- Naturally occurring 2'-O-methylpurine nucleosides with hypotensive properties
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2'-O-Methylinosine (1) has been isolated for the first time and shown to be an intrinsic hypotensive principle. Its probable in vivo precursor. 2'-O-methyladenosine (3), showed stronger and even orally potent hypotensive activity. Resistance of the methyladenosine (3) against adenosine deaminase is thought to contribute to its long-lasting activity. The effect of both nucleosides (1 and 3) was not accompanied with any significant change in heart rate, which is often observed with adenosine.
- Yamada,Kageyama,Joh,Konishi,Ienaga
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Read Online
- Identification of Flavin Mononucleotide as a Cell-Active Artificial N6-Methyladenosine RNA Demethylase
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N6-Methyladenosine (m6A) represents a common and highly dynamic modification in eukaryotic RNA that affects various cellular pathways. Natural dioxygenases such as FTO and ALKBH5 are enzymes that demethylate m6A residues in mRNA. Herein, the first identification of a small-molecule modulator that functions as an artificial m6A demethylase is reported. Flavin mononucleotide (FMN), the metabolite produced by riboflavin kinase, mediates substantial photochemical demethylation of m6A residues of RNA in live cells. This study provides a new perspective to the understanding of demethylation of m6A residues in mRNA and sheds light on the development of powerful small molecules as RNA demethylases and new probes for use in RNA biology.
- Xie, Li-Jun,Yang, Xiao-Ti,Wang, Rui-Li,Cheng, Hou-Ping,Li, Zhi-Yan,Liu, Li,Mao, Lanqun,Wang, Ming,Cheng, Liang
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supporting information
p. 5028 - 5032
(2019/03/17)
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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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- Selective inhibition of TRPM2 channel by two novel synthesized ADPR analogues
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Transient receptor potential melastatin-2 (TRPM2) channel critical for monitoring internal body temperature is implicated in the pathological processes such as neurodegeneration. However, lacking selective and potent TRPM2 inhibitors impedes investigation and validation of the channel as a drug target. To discover novel and selective TRPM2 inhibitors, a series of adenosine 5′-diphosphoribose analogues were synthesized, and their activities and selectivity were evaluated. Whole-cell patch-clamp recordings were employed for screen and evaluation of synthesized compounds. Two compounds, 7i and 8a, were identified as TRPM2 inhibitors with IC50 of 5.7 and 5.4?μm, respectively. Both 7i and 8a inhibited TRPM2 current without affecting TRPM7, TRPM8, TRPV1 and TRPV3. These two TRPM2 inhibitors can serve as new pharmacological tools for further investigation and validation of TRPM2 channel as a drug target, and the summarized structure–activity relationship (SAR) may also provide insights into further improving existing inhibitors as potential lead compounds.
- Luo, Xiao,Li, Meng,Zhan, Kaiyu,Yang, Wei,Zhang, Lihe,Wang, KeWei,Yu, Peilin,Zhang, Liangren
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p. 552 - 566
(2017/11/21)
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- Improved synthesis and isolation of 2'-O-methyladenosine: Effective and scalable enzymatic separation of 2'/3'-O-methyladenosine regioisomers
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An efficient separation of a mixture of 2'/3'-O-methyladenosine regioisomers (1 + 2: 1:1) has been developed by selective enzymatic acylation using immobilized Pseudomonas cepacia lipase (PSL-C) in combination with acetonoxime levulinate as acyl donor. Th
- Martinez-Montero, Saul,Fernandez, Susana,Rodriguez-Perez, Tatiana,Sanghvi, Yogesh S.,Wen, Ke,Gotor, Vicente,Ferrero, Miguel
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experimental part
p. 3265 - 3271
(2009/12/24)
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- Antiviral amphipathic oligo- and polyribonucleotides: Analogue development and biological studies
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A series of novel N1 alkylated purine nucleic acids were polymerized either enzymatically or by automated synthesis to further establish the SAR requirements for HIV, RT, and HCMV activity. Out of the series, two constructs, 2′-O-methyl-1-allylinosinic ac
- Hyde, Robyn M.,Broom, Arthur D.,Buckheit Jr., Robert W.
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p. 1878 - 1885
(2007/10/03)
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- Novel fluoride-labile nucleobase-protecting groups for the synthesis of 3'(2')-O-aminoacylated RNA sequences
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With the aim to develop a general approach to a total synthesis of aminoacylated t-RNAs and analogues, we describe the synthesis of stabilized, aminoacylated RNA fragments, which, upon ligation, could lead to aminoacylated t-RNA structures. Novel RNA phosphoramidites with fluoride-labile 2'-O-[(triisopropylsilyl)-oxy]methyl (=tom) sugar-protecting and N-{{2-[(triisopropylsilyl)oxy]benzyl}oxy}carbonyl (=tboc) base-protecting groups were prepared (Schemes 4 and 5), as well as a solid support containing an immobilized N6-tboc-protected adenosine with an orthogonal (photolabile) 2'-O-[(S)-1-(2-nitrophenyl)ethoxy]methyl (=(S)-npeom) group (Scheme 6). From these building blocks, a hexameric oligoribonucleotide was prepared by automated synthesis under standard conditions (Scheme 7). After the detachment from the solid support, the resulting fully protected sequence 34 was aminoacylated with L-phenylalanine derivatives carrying photolabile N-protecting groups (→42 and 43; Scheme 9). Upon removal of the fluoride-labile sugar- and nucleobase-protecting groups, the still stabilized, partially with the photolabile group protected precursors 44 and 45, respectively, of an aminoacylated RNA sequence were obtained (Scheme 9 and Fig. 3). Photolysis of 45 under mild conditions resulted in the efficient formation of the 3'(2')-O-aminoacylated RNA sequence 46 (Fig. 4). Additionally, we carried out model investigations concerning the stability of ester bonds of aminoacylated ribonucleotide derivatives under acidic conditions (Table) and established conditions for the purification and handling of 3'(2')-O-aminoacylated RNA sequences and their stabilized precursors.
- Stutz, Alfred,Hoebartner, Claudia,Pitsch, Stefan
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p. 2477 - 2503
(2007/10/03)
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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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- 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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- Antisense inhibition of ras gene with chimeric and alternating oligonucleotides
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Compositions and methods are provided for the modulation of expression of the human ras gene in both the normal and activated forms. Oligonucleotides are provided that have methylene(methylimino) linkages alternating with phosphorothioate or phosphodiester linkages. Further oligonucleotides are provide that have a first region having a methylene(methylimino) linkage alternating with a phosphorothioate or phosphodiester linkage and a second region having phosphorothioate linkages. Such oligonucleotides can be used for diagnostics as well as for research purposes including methods for diagnosis, detection and treatment of conditions arising from the activation of the H-ras gene.
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- Solid-phase synthesis of carbohydrate and phosphodiester modified 2'-5' oligoadenylate analogs
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A series of 2'-5' oligoadenylate analogs containing internucleotide and ribose modifications were prepared by solid-phase methods as potential interferon mimetics. All syntheses were carried out using automated methodologies with precursors that allow for the generation of multiple combinations of modification.
- Hartsel, Stephanie A.,Marshall, William S.
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p. 2993 - 2998
(2007/10/03)
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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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- Novel adenosine derivatives and pharmaceutical composition containing them as an active ingredient
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Novel adenosine compounds of the formula (I): STR1 wherein R1, R2 and R3 are hydrogen or a lower alkyl group; X is hydrogen, a lower alkyl group, an amino group or halogen; and Y is hydrogen or a lower alkyl group, exhibit utility as antihypertensive agents.
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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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