- Efficient large scale synthesis of 2′-O-alkyl pyrimidine ribonucleosides
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An efficient process to synthesize 2′-O-alkyl pyrimidine ribonucleosides in high yield has been described. The inexpensive method was used on a multikilogram-scale synthesis and optimized reaction conditions have been investigated.
- Roy, Saroj K.,Tang, Jin-Yan
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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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- Synthesis and solution conformation studies of the modified nucleoside N4,2′-O-dimethylcytidine (m4Cm) and its analogues
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The dimethylated ribosomal nucleoside m4Cm and its monomethylated analogues Cm and m4C were synthesized. The conformations (syn vs anti) of the three modified nucleosides and cytidine were determined by CD and 1D NOE difference spectroscopy. The ribose sugar puckers were determined by the use of proton coupling constants. The position of modification (e.g., O vs N methylation) was found to have an effect on the sugar pucker of cytidine.
- Mahto, Santosh K.,Chow, Christine S.
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p. 8795 - 8800
(2008/12/23)
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- Sugar modified oligonucleotides
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Compositions and methods are provided for the treatment and diagnosis of diseases amenable to modulation of the production of selected proteins. In accordance with preferred embodiments, oligonucleotides and oligonucleotide analogs are provided which are specifically hybridizable with a selected sequence of RNA or DNA wherein at least one of the 2′-deoxyfuranosyl moieties of the nucleoside unit is modified. Treatment of diseases caused by various viruses and other causative agents is provided.
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- 2'modified oligonucleotides
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Compositions and methods are provided for the treatment and diagnosis of diseases amenable to modulation of the production of selected proteins. In accordance with preferred embodiments, oligonucleotides and oligonucleotide analogs are provided which are specifically hybridizable with a selected sequence of RNA or DNA wherein at least one of the 2′-deoxyfuranosyl moieties of the nucleoside unit is modified. Treatment of diseases caused by various viruses and other causative agents is provided.
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- Improved synthetic approaches toward 2'-O-methyl-adenosine and guanosine and their N-acyl derivatives
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We developed several improved approaches toward 2'-O-methyl adenosine and guanosine and their N-acyl derivatives. (a) Transglycosylation of N4- acetyl-5', 3'-di-O-acetyl-2'-O-methyl cytidine with N6-Bz-adenine provided N6-benzoyl-5'3'-di-O-acetyl-2'-O-methyl adenosine in 50% yield. (b) Regioselective methylation of 2-amino-6-chloro purine riboside with MeI/NaH followed by hydrolysis provided 2'-O-Me-guanosine in high yield. The same 2'- O-Me-precursor was transformed into 2'-O-Me-adenosine in 58% yield. (c) Very efficient transformation of 2,6-diamino-purine riboside into N2-isobutyryl (isopropylphenoxyacetyl) 2'-O-Me-guanosine through methylation of 5',3'-O- TIPDSi derivative followed by selective N2-acylation, deamination and desylilation provided target compounds in 70% combined yield. (d) Mg2+ and Ag+ directed methylation of N1-Bzl-guanosine proceeded in >80% yield with ratio of 2'-O-Me-3'-O-Me=9:1. The same methylation of adenosine with Ag+ and Sr2+ acetylacetonates provided 2'-O-Me-adenosine in 75-80% yield. (C) 2000 Elsevier Science Ltd.
- Beigelman, Leonid,Haeberli, Peter,Sweedler, David,Karpeisky, Alexander
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p. 1047 - 1056
(2007/10/03)
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- 2'-modified oligonucleotides
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Compositions and methods are provided for the treatment and diagnosis of diseases amenable to modulation of the production of selected proteins. In accordance with preferred embodiments, oligonucleotides and oligonucleotide analogs are provided which are specifically hybridizable with a selected sequence of RNA or DNA wherein at least one of the 2'-deoxyfuranosyl moieties of the nucleoside unit is modified. Treatment of diseases caused by various viruses and other causative agents is provided.
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- 2'-O-modified oligonucleotides
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Compositions and methods are provided for the treatment and diagnosis of diseases amenable to modulation of the production of selected proteins. In accordance with preferred embodiments, oligonucleotides and oligonucleotide analogs are provided which are specifically hybridizable with a selected sequence of RNA or DNA wherein at least one of the 2'-deoxyfuranosyl moieties of the nucleoside unit is modified. Treatment of diseases caused by various viruses and other causative agents is provided.
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- 2'-modified oligonucleotides
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Compositions and methods are provided for the treatment and diagnosis of diseases amenable to modulation of the production of selected proteins. In accordance with preferred embodiments, oligonucleotides and oligonucleotide analogs are provided which are specifically hybridizable with a selected sequence of RNA or DNA wherein at least one of the 2'-deoxyfuranosyl moieties of the nucleoside unit is modified. Treatment of diseases caused by various viruses and other causative agents is provided.
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- Chemical syntheses of 2'-O-methoxy purine nucleosides
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Several processes for the chemical synthesis of 2'-O-methoxy purine nucleosides are herein disclosed.
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- Process for the preparation of 2'-O-alkyl purine phosphoramidites
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2'-O-alkylated guanosine, uridine, cytidine, and 2,6-diaminopurine 3'-O-phosphoramidites are prepared by alkylating nucleoside precursors, adding suitable blocking groups and phosphitylating. Alkylation is effected on 2,6-diamino-9-(β-D-ribofuranosyl)purine followed by deamination to prepare guanosine 2'-O-alkylated 3'-O-phosphormidites. Alkylation is effected on a dialkyl stannylene derivative of uridine to prepare uridine 2'-O-alkylated 3'-O-phosphormidites. Alkylation is effected directly on cytidine to prepare cytidine 2'-O-alkylated 3'-O-phosphormidites. Alkylation is effected directly on 2,6-diaminopurine to prepare 2,6-diaminopurine 2'-O-alkylated 3'-O-phosphormidites.
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- 176. Nucleosides part LXI: A simple procedure for the monomethylation of protected and unprotected ribonucleosides in the 2′-O- and 3′-O-position using diazomethane and the catalyst stannous chloride
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Intensive studies on the diazomethane methylation of the common ribonucleosides uridine, cytidine, adenosine, and guanosine and its derivatives were performed to obtain preferentially the 2′-O-methyl isomers. Methylation of 5′-O-(monomethoxytrityl)-N 2-[2-(4-nitrophenyl)ethoxycarbonyl]-O 6-[2-(4-nitrophenyl)ethyl]-guanosine (1) with diazomethane resulted in an almost quantitative yield of the 2′-nd 3′-O-methyl isomers which could be separated by simple silica-gel flash chromatography (Scheme 1). Adenosine, cytidine, and uridine were methylated with diazomethane with and without protection of the 5′-O-position by a mono- or dimethoxytrityl group and the aglycone moiety of adenosine and cytidine by the 2-(4-nitrophenyl)ethoxycarbonyl (npeoc) group (Schemes 2-4). Attempts to increase the formation of the 2′-O-methyl isomer as much as possible were based upon various solvents, temperatures, catalysts, and concentration of the catalysts during the methylation reaction.
- Cramer, Hagen,Pfleiderer, Wolfgang
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p. 2114 - 2136
(2007/10/03)
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- Alternate approaches to the synthesis of 2'-O-Me nucleosides
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Three different approaches to the synthesis of 2'-O-methyl nucleosides starting from the corresponding nucleoside or commercially available 1,2:5,6-di-O-isopropylidene-α-D-allofuranose 1 are described.
- Beigelman,Karpeisky,Matulic-Adamic,Usman
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p. 421 - 425
(2007/10/02)
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- Synthesis and Conformational Analysis of Phosphate-Methylated RNA Dinucleotides
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Synthesis of RNA dimers having a methyl phosphotriester group as the internucleoside linkage is reported; six pairs of diastereoisomerically pure systems were prepared, i.e., r(CpU) (15), r(ApU) (16), r(CpC) (17), r(ApC) (18), r(CpG) (19), and r(ApG) (20).Compounds 15-20 are stabilized by a 2'-O-methyl group in the 5'-terminal residue.The present systems represent the third class of backbone-modified RNA oligomers, following the 2'-O-methylribonucleotide phosphorothioates and the 2'-O-methylribonucleotide methyl phosphonates.Our synthetic approach comprises the use of 9-fluorenylmethoxycarbonyl (Fmoc) groups for transient protection of the exocyclic NH2 groups of the bases A, C, and G, levulinoyl (Lev) groups for the transient protection of the 2'- and 3'-OH groups of the 3'-terminal residue, methanolic K2CO3 for the simultaneous removal of Fmoc and Lev groups with full preservation of the methyl phosphotriester function, and finally reversed-phase HPLC separation of the SP and RP diastereoisomers.The availability of the six dimers in diastereoisomerically pure form enabled us to examine the molecular conformation using high-field NMR and circular dichroism (CD) spectroscopy.These studies led to the following conclusions: (i) NMR J-coupling analysis: the central C4'-C5' (γ) and C5'-O5' (β) bonds in 15-20 show less preference for the γ+ and βt rotamers, in comparison with their natural analogues, i.e., base stacking is diminished upon introduction of the two methyl groups on O2' and on the phosphate group; (ii) CD analysis: 15-20 show substantially reduced molecular ellipticities when compared to the natural counterparts, which also reveals that base stacking is reduced; (iii) UV and variable-temperature 1H NMR measurements: (SP)- and (RP)-19 show self-association, via the formation of a right-handed miniduplex with two C-G base pairs ((SP)-19, Tm = 9.3 deg C, concn = 36.6 μM; (RP)-19, Tm = 8.7 deg C, concn = 48.1 μM).The present conformational data on (RP)- and (SP)-15-20 are in agreement with literature data on other phosphate-triesterified oligonucleotides, e.g., the trimer d(TPOEtGPOEtG) and the tetramer d(TPOEtTPOEtCPOEtA).While the latter systems also showed little base-base stacking, it was estabished that they readily form a local duplex with a complementary natural RNA sequence.Hence we anticipate that phosphate-methylated 2'-O-methyl RNA oligomers, longer than the dimer systems described in the present work, will also hybridize easily with complementary natural RNA.
- Quaedflieg, Peter J. L. M.,Heiden, Arthur P. van der,Koole, Leo H.,Coenen, Annie J. J. M.,Wal, Sjoerd van der,Meijer, Emmo M.
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p. 5846 - 5859
(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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- Synthesis of O2'-methyluridine, O2'-methylcytidine, N4,O2'-dimethylcytidine and N4,N4,O2'-trimethylcytidine from a common intermediate.
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A facile synthesis of the title compounds from a readily accessible precursor, 3',5'-O-bis-protected O4-(2-nitrophenyl)uridine, is described.
- Nyilas,Chattopadhyaya
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p. 826 - 830
(2007/10/02)
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- Synthesis of 2',3'-Differentiated Ribonucleosides via Glycosylation. Reactions with 2-O-Me or 2-O-TBDMS Ribofuranose Derivatives. 1. Pyrimidine Series
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The synthesis of 2',3' asymmetrically substituted pyrimidine ribonucleosides in 70-95percent yields by using modified Vorbruggen conditions with "nonparticipating" 2-O-CH3 and 2-O-TBDMS ribofuranoses is described.Such compounds are useful synthons for oligoribonucleotide synthesis, including incorporation of "rare" bases.New and practically useful conditions for placement (using 1,2,4-triazole) and removal (KF/crown ether) of the tert-butyldimethylsilyl (TBDMS) protecting group are also reported.
- Chavis, C.,Dumont, F.,Wightman, R. H.,Ziegler, J. C.,Imbach, J. L.
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p. 202 - 206
(2007/10/02)
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- MECHANISM OF METHYLATION OF NUCLEOSIDE SUGAR HYDROXYL GROUPS BY DIAZOMETHANE IN THE PRESENCE OF STANNOUS CHLORIDE
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Diazomethane rapidly reacts with SnCl2 in methanol to give MeCl and Sn(OMe)2, both of which were isolated and identified.This reaction is the initial step in the apparent SnCl2*2H2O-catalysed methylation of nucleoside by diazomethane.The actual catalyst, Sn(OMe)2, readily reacts with Broensted acids, with exchange of ligands.For ribofuranosyl nucleusides, Sn2+ binds to site(s) having a labile proton, the effect being particulary predominant with 5- and 6-membered cyclic structures, with the tin ion co-ordinated to the ionised hydroxyl groups of the sugar moiety.These cyclic structures account for the high reactivity of the hydroxyl groups towards Me+, as in the complexes of ribofuranosyl nucleosides with Bu2SnO.A similar, if not identical, mechanism operates in the case of glucopyranosides.
- Dudycz, Lech,Kotlicki, Andrzej,Shugar, David
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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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