- Adenosine N1-oxide analogues as inhibitors of orthopox virus replication
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Several new types of adenosine N1-oxide (ANO) derivatives including N1-alkoxy and N6-alkyl as well as the analogues with a trihydroxycyclopentane ring in place of the ribose residue were synthesized and their antiviral properties were evaluated in Vero and LLC-MK2 cell cultures infected with vaccinia, mousepox, monkeypox, cowpox, and different isolates of smallpox viruses. The antiviral activity of ANO and its derivatives significantly depended on the virus type and cell cultures. Mousepox and monkeypox viruses were the most sensitive to these compounds, while vaccinia and cowpox viruses were inhibited at the concentrations 1-1.5 orders of magnitude higher. The toxicity of the synthesized compounds was much lower than that of ANO. Modifications of the ANO N6-position did not offer any advantages over the parent compound. The synthesized N1-oxide derivatives of noraristeromycin retained the activity comparable with noraristeromycin and displayed a decreased toxicity. No direct correlation between antiviral activity and stability of the compounds was found.
- Khandazhinskaya, Anastasiya L.,Shirokova, Elena A.,Shipitsin, Alexander V.,Karpenko, Inna L.,Belanov, Evgenii F.,Kukhanova, Marina K.,Yasko, Maksim V.
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Read Online
- 6-Iodopurine as a Versatile Building Block for RNA Purine Architecture Modifications
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Natural modified bases in RNA were found to be indispensable for basic biological processes. In addition, artificial RNA modifications have been a versatile toolbox for the study of RNA interference, structure, and dynamics. Here, we present a chemical method for the facile synthesis of RNA containing C6-modified purine. 6-Iodopurine, as a postsynthetic building block with high reactivity, was used for metal-free construction of C-N, C-O, and C-S bonds under mild conditions and C-C bond formation by Suzuki-Miyaura cross-coupling. Our strategy provides a convenient approach for the synthesis of various RNA modifications, especially for oligonucleotides containing specific structures.
- Chen, Kun,Fang, Zhentian,He, Zhiyong,Heng, Panpan,Wang, Baoshan,Xie, Yalun,Yang, Wei,Zhou, Xiang
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p. 353 - 362
(2022/02/17)
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- Synthesis of Fluorescent Probes Targeting Tumor-Suppressor Protein FHIT and Identification of Apoptosis-Inducing FHIT Inhibitors
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For the early diagnosis of cancer, leading to a better chance of full recovery, marker genes whose expression is already altered in precancerous lesions are desirable, and the tumor-suppressor gene FHIT is one candidate. The gene product, FHIT protein, has a unique dinucleoside triphosphate hydrolase (AP3Aase) activity, and in this study, we designed and synthesized a series of FHIT fluorescent probes utilizing this activity. We optimized the probe structure for high and specific reactivity with FHIT and applied the optimized probe in a screening assay for FHIT inhibitors. Screening of a compound library with this assay identified several hits. Structural development of a hit compound afforded potent FHIT inhibitors. These inhibitors induce apoptosis in FHIT-expressing cancers via caspase activation. Our results support the idea that FHIT binders, no matter whether inhibitors or agonists of AP3Aase activity, might be promising anticancer agents.
- Kawaguchi, Mitsuyasu,Sekimoto, Eriko,Ohta, Yuhei,Ieda, Naoya,Murakami, Takashi,Nakagawa, Hidehiko
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supporting information
p. 9567 - 9576
(2021/07/19)
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- Nucleotide Analog ARL67156 as a Lead Structure for the Development of CD39 and Dual CD39/CD73 Ectonucleotidase Inhibitors
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Nucleoside triphosphate diphosphohydrolase1 (NTPDase1, CD39) inhibitors have potential as novel drugs for the (immuno)therapy of cancer. They increase the extracellular concentration of immunostimulatory ATP and reduce the formation of AMP, which can be further hydrolyzed by ecto-5’-nucleotidase (CD73) to immunosuppressive, cancer-promoting adenosine. In the present study, we synthesized analogs and derivatives of the standard CD39 inhibitor ARL67156, a nucleotide analog which displays a competitive mechanism of inhibition. Structure-activity relationships were analyzed at the human enzyme with respect to substituents in the N6- and C8-position of the adenine core, and modifications of the triphosph(on)ate chain. Capillary electrophoresis coupled to laser-induced fluorescence detection employing a fluorescent-labeled ATP derivative was employed to determine the compounds’ potency. Selected inhibitors were additionally evaluated in an orthogonal, malachite green assay versus the natural substrate ATP. The most potent CD39 inhibitors of the present series were ARL67156 and its derivatives 31 and 33 with Ki values of around 1 μM. Selectivity studies showed that all three nucleotide analogs additionally blocked CD73 acting as dual-target inhibitors. Docking studies provided plausible binding modes to both targets. The present study provides a full characterization of the frequently applied CD39 inhibitor ARL67156, presents structure-activity relationships, and provides a basis for future optimization towards selective CD39 and dual CD39/CD73 inhibitors.
- Idris, Riham M.,Lee, Sang-Yong,Lopez, Vittoria,Luo, Xihuan,Müller, Christa E.,Mirza, Salahuddin,Namasivayam, Vigneshwaran,Pelletier, Julie,Sévigny, Jean,Sch?kel, Laura,Schmies, Constanze C.,Vu, The Hung
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- OLIGONUCLEOTIDE HAVING NON-NATURAL NUCLEOTIDE AT 5'-TERMINAL THEREOF
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An oligonucleotide having a nucleotide residue or a nucleoside residue represented by formula (I) {wherein X1 is an oxygen atom or the like, R1 is formula (IIA) (wherein R5A is halogen or the like, and R6A is a hydrogen atom or the like), formula (IVA) (wherein Y3A is a nitrogen atom or the like, and Y4A is CH or the like), or the like, R2 is a hydrogen atom, hydroxy, halogen, or optionally substituted lower alkoxy, and R3 is a hydrogen atom or the like, or formula (VI) (wherein n2 is 1, 2 or 3)} at the 5′ end thereof, wherein the nucleotide residue or the nucleoside residue binds to an adjacent nucleotide residue through the oxygen atom at position 3, is provided.
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Paragraph 0715; 0716; 0717
(2018/01/19)
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- OLIGONUCLEOTIDE
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The present invention provides an oligonucleotide having improved affinity for AGO2, and the like. The oligonucleotide has a nucleotide residue or a nucleoside residue represented by formula (I) {wherein X1 is an oxygen atom or the like, R1 is formula (IIA) (wherein R5A is halogen or the like, and R6A is a hydrogen atom or the like) or formula (IVA) (wherein Y3A is a nitrogen atom or the like, and Y4A is CH or the like), or the like, R2 is a hydrogen atom, hydroxy, halogen, or optionally substituted lower alkoxy, and R3 is a hydrogen atom or the like} at the 5′ end thereof, and the nucleotide residue or the nucleoside residue binds to an adjacent nucleotide residue through the oxygen atom at position 3.
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Paragraph 0489; 0490
(2016/01/25)
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- α,β-Methylene-ADP (AOPCP) Derivatives and Analogues: Development of Potent and Selective ecto-5′-Nucleotidase (CD73) Inhibitors
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ecto-5′-Nucleotidase (eN, CD73) catalyzes the hydrolysis of extracellular AMP to adenosine. eN inhibitors have potential for use as cancer therapeutics. The eN inhibitor α,β-methylene-ADP (AOPCP, adenosine-5′-O-[(phosphonomethyl)phosphonic acid]) was used as a lead structure, and derivatives modified in various positions were prepared. Products were tested at rat recombinant eN. 6-(Ar)alkylamino substitution led to the largest improvement in potency. N6-Monosubstitution was superior to symmetrical N6,N6-disubstitution. The most potent inhibitors were N6-(4-chlorobenzyl)- (10l, PSB-12441, Ki 7.23 nM), N6-phenylethyl- (10h, PSB-12425, Ki 8.04 nM), and N6-benzyl-adenosine-5′-O-[(phosphonomethyl)phosphonic acid] (10g, PSB-12379, Ki 9.03 nM). Replacement of the 6-NH group in 10g by O (10q, PSB-12431) or S (10r, PSB-12553) yielded equally potent inhibitors (10q, 9.20 nM; 10r, 9.50 nM). Selected compounds investigated at the human enzyme did not show species differences; they displayed high selectivity versus other ecto-nucleotidases and ADP-activated P2Y receptors. Moreover, high metabolic stability was observed. These compounds represent the most potent eN inhibitors described to date.
- Bhattarai, Sanjay,Freundlieb, Marianne,Pippel, Jan,Meyer, Anne,Abdelrahman, Aliaa,Fiene, Amelie,Lee, Sang-Yong,Zimmermann, Herbert,Yegutkin, Gennady G.,Str?ter, Norbert,El-Tayeb, Ali,Müller, Christa E.
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p. 6248 - 6263
(2015/08/24)
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- 2-Hexylthio-β,γ-CH2-ATP is an effective and selective NTPDase2 inhibitor
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NTPDase2 catabolizes nucleoside triphosphates and consequently, through the interaction of nucleotides with P2 receptors, controls multiple biological responses. NTPDase2 inhibitors could modulate responses induced by nucleotides in thrombosis, inflammation, cancer, etc. Here we developed a set of ATP analogues as potential NTPDase inhibitors and identified a subtype-selective and potent NTPDase2 inhibitor, 2-hexylthio-β,γ-methylene-ATP, 2. Analogue 2 was stable to hydrolysis by NTPDase1, -2, -3, and -8. It inhibited hNTPDase2 with Ki 20 μM, while only marginally (5-15%) inhibiting NTPDase1, -3, and -8. Homology models of hNTPDase1 and -2 were constructed. Docking and subsequent linear interaction energy (LIE) simulations provided a correlation with r2 = 0.94 between calculated and experimental inhibition data for the triphosphate analogues considered in this work. The origin of selectivity of 2 for NTPDase2 over NTPDase1 is the thiohexyl moiety of 2 which is favorably located within a hydrophobic pocket, whereas in NTPDase1 it is exposed to the solvent.
- Gillerman, Irina,Lecka, Joanna,Simhaev, Luba,Munkonda, Mercedes N.,Fausther, Michel,Martín-Satué, Mireia,Senderowitz, Hanoch,Sévigny, Jean,Fischer, Bilha
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p. 5919 - 5934
(2014/08/18)
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- The optimized microwave-assisted decomposition of formamides and its synthetic utility in the amination reactions of purines
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The microwave-assisted decomposition of DMF was thoroughly studied and the reaction conditions (temperature, solvent effect, and effect of additives, such as acids, bases, and salts) were optimized for its use in amination reactions. The applicability of this expedient methodology in purine chemistry and with various formamides is demonstrated.
- ?echová, Lucie,Jansa, Petr,?ála, Michal,Dra?ínsky, Martin,Holy, Antonín,Janeba, Zlatko
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experimental part
p. 866 - 871
(2011/03/19)
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- Inhibition of siderophore biosynthesis in Mycobacterium tuberculosis with nucleoside bisubstrate analogues: Structure-activity relationships of the nucleobase domain of 5′-O-[N-(salicyl)sulfamoyl]adenosine
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5′-O-[N-(salicyl)sulfamoyl]adenosine (Sal-AMS) is a prototype for a new class of antitubercular agents that inhibit the aryl acid adenylating enzyme (AAAE) known as MbtA involved in biosynthesis of the mycobactins. Herein, we report the structure-based design, synthesis, biochemical, and biological evaluation of a comprehensive and systematic series of analogues, exploring the structure-activity relationship of the purine nucleobase domain of Sal-AMS. Significantly, 2-phenyl-Sal-AMS derivative 26 exhibited exceptionally potent antitubercular activity with an MIC99 under iron-deficient conditions of 0.049 μM while the N-6-cyclopropyl-Sal-AMS 16 led to improved potency and to a 64-enhancement in activity under iron-deficient conditions relative to iron-replete conditions, a phenotype concordant with the designed mechanism of action. The most potent MbtA inhibitors disclosed here display in vitro antitubercular activity superior to most current first line TB drugs, and these compounds are also expected to be useful against a wide range of pathogens that require aryl-capped siderphores for virulence.
- Neres, Jo?o,Labello, Nicholas P.,Somu, Ravindranadh V.,Boshoff, Helena I.,Wilson, Daniel J.,Vannada, Jagadeshwar,Chen, Liqiang,Barry III, Clifton E.,Bennett, Eric M.,Aldrich, Courtney C.
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experimental part
p. 5349 - 5370
(2009/07/01)
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- High-throughput five minute microwave accelerated glycosylation approach to the synthesis of nucleoside libraries
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The Vorbrueggen glycosylation reaction was adapted into a one-step 5 min/130 °C microwave assisted reaction. Triethanolamine in acetontrile containing 2% water was determined to be optimal for the neutralization of trimethylsilyl inflate allowing for direct MPLC purification of the reaction mixture. When coupled with a NH3/methanol deprotection reaction, a high-throughput method of nucleoside library synthesis was enabled. The method was demonstrated by examining the ribosylation of 48 nitrogen containing heteroaromatic bases that included 25 purines, four pyrazolopyrimidines, two 8-azapurines, one 2-azapurine, two imidazopyridines, two benzimidazoles, three imidazoles, three 1,2,4-triazoles, two pyrimidines, two 3-deazapyrimidines, one quinazolinedione, and one alloxazine. Of these, 32 yielded single regioisomer products, and six resulted in separable mixtures. Seven examples provided inseparable regioisomer mixtures of -two to three compounds (16 nucleosides), and three examples failed to yield isolable products. For the 45 single isomers isolated, the average two-step overall yield ± SD was 26 ± 16%, and the average purity ± SD was 95 ± 6%. A total of 58 different nucleosides were prepared of which 15 had not previously been accessed directly from glycosylation/deprotection of a readily available base.
- Bookser, Brett C.,Raffaele, Nicholas B.
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p. 173 - 179
(2007/10/03)
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- The nucleoside transport proteins, NupC and NupG, from Escherichia coli: Specific structural motifs necessary for the binding of ligands
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A series of 46 natural nucleosides and analogues (mainly adenosine-based) were tested as inhibitors of [U-14C]uridine uptake by the concentrative, H+-linked nucleoside transport proteins NupC and NupG from Escherichia coli. The two evolutionarily unrelated transporters showed similar but distinct patterns of inhibition, revealing differing selectivities for the different nucleosides and their analogues. Binding of nucleosides to NupG required the presence of hydroxyl groups at each of the C-3′ and C-5′ positions of ribose, while binding to NupC required only the C-3′ hydroxyl substituent. The greater importance of the ribose moiety for binding to NupG is consistent with the evolutionary relationship between this protein and the oligosaccharide: H+ symporter (OHS) subfamily of the major facilitator superfamily (MFS) of transporters. For both proteins the natural α-configuration at C-3′ and the natural β-configuration at C-1′ was mandatory for ligand binding. N-7 in the imidazole ring of adenosine and the amino group at C-6 were found not to be important for binding and both transporters showed flexibility for substitution at C-6/N6; one or both of N-l and N-3 were important for adenosine analogue binding to NupC but significantly less so for binding to NupG. From the different effects of 8-bromoadenosine on the two transporters it appears that adenosine selectively binds to NupC in an anti- rather than a syn-conformation, whereas NupG is less prescriptive. The pattern of inhibition of NupC by differing nucleoside analogues confirmed the functional relationship of the bacterial transporter to members of the human concentrative nucleoside transporter (CNT) family and reaffirmed the use of the bacterial protein as an experimental model for these physiologically and clinically important mammalian proteins. The specificity data for NupG have been used to develop a homology model of the protein's binding site, based on the X-ray crystallographic structure of the disaccharide transporter LacY from E. coli. We have also developed an efficient general protocol for the synthesis of adenosine and three of its analogues, which is illustrated by the synthesis of [1′-13C]adenosine.
- Patching, Simon G.,Baldwin, Stephen A.,Baldwin, Alexander D.,Young, James D.,Gallagher, Maurice P.,Henderson, Peter J. F.,Herbert, Richard B.
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p. 462 - 470
(2007/10/03)
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- Anti-HCV nucleoside derivatives
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The present invention comprises novel and known purine and pyrimidine nucleoside derivatives which have been discovered to be active against hepatitis C virus (HCV). The use of these derivatives for the treatment of HCV infection is claimed as are the novel nucleoside derivatives disclosed herein.
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- The Synthesis of 2′-O-[(Triisopropylsilyl)oxy] methyl (TOM) Phosphoramidites of Methylated Ribonucleosides (m1G, m2G, m22G, m1I, m3U, m4C, m6A, m62A) for Use in Automated RNA Solid-Phase Synthesis
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The straightforward synthesis of eight methylated ribonucleoside phosphoramidites is described. These building blocks allow for incorporation of the naturally occuring nucleosides 1-methylguanosine (m1G), N 2-methylguanosine (m2G), N2N 2-dimethylguanosine (m22G), 1-methylinosine (m1I), 3-methyluridine (m3U), N4- methylcytidine (m4C), N6-methyladenosine (m6A), and N6,N6-dimethyladenosine (m62A) into oligoribonucleotides by automated RNA solid-phase synthesis. In all cases, the ribose 2′-hydroxyl group of the building blocks is masked by the recently introduced [(triisopropylsilyl)oxy]methyl (TOM) group.
- Hoebartner, Claudia,Kreutz, Christoph,Flecker, Elke,Ottenschlaeger, Elke,Pils, Werner,Grubmayr, Karl,Micura, Ronald
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p. 851 - 873
(2007/10/03)
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- Design of allele-specific protein methyltransferase inhibitors
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Protein arginine methyltransferases, which catalyze the transfer of methyl groups from S-adenosylmethionine (SAM) to arginine side chains in target proteins, regulate transcription, RNA processing, and receptor-mediated signaling. To specifically address the functional role of the individual members of this family, we took a "bump-and-hole" approach and designed a series of N6-substituted S-adenosylhomocysteine (SAH) analogues that are targeted toward a yeast protein methyltransferase RMT1. A point mutation was identified (E117G) in Rmt1 that renders the enzyme susceptible to selective inhibition by the SAH analogues. A mass spectrometry based enzymatic assay revealed that two compounds, N6-benzyl- and N6-naphthylmethyl-SAH, can inhibit the mutant enzyme over the wild-type with the selectivity greater than 20. When the E117G mutation was introduced into the Saccharomyces cerevisiae chromosome, the methylation of Np13p, a known in vivo Rmt1 substrate, could be moderately reduced by N6-naphthylmethyl-SAH in the resulting allele. In addition, an N6-benzyl-SAM analogue was found to serve as an orthogonal SAM cofactor. This analogue is preferentially utilized by the mutant methyltransferase relative to the wild-type enzyme with a selectivity greater than 67. This specific enzyme/inhibitor and enzyme/substrate design should be applicable to other members of this protein family and facilitate the characterization of protein methyltransferase function in vivo when combined with RNA expression analysis.
- Lin,Jiang,Schultz,Gray
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p. 11608 - 11613
(2007/10/03)
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- The synthesis of RNA containing the modified nucleotides N2- methylguanosine and N6,N6-dimethyladenosine
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The phosphoramidites of the naturally occurring modified nucleotides N2-methylguanosine and N6, N6-dimethyladenosine were synthesized and incorporated into short oligoribonucleotides. Described are the syntheses of the phosphoramidites and the procedures used to deprotect oligoribonucleotides in which the O6 of m2G is protected with a 2-(p- nitrophenyl)ethyl group.
- Rife, Jason P.,Cheng, Charles S.,Moore, Peter B.,Strobel, Scott A.
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p. 2281 - 2288
(2007/10/03)
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- Nucleic acid related compounds. 86. Nucleophilic functionalization of adenine, adenosine, tubercidin, and formycin derivatives via elaboration of the heterocyclic amino group into a readily displaced 1,2,4-triazol-4-yl substituent
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Treatment of 9-methyladenine and hydroxyl-protected derivatives of adenosine and 2′-deoxyadenosine with 1,2-bis[(dimethylamino)methylene]hydrazine and/or its dihydrochloride at elevated temperatures in appropriate solvents resulted in elaboration of the 6-amino group into a 6-(1,2,4-triazol-4-yl) substituent in excellent yields. Analogous functionalization of the amino groups of tubercidin {4-amino-7-(β-D-ribofuranosyl)pyrrolo[2,3-d]-pyrimidine} and formycin {7-amino-3-(β-D-ribofuranosyl)pyrazolo[4,3-d]pyrimidine} gave the respective 4- and 7-(1,2,4-triazol-4-yl) derivatives. Nucleophilic replacement of the triazole moiety gave the respective 6-, 4-, and 7-substituted purine, pyrrolo[2,3-d]pyrimidine, and pyrazolo[4,3-d]pyrimidine products. This first general method for "direct" nucleophilic replacement of an amino group on these nitrogen heterocycles also provides a new class of compounds for potential postsynthetic modifications after incorporation into oligonucleotides.
- Miles, Robert W.,Samano, Vicente,Robins, Morris J.
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p. 5951 - 5957
(2007/10/02)
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- Synthesis of 5-(Methylamino)-1-β-D-ribofuranosylimidazole-4-carboxamide, a Synthetic Intermediate for 3-Methyl-9-β-D-ribofuranosylpurines
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Treatment of 2',3',5'-tri-O-benzoyl-N,N-dimethyladenosine (2c) with methyl iodide in AcNMe2 gave the 3-methyl derivative (3c) as a sole product.Alkaline hydrolysis of 3c afforded the title imidazolecarboxamide (4a), whose hydroxy groups were acetylated selectively with Ac2O-pyridine.Similar methylation of 2',3',5'-tri-O-benzyl-N,N-dimethyladenosine (2d) followed by alkaline hydrolysis provided 2',3',5'-tri-O-benzyl-4a (4d) in good yield.
- Itaya, Taisuke,Matsumoto, Hiroo,Watanabe, Tomoko
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- Methylation study of ribonucleosides, deoxyribonucleosides, and 2′-O-methylribonucleosides with trimethylsulphonium hydroxide and trimethylsulphonium iodide. Influence of the 2′-hydroxy-groups on the reactivity of the base moieties of ribonucleosides
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Methylations of the naturally occuring ribonucleoside (1), deoxyribonucleoside (2), and 2′-O-methylribonucleoside (3) were carried out using trimethylsulphonium hydroxide (Me3SOH) and trimethylsulphonium iodide (Me3Sl). The base moiety of (2) and (3) are more reactive than the corresponding base moiety of (1). The sites and extent of methylation of (2) are considerably different from those of (1), but are almost identical with those of (3). The reactivities of (1)-(3) are discussed in connection to an intramolecular interaction of the 2′-OH groups with the base moiety of (1). The methylating characteristics of Me 3SOH and Me3Sl are also described. The kinetics indicate an SN2 mechanism for methylation of nucleosides by Me 3S+ ions.
- Yamauchi, Kiyoshi,Nakagima, Toru,Kinoshita, Masayoshi
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p. 2787 - 2792
(2007/10/02)
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