146-78-1Relevant articles and documents
The synthesis of 2-fluoropurine nucleosides
Krolikiewicz,Vorbruggen
, p. 673 - 678 (1994)
2-Aminoadenosine, obtained by silylation-amination from guanosine, is readily converted by KNO2/HF/Pyridine in up to 80% yield into 2- fluoradenosine, which is a convenient starting material for the preparation of 9(β-D-arabinofuranosyl)-2-fluoroadenine 5'-phosphate (Fludara). N6,N6- Pentamethylene-2-aminoadenosine and guanosine afford likewise the corresponding 2-fluoropurine nucleosides in high yields.
Use of Citrobacter koseri whole cells for the production of arabinonucleosides: A larger scale approach
Nóbile, Matías,Médici, Rosario,Terreni, Marco,Lewkowicz, Elizabeth S.,Iribarren, Adolfo M.
, p. 2182 - 2188 (2012)
Purine arabinosides are well known antiviral and antineoplastic drugs. Since their chemical synthesis is complex, time-consuming, and polluting, enzymatic synthesis provides an advantageous alternative. In this work, we describe the microbial whole cell synthesis of purine arabinosides through nucleoside phosphorylase-catalyzed transglycosylation starting from their pyrimidine precursors. By screening of our microbial collection, Citrobacter koseri (CECT 856) was selected as the best biocatalyst for the proposed biotransformation. In order to enlarge the scale of the transformations to 150 mL for future industrial applications, the biocatalyst immobilization by entrapment techniques and its behavior in different reactor configurations, considering both batch and continuous processes, were analyzed. C. koseri immobilized in agarose could be used up to 68 times and the storage stability was at least 9 months. By this approach, fludarabine (58% yield in 14 h), vidarabine (71% yield in 26 h) and 2,6-diaminopurine arabinoside (77% yield in 24 h), were prepared.
The preparative method for 2-fluoroadenosine synthesis
Berzin,Dorofeeva,Leonov,Miroshnikov
, p. 193 - 196 (2009)
The preparative method for the synthesis of 2-fluoroadenosine starting from commercially available guanosine was developed. It included the intermediate formation of 2-amino-6-azido-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl) purine, which was isolated exclu
The arsenolysis reaction in the biotechnological method of synthesis of modified purine β-D-arabinonucleosides
Konstantinova,Fateev,Miroshnikov
, p. 372 - 380 (2016)
We found a unique property of E. coli purine nucleoside phosphorylases to selectively perform the arsenolysis reaction of ribonucleosides in their active site without affecting β-D-arabinonucleosides. In the synthesis of modified β-D-arabinonucleosides from the corresponding ribonucleosides, the catalytical amount of sodium arsenate in the transglycosylation reaction provided a 95 to 98% conversion rate. Such an approach was shown to simplify the composition of the reaction mixtures and facilitate the isolation of the target nucleosides, particularly, vidarabine, fludarabine, and nelarabine.
Simple modification to obtain high quality fludarabine
Kshirsagar, Siddheshwar W.,Deshpande, Mangesh S.,Sonawane, Swapnil P.,Maikap, Golak C.,Gurjar, Mukund K.
, p. 840 - 842 (2012)
A simple and improved debenzylation process is described to obtain fludarabine in greater than 99.8% purity and 90-95% yield.
Practical Synthesis of Fludarabine and Nelarabine
Bai, Jiang,Ding, Haixin,Liu, Jiang,Ouyang, Wenliang,Shen, Chunyang,Xiao, Qiang
, p. 417 - 423 (2020)
A new practical synthesis strategy has been developed to access the β- d -arabinofuranosyl purine nucleosides fludarabine and nelarabine. In our approach, an ortho -alkyne benzoyl ester is transiently introduced as a neighbouring-participation group in Vorbrüggen glycosylation to afford the corresponding β-nucleoside exclusively. The latter was further removed efficiently by using freshly prepared Ph 3 PAuOTFA to give the corresponding 2′-OH nucleosides without transesterification. After reversion of the configuration of 2′-OH and deprotection, fludarabine and nelarabine were obtained in high yield and purity.
F-ara-AMP is a substrate of cytoplasmic 5′-nucleotidase II (cN-II): HPLC and NMR studies of enzymatic dephosphorylation
Jordheim, Lars,Cros, Emeline,Galmarini, Carlos,Dumontet, Charles,Bretonnet, Anne-Sophie,Krimm, Isabelle,Lancelin, Jean-Marc,Gagnieu, Marie-Claude
, p. 289 - 297 (2006)
Intracellular accumulation of triphosphorylated derivatives is essential for the cytotoxic activity of nucleoside analogues. Different mechanisms opposing this accumulation have been described. We have investigated the dephosphorylation of monophosphorylated fludarabine (F-ara-AMP) by the purified cytoplasmic 5′-nucleotidase cN-II using HPLC and NMR. These studies clearly showed that cN-II was able to convert F-ara-AMP into its non phosphorylated form, F-ara-A, with a K m in the millimolar range and V max = 35 nmol/min/mg, with both methods. Cytoplasmic 5′-nucleotidase cN-II can degrade this clinically useful cytotoxic nucleoside analogue and its overexpression is thus likely to be involved in resistance to this compound. Copyright Taylor & Francis Group, LLC.
Enzymatic transglycosylation of natural and modified nucleosides by immobilized thermostable nucleoside phosphorylases from Geobacillus stearothermophilus
Taran,Verevkina,Feofanov,Miroshnikov
, p. 739 - 745 (2009)
Natural and modified purine nucleosides have been synthesized using the recombinant thermostable enzymes purine nucleoside phosphorylase II (E. C. 2.4.2.1) and pyrimidine nucleoside phosphorylase (E. C. 2.4.2.2) from Geobacillus stearothermophilus B-2194. The enzymes were produced in recombinant E. coli strains and covalently immobilized on aminopropylsilochrom AP-CPG-170 after heating the cell lysates and the removal of coagulated thermolabile proteins. The resulting preparations of thermostable nucleoside phosphorylases retained a high activity after 20 reuses in nucleoside transglycosylation reactions at 70-75°C with a yield of the target products as high as 96%. Owing to the high catalytic activity, thermal stability, the ease of application, and the possibility of repeated use, the immobilized preparations of thermostable nucleoside phosphorylases are suitable for the production of pharmacologically important natural and modified nucleosides.
Thermodynamic Reaction Control of Nucleoside Phosphorolysis
Kaspar, Felix,Giessmann, Robert T.,Neubauer, Peter,Wagner, Anke,Gimpel, Matthias
supporting information, p. 867 - 876 (2020/01/24)
Nucleoside analogs represent a class of important drugs for cancer and antiviral treatments. Nucleoside phosphorylases (NPases) catalyze the phosphorolysis of nucleosides and are widely employed for the synthesis of pentose-1-phosphates and nucleoside analogs, which are difficult to access via conventional synthetic methods. However, for the vast majority of nucleosides, it has been observed that either no or incomplete conversion of the starting materials is achieved in NPase-catalyzed reactions. For some substrates, it has been shown that these reactions are reversible equilibrium reactions that adhere to the law of mass action. In this contribution, we broadly demonstrate that nucleoside phosphorolysis is a thermodynamically controlled endothermic reaction that proceeds to a reaction equilibrium dictated by the substrate-specific equilibrium constant of phosphorolysis, irrespective of the type or amount of NPase used, as shown by several examples. Furthermore, we explored the temperature-dependency of nucleoside phosphorolysis equilibrium states and provide the apparent transformed reaction enthalpy and apparent transformed reaction entropy for 24 nucleosides, confirming that these conversions are thermodynamically controlled endothermic reactions. This data allows calculation of the Gibbs free energy and, consequently, the equilibrium constant of phosphorolysis at any given reaction temperature. Overall, our investigations revealed that pyrimidine nucleosides are generally more susceptible to phosphorolysis than purine nucleosides. The data disclosed in this work allow the accurate prediction of phosphorolysis or transglycosylation yields for a range of pyrimidine and purine nucleosides and thus serve to empower further research in the field of nucleoside biocatalysis. (Figure presented.).
Synthesis method of fludarabine phosphate
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Paragraph 0041-0043; 0056-0060, (2020/08/22)
The invention provides a synthesis method of fludarabine phosphate, and the synthesis route is as follows: with vidarabine as a starting raw material, fludarabine is obtained through upper protection,nitrification, fluorination denitration and deprotection, so that the fludarabine is prepared by adopting a brand-new synthesis route; meanwhile, by improving the process of phosphorylation and refining of fludarabine, the reaction time is shortened, the generation of by-products is reduced, and the product quality is improved. The method has the following advantages: 1, the initial raw materialis beta-configuration, isomer separation is avoided, and the yield is improved; raw materials are easy to obtain, the route is simple, and the price is low; 3, salification and column-passing purification and separation are avoided, so that the method is suitable for industrialization.
