Nucleoside phosphomonoester

A large variety of metal ions catalyze the cleavage of RNA through the transesterification mechanism, and some of them can also catalyze hydrolysis of cyclic phosphates (e.g. Pb +, Zn +, and Cd +) and nucleoside phosphomonoesters (e.g. Pb +, La +, and Th +). The most efficient cleavage of RNA in aqueous solutions by free metal ions is achieved by the action of rare metal ions (e.g. Eu +, La +, and Tb +), Pb +, and Zn +. Zn + is only about 4% as efficient as Pb2+,327 other catalytically active metal ions (e.g. AP+, Cd +, Mn +, Cu +, Co +, Ni +, or Mg +) are 1-2 orders of magnitude less efficient than Zn +. As a rule, RNA cleavage has a maximum rate at pH values around the pKaS of the first metal-bound H2O (see Table 1), that is, when the hydroxo-metal species still bear positive charge. ... 

Figure 36 Neighboring group-catalyzed formation of a nucleoside-phosphomonoester initiated...

E. J. Mclntee, R. P. Remmel, R. F. Schinazi, T. W. Abraham, C. R. Wagner, Probing the Mechanism of Action and Decomposition of Amino Acid Phosphomonoester Amidates of Antiviral Nucleoside Prodrugs , J. Med. Chem. 1997, 40, 3323-3331. 

It was found that the polymer exhibited selectivity towards phosphomonoester dianions. Less polar compounds were found to bind non-specifically to the polymer. The polymer was then used as a stationary phase for a HPLC column. A mixture containing dA, 5 -dAMP and 3, 5 -cAMP was thus separated. As expected, the retention time of 5 -AMP was larger than those for dA and 3, 5 -cAMP. The same was tme for other nucleotides compared to the corresponding nucleosides. When the Zn2+-free control polymer was used, all compounds were immediately eluted. The possibility to use polymer-anchored recognition units to separate biologically important phosphates was thus proved. 

Phosphorus oxychloride is a suitable reagent for preparation of the symmetrically substituted phospho-triesters of type (RO)3PO. The preparation is easily achieved by treatment of phosphorus oxychloride with 3 equiv. of alcohols or their metal salts. The reaction is generally promoted by a base or acid. Titanium trichloride is a particularly effective catalyst for the reaction. Conversion of POCI3 to unsymmetri-cally substituted phosphotriesters is achievable with difficulty. Phosphorochloridates and phosphorodichloridates have been used for the preparation of mixed tertiary phosphoric esters of type (ROlmPOfOROn (ffi = 1, n = 2, or m = 2, n = 1) in a very wide variety. Reaction of phosphorus oxychloride and 1 or 2 equiv. of alcohols followed by hydrolysis forms phosphomonoesters or phosphodi-esters, respectively. The hydrolysis may be generally effected by dilute aqueous alkali. Some phosphoFodichlori te intermediates are easily hydrolyzed by water. For example, the phosphorylation of a ribonucleoside (1 equation 4) with phosphorus oxychloride in an aqueous pyridine-acetonitrile mixture furnishes the nucleoside S -monophosphate (2) in excellent yield. ... 

Nucleoside Acyclic Phosphates - It is well established that most nucleoside analogues become biologically active as a result of cellular conversion to phosphomonoesters. For this reason there has been increasing interest in the synthesis of nucleoside phosphotriesters and in some cases, i osphodiesters which might act as membrane soluble pro-drugs of the bioactive nucleotides. The diethyl-, dipropyl- and dibutyl-phosphates (1) of 2, 3 -dideoxy-3-deaza-adenosine have been synthesis and shown to possess anti-HIV-1 activity at non-cytotoxic doses. Phosphate triester derivatives of the anti-leukaemic nucleoside nmbi/io-cytidine have... 

Such specificity for the primary hydroxyl indicates that preparation of desired 3 -phosphomonoesters may be difficult. For example, diphenyl phosphorochloridate will not react with 2, 5 -bis-0-methoxytetrahydropyran-4-yl uridine in a pyridine solvent, at room temperature. The free 3 -hydroxyl is too hindered to react with this bulky phosphorylating agent. However, replacement of pyridine with a more potent nucleophilic catalyst, 5-chloro-1-methylimidazole will allow product formation to occur. Other phos-phorodichloridates have been examined for the purpose of synthesis of nucleoside monophosphates. Perhaps one which has found the most use for the preparation of nucleoside T-phosphates is 2,2,2-trichloroethyl-2-chlorophenyl-phosphorochloridate. While phosphorylation will occur in pyridine, use of 1-methylimidazole provides a quicker reaction rate. This is... 

By such a P-NMR analysis, Webb and Trentham have also elucidated the stereochemical course of a number of nucleoside triphosphatases (Webb, 1982). The P-NMR analysis based on the combined effects of and 0 is the only method available for configurational analysis of chiral [ 0, 0, 0]Psi, and is also a commonly used method for configurational analysis of chiral [ 0, 0, 0]phosphomonoesters, which are covered by Gerlt (Chapter 7.)... 

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