- Synthesis of Rovafovir Etalafenamide (Part IV): Evolution of the Synthetic Process to the Fluorinated Nucleoside Fragment
-
Fluorinated nucleoside 1 is a key starting material in the synthesis of rovafovir etalafenamide (2), a novel nucleotide reverse transcriptase inhibitor under development at Gilead Sciences for the treatment of HIV. While an initial manufacturing route enabled the production of 1 to support clinical development, alternative approaches were explored to further enhance manufacturing effectiveness, improve processing time, reduce cost, and minimize the environmental impact. Toward this end, two new routes were developed to a key synthetic intermediate, which was converted to 1 using a new protecting group strategy. The new chemistry led to improvements in the manufacturing process while reducing the overall process mass intensity (PMI).
- Siler, David A.,Calimsiz, Selcuk,Doxsee, Ian J.,Kwong, Bernard,Ng, Jeffrey D.,Sarma, Keshab,Shen, Jinyu,Curl, Jonah W.,Davy, Jason A.,Garber, Jeffrey A. O.,Ha, Sura,Lapina, Olga,Lee, Jisung,Lin, Lennie,Park, Sangsun,Rosario, Mary,St-Jean, Olivier,Yu, Guojun
-
p. 1263 - 1274
(2021/05/29)
-
- ANTIVIRAL DRUG
-
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
- -
-
Paragraph 0184; 0185; 0188; 0189
(2020/11/03)
-
- 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)
-
- Discovery of novel purine nucleoside derivatives as phosphodiesterase 2 (PDE2) inhibitors: Structure-based virtual screening, optimization and biological evaluation
-
Phosphodiesterase 2 (PDE2) has received much attention for the potential treatment of the central nervous system (CNS) disorders and pulmonary hypertension. Herein, we identified that clofarabine (4), an FDA-approved drug, displayed potential PDE2 inhibitory activity (IC50 = 3.12 ± 0.67 μM) by structure-based virtual screening and bioassay. Considering the potential therapeutic benefit of PDE2, a series of purine nucleoside derivatives based on the structure and binding mode of 4 were designed, synthesized and evaluated, which led to the discovery of the best compound 14e with a significant improvement of inhibitory potency (IC50 = 0.32 ± 0.04 μM). Further molecular docking and molecular dynamic (MD) simulations studies revealed that 5′-benzyl group of 14e could interact with the unique hydrophobic pocket of PDE2 by forming extra van der Waals interactions with hydrophobic residues such as Leu770, Thr768, Thr805 and Leu809, which might contribute to its enhancement of PDE2 inhibition. These potential compounds reported in this article and the valuable structure-activity relationships (SARs) might bring significant instruction for further development of potent PDE2 inhibitors.
- Qiu, Xiaoxia,Huang, Yiyou,Wu, Deyan,Mao, Fei,Zhu, Jin,Yan, Wenzhong,Luo, Hai-Bin,Li, Jian
-
p. 119 - 133
(2017/11/30)
-
- 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
-
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.
- Sivets, Grigorii G.
-
supporting information
p. 268 - 271
(2016/01/12)
-
- Investigation and Conformational Analysis of Fluorinated Nucleoside Antibiotics Targeting Siderophore Biosynthesis
-
(Chemical Equation Presented) Antibiotic resistance represents one of the greatest threats to public health. The adenylation inhibitor 5′-O-[N-(salicyl)sulfamoyl]adenosine (SAL-AMS) is the archetype for a new class of nucleoside antibiotics that target iron acquisition in pathogenic microorganisms and is especially effective against Mycobacterium tuberculosis, the causative agent of tuberculosis. Strategic incorporation of fluorine at the 2′ and 3′ positions of the nucleoside was performed by direct fluorination to enhance activity and improve drug disposition properties. The resulting SAL-AMS analogues were comprehensively assessed for biochemical potency, whole-cell antitubercular activity, and in vivo pharmacokinetic parameters. Conformational analysis suggested a strong preference of fluorinated sugar rings for either a 2′-endo, 3′-exo (South), or a 3′-endo,2′-exo (North) conformation. The structure-activity relationships revealed a strong conformational bias for the C3′-endo conformation to maintain potent biochemical and whole-cell activity, whereas improved pharmacokinetic properties were associated with the C2′-endo conformation.
- Dawadi, Surendra,Viswanathan, Kishore,Boshoff, Helena I.,Barry, Clifton E.,Aldrich, Courtney C.
-
p. 4835 - 4850
(2015/05/27)
-
- Recombinant purine nucleoside phosphorylases from thermophiles: Preparation, properties and activity towards purine and pyrimidine nucleosides
-
Thermostable nucleoside phosphorylases are attractive biocatalysts for the synthesis of modified nucleosides. Hence we report on the recombinant expression of three 'high molecular mass' purine nucleoside phosphorylases (PNPs) derived from the thermophilic bacteria Deinococcus geothermalis, Geobacillus thermoglucosidasius and from the hyperthermophilic archaeon Aeropyrum pernix (5′-methythioadenosine phosphorylase; ApMTAP). Thermostability studies, kinetic analysis and substrate specificities are reported. The PNPs were stable at their optimal temperatures (DgPNP, 55 °C; GtPNP, 70 °C; ApMTAP, activity rising to 99 °C). Substrate properties were investigated for natural purine nucleosides [adenosine, inosine and their C2′-deoxy counterparts (activity within 50-500 U·mg-1)], analogues with 2′-amino modified 2′-deoxy-adenosine and -inosine (within 0.1-3 U·mg-1) as well as 2′-deoxy-2′-fluoroadenosine (9) and its C2′-arabino diastereomer (10, within 0.01-0.03 U·mg -1). Our results reveal that the structure of the heterocyclic base (e.g. adenine or hypoxanthine) can play a critical role in the phosphorolysis reaction. The implications of this finding may be helpful for reaction mechanism studies or optimization of reaction conditions. Unexpectedly, the diastereomeric 2′-deoxyfluoro adenine ribo- and arabino-nucleosides displayed similar substrate properties. Moreover, cytidine and 2′-deoxycytidine were found to be moderate substrates of the prepared PNPs, with substrate activities in a range similar to those determined for 2′-deoxyfluoro adenine nucleosides 9 and 10. C2′-modified nucleosides are accepted as substrates by all recombinant enzymes studied, making these enzymes promising biocatalysts for the synthesis of modified nucleosides. Indeed, the prepared PNPs performed well in preliminary transglycosylation reactions resulting in the synthesis of 2′-deoxyfluoro adenine ribo- and arabino- nucleosides in moderate yield (24%).
- Zhou, Xinrui,Szeker, Kathleen,Janocha, Bernd,B?hme, Thomas,Albrecht, Dirk,Mikhailopulo, Igor A.,Neubauer, Peter
-
p. 1475 - 1490
(2013/06/04)
-
- 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
-
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.
- Yamada, Kohei,Matsumoto, Noritake,Hayakawa, Hiroyuki
-
experimental part
p. 1117 - 1130
(2010/10/01)
-
- INHIBITORS OF S-ADENOSYL-L-METHIONINE DECARBOXYLASE
-
Novel mechanism-based inhibitors of S-adenosyl-L-methionine decarboxylase are provided. These compounds of formula (1) inhibit the life cycle of trypanosomes, and are useful to treat subjects infected with African trypanosomes. The invention includes pharmaceutical compositions and methods of using the compounds of formula (1).
- -
-
Page/Page column 15; 22-23
(2009/01/23)
-
- ALPHA-1-PHOSPHORYLATED-2-DEOXY-2-FLUOROARABINOSIDE AND PROCESS FOR PRODUCING 2 -DEOXY-2 -FLUORO-BETA-D-ARABINONUCLEOSID E
-
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.
- -
-
Page/Page column 18
(2008/06/13)
-
- Modulation of DC-SIGN expression
-
Compounds, compositions and methods are provided for modulating the expression of DC-SIGN. The compositions comprise oligonucleotides, targeted to nucleic acid encoding DC-SIGN. Methods of using these compounds for modulation of DC-SIGN expression and for diagnosis and treatment of diseases and conditions associated with expression of DC-SIGN are provided.
- -
-
Page/Page column 12
(2008/06/13)
-
- Modulation of diacylglycerol acyltransferase 1 expression
-
Compounds, compositions and methods are provided for modulating the expression of diacylglycerol acyltransferase 1. The compositions comprise oligonucleotides, targeted to nucleic acid encoding diacylglycerol acyltransferase 1. Methods of using these compounds for modulation of diacylglycerol acyltransferase 1 expression and for diagnosis and treatment of disease associated with expression of diacylglycerol acyltransferase 1 are provided.
- -
-
Page/Page column 12
(2008/06/13)
-
- ANTISENSE MODULATION OF ENDOTHELIAL LIPASE EXPRESSION
-
Antisense compounds, compositions and methods are provided for modulating the expression of Endothelial Lipase (EL). The compositions comprise antisense compounds, particularly antisense oligonucleotides, targeted to nucleic acids encoding EL. Methods of using these compounds for modulation of EL expression and for treatment of diseases associated with expression of EL are provided.
- -
-
-
- Process for the preparation of 9-beta-anomeric nucleoside analogs
-
A process for substantially enhancing the regio and stereoselective synthesis of 9-β-anomeric nucleoside analogs is described. The introduction of the sugar moiety onto a 6-substituted purine base was preformed so that only the 9-β-D- or L-purine nucleoside analogs were obtained. This regio and stereoselective introduction of the sugar moiety allows the synthesis of nucleoside analogs and in particular 2′-deoxy, 3′-deoxy, 2′-deoxy-2′-β-fluoro and 2′,3′-dideoxy-2′-β-fluoro purine nucleoside analogs in high yield without virtually any formation of the 7-positional isomers. The compounds are drugs or intermediates to drugs.
- -
-
-
- An industrial process for synthesizing lodenosine (FddA)
-
Two industrial synthetic approaches to Lodenosine (1, FddA, 9-(2,3-dideoxy-2-fluoro-β-D-threo-pentofuranosyl) adenine) via a purine riboside or a purine 3′-deoxyriboside are described. Several novel applications of deoxygenation and fluorination methods are compared considering reaction yields, economy, safety and environmental concerns.
- Izawa, Kunisuke,Takamatsu, Satoshi,Katayama, Satoshi,Hirose, Naoko,Kozai, Shigetaka,Maruyama, Tokumi
-
p. 507 - 517
(2007/10/03)
-
- Striking ability of adenosine-2′(3′)-deoxy-3′(2′)-triphosphates and related analogues to replace ATP as phosphate donor for all four human, and the Drosophila Melanogaster, deoxyribonucleoside kinases
-
In extension of an earlier report, six non-conventional analogues of ATP, three adenosine-2′-triphosphates (3′-deoxy, 3′-deoxy-3′-fluoro- and 3′-deoxy-3′-fluoroxylo-), and three adenosine-3′-triphosphates (2′-deoxy-, 2′-deoxy-2′-fluoro- and 2′-deoxy-2′-fluoroara-), were compared with ATP as potential phosphate donors for human deoxycytidine kinase (dCK), cytosolic thymidine kinase (TK1), mitochondrial TK2, deoxyguanosine kinase (dGK), and the deoxyribonucleoside kinase (dNK) from Drosophila melanogaster. With one group of enzymes, comprising TK1, TK2, dNK and dCK (with dAdo as acceptor), only 3′-deoxyadenosine-2′-triphosphate was an effective donor (5-60% that for ATP), and the other five analogues much less so, or inactive. With a second set, including dCK (dCyd, but not dAdo, as acceptor) and dGK (dGuo as acceptor), known to share high sequence similarity (≈45% sequence identity), all six analogues were good to excellent donors (13-119% that for ATP). With dCK and ATP], products were shown to be 5′-phosphates. With dCK, donor properties of the analogues were dependent on the nature of the acceptor, as with natural 5′-triphosphate donors. With dCK (dCyd as acceptor), Km and Vmax for the two 2′(3′)-deoxyadenosine-3′(2′)-triphosphates are similar to those for ATP. With dGK, Km values are higher than for ATP, while Vmax values are comparable. Kinetic studies further demonstrated Michaelis-Menten (non-cooperative) or cooperative kinetics, dependent on the enzyme employed and the nature of the donor. The physiological significance, if any, of the foregoing remains to be elucidated. The overall results are, on the other hand, highly relevant to studies on the modes of interaction of nucleoside kinases with donors and acceptors; and, in particular, to interpretations of the recently reported crystal structures of dGK with bound ATP, of dNK with bound dCyd, and associated modeling studies.
- Krawiec, Krzysztof,Kierdaszuk, Borys,Kalinichenko, Elena N.,Rubinova, Elena B.,Mikhailopulo, Igor A.,Eriksson, Staffan,Munch-Petersen, Birgitte,Shugar, David
-
p. 153 - 173
(2007/10/03)
-
- Synthesis of [18F]-labeled adenosine analogues as potential PET imaging agents
-
The syntheses of adenosine analogues, 2′-deoxy-2′-[ 18F]fluoro-9-β-D-arabinofuranosyladenine ([18F]-FAA) and 3′-deoxy-3′-[18F]fluoro-9-β -D-xylofuranosyladenine ([18F]-FXA) are reported. Adenosine (1) was converted to its methoxytrityl derivatives 2 and 3 as a mixture. After separation, these derivatives were converted to their respective triflates 4 and 5. Each triflate was reacted with tetrabutylammonium[18F] fluoride to produce 6b or 7b, which by acidic hydrolysis yielded compounds 8b and 9b. Crude preparations were purified by HPLC to obtain the desired pure products. The radiochemical yields were 10-18 % decay corrected (d.c.) for 8b and 30-40% (d.c.) for 9b in 4 and 3 runs, respectively. Radiochemical purity was > 99% and specific activity was > 74 GBq/μmol at the end of synthesis (EOS). The synthesis time was 90-95 min from the end of bombardment (EOB). Copyright
- Alauddin, Mian M.,Fissekis, John D.,Conti, Peter S.
-
p. 805 - 814
(2007/10/03)
-
- Oligonucleotides containing 9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-adenine and -guanine: Synthesis, hybridization and antisense properties
-
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.
- 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 bearing a selectively removable protecting group
-
A facile and practical method to introduce fluorine at the up-side of the 2'-carbon of nucleosides is described. 6-Chloropurine riboside 3 was converted to the 3'-O-benzoate 4a via a stannylene complex, then converted to the 3'-O-benzoyl-5'-O-tritylriboside 5a. In the presence of pyridine, migration of the 3'-benzoyl groups of 4a and 5a to 2'-OH was rather slow. Hence, 5a was reacted with diethylaminosulfur trifluoride (DAST) in CH2Cl2 in the presence of pyridine to give the 2'-deoxy-2'-fluoroarabinoside 6 in good yield. The 3'-O-benzoyl-5'-O-trityl protecting system was easy to deprotect selectively. Thus, treatment of 6 with ammonia in MeOH gave the 5'- O-trityl compound 7, which was subjected to esterification with phenyl chlorothionoformate, radical deoxygenation with tris(trimethylsilyl)silane and acid treatment to afford 9-(2,3-dideoxy-2-fluoro-β-D-threo- pentofuranosyl)adenine (FddA) 2. In addition, acid treatment of 7 gave 9-(2- deoxy-2-fluoro-β-D-arabinofuranosyl)adenine (FdaraA) 1.
- Maruyama, Tokumi,Takamatsu, Satoshi,Kozai, Shigetada,Satoh, Yoshiko,Izawa, Kunisuke
-
p. 966 - 970
(2007/10/03)
-
- A new synthetic approach to the clinically useful, anti-HIV-active nucleoside, 9-(2,3-dideoxy-2-fluoro-β-D-threo-pentofuranosyl)adenine (β- FddA). Introduction of a 2'-β-fluoro substituent via inversion of a readily obtainable 2'-α-fluoro isomer
-
A convenient route to the anti-HIV active compound, 9-(2,3-dideoxy-2- fluoro-β-D-threo-pentofuranosyl)adenine (1, β-FddA) started with the facile introduction of fluorine at C2' from the α-side of protected 9-(β-D- arabinofuranosyl)adenine (ara-A). Inversion of the stereochemistry at C2' was accomplished via a stable vinyl intermediate (6), which underwent stereoselective reduction of the double bond to give the desired 2'-F-threo isomer with the opposite β-fluoro stereochemistry.
- Siddiqui, Maqbool A.,Driscoll, John S.,Marquez, Victor E.
-
p. 1657 - 1660
(2007/10/03)
-
- Synthesis and antiviral activity of 6-chloropurine arabinoside and its 2'-deoxy-2'-fluoro derivative
-
6-Chloropurine arabinoside (3a) was obtained by treatment of the 2'-O- acetylated congener (2) with ammonia in methanol. The 3',5'-di-O-tritylated riboside (6) was allowed to react with diethylaminosulfur trifluoride (DAST) in the presence of pyridine to give the 2'-deoxy-2'-fluoroarabinoside (7), from which 6-chloro-9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)purine (3b) was obtained. The antiviral effects of 3a and 3b were assayed against several DNA and RNA viruses. Only 3a displayed potent activity against varicella-zoster virus (VZV). This antiviral activity was dependent on phosphorylation by the VZV-induced thymidine kinase (TK). Compound 3a showed moderate activity against other DNA viruses, herpes simplex type 1 (HSV-1) and type 2 (HSV-2), and vaccinia virus. They were equally active against TK and TK+ strains of HSV-1, which suggests that the HSV-1-encoded TK does not play a role in the anti-HSV-1 activity. No activity was noted with any of the compounds against various RNA viruses, including human immunodeficiency virus, at subtoxic concentrations.
- Maruyama,Sato,Oto,Takahashi,Snoeck,Andrei,Witvrouw,De Clercq
-
p. 2331 - 2334
(2007/10/03)
-
- Oxidation-reduction sequence for the synthesis of peracylated fluorodeoxy pentofuranosides
-
The oxidation of methyl 5-O-benzyl-3(2)-deoxy-3(2)-fluoro-α-D-pentofuranosides with dimethyl sulfoxide-acetic (trifluoroacetic) anhydride was accompanied by epimerization at the carbon atom bearing a fluoro function, resulting in the formation of the corresponding 2- or 3-keto derivatives as mixtures of two epimers in high combined yield.Reduction of a mixture of the erythro/threo epimeric 2-keto sugars (isolated as stable hydrates) with sodium borohydride in benzene-ethanol proceeded stereoselectively leading to the formation of 3-deoxy-3-fluoro ribo- and lyxo-furanosides, respectively.In the case of the ribo and arabino epimers of the 3-keto sugar (isolated as free ketones), reduction stereoselectivity of the former was >95percent for the 2-deoxy-2-fluoro ribo sugar, whereas a ca. 3:1 lyxo/arabino ratio of products was obtained for the latter.Treatment of a mixture of the 2-epimeric 3-keto sugars with triethylamine in carbon tetrachloride at room temperature for 3-5 h afforded the 2-deoxy-2-fluoro ribo ketone (ca. 90percent).The synthesis of 1-O-acetyl-2,5-di-O-benzoyl-3-deoxy-3-fluoro-α,β-D-lyxofuranose (8) and 1-O-acetyl-3,5-di-O-benzoyl-2-deoxy-2-fluoeo-β-D-ribofuranose (16) and their use as glycosylating agents for bis-trimethylsilylated N6-benzoyladenine is described.Keywords: Fluorodeoxy pentafuranosides; Keto sugars; Epimerization
- Mikhailopulo, Igor A.,Sivets, Grigorii G.,Poopeiko, Nicolai E.,Khripach, Natalia B.
-
-
- Epimerization at C2 of methyl 5-O-benzyl-2-deoxy-2-fluoro-α-D- pentofuranosides upon oxidation
-
Oxidation of 1 with DMSO-acetic anhydride resulted in the formation of a mixture of epimeric ketones 2 and 3 in the ratio of ?3:1 in high combined yield. Acetolysis of methyl glycoside 5 afforded 1-O-acetyl-3,5-di-O- benzoyl-2-deoxy-2-fluoro-β-D-ribofuranoside (6)(83%). The latter was reacted with silylated N6-benzoyladenine to give α- and β-ribosides (1:3.7; 61%, combined).
- Mikhailopulo,Sivets,Poopeiko,Khripach
-
p. 381 - 382
(2007/10/02)
-
- Role of the stereochemistry of 3'-fluoro-3'-deoxy analogues of 2-5A in binding to and activation of mouse RNase L
-
The synthesis of two sets of analogues of 2-5A trimer containing 9-(3-fluoro-3-deoxy-β-D-xylo-furanosyl)adenine (AF) or 3'-fluoro-3'-deoxyadenosine (AF) at different positions of the chain is described, along with the preparation of the corresponding 5'-monophosphates and 5'-diphosphorylated (core) trimers.The ability of each ribo and xylo isomeric pair of fluorodeoxy analogues of 2-5A (i) to compete with p3(A2'p)3A3'pC3'p for binding to RNase L in L929 cell extracts, and (ii) to activate the partially purified RNase L from L929 cell extracts to hydrolyze poly(U), was compared to that of the related 3'-deoxy analogue and the parent trimer, p3A3, using radiobinding and RNase L-(2',5')pentaadenylate(core)-agarose assays, respectively.Evidence is presented to show that the stereochemistry of the trimers plays an important role, specifically in the second process.The most striking observation is that, compared to 2-5A, p3A(AF)A was found to be nine times more effective an activator of RNase L, whereas isomeric p3A(AF)A is 30 times less effective.
- Kalinichenko, Elena N.,Podkopaeva, Tatjana L.,Poopeiko, Nicolai E.,Kelve, Merike,Saarma, Mart,et al.
-
-
- Synthesis and anti-HIV activity of 6-substituted purine 2'-deoxy-2'- fluororibosides
-
3',5'-Di-O-protected 6-chloropurine arabinoside 4b was treated with diethylaminosulfur trifluoride (DAST) and subsequently deprotected with pyridinium p-toluenesulfonate to give 6-chloropurine 2'-deoxy-2'- fluororiboside 6a. The displacement with nucleophile afforded the 6- substituted congener 6b-e. Treatment of 5'-O-protected 6-chloropurine arabinoside 3c with DAST gave lyxoepoxide 7.
- Maruyama,Utzumi,Sato,Richman
-
p. 527 - 537
(2007/10/02)
-
- SYNTHESIS OF FLUORO AND AZIDO DERIVATIVES OF PURINE NUCLEOSIDES STARTING FROM NUCLEOSIDE 2',3'-CYCLIC SULFATES
-
The interaction of 5'-O-benzoyl-substituted inosine and N6,5'-O-dibenzoyl-substituted adenosine with sulfuryl chloride has given their 2',3'-cyclic sulfoester derivatives, and these, in a substitution reaction with tetrabutylammonium fluoride and lithium azide, have been converted into 3'-fluoro- and 3'-azido-substituted 3'-deoxynucleosides.The structures of the hypoxanthine and adenine 3'-fluoro-(azido)-3'-deoxyxylofuranosides and also of adenine 2'-fluoro-2'-deoxyarabinofuranoside have shown with the aid of H and 19F NMR spectra.Key words: nucleoside cyclic sulfate; fluoro- and azido-substituted nucleoside; nucleophilic substitution.
- Kobylinskaya, V. I.,Shalamai, A. S.,Gladkaya, V. A.,Makitruk, V. L.,Kondratyuk, I. V.
-
p. 712 - 715
(2007/10/02)
-
- Synthesis of thiazole-4-carboxamide-adenine difluoromethylenediphosphonates substituted with fluorine at C-2' of the adenosine
-
Synthesis of an analogue 3 of thiazole-4-carboxamide adenine-dinucleotide (TAD) in which the β-oxygen atom of the pyrophosphate bridge is replaced by a difluoromethylene group has been achieved. Likewise, 2'-deoxy-2'-fluoroadenosine containing analogues of TAD (4) and its difluoromethylenediphosphonate congener (5) have been synthesized. Adenosine 5'-difluoromethylenediphosphonate (8) was prepared from 5'-O-tosyladenosine (6) and tris(tetra-n-butylammonium)difluoromethylenediphosphonate (7) by a modified procedure of Poulter's. Compound 8 was converted into the 2',3'-cyclic carbonate 9 by treatment with triethyl orthoformate. Treatment of 9 with 2',3'-O-isopropylidenetiazofurin (10) in pyridine in the presence of DCC gave a mixture of dinucleotide 11 and the isopropylidene-protected diadenosine tetraphosphonate 12. After deprotection of 11, the desired β-difluoromethylene TAD (3) was separated by HPLC as the minor product. The diadenosine tetraphosphonate 12, an analogue of Ap4A, was obtained as the major component. Alternatively, 2',3'-O-isopropylidenetiazofurin (10) was tosylated, and the product 13 was further converted into the corresponding difluoromethylenediphosphonate 14 by coupling with 7. DCC-catalyzed coupling of 14 with 2'-deoxy-2'-fluoroadenosine (15) followed by deisopropylidenation afforded the analogue 5. Again the corresponding tetraphosphonate analogue of tiazofurin 17 was the predominant product. Dinucleotide 4 was obtained by coupling of the carbonyldiimidazole-activated tiazofurin 5'-monophosphate with 2'-deoxy-2'-fluoroadenosine 5'-monophosphate. 2'-Deoxy-2'-fluoroadenosine (15) was prepared efficiently from the known N6-benzoyl-3'-O-tetrahydropyranyladenosine (18), which was converted into 3'-O-tetrahydropyranyl-2'-O-triflyl-5'-O-trityladenosine (20) by tritylation and triflation. Treatment of 20 with sodium acetate in hexamethylphosphoric triamide, followed by deacetylation afforded 9-(3-O-tetrahydropyranyl-5-O-trityl-β-D-arabinofuranosyl)-N6-benzoyl adenine (22), which was then treated with DAST. After deprotection of the product, 15 was obtained in good yield. Synthesis of an analogue 3 of thiazole-4-carboxamide adenine-dinucleotide (TAD) in which the B-oxygen atom of the pyrophosphate bridge is replaced by a difluoromethylene group has been achieved. Likewise, 2'-deoxy-2'-fluoroadenosine containing analogues of TAD (4) and its difluoromethylenediphosphonate congener (5) have been synthesized.
- Zatorski,Lipka,Mollova,Schram,Goldstein,Watanabe,Pankiewicz
-
-
- Purine 2'-deoxy-2'-fluororibosides as antiinfluenza virus agents
-
Twenty purine 2'-deoxy-2'-fluororibosides were synthesized by enzymic pentosyl transfer from 2'-deoxy-2'-fluorouridine. Each nucleoside analogue was assayed for cytotoxicity in uninfected Madin-Darby canine kidney cells and for their ability to suppress influenza A virus infections in these cells. The most potent antivirial activity was observed with analogues having an amino group in the 2-position of the purine moiety. All 2-unsubstituted analogues were less potent than their 2-amino counterparts. Furthermore, 2- methyl, 2-methoxy, or 2-fluoro substitution obliterated antivirial activity. The most cytotoxic member of the series was the 2-fluoro-6-amino analogue (IC50 = 120 μM). 2'-Deoxy-2'-fluoroguanosine and those congeners readily converted to it by adenosine deaminase showed the most potent antivirial activity (IC50 = 15-23 μM). Little cytotoxicity was observed with this subgroup of analogues which renders them worthy of further investigation as potential antiinfluenza agents.
- Tuttle,Tisdale,Krenitsky
-
p. 119 - 125
(2007/10/02)
-
- Uniformly modified 2'-deoxy-2'-fluoro phosphorothioate oligonucleotides as nuclease-resistant antisense compounds with high affinity and specificity for RNA targets
-
'Uniformly' modified phosphodiester or phosphorothioate oligonucleotides incorporating 2'-deoxy-2'-fluoroadenosine, -guanosine, -uridine, and - cytidine, reported herein for the first time, when hybridized with RNA afforded consistent additive enhancement of duplex stability without compromising base-pair specificity. CD spectra of the 2'-deoxy-2'-fluoro- modified oligonucleotides hybridized with RNA indicated that the duplex adopts a fully A-form conformation. The 2'-deoxy-2'-fluoro-modified oligonucleotides in phosphodiester form were not resistant to nucleases; however, the modified phosphorothioate oligonucleotides were highly nuclease resistant and retained exceptional binding affinity to the RNA targets. The stabilizing effects of the 2'-deoxy-2'-fluoro modifications on RNA-DNA duplexes were shown to be superior to those of the 2'-O-methylribo substitutions. RNA hybrid duplexes with uniformly 2'-deoxy-2'-fluoro-modified oligonucleotides did not support HeLa RNase H activity; however, incorporation of the modifications into 'chimeric' oligonucleotides has been shown to activate mammalian RNase H. 'Uniformly' modified 2'-deoxy-2'-fluoro phosphorothioate oligonucleotides afforded antisense molecules with (1) high binding affinity and selectivity for the RNA target and (2) stability toward nucleases.
- Kawasaki,Casper,Freier,Lesnik,Zounes,Cummins,Gonzalez,Cook
-
p. 831 - 841
(2007/10/02)
-
- Deoxyfluoronucleoside process
-
There is disclosed a process for synthesizing 2?--fluoro-2?,3?-dideoxyarabinofuranose derivatives of inosine and adenine on a large scale which involves coupling of a fluorosugar derivative and a purine reactant to provide a purine nucleoside intermediate which is then deoxygenated. 6-Chloro or 6-benzamidopurine and 1,3,5-tri-O-benzoyl-2--deoxy-2-fluoroarabinofuranose are used as starting materials.
- -
-
-
- Acid-stable 2'-fluoro purine dideoxynucleosides as active agents against HIV
-
2',3'-Dideoxy purine nucleosides have anti-HIV activity in vitro and the inosine analogue is being clinically evaluated. The instability of these compounds toward acidic conditions complicates oral administration. The effect of the addition of a fluorine atom to the 2'-position was investigated by preparing the fluorine-containing 2'-erythro and 2'-threo isomers of ddA and the threo of isomer ddI. All fluorine-containing compounds were indefinitely stable to acidic conditions which completely decomposed ddI (1) and ddA (2) in minutes. While the fluorine-containing erythro isomer, 5, was inactive, the threo isomers, 2'-F-dd-ara-A (3) and 2'-F-dd-ara-I (4), were just as potent and active in protecting CD4+ ATH8 cells from the cytopathogenic effects of HIV-1 as the parent drugs. Exposure to pH1 at 37°C prior to testing destroyed the activity of ddA and ddI but left the anti-HIV properties of 3 and 4 unchanged. The fluorinated analogues also protected cells exposed to HIV-2 and inhibited gag gene product expression but not as effectively as the parent compounds. The fluorine-containing analogues appear to be somewhat more toxic in vitro to the antigen- and mitogen-driven proliferation of immunocompetent cells than their corresponding parent compounds.
- Marquez,Tseng,Mitsuya,Aoki,Kelley,Ford Jr.,Roth,Broder,Johns,Driscoll
-
p. 978 - 985
(2007/10/02)
-
