103884-97-5Relevant articles and documents
The chemoenzymatic synthesis of clofarabine and related 2′-deoxyfluoroarabinosyl nucleosides: The electronic and stereochemical factors determining substrate recognition by E. coli nucleoside phosphorylases
Fateev, Ilja V.,Antonov, Konstantin V.,Konstantinova, Irina D.,Muravyova, Tatyana I.,Seela, Frank,Esipov, Roman S.,Miroshnikov, Anatoly I.,Mikhailopulo, Igor A.
, p. 1657 - 1669 (2014)
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.
ANTI-HEPATITIS B VIRUS AGENT
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Paragraph 0036, (2020/10/09)
PROBLEM TO BE SOLVED: To provide an anti-hepatitis B virus agent and a prophylactic or therapeutic agent for hepatitis B virus-associated diseases, containing a nucleic acid analog as an active ingredient. SOLUTION: The anti-hepatitis B virus agent and pr
Stereoselective synthesis of 2-deoxy-2-fluoroarabinofuranosyl-α-1- phosphate and its application to the synthesis of 2′-Deoxy-2′- fluoroarabinofuranosyl purine nucleosides by a chemo-enzymatic method
Yamada, Kohei,Matsumoto, Noritake,Hayakawa, Hiroyuki
experimental part, p. 1117 - 1130 (2010/10/01)
Stereoselective introduction of a phosphate moiety into 2-deoxy-2-fluoroarabinofuranose derivatives at the anomeric position was investigated by two methods. One involved a stereoselective hydrolysis of 1-bromo-derivative, and the consecutive phosphorylation of 2-deoxy-2-fluoro- α-D-arabinofuranose via a phosphoramidite derivative. The other method involved stereoselective α-phosphorylation of the 1-bromo-derivative at the 1-position. The resulting α-1-phosphate was utilized to prepare 2′-deoxy-2′-fluoroarabinofuranosyl purine nucleosides by an enzymatic glycosylation reaction. This chemo-enzymatic method will be applicable to the synthesis of some 2′F-araNs, and three important 2′F-araNs were actually obtained in 30-40% yields from 1,3,5-tri-O-benzoyl-2-deoxy-2- fluoro-α-D-arabinose with high purity.
Synthesis and anti-HIV activity of 2′-fluorine modified nucleoside phosphonates: Analogs of GS-9148
Mackman, Richard L.,Lin, Kuei-Ying,Boojamra, Constantine G.,Hui, Hon,Douglas, Janet,Grant, Deborah,Petrakovsky, Oleg,Prasad, Vidya,Ray, Adrian S.,Cihlar, Tomas
, p. 1116 - 1119 (2008/09/19)
Modified purine analogs of GS-9148 [5-(6-amino-purin-9-yl)-4-fluoro-2,5-dihydro-furan-2-yloxymethyl]-phosphonic acid (2′-Fd4AP) were synthesized and their anti-HIV potency evaluated. The antiviral activity of guanosine analog (2′-Fd4GP) was comparable that of to 2′-Fd4AP in MT-2 cells, but selectivity was reduced.
Isolation, synthesis, and characterization of impurities and degradants from the clofarabine process
Anderson, Bruce G.,Bauta, William E.,Cantrell Jr., William R.,Engles, Tracy,Lovett, Dennis P.
, p. 1229 - 1237 (2013/01/03)
The identification of clofarabine process impurities and their subsequent isolation, synthesis, and characterization is described. Two isomeric process impurities resulting from N6-attachment of a fluoroarabinose to clofarabine were found. Clofarabine's base degradation products, which were different from the process impurities, were also synthesized and characterized. These compounds resulted from modifications to the sugar moiety, the purine ring, or both. A mechanistic rationale for the formation of the various process impurities and degradation products is provided.
ALPHA-1-PHOSPHORYLATED-2-DEOXY-2-FLUOROARABINOSIDE AND PROCESS FOR PRODUCING 2 -DEOXY-2 -FLUORO-BETA-D-ARABINONUCLEOSID E
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Page/Page column 18, (2008/06/13)
A method for producing 2'-deoxy-2'-fluoro-β-D-arabinonucleoside represented by formula (II): (wherein B represents a base), in particular, 2'-deoxy-2'-fluoro-β-D-arabinopurinenucleoside, which method comprises causing a nucleoside phosphorylase to act on α-1-phosphorylated-2-deoxy-2-fluoroarabinoside represented by formula (I): or a mixture of α- and β-isomers of 1-phosphorylated-2-deoxy-2-fluoroarabinoside represented by formula (V'): and on a base. The compound can be produced at high yield and in a convenient and highly stereoselective manner.
Oligonucleotides containing 9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-adenine and -guanine: Synthesis, hybridization and antisense properties
Tennilae, Tuula,Azhayeva, Elena,Vepsaelaeinen, Jouko,Laatikainen, Reino,Azhayev, Alex,Mikhailopulo, Igor A.
, p. 1861 - 1884 (2007/10/03)
Synthesis of 9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-adenine (7, ara-A2′F) and -guanine (12, ara-G2′F) was accomplished via the condensation of 2,6-dichloropurine (1) with 2-deoxy-2-fluoro-1,3,5-tri-O-benzoyl-α-D-arabinofuranose (2) as a key chemical step. Condensation of silylated N6-benzoyladenine (6) with 2 gave, after deblocking and chromatographic separation, ara-A2′F (7) (14%), it's α-anomer 8 (14%) and N7-α-isomer 9 (25%). The PSEUROT analysis of N9-β-D-arabinosides 7 and 12 manifested slight preference for the S rotamer (64%) for the former, and an equal population of the N and S rotamers for the latter. The arabinosides 7 and 12 were used for the preparation of the respective phosphoamidite building blocks 13 and 14 for automated oligonucleotide synthesis. Four 15-mer oligonucleotides (ONs) complementary to the initiation codon region of firefly luciferase mRNA were prepared: unmodified 2′-deoxy-ON (AS 1) and containing (i) ara-A2′F instead of the only A (AS2), (ii) ara-G2′F vs. 3-G from the 5′-terminus (AS3), and (iii) both arabinosides at the same positions (AS4). All these ONs display practically the same (i) affinity to both complementary DNA and RNA, and (ii) ability to inhibit a luciferase gene expression in a cell-free transcription-translation system.
