Phosphorylation of Nucleosides and Nucleotides with Inorganic Monoimido-cyclo-Triphosphate

Maeda, Hideko; Chiba, Takeshi; Tsuhako, Mitsutomo

doi:10.1248/cpb.56.1698

Cited by 9 publications

(7 citation statements)

References 23 publications

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“…1). The main industrial applications of a series of imidophosphates as phosphorus-nitrogen compounds are flame retardants for organic materials [3–9] and solubilizers for medicine [10–14]. The clarification of the protonation equilibria and the estimation of the basicities of the imidophosphates will be useful, since the hydrolysis reactions of the imidophosphates play important parts in these industrial applications.…”

Section: Introductionmentioning

confidence: 99%

Intrinsic 31P NMR Chemical Shifts and the Basicities of Phosphate Groups in a Short-Chain Imino Polyphosphate

2013

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The stepwise protonation constants of two linear triphosphate ligand anions, triphosphate, and di-imidotriphosphate, , were investigated by potentiometric titration, and the intrinsic chemical shifts of the stepwise protonated species of these anions were determined from the pH-dependence of the 31P NMR chemical shifts. All stepwise protonation constants of were found to be larger than those of , and the 31P NMR signals due to P3O8(NH)2 always appeared at a lower magnetic field compared to the signals due to P3O10. These results indicate higher basicity of the P3O8(NH)2 ligand, because it contains two imino groups in the ligand molecule. The 31P NMR signals for the end phosphate groups appear at a lower magnetic field than those for the middle phosphate groups, indicating that the basicity of the end phosphate group is higher than that of the middle phosphate group. It can be expected that the high basicity of the P3O8(NH)2 ligand brings about the formation of high stability complexes with various metal ions. Furthermore, the only 31P NMR signal due to the middle phosphate group of P3O8(NH)2 ligand molecule clearly showed a low-field shift in the range of pH < 2.5. The reason for this peculiar low-field shift should be the change of the localization of imino protons around the nitrogen atom in P3O8(NH)2.Graphical Abstract

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Section: Introductionmentioning

confidence: 99%

Intrinsic 31P NMR Chemical Shifts and the Basicities of Phosphate Groups in a Short-Chain Imino Polyphosphate

2013

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“…In recent years, a series of imidophosphates have been applied to the fields of the flame retardants for various organic materials and the phosphorylation agents for various polysaccharides and biochemical compounds . However, the chemical stabilities of the imidophosphates are not so high because of the nucleophilic attack from water molecules by the coexistence of metal ions; thus, the complexation behavior of various imidopolyphosphate anions is quite important.…”

Section: Introductionmentioning

confidence: 99%

“…In recent years, a series of imidophosphates have been applied to the fields of the flame retardants for various organic materials [29][30][31][32][33][34][35] and the phosphorylation agents for various polysaccharides and biochemical compounds. [36][37][38][39][40] However, the chemical stabilities of the imidophosphates are not so high because of the nucleophilic attack from water molecules by the coexistence of metal ions; thus, the complexation behavior of various imidopolyphosphate anions is quite important. The Be 2+ complex stabilities of the ligands are quantitatively compared with the basicity of this series of ligands, which has been reported, [41,42] and the number of bridging nitrogen donors, and the coordination structures are discussed herein.…”

Section: Introductionmentioning

confidence: 99%

⁹Be and ³¹P NMR analyses on the influence of imino groups on Be²⁺ complex stabilities of a series of cyclo‐μ‐imido triphosphate anions

Maki

Tsujito

Nariai

et al. 2013

Magnetic Reson in Chemistry

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The complexation behaviors of Be²⁺ with cyclo-μ-imido triphosphate anions, cP₃O₉-n(NH)n(3-)n= 1, 2),have been investigated by both ⁹Be and ³¹P NMR techniques at -2.3 °C in order to clarify the coordination structures of the complexes. The spectra showed that cP₃O₉n(NH)n (n = 1, 2) ligands form ML, ML₂, and M₂L complexes with Be²⁺ ions, and the formation of complexes coordinating with nitrogen atoms of the cyclic framework in the ligand molecule has been excluded. These complexation trends are very similar to those of Be²⁺-cP₃O₆(NH)⁻³₃system, which has been reported by us. The peak deconvolution of ⁹BeNMR spectra made these beryllium complexes amenable to stability constant determinations. The stability constants of the complexes increase with an increase in the protonation constants of the ligands as the number of imino groups, which constitute the ligand molecules, is ascended. This increase is primarily attributable to the lower electronegativity of nitrogen atoms than oxygen atoms, which are directly bonded to central phosphorus atoms; moreover, tautomerism equilibrium in the entire of the imidopolyphosphate molecule is also responsible to the higher basicity. ³¹P NMR spectra measured concurrently have verified the formation of the complexes estimated by the ⁹Be NMR measurement. Intrinsic ³¹P NMR chemical shift values of the phosphorus atoms belonging to ligand molecules complexed with Be²⁺ cations have been determined. Not only the protonation constants but also the stability constants of all Be²⁺ complexes increase approximately linearly with an increase in the number of imino groups.

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“…Table 2 summarizes the total yield of 3 and 4 obtained from the reaction of 5Ј-DFUR with MCTP under various conditions. Considering the yield and reaction time, the appropriate condition for phosphorylation of 5Ј-DFUR and nucleotides 11) were phosphorylated with the yield of 30-60 and 14-22%, respectively. The reactivity of 5Ј-DFUR with MCTP was higher than the other substrates except adenosine.…”

Section: Resultsmentioning

confidence: 99%

Phosphorylation of 5'-Deoxy-5-fluorouridine with Inorganic Phosphorylating Agents

Maeda

Kusuhara

Tsuhako

2011

CHEMICAL & PHARMACEUTICAL BULLETIN

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Regular ArticleThe anti-cancer drug, fluorouracil (5-FU), has been used to treat stomach cancer and breast cancer, but strong side effects are a serious problem.1) Therefore, the chemical modification of 5-FU has been attempted to improve absorption and reduce side effects.2,3) 5Ј-Deoxy-5-fluorouridine (doxifluridine, 5Ј-DFUR), which is a prodrug of 5-FU, has been applied to malignant tumors.The synthetic methods for nucleotides were reported using mixture of diphosphorus pentaoxide and phosphoric acid, 4) and polyphosphoric acid. 5,6) The phosphorylation reaction by these agents required high temperature such as 85-100°C. Since then, Yoshikawa et al. demonstrated the synthesis of adenosine 5Ј-phosphate by the reaction of adenosine with phosphoryl chloride in triethyl phosphate at Ϫ10-0°C. 7)Furthermore, the synthetic method for guanosine derivatives with phosphorus trichloride 8) were demonstrated. Because of the phosphorylation with these agents was accompanied by various side reactions, the protection of the other functional groups was required before phosphorylation. In addition, the experimental operation of phosphorylation with these agents was extremely complicated.We succeeded in the phosphorylation of nucleosides and nucleotides using inorganic phosphorylating agents such as cyclo-triphosphate 9,10) and monoimido-cyclo-triphosphate. 11)Phosphorylation with these agents can be achieved by a onepot reaction in aqueous solution at 25-40°C without side reactions. Sodium cyclo-triphosphate, Na 3 P 3 O 9 (P 3m ), and sodium monoimido-cyclo-triphosphate, Na 3 P 3 O 8 NH (MCTP) are simple and efficient inorganic phosphorylating agents. As shown Fig. 1, P 3m and MCTP have six-membered rings composed of three and two P-O-P linkages, respectively. In the phosphorylation of nucleosides 9) and nucleotides 10) by P 3m , the 2Ј-and 3Ј-OH groups of the b-D-ribofuranosyl unit on the nucleosides and nucleotides were selectively phosphorylated with the yield of 80-97% without protection of the other hydroxyl groups. In the reaction of nucleoside or nucleotides and P 3m , the main products were 3Ј-monophosphate or 3Ј,5Ј-diphosphate derivatives. In the case of MCTP, the 2Ј-and 3Ј-OH groups of the b-D-ribofuranosyl unit on the nucleosides and nucleotides were phosphorylated to give 2Ј-and 3Ј-diphosphoramidophosphate esters with the yield of 14-60%.11) And 2Ј-diphosphoramidophosphate esters were dominant.In the present work, we studied the reaction of 5Ј-DFUR with P 3m or MCTP in aqueous solution in order to synthesize phosphate derivatives of 5Ј-DFUR, and then investigated the reactivity of the 2Ј-and 3Ј-OH groups of the b-D-ribofuranosyl unit. Results and DiscussionPhosphorylation of 5 -DFUR with P 3m Phosphorylation was carried out according to the previously described method. [12][13][14] HPLC analysis served as a tool for evaluating the yields of products by their peak areas. HPLC condition was as follow; TSKgel SAX column, column temperature of 40°C, 0.33 M potassium chloride solution as eluent, flow rate of 1.0 ml/min,...

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Phosphorylation of Nucleosides and Nucleotides with Inorganic Monoimido-cyclo-Triphosphate

Cited by 9 publications

References 23 publications

Intrinsic 31P NMR Chemical Shifts and the Basicities of Phosphate Groups in a Short-Chain Imino Polyphosphate

Intrinsic 31P NMR Chemical Shifts and the Basicities of Phosphate Groups in a Short-Chain Imino Polyphosphate

⁹Be and ³¹P NMR analyses on the influence of imino groups on Be²⁺ complex stabilities of a series of cyclo‐μ‐imido triphosphate anions

Phosphorylation of 5'-Deoxy-5-fluorouridine with Inorganic Phosphorylating Agents

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Phosphorylation of Nucleosides and Nucleotides with Inorganic Monoimido-cyclo-Triphosphate

Cited by 9 publications

References 23 publications

Intrinsic 31P NMR Chemical Shifts and the Basicities of Phosphate Groups in a Short-Chain Imino Polyphosphate

Intrinsic 31P NMR Chemical Shifts and the Basicities of Phosphate Groups in a Short-Chain Imino Polyphosphate

9Be and 31P NMR analyses on the influence of imino groups on Be2+ complex stabilities of a series of cyclo‐μ‐imido triphosphate anions

Phosphorylation of 5'-Deoxy-5-fluorouridine with Inorganic Phosphorylating Agents

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⁹Be and ³¹P NMR analyses on the influence of imino groups on Be²⁺ complex stabilities of a series of cyclo‐μ‐imido triphosphate anions