- Structure-activity relationship of leucyladenylate sulfamate analogues as leucyl-tRNA synthetase (LRS)-targeting inhibitors of Mammalian target of rapamycin complex 1 (mTORC1)
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Leucyl-tRNA synthetase (LRS) plays an important role in amino acid-dependent mTORC1 signaling, which is known to be associated with cellular metabolism and proliferation. Therefore, LRS-targeting small molecules that can suppress mTORC1 activation may provide an alternative strategy to current anticancer therapy. In this work, we developed a library of leucyladenylate sulfate analogues by extensively modifying three different pharmacophoric regions comprising adenine, ribose and leucine. Several effective compounds were identified by cell-based mTORC1 activation assays and further tested for anticancer activity. The selected compounds mostly exhibited selective cytotoxicity toward five different cancer cell lines, supporting the hypothesis that the LRS-mediated mTORC1 pathway is a promising alternative target to current therapeutic approaches.
- Yoon, Suyoung,Kim, Sung-Eun,Kim, Jong Hyun,Yoon, Ina,Tran, Phuong-Thao,Ann, Jihyae,Kim, Changhoon,Byun, Woong Sub,Lee, Sangkook,Kim, Sunghoon,Lee, Jiyoun,Lee, Jeewoo
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Read Online
- Visible-light-mediated oxidative demethylation of: N 6-methyl adenines
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We report a simple protocol that affords oxidative demethylation of N6-methyl groups in N6-methyl adenines (m6A). The biologically compatible photocatalyst riboflavin prompts a highly selective C-H abstraction from N6-methyl in adenines under the irradiation of a visible blue LED light, affording a novel and highly selective biomimetic demethylation of m6A and related N-methyl adenine analogues. andcopy; 2017 The Royal Society of Chemistry.
- Xie, Li-Jun,Wang, Rui-Li,Wang, Dong,Liu, Li,Cheng, Liang
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Read Online
- 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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- SYNTHESIS AND STRUCTURE OF HIGH POTENCY RNA THERAPEUTICS
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This invention provides expressible polynucleotides, which can express a target protein or polypeptide. Synthetic mRNA constructs for producing a protein or polypeptide can contain one or more 5′ UTRs, where a 5′ UTR may be expressed by a gene of a plant. In some embodiments, a 5′ UTR may be expressed by a gene of a member of Arabidopsis genus. The synthetic mRNA constructs can be used as pharmaceutical agents for expressing a target protein or polypeptide in vivo.
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- Noncanonical RNA Nucleosides as Molecular Fossils of an Early Earth—Generation by Prebiotic Methylations and Carbamoylations
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The RNA-world hypothesis assumes that life on Earth started with small RNA molecules that catalyzed their own formation. Vital to this hypothesis is the need for prebiotic routes towards RNA. Contemporary RNA, however, is not only constructed from the four canonical nucleobases (A, C, G, and U), it also contains many chemically modified (noncanonical) bases. A still open question is whether these noncanonical bases were formed in parallel to the canonical bases (chemical origin) or later, when life demanded higher functional diversity (biological origin). Here we show that isocyanates in combination with sodium nitrite establish methylating and carbamoylating reactivity compatible with early Earth conditions. These reactions lead to the formation of methylated and amino acid modified nucleosides that are still extant. Our data provide a plausible scenario for the chemical origin of certain noncanonical bases, which suggests that they are fossils of an early Earth.
- Schneider, Christina,Becker, Sidney,Okamura, Hidenori,Crisp, Antony,Amatov, Tynchtyk,Stadlmeier, Michael,Carell, Thomas
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supporting information
p. 5943 - 5946
(2018/04/30)
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- New tools in nucleoside toolbox of tick-borne encephalitis virus reproduction inhibitors
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Design and development of nucleoside analogs is an established strategy in the antiviral drug discovery field. Nevertheless, for many viruses the coverage of structure-activity relationships (SAR) in the nucleoside chemical space is not sufficient. Here we present the nucleoside SAR exploration for tick-borne encephalitis virus (TBEV), a member of Flavivirus genus. Promising antiviral activity may be achieved by introduction of large hydrophobic substituents in the position 6 of adenosine or bulky silyl groups to the position 5′. Introduction of methyls to the ribose moiety does not lead to inhibition of TBEV reproduction. Possible mechanisms of action of these nucleosides include the inhibition of viral entry or interaction with TBEV non-structural protein 5 methyltransferase or RNA-dependent RNA polymerase domains.
- Orlov, Alexey A.,Drenichev, Mikhail S.,Oslovsky, Vladimir E.,Kurochkin, Nikolay N.,Solyev, Pavel N.,Kozlovskaya, Liubov I.,Palyulin, Vladimir A.,Karganova, Galina G.,Mikhailov, Sergey N.,Osolodkin, Dmitry I.
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supporting information
p. 1267 - 1273
(2017/06/19)
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- Synthesis and ability of new ligands for G protein-coupled receptors 17 (GPR17)
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Background: GPR17 is believed to be a novel target for the development of new therapeutic approaches to human stroke and multiple sclerosis. Hence, the selection of GPR17 ligands may be a potent way to reduce the progression of ischemic damage. Material/Methods: New potential ligands for GPR17, mono-, di-, and triphosphate adenosine nucleotides substituted at N6-position with a methyl and a cyclopentyl group were synthesized. The ability of new ligands to bind GPR17 was evaluated using frontal affinity chromatography-mass spectrometry (FAC-MS) method. Cangrelor, MRS2179, and uridine diphosphate were selected as the reference compounds. Results: The new triphosphate derivatives 9 and 10 were considered as the new GPR17 ligands. The compound 10 was eluted with breakthrough time (bt) between cangrelor and MRS 2179 (compound 10, bt=12.25; cangrelor, bt=24.55, and MRS 2179, bt=7.10), while the breakthrough volume of compound 9 was similar to that of MRS 2179 (compound 9, bt=7.53 and MRS 2179, bt=7.10). Conclusions: N6-cyclopentyATP 10 is medium-high affinity ligand of GPR17, while the corresponding N6-methyl derivative 9 is a medium affinity ligand similar to MRS 2179. Hence, the new N6-cyclopentylATP 10 might be a good candidate for the pharmacological characterization of GPR17.
- Zhuo, Tongyou,Zhou, Shengxue,Zhang, Wei,Lambertucci, Catia,Volpini, Rosaria
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p. 953 - 959
(2017/03/20)
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- New highly active antiplatelet agents with dual specificity for platelet P2Y1 and P2Y12 adenosine diphosphate receptors
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Currently approved platelet adenosine diphosphate (ADP) receptor antagonists target only the platelet P2Y12 receptor. Moreover, especially in patients with acute coronary syndromes, there is a strong need for rapidly acting and reversible antiplatelet agents in order to minimize the risk of thrombotic events and bleeding complications. In this study, a series of new P1,P4-di(adenosine-5′) tetraphosphate (Ap4A) derivatives with modifications in the base and in the tetraphosphate chain were synthesized and evaluated with respect to their effects on platelet aggregation and function of the platelet P2Y1, P2Y12, and P2X1 receptors. The resulting structure-activity relationships were used to design Ap4A analogs which inhibit human platelet aggregation by simultaneously antagonizing both P2Y1 and P2Y12 platelet receptors. Unlike Ap4A, the analogs do not activate platelet P2X1 receptors. Furthermore, the new compounds exhibit fast onset and offset of action and are significantly more stable than Ap4A to degradation in plasma, thus presenting a new promising class of antiplatelet agents.
- Yanachkov, Ivan B.,Chang, Hung,Yanachkova, Milka I.,Dix, Edward J.,Berny-Lang, Michelle A.,Gremmel, Thomas,Michelson, Alan D.,Wright, George E.,Frelinger, Andrew L.
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supporting information
p. 204 - 218
(2015/11/24)
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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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- Identification of 8-aminoadenosine derivatives as a new class of human concentrative nucleoside transporter 2 inhibitors
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Purine-rich foods have long been suspected as a major cause of hyperuricemia. We hypothesized that inhibition of human concentrative nucleoside transporter 2 (hCNT2) would suppress increases in serum urate levels derived from dietary purines. To test this hypothesis, the development of potent hCNT2 inhibitors was required. By modifying adenosine, an hCNT2 substrate, we successfully identified 8-aminoadenosine derivatives as a new class of hCNT2 inhibitors. Compound 12 moderately inhibited hCNT2 (IC50 = 52 ± 3.8 μM), and subsequent structure-activity relationship studies led to the discovery of compound 48 (IC50 = 0.64 ± 0.19 μM). Here we describe significant findings about structural requirements of 8-aminoadenosine derivatives for exhibiting potent hCNT2 inhibitory activity.
- Tatani, Kazuya,Hiratochi, Masahiro,Nonaka, Yoshinori,Isaji, Masayuki,Shuto, Satoshi
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supporting information
p. 244 - 248
(2015/03/30)
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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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- Identification of a selective polymerase enables detection of N 6-methyladenosine in RNA
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N6-methyladenosine (m6A) is the most abundant mRNA modification and has important links to human health. While recent studies have successfully identified thousands of mammalian RNA transcripts containing the modification, it is extr
- Harcourt, Emily M.,Ehrenschwender, Thomas,Batista, Pedro J.,Chang, Howard Y.,Kool, Eric T.
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supporting information
p. 19079 - 19082
(2014/01/17)
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- Aberrant cyclization affords a C-6 modified cyclic adenosine 5′-diphosphoribose analogue with biological activity in Jurkat T cells
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Two nicotinamide adenine dinucleotide (NAD+) analogues modified at the 6 position of the purine ring were synthesized, and their substrate properties toward Aplysia californica ADP-ribosyl cyclase were investigated. 6-N-Methyl NAD+ (6-N-methyl nicotinamide adenosine 5′-dinucleotide 10) hydrolyzes to give the linear 6-N-methyl ADPR (adenosine 5′-diphosphoribose, 11), whereas 6-thio NHD+ (nicotinamide 6-mercaptopurine 5′-dinucleotide, 17) generates a cyclic dinucleotide. Surprisingly, NMR correlation spectra confirm this compound to be the N1 cyclic product 6-thio N1-cIDPR (6-thio cyclic inosine 5′-diphosphoribose, 3), although the corresponding 6-oxo analogue is well-known to cyclize at N7. In Jurkat T cells, unlike the parent cyclic inosine 5′-diphosphoribose N1-cIDPR 2, 6-thio N1-cIDPR antagonizes both cADPR- and N1-cIDPR-induced Ca2+ release but possesses weak agonist activity at higher concentration. 3 is thus identified as the first C-6 modified cADPR (cyclic adenosine 5′-diphosphoribose) analogue antagonist; it represents the first example of a fluorescent N1-cyclized cADPR analogue and is a new pharmacological tool for intervention in the cADPR pathway of cellular signaling.
- Moreau, Christelle,Kirchberger, Tanja,Zhang, Bo,Thomas, Mark P.,Weber, Karin,Guse, Andreas H.,Potter, Barry V. L.
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p. 1478 - 1489
(2012/04/23)
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- Synthesis and structure-activity relationship investigation of adenosine-containing inhibitors of histone methyltransferase DOT1L
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Histone3-lysine79 (H3K79) methyltransferase DOT1L has been found to be a drug target for acute leukemia with MLL (mixed lineage leukemia) gene translocations. A total of 55 adenosine-containing compounds were designed and synthesized, among which several potent DOT1L inhibitors were identified with Ki values as low as 0.5 nM. These compounds also show high selectivity (>4500-fold) over three other histone methyltransferases. Structure-activity relationships (SAR) of these compounds for their inhibitory activities against DOT1L are discussed. Potent DOT1L inhibitors exhibit selective activity against the proliferation of MLL-translocated leukemia cell lines MV4;11 and THP1 with EC50 values of 4-11 μM. Isothermal titration calorimetry studies showed that two representative inhibitors bind with a high affinity to the DOT1L:nucleosome complex and only compete with the enzyme cofactor SAM (S-adenosyl-l-methionine) but not the substrate nucleosome.
- Anglin, Justin L.,Deng, Lisheng,Yao, Yuan,Cai, Guobin,Liu, Zhen,Jiang, Hong,Cheng, Gang,Chen, Pinhong,Song, Yongcheng,Dong, Shuo
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p. 8066 - 8074,9
(2020/09/15)
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- N6-acetyl-2,3,5-tri-O-acetyladenosine; A convenient, missed out substrate for regioselective N6-alkylations
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A simple and efficient route to N6-acetyl-2,3,5-tri-O- acetyladenosine (1) was developed based on selective N-deacetylation of pentaacetylated adenosine 2 with methanol at room temperature in the presence of imidazole. Preparative synthesis of 1 was elaborated utilizing a crude mixture of 2 and 1 which is produced by reaction of adenosine with acetic anhydride in pyridine at elevated temperatures. The total yield of 1 was 80-85% starting with adenosine. It was shown that 1 is a convenient substrate for selective N 6-alkylations. The study revealed the same regioselectivity in base-promoted reactions of 1 with activated alkyl halides and Mitsunobu reactions of 1 with alcohols. A series of N6-alkyladenosines 5a-f were prepared. Cytokinins 6b,d,e were prepared by enzymatic transformation of parent nucleoside derivatives 5b,d,e using a combination of nucleoside phosphorylase and alkaline phosphatase. Georg Thieme Verlag Stuttgart, New York.
- Tararov, Vitali I.,Kolyachkina, Svetlana V.,Alexeev, Cyril S.,Mikhailov, Sergey N.
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experimental part
p. 2483 - 2489
(2011/09/20)
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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 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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- Convenient synthesis of 8-amino-2′-deoxyadenosine
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We studied the behaviour of 8-azido-2′-deoxyadenosine and 8-bromo-2′-deoxyadenosine in aqueous solutions of ammonia and primary and secondary amines. Unexpectedly, 8-Azido-2′-deoxyadenosine is converted to 8-amino-2′-deoxyadenosine in excellent yields. The use of this reaction for the preparation of 8-aminoadenine derivatives needed for the preparation of oligonucleotides carrying 8-aminoadenine is discussed.
- Frieden, Miriam,Avino, Anna,Eritja, Ramon
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p. 193 - 202
(2007/10/03)
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- Chemical incorporation of 1-methyladenosine, minor tRNA component, into oligonucleotides
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The synthesis of suitably protected 1-methyladenosine derivatives has been developed and its successful chemical incorporation into oligonucleotides was achieved.
- Efimtseva, Ekaterina V.,Mikhailov,Rozenski,Busson,Van Aerschot,Herdewijn
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p. 1113 - 1115
(2007/10/03)
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- Substrate analogues for an RNA-editing adenosine deaminase: Mechanistic investigation and inhibitor design
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ADARs are adenosine deaminases that act on RNA and are responsible for RNA-editing reactions that occur in eukaryotic mRNAs, including the mRNAs of glutamate and serotonin receptors. ADARs capable of editing biologically relevant RNA substrates have been
- Veliz, Eduardo A.,Easterwood, LaHoma M.,Beal, Peter A.
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p. 10867 - 10876
(2007/10/03)
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- 6-Bromopurine nucleosides as reagents for nucleoside analogue synthesis
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Surprisingly facile direct substitution reactions with acetyl-protected 6-bromopurine nucleosides are described. Included in the series of bromonucleosides studied is the guanosine derivative N2-2′,3′,5′-tetraacetyl-6-bromopurine ribonucleoside, the synthesis of which is reported here for the first time. Brominated nucleosides had not previously been considered optimal substrates for SNAr reactions given the general reactivity trend for halogenated aromatic systems (i.e. F > Cl > Br > I). However, even weakly nucleophilic aromatic amines give high yields of the substitution products in polar solvents with these 6-bromopurine nucleosides. For primary aromatic amines, secondary aliphatic amines, and imidazole, reaction takes place only at C6, with no effect on the acetyl-protected ribose. In addition, we report the first synthesis of 3′,5′-di-O-acetyl-6-bromopurine-2′-deoxyribonucleoside and its reaction with an arylamine in MeOH in the absence of added metal catalyst. Thus, C6-arylamine derivatives of both adenosine and 2′-deoxyadenosine can be prepared via simple SNAr reactions with the corresponding 6-bromo precursor. We also describe high yielding and C6-selective substitution reactions with 6-bromonucleosides using alcohol and thiol nucleophiles in the presence of added base (DBU). Finally, C6-bromonucleosides are shown to be readily hydrogenated to give purine or 2-aminopurine products in good yield. This work increases the arsenal of reactions and strategies available for the synthesis of nucleoside analogues as potential biochemical tools or new therapeutics.
- Veliz,Beal
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p. 8592 - 8598
(2007/10/03)
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- Reductive monoalkylation of aromatic amines via amidine intermediates
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The convenience and efficiency of using amidines as intermediates in the reductive monoalkylation of aromatic amines has been demonstrated. This monoalkylation can be performed as either a two-step synthesis or a one-pot procedure. Several examples are presented which clearly demonstrate the utility of this new method for the methylation or ethylation of aromatic amines, including unprotected nucleosides.
- Zhang, Jianxing,Chang, Hui-Min,Kane, Robert R.
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p. 643 - 645
(2007/10/03)
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- Reactions of adenosine with bromo- and chloromalonaldehydes in aqueous solution: Kinetics and mechanism
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Reactions of adenosine nucleosides with halogen substituted acetaldehydes and malonaldehydes have been studied and pseudo first-order rate constants have been determined. All the reactions yield 1,N6-etheno adducts, and with malonaldehydes; in addition to this, 11-formyl-1,N6-etheno adducts are also formed. Particular attention has been paid to the formation of the formyletheno products. The results obtained suggest that the reactions of adenine base with halogenated acetaldehydes and malonaldehydes are basically similar. It also seems that in reactions of halomalonaldehydes with adenosine, the etheno and formyletheno products are formed through the same initial reaction pathway i.e. the attack of the 6-amino group of the adenine base at the carbonyl carbon atom of the aldehyde.
- Mikkola, Satu,Koissi, Niangoran,Ketomaeki, Kaisa,Rauvala, Susanna,Neuvonen, Kari,Loennberg, Harri
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p. 2315 - 2323
(2007/10/03)
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- Transformations of thiopyrimidine and thiopurine nucleosides following oxidation with dimethyldioxirane
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A general and convenient method for the synthesis of several pyrimidine and purine nucleosides by selective oxidation of thionucleosides with dimethyldioxirane is reported. Thioketo moieties in the C-4 position of the pyrimidine ring, and in the C-6, and C-8 positions of the purine ring are the domain of oxidative nucleophilic substitution. Thioketo moieties in the C-2 position of both purine and pyrimidine rings are the domain of desulfurization or formation of disulfides.
- Saladino, Raffaele,Mincione, Enrico,Crestini, Claudia,Mezzetti, Maurizio
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p. 6759 - 6780
(2007/10/03)
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- Alkylation of 6-N-acylated adenosine derivatives by the use of phase transfer catalysis
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6-N- or N1-Alkylation of 6-N-acyl adenosine derivatives with alkyl halides in CH2Cl2 - 1 mol dm-3 NaOH in the presence of Bu4NBr has been studied.A variety of N-acyl groups have been examined.Consequently, the use of the acetyl and 2-(trimethylsilyl)ethoxycarbonyl groups resulted in the corresponding 6-N-alkylated products in high yields.It was also found that, when the benzoyl group was chosen as the N-acyl group, N1-alkylated products were obtained along with 6-N-alkylated products were obtained along with 6-N-alkylated products.The structure of the 6-N- and N1-alkylated adenosine derivatives has been determined by 1H and 13C NMR spectroscopy.
- Aritomo, Keiichi,Wada, Takeshi,Sekine, Mitsuo
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p. 1837 - 1844
(2007/10/02)
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- Nucleosides. Part LVI. Aminolysis of carbamates of adenosine and cytidine
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The 2-(4-nitrophenyl)ethoxycarbonyl (npeoc) group, introduced 1984 as protecting group for exocyclic amino functions of nucleic-acid bases, reacts with amines under mild conditions to urea derivatives. Treatment of 2',5'-di-O-acetyl-N6-[2-(4-nitrophenyl)ethoxycarbonyl]cordycepin (3) with NH3/MeOH overnight at room temperature affords cordycepin (4) and N6-carbamoylcordycepin (5). Preliminary investigations towards the elucidation of the reaction mechanism indicate that the aminolysis proceeds via an addition-elimination or an isocyanate mechanism, depending on the reaction conditions. The phenoxycarbonyl (phoc) group at N6 or N4 was chosen to study the mild conversion of carbamates with aromatic amines into ureas of adenosine and cytidine, respectively.
- Sigmund,Pfleiderer
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p. 1267 - 1280
(2007/10/02)
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- Anti-dementia agents
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An anti-dementia agent comprising as an active ingredient an adenosine derivative is disclosed. The anti-dementia agent is useful in the therapy of various types of dementia, especially senile dementia. Examples of the adenosine derivative include L-N6 -phenylisopropyl-adenosine, 2-chloroadenosine, N6 -cyclohexyladenosine, adenosine-5'-(N-cyclopropyl)carboxamide.
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- Oxidative Transformations of Minor Components of Nucleic Acids. An Anomalous Reaction Course of Oxidation of N6,N6-Dialkyladenosines and Related Compounds with m-Chloroperoxybenzoic Acid
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Oxidation of N6-methyladenosine (1a) or the corresponding tribenzoate 1b with m-chloroperoxybenzoic acid gave N1-oxides 2a and 2b whereas N6,N6-dimethyladenosine tribenzoate (3a) afforded 2',3',5'-tri-O-benzoylinosine (4a) and N6-methyl-N6-formyl derivative 5.The N6,N6-diethyladenosine 3b and piperidine derivative 3c yielded only 4a, but N6,N6-dibenzyl compound 3d was not oxidized.N,N-Dimethyl-2,4-dinitroaniline (6a) was oxidized with m-chloroperoxybenzoic acid to give N-methyl-N-formyl derivative 7a, N-methyl-2,4-dinitroaniline (8a), N-oxide 10a, and only traces of 2,4-dinitrophenol (9a).By contrast, 2-(dimethylamino)-5-nitropyridine (6b) afforded 5-nitro-2-pyridone (9b) and N-demethylated N1-oxide 11. 2-(Dimethylamino)pyridine (6c) and 2-(methylamino)-5-nitropyridine (8b) gave the respective N2- and N1-oxides 10c and 11.The reaction of 6-chloropurine nucleosides 15a and 15b with N,N-dimethylhydroxylamine gave inosine 4a or 4b accompanied by a smaller amount of 3a or 3e. 2,4-Dinitrofluorobenzene (16) afforded O-(2,4-dinitrophenyl)-N,N-dimethylhydroxylamine (17).Mass spectra of compounds 10a, 10c, and 17 provided evidence for Meisenheimer rearrangement and subsequent cyclic transformation.The N-oxide 10a and hydroxylamino derivative 17 gave 2,4-dinitrophenol (9a), and N2-oxide 10c afforded fragments belonging to 2-pyridone (9c).Compound 17 is thermally stable whereas N-oxide 10a yielded at 100 deg C a mixture of 8a, 8b, 9a, and 17.
- Endo, Takeshi,Zemlicka, Jiri
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p. 1887 - 1894
(2007/10/02)
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- A 15N-STUDY ON THE DEAMINATION OF 1-AMINOPURINIUM SALTS WITH AMINES
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Reaction of 1-aminoadenosinium mesitylenesulphonate, 1a, with methanolic ammonia for 10 h at 80 deg C yields adenosine, 7a, and nebularine, 6a.With methanolic methylamine 1a gives 6-methylamino-9-β-D-ribofuranosylpurine, 8a, and adenosine, 7a, respectively.Similar results are obtained with the salt of 1-amino-2',3'-O-isopropylideneadenosine, 1b. 1-Aminoadeninium mesitylenesulphonate, 1c, with methanolic methylamine only yields 6-(methylamino)purine, 8c.In contrast, the mesitylenesulphonate salt of 1,2-diaminopurine, 11, with methanolic methylamine gives only deamination at N1, affording 2-aminopurine, 12.Studies with 15N-labelled methanolic ammonia or 15N-labelled purinium compounds show that in all these reactions, except that of 11, a ring-opening mechanism (ANRORC-mechanism) is involved.
- Kos, Nico J.,Jongejan, Hugo,Plas, Henk C. van der
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p. 369 - 374
(2007/10/02)
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- Selective 2'-O-Methylation of Pyrimidine-Ribonucleosides by Trimethylsulfonium Hydroxide in the Presence of Mg2+ and Ca2+ Ions
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Reactions of various ribonucleosides with trimethylsulfonium hydroxide were investigated in the presence of Mg2+ and Ca2+ ions.The 2'-OH groups of pyrimidine-ribonucleosides were methylated selectively.
- Yamauchi, Kiyoshi,Nakagima, Toru,Kinoshita, Masayoshi
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p. 2947 - 2949
(2007/10/02)
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- Methylation of Adenosine and Related Nucleosides with Trimethylselenonium Hydroxyde, and Regiospecific Effects of Copper(II) Ions
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Methylation of adenosine, deoxyadenosine, 6-N-methyladenosine and 2'(3')-O-methyladenosines with trimethylselenonium hydroxyde was studied in the presence and absence of copper(II) acetylacetonate .It was found that copper(II) ions promoted methylation of the 2'(3')-OH groups of the ribonucleosides but suppressed methylation at the N-1 position of the adenine rings.The metal-ion effects are discussed in conjunction with a catalytic role for Cu(AA)2 in the reactions.
- Yamauchi, Kiyoshi,Hattori, Kazue,Kinoshita, Masayoshi
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p. 1327 - 1330
(2007/10/02)
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- The Methylation of Ribonucleosides by Trimethyl Phosphate or Dimethyl Sulfate in the Presence of Boric Acid
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Uridine, inosine, adenosine, and thymidine were methylated selectively at the base moieties by the use of trimethyl phosphate or dimethyl sulfate in the presence of boric acid.A suppressing effect of boric acid on the methylation of the ribose-hydroxyl groups was discussed briefly.
- Hisanaga, Yorisato,Tanabe, Toshizumi,Yamauchi, Kiyoshi,Kinoshita, Masayoshi
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p. 1569 - 1570
(2007/10/02)
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- Methylation of Nucleosides with Trimethylsulfonium Hydroxide. Effects of Transition Metal Ions
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The effect of transition metal acetylacetonates on the methylation of ribo- and deoxyribonucleosides with trimethylsulfonium hydroxide was studied.With ribonucleosides the metal complexes promoted O'-methylation at the 2' and 3' positions of the ribosyl group.A comparable effect was not observed in methylation of deoxyribonucleosides.These results are attributed to an increase in the nucleophilicity of the 2'-OH and 3'-OH groups of the ribosides through complex formation with the metal ion; such a complex cannot form with the deoxyribose derivatives.The activity of the metal ions studied for promoting this O'-methylation increased in the order Mn2+ 2+ = Zn2+ 2+ 2+ 3+.These M(AA)n also suppressed N-methylation of the purine and pyrimidine rings of adenosine and cytidine.It is suggested that this result may be caused by coordination of the metal ions with ring nitrogens.
- Yamauchi, Kiyoshi,Nakagima, Toru,Kinoshita, Masayoshi
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p. 3865 - 3868
(2007/10/02)
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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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- Unusual Competition between Nitrogen and Carbon Methylation of Nucleosides by Methyl Radical in Various Aqueous Media
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Five nucleosides, adenosine, guanosine, cytidine, thymidine, and uridine, were allowed to react with methyl radical produced by homolysis of tert-butyl peracetate.The extent and sites of reaction exhibited a marked dependence on the pH of the aqueous medium.In the region of pH 1-4, the major products arose from C-methylation of the nucleosides.The purines were more reactive than the pyrimidines under these acidic conditions.In the pH range of 4-10, the extent of C-methylation decreased steadily with increasing pH while N-methylated products arising from methylationof the ring nitrogen and/or exocyclic amino groups predominated.In this pH range, the pyrimidine nucleosides were the more reactive.Beyond pH 10, the extent of methylation diminished in all cases as decomposition of tert-butyl peracetate became rampant.The C-methylation occurs by way of an addition mechanism while N-methylation appears to proceed via radical abstraction of a hydrogen from the N-H group followed by combination with methyl radical.The implications of these reactivity and methylation patterns in radical carcinogenesis are discussed.
- Zady, Mona F.,Wong, John L.
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p. 2373 - 2377
(2007/10/02)
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