scholarly journals Synthesis of Ribavirin, Tecadenoson, and Cladribine by Enzymatic Transglycosylation

Catalysts ◽  
2019 ◽  
Vol 9 (4) ◽  
pp. 355 ◽  
Author(s):  
Marco Rabuffetti ◽  
Teodora Bavaro ◽  
Riccardo Semproli ◽  
Giulia Cattaneo ◽  
Michela Massone ◽  
...  
Keyword(s):  
Aeromonas Hydrophila ◽  
Purine Nucleoside Phosphorylase ◽  
Chemoenzymatic Synthesis ◽  
Nucleoside Analogues ◽  
Specific Substrate ◽  
One Pot ◽  
Preparative Scale ◽  
Heterocyclic Base ◽  
Novel Approach ◽  
New Synthesis

Despite the impressive progress in nucleoside chemistry to date, the synthesis of nucleoside analogues is still a challenge. Chemoenzymatic synthesis has been proven to overcome most of the constraints of conventional nucleoside chemistry. A purine nucleoside phosphorylase from Aeromonas hydrophila (AhPNP) has been used herein to catalyze the synthesis of Ribavirin, Tecadenoson, and Cladribine, by a “one-pot, one-enzyme” transglycosylation, which is the transfer of the carbohydrate moiety from a nucleoside donor to a heterocyclic base. As the sugar donor, 7-methylguanosine iodide and its 2′-deoxy counterpart were synthesized and incubated either with the “purine-like” base or the modified purine of the three selected APIs. Good conversions (49–67%) were achieved in all cases under screening conditions. Following this synthetic scheme, 7-methylguanine arabinoside iodide was also prepared with the purpose to synthesize the antiviral Vidarabine by a novel approach. However, in this case, neither the phosphorolysis of the sugar donor, nor the transglycosylation reaction were observed. This study was enlarged to two other ribonucleosides structurally related to Ribavirin and Tecadenoson, namely, Acadesine, or AICAR, and 2-chloro-N6-cyclopentyladenosine, or CCPA. Only the formation of CCPA was observed (52%). This study paves the way for the development of a new synthesis of the target APIs at a preparative scale. Furthermore, the screening herein reported contributes to the collection of new data about the specific substrate requirements of AhPNP.

scholarly journals The chemoenzymatic synthesis of clofarabine and related 2′-deoxyfluoroarabinosyl nucleosides: the electronic and stereochemical factors determining substrate recognition by E. coli nucleoside phosphorylases

2014 ◽  
Vol 10 ◽  
pp. 1657-1669 ◽  
Author(s):  
Ilja V Fateev ◽  
Konstantin V Antonov ◽  
Irina D Konstantinova ◽  
Tatyana I Muravyova ◽  
Frank Seela ◽  
...  
Keyword(s):  
Electronic Structure ◽  
Chemical Synthesis ◽  
Purine Nucleoside Phosphorylase ◽  
Substrate Recognition ◽  
Chemoenzymatic Synthesis ◽  
Similar Reaction ◽  
One Pot ◽  
E Coli ◽  
Enzymatic Transformation ◽  
Nucleoside Phosphorylases

Two approaches to the synthesis of 2-chloro-9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)adenine (1, clofarabine) were studied. The first approach consists in the chemical synthesis of 2-deoxy-2-fluoro-α-D-arabinofuranose-1-phosphate (12a, 2FAra-1P) via three step conversion of 1,3,5-tri-O-benzoyl-2-deoxy-2-fluoro-α-D-arabinofuranose (9) into the phosphate 12a without isolation of intermediary products. Condensation of 12a with 2-chloroadenine catalyzed by the recombinant E. coli purine nucleoside phosphorylase (PNP) resulted in the formation of clofarabine in 67% yield. The reaction was also studied with a number of purine bases (2-aminoadenine and hypoxanthine), their analogues (5-aza-7-deazaguanine and 8-aza-7-deazahypoxanthine) and thymine. The results were compared with those of a similar reaction with α-D-arabinofuranose-1-phosphate (13a, Ara-1P). Differences of the reactivity of various substrates were analyzed by ab initio calculations in terms of the electronic structure (natural purines vs analogues) and stereochemical features (2FAra-1P vs Ara-1P) of the studied compounds to determine the substrate recognition by E. coli nucleoside phosphorylases. The second approach starts with the cascade one-pot enzymatic transformation of 2-deoxy-2-fluoro-D-arabinose into the phosphate 12a, followed by its condensation with 2-chloroadenine thereby affording clofarabine in ca. 48% yield in 24 h. The following recombinant E. coli enzymes catalyze the sequential conversion of 2-deoxy-2-fluoro-D-arabinose into the phosphate 12a: ribokinase (2-deoxy-2-fluoro-D-arabinofuranose-5-phosphate), phosphopentomutase (PPN; no 1,6-diphosphates of D-hexoses as co-factors required) (12a), and finally PNP. The substrate activities of D-arabinose, D-ribose and D-xylose in the similar cascade syntheses of the relevant 2-chloroadenine nucleosides were studied and compared with the activities of 2-deoxy-2-fluoro-D-arabinose. As expected, D-ribose exhibited the best substrate activity [90% yield of 2-chloroadenosine (8) in 30 min], D-arabinose reached an equilibrium at a concentration of ca. 1:1 of a starting base and the formed 2-chloro-9-(β-D-arabinofuranosyl)adenine (6) in 45 min, the formation of 2-chloro-9-(β-D-xylofuranosyl)adenine (7) proceeded very slowly attaining ca. 8% yield in 48 h.

scholarly journals Chemoenzymatic synthesis of α-dystroglycan core M1 O-mannose glycans

2015 ◽  
Vol 51 (58) ◽  
pp. 11654-11657 ◽  
Author(s):  
Yan Zhang ◽  
Caicai Meng ◽  
Lan Jin ◽  
Xi Chen ◽  
Fengshan Wang ◽  
...  
Keyword(s):  
Chemoenzymatic Synthesis ◽  
One Pot ◽  
Preparative Scale

A diversity-oriented chemoenzymatic synthesis of α-dystroglycan (α-DG) core M1 O-mannose glycans at the preparative scale via sequential one-pot multienzyme (OPME) glycosylation of a chemically prepared disaccharyl serine intermediate was reported.

The Chemoenzymatic Synthesis of 2-Chloro- and 2-Fluorocordycepins

Synthesis ◽  
2017 ◽  
Vol 49 (21) ◽  
pp. 4853-4860 ◽  
Author(s):  
Igor Mikhailopulo ◽  
Alexandra Denisova ◽  
Yulia Tokunova ◽  
Ilja Fateev ◽  
Alexandra Breslav ◽  
...  
Keyword(s):  
Efficient Method ◽  
Purine Nucleoside Phosphorylase ◽  
Chemoenzymatic Synthesis ◽  
Purine Nucleoside ◽  
Limiting Factor ◽  
One Pot ◽  
Nucleoside Phosphorylase ◽  
E Coli ◽  
Poor Solubility ◽  
Practical Synthesis

Two approaches to the chemoenzymatic synthesis of 2-fluorocordycepin and 2-chlorocordycepin were studied: (i) the use of 3′-deoxyadenosine (cordycepin) and 3′-deoxyinosine (3′dIno) as donors of 3-deoxy-d-ribofuranose in the transglycosylation of 2-fluoro- (2FAde) and 2-chloroadenine (2ClAde) catalyzed by the recombinant E. coli purine nucleoside phosphorylase (PNP), and (ii) the use of 2-fluoroadenosine and 3′-deoxyinosine as substrates of the cross-glycosylation and PNP as a biocatalyst. An efficient method for 3′-deoxyinosine synthesis starting from inosine was developed. However, the very poor solubility of 2ClAde and 2FAde is the limiting factor of the first approach. The second approach enables this problem to be overcome and it appears to be advantageous over the former approach from the viewpoint of practical synthesis of the title nucleosides. The 3-deoxy-α-d-ribofuranose-1-phosphate intermediary formed in the 3′dIno phosphorolysis by PNP was found to be the weak and marginal substrate of E. coli thymidine (TP) and uridine (UP) phosphorylases, respectively. Finally, one-pot cascade transformation of 3-deoxy-d-ribose in cordycepin in the presence of adenine and E. coli ribokinase, phosphopentomutase, and PNP was tested and cordycepin formation in ca. 3.4% yield was proved.

A One-Pot Chemoenzymatic Synthesis of (2S,4R)-4-Methylproline Enables the First Total Synthesis of Antiviral Lipopeptide Cavinafungin B

2018 ◽  
Author(s):  
Christian R. Zwick ◽  
Hans Renata
Keyword(s):  
Total Synthesis ◽  
Natural Product ◽  
Complex Molecule ◽  
Molecular Target ◽  
Chemoenzymatic Synthesis ◽  
General Strategy ◽  
One Pot

We report an efficient ten-step synthesis of antiviral natural product cavinafungin B in 37% overall yield. By leveraging a one-pot chemoenzymatic synthesis of (2S,4R)-4-methylproline and oxazolidine-tethered (Rink-Boc-ATG-resin) SPPS methodology, the assembly of our molecular target could be conducted in an efficient manner.This general strategy could prove amenable to the construction of other natural and unnatural linear lipopeptides. The value of incorporating biocatalytic steps in complex molecule synthesis is highlighted by this work.

One-Pot Chemoenzymatic Synthesis of 3‘-Functionalized Cephalosporines (Cefazolin) by Three Consecutive Biotransformations in Fully Aqueous Medium

1997 ◽  
Vol 62 (26) ◽  
pp. 9099-9106 ◽  
Author(s):  
O. H. Jústiz ◽  
R. Fernández-Lafuente ◽  
J. M. Guisán ◽  
P. Negri ◽  
G. Pagani ◽  
...  
Keyword(s):  
Aqueous Medium ◽  
Chemoenzymatic Synthesis ◽  
One Pot
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