cas 3181-38-2, 2',3',5'-TRIACETYLINOSINE | Articles data

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Synthesis of isotopically labelled versions of adenosine agonist GR79236
Versions of adenosine receptor agonist GR79236, labelled either with carbon-14 at C-8 of the purine ring or with tritium in the cyclopentyl ring, were prepared in overall yields of 64% and 25% respectively. A mass labelled [M + 4] version containing carbon-13, nitrogen-15, and deuterium was also prepared in 3% yield.
Wadsworth, Alan H.,Newman, John J.,Wipperman, Mark D.,Fellows, Ian,Sutherland, Derek R.
p. 11 - 28
(2000)
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The "speedy" Synthesis of Atom-Specific 15N Imino/Amido-Labeled RNA
Although numerous reports on the synthesis of atom-specific 15N-labeled nucleosides exist, fast and facile access to the corresponding phosphoramidites for RNA solid-phase synthesis is still lacking. This situation represents a severe bottleneck for NMR spectroscopic investigations on functional RNAs. Here, we present optimized procedures to speed up the synthesis of 15N(1) adenosine and 15N(1) guanosine amidites, which are the much needed counterparts of the more straightforward-to-achieve 15N(3) uridine and 15N(3) cytidine amidites in order to tap full potential of 1H/15N/15N-COSY experiments for directly monitoring individual Watson-Crick base pairs in RNA. Demonstrated for two preQ1 riboswitch systems, we exemplify a versatile concept for individual base-pair labeling in the analysis of conformationally flexible RNAs when competing structures and conformational dynamics are encountered.
Neuner, Sandro,Santner, Tobias,Kreutz, Christoph,Micura, Ronald
p. 11634 - 11643
(2015)
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SAICAR Synthesis method
A method of synthesizing SAICAR of the present invention is carried out at 5 - amino -1 - ((). 2R. 3R. 4S. 5R-3, 4 -dihydroxy -5 - (hydroxymethyl) tetrahydrofuran -2 -yl) -1H- Imidazol -4 - formamide is the starting material and is sequentially subjected to 5 - amino -1 - ((). 3aR. 4R. 6R. 6aR) -6 - (Hydroxymethyl) -2, 2 -dimethyltetrahydrofuran [3,4 -]d] [1, 3] Diox -4 - group) -1H-imidazole -4 -carboxamide. 5 - Amino -1 - (()3aR. 4R. 6R. 6aR) -6 - (Hydroxymethyl) -2, 2 -dimethyltetrahydrofuran [3,4 -]d] [1, 3] Diox -4 - group) -1H- Imidazole -4 - carboxylic acid, dibenzyl (5 - amino -1 -) (()3aR. 4R. 6R. 6aR) -6 - (Hydroxymethyl) -2, 2 -dimethyltetrahydrofuran [3,4 -]d] [1, 3] Diox -4 - group) -1H- Imidazol -4 - carbonyl) . LOf - aspartic acid and the like to obtain a finished product purity of up to 99.6%, impurities 0.4%, diastereomeric excess (de) values 97.3% and a yield 16.9%.
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Paragraph 0053-0056; 0076-0078; 0098-0100

(2021/11/06)

Crystal form, preparation method and purpose of triacetyl-3-hydroxyphenyl adenosine
The invention relates to a crystal form, a preparation method and a purpose of hyperlipemia-treating medicine of triacetyl-3-hydroxyphenyl adenosine. The crystal form of the triacetyl-3-hydroxyphenyl adenosine comprises a type I crystal and a type II crystal of 2',3',5'-tri-O-acetyl-N6-(3-hydroxyphenyl) adenosine with a blood-lipid regulating effect, wherein the type I crystal has an X-ray powder diffraction pattern as shown in Figure 1, and the type II crystal has an X-ray powder diffraction pattern as shown in Figure 4.
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Paragraph 0006; 0036-0037

(2021/06/22)

A process for preparing natural nucleoside powder clitocybin method
The invention discloses a new method for preparing natural nucleoside nebularine. According to the method disclosed by the invention, cheap inosine is used as a raw material and is subjected to three reactions including acyl protection, sulfuration and desulfuration to finally obtain the target product nebularine; in the desulfuration step, since 50% nitric acid is used as a desulfuration agent, such reaction conditions easily causing explosion as diazotization in the conventional synthesis method can be avoided, no heavy metal catalyst is used, no column chromatography is needed in the whole process, large-scale synthesis can be realized easily; and moreover, the new method for preparing natural nucleoside nebularine is suitable for research on medicine activity and further large-scale preparation.
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Paragraph 0021; 0025-0027

(2017/10/26)

The isoprenoid derivative N6-benzyladenosine CM223 exerts antitumor effects in glioma patient-derived primary cells through the mevalonate pathway
Background and Purpose: N6-Isopentenyladenosine (i6A) is a modified nucleoside exerting in vitro and in vivo antiproliferative effects. We previously demonstrated that the actions of i6A correlate with the expression and activity of farnesyl pyrophosphate synthase (FPPS), a key enzyme involved in the mevalonate (MVA) pathway, which is aberrant in brain cancer. To develop new anti-glioma strategies, we tested related compounds exhibiting greater activity than i6A. Experimental Approach: We designed and synthesized i6A derivatives characterized by the introduction of diverse chemical moieties in the N6 position of adenosine and tested for their efficacy in U87 cells and in primary glioma cultures, derived from patients. NMR-based structural analysis, molecular docking calculations and siRNA mediated knockdown were used to clarify the molecular basis of their action, targeting FPPS protein. Key Results: CM223, the i6A derivative including a benzyl moiety in N6 position of adenine, showed marked activity in selectively targeting glioma cells, but not normal human astrocytes. This was due to induction of intrinsic pathways of apoptosis and inhibition of proliferation, along with blockade of FPPS-dependent protein prenylation, which counteracted oncogenic signalling mediated by EGF receptors. Conclusion and Implications: The biological effects together with structural data on interaction of CM223 with FPPS, provided additional evidence for the correlation of the i6A/CM223 antitumor activity with FPPS modulation. Because the MVA pathway is an important promising target, CM223 and its derivatives should be considered interesting active molecules in antiglioma research.
Ciaglia, Elena,Grimaldi, Manuela,Abate, Mario,Scrima, Mario,Rodriquez, Manuela,Laezza, Chiara,Ranieri, Roberta,Pisanti, Simona,Ciuffreda, Pierangela,Manera, Clementina,Gazzerro, Patrizia,D'Ursi, Anna Maria,Bifulco, Maurizio
supporting information
p. 2287 - 2301
(2017/06/28)

Selective Acylation of Nucleosides, Nucleotides, and Glycerol-3-phosphocholine in Water
A convenient selective synthesis of 2′,3′-di-O-acetyl-nucleotide-5′-phosphates, 2′,3′-di-O-acetyl-nucleotide-5′-triphosphates and 2′,3′,5′-tri-O-acetyl-nucleosides in water has been developed. Furthermore, a long-chain selective glycerol-3-phosphocholine diacylation is elucidated. These reactions are environmentally benign, rapid, high yielding, and the products are readily purified. Importantly, this reaction may indicate a prebiotically plausible reaction pathway for the selective acylation of key metabolites to facilitate their incorporation into protometabolism.
Fernández-García, Christian,Powner, Matthew W.
supporting information
p. 78 - 83
(2016/12/26)

α,β-Methylene-ADP (AOPCP) Derivatives and Analogues: Development of Potent and Selective ecto-5′-Nucleotidase (CD73) Inhibitors
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.
supporting information
p. 6248 - 6263
(2015/08/24)

Tosvinyl and besvinyl as protecting groups of imides, azinones, nucleosides, sultams, and lactams. Catalytic conjugate additions to tosylacetylene
The use of the 2-(4-methylphenylsulfonyl)-ethenyl (tosvinyl, Tsv) group for the protection of the NH group of a series of imides, azinones (including AZT), inosines, and cyclic sulfonamides has been examined. The Tsvprotected derivatives are obtained in excellent yields by conjugate addition to tosylacetylene (ethynyl p-tolyl sulfone). The stereochemistry of the double bond can be controlled at will: with only 1 mol % of Et3N or with catalytic amounts of NaH, the Z stereoisomers are generated almost exclusively, while the E isomers are obtained using a stoichiometric amount of DMAP. Analogous phenylsulfonylvinyl-protected groups (with the besvinyl or Bsv group instead of Tsv) are obtained stereospecifically by reaction with (Z)- or (E)-bis(phenylsulfonyl)ethene. For lactams and oxazolidinones, this last method is much better. The Tsv and Bsv groups are stable in the presence of non-nucleophilic bases and to acids. They can be removed highly effectively via a conjugate addition-elimination mechanism using pyrrolidine or sodium dodecanethiolate as nucleophiles.
Petit, Elena,Bosch, Llus,Font, Joan,Mola, Laura,Costa, Anna M.,Vilarrasa, Jaume
p. 8826 - 8834
(2015/01/08)

Nucleophile-catalyzed additions to activated triple bonds. protection of lactams, imides, and nucleosides with MocVinyl and related groups
Additions of lactams, imides, (S)-4-benzyl-1,3-oxazolidin-2-one, 2-pyridone, pyrimidine-2,4-diones (AZT derivatives), or inosines to the electron-deficient triple bonds of methyl propynoate, tert-butyl propynoate, 3-butyn-2-one, N-propynoylmorpholine, or
Mola, Laura,Font, Joan,Bosch, Lluis,Caner, Joaquim,Costa, Anna M.,Etxebarria-Jardi, Gorka,Pineda, Oriol,De Vicente, David,Vilarrasa, Jaume
p. 5832 - 5842
(2013/07/26)

TRIACETYL-3-HYDROXYPHENYLADENOSINE AND ITS USE FOR REGULATING BLOOD FAT
The invention discloses triacetyl-3-hydroxyphenyladenosine represented by formula (I), the preparation, the pharmaceutical composition and the use thereof. Specially, the invention discloses a new compound of 2',3',5'-tri-O-acetyl-N6-(3-hydroxyphenyl)adenosine. Using hypoxanthine nucleoside as starting material, the compound is prepared by acetylating with acetic anhydride, chlorinating with thionyl chloride, and being substituted with 3-hydroxy aniline. The invention also discloses the pharmaceutical composition comprising triacetyl-3-hydroxyphenyladenosine. The dosage forms of the said pharmaceutical composition include tablet, capsule, pill, injection, sustained release preparation, controlled release preparation or particulate delivery system. The medicament for treatment or precaution of hyperlipemia prepared by the compound of the invention has the advantages of significant hypolipidemic activity, less toxicity and adverse effect as well as slow metabolism in vivo.
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Page/Page column 5

(2012/02/04)

Simple method for fast deprotection of nucleosides by triethylamine- catalyzed methanolysis of acetates in aqueous medium
A straightforward methodology for deacetylation of protected ribonucleosides was developed based on triethylamine-catalyzed solvolysis in aqueous methanol. Reactions are completed in a few minutes under microwave irradiation and the free nucleosides are obtained in high yield after simple evaporation of volatiles. Other important features include the involvement of readily available reagents and the compatibility with diverse functional groups, which make this process very attractive for broad application.
Meier, Lidiane,Monteiro, Gustavo C.,Baldissera, Rodrigo A.M.,Sa?, Marcus Mandolesi
scheme or table
p. 859 - 866
(2010/09/11)

Design, synthesis and biological evaluation of a bivalent μ opiate and adenosine A1 receptor antagonist
The cross talk between different membrane receptors is the source of increasing research. We designed and synthesized a new hetero-bivalent ligand that has antagonist properties on both A1 adenosine and μ opiate receptors with a Ki of 0.8 ± 0.05 and 0.7 ± 0.03 μM, respectively. This hybrid molecule increases cAMP production in cells that over express the μ receptor as well as those over expressing the A1 adenosine receptor and reverses the antalgic effects of μ and A1 adenosine receptor agonists in animals.
Mathew, Smitha C.,Ghosh, Nandita,By, Youlet,Berthault, Aurelie,Virolleaud, Marie-Alice,Carrega, Louis,Chouraqui, Gaelle,Commeiras, Laurent,Condo, Jocelyne,Attolini, Mireille,Gaudel-Siri, Anouk,Ruf, Jean,Parrain, Jean-Luc,Rodriguez, Jean,Guieu, Regis
scheme or table
p. 6736 - 6739
(2010/06/14)

COMPOUND HAVING INHIBITORY ACTIVITY ON A RHO-GTPASE CELL PROTEIN, A PROCESS FOR OBTAINING THE SAME, PHARMACEUTICAL COMPOSITIONS COMPRISION THEREOF AND A METHOD FOR THE TREATMENT OF A RHO-GTPASE CELL PROTEIN-MEDIATED CONDITION
The present invention relates to a compound having inhibitory activity on a Rho-GTPase cell protein, the compound having the formula I (Formula I ) wherein A is selected from N and N-H, R1 is selected from H and NHR3, R2 is selected from NHR4, OR4, O and halogen, R3 is selected from H and -COR5, R4 is selected from H, a C1-C6 alkyl and a substituted or unsubstituted phenyl, R5 is selected from a C1-C12 alkyl and a substituted or unsubstituted phenyl, R6 is selected from H, -COR5, -CO2R5, -PR7R8 and -PR7R8OPR7R8R8R7, R7 is selected from O and S, R8 is selected from H, OR4 and OSATE (-OCH2CH2SCOR5), and wherein each represents a single bond or a double bond, provided that when one of them is a double bond the other one is a single bond, and pharmaceutically acceptable salts and derivatives thereof. In particular, the compounds of the invention may be used as antitumor agents the action of which interfere with the signaling pathways normally involved in tumor development processes. The invention also relates to processes for obtaining of compounds having inhibitory activity of a Rho- GTPase cell protein, to the pharmaceutical compositions thereof and to the therapeutic methods comprising the use of said compounds and compositions.
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Page/Page column 25-26

(2008/12/05)

New fluorescent adenosine A1-receptor agonists that allow quantification of ligand-receptor interactions in microdomains of single living cells
Fluorescence spectroscopy is becoming a valuable addition to the array of techniques available for scrutinizing ligand-receptor interactions in biological systems. In particular, scanning confocal microscopy and fluorescence correlation spectroscopy (FCS) allow the noninvasive imaging and quantification of these interactions in single living cells. To address the emerging need for fluorescently labeled ligands to support these technologies, we have developed a series of red-emitting agonists for the human adenosine A1-receptor that, collectively, are N6-aminoalkyl derivatives of adenosine or adenosine 5′-N-ethyl carboxamide. The agonists, which incorporate the commercially available fluorophore BODIPY [630/650], retain potent and efficacious agonist activity, as demonstrated by their ability to inhibit cAMP accumulation in chinese hamster ovary cells expressing the human adenosine A1-receptor. Visualization and confirmation of ligand-receptor interactions at the cell membrane were accomplished using confocal microscopy, and their suitability for use in FCS was demonstrated by quantification of agonist binding in small areas of cell membrane.
Middleton, Richard J.,Briddon, Stephen J.,Cordeaux, Yolande,Yates, Andrew S.,Dale, Clare L.,George, Michael W.,Baker, Julian G.,Hill, Stephen J.,Kellam, Barrie
p. 782 - 793
(2008/01/27)

Pyridine-free and solvent-free acetylation of nucleosides promoted by molecular sieves
A practical method for the acetylation of purine and pyrimidine nucleosides employing a combination of acetic anhydride and potassium-exchanged molecular sieves is described. Besides the high yields obtained for the acylated nucleosides, the procedure is simple, inexpensive and environmentally benign, avoiding the use of pyridine or co-solvents as additives. Georg Thieme Verlag Stuttgart.
Sá, Marcus Mandolesi,Meier, Lidiane
p. 3474 - 3478
(2007/10/03)

A novel nucleophilic approach to 1-alkyladenosines. A two-step synthesis of [1-15N]adenosine from inosine
A novel ANRORC mechanism in the reaction of 1-(2,4-dinitrobenzenesulfonyl) inosines with amines has allowed the preparation of 1-alkyladenosines and [1-15N]adenosines in a straightforward way from inosines. The Royal Society of Chemistry 2005.
Terrazas, Montserrat,Ariza, Xavier,Farras, Jaume,Vilarrasa, Jaume
p. 3968 - 3970
(2007/10/03)

The nucleoside transport proteins, NupC and NupG, from Escherichia coli: Specific structural motifs necessary for the binding of ligands
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.
p. 462 - 470
(2007/10/03)

IMPROVED SYNTHESIS OF 2-SUBSTITUTED ADENOSINES
A method of synthesis of a 2-substituted adenosine of formula I which comprises converting a compound of formula II to a compound of formula (I), wherein: R is C 1-6 alkoxy (straight or branched), a phenoxy group (unsubstituted, or mono-, or di-substituted by halo, amino, CF3-, cyano, nitro, C 1-6 alkyl, or C 1-6 alkoxy), a benzyloxy group (unsubstituted, or mono-, or di-substituted by halo, amino, CF3-, cyano, nitro, Cl_6 alkyl, or Cl_6 alkoxy), or a benzoyl group (unsubstituted, or mono-, or di-substituted by halo, amino, CF3-, cyano, nitro, C 1-6 alkyl, or C 1-6 alkoxy); R' = H, or a protecting group.
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Page/Page column 14

(2008/06/13)

THERAPEUTIC COMPOUNDS
Use of compounds of general formula (A) as medicaments is described, in particular for the treatment of pain or inflammation; wherein: (I) when X = OH, R2 = NH2, R5 = CH2OH, R6 = H , R1 is C5-C6 alkoxy, OCH2Cyclopropyl, O-(2,2,3,3-tetrafluoro-cycloButyl), phenoxy, substituted phenoxy, OCH2CH2OH, or OCH2CHF2, (5-indanyl)oxy, C1, C2, C5, or C6 alkylamino, (R) or (S)-sec-Butylamino, C5 or C6 cycloalkylamino, exo-norbornane amino, (N-methyl, N--isoamylamino), phenylamino, phenylamino with either rnethoxy or fluoro substituents, a C2 sulfone group, a C2 alkyl group, a cyano group, a CONH2 group, or 3,5-dimethylphenyl; or when X = H, R2 = NH2, R5 = CH2OH , R6 = H, R1 is n-hexyloxy; or (II) when X = OH , R1 = H, R5 = CH2OH, R6 = H, R2 is NMe2, N-(2-isopentenyl), piperazinyl, (N-Me, N-benzyl), (N-Me, N-CH2Ph(3-Br)), (N-Me, N--CH2Ph(3-CF3)), or (N-Me, N-(2-rnethoxyethyl)), or OCH2Cyclopentyl; or (III) when X = OH, R5 = CONHR3, R6 = H: R1 is H, R3 is an isopropyl group, and R2 is either NH2 or a methylamino group (NHMe) or an isoamyl group (CH2CH2CHMe2); or R1 is H, R3 is H, and R2 is NH2; or R1 is OMe, R3 is Ph, and R2 is NH2; or R1 is NHCH2CH2CH2CH2CH2Me, R3 is CH2CH2CH2Me, and R2 is NH2; or (IV) when X = OH, R1 = H, R2 = NH2, R5 = CH2NHCOR.4, R6 = H, R4 is n-propyl or NHCH2CH3; or (V) when X = OH, R5 = CH2OH, R6 = H: R1 is NHCyclohexyl when R2 is NMe2; or R1 is OMe when R2 is NHBenzyl; or (VI) when X = OH , R2 = NH2, R5 = CH2OH, R6 = Me, R1 is NHCyclohexyl or NHCyclopentyl.
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Page/Page column 42

(2008/06/13)

Advantages of the Ns group in the reactions of N1-SO 2R inosines with benzylamine and with 15NH3
The reactivity of N1-alkylsulfonyl- and N1- arylsulfonyl-2′,3′,5′-tri-O-acetylinosine with benzylamine and with 15NH3, regarding the attack on C2, has been shown to be in the order CF3SO2 (Tf) > 2,4-(NO 2)2C6H3SO2 (DNs) ≥ 4-NO2C6H4SO2 (pNs) ≈ C 6F5SO2 (PFBs) > 2-NO2C 6H4SO2 (Ns) ? CH3SO2 (Ms) > 4-CH3C6H4SO2 (Ts) > 2,4,6-(CH3)3C6H2SO2 (Mts). In spite of its intermediate reactivity, the Ns group is the most appropriate, since in this case the formation of by-products is minimised during the ring-opening and ring-closing steps of the process. Another advantage of the Ns group is thus disclosed.
Terrazas, Montserrat,Ariza, Xavier,Vilarrasa, Jaume
p. 5127 - 5130
(2007/10/03)

A Facile Synthesis of AICAR from Inosine
5-Amino-1-β-D-ribofuranosylimidazole-4-carboxamide (AICAR; 1) (Figure 1) was efficiently prepared from inosine through its 1-alkoxymethylderivatives. The stability of these derivatives enabled their purification by column chromatography (silica gel). The operation ensured the high quality of 1, which was obtained in good yield through alkaline hydrolysis of the derivatives.
Kohyama, Naoki,Yamamoto, Yukio
p. 2639 - 2642
(2007/10/03)

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
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
p. 851 - 873
(2007/10/03)

Nucleic acid related compounds. 116. Nonaqueous diazotization of aminopurine nucleosides. Mechanistic considerations and efficient procedures with tert-butyl nitrite or sodium nitrite
Nonaqueous diazotization-dediazoniation of two types of aminopurine nucleoside derivatives has been investigated. Treatment of 9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-2-amino-6-chloropurine (1) with SbCl3/CH2Cl2 was examined with benzyltriethylammonium (BTEA) chloride as a soluble halide source and tert-butyl nitrite (TBN) or sodium nitrite as the diazotization reagent. Optimized yields (>80%) of the 2,6-dichloropurine derivative were obtained with SbCl3. Combinations with SbBr3/CH2Br2 gave the 2-bromo-6-chloropurine product (>60%), and SbI3/CH2I2/THF gave the 2-iodo-6-chloropurine derivative (>45%). Antimony trihalide catalysis was highly beneficial. Mixed combinations (SbX3/CH2X′2; X/X′ = Bt/Cl) gave mixtures of 2-(bromo, chloro, and hydro)-6- chloropurine derivatives that were dependent on reaction conditions. Addition of iodoacetic acid (IAA) resulted in diversion of purine radical species into a 2-iodo-6-chloropurine derivative with commensurate loss of other radical-derived products. This allowed evaluation of the efficiency of SbX3-promoted cation-derived dediazoniations relative to radical-derived reactions. Efficient conversions of adenosine, 2′-deoxyadenosine, and related adenine nucleosides into 6-halopurine derivatives of current interest were developed with analogous combinations.
Francom, Paula,Janeba, Zlatko,Shibuya, Susumu,Robins, Morris J.
p. 6788 - 6796
(2007/10/03)

A chemical method for site-specific modification of RNA: The convertible nucleoside approach
Knowledge of RNA structure can greatly facilitate the understanding of its biological function. However, the physical properties of RNA, especially its conformational heterogeneity, present an impediment to high-resolution structural analysis. Thus,lower resolution methods such as biochemical probing, phylogenetic analysis, and molecular modeling have come to serve an important role in RNA science. This situation has created the need for a means by which to constrain RNA structure, either to reduce its conformational flexibility or to help distinguish between alternative structural models. To address this need, we have developed chemistry that permits the site-specific introduction of functionalizable tethers into RNA. Here we report the design and synthesis of reagents for use in solid-phase RNA synthesis that allow the functionalization of the base moiety of C, C, and A residues. Upon incorporation into oligonucleotides and subsequent treatment with alkylamines, the convertible nucleoside derivatives reported here give rise to functionally tethered N4-alkyl-C, N6-alkyl-A, and N2-alkyl-G residues in RNA. The derivatized RNAs can then be used to target the attachment of chemical probes or the placement of disulfide cross-links as structural constraints. The attachment of nonnatural functional groups to RNA in this fashion provides a powerful means of both probing its structural environment and constraining its conformation. The size and functionality of the N-alkyl modification is determined solely by the choice of alkylamine, thereby permitting the preparation of a wide range of functionally tethered RNAs.
Allerson, Charles R.,Chen, Swaine L.,Verdine, Gregory L.
p. 7423 - 7433
(2007/10/03)

Methods of making novel R and S diastereomers of N6 -[(2-hydroxypropyl)aryl]adenosines
A method of making novel R and S diastereomers of an N6 -[(2-hydroxypropyl)aryl] adenosine, which diastereomers exhibit fewer CNS side effects than the racemate, but with no decrease in cardiovascular activity.
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(2008/06/13)

An Unambiguous Synthesis of Adenylosuccinic Acid and its Constituent Nucleoside
6-(4-Chlorophenylthio)-9-(2,3-O-cyclopentylidene-β-D-ribofuranosyl)-9H-purine (7) is prepared from 6-chloro-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-9H-purine (5) in three steps and is then converted, by treatment with 3-chloroperbenzoic acid, into the corresponding sulphoxide (9) and crystalline sulphone (8) in ca. 88 and 65percent isolated yield, respectively.When the sulphoxide (9) is heated with dibenzyl L-aspartate in N,N-dimethylacetamide solution at 70-75 deg C for 28 hr, compound (11) is obtained in ca. 70percent isolated yield.Removal of the protecting groups from compound (11) gives N--L-aspartic acid (3) as a crystalline solid in ca. 68percent yield; phosphorylation of compound (11) with dibenzyl phosphorochloridate and removal of the protecting groups gives adenylosuccinic acid (1), isolated as its ammonium salt, in ca. 66percent yield.When the sulphone (8) is converted via compound (11) into the diacids (3) and (1), the products obtained appear to be contaminated with the D-acids (12) and (14), respectively, which are diastereomers of compounds (3) and (1).
Buck, Ildiko M.,Reese, Colin B.
p. 2937 - 2942
(2007/10/02)

An Efficient Regioselective Synthesis of Substituted Purine Analogues of Guanosine and Inosine
Condensation of 2-bromo-6-(4-nitrophenylethoxy)purine as the trimethylsilyl derivative (5a) with 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose, 1-O-acetyl-2,3-di-O-benzoyl-5-deoxy-5-diethoxy-phosphinyl-β-D-ribofuranose, and (2-acetoxyethoxy)methyl bromide resulted in N9-regioselective alkylation to give (6a-c), which were then converted to guanine and hypoxanthine nucleosides, nucleotides, and Acyclovir analogues, respectively.
Raju, Natarajan,Robins, Roland K.,Vaghefi, Morteza M.
p. 1769 - 1770
(2007/10/02)

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
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
p. 1887 - 1894
(2007/10/02)

Nucleic Acid Related Compounds. 48. Photoaddition of Methanol to 9-(β-D-Ribofuranosyl)purine (Nebularine) To Give Inhibitors of Adenosine Deaminase
Photolysis of anaerobic solutions of 9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine (2',3',5'-tri-O-acetylnebularine) (1b) in methanol at 2537 Angstroem gave a diastereomeric mixture of 9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-1,6-dihydro-6(R,S)-(hydroxymethyl)purines (2b) plus secondary photoproducts.The presence of oxygen resulted in more rapid formation of the 6-(hydroxymethyl)- (3b), 1,6-dihydro-6,6-bis(hydroxymethyl)- (4b), 6-methyl- (5b), and (R,S)-1,6-dihydro-6-(hydroxymethyl)-6-methyl-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine (6b) byproducts.Reevaluation of recently published claims that photoaddition of methanol to nebularine proceeded with high stereoselectivity is presented based on definitive 1H and 13C NMR spectral data and FAB mass spectrometry.
Buffel, Diederik K.,McGuigan, Christopher,Robins, Morris J.
p. 2664 - 2667
(2007/10/02)

PREPARATION OF 2 prime ,3 prime ,5 prime -TRIACETYLINOSINE.
The authors investigated different variants of acetylation of inosine. The simplest and most convenient method fo obtaining 2 prime ,3 prime ,5 prime -triacetyl inosine is brief boiling of inosine with acetic anhydride without a diluent in presence of a catalyst. Acetylation in this case is complete and hydrolysis of inosine does not occur under these reaction conditions (indicated by absence of the hydrolysis product, hypoxanthine, in the reaction mixture). It is found that in addition to sodium acetate, potassium acetate and tertiary amines (such as pyridine) have an accelerating effect on acetylation of inosine. Magnesium acetate is inactive. In absence of catalysts the reaction rate is lower by a factor of 5-7, and by-products can be detected (by TLC on Silufol) in the reaction mixture; there are probably products of incomplete acetylation of inosine.
Davidenkov,Ratsino,Antonenko,Komarov
p. 1991 - 1992
(2007/10/02)

Synthetic Transformations of Transient Purinyl Radicals: Formation of Mono- and Diarylated and Heteroarylated Nucleosides
Photolysis of 2,6-dihalogenated purine nucleosides produced, through cleavage of the carbon-halogen bond, both purin-2-yl and purin-6-yl radicals (or caged radical pairs) which were intercepted by aromatic solvents such as benzene to produce 2-aryl- or 2,6-diarylpurine nucleosides.Heteroarylations and their selectivities involving pyrrole, thiophene, furan, and pyridine systems were als explored.In all cases, except for the "?-deficient" pyridine, the photoinduced heteroarylations were regiospecific and the products photostable.Photoinduced hydration of 2-substituted 6-chloropurine nucleosides provides an excellent approach for the synthesis of uncommon 2-substituted inosine analogues.High-field 13C NMR data suggest that the 2,6-disubstituted purine nucleosides prefer the anti conformation in solution.
Nair, Vasu,Young, David A.
p. 4340 - 4344
(2007/10/02)