103884-98-6Relevant articles and documents
A new synthesis of 9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)guanine (araF-G)
Elzagheid, Mohamed I.,Viazovkina, Ekaterina,Damha, Masad J.
, p. 1339 - 1342 (2003)
Interesting and very promising antisense properties of 2′ -deoxy-2′-fluoroarabinonucleic acids ((a) Wilds, C.J.; Damha, M.J. 2′-Deoxy-2′-fluoroarabinonucleosides and oligonucleotides (2′F-ANA): synthesis and physicochemical studies. Nucl. Acids Res. 2000, 28, 3625-3635; (b) Viazovkina, E.; Mangos, M.; Elzagheid, M.I.; Damha, M.J. Current Protocols in Nucleic Acid Chemistry 2002, 4.15.1-4.15.21) (2′F-ANA) has encouraged our research group to optimize the synthetic procedures for 2′-deoxy-2′-fluoro-β-D-arabinonucleosides (araF-N). The synthesis of araF-U, araF-T, araF-A and araF-C is straightforward, (Tann, C.H.; Brodfuehrer, P.R.; Brundidge, S.P.; Sapino, C., Jr. Howell H.G. Fluorocarbohydrates in synthesis. An efficient synthesis of 1-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-5-iodouracil (β-FIAU) and 1-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)thymine (β-FMAU). J. Org. Chem. 1985, 50, 3644-3647; Howell, H.G.; Brodfuehrer, P.R.; Brundidge, S.P.; Benigni, D.A.; Sapino, C., Jr. Antiviral nucleosides. A stereo-specific, total synthesis of 2′-fluoro-2′-deoxy-β-D-arabinofuranosyl nucleosides. J. Org. Chem. 1988, 53, 85-88; Maruyama, T.; Takamatsu, S.; Kozai, S.; Satoh, Y.; Izana, K. Synthesis of 9-(2-deoxy-2-fluoro-β -D-arabinofuranosyl)adenine bearing a selectively removable protecting group. Chem. Pharm. Bull. 1999, 47, 966-970) however, the synthesis of the guanine analogue is more complicated and affords poor to moderate yields of araF-G (4) ((a) Elzagheid, M.I.; Viazovkina, E.; Masad, M.J. Synthesis of protected 2′-deoxy-2′-fluoro-β-D-arabinonucleosides. Synthesis of 2′-fluoroarabino nucleoside phosphoramidites and their use in the synthesis of 2′F-ANA. Current Protocols in Nucleic Acid Chemistry 2002, 1.7.1-1.7.19; (b) Tennila, T.; Azhayeva, E.; Vepsalainen, J.; Laatikainen, R.; Azhayev, A.; Mikhailopulo, I. Oligonucleotides containing 9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-adenine and -guanine: synthesis, hybridization and antisense properties. Nucleosides, Nucleotides and Nucl. Acids 2000, 19, 1861-1884). Here we describe an efficient synthesis of araF-G (4) that involves coupling of 2-deoxy-2-fluoro-3,5-di-O-benzoyl-α -D-arabinofuranosyl bromide (1) with 2-chlorohypoxanthine (2) to afford 2-chloro-β-araF-I (3) in 52% yield. Nucleoside (3) was transformed into araF-G (4) by treatment with methanolic ammonia (150°C, 6h) in 67% yield.
ANTIVIRAL DRUG
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Paragraph 0177; 0178; 0182; 0183, (2020/11/03)
PROBLEM TO BE SOLVED: To provide a nucleic acid analog having excellent antiviral activity (particularly anti-hepatitis B virus activity). SOLUTION: The invention provides a compound represented by the formula (I) in the figure, where each symbol is as defined in the specification, or a salt thereof. SELECTED DRAWING: None COPYRIGHT: (C)2021,JPOandINPIT
Syntheses of 2′-deoxy-2′-fluoro-β-d-arabinofuranosyl purine nucleosides via selective glycosylation reactions of potassium salts of purine derivatives with the glycosyl bromide
Sivets, Grigorii G.
supporting information, p. 268 - 271 (2016/01/12)
Syntheses of 9-(2-deoxy-2-fluoro-β-d-arabinofuranosyl)-guanine (1) and -adenine (2) were accomplished from readily available 1,3,5-tri-O-benzoyl-2-deoxy-2-fluoro-α-d-arabinofuranose (3). A new and efficient approach for the synthesis of 1-α-bromide was developed using the mild bromination of α-1-O-benzoate (3). Selective coupling reactions of the bromosugar with purine potassium salts followed by derivatization/and or deprotection of the intermediate blocked 2′-fluoro β-arabinonucleosides resulted in formation of the target compounds with high overall yields.
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.
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.
Synthesis of 2'-β-Fluoro- and 3'-α-Fluoro-Substituted Guanine Nucleosides. Effects of Sugar Conformational Shifts on Nucleophilic Displacement of the 2'-Hydroxy and 3'-Hydroxy Group with DAST
Pankiewicz, Krzysztof W.,Krezeminski, Jacek,Watanabe, Kyoichi A.
, p. 7315 - 7321 (2007/10/02)
Tritylation of 2-N-acetyl-6-O-((4-nitrophenyl)ethyl)guanosine (4) with TrCl/DMAP followed by TrCl/AgNO3 afforded a mixture of isomeric 3',5'-di-O-trityl and 2',5'-di-O-trityl derivatives 6 and 7, which were separated on a silica gel column to give 6 and 7 in 40percent and 50percent yield, respectively.Upon treatment with DAST, 6 was converted into the corresponding 2'-β-fluoro nucleoside 8 in 43percent yield.Deprotection of the 2-N-acetyl group occurred during the reaction.Removal of the 6-O-NPE group from 8 with DBU/pyridine, followed by detritylation with CF3COOH/CHCl3, gave F-ara-G (1b) in good yield.The same treatment of 7 with DAST did not lead to nucleophilic substitution with fluoride ion, but only decomposition took place.Treatment of the 2',5'-di-O-trityl nucleoside 7 with CF3SO2Cl/DMAP in CH2Cl2, followed by PhCO2K/HMPA, afforded the corresponding xylofuranosyl derivative 16 along with 6-O-deprotected nucleoside 19.The 6-O-NPE group was completely removed in the reaction of triflate nucleoside 15 with CH3CO2Na/HMPA.The obtained diacetyl nucleoside 20 under hydrolysis with Et3N/MeOH/H2O gave 9-(2,5-di-O-trityl-β-D-xylofuranosyl)guanine (22).Upon reaction of derivative 22 with DAST no formation of the desired 3'-fluoro nucleoside 23 was observed, but only decomposition took place.When, however, the triflate nucleoside 15 was treated with CH3COONa in DMF instead of HMPA the corresponding diacetyl nucleoside 17 with intact 6-O-NPE group was obtained.This compound was hydrolyzed with Et3N/MeOH/H2O to give the 2-N-acetyl derivative 18, which was smoothly converted into the desired 3'-α-fluoro-substituted nucleoside 24 in 76percent yield.Again, removal of the 2-N-acetyl group occured during the reaction with DAST.Compound 24 was deprotected with DBU/pyridine followed by CF3COOH/CHCl3 to give 3'-fluoro-3'-deoxyguanosine in good yield (3b).In a similar manner the O2,O5,N6-tritrityladenosine (25) was converted into the corresponding 3'-deoxy-3'-fluoroadenosine (3a).
Fluorocarbocyclic nucleosides: Synthesis and antiviral activity of 2'- and 6'-fluorocarbocyclic 2'-deoxy guanosines
Borthwick,Kirk,Biggadike,Exall,Butt,Roberts,Knight,Coates,Ryan
, p. 907 - 914 (2007/10/02)
A series of four isomeric 2'- and 6'-fluorocarbocyclic guanosine analogues have been prepared and evaluated as potential anti-herpes agents. The racemic 2'β-fluoro isomer 2-amino-1,9-dihydro-9-[(1α,2α,3β,4α)-2-fluoro-3-hydroxy-4- (hydroxymethyl)cyclopentyl]-6H-purin-6-one (11a, C-AFG) and its 2'α-fluoro epimer 11b plus the chiral 6'β-fluoro isomer 2-amino-1,9-dihydro-9-[[1S-(1α,2α,3α,4β)]-2-fluoro-4- hydroxy-3-(hydroxymethyl)cyclopentyl]-6H-purin-6-one (11c) and its 6'α-fluoro epimer 11d were prepared from their respective fluoro amino diol hydrochlorides (6a,d). For comparison, the furanosyl compound 9-(2'-deoxy-2'-fluoro-β-D-arabinofuranosyl)guanine (17, AFG) was prepared by coupling 2-amino-6-chloropurine with 2-deoxy-2-fluoro-3,5-di-O- benzoyl-α-D-arabinofuranosyl bromide followed by base hydrolysis. The 6'α-fluoro derivative 11d exhibited comparable activity to that of acyclovir (ACV) against herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) in vitro but was >30-fold more active than ACV against HSV-1 and HSV-2 in vivo in the mouse systemic model. The 2'β-fluoro derivative (11a, C-AFG) was extremely potent in vitro against HSV-1 and HSV-2 (ID50 0.006 and 0.005 μg/mL) and in vivo it was greater than 2 orders of magnitude more potent than ACV against HSV-1 and 70-fold more potent against HSV-2. The 2'α-fluoro 11b and 6'β-fluoro 11c isomers were much less active.
