- Synthesis of 2'-iodo- and 2'-bromo-ATP and GTP analogues as potential phasing tools for X-ray crystallography
-
Ara-adenosine (adenine 9-β-D-arabinofuranoside) and ara-guanosine (guanine 9-β-D-arabinofuranoside) are converted into 2' halogenated ATP and GTP analogues by triflation and subsequent inversion of configuration at C- 2'. For the commercially unavailable ara-guanosine a short synthesis starting from guanosine is presented. The nucleotide analogues could serve for the preparation of heavy atom derivatives of ATP- and GTP-binding proteins useful for protein crystal structure determination by MIR/MAD phasing.
- Gruen, Mathias,Becker, Christian,Beste, Andrea,Siethoff, Christoph,Scheidig, Axel J.,Goody, Roger S.
-
-
Read Online
- MODIFIED OLIGONUCLEOTIDES AND METHODS OF USE IN TAUOPATHIES
-
Oligonucleotides comprising modifications at the 2' and/or 3' positions(s) along with methods of 5 making and use against Alzheimer disease and other tauopathies are disclosed.
- -
-
Paragraph 0241
(2019/10/04)
-
- MODIFIED OLIGONUCLEOTIDES AND METHODS OF USE
-
Modified oligonucleotides comprising modifications at the 2' and/or 3' positions(s) along with methods of making and use, e.g., against HBV are disclosed.
- -
-
Paragraph 0230
(2018/04/12)
-
- Enzymatic Synthesis of Therapeutic Nucleosides using a Highly Versatile Purine Nucleoside 2’-DeoxyribosylTransferase from Trypanosoma brucei
-
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
-
p. 4406 - 4416
(2018/09/14)
-
- Use of Citrobacter koseri whole cells for the production of arabinonucleosides: A larger scale approach
-
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.
-
p. 2182 - 2188
(2013/02/25)
-
- Synthesis of 9-β-d-arabinofuranosylguanine by combined use of two whole cell biocatalysts
-
Unlike the preparation of other purine nucleosides, transglycosylation from a pyrimidine nucleoside and guanine is difficult because of the low solubility of this base. Thus, another strategy, based on the coupled action of two whole cell biocatalyzed reactions, transglycosylation and deamination, was used. Enterobacter gergoviae and Arthrobacter oxydans were employed to synthesize 9-β-d-arabinofuranosylguanine (AraG), an efficient anti leukemic drug.
- Medici, Rosario,Iribarren, Adolfo M.,Lewkowicz, Elizabeth S.
-
scheme or table
p. 4210 - 4212
(2010/04/05)
-
- Stereoselective synthesis of 9-β-d-arabianofuranosyl guanine and 2-amino-9-(β-d-arabianofuranosyl)purine
-
9-β-d-Arabianofuranosyl guanine (6) and 2-amino-9-(β-d- arabianofuranosyl)purine (8) were prepared from 2-amino-6-chloro-9-(2,3,5- triphenylmethoxyl-β-d-arabianofuranosyl)purine (4), a key intermediate which was stereoselectively prepared from 2,3,5-triphenylmethoxyl-d- arabianofuranose and 2-amino-6-chloro-purine. The yield of the intermediate was obviously improved and only β-isomer was formed by using the activated molecular sieve as environmental friendly catalyst, overcoming the defect that a 1:1 mixture of α- and β-isomers was formed, which was difficult to separate, when toxic mercury cyanide was previously used as catalyst.
- Yu, Xue-Jun,Li, Gai-Xia,Qi, Xiou-Xiang,Deng, You-Quan
-
p. 683 - 685
(2007/10/03)
-
- Synthesis of sugar-modified 2,6-diaminopurine and guanine nucleosides from guanosine via transformations of 2-aminoadenosine and enzymatic deamination with adenosine deaminase
-
Treatment of 2,6-diaminopurine riboside (2-aminoadenosine) with α- acetoxyisobutyryl bromide in acetonitrile gave mixtures of the trans 2',3'- bromohydrin acetates 2. Treatment of 2 with zinc-copper couple effected reductive elimination, and deprotection gave 2,6-diamino-9-(2,3-dideoxy-β- D-erythro-pent-2-enofuranosyl)purine (3a). Treatment of 2 with Dowex 1 x 2 (OH-) resin in methanol gave the 2',3-anhydro derivative 4. Stannyl radical- mediated hydrogenolysis of 2 and deprotection gave the 2'-deoxy 6a and 3'- deoxy 7a nucleosides. Treatment of the 3',5'-O-(tetraisopropyldisiloxanyl) derivative (5a) with trifluoromethanesulfonyl chloride - 4- (dimethylamino)pyridine gave 2'-triflate 5c. Displacement with lithium azide -dimethylformamide and deprotection gave the arabino 2'-azido derivative 8a, which was reduced to give 2,6-diamino-9 (2-amino-2-deoxy-β-D- arabinofuranosyl)purine (8b). Sugar-modified 2,6-diaminopurine nucleosides were treated with adenosine deaminase to give the corresponding guanine analogues. Treatment of 2,6-diaminopurine riboside (2-aminoadenosine) with α-acetoxyisobutyryl bromide in acetonitrile gave mixtures of the trans 2',3'-bromohydrin acetates 2. Treatment of 2 with zinc-copper couple effected reductive elimination, and deprotection gave 2,6-diamino-9-(2,3-dideoxy-β-D-erythro-pent-2-enofuranosyl) purine (3a). Treatment of 2 with Dowex 1 × 2 (OH-) resin in methanol gave the 2',3'-anhydro derivative 4. Stannyl radical-mediated hydrogenolysis of 2 and deprotection gave the 2'-deoxy 6a and 3'-deoxy 7a nucleosides. Treatment of the 3',5'-O-(tetraisopropyldisiloxanyl) derivative (5a) with trifluoromethanesulfonyl chloride - 4-(dimethylamino)pyridine gave 2'-triflate 5c. Displacement with lithium azide - dimethylformamide and deprotection gave the arabino 2'-azido derivative 8a, which was reduced to give 2,6-diamino-9-(2-amino-2-deoxy-β-D-arabinofuranosyl)purine (8b). Sugar-modified 2,6-diaminopurine nucleosides were treated with adenosine deaminase to give the corresponding guanine analogues.
- Robins, Morris J.,Zou, Ruiming,Hansske, Fritz,Wnuk, Stanislaw F.
-
p. 762 - 767
(2007/10/03)
-
- An efficient and scalable synthesis of arabinosylguanine and 2′-deoxy-2′-fluoro-guanosine
-
An efficient conversion from commercially available 2,6-diaminopurine-2′,3′,5′-tri-O-benzyl arabinoside to arabinosylguanine and its further transformation to 2′-deoxy-2′-fluoro-guanosine is outlined. This process has been used to produce more than one hundred grams of final product. Copyright
- Ross, Bruce S.,Springer, Robert H.,Sprankle, Kelly G.,Vasquez, Guillermo
-
p. 1645 - 1647
(2007/10/03)
-
- Nucleosides. Part LV. Efficient synthesis of arabinoguanosine building blocks
-
From guanosine (1) as starting molecule, protected arabinoguanosine derivatives such as phosphoramidite precursors and arabinoguanosine (18) itself were prepared in high yields. Inversion of the configuration at C(2') was achieved by introduction of the (trifluoromethyl)sulfonyl residue and subsequent displacement by nucleophiles like acetate, bromide, and azide. The guanine moiety was protected at the amide function by the 2-(4-nitrophenyl)ethyl (npe) group on O6 and at the NH2 function by the 2-(4-nitrophenyl)ethoxycarbonyl (npeoc) group.
- Resmini,Pfleiderer
-
p. 429 - 434
(2007/10/02)
-
- A convenient synthesis of 2'-deoxy-6-thioguanosine, ara-guanine, ara-6-thioguanine and certain related purine nucleosides by the stereospecific sodium salt glycosylation procedure [1]
-
A simple and high-yield synthesis of biologically significant 2'-deoxy-6-thioguanosine, ara-6-thioguanine and araG has been accomplished employing the stereospecific sodium salt glycosylation method. Glycosylation of the sodium salt of 6-chloro- and 2-amino-6-chloropurine (1 and 2, respectively) with 1-chloro-2-deoxy-3,5-di-O-(p-toluoyl)-α-D-erythro-pentofuranose gave the corresponding N-9 substituted nucleosides as major products with the β-anomeric configuration (4 and 5, respectively) along with a minor amount of the N-7 positional isomers (6 and 7). Treatment of 4 with hydrogen sulfide in methanol containing sodium methoxide gave 2'-deoxy-6-thioinosine in 93% yield. Similarly, 5 was transformed into 2'-deoxy-6-thioguanosine (β-TGdR, 11) in 71% yield. Reaction of the sodium salt of 2 with 1-chloro-2,3,5-tri-O-benzyl-α-D-arabinofuranose gave N-7 and N-9 glycosylated products 13 and 9, respectively. Debenzylation of 9 with boron trichloride at -78° gave the versatile intermediate 2-amino-6-chloro-9-β-D-arabinofuranosylpurine 62% yield. Direct treatment of 14 with sodium hydrosulfide furnished ara-6-thioguanine. Alkaline hydrolysis of 14 readily gave 9-β-D-arabinofuranosylguanine (araG, 17), which on subsequent phosphorylation with phosphorus oxychloride in trimethyl phosphate afforded araG 5'-monophosphate.
- Hanna,Ramasamy,Robins,Revankar
-
p. 1899 - 1903
(2007/10/02)
-
- 2' AND 3'-KETONUCLEOSIDES AND THEIR ARABINO AND XYLO REDUCTION PRODUCTS CONVENIENT ACCESS VIA SELECTIVE PROTECTION AND OXIDATION OF RIBONUCLEOSIDES
-
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.
-
p. 125 - 135
(2007/10/02)
-
- A NEW METHOD FOR THE SYNTHESIS OF SOME 9-β-D-ARABINOFURANOSYLPURINES BY A COMBINATION OF CHEMICAL AND ENZYMATIC REACTIONS
-
An enzymatic transarabinosylation between 2-chlorohypoxanthine and 1-β-D arabinofuranosyluracil gave 9-β-D-arabinofuranosyl-2-chlorohypoxanthine which was chemically converted to 9-β-D-arabinofuranosylguanine and its derivatives.
- Morisawa, Hirokazu,Utagawa, Takashi,Miyoshi, Takeshi,Yoshinaga, Fumihiro,Yamazaki, Akihiro,Mitsugi, Koji
-
p. 479 - 482
(2007/10/02)
-
