- Synthesis of adenosine cyclic 3′,5′ -phosphorofuoridate (camp-f)
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Work aimed at the chiral synthesis of both diastereomers of adenosine cyclic 3′,5′phosphorofluoridate, cAMP-F 7, is described. Attempted debenzoylation of the intermediate N6,N6,O2′tribenzoyladenosine cyclic 3′,5′-phosphorofluoridate 4 by ammonolysis resulted in cleavage of the P-F bond. Reaction of [Sp]-S-methyl adenosine 3′,5′-cyclophosphorothioate 6 with AgF gives a mixture of the two diastereoisomers of the cyclic phosphore fluoridate 7 along with adenosine 2′ ,3′-cyclic phosphate 8. The conversion of 7 into 8 can be completed under remarkably mild conditions. Possible mechanisms for this unusual transformation are discussed.
- Baraniak, Janina,Stec, Wojciech J.,Blackburn, G. Michael
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- Cyanamide as a prebiotic phosphate activating agent-catalysis by simple 2-oxoacid salts
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Cyanamide is a prebiotically plausible compound that has previously been invoked as a phosphate activating agent. However, its reactions with phosphate monoesters are very slow and tend to be low yielding. We now report a fast and efficient phosphate activation reaction using cyanamide in the presence of glyoxylate or pyruvate. These simple 2-oxoacid salts are shown to function as catalysts and in an optimised system, adenosine-3′-phosphate was converted to adenosine-2′,3′-cyclic phosphate in 95% yield.
- Tsanakopoulou, Maria,Sutherland, John D.
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Read Online
- The Stereochemical Course of Substitution of Sulfur by Oxygen Nucleophiles in Five-membered Cyclic Phosphorothioates
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The replacement of non-bridging sulfur in five-membered cyclic phosphorothioates by oxygen nucleophiles in the presence of bromine occurs with retention of configuration and has allowed the 31P NMR signals of the diastereoisomeric tert-butyldiphenyl silyl esters of 2',3'-cyclic adenosine monophosphate to be assigned.
- Lowe, Gordon,Thelin, Mats
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Read Online
- Prebiotically Plausible RNA Activation Compatible with Ribozyme-Catalyzed Ligation
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RNA-catalyzed RNA ligation is widely believed to be a key reaction for primordial biology. However, since typical chemical routes towards activating RNA substrates are incompatible with ribozyme catalysis, it remains unclear how prebiotic systems generated and sustained pools of activated building blocks needed to form increasingly larger and complex RNA. Herein, we demonstrate in situ activation of RNA substrates under reaction conditions amenable to catalysis by the hairpin ribozyme. We found that diamidophosphate (DAP) and imidazole drive the formation of 2′,3′-cyclic phosphate RNA mono- and oligonucleotides from monophosphorylated precursors in frozen water-ice. This long-lived activation enables iterative enzymatic assembly of long RNAs. Our results provide a plausible scenario for the generation of higher-energy substrates required to fuel ribozyme-catalyzed RNA synthesis in the absence of a highly evolved metabolism.
- Song, Emilie Yeonwha,Jiménez, Eddy Ivanhoe,Lin, Huacan,Le Vay, Kristian,Krishnamurthy, Ramanarayanan,Mutschler, Hannes
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supporting information
p. 2952 - 2957
(2020/12/13)
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- Harnessing chemical energy for the activation and joining of prebiotic building blocks
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Life is an out-of-equilibrium system sustained by a continuous supply of energy. In extant biology, the generation of the primary energy currency, adenosine 5′-triphosphate and its use in the synthesis of biomolecules require enzymes. Before their emergence, alternative energy sources, perhaps assisted by simple catalysts, must have mediated the activation of carboxylates and phosphates for condensation reactions. Here, we show that the chemical energy inherent to isonitriles can be harnessed to activate nucleoside phosphates and carboxylic acids through catalysis by acid and 4,5-dicyanoimidazole under mild aqueous conditions. Simultaneous activation of carboxylates and phosphates provides multiple pathways for the generation of reactive intermediates, including mixed carboxylic acid–phosphoric acid anhydrides, for the synthesis of peptidyl–RNAs, peptides, RNA oligomers and primordial phospholipids. Our results indicate that unified prebiotic activation chemistry could have enabled the joining of building blocks in aqueous solution from a common pool and enabled the progression of a system towards higher complexity, foreshadowing today’s encapsulated peptide–nucleic acid system. [Figure not available: see fulltext.].
- Liu, Ziwei,Wu, Long-Fei,Xu, Jianfeng,Bonfio, Claudia,Russell, David A.,Sutherland, John D.
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p. 1023 - 1028
(2020/10/26)
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- A Stark Contrast to Modern Earth: Phosphate Mineral Transformation and Nucleoside Phosphorylation in an Iron- and Cyanide-Rich Early Earth Scenario
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Organophosphates were likely an important class of prebiotic molecules. However, their presence on the early Earth is strongly debated because the low availability of phosphate, which is generally assumed to have been sequestered in insoluble calcium and iron minerals, is widely viewed as a major barrier to organophosphate generation. Herein, we demonstrate that cyanide (an essential prebiotic precursor) and urea-based solvents could promote nucleoside phosphorylation by transforming insoluble phosphate minerals in a “warm little pond” scenario into more soluble and reactive species. Our results suggest that cyanide and its derivatives (metal cyanide complexes, urea, ammonium formate, and formamide) were key reagents for the participation of phosphorus in chemical evolution. These results allow us to propose a holistic scenario in which an evaporitic environment could concentrate abiotically formed organics and transform the underlying minerals, allowing significant organic phosphorylation under plausible prebiotic conditions.
- Burcar, Bradley,Casta?eda, Alma,Lago, Jennifer,Daniel, Mischael,Pasek, Matthew A.,Hud, Nicholas V.,Orlando, Thomas M.,Menor-Salván, César
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p. 16981 - 16987
(2019/11/11)
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- Cleavage of short oligoribonucleotides by a Zn2+binding multi-nucleating azacrown conjugate
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A multi-nucleating azacrown conjugate (5a) consisting of two 3,5-bis(1,5,9-triazacyclododecan-3-yloxymethyl)benzyl groups attached to 1 and 7 sites of cyclen was prepared and tested as an artificial ribonuclease. The conjugate in the presence of five equivalents of zinc nitrate expectedly showed uridine selectivity comparable to that 1,3,5-tris(1,5,9-triazacyclododecan-3-yl)benzene (2), a compound known to bind to two adjacent uridine residues and cleave the intervening phosphodiester bond. 5a was, however, unable to discriminate between two and three adjacent uridine residues, but cleaved oligonucleotides containing a UpU and UpUpU site at a comparable rate, even when present at sub-saturating concentrations.
- Laine, Maarit,L?nnberg, Tuomas,Helkearo, Mia,L?nnberg, Harri
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p. 111 - 117
(2016/10/04)
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- Catalysis of diribonucleoside monophosphate cleavage by water soluble copper(II) complexes of calix[4]arene based nitrogen ligands
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Calix[4]arenes functionalized at the 1,2-, 1,3-, and 1,2,3-positions of the upper rim with [12]ane-N3 ligating units were synthesized, and their bi- and trimetallic zinc(II) and copper(II) complexes were investigated as catalysts in the cleavage of phosphodiesters as RNA models. The results of comparative kinetic studies using monometallic controls indicate that the subunits of all of the zinc(II) complexes and of the 1,3-distal bimetallic copper(II) complex 7-Cu2 act as essentially independent monometallic catalysts. The lack of cooperation between metal ions in the above complexes is in marked contrast with the behavior of the 1,2-vicinal bimetallic copper(II) complex 6-Cu2, which exhibits high catalytic efficiency and high levels of cooperation between metal ions in the cleavage of HPNP and of diribonucleoside monophosphates NpN′. A third ligated metal ion at the upper rim does not enhance the catalytic efficiency, which excludes the simultaneous cooperation in the catalysis of the three metal ions in 8-Cu 3. Rate accelerations relative to the background brought about by 6-Cu2 and 8-Cu3 (1.0 mM catalyst, water solution, pH 7.0, 50 °C) are on the order of 104-fold, largely independent of the nucleobase structure, with the exception of the cleavage of diribonucleoside monophosphates in which the nucleobase N is uracil, namely UpU and UpG, for which rate enhancements rise to 105-fold. The rationale for the observed selectivity is discussed in terms of deprotonation of the uracil moiety under the reaction conditions and complexation of the resulting anion with one of the copper(II) centers.
- Cacciapaglia, Roberta,Casnati, Alessandro,Mandolini, Luigi,Reinhoudt, David N.,Salvio, Riccardo,Sartori, Andrea,Ungaro, Rocco
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p. 12322 - 12330
(2007/10/03)
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- Simultaneous interaction with base and phosphate moieties modulates the phosphodiester cleavage of dinucleoside 3′,5′-monophosphates by dinuclear Zn2+complexes of Di(azacrown) ligands
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Five dinucleating ligands (1-5) and one trinucleating ligand (6) incorporating 1,5,9-triazacyclododecan-3-yloxy groups attached to an aromatic scaffold have been synthesized. The ability of the Zn2+ complexes of these ligands to promote the transesterification of dinucleoside 3′,5′-monophosphates to a 2′,3′-cyclic phosphate derived from the 3′-linked nucleoside by release of the 5′-linked nucleoside has been studied over a narrow pH range, from pH 5.8 to 7.2, at 90 °C. The dinuclear complexes show marked base moiety selectivity. Among the four dinucleotide 3′,5′-phosphates studied, viz. adenylyl-3′,5′-adenosine (ApA), adenylyl-3′,5′-uridine (ApU), uridylyl-3′,5′-adenosine (UpA), and uridylyl-3′, 5′-uridine (UpU), the dimers containing one uracil base (ApU and UpA) are cleaved up to 2 orders of magnitude more readily than those containing either two uracil bases (UpU) or two adenine bases (ApA). The trinuclear complex (6), however, cleaves UpU as readily as ApU and UpA, while the cleavage of ApA remains slow. UV spectrophotometric and 1H NMR spectroscopic studies with one of the dinucleating ligands (3) verify binding to the bases of UpU and ApU at less than millimolar concentrations, while no interaction with the base moieties of ApA is observed. With ApU and UpA, one of the Zn2+- azacrown moieties in all likelihood anchors the cleaving agent to the uracil base of the substrate, while the other azacrown moiety serves as a catalyst for the phosphodiester transesterification. With UpU, two azacrown moieties are engaged in the base moiety binding. The catalytic activity is, hence, lost, but it can be restored by addition of a third azacrown group on the cleaving agent.
- Wang, Qi,Loennberg, Harri
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p. 10716 - 10728
(2007/10/03)
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- Expeditious, potentially primordial, aminoacylation of nucleotides
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(Chemical Equation Presented) In the beginning: Mixed carboxylic phosphoric anhydrides 3, formed from 3′-nucleotides 1 and amino acid N-carboxyanhydrides 2, undergo competing rearrangement to 2′-aminoacyl esters 4 and cyclization to 2′,3′-cyclic phosphates 5. The intramolecular aminoacyl transfer is faster than the cyclization despite the ease with which 2′,3′-cyclic phosphates are formed through any other form of phosphate activation.
- Biron, Jean-Philippe,Parkes, Alastair L.,Pascal, Robert,Sutherland, John D.
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p. 6731 - 6734
(2007/10/03)
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- The pKa of the internucleotidic 2′-hydroxyl group in diribonucleoside (3′→5′) monophosphates
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Ionization of the internucleotidic 2′-hydroxyl group in RNA facilitates transesterification reactions in Group I and II introns (splicing), hammerhead and hairpin ribozymes, self-cleavage in lariatRNA, and leadzymes and tRNA processing by RNase P RNA, as well as in some RNA cleavage reactions promoted by ribonucleases. Earlier, the pKa of 2′-OH in mono- and diribonucleoside (3′-5′) monophosphates had been measured under various nonuniform conditions, which make their comparison difficult. This work overcomes this limitation by measuring the pKa values for internucleotidic 2′-OH of eight different diribonucleoside (3′-5′) monophosphates under a set of uniform noninvasive conditions by 1H NMR. Thus the pKa is 12.31 (±0.02) for ApG and 12.41 (±0.04) for ApA, 12.73 (±0.04) for GpG and 12.71 (±0.08) for GpA, 12.77 (±0.03) for CpG and 12.88 (±0.02) for CpA, and 12.76 (±0.03) for UpG and 12.70 (±0.03) for UpA. By comparing the pKas of the respective 2′-OH of monomeric nucleoside 3′-ethyl phosphates with that of internucleotidic 2′-OH in corresponding diribonucleoside (3′→5′) monophosphates, it has been confirmed that the aglycons have no significant effect on the pKa values of their 2′-OH under our measurement condition, except for the internucleotidic 2′-OH of 9-adeninyl nucleotide at the 5′-end (ApA and ApG), which is more acidic by 0.3-0.4 pKα units.
- Acharya,Foeldesi,Chattopadhyaya
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p. 1906 - 1910
(2007/10/03)
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- Hydrolysis of diribonucleoside monophosphate diesters assisted by a manganese(II) complex
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An Mn2+ complex with 2,2′:6′,2″-terpyridine (terpy) was found to promote the hydrolysis of NpN (NpN = diribonucleoside monophosphate diester) efficiently at pH 7.0 and 50 °C under ambient conditions. The structure of the Mn2+ complex involving a phosphodiester molecule, [(terpy)(dpp)MnII(μ-dpp) 2MnII(dpp)(terpy)], dpp = diphenyl phosphate anion, was established by X-ray crystallography, and the coordination mode of Mn 2+ to a phosphodiester molecule was considered.
- Yashiro, Morio,Higuchi, Maiko,Komiyama, Makoto,Ishii, Youichi
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p. 1813 - 1817
(2007/10/03)
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- Effect of alkaline earth metal ions on the phosphodiester hydrolysis of RNA
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Hydrolyses of di- and triribonucleotides assisted by alkaline earth metal ions were investigated at pH 7.3 and 50 °C. Mg2+ was the most effective for the phosphodiester hydrolysis, and the rate exhibited first-order dependence on the concentration of Mg2+ in a range of 0.1-1.0 mol dm-3.
- Yashiro, Morio,Higuchi, Maiko,Washizu, Yusuke,Komiyama, Makoto
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p. 1843 - 1844
(2007/10/03)
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- RNA hydrolysis by cobalt(III) complexes
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Adenylyl(3′-5′)adenosine (ApA) and uridylyl(3′-5′)uridine (UpU) are hydrolyzed at pH 7.0 and 50°C by [Co(N)4(OH2)2]3+ complexes (N: coordinated nitrogen atom). The pseudo-first-order rate constants for ApA hydrolysis by the triethylenetetramine and the tris(2-aminoethyl)amine complexes (0.1 mol dm-3) are 1.5 x 10-2 h-1, corresponding to 105-fold acceleration. The CoIII complexes are also active for the hydrolysis of 2′,3′-cyclic monophosphates of ribonucleotides. The pH-rate constant profile for ApA hydrolysis is bell-shaped with a maximum around pH 7, and a notable D2O solvent isotope effect (2.0) is observed. It is proposed that the coordination water molecules on the CoIII ions promote (as general acid catalysts) the departure of the alkoxide ion of 5′-OH from the phosphorus atom.
- Komiyama, Makoto,Matsumoto, Yoichi,Takahashi, Hideyuki,Shiiba, Tetsuro,Tsuzuki, Hidetoshi,Yajima, Hideaki,Yashiro, Morio,Sumaoka, Jun
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p. 691 - 695
(2007/10/03)
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- Hydrolysis of an RNA dinucleoside monophosphate by neomycin B
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Neomycin B is shown to accelerate the phosphodiester hydrolysis of adenylyl(3′-5′)adenosine (ApA) more effectively than a simple unstructured diamine.
- Kirk, Sarah R.,Tor, Yitzhak
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p. 147 - 148
(2007/10/03)
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- Direct phosphorylation of nucleosides by oxyphosphorane
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Ester exchange reaction of oxyphosphorane 1 with unprotected ribonucleosides cytidine 2a and adenosine 2b generated selectively spirooxyphosphoranes 3a and 3b respectively. Upon hydrolysis, the labile spirooxyphosphoranes were converted into stable ribonucleoside 2',3'-cyclic monophosphates 4a and 4b in good yields. Some polyribonucleotides were also detected from the hydrolytic products. Reaction of 1 with a 2'-deoxyribonucleoside such as thymidine 5 followed by hydrolysis afforded thymidine acyclic monophosphates (7, 8). Hence, the ester exchange reaction of oxyphosphorane might provide an efficient one-pot phosphorylation methodology for ribonucleosides and 2'-deoxyribonucleosides without any protection.
- Chen, Xin,Zhang, Nan-Jing,Li, Yan-Mei,Jiang, Yang,Zhang, Xiang,Zhao, Yu-Fen
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p. 1615 - 1618
(2007/10/03)
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- Zn2+ -promoted hydrolysis of 3',5'-dinucleoside monophosphates and polyribonucleotides. The effect of nearest neighbours on the cleavage of phosphodiester bonds
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Pseudo first-order rate constants for the Zn2+ -promoted cleavage of 15 different dinucleoside monophosphates, 4 different ribo homopolymers and RNA III from baker's yeast have been determined. Furthermore, the distribution of various nucleosides at the 3'- and 5'-terminus of the oligomeric hydrolysis products of RNA has been quantified. On these bases, the effect of nearest neighbours on the metal-ion-promoted hydrolysis of the internucleosidic phosphodiester bonds of RNA is discussed.
- Kuusela, Satu,Loennberg, Harri
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p. 1669 - 1678
(2007/10/03)
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- The effect of the 3'-terminal monophosphate group on the metal-ion-promoted hydrolysis of the phosphodiester bonds of short oligonucleotides
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The effect of 3'-terminal monophosphate group on the metal-ion-promoted hydrolysis of the phosphodiester bonds of oligonucleotides has been studied.For this purpose, the rate constants for the hydrolysis of the following oligomers in the presence of Zn2+ and its 1,5,9-triazacyclododecane chelate, Zn2+aneN3, have been determined: (i) ApUpUp(2') and ApUpUp(3'), (ii) Up(Tp)nT (n = 0-4 and 7), (iii) Up(Tp)nTp (n = 0-4 and 7).The results obtained are used to propose a mechanism for the Zn2+ and Zn2+aneN3 promoted hydrolysis of polynucleotides.
- Kuusela, Satu,Azhayev, Alex,Guzaev, Andrei,Loennberg, Harri
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p. 1197 - 1202
(2007/10/02)
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- Synergetic Catalysis by Two Non-lanthanide Metal Ions for Hydrolysis of Diribonucleotides
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Adenylyl(3'-5')adenosine and uridylyl(3'-5')uridine are efficiently hydrolysed at pH 7 by bimetallic cooperation of zinc(ii) with tin(iv), indium(iii), iron(iii) or aluminium(iii).
- Irisawa, Makoto,Takeda, Naoya,Komiyama, Makoto
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p. 1221 - 1222
(2007/10/02)
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- Preparation and Study of Dinuclear Zinc(II) Complex for the Efficient Hydrolysis of the Phosphodiester Linkage in a Diribonucleotide
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A dinuclear zinc(II) complex with N,N,N',N'-tetrakis-2-hydroxy-1,3-diaminopropane efficiently hydrolyses ApA at pH 7 and 50 deg C; the complex can thus be regarded as a good artificial ribonuclease which effectively mimics enzyme active sites.
- Yashiro, Morio,Ishikubo, Akira,Komiyama, Makoto
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p. 1793 - 1794
(2007/10/02)
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- Lanthanide Complexes with High Stability and Efficiency for the Hydrolysis of a Ribonucleotide Dimer
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Lanthanide complexes with N,N,N'N'-tetrakisethylenediamine (TPEN) efficiently hydrolyze a ribonucleotide dimer, ApA, at 35 deg C, pH = 7.2.The activity of La3+-TPEN is greater than of free La3+ ion.The Ln3+-TPEN complexes are sufficiently stable in neutral aqueous solutions (the formation constants are in the range log K/mol-1dm3 = 3.9 - 6.2).These complexes are promising for the active site of artificial ribonucleases.
- Yashiro, Morio,Ishikubo, Akira,Takarada, Tohru,Komiyama, Makoto
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p. 665 - 666
(2007/10/02)
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- Phenyl Ester of Adenosine 3'-Phosphate as a Novel Probe for the Rate-Limiting Step in RNA Hydrolysis
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Phenyl ester of adenosine 3'-phosphate is synthesized as a probe for the rate-limiting steps in enzymatic and non-enzymatic RNA hydrolyses.
- Shiiba, Tetsuro,Komiyama, Makoto
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p. 5571 - 5574
(2007/10/02)
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- ADENOSINE CYCLIC 3',5'-PHOSPHORAMIDATE AND N,N-DIMETHYLPHOSPHORAMIDATE: SYNTHESIS VIA SYMMETRICAL AND MIXED ANHYDRIDES AND HYDROLYSIS
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The title compounds were synthesized by converting cyclic AMP with a sulfonyl chloride to the symmetrical anhydride or with diphenyl phosphorochloridate to the mixed anhydride, then aminolyzing the anhydrides without isolation.The synthesis preferentially gave SP-amides.Characteristic differences were observed in the behavior of the unsubstituted amide and the dimethylamide under hydrolysis conditions.
- Tomasz, Jenoe,Bottka, Sandor,Ludwig, Janos,Pelczer, Istvan
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p. 597 - 600
(2007/10/02)
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- SYNTHESIS OF 2'(3')-PHOSPHATES AND 2'(3')-PHOSPHOROTHIOATES OF 5'-O-CARBOXYMETHYLINOSINE AND RELATED COMPOUNDS
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5'-O-Carboxymethylinosine (IX) was prepared from disodium salt of 2',3'-O-isopropylideneinosine (VIII) by treatment with sodium chloroacetate, followed by acid hydrolysis. 5'-O-(2-Aminoethylamidocarbonylmethyl)inosine (XIII) was obtained by reaction of IX with p-nitrophenol and subsequent treatment with ethylenediamine.Action of triethyl phosphite on the compounds IX and XIII afforded the corresponding 5'-O-substituted 2'(3')-phosphites X and XIV which on reaction with trimethylsilyl chloride and sulfur gave the 2'(3')-phosphorothioates XI and XV.The compound IX was transformed by phosphorus oxychloride in 5'-O-carboxymethylinosine 2'(3')-phosphate (XII).Uridine, adenosine and inosine 2'(3')-phosphorothioates (Ia-Ic) were obtained from 2',3'-O-di-n-butylstannylene derivatives of the nucleosides IV by treatment with thiophosphoryl chloride followed by alkaline hydrolysis; inosine and guanosine 2'(3')-phosphorothioates (Ic, Id) were prepared by reaction of the corresponding 2'(3')-phosphites VIc, VId with trimethylsilyl chloride and sulfur.Cyclisation of Ic and Id with ethyl chloroformate in the presence of tri-n-butylamine afforded inosine 2',3'-O,O-cyclophosphorothioate (VIIc) and the corresponding guanosine derivative VIId.Compounds VIIc and VIId are not cleaved by Streptomyces aureofaciens ribonuclease.
- Holy, Antonin,Kois, Pavol
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p. 2817 - 2829
(2007/10/02)
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