- Nucleoside phosphorylases from clostridium perfringens in the synthesis of 2',3'-dideoxyinosine
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Four Clostridium perfringens phosphorylases were subcloned, overexpressed and analyzed for their substrate specificity. DeoD(1) and PunA could use a variety of purine substrates, including an antiviral drug 2',3'-dideoxyinosine (ddI). In one-pot synthesis using Clostridium phosphorylases, 2',3'-dideoxyuridine and hypoxanthine were converted to ddI at yield of about 30%. Copyright
- Christoffersen,Serra,Terreni,Piskur
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Read Online
- 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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- 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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- Continuous flow photochemistry for the rapid and selective synthesis of 2′-deoxy and 2′,3′-dideoxynucleosides
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A new photochemical flow reactor has been developed for the photo-induced electron-transfer deoxygenation reaction to produce 2′-deoxy and 2′,3′-dideoxynucleosides. The continuous flow format significantly improved both the efficiency and selectivity of the reaction, with the streamlined multi-step sequence directly furnishing the highly desired unprotected deoxynucleosides.
- Shen, Bo,Jamison, Timothy F.
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p. 157 - 164
(2013/04/10)
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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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- Continuous flow photocatalysis enhanced using an aluminum mirror: Rapid and selective synthesis of 2′-deoxy and 2′,3′-dideoxynucleosides
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A unique photochemical flow reactor featuring quartz tubing, an aluminum mirror and temperature control has been developed for the photo-induced electron-transfer deoxygenation reaction to produce 2′-deoxy and 2′,3′-dideoxynucleosides. The continuous flow format significantly increased the efficiency and selectivity of the reaction.
- Shen, Bo,Bedore, Matthew W.,Sniady, Adam,Jamison, Timothy F.
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supporting information; experimental part
p. 7444 - 7446
(2012/10/08)
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- Aeromonas hydrophila strains as biocatalysts for transglycosylation
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Microbial transglycosylation is useful as a green alternative in the preparation of purine nucleosides and analogues, especially for those that display pharmacological activities. In a search for new transglycosylation biocatalysts, two Aeromonas hydrophila strains were selected. The substrate specificity of both micro-organisms was studied and, as a result, several nucleoside analogues have been prepared. Among them, ribavirin, a broad spectrum antiviral, and the well-known anti HIV didanosine, were prepared, in 77 and 62% yield using A. hydrophila CECT 4226 and A. hydrophila CECT 4221, respectively. In order to scale-up the processes, the reaction conditions, product purification and biocatalyst preparation were analyzed and optimized.
- Nbile, Matas,Terreni, Marco,Lewkowicz, Elizabeth,Iribarren, Adolfo M.
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experimental part
p. 395 - 402
(2011/10/08)
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- A PROCESS FOR PREPARING DIDANOSINE
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This invention provides a method for preparing didanosine. The method comprises removing a protecting group in position 5' of compound II by hydrolysis under basic reaction conditions, and simultaneously enolizing of the carbonyl group of the purine ring to obtain a stable salt, and then producing the salt of 2',3-dideoxyinosine through catalytic hydrogenation, which salt is finally converted with acid to yield the finished product.
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Page/Page column 3-4
(2008/06/13)
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- METHOD FOR PRODUCING NUCLEOSIDE DERIVATIVE
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The present invention relates to a method for producing a nucleoside derivative represented by formula (2), comprising the step of reducing a nucleoside of formula (1) in the presence of a noble metal catalyst comprising a carrier and a noble metal supported thereby, selected from the group consisting of (A) a homogeneously supported catalyst where the specific surface area of the noble metal is 95.0 m2/g or more and the particle size of the noble metal is 4.3 nm or less, and (B) a surface-loaded catalyst where the specific surface area of the noble metal is 56.0 m2/g or more and the particle size of the noble metal is 8.0 nm or less, wherein R1 is hydrogen or a protective group, R2 is NH2 or OH, R3 is an acyl group, and X is a chlorine or bromine atom. According to the present invention, the yield can be made equal even when the amount of catalyst is smaller than that used for the conventional products.
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Page/Page column 10
(2008/06/13)
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- A NOVEL PROCESS FOR THE PREPARATION OF DIDANOSINE USING NOVEL INTERMEDIATES
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The present invention relates to novel crystalline alkali metal and alkaline earth metal salts of 2',3'-dideoxy-2',3'-didehydroinosine. The present invention also provides a novel process for preparation of didanosine in high yield and purity using novel intermediates. Thus, for example, 5'-O-acetyl-2',3'-dideoxy-2',3'-didehydroinosine is reacted with monomethyl amine to give 2',3'-dideoxy-2',3'-didehydro inosine, which is then reacted with sodium hydroxide and crystallized to give crystalline 2',3'-dideoxy-2',3'-didehydroinosine sodium salt. 2',3'-Dideoxy-2',3'-didehydroinosine sodium salt is hydrogenated using raney nickel catalyst in aqueous medium and then neutralized with hydrochloric acid to yield didanosine.
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Page/Page column 6-7
(2008/06/13)
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- Synthesis of 2′,3′-dideoxyinosine via radical deoxygenation
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A synthetic method for 2′,3′-dideoxyinosine (ddI) from inosine was established via radical deoxygenation of N1,5′-O-diprotected-2′, 3′-bis-S-methyl dithiocarbonate of inosine derivatives. The radical deoxygenation proceeded smoothly to give the desired dideoxy compounds in good yields using 1-ethylpiperidinium hypophosphite and triethylborane. Benzyl or p-methoxybenzyl protection of inosine at the N1, 5′-O-positions were effective for the ddI synthesis. Copyright Taylor & Francis Group, LLC.
- Torii, Takayoshi,Izawa, Kunisuke,Cho, Dae Hyan,Jang, Doo Ok
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p. 985 - 988
(2008/03/28)
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- INOSINE DERIVATIVE AND PROCESS FOR PRODUCING THE SAME
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The present invention provides a method for producing an inosine derivative represented by the following general formula (1) including the steps of subjecting an inosine derivative of general formula (3) to dithiocarbonylation and carrying out radical reduction of the obtained compound. According to the present invention there can be produced compounds useful as anti-AIDS drugs on industrial scale. wherein R1 may be the same or different and are each benzyl group, benzhydryl group or trityl group, each of which may have a substituent in general formulas (1) and (3).
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Page/Page column 11; 12
(2010/11/08)
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- Process for preparing dideoxyinosine using adenosine deaminase enzyme
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A method of making didanosine (ddI) including the steps of: (a) obtaining an enzyme expressing ddA deaminase activity; (b) immobilizing the enzyme onto an insoluble support; (c) contacting the enzyme with a dideoxyadenosine (ddA) solution of at least about 4% weight volume ddA in water for a time and under conditions to produce a ddI solution; and (d) isolating the ddI from the ddI solution. Optionally, the ddI mother liquor is reused in subsequent runs to improve yield.
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- Specific lipid conjugates to nucleoside diphosphates and their use as drugs
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The present invention concerns new phospholipid derivatives of nucleosides of the general formula (I) in which R1represents a straight-chained or branched, saturated or unsaturated aliphatic residue with 9-14 carbon atoms which can optionally be substituted once or several times; R2can represent a straight-chained or branched, saturated or unsaturated aliphatic residue with 8-12 carbon atoms which can optionally be substituted once or several times; m is 2 or 3; A can represent a methylene group or an oxygen; Nuc can be a nucleoside or a residue derived from a nucleoside derivative; and tautomers thereof and their physiologically tolerated salts of inorganic and organic acids and bases as well as pharmaceutical preparations containing these compounds.
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- Synthesis and anti-HIV evaluation of 2',3'-dideoxy imidazo- and ν- triazolo[4,5-d]pyridazine nucleosides
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The syntheses of the 2'-deoxy and 2',3'-dideoxynucleosides of 2,8-diaza- 3-deazainosine and the 2',3'-dideoxynucleoside of 2-aza-3-deazainosine were achieved and the pathways leading to these novel nucleosides are described. The preparation of the 2',3'-dideoxynucleoside (1) of 2-aza-3-deazainosine involved deoxygenation of the 2'-deoxy-3'-imidazolide intermediate with n- Bu3SnH and AIBN. The latter nucleoside was synthesized from the known 2'- deoxy derivative of 2-aza-3-deazainosine. The three-step synthesis of 1 from the 2'-deoxy analogue was accomplished in 40% overall yield. Rather than synthesize the corresponding 2',3'-dideoxynucleoside (2) of 2,8-diaza-3- deazainosine in the same manner, i.e. deoxygenation of the 2'- deoxynucleoside, a more cost-effective route was chosen. This pathway involved reductive cleavage of the 5'-protected, 2',3'-thiocarbonate derivative to furnish a mixture of the 2'- and 3'-deoxy isomers. This mixture was not separated, but was deoxygenated by the aforementioned imidazolide method. Using this methodology, 2 was prepared in 23% overall yield from 2,8- diaza-3-deazainosine. Nucleosides 1 and 2 were evaluated for antiretroviral activity and were found to be inactive. (C) 1999 Elsevier Science Ltd.
- Bussolari, Jacqueline C.,Panzica, Raymond P.
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p. 2373 - 2379
(2007/10/03)
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- Lipase-catalyzed protection of the hydroxy groups of the nucleosides inosine and 2'-deoxyinosine: A new chemoenzymatic synthesis of the antiviral drug 2',3'-dideoxyinosine
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The selective acylation of the hydroxy groups of the nucleosides inosine 1a and 2'-deoxyinosine lb has been achieved in the presence of Candida antarctica and Pseudomonas sp. lipases in organic solvents; starting from the 5'-acetyl derivative of 2'-deoxyinosine, compound 5a, an efficient chemoenzymatic synthesis of the antiviral drug 2',3'-dideoxyinosine 1c has been achieved.
- Ciuffreda, Pierangela,Casati, Silvana,Santaniello, Enzo
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p. 1577 - 1582
(2007/10/03)
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- New approach to the synthesis of 2',3',-dideoxyadenosine and 2',3'- dideoxyinosine
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A new approach to the synthesis of 2',3'-dideoxyadenosine and 2',3'dideoxyinosine based on deoxygenation of 2',3'-di-O-mesylnucleosides was developed.
- Antonov,Konstantinova,Miroshnikov
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p. 153 - 159
(2007/10/03)
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- Process for the production of asymmetrical phosphoric acid diesters
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The present invention concerns a process for the production of asymmetrical phosphoric acid diesters. The process is characterized in that a phosphoric acid ester is condensed with a compound containing hydroxy groups in the presence of an arylsulfonic acid chloride and an organic base, the residue of evaporation is stirred out with an organic solvent after the hydrolysis, the arylsulfonic acid pyridine salt which forms is nearly completely crystallized and recycled, the lipid derivative that is formed is precipitated as a sparingly soluble salt by addition of a solution containing alkaline-earth ions and isolated, the sparingly soluble salt is isolated as the free acid in an organic solvent by suspension in a water-immiscible organic solvent and a dilute aqueous mineral acid, the crude product is purified if desired, by means of preparative chromatography on a RP phase and subsequently the free acid is converted if desired into any desired salt.
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- ADA-Bypass by lipophilic cycloSal-ddAMP pro-nucleotides. A second example of the efficiency of the cycloSal-concept
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The synthesis of lipophilic pro-nucleotides of ddAMP 2 based on cycloSal-ddAMP 3a-c is described. Phosphotriesters 3 released ddAMP 2 selectively by a controlled, chemically induced tandem reaction. CycloSal-phosphotriesters 3 exhibited antiviral activity against HIV-1/HIV-2 in CEM cells that where by a factor up to hundred higher as compared to ddA 1.
- Meier, Chris,Knispel, Tina,De Clercq,Balzarini, Jan
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p. 1577 - 1582
(2007/10/03)
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- Controlled release pharmaceutical formulations of 3'-azido-3'-deoxythymidine and methods of use
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This invention is directed to controlled release pharmaceutical formulations of 3'-azido-3'-deoxythymidine, also known as AZT or zidovudine and methods of use thereof. The controlled release formulations of AZT achieve and maintain a therapeutic level of AZT, while substantially reducing the side effects of AZT caused by its catabolite 3'-amino-3'-deoxythymidine (AMT) by reducing the amount of AMT produced.
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- Localization of purine metabolizing enzymes in bovine brain microvessel endothelial cells: An enzymatic blood-brain barrier for dideoxynucleosides?
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Purpose. The specific activities of the purine and pyrimidine metabolizing enzymes, purine nucleoside phosphorylase (PNP), adenosine deaminase (ADA) and cytidine deaminase (CDA) were determined in bovine brain microvessel endothelial cells, (BBMECs), whole cerebral tissue and erythrocytes. In addition, the substrate specificities (K(m) and V(max)) of purified calf spleen PNP for inosine and 2',3'-dideoxyinosine (ddI) and of purified calf intestinal ADA for 2',3'-dideoxyadenosine (ddA), 6-chloro-2',3'-dideoxypurine (6-Cl-ddP), and 2'-β-fluoro-2',3'-dideoxyadenosine (F-ddA) have been explored. Methods. BBMECs were isolated from bovine cerebral cortex by a two step enzymatic dispersion treatment followed by centrifugation over 50% Percoll density gradients. Activities of alkaline phosphatase, γ-glutamyl transpeptidase, ADA, PNP and CDA were determined in various tissue homogenates (cerebral cortex, BBMECs and erythrocytes). Enzyme kinetic studies were also conducted using commercially available enzymes and several nucleoside analogs of interest. Results. The activities of ADA and PNP were 42-fold and 247-fold higher in the cerebral microvessels than in the cerebral cortex, respectively, while there was no detectable CDA activity in the microvessel fraction and very little overall activity in the cortex. Conclusions. ADA and PNP may serve as an enzymatic blood-brain barrier for some of the anti-HIV dideoxynucleosides. Simulations of brain availability for ddI, ddA, 6-Cl-ddP, and FddA demonstrated that the quantitative significance of enzyme localization may vary dramatically, however, depending on the membrane permeability of the drug and its bioconversion rate constant within the endothelial cell.
- Johnson, Mark D.,Andersen, Bradley D.
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p. 1881 - 1886
(2007/10/03)
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- Synthesis of 2′,3′-dideoxypurinenucleosides via the palladium catalyzed reduction of 9-(2,5-di-O-acetyl-3-bromo-3-deoxy-β-D-xylofuranosyl)purine derivatives
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Practical method to produce 2′,3′-dideoxypurinenucleosides from 9-(2,5-di-O-acetyl-3-bromo-3-deoxy-β-D-xylofuranosyl)purines (1) was developed. High ratio of 2′,3′-dideoxynucleoside to 3′-deoxyribonucleoside was obtained by selecting the reaction conditions (solvent, pH and/or base), or changing 2′-acyloxy leaving group. The reaction mechanism was studied by deuteration experiments of 1a and 1-(3,5-di-O-acetyl-2-bromo-2-deoxy-β-D-ribofuranosyl)thymine (12).
- Shiragami, Hiroshi,Amino, Yusuke,Honda, Yutaka,Arai, Masayuki,Tanaka, Yasuhiro,Iwagami, Hisao,Yukawa, Toshihide,Izawa, Kunisuke
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- Method for treating HBV infections with L-2',3'-didehydro-dideoxy-5-fluorocytidine
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The present invention relates to the surprising discovery that certain dideoxynucleoside analogs which contain a dideoxy ribofuranosyl moiety having an L-configuration (as opposed to the naturally occurring D- configuration) exhibit unexpected activity against Hepatitis B virus (HBV). In particular, the compounds according to the present invention show potent inhibition of the replication of the virus in combination with very low toxicity to the host cells (i.e., animal or human tissue). Compounds according to the present invention exhibit primary utility as agents for inhibiting the growth or replication of HBV, HIV and other retroviruses, most preferably HBV.
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- Synergistic antiviral nucleoside combinations
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An antiviral composition comprising in combination an effective antiviral amount of 3'-fluoro-2',3'-dideoxy nucleoside compound I of the formula STR1 wherein B is adenine, thymine, guanine, cytosine, inosine, uracil, 5-ethyluracil, 2,6-diaminopurine; and an effective antiviral amount of 2',3'-dideoxy nucleoside compound II of the formula STR2 wherein X is N3 or H or together with Y forms an additional carbon-carbon bond, Y and Z are independently H, OH or F, and B is adenine, thymine, guanine, cytosine, inosine, uracil, 5-ethyluracil, 2,6-diaminopurine, and a physiologically acceptable carrier.
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- Synthesis and 1H and 13C NMR spectral characteristics of 8-bromo-2′,3′-dideoxyguanosine and 8-bromo-2′,3′-dideoxyinosine
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Reaction of 2′,3′-dideoxyguanosine 1a as 5′-O-tert-butyldimethylsilyl derivative 1b and 2′,3′-dideoxyinosine 2a with bromine in acetate buffer conducted in heterogeneous medium afforded 8-bromo-2′,3′-dideoxyguanosine 3a (44% after deprotection) and 8-bromo-2′,3′-dideoxyinosine 4a (12%) respectively. The change of conformational preferences anti → syn on 8-bromo substitution of 2′,3′-dideoxynucleosides is reflected in the 1H and 13C NMR spectra by characteristic shifts of H-2′, H-3′, C-2′ and C-3′ signals.
- Zeidler, Joanna,Golankiewicz, Bozenna
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p. 1077 - 1095
(2007/10/03)
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- Lipophilic, acid-stable, adenosine deaminase-activated anti-HIV prodrugs for central nervous system delivery. 2. 6-Halo and 6-alkoxy prodrugs of 2'- β-fluoro-2',3'-dideoxyinosine
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A series of 6-halo-(F-, Cl-, Br-, I-) and 6-alkoxy-(OMe-, OEt-) 9-(2,3- dideoxy-2-fluoro-β-D-threopentofuranosyl) purines (F-ddN) have been synthesized and characterized with the objective of finding compounds which might be superior to existing drugs for the treatment of HIV in the central nervous system. These compounds, which contain lipophilic 6-substituents, were chosen as acid-stable prodrugs for the anti-HIV-active F-ddN, 9-(2,3- dideoxy-2-fluoro-β-D-threopentofuranosyl) hypoxanthine (F-ddI), because of their potential to increase blood-brain-barrier penetration relative to F- ddI. All the new compounds were more lipophilic than the currently approved anti-AIDS drugs. Partition coefficient increases of 30- and 110-fold were achieved, relative to didanosine (ddI), for the 6-chloro- and 6-ethoxy analogues. 2'-Fluoro substitution abolished the pH 1, acid-catalyzed cleavage of the nucleoside glycosylic bond. However, pH 1, acid-catalyzed hydrolysis of the 6-fluoro substituent to produce F-ddI was observed to occur at a rate (t 1/2 0.54 h) which was ca. 40-170 times faster than that of the other prodrugs. The utility of the F-ddNs as prodrugs for F-ddI depends upon their ability to act as substrates for adenosine deaminase. The relative rates of adenosine deaminase-catalyzed prodrug hydrolysis to F-ddI varied by a factor of >25 000 with the 6-fluoro- and 6-ethoxy analogues reacting the fastest and slowest, respectively. All of the prodrugs possessed anti-HIV activity in the phytohemagglutinin-stimulated peripheral blood mononuclear cell test system and a qualitative correlation exists between prodrug anti-HIV activity and adenosine deaminase hydrolysis rates.
- Ford Jr.,Siddiqui,Driscoll,Marquez,Kelley,Mitsuya,Shirasaka
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p. 1189 - 1195
(2007/10/02)
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- Antiviral agents
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Nucleoside compounds of the formula STR1 wherein: B is a purine or a pyrimidine; X and X' are H, OH or F, provided that at least one is H; Y and Y' are H, OH, OCH3 or F, provided that at least one is H; Y' and Z together form a cyclic phosphate ester, provided that Y is H; or Z is STR2 where n is zero, one, two or three; and Z' is N3 or OCH3 ; provided that when X' and Y' are OH and Z' is N3, B is not cytosine, and when X' and Y' are OH and Z' is OCH3, B is not uracil, adenine or cytosine; and the pharmaceutically acceptable esters, ethers and salts thereof, have been found to have potent antiviral activity with a high therapeutic ratio.
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- SYNTHESIS OF 2-DEOXY-β-D-RIBONUCLEOSIDES AND2,3-DIDEOXY.β-D-PENTOFURANOSIDES ON IMMOBILIZED BACTERIAL CELLS
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Alginate gel-entrapped cells of auxotrophic thymine-dependent strain of E. coli catalyze the transfer of 2-deoxy-D-ribofuranosyl moiety of 2'-deoxyuridine to purine and pyrimidine bases as well as their aza and deaza analogs.All experiments invariably gave β-anomers; in most cases, the reaction was regiospecific, affording N9-isomers in the purine and N1-isomers in the pyrimidine series.Also a 2,3-dideoxynucleoside can serve as donor of the glycosyl moiety.The acceptor activity of purine bases depends only little on substitution, the only condition being the presence of N7-nitrogen atom.On the other hand, in the pyrimidine series the activity is limited to only a narrow choice of mostly short 5-alkyl and 5-halogeno uracil derivatives.Heterocyclic bases containing amino groups are deaminated; this can be avoided by conversion of the base to the corresponding N-dimethylaminomethylene derivative which is then ammonolyzed.The method was verified by isolation of 9-(2-deoxy-β-D-ribofuranosyl) derivatives of adenine, guanine, 2-chloroadenine, 6-methylpurine, 8-azaadenine, 8-azaguanine, 1-deazaadenine, 3-deazaadenine, 1-(2-deoxy-β-D-ribofuranosyl) derivatives of 5-ethyluracil, 5-fluorouracil, and 9-(2,3-deoxy-β-D-pentofuranosyl)hypoxanthine, 9-(2,3-deoxy-β-D-pentofuranosyl)-6-methylpurine, and other nucleosides.
- Votruba, Ivan,Holy, Antonin,Dvorakova, Hana,Guenter, Jaroslav,Hockova, Dana,et al.
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p. 2303 - 2330
(2007/10/02)
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- Process for preparing 2',3'-dideoxyadenosine
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A process for preparing 2',3'-dideoxyadenosine of the formula STR1 wherein B is adenine, wherein R1 is hydrogen, C1-12 acyl, C1-12 alkyl, C7-8 aralkyl, or silyl, said process comprising: reducing a nucleoside of the formula IIIa or IIIb STR2 wherein R2 is hydrogen, C1-12 acyl, C1-12 alkyl, C7-8 aralkyl or silyl; X is Cl, Br or I; R5 is C1-12 acyl and B is adenine, with hydrogen in the presence of a palladium catalyst and aqueous solvent mixture of acetonitrile or ethyl acetate and water, said aqueous solvent containing a base selected from the group consisting of sodium hydroxide/sodium acetate and sodium carbonate/sodium acetate, wherein said solvent has a pH of 9-11.
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- A Highly Stereoselective Synthesis of Anti-HIV 2',3'-Dideoxy- and 2',3'-Didehydro-2',3'-dideoxynucleosides
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A general total synthesic method for the stereocontrolled synthesis of 2',3'-dideoxy- as well as 2',3'-didehydro-2',3'-dideoxynucleosides is presented.Introduction of an α-phenylselenenyl group at the 2-position of 2,3-dideoxyribosyl acetate directs the glycosyl bond formation to give >/=95percent β-isomer.This 2'-phenylselenenyl nucleoside may be converted to either the 2',3'-dideoxynucleoside by treatment with n-Bu3SnH and Et3B at room temperature or to the unsaturated derivative by treatment with H2O2/cat. pyridine.The application of this method to the syntheses of pyrimidines (ddU, ddT, ddC), 6-substituted purines (ddA, ddI, 6-chloro-ddP, N6-Me-ddA), and 2,6-disubstituted purines (2-F-ddA, 6-chloro-2-amino-ddP) as well as selected 2',3'-didehydro-2',3'-dideoxy derivatives is reported.
- Beach, J. Warren,Kim, Hea O.,Jeong, Lak S.,Nampalli, Satyanarayana,Islam, Qamrul,et al.
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p. 3887 - 3894
(2007/10/02)
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- A NEW SYNTHESIS OF 2',3'-DIDEOXYNUCLEOSIDES FOR AIDS CHEMOTHERAPY
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Dideoxynucleosides were prepared in high optical purity from L-glutamic acid.The condensation reactions between activated 2,3-dideoxypentofuranoses and silylated purines or pyrimidines afforded separable β/α mixtures of dideoxynucleosides.
- Farina, Vittorio,Benigni, Daniel A.
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p. 1239 - 1242
(2007/10/02)
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