- Evaluation of BBB permeable nucleolipid (NLDPU): A di-C15-ketalised palmitone appended uridine as neuro-tracer for SPECT
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Despite being in routine for onco-diagnostics for years, the applicability of nucleosidic molecular imaging probes is severely restricted in neurological applications due to their low permeability across blood-brain-barrier (BBB). For extending nucleoside tracers utility for neuro-onco early diagnostics, suitable modification which enhances their BBB permeation needs investigation. Among various modifications, lipidization of nucleosides has been reported to enhance cellular permeability. Extending the concept, the aim was to exemplify the possibility of lipidized nucleosides as potential brain tracer with capability to cross intact BBB and evaluate as metal based neuro-imaging SPECT agent. Uridine based non-lipidic (NSDAU)and di-C15-ketal appended lipidic (NLDPU)ligands were conjugated to chelator, DTPA (DTPA-NSDAU and DTPA-NLDPU)using multi-step chemistry. The ligands were evaluated in parallel for comparative physical and biological parameters. Additionally, effects of enhanced lipophilicity on UV-absorption, acid strength, fluorescence and non-specific protein binding were evaluated. Fluorescence quenching of BSA indicated appreciable interaction of DTPA-NLDPU with protein only above 10 mM without inducing conformational changes. In addition, DTPA-NLDPU was found to be haematocompatible and cytocompatible with low dose-dependent toxicity in HEK-cells. The chelator DTPA was used for 99mTc-complexation for SPECT imaging. Optimized 99mTc-radiolabeling parameters resulted in quantitative (≥97%)labeling with good stability parameters in in-vitro serum and cysteine challenge studies. We demonstrate that the nucleolipid radiotracer (99mTc-DTPA-NLDPU)was successfully able to permeate the BBB with brain uptake of 0.2% ID/g in normal mice as compared to 0.06% ID/g uptake of 99mTc-DTPA-NSDAU at 5 min. Blood kinetics indicate biphasic profile and t1/2(distribution)46 min for 99mTc-DTPA-NLDPU. The preferential accumulation of 99mTc-DTPA-NLDPU in brain tumor intracranial xenograft indicate the targeting capability of the nucleoside. We conclude that as first-of-its-kind, this work presents the potential of the biocompatible nucleolipidic system for brain targeting and early diagnostics.
- Swastika,Chaturvedi, Shubhra,Kaul, Ankur,Hazari, Puja Panwar,Jha, Preeti,Pal, Sunil,Lal, Sangeeta,Singh,Barthélémy, Philippe,Mishra, Anil K.
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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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- Photophysical properties of zinc phthalocyanine-uridine single walled carbon nanotube - Conjugates
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The photophysical properties of the conjugate of uridine and zinc mono carboxy phenoxy phthalocyanine (ZnMCPPc-uridine, 4) are reported in this work. The conjugate was also adsorbed onto single walled carbon nanotubes (ZnMCPPc-uridine-SWCNT, 5). The X-ray photoelectron spectroscopy of 4 showed three N 1s peaks while that of 5 showed four N 1s peak, a new peak at 399.4 eV of 5 was assigned to pyrrolidonic nitrogen, due to the interaction of the pyrrolic nitrogen of 4 with the oxygen moiety of SWCNT-COOH in 5. The triplet lifetime, triplet and singlet oxygen quantum yields of the zinc mono carboxy phenoxy phthalocyanine increased by over 40% in the presence of uridine. SWCNTs resulted in only a small quenching of the triplet state parameters of 4.
- Ogbodu, Racheal O.,Amuhaya, Edith K.,Mashazi, Philani,Nyokong, Tebello
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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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- 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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- Selectivity in C-alkylation of dianions of protected 6-methyluridine
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A regioselective synthesis of 6-ω-alkenyluridines 3, precursors of potent antiviral and antitumor cyclonucleosides 5, is described. While ω-alkenyl halides do not alkylate 6-lithiouridine, compounds 3 were prepared in a regioselective manner by sequential treatment of 6-methyluridine 2 with LTMP or LDA (4 equiv) in THF at ?30 °C followed by alkylation with ω-alkenyl bromides.
- Nguyen, Ngoc Hoa,Castanet, Anne-Sophie,Mortier, Jacques,Len, Christophe
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- 4-(Acetylthio)-2,2-dimethyl-3-oxobutyl and 4-(tert-Butyldisulfanyl)-2,2-dimethyl-3-oxobutyl as Protecting Groups for Nucleoside 5′-Phosphoramidates Derived from L -Alanine Methyl Ester
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Phosphoramidates 1 and 2 were synthesized by H-phosphonate methodology and subsequent oxidative amination with L-alanine methyl ester. The removal of the protecting groups at pH = 7.5 and 37°C in the absence and presence of porcine liver esterase (PLE) or glutathione (GSH) was monitored by HPLC. The stability of phosphoramidate 1 was additionally studied at pH = 9 and 10. The reduction of the disulfide bond with glutathione from 2 triggers the removal of the protecting group by cyclization releasing quantitatively nucleoside 5′-{N-[(1S)-2-oxo-2-methoxy-1-methylethyl]phosphoramidate} (7) as the desired product. With 1, enzymatic deacetylation or acetyl migration from the sulfur atom to the adjacent hydrated oxo group followed by chemical cyclization produces 7. The S-S-bond-mediated dimerization (8) competes as a side reaction. Prolonged treatment, however, resulted in the conversion of the S-S dimer 8 into 7 that undergoes slow alanine methyl ester hydrolysis to form 10.
- Sontakke, Vyankat A.,L?nnberg, Harri,Ora, Mikko
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- A potent, covalent inhibitor of orotidine 5′-monophosphate decarboxylase with antimalarial activity
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Orotidine 5′-monophosphate decarboxylase (ODCase) has evolved to catalyze the decarboxylation of orotidine 5′-monophosphate without any covalent intermediates. Active site residues in ODCase are involved in an extensive hydrogen-bonding network. We discovered that 6-iodouridine 5′-monophosphate (6-iodo-UMP) irreversibly inhibits the catalytic activities of ODCases from Methanobacterium thermoautotrophicum and Plasmodium falciparum. Mass spectral analysis of the enzyme-inhibitor complex confirms covalent attachment of the inhibitor to ODCase accompanied by the loss of two protons and the iodo moiety. The X-ray crystal structure (1.6 ? resolution) of the complex of the inhibitor and ODCase clearly shows the covalent bond formation with the active site Lys-42 residue. 6-Iodo-UMP inhibits ODCase in a time- and concentration-dependent fashion. 6-Iodouridine, the nucleoside form of 6-iodo-UMP, exhibited potent antiplasmodial activity, with IC50S of 4.4 ± 1.3 μM and 6.2 ± 0.7 μM against P. falciparum ItG and 3D7 isolates, respectively. 6-Iodouridine 5′-monophosphate is a novel covalent inhibitor of ODCase, and its nucleoside analogue paves the way to a new class of inhibitors against malaria.
- Bello, Angelica M.,Poduch, Ewa,Fujihashi, Masahiro,Amani, Merhnaz,Li, Yan,Crandall, Ian,Hui, Raymond,Lee, Ping I.,Kain, Kevin C.,Pai, Emil F.,Kotra, Lakshmi P.
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- An efficient method for the synthesis of selenium modified nucleosides: its application in the synthesis of Se-adenosyl-l-selenomethionine (SeAM)
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In this paper, we report that a versatile method for the synthesis of 5′-selenium modified nucleosides has been explored on the basis of a 2-(trimethylsilyl)ethyl (TSE) selenyl group as a selenating donor. We demonstrate the broad utility of this method through direct introduction of various functional groups into 5′-TSE-selenonucleosides. This original method offers additional advantages for the preparation of these compounds, such as high functional group tolerance, ready availability of various electrophilic reagents, mild conditions, simple operation, and good yields. The utility of this approach is further demonstrated by the synthesis of Se-adenosyl-l-selenomethionine (SeAM) as a chemical reporter for methyltransferases.
- Kogami, Masakazu,Koketsu, Mamoru
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- Clay catalyzed acetonation: A simple method for the preparation of isopropylidene carbohydrates
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This paper reports a simple method for the preparation of isopropylidene carbohydrates using clay as a catalyst. Treatment of various monosaccharides and/or ribonucleosides with acetone in the presence of clay such as a montmorillonite K 10 (K 10) under mild reaction conditions gave isopropylidene carbohydrates (1-7) in good yields.
- Asakura, Jun-Ichi,Matsubara, Yoshio,Yoshihara, Masakuni
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- Synthesis of [60]fullerene-glycopyranosylaminopyrimidin-4-one conjugates
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The synthesis of several C60 derivatives containing a 6-(β-d-glycopyranosylamino)pyrimidin-4-one unit and a C60-uridine conjugate is described. The fullerene derivatives bearing a 4-(β-d-glycopyranosylamino)pyrimidin-4-one moiety were synthesised by 1,3-dipolar cycloaddition reactions of C60 with azomethine ylides generated in situ from the corresponding 5-formylpyrimidin-4-one derivatives and N-methylglycine. The synthesis of the C60-uridine conjugate involved the selective protection of the 2′- and 3′-hydroxyl groups of uridine, esterification, cyclopropanation of C60 and, finally, the deprotection of the hydroxyl groups. One of the fullerene-glycopyranosylaminopyrimidin-4-one conjugates was characterised by single-crystal X-ray crystallography. Differentiation between pairs of diastereoisomers, for several fullerene derivatives, was achieved through the study of their gas-phase fragmentations.
- Jord?o, Carina I.C.,Farinha, Andreia S.F.,Enes, Roger F.,Tomé, Augusto C.,Silva, Artur M.S.,Cavaleiro, José A.S.,Ramos, Catarina I.V.,Santana-Marques,Almeida Paz, Filipe A.,de la Torre Ramirez, José M.,de la Torre, Maria D.L.,Nogueras, Manuel
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- Pac13 is a Small, Monomeric Dehydratase that Mediates the Formation of the 3′-Deoxy Nucleoside of Pacidamycins
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The uridyl peptide antibiotics (UPAs), of which pacidamycin is a member, have a clinically unexploited mode of action and an unusual assembly. Perhaps the most striking feature of these molecules is the biosynthetically unique 3′-deoxyuridine that they share. This moiety is generated by an unusual, small and monomeric dehydratase, Pac13, which catalyses the dehydration of uridine-5′-aldehyde. Here we report the structural characterisation of Pac13 with a series of ligands, and gain insight into the enzyme's mechanism demonstrating that H42 is critical to the enzyme's activity and that the reaction is likely to proceed via an E1cB mechanism. The resemblance of the 3′-deoxy pacidamycin moiety with the synthetic anti-retrovirals, presents a potential opportunity for the utilisation of Pac13 in the biocatalytic generation of antiviral compounds.
- Michailidou, Freideriki,Chung, Chun-Wa,Brown, Murray J. B.,Bent, Andrew F.,Naismith, James H.,Leavens, William J.,Lynn, Sean M.,Sharma, Sunil V.,Goss, Rebecca J. M.
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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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- Unexpected side product formed during LDA-induced phosphonylation of uridine
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The LDA-induced coupling of 2′,3′,5′-O-protected uridine with diethyl chlorophosphate, during the synthesis of 6-phosphonouridine, is accompanied by the formation of an unexpected side product. LDA adds slowly to the C4 position of the 2′,3′,5′-O-protected uridine after the initial reaction with diethyl chlorophosphate. The presence of the phosphorochloridate facilitates the side reaction. This observation accounts for the previously reported low yield when conducting the coupling reaction for longer durations and suggests a new route for the synthesis of N-alkylated 6-phosphonocytidine analogues.
- Bhar, Palash,Bearne, Stephen L.
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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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- Synthesis and biological evaluation of selective phosphonate-bearing 1,2,3-triazole-linked sialyltransferase inhibitors
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The critical role of sialyltransferase (ST) enzymes in tumour cell growth and metastasis, as well as links to multi-drug and radiation resistance, has seen STs emerge as a target for potential antimetastatic cancer treatments. One promising class of ST inhibitors that improve upon the pharmacokinetic issues of previous inhibitors is the 1,2,3-triazole-linked transition-state analogues. Herein, we present the design and synthesis of a new generation of 1,2,3-triazole-linked sialyltransferase inhibitors, along with their biological evaluation demonstrating increased potency for phosphonate bearing compounds. The six most promising inhibitors presented in this work exhibited a greater number of binding modes for hST6Gal I over hST3Gal I, withKiranging from 3-55 μM. This work highlights phosphonate bearing triazole-linked compounds as a promising class of synthetically accessible ST inhibitors that warrant further investigation.
- Dobie, Christopher,Montgomery, Andrew P.,Skropeta, Danielle,Yu, Haibo,Szabo, Rémi
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- Simamycin (5′-O-geranyluridine): A new prenylated nucleoside from Streptomyces sp. A
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A new nucleoside modified by prenylation, simamycin (1), was isolated from the culture broth of a soil-derived Streptomyces sp. Its structure was determined by spectroscopic analysis and chemical synthesis as 5′-O-geranyluridine. Compound 1 induced differentiation of preadipocytes into matured adipocytes.
- Igarashi, Yasuhiro,Kyoso, Takayuki,Kim, Youngju,Oikawa, Tsutomu
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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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- Synthetic Sansanmycin Analogues as Potent Mycobacterium tuberculosis Translocase i Inhibitors
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Herein, we report the design and synthesis of inhibitors of Mycobacterium tuberculosis (Mtb) phospho-MurNAc-pentapeptide translocase I (MurX), the first membrane-associated step of peptidoglycan synthesis, leveraging the privileged structure of the sansanmycin family of uridylpeptide natural products. A number of analogues bearing hydrophobic amide modifications to the pseudo-peptidic end of the natural product scaffold were generated that exhibited nanomolar inhibitory activity against Mtb MurX and potent activity against Mtb in vitro. We show that a lead analogue bearing an appended neopentylamide moiety possesses rapid antimycobacterial effects with a profile similar to the frontline tuberculosis drug isoniazid. This molecule was also capable of inhibiting Mtb growth in macrophages where mycobacteria reside in vivo and reduced mycobacterial burden in an in vivo zebrafish model of tuberculosis.
- Tran, Wendy,Kusay, Ali S.,Hawkins, Paige M. E.,Cheung, Chen-Yi,Nagalingam, Gayathri,Pujari, Venugopal,Ford, Daniel J.,Stoye, Alexander,Ochoa, Jessica L.,Audette, Rebecca E.,Hortle, Elinor,Oehlers, Stefan H.,Charman, Susan A.,Linington, Roger G.,Rubin, Eric J.,Dowson, Christopher G.,Roper, David I.,Crick, Dean C.,Balle, Thomas,Cook, Gregory M.,Britton, Warwick J.,Payne, Richard J.
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supporting information
p. 17326 - 17345
(2021/12/13)
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- Bisubstrate Ether-Linked Uridine-Peptide Conjugates as O-GlcNAc Transferase Inhibitors
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The O-linked β-N-acetylglucosamine (O-GlcNAc) transferase (OGT) is a master regulator of installing O-GlcNAc onto serine or threonine residues on a multitude of target proteins. Numerous nuclear and cytosolic proteins of varying functional classes, including translational factors, transcription factors, signaling proteins, and kinases are OGT substrates. Aberrant O-GlcNAcylation of proteins is implicated in signaling in metabolic diseases such as diabetes and cancer. Selective and potent OGT inhibitors are valuable tools to study the role of OGT in modulating a wide range of effects on cellular functions. We report linear bisubstrate ether-linked uridine-peptide conjugates as OGT inhibitors with micromolar affinity. In vitro evaluation of the compounds revealed the importance of donor substrate, linker and acceptor substrate in the rational design of bisubstrate analogue inhibitors. Molecular dynamics simulations shed light on the binding of this novel class of inhibitors and rationalized the effect of amino acid truncation of acceptor peptide on OGT inhibition.
- Makwana, Vivek,Ryan, Philip,Malde, Alpeshkumar K.,Anoopkumar-Dukie, Shailendra,Rudrawar, Santosh
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supporting information
p. 477 - 483
(2020/10/26)
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- Development of a Robust Manufacturing Route for Molnupiravir, an Antiviral for the Treatment of COVID-19
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Herein is described the development of a large-scale manufacturing process for molnupiravir, an orally dosed antiviral that was recently demonstrated to be efficacious for the treatment of patients with COVID-19. The yield, robustness, and efficiency of each of the five steps were improved, ultimately culminating in a 1.6-fold improvement in overall yield and a dramatic increase in the overall throughput compared to the baseline process.
- Bade, Rachel,Bernardoni, Frank,Bothe, Jameson,Brito, Gilmar,Castro, Steve,Chang, Darryl,Diaz-Santana, Anthony,Diribe, Ike,Emerson, Khateeta M.,Fier, Patrick S.,Humphrey, Guy R.,Krishnamurthi, Bharath,Morris, William J.,Ouyand, Honggui,Poirier, Marc,Sirk, Kevin M.,Sirota, Eric,Stone, Kevin,Tan, Lushi,Taylor, Jerry,Ward, Michael,Xiao, Chengqian,Xu, Yingju,Zhan, Jianfeng,Zhang, Yongqian,Zhao, Ralph,Zheng, Michelle,Zompa, Michael A.
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supporting information
p. 2806 - 2815
(2021/12/30)
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- N4 - hydroxycytidine derivative as well as preparation method and application thereof
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The invention relates to N4 - hydroxycytidine derivatives as shown in general formula I. A pharmaceutically acceptable salt, a tautomer thereof, a stereoisomer thereof, a metabolite thereof, a metabolic precursor thereof, or a prodrug thereof, and the substituted N4 - hydroxycytidine derivative structure of the structure of Formula I. The pharmaceutical composition is used for preparing medicaments for treating infections such as SARS-CoV, HBV, HCV, H1N1, Ebola and SARS-CoV - 2, can effectively inhibit influenza viruses and SARS-CoV - 2 viruses, and can have the same result on other RNA viruses. The series of compounds can be applied to preparation of anti RNA virus drugs. The medicine is used for preparing a medicine for treating virus infection and is used for preparing a vaccine adjuvant for treating virus infection.
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Paragraph 0076-0080
(2021/09/01)
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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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supporting information
p. 8711 - 8721
(2021/10/22)
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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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Page/Page column 296-297; 351-352; 355-356
(2021/07/10)
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- N4-HYDROXYCYTIDINE AND DERIVATIVES AND ANTI-VIRAL USES RELATED THERETO
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This disclosure relates to certain N4-hydroxycytidine derivatives, pharmaceutical compositions, and methods related thereto. In certain embodiments, the disclosure relates to the treatment or prophylaxis of human coronavirus 2019-nCoV.
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Page/Page column 137; 138; 141; 143
(2021/08/13)
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- Me3SI-promoted chemoselective deacetylation: a general and mild protocol
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A Me3SI-mediated simple and efficient protocol for the chemoselective deprotection of acetyl groups has been developedviaemploying KMnO4as an additive. This chemoselective deacetylation is amenable to a wide range of substrates, tolerating diverse and sensitive functional groups in carbohydrates, amino acids, natural products, heterocycles, and general scaffolds. The protocol is attractive because it uses an environmentally benign reagent system to perform quantitative and clean transformations under ambient conditions.
- Gurawa, Aakanksha,Kashyap, Sudhir,Kumar, Manoj
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p. 19310 - 19315
(2021/06/03)
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- Synthesis and conformational analysis of fluorinated uridine analogues provide insight into a neighbouring-group participation mechanism
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Fluorinated nucleoside analogues have attracted much attention as anticancer and antiviral agents and as probes for enzymatic function. However, the lack of direct synthetic methods, especially for 2′,3′-dideoxy-2′,3′-difluoro nucleosides, hamper their practical utility. In order to design more efficient synthetic methods, a better understanding of the conformation and mechanism of formation of these molecules is important. Herein, we report the synthesis and conformational analysis of a 2′,3′-dideoxy-2′,3′-difluoro and a 2′-deoxy-2′-fluoro uridine derivative and provide an insight into the reaction mechanism. We suggest that the transformation most likely diverges from the SN 1 or SN 2 pathway, but instead operates via a neighbouring-group participation mechanism.
- Brown, Murray J. B.,Goss, Rebecca Jane Miriam,Lebl, Tomas,Michailidou, Freideriki,Sharma, Sunil Vishnuprasadji,Slawin, Alexandra M. Z.
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- Triazoxins: Novel nucleosides with anti-Giardia activity
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Novel nucleoside analogues named “triazoxins” were synthesized. Of these, two analogues were found to be highly effective against Giardia lamblia, an intestinal parasite and a major cause of waterborne infection, worldwide. While compound 7 reduced the growth of trophozoites in culture (IC50, ~5 μM), compound 21 blocked the in vitro cyst production (IC50 ~5 μM). Compound 21 was also effective against trophozoites (IC50, ~36 μM). A third analogue (compound 8) was effective against both trophozoites (IC50, ~36 μM) and cysts (IC50, ~20 μM) although at higher concentration. Thus triazoxin analogues are unique and exhibit morphology (i.e., trohozoites or cysts) -specific effects against Giardia.
- Chi, Miguel,Das, Siddhartha,De Chatterjee, Atasi,Patterson, Steven E.,Pogula, Praveen K.,VanKoten, Harrison W.
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- A High-Yielding Synthesis of EIDD-2801 from Uridine**
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A simple reordering of the reaction sequence allowed the improved synthesis of EIDD-2801, an antiviral drug with promising activity against the SARS-CoV-2 virus, starting from uridine. Compared to the original route, the yield was enhanced from 17 % to 61 %, and fewer isolation/purification steps were needed. In addition, a continuous flow procedure for the final acetonide deprotection was developed, which proved to be favorable toward selectivity and reproducibility.
- ?tv?s, Sándor B.,Dallinger, Doris,Kappe, C. Oliver,Snead, David R.,Steiner, Alexander,Znidar, Desiree
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supporting information
p. 6736 - 6739
(2020/11/23)
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- Dehydroxymethylation of alcohols enabled by cerium photocatalysis
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Dehydroxymethylation, the direct conversion of alcohol feedstocks as alkyl synthons containing one less carbon atom, is an unconventional and underexplored strategy to exploit the ubiquity and robustness of alcohol materials. Under mild and redox-neutral reaction conditions, utilizing inexpensive cerium catalyst, the photocatalytic dehydroxymethylation platform has been furnished. Enabled by ligand-to-metal charge transfer catalysis, an alcohol functionality has been reliably transferred into nucleophilic radicals with the loss of one molecule of formaldehyde. Intriguingly, we found that the dehydroxymethylation process can be significantly promoted by the cerium catalyst, and the stabilization effect of the fragmented radicals also plays a significant role. This operationally simple protocol has enabled the direct utilization of primary alcohols as unconventional alkyl nucleophiles for radical-mediated 1,4-conjugate additions with Michael acceptors. A broad range of alcohols, from simple ethanol to complex nucleosides and steroids, have been successfully applied to this fragment coupling transformation. Furthermore, the modularity of this catalytic system has been demonstrated in diversified radical-mediated transformations including hydrogenation, amination, alkenylation, and oxidation.
- Zhang, Kaining,Chang, Liang,An, Qing,Wang, Xin,Zuo, Zhiwei
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supporting information
p. 10556 - 10564
(2019/08/20)
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- Dehydroxymethylation of Alcohols Enabled by Cerium Photocatalysis
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Dehydroxymethylation, the direct conversion of alcohol feedstocks as alkyl synthons containing one less carbon atom, is an unconventional and underexplored strategy to exploit the ubiquity and robustness of alcohol materials. Under mild and redox-neutral reaction conditions, utilizing inexpensive cerium catalyst, the photocatalytic dehydroxymethylation platform has been furnished. Enabled by ligand-to-metal charge transfer catalysis, an alcohol functionality has been reliably transferred into nucleophilic radicals with the loss of one molecule of formaldehyde. Intriguingly, we found that the dehydroxymethylation process can be significantly promoted by the cerium catalyst, and the stabilization effect of the fragmented radicals also plays a significant role. This operationally simple protocol has enabled the direct utilization of primary alcohols as unconventional alkyl nucleophiles for radical-mediated 1,4-conjugate additions with Michael acceptors. A broad range of alcohols, from simple ethanol to complex nucleosides and steroids, have been successfully applied to this fragment coupling transformation. Furthermore, the modularity of this catalytic system has been demonstrated in diversified radical-mediated transformations including hydrogenation, amination, alkenylation, and oxidation.
- Zhang, Kaining,Chang, Liang,An, Qing,Wang, Xin,Zuo, Zhiwei
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supporting information
p. 10556 - 10564
(2019/08/28)
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- N4-HYDROXYCYTIDINE AND DERIVATIVES AND ANTI-VIRAL USES RELATED THERETO
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This disclosure relates to certain N4-hydroxycytidine derivatives, pharmaceutical compositions, and methods related thereto. In certain embodiments, the disclosure relates to the treatment or prophylaxis of viral infections, such as Eastern, Western, and Venezuelan Equine Encephalitis (EEE, WEE and VEE, respectively), Chikungunya fever (CHIK), Ebola, Influenza, RSV, and Zika virus infection with the disclosed compounds.
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Page/Page column 123; 133; 134
(2019/06/23)
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- Compositions and Methods for Reverse Automated Nucleic Acid Synthesis
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Methods for reverse automated nucleic acid synthesis, and 5′-H-phosphonates suitable for use in the same, as well as methods for making 5′-H-phosphonates, are described.
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Paragraph 0102-0103
(2019/10/29)
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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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Page/Page column 276; 277; 332; 336
(2019/10/01)
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- Total Synthesis of Tunicamycin v
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The total synthesis of tunicamycin V is described. This strategy is based on the initial construction of tunicaminyluracil, which is regarded to play an important role in the observed biological activities. The key to the synthesis was a Mukaiyama aldol reaction followed by a furan-oxidation to construct the undecose skeleton, a [3,3] sigmatropic rearrangement of a cyanate, and a highly selective trehalose-type glycosylation.
- Yamamoto, Kazuki,Yakushiji, Fumika,Matsumaru, Takanori,Ichikawa, Satoshi
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supporting information
p. 256 - 259
(2018/01/17)
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- Synthesis of disaccharide nucleosides utilizing the temporary protection of the 20,30-cis-diol of ribonucleosides by a boronic ester
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Disaccharide nucleosides are an important class of natural compounds that have a variety of biological activities. In this study, we report on the synthesis of disaccharide nucleosides utilizing the temporary protection of the 20,30-cis-diol of ribonucleosides, such as adenosine, guanosine, uridine, 5-metyluridine, 5-fluorouridine and cytidine, by a boronic ester. The temporary protection of the above ribonucleosides permits the regioselective O-glycosylation of the 5'-hydroxyl group with thioglycosides using a p-toluenesulfenyl chloride (p-TolSCl)/silver triflate (AgOTf) promoter system to afford the corresponding disaccharide nucleosides in fairly good chemical yields. The formation of a boronic ester prepared from uridine and 4-(trifluoromethyl)phenylboronic acid was examined by 1H, 11B and 19F NMR spectroscopy.
- Someya, Hidehisa,Itoh, Taiki,Aoki, Shin
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supporting information
(2017/11/06)
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- Design and synthesis of chitin synthase inhibitors as potent fungicides
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Chitin is a structural component of fungal cell walls but is absent in vertebrates, mammals, and humans. Chitin synthase is thus an attractive molecular target for developing fungicides. Based on the structure of its donor substrate, UDP-N-acetyl-glucosamine, as well as the modelled structure of the bacterial chitin synthase NodC, we designed a novel scaffold which was then further optimized into a series of chitin synthase inhibitors. The most potent inhibitor, compound 13, exhibited high chitin synthase inhibitory activity with an IC50 value of 64.5?μmol/L. All of the inhibitors exhibited antifungal activities against the growth of agriculturally-destructive fungi, Fusarium graminearum, Botrytis cinerea, and Colletotrichum lagenarium. This work presents a new scaffold which can be used for the development of novel fungicides.
- Chen, Qi,Zhang, Ji-Wei,Chen, Lu-Lu,Yang, Jun,Yang, Xin-Ling,Ling, Yun,Yang, Qing
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p. 1232 - 1237
(2017/06/19)
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- Unified Total Synthesis of Polyoxins J, L, and Fluorinated Analogues on the Basis of Decarbonylative Radical Coupling Reactions
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Polyoxins J (1 a) and L (1 b) are important nucleoside antibiotics. The complex and densely functionalized dipeptide structures of 1 a and 1 b contain thymine and uracil nucleobases, respectively. Herein we report the unified total synthesis of 1 a, 1 b, and their artificial analogues 1 c and 1 d with trifluorothymine and fluorouracil structures. Decarbonylative radical coupling between α-alkoxyacyl tellurides and a chiral glyoxylic oxime ether led to chemo- and stereoselective construction of the ribonucleoside α-amino acid structures of 1 a–d without damaging the preinstalled nucleobases. The high applicability of the radical-based methodology was further demonstrated by preparation of the trihydroxynorvaline moiety of 1 a–d. The two amino acid fragments were connected and elaborated into 1 a–d (longest linear sequence: 11 steps). Compounds 1 a and 1 b assembled in this way exhibited potent activity against true fungi, while only 1 d was active against Gram-positive bacteria.
- Fujino, Haruka,Nagatomo, Masanori,Paudel, Atmika,Panthee, Suresh,Hamamoto, Hiroshi,Sekimizu, Kazuhisa,Inoue, Masayuki
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supporting information
p. 11865 - 11869
(2017/09/20)
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- An axial nucleoside asymmetric modified silicon phthalocyanine and its preparation method and application
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The invention discloses axial nucleoside asymmetrically-modified silicon phthalocyanine and a preparation method and application thereof, belonging to the preparation field of a photodynamic medicine or a photosensitizer. The axial nucleoside asymmetrically-modified silicon phthalocyanine disclosed by the invention can be applied to photodynamic treatment, photodynamic diagnosis or photodynamic disinfection as a photosensitizer, has the structural characteristic of axial asymmetric substitution, and shows good amphipathicity and excellent photodynamic activity.
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Paragraph 0043; 0044
(2016/10/10)
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- Design, synthesis, anticancer, antimicrobial activities and molecular docking studies of theophylline containing acetylenes and theophylline containing 1,2,3-triazoles with variant nucleoside derivatives
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A new series of theophylline containing acetylene derivatives (6a–6b and 7–13) and theophylline containing 1,2,3-triazoles with variant nucleoside derivatives (20–32) have been designed and synthesized. These compounds were screened for anticancer and antimicrobial activity. Further the computational docking and 2D QSAR were performed using MOE software to identify novel scaffolds. The results showed that compound 29 and 30 exhibit significant cytotoxic effect on all four cancer cells such as lung (A549), colon (HT-29), breast (MCF-7) and melanoma (A375) with IC50values of 2.56, 2.19, 1.89, 4.89?μM and 3.57, 2.90, 2.10, 5.81?μM respectively. Whereas quite different results were observed for these compounds in antimicrobial studies. Compounds 11, 21 and 26 have exhibited significant minimum inhibitory concentrations (MIC) against Staphylococcus aureus, Bacillus cereus, Escherichia coli and Pseudomonas aeruginosa. The docking studies demonstrate that compound 27, 28, 29 and 30 have good dock score and binding affinities with various therapeutic targets in cancer cell proliferation. In addition these compounds have shown acceptable correlation with bioassay results in the regression plots generated in 2D QSAR models. This is the first report to demonstrate the theophylline containing acetylene derivatives and theophylline containing 1,2,3-triazole nucleoside hybrids as potential anticancer and antimicrobial agents with comprehensive in silico analysis.
- Ruddarraju, Radhakrishnam Raju,Murugulla, Adharvana Chari,Kotla, Ravindar,Chandra Babu Tirumalasetty, Muni,Wudayagiri, Rajendra,Donthabakthuni, Shobha,Maroju, Ravichandar,Baburao,Parasa, Lakshmana Swamy
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p. 379 - 396
(2016/08/04)
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- NMR-based conformational analysis of 2′,6-disubstituted uridines and antiviral evaluation of new phosphoramidate prodrugs
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Six novel phosphoramidate prodrugs of uridine analogues, with structural modifications introduced at the 6- and 2′,6-positions, have been prepared and evaluated for selective antiviral activity against hepatitis C virus, as well as other positive-stranded RNA viruses. An analysis of the conformational properties of the parent nucleosides was carried out using two-dimensional NMR spectroscopy based experiments, highlighting a 3′-endo (North) sugar puckering preference and syn orientation.
- Da Paix?o Soares, Fábio,Groaz, Elisabetta,Lescrinier, Eveline,Neyts, Johan,Leyssen, Pieter,Herdewijn, Piet
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p. 5809 - 5815
(2015/11/11)
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- A tractable and efficient one-pot synthesis of 5′-azido-5′- deoxyribonucleosides
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Synthetic routes to 5′-azidoribonucleosides are reported for adenosine, cytidine, guanosine, and uridine, resulting in a widely applicable one-pot methodology for the synthesis of these and related compounds. The target compounds are appropriate as precursors in a variety of purposive syntheses, as the synthetic and therapeutic relevance of azido- and amino-modified nucleosides is expansive. Furthermore, in the conversion of alcohols to azides, these methods offer a tractable alternative to the Mitsunobu and other more difficult reactions.
- Peterson, Theodore V.,Streamland, Tobin U. B.,Awad, Ahmed M.
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p. 2434 - 2444
(2014/03/21)
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- Synthesis and anti-HIV activity of triazolo-fused, medium-sized cyclic nucleoside analogs prepared by an intramolecular huisgen 1,3-dipolar cycloaddition
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Medium-sized cyclic nucleosides containing a fused triazole ring were synthesized via intramolecular Huisgen 1,3-dipolar cycloadditon reaction. 2′,3′-seco-Uridine was employed as the key intermediate for the introduction of azido and alkynyl moieties in the defined positions of the reaction precursors. The cycloaddition reactions were achieved in high yields by heating the precursor in refluxing toluene. The uracil base in these target compounds was successfully transformed to the corresponding cytosine. The synthesized compounds were evaluated in a MAGI assay for their anti-HIV activities, and in a H9 T lymphocytes assay for their cell toxicities. Copyright
- Sun, Jingbo,Liu, Rongwang,Fu, Qiang,Zang, Jian,Tao, Qiangqiang,Wu, Jinchang,Zhu, Hui
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p. 733 - 743
(2014/06/09)
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- Substrate distortion contributes to the catalysis of orotidine 5′-monophosphate decarboxylase
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Orotidine 5′-monophosphate decarboxylase (ODCase) accelerates the decarboxylation of orotidine 5′-monophosphate (OMP) to uridine 5′-monophosphate (UMP) by 17 orders of magnitude. Eight new crystal structures with ligand analogues combined with computational analyses of the enzyme's short-lived intermediates and the intrinsic electronic energies to distort the substrate and other ligands improve our understanding of the still controversially discussed reaction mechanism. In their respective complexes, 6-methyl-UMP displays significant distortion of its methyl substituent bond, 6-amino-UMP shows the competition between the K72 and C6 substituents for a position close to D70, and the methyl and ethyl esters of OMP both induce rotation of the carboxylate group substituent out of the plane of the pyrimidine ring. Molecular dynamics and quantum mechanics/molecular mechanics computations of the enzyme-substrate complex also show the bond between the carboxylate group and the pyrimidine ring to be distorted, with the distortion contributing a 10-15% decrease of the ΔΔGa value. These results are consistent with ODCase using both substrate distortion and transition-state stabilization, primarily exerted by K72, in its catalysis of the OMP decarboxylation reaction.
- Fujihashi, Masahiro,Ishida, Toyokazu,Kuroda, Shingo,Kotra, Lakshmi P.,Pai, Emil F.,Miki, Kunio
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supporting information
p. 17432 - 17443
(2014/01/06)
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- Nano n-propylsulfonated magnetic γ-Fe 2O 3 as an efficient and reusable catalyst for the synthesis O-isopropylidene derivatives of carbohydrates
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Nano n-propylsulfonated γ-Fe2O3 was found to be a highly efficient, reusable heterogeneous catalyst for the conversion of a range of monosaccharides and some of their derivatives to the corresponding O-isopropylidene derivatives in good to excellent yields by refluxing the reaction mixture in dry acetone. The magnetic property of the catalyst enabled its separation from the reaction mixture by a simple process of filtration along with the aid of an external magnet. The efficiency of the catalyst was found to be largely unaffected for at least up to six cycles of reuse, thus proving the new methodology to be environmentally rewarding besides being simple and facile in operation.
- Zhang, Xiaoran,Zhang, Changqiang
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p. 249 - 258
(2013/08/15)
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- A reliable Pd-mediated hydrogenolytic deprotection of BOM group of uridine ureido nitrogen
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The benzyloxymethyl (BOM) group has been utilized widely in syntheses of a variety of natural and non-natural products. The BOM group is also one of few choices to protect uridine ureido nitrogen. However, hydrogenolytic cleavage of the BOM group of uridine derivatives has been unreliably performed via heterogeneous conditions using Pd catalysts. One of the undesirable by-products formed by Pd-mediated hydrogenation conditions is the over-reduced product in which the C5-C6 double bond of the uracil moiety was saturated. To date, we have generated a wide range of uridine-containing antibacterial agents, where the BOM group has been utilized in their syntheses. In screening of deprotection conditions of the BOM group of uridine ureido nitrogen under Pd-mediated hydrogenation conditions, we realized that the addition of water to the iPrOH-based hydrogenation conditions can suppress the formation of over-reduced uridine derivatives and the addition of HCO2H (0.5%) dramatically improve the reaction rate. An optimized hydrogenation condition described here can be applicable to the BOM-deprotections of a wide range of uridine derivatives.
- Aleiwi, Bilal A.,Kurosu, Michio
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experimental part
p. 3758 - 3762
(2012/09/25)
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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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supporting information; experimental part
p. 15288 - 15291
(2011/11/11)
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- An efficient approach to the synthesis of nucleosides: Gold(I)-catalyzed N-glycosylation of pyrimidines and purines with glycosyl ortho-alkynyl benzoates
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Persuaded with gold: The title reaction in the presence of [Ph 3PAuNTf2] (Tf=trifluoromethanesulfonyl) led conveniently to the corresponding nucleosides with excellent regioselectivity (see scheme). Even purine derivatives underwent this transformation owing to the mild conditions, which enabled the use of protecting groups that would not usually be compatible with N-glycosylation conditions. Copyright
- Zhang, Qingju,Sun, Jiansong,Zhu, Yugen,Zhang, Fuyi,Yu, Biao
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supporting information; experimental part
p. 4933 - 4936
(2011/06/24)
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- Synthesis of pyrimidine-containing nucleoside β-(R/S)- hydroxyphosphonate analogues
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A concise route to nucleoside β-hydroxyphosphonate analogues is described. The use of a nucleoside β-ketophosphonate as the key intermediate allowed both the (R) and (S) isomers of β-hydroxyphosphonate analogues in the pyrimidine series to be accessed. Such derivatives may be considered as stable mimics of 5′-monophosphate nucleosides and, therefore, could be the starting point for the development of potential therapeutic agents. Copyright
- Meurillon, Maia,Chaloin, Laurent,Perigaud, Christian,Peyrottes, Suzanne
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supporting information; experimental part
p. 3794 - 3802
(2011/09/30)
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