- An enzymatic flow-based preparative route to vidarabine
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The bi-enzymatic synthesis of the antiviral drug vidarabine (arabinosyladenine, ara-A), catalyzed by uridine phosphorylase from Clostridium perfringens (CpUP) and a purine nucleoside phosphorylase fromAeromonas hydrophila (AhPNP), was re-designed under continuous-flow conditions. Glyoxyl-agarose and EziGTM1 (Opal) were used as immobilization carriers for carrying out this preparative biotransformation. Upon setting-up reaction parameters (substrate concentration and molar ratio, temperature, pressure, residence time), 1 g of vidarabine was obtained in 55% isolated yield and >99% purity by simply running the flow reactor for 1 week and then collecting (by filtration) the nucleoside precipitated out of the exiting flow. Taking into account the substrate specificity of CpUP and AhPNP, the results obtained pave the way to the use of the CpUP/AhPNP-based bioreactor for the preparation of other purine nucleosides.
- Annunziata, Francesca,Bavaro, Teodora,Calleri, Enrica,Conti, Paola,Pinto, Andrea,Previtali, Clelia,Rinaldi, Francesca,Speranza, Giovanna,Tamborini, Lucia,Terreni, Marco,Ubiali, Daniela
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Read Online
- Prebiotic Photochemical Coproduction of Purine Ribo- And Deoxyribonucleosides
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The hypothesis that life on Earth may have started with a heterogeneous nucleic acid genetic system including both RNA and DNA has attracted broad interest. The recent finding that two RNA subunits (cytidine, C, and uridine, U) and two DNA subunits (deoxyadenosine, dA, and deoxyinosine, dI) can be coproduced in the same reaction network, compatible with a consistent geological scenario, supports this theory. However, a prebiotically plausible synthesis of the missing units (purine ribonucleosides and pyrimidine deoxyribonucleosides) in a unified reaction network remains elusive. Herein, we disclose a strictly stereoselective and furanosyl-selective synthesis of purine ribonucleosides (adenosine, A, and inosine, I) and purine deoxynucleosides (dA and dI), alongside one another, via a key photochemical reaction of thioanhydroadenosine with sulfite in alkaline solution (pH 8-10). Mechanistic studies suggest an unexpected recombination of sulfite and nucleoside alkyl radicals underpins the formation of the ribo C2′-O bond. The coproduction of A, I, dA, and dI from a common intermediate, and under conditions likely to have prevailed in at least some primordial locales, is suggestive of the potential coexistence of RNA and DNA building blocks at the dawn of life.
- Xu, Jianfeng,Green, Nicholas J.,Russell, David A.,Liu, Ziwei,Sutherland, John D.
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supporting information
p. 14482 - 14486
(2021/09/18)
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- Production process of arabinoside
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The invention discloses a production process of arabinoside, relates to the technical field of arabinoside synthesis, and solves the technical problems that in the existing production process of arabinoside, after-treatment of an acetic acid buffer agent reaction solution is difficult, a 1, 2-dichloroethane solvent is difficult to recover, potassium permanganate is slow to charge, and the reactiontime is too long. The production process of arabinoside comprises the following steps: synthesis of 8-bromoadenosine, synthesis of 8-bromo-2'-O-p-toluenesulfonyl adenosine, synthesis of 8-hydroxy-4'-acetoxy-5'-acetoxymethyl-3'-p-toluenesulfonyl adenosine and synthesis of arabinoside. In the production process of arabinoside, after-treatment of wastewater is convenient, hazardous waste is convenient to treat, the process cost is low, and the reaction time is short.
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Paragraph 0026; 0031-0032; 0033; 0038-0039; 0040; 0045-0046
(2020/12/31)
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- A method for synthesizing arabinosyladenosine (by machine translation)
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The invention discloses a method for synthesizing arabinosyladenosine method, which belongs to the field of nucleoside in organic chemistry synthesis. The reaction steps are as follows: in order to adenosine as raw material, in a catalytic amount of dibutyl tin oxide or borate and under the action of the nitrobenzene sulfonyl chloride reaction, to obtain the 2 '- to the nitrobenzene sulfonyl protecting adenosine, then under the action of the potassium acetate and catalyst, undergo the substitution reaction to obtain the 2' - acetyl arabinosyladenosine, finally ammonolysis to obtain arabinosyladenosine. The synthesis method cheap raw materials, the step is short, easy to industrial production, with the actual application prospect. (by machine translation)
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Paragraph 0019; 0020
(2018/04/01)
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- Enzymatic Synthesis of Therapeutic Nucleosides using a Highly Versatile Purine Nucleoside 2’-DeoxyribosylTransferase from Trypanosoma brucei
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The use of enzymes for the synthesis of nucleoside analogues offers several advantages over multistep chemical methods, including chemo-, regio- and stereoselectivity as well as milder reaction conditions. Herein, the production, characterization and utilization of a purine nucleoside 2’-deoxyribosyltransferase (PDT) from Trypanosoma brucei are reported. TbPDT is a dimer which displays not only excellent activity and stability over a broad range of temperatures (50–70 °C), pH (4–7) and ionic strength (0–500 mM NaCl) but also an unusual high stability under alkaline conditions (pH 8–10). TbPDT is shown to be proficient in the biosynthesis of numerous therapeutic nucleosides, including didanosine, vidarabine, cladribine, fludarabine and nelarabine. The structure-guided replacement of Val11 with either Ala or Ser resulted in variants with 2.8-fold greater activity. TbPDT was also covalently immobilized on glutaraldehyde-activated magnetic microspheres. MTbPDT3 was selected as the best derivative (4200 IU/g, activity recovery of 22 %), and could be easily recaptured and recycled for >25 reactions with negligible loss of activity. Finally, MTbPDT3 was successfully employed in the expedient synthesis of several nucleoside analogues. Taken together, our results support the notion that TbPDT has good potential as an industrial biocatalyst for the synthesis of a wide range of therapeutic nucleosides through an efficient and environmentally friendly methodology.
- Pérez, Elena,Sánchez-Murcia, Pedro A.,Jordaan, Justin,Blanco, María Dolores,Manche?o, José Miguel,Gago, Federico,Fernández-Lucas, Jesús
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p. 4406 - 4416
(2018/09/14)
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- Vidarabine synthesis method
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The invention relates to a vidarabine synthesis method. The method comprises the steps that 8-hydroxy-N,3',5'-O-triethyl-2'-O-p-tosyl adenosine is added, hydrazine hydrate with the mass time being 1.1-1.4 and the mass percent being 80% is added, heating is conducted to reach 78-85 DEG C, and a thermal reaction is conducted for 45-50 h; distillation is conducted under pressure reduction, and the hydrazine hydrate is removed; the original raw materials of water with the mass time being 5-8 and catalytic oxidizer potassium permanganate with the mass time being 0.03-0.12 are added, a stirring reaction is conducted at the room temperature for 6-8 h, a solid obtained after reaction liquid is filtered is a vidarabine crude product; the crude product is subjected to actived carbon decoloration andrecrystallization in sequence, and a vidarabine pure product is obtained. Accordingly, a cascade reaction is conducted through a one-pot two-step method, overturning and deprotection of configurationare completed through a hydrazine hydrate one pot method, the configuration overturning purpose is achieved by replacing two reactions of methanol ammonia system cyclization and hydrogen sulfide system hydrogenation ring opening, and meanwhile an inflammable catalyst raney nickel dehydroxyl is avoided, and the safety of the overall reaction is improved. Dehydrazination is conducted with potassiumpermanganate, the activity of the reaction is improved, and the content of heavy metal in waste water is lowered.
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Paragraph 0014-0019; 0022-0027; 0030-0031; 0034-0035
(2018/04/21)
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- Synthesis of Adenine Nucleosides by Transglycosylation using Two Sequential Nucleoside Phosphorylase-Based Bioreactors with On-Line Reaction Monitoring by using HPLC
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Uridine phosphorylase from Clostridium perfringens (CpUP, EC 2.4.2.3) was immobilized covalently in an aminopropylsilica monolithic column (25 mm×4.6 mm) upon functionalization with glutaraldehyde. Imino bonds that result from the reaction between the enzyme and the support were reduced chemically to afford a 66 % yield (13 mg) determined spectrophotometrically. The CpUP immobilized enzyme reactor (IMER) was connected to a silica particle-based IMER that contained a purine nucleoside phosphorylase from Aeromonas hydrophila (AhPNP, EC 2.4.2.1), which was developed previously and used successfully for the fast synthesis of some purine ribonucleosides by a “one-enzyme” transglycosylation. CpUP-IMER and AhPNP-IMER were connected to a HPLC system by a six-way switching valve. In this set-up, the synthesis of 2′-deoxyadenosine (dAdo, 8), adenosine (Ado, 9), and arabinosyladenine (araA, 10) by a “two-enzyme” transglycosylation is coupled directly to on-line reaction monitoring. Under the optimized transglycosylation conditions (2:1 ratio sugar donor/base acceptor; 10 mm phosphate buffer; pH 7.25; temperature 37 °C, flow rate 0.1 mL min?1), defined by a 2(5-2) III experimental design, the conversion of dAdo and Ado was approximately 90 %, and araA was synthesized in 20 % yield.
- Cattaneo, Giulia,Rabuffetti, Marco,Speranza, Giovanna,Kupfer, Tom,Peters, Benjamin,Massolini, Gabriella,Ubiali, Daniela,Calleri, Enrica
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p. 4614 - 4620
(2017/12/13)
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- The arsenolysis reaction in the biotechnological method of synthesis of modified purine β-D-arabinonucleosides
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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.
- Konstantinova,Fateev,Miroshnikov
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p. 372 - 380
(2016/08/03)
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- Redesigning the synthesis of vidarabine via a multienzymatic reaction catalyzed by immobilized nucleoside phosphorylases
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We here report on the enzymatic synthesis of the antiviral drug vidarabine (arabinosyladenine, araA) starting from arabinosyluracil and adenine. To this aim, uridine phosphorylase from Clostridium perfringens (CpUP) and a purine nucleoside phosphorylase from Aeromonas hydrophila (AhPNP) were used as covalently immobilized biocatalysts. Upon investigation of the optimal conditions for the enzyme activity (phosphate buffer 25 mM, pH 7.5, 25 °C, DMF 12.5-30%), the synthesis of araA was scaled up (2 L) and the product was isolated in 53% yield (3.5 g L-1) and 98.7% purity. An E-factor comparison between the enzymatic synthesis of araA and the classical chemical procedure clearly highlighted the greenness of the enzymatic route over the chemical one (E-factor: 423 vs. 1356, respectively). copy; The Royal Society of Chemistry 2015.
- Serra, Immacolata,Daly, Simona,Alcantara, Andres R.,Bianchi, Davide,Terreni, Marco,Ubiali, Daniela
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p. 23569 - 23577
(2015/04/14)
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- Efficient synthesis of nebularine and vidarabine via dehydrazination of (hetero)aromatics catalyzed by CuSO4 in water
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A simple dehydrazination reaction has been achieved in the presence of a catalytic amount of CuSO4 for the first time. With CuSO4 (2 mol%) as a catalyst and water as a solvent, the dehydrazination products were obtained in good yields (66-95%). Moreover, the drugs nebularine and vidarabine were afforded successfully, and vidarabine could be produced on a 0.923 kg scale, which shows good potential for industrial applications.
- Xia, Ran,Xie, Ming-Sheng,Niu, Hong-Ying,Qu, Gui-Rong,Guo, Hai-Ming
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p. 1077 - 1081
(2014/03/21)
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- Developing a collection of immobilized nucleoside phosphorylases for the preparation of nucleoside analogues: Enzymatic synthesis of arabinosyladenine and 2',3'-dideoxyinosine
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The use of nucleoside phosphorylases (NPs; EC 2.4.2.n) represents a convenient alternative to the chemical route for the synthesis of natural and modified nucleosides. We purified four recombinantly expressed nucleoside phosphorylases from the bacterial pathogens Citrobacter koseri, Clostridium perfringens, and Streptococcus pyogenes (CkPNPI, CkPNPII, CpUP, SpUP) and their substrate specificity was investigated towards either natural pyrimidine or purine nucleosides and some analogues, namely, arabinosyladenine (araA) and 2',3'-dideoxyinosine (ddI). A 2-3 % activity towards these latter compounds (compared to the natural substrates) was observed. Enzyme activities were compared to the specificities obtained for the enzymes pyrimidine nucleoside phosphorylase from Bacillus subtilis (BsPyNP) and purine nucleoside phosphorylase from Aeromonas hydrophila (AhPNPII) previously reported by some of the authors. The enzymes displaying the suitable specificity for the synthesis of araA and ddI were immobilized on aldehyde-agarose. The immobilized preparations were highly stable at alkaline pH and in the presence of methanol or acetonitrile as cosolvent. They were used in the synthesis of araA and ddI by a one-pot, bienzymatic transglycosylation achieving 74 and 44 % conversion, respectively. Something different: Nucleoside phosphorylases are a convenient alternative to the chemical route for the synthesis of natural and modified nucleosides. Four new nucleoside phosphorylases have been prepared, characterized, and tested for their use in biocatalyzed syntheses of araA and ddI (see scheme). A generally applicable immobilization technique has been found to provide active and stable biocatalysts.
- Serra, Immacolata,Ubiali, Daniela,Piskur, Jure,Christoffersen, Stig,Lewkowicz, Elizabeth S.,Iribarren, Adolfo M.,Albertini, Alessandra M.,Terreni, Marco
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p. 157 - 165
(2013/04/24)
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- Use of Citrobacter koseri whole cells for the production of arabinonucleosides: A larger scale approach
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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.
- Nóbile, Matías,Médici, Rosario,Terreni, Marco,Lewkowicz, Elizabeth S.,Iribarren, Adolfo M.
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p. 2182 - 2188
(2013/02/25)
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- Enzymatic regioselective and complete deacetylation of two arabinonucleosides
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Candida antarctica lipase B (CAL-B)-catalysed regioselective deacetylation of 2′,3′,5′-tri- O-acetyl-1-β- d-arabinofuranosyluracil (1) and 2′,3′,5′-tri- O-acetyl-9-β- d-arabinofuranosyladenine (2) was studied. The choice of the reaction medium allowed the regioselective formation of products bearing different degree of acetylation: in isopropanol, CAL-B catalysed the formation of the corresponding 2′- O-acetylated arabinonucleosides, while hydrolyses afforded the 2′,3′-di- O-acetylated products. In particular, the procedure herein described allows a simple and efficient preparation of the reported vidarabine prodrug 2′,3′-di- O-acetyl-9-β- d-arabinofuranosyladenine, avoiding the utilisation of protective groups. Moreover, to achieve full deacetylation of the assayed substrates, a set of commercial hydrolases and fungal keratinases from Doratomyces microsporus (DMK) and Paecilomyces marquandii (PMK) were tested. While only PMK and DMK catalysed the quantitative complete deacetylation of 1, DMK accomplished full deacetylation of 2 in shorter time than the other assayed enzymes.
- Sabaini, Maria B.,Zinni, Maria A.,Mohorcic, Martina,Friedrich, Jozefa,Iribarren, Adolfo M.,Iglesias, Luis E.
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experimental part
p. 225 - 229
(2010/11/02)
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- Enzymatic transglycosylation of natural and modified nucleosides by immobilized thermostable nucleoside phosphorylases from Geobacillus stearothermophilus
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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.
- Taran,Verevkina,Feofanov,Miroshnikov
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experimental part
p. 739 - 745
(2010/08/07)
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- Chemoenzymatic preparation of nucleosides from furanoses
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Chemoenzymatic preparation of ribose, deoxyribose and arabinose 5-phosphates was accomplished. These compounds were tested as starting materials in the enzymatic preparation of natural and modified purine and pyrimidine nucleosides, using an overexpressed Escherichia coli phosphopentomutase.
- Taverna-Porro, Marisa,Bouvier, Leon A.,Pereira, Claudio A.,Montserrat, Javier M.,Iribarren, Adolfo M.
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p. 2642 - 2645
(2008/09/19)
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- BIOREDUCTIVELY-ACTIVATED PRODRUGS
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The present invention relates to a compound of formula (1), or a pharmaceutically acceptable salt thereof, Formula: (1); wherein: R1 is a substituted aryl or heteroaryl group bearing at least one nitro or azido group or is an optionally substituted benzoquinone, optionally substituted naphthoquinone or optionally substituted fused heterocycloquinone; R2 is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, aryl or heteroaryl; and R3 is selected such that R3NH2 represents a cytotoxic nucleoside analogue or an ester or phosphate ester prodrug of a cytotoxic nucleoside analogue, with the proviso that if R1 is an aryl group then R2 is not H.
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Page/Page column 25
(2010/10/20)
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- The nucleoside transport proteins, NupC and NupG, from Escherichia coli: Specific structural motifs necessary for the binding of ligands
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A series of 46 natural nucleosides and analogues (mainly adenosine-based) were tested as inhibitors of [U-14C]uridine uptake by the concentrative, H+-linked nucleoside transport proteins NupC and NupG from Escherichia coli. The two evolutionarily unrelated transporters showed similar but distinct patterns of inhibition, revealing differing selectivities for the different nucleosides and their analogues. Binding of nucleosides to NupG required the presence of hydroxyl groups at each of the C-3′ and C-5′ positions of ribose, while binding to NupC required only the C-3′ hydroxyl substituent. The greater importance of the ribose moiety for binding to NupG is consistent with the evolutionary relationship between this protein and the oligosaccharide: H+ symporter (OHS) subfamily of the major facilitator superfamily (MFS) of transporters. For both proteins the natural α-configuration at C-3′ and the natural β-configuration at C-1′ was mandatory for ligand binding. N-7 in the imidazole ring of adenosine and the amino group at C-6 were found not to be important for binding and both transporters showed flexibility for substitution at C-6/N6; one or both of N-l and N-3 were important for adenosine analogue binding to NupC but significantly less so for binding to NupG. From the different effects of 8-bromoadenosine on the two transporters it appears that adenosine selectively binds to NupC in an anti- rather than a syn-conformation, whereas NupG is less prescriptive. The pattern of inhibition of NupC by differing nucleoside analogues confirmed the functional relationship of the bacterial transporter to members of the human concentrative nucleoside transporter (CNT) family and reaffirmed the use of the bacterial protein as an experimental model for these physiologically and clinically important mammalian proteins. The specificity data for NupG have been used to develop a homology model of the protein's binding site, based on the X-ray crystallographic structure of the disaccharide transporter LacY from E. coli. We have also developed an efficient general protocol for the synthesis of adenosine and three of its analogues, which is illustrated by the synthesis of [1′-13C]adenosine.
- Patching, Simon G.,Baldwin, Stephen A.,Baldwin, Alexander D.,Young, James D.,Gallagher, Maurice P.,Henderson, Peter J. F.,Herbert, Richard B.
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p. 462 - 470
(2007/10/03)
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- ANTISENSE MODULATION OF STEAROYL-COA DESATURASE EXPRESSION
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Antisense compounds, compositions and methods are provided for modulating the expression of stearoyl-CoA desaturase. The compositions comprise antisense compounds, particularly antisense oligonucleotides, targeted to nucleic acids encoding stearoyl-CoA desaturase. Methods of using these compounds for modulation of stearoyl-CoA desaturase expression and for treatment of diseases associated with expression of stearoyl-CoA desaturase are provided.
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Page/Page column 89
(2010/02/10)
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- Ribavirin: Biotechnological synthesis and effect on the reproduction of Vaccinia virus
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The biotechnological method of synthesis of ribavirin, vidarabin, and 6-azauridine by the use of immobilized recombinant enzymatic preparations of nucleoside phosphorylase was improved. The effect of ribavirin and its combinations with the other synthesized nucleosides on the reproduction of Vaccinia virus was studied on the culture of Vero cells. The combination of ribavirin and vidarabin was shown to provide the antiviral effect at lesser concentrations than with these compounds taken separately.
- Konstantinova,Leont'eva,Galegov,Ryzhova,Chuvikovskii,Antonov,Esipov,Taran,Verevkina,Feofanov,Miroshnikov
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p. 553 - 560
(2007/10/03)
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- Selective Generation and Reactivity of 5′-Adenosinyl and 2′-Adenosinyl Radicals
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The reaction of hydrated electrons (eaq-) with 8-bromoadenosine 7 has been investigated by radiolytic methods coupled with product studies. Pulse radiolysis revealed that one-electror reductive cleavage of the C-Br bond gives the C8 radical 8 followed by a fast radical translocation to the sugar moiety. The reaction is partitioned between C5′ and C2′ positions in a 60:40 ratio leading to 5′-adenosinyl radical 9 and 2′-adenosinyl radical 11. This radical translocation from C8 to different sites of the sugar moiety has also been addressed computationally by means of DFT B3LYP calculations. In addition, ketone 21 was prepared and photolyzed providing an independent generation of C2′ radical 11. Both C5′ and C2′ radicals undergo unimolecular reactions. Radical 9 attacks adenine with a rate constant of 1.0 × 104 s-1 and gives the aromatic aminyl radical 10, whereas C2′ radical 11 liberates adenine with a rate constant of 1.1 × 105 s-1.
- Chatgilialoglu, Chryssostomos,Duca, Maria,Ferreri, Carla,Guerra, Maurizio,Ioele, Marcella,Mulazzani, Quinto G.,Strittmatter, Harald,Giese, Bernd
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p. 1249 - 1255
(2007/10/03)
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- Generation of C-1' radicals through a β-(acyloxy)alkyl rearrangement in modified purine and pyrimidine nucleosides
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The synthesis of protected 1',2'-didehydro-2'-deoxyadenosines has been optimized by incorporating a phosphoranylidene protection of the adenine amine function. These unsaturated adenosines have served as substrates for the electrophilic iodopivaloyloxylation leading to new nucleosides modified at the anomeric position. Reaction of halopivaloates 10, 11 and 12 with tributyltin hydride generates indirectly C-1' radicals through a β- (acyloxy)alkyl rearrangement. Rate constants for these rearrangements have been measured by using free-radical clock methodology and comparison of these data with previous reported results provides structural information about the nature of this important class of radicals.
- Gimisis, Thanasis,Ialongo, Giuseppina,Chatgilialoglu, Chryssostomos
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p. 573 - 592
(2007/10/03)
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- Generation and Characterization of Psoralen Radical Cations
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Radical cations of psoralen, 8-methoxypsoralen (8-MOP) and 5-methoxypsoralen have been generated by photosensitized electron transfer in acetonitrile and aqueous buffer/acetonitrile (1:1) and have absorption maxima at 600, 650 and 550 nm, respectively. The radical cations have lifetimes of ～5 us under these conditions, are unreactive toward oxygen and show behavior typical of arylalkene radical cations in their reactivity toward nucleophiles and the precursor psoralens. Direct 355 nm excitation of 8-MOP in aqueous buffer at physiological pH results in monophotonic photoionization to give 8-MOP.+ with a quantum yield of 0.015. The 8-MOP.+ reacts with both guanosine and adenosine mononucleotides (k = 2.5 × 109 and 3.4 × 107 M-1 s-1, respectively) via electron transfer to give the purine radical cations, but does not react with pyrimidine mononucleotides. These results suggest that reactions of psoralen radical cations generated by electron transfer or photoionization may be involved in psoralen/UVA therapy.
- Wood, Paul D.,Johnston, Linda J.
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p. 642 - 648
(2007/10/03)
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- Ionization of purine nucleosides and nucleotides and their components by 193-nm laser photolysis in aqueous solution: Model studies for oxidative damage of DNA 1
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The effect of 20-ns pulses of 193-nm laser light on aqueous solutions of purine bases, (2′-deoxy)nucleosides, and (2′-deoxy)nucleotides was investigated, and monophotonic ionization was observed. Although (deoxy)ribose and (deoxy)ribose phosphates are also ionized by 193-nm light, the photoionization of the (deoxy)nucleosides and -tides takes place predominantly (90%) at the purine moiety, due to the much higher extinction coefficients at 193 nm of the bases as compared to the (deoxy)ribose phosphates. The quantum yields of photoionization (φPl) of the purines are in the range 0.01 to 0.08, based on φ(Cl-) at 193 nm of 0.46. As shown by comparison with data obtained from pulse radiolysis, the ionized purines, i.e., the radical cations, deprotonate in neutral solution, yielding neutral radicals. The radical cation of 1-methylguanosine, produced by photoionization in oxygen-saturated aqueous solution, deprotonates with the rate constant 3.5 × 105 s-1. In the absence of oxygen, the hydrated electrons resulting from the photoionization react with the untransformed purine derivatives to yield the corresponding radical anions. As these are rapidly protonated by water (as concluded from pulse radiolysis), the photoionization in deaerated neutral solution results in two different neutral radicals: a deprotonated radical cation and a protonated radical anion.
- Candeias,Steenken
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p. 699 - 704
(2007/10/02)
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- Use of 9-(beta-D-arabinofuranosyl) adenine derivatives for the preparation of pharmaceutical compositions for the treatment of aids
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9-(β-D-arabinofuranosyl)adenine, also commonly known as Ara-A or vidarabine, esters thereof, or a pharmaceutically acceptable salt thereof, possess antiviral activity against the HTLV-III/LAV virus implicated in acquired immune deficiency syndrome (AIDS). The invention is related to the use of compounds of formula I for the preparation of pharmaceutical compositions useful in the treatment of infections of the HTLV-III/LAV virus in patients.
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- THE RAPID CHEMICAL SYNTHESIS OF ARABINONUCLEOTIDES
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A fast and convenient procedure for the chemical synthesis of arabinonucleotides which eliminates the multistep protection of the arabinonucleoside building blocks is described.Both solution and solid phase phosphite triester procedures are described.
- Damha, Masad J.,Usman, Nassim,Ogilvie, Kelvin K.
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p. 1633 - 1636
(2007/10/02)
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- Hydrolysis and solvent-dependent 2'→5' and 3'→5' acyl migration in prodrugs of 9-β-D-arabinofuranosyladenine
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As a prerequisite to quantitative in vivo studies to further explore the promising topical activity of the 2',3'-di-O-acetyl derivative of 9-β-D-arabinofuranosyladenine (ara-A) against herpes virus infections, the kinetics of solution degradation of the 2',3'-di-O-acetyl derivative and the 2'-, 3'-, and 5'-monoacetates were investigated. The rates of aqueous solution hydrolysis were found to be consistent with rank order predictions based on a consideration of substituent effects. Preliminary in vivo hydrolysis data, however, do not correlate with such predictions, indicating a need for more systematic studies of the effect of molecular structure on enzyme-catalyzed hydrolysis. An important reaction of the 2',3'-diester and the 3'-monoester in aqueous solution, in addition to ester hydrolysis, is 3'→5' acyl migration. 2'→5' Acyl migration does not occur in water but is the predominant migration pathway in organic solvents, as verified by studies in acetonitrile. 1H NMR spectroscopy was employed to study the dependence of the conformation of the sugar ring on the solvent environment. Although a change in the equilibrium between the C(2')endo and C(3')endo conformational states does occur, it is not a dramatic change and cannot explain the solvent selectivity observed in the acyl migration kinetics.
- Anderson,Fung,Kumar,Baker
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p. 825 - 830
(2007/10/02)
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- 2' AND 3'-KETONUCLEOSIDES AND THEIR ARABINO AND XYLO REDUCTION PRODUCTS CONVENIENT ACCESS VIA SELECTIVE PROTECTION AND OXIDATION OF RIBONUCLEOSIDES
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A number of 2',5'- or 3',5'-diprotected ribonucleosides and 5'-protected 2'- or 3'-deoxy-β-D-erythro-pentofuranosyl nucleosides have been oxidized to the corresponding 3' or 2'-ketonucleoside derivatives using chromium trioxide/pyridine/acetic anhydride or dimethyl sulfoxide/acetic anhydride.Reduction of the carbonyl functions with sodium borohydride gave the inverted arabino, xylo, or deoxy-threo isomers as predominant products by attack at the less hindered α-face of the sugar ring.Parallel reductions using sodium borodeuteride corroborated the epimeric ratios by demonstrating that complete oxidation of the original hydroxyl groups had occured.The deuterium labeling also aided in making NMR spectral assignments.
- Hansske, Fritz,Madej, Danuta,Robins, Morris J.
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p. 125 - 135
(2007/10/02)
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- Photochemical Reactions of Triplet Acetone with Indole, Purine, and Pyrimidine Derivatives
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The photochemical reactions of triplet acetone with indole, indole derivatives (1-methyl-, 2-methyl-, 3-methyl-, 5-methyl-, and 7-methylindole, and tryptophan), purine derivatives (caffeine, 7-methylguanine, adenine, adenosine, and guanosine), and a pyrimidine derivative (thymine) have been studied in aqueous solutions by using a KrF or ArF laser.The quenching processes of triplet acetone by indoles, being diffusion controlled, occur via the following paths: triplet-triplet energy transfer, electron transfer, photoaddition of triplet acetone to the 2-carbon atom of the indole ring, and deactivation without a chemical change.The yields of energy transfer, electron transfer, and photoaddition were determined from absorbance measurements.The transient absorptions due to triplet states were observed for caffeine, 7-methylguanine, and thymine, while weak transient absorptions which showed apparent second-order decays were observed for adenine, adenosine, and guanosine.Triplet acetone is quenched mainly via T-T energy transfer in caffeine, 7-methylguanine, and thymine.The weak absorptions may be attributed to neutral radicals in adenine and adenosine and to a cation radical in guanosine.
- Kasama, Kunihiko,Takematsu, Akiko,Arai, Shigeyoshi
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p. 2420 - 2427
(2007/10/02)
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- AN ENZYMIC SYNTHESIS OF PURINE D-ARABINONUCLEOSIDES
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A method is described for the synthesis of purine D-arabinonucleosides that uses purine bases and 2,2'-anhydro-(1-β-D-arabinofuranosylcytosine), AraC-an, as the starting materials.AraC-an was chosen as the precursor to the D-arabinosyl donor, because it is more readily available than any of the products that may be sequentially derived from it, namely, 1-β-D-arabinofuranosylcytosine ( AraC ), 1-β-D-arabinofuranosyluracil ( AraU ), and α-D-arabinofuranosyl-1-phosphate ( Araf 1-P ), a D-arabinofuranosyl donor.Four reactions were involved in the ovarall procass; ( a ) AraC-an was nonenzymically hydrolyzed at alkaline pH to AraC which was then ( b ) deaminated by deaminase to AraU, a nucleoside, ( c ) phosphorylyzed by uridine phosphorylase to Araf 1-P, and ( d ) this ester caused to react with a purine base to afford a purine D-arabinonucleoside, the reaction being catalyzed by purine nucleoside phosphorylase.All four rections occured in situ, the first and second being performed sequentially, whereas the third and fourth were combined in a single step.The three enzyme catalysts were purified from Escherichia coli.The efficiency of the method is exemplified by the synthesis of the D-arabinonucleosides of 2,6-diaminopurine and adenine; the overall yields, based on AraC-an, were 60 and 80 percent respectively.
- Krenitski, Thomas A.,Koszalka, George, W.,Tuttle, Joel V.,Rideout, Janet L.,Elion, Gertrude B.
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p. 139 - 146
(2007/10/02)
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- Purines, Pyrimidines, and Imidazoles. Part 52. New Syntheses of Some 1-β-D-Arabinofuranosylaminoimidazoles and of Related Purine Nucleosides, including 9-β-D-Arabinofuranosyladenine
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Ethyl 5-amino-1-β-D-arabinofuranosylimidazole-4-carboxylate and the corresponding carboxamide have been prepared by reaction of ethyl 5-aminoimidazole-4-carboxylate or the carboxamide, respectively with 2,3,5-tri-O-benzyl-α-D-arabinofuranosyl chloride (but not the bromide or iodide) and deblocking.Reaction of the nucleoside ester with formamidine acetate gave 9-β-D-arabinofuranosylhypoxanthine. 5-Amino-4-cyano-1-β-D-arabinofuranosylimidazole obtained by dehydration of the benzylated carboxamide or by direct glycosylation of 5-amino-4-cyanoimidazole and debenzylation of the product, when heated with triethyl orthoformate and ammonia, gave 9-β-D-arabinofuranosyladenine. 2,3,5-Tri-O-benzylarabinofuranosyl chloride with sodium azide, followed by reduction of the glycosyl azide formed with platinic oxide, and condensation of the arabinosylamine produced with ethyl N-(carbamoylcyanomethyl)formimidate gave a mixture of 2,3,5-tri-O-benzyl 1-α- and -β-D-arabinofuranosylimidazole 4-carboxamides.Reduction of the azide with lithium aluminium hydride followed by debenzylation of the product gave, in addition to tho two anomers, 5-amino-1-D-arabinitylimidazole-4-carboxamide.
- Kadir, Kamaliah,Mackenzie, Grahame,Shaw, Gordon
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p. 2304 - 2309
(2007/10/02)
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- The Cyclization of 8-Carboxamido-2'-O-tosyladenosine. A New Preparation of 9-β-D-Arabinofuranosyladenine (ara-A)
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In alkaline solution, 8-carboxamido-2'-O-tosyladenosine (4e; R2 = R3 = H), which may be prepared from adenosine in 7 steps, readily cyclizes to give (5); in neutral or weakly basic solution, it undergoes virtually quantitative conversion into ara-A (1a).
- Divakar, K. J.,Reese, Colin B.
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p. 1191 - 1193
(2007/10/02)
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- Partial Protection of Carbohydrate Derivatives. Part 4. Regioselective 2'-O-Deacylation of Fully Acylated Purine and Pyrimidine Ribonucleosides with Hydroxylaminium Acetate
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Like hydrazine hydrate, hydroxylamine was found to be useful for the regioselective 2'-O-deacylation of fully acylated purine and pyrimidine ribonucleosides as its salt with acetic acid; the partial O-deacylation reactions (which were not accompanied by undesirable discolouration as happens with hydrazine hydrate) gave the corresponding di-O-acylribonucleosides in superior yields; e.g. 2',3'-di-O-benzoyladenosine (74percent yield), 3',5'- (64percent yield) and 2',5'-di-O-benzoyl-N6-benzyladenosine (63percent yield on performing the reaction in ethanol), N2,3',5'-tri-O-benzoylguanosine (66percent yield), N2,2',5'-tri-isobutyrylguanosine (48percent yield), and 3',5'-di-O-benzoyluridine (61percent yield) were obtained using hydroxylaminium acetate in pyridine.Treatment of fully acetylated ribonucleosides with an excess of hydroxylaminium acetate gave the corresponding 5'-O-acetylribonucleosides in quantitative yields.The excellent regioselectivity observed in the present partial O-decyclation was confirmed on the basis of chromatographic separation; the mixtures of di-O-acylribonucleosides, which had already been equilibrated in pyridine, were re-equilibrated on the silica gel during separation, e.g. a 70 : 30 mixture of 3',5'- and 2',5'-di-O-benzoyladenosine was completely converted into the former based on 1H n.m.r spectroscopy.The acetates of 9-β-D-xylo- and -arabino-furanosyladenine were also found to give predominantly the corresponding 3',5'-diacetates on hydroxylaminolysis.
- Ishido, Yoshiharu,Sakairi, Nobuo,Okazaki, Kei,Nakazaki, Nobuo
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p. 563 - 573
(2007/10/02)
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