- Hexofuranosyl thymidines inserted into oligodeoxynucleotides via their two exocyclic hydroxy groups. Oligo synthesis and RNase H activity
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Hexofuranosyl nucleosides are considered as conformationally restricted acyclic nucleosides using a furanose ring to link the diol backbone to the nucleobase. The phosphoramidite of 1-(2,3-dideoxy-β-D-erythro- hexofuranosyl)thymine was synthesized from thymidine with formation of a new stereocentre at C-5′ and the nucleoside was used in oligodeoxynucleotide (ODN) synthesis. Binding of mixed sequence ODNs towards complementary DNA and RNA showed decreased affinity compared to the wild-type oligos. Insertion in the middle of poly αT sequence led to stabilization of ODN/dA14 duplexes at low ionic strength, but a decrease was observed in medium and high salt buffers compared to d(αT)14/dA14. Both β and α hexofuranosyl thymidines allowed cleavage of complementary mixed-sequence RNA by RNase H to the 3′-site of the modification in ODNs whereas a limited inhibition was detected from the 5′-site.
- Filichev, Vyacheslav V.,Vester, Birte,Pedersen, Erik B.
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Read Online
- Synthesis of C3′ modified nucleosides for selective generation of the C3′-deoxy-3′-thymidinyl radical: A proposed intermediate in LEE induced DNA damage
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DNA damage pathways induced by low-energy electrons (LEEs) are believed to involve the formation of 2-deoxyribose radicals. These radicals, formed at the C3′ and C5′ positions of nucleotides, are the result of cleavage of the C-O phosphodiester bond throu
- Audat, Suaad A. S.,Trzasko Love, Cherylann,Al-Oudat, Buthina A. S.,Bryant-Friedrich, Amanda C.
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p. 3829 - 3837
(2012/06/29)
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- Synthesis of 2', 3'-Dideoxynucleosides for Automated DNA Synthesis and Pyrophosphorolysis Activated Polymerization
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Methods for preparation of 2′,3′-dideoxynucleotides support structures, such as 2′,3′-dideoxyguanosine, 2′,3′-dideoxyadenosine, and 3′-deoxythymidine support structures are disclosed. Various methods of using such structures are also provided, such as their use for automated DNA synthesis and pyrophosphorolysis activated polymerization.
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- A new concept for the preparation of beta-L- and beta-D-2',3'-dideoxynucleoside analogues.
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[reaction: see text] A new method for the synthesis of 2',3'-dideoxynucleoside analogues has been developed. An electrochemical activation of 2-substituted furans is followed by the coupling with a pyrimidine or purine base. This gives planar furyl nucleosides as key intermediates, which are hydrogenated cis-selectively to give the corresponding beta-2',3'-dideoxynucleosides as racemic mixtures. An enzymatic kinetic resolution gives rise to beta-D- and beta-L-configured derivatives in high optical purity. This is exemplified by the synthesis of beta-D- and beta-L-3'-deoxythymidine.
- Albert, Martin,De Souza, Dominic,Feiertag, Petra,Hoenig, Helmut
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p. 3251 - 3254
(2007/10/03)
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- Compositions for treating viral infections, and methods therefor
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Methods and combinations of an agent that promotes DNA synthesis in a virally-targeted cell and a nucleoside analogue having antiviral activity are provided for treating a viral infection in a subject in need thereof. Such compositions are particularly effective where the subject has resistance to a nucleoside analogue, where the subject has resting cellular reservoirs of such a virus, or to induce a post-treatment period of replication incompetence of such a virus.
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- Aryl phosphate derivatives of d4T having anti-HIV activity
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Aryl phosphate derivatives of d4T with para-bromo substitution on the aryl group show markedly increased potency as anti-HIV agents without undesirable levels of cytotoxic activity. In particular, these derivatives are potent inhibitors of HIV reverse transcriptase. In a preferred aspect of the present invention, the phosphorus of the aryl phosphate group is further substituted with an amino acid residue that may be esterified or substituted, such as a methoxy alaninyl group.
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Page column 9
(2008/06/13)
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- Synthesis of diverse and useful collections of oligonucleotidies
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A new technique for generating mixtures of oligonucleotides in a single automated synthesis is taught. The method can be used to prepare mixed oligonucleotides ideally suited for creation of useful mixtures of oligo- or polypeptides or proteins. Additionally, the technique enables insertion and/or substitution and/or deletion of a nucleotide sequence at one or more sites. For protein mutagenesis, a trinucleotide can be inserted or substituted at codon boundaries. The invented technique makes possible the encoding of all possible single amino acid insertions, or any desired mixture of substitutions and insertions.
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- Synthesis of 5'-thioalkyl, sulfoxide and sulfone pyrimidine nucleosides
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The preparation of 5'-thioalkyl, sulfoxide and sulfone pyrimidine nucleosides is [4-11] is described. The key steps of this synthesis are the nucleophilic displacements of a chlorine by a thioalkyl sodium salt or the direct introduction of the thioalkyl group under Mitsunobu conditions.
- Agrofoglio,Girard,Fleury,Leonce
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p. 599 - 600
(2007/10/03)
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- Stereoselective synthesis of 2',3'-dideoxy-nucleosides via intramolecular glycosylation of phenyl 1-seleno-glycosides. Synthesis of 2',3'-dideoxythymidine
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4-methoxy and 4-(2-trimethylsilylethoxy)pyrimidine bases were attached to the 5-position of the phenyl 2,3-dideoxy-1-seleno-glycero-pentofuranoside moiety. The presence of the silyl protecting group in the base is necessary to lead to neutral β-anhydro nucleosides by intramolecular glycosylation. The subsequent ring opening affords 3'-deoxythymidine with complete stereocontrol.
- Lluis, Jordi,Matheu, Ma. Isabel,Castillon, Sergio
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p. 1807 - 1810
(2007/10/03)
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- Process for the production of asymmetrical phosphoric acid diesters
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The present invention concerns a process for the production of asymmetrical phosphoric acid diesters. The process is characterized in that a phosphoric acid ester is condensed with a compound containing hydroxy groups in the presence of an arylsulfonic acid chloride and an organic base, the residue of evaporation is stirred out with an organic solvent after the hydrolysis, the arylsulfonic acid pyridine salt which forms is nearly completely crystallized and recycled, the lipid derivative that is formed is precipitated as a sparingly soluble salt by addition of a solution containing alkaline-earth ions and isolated, the sparingly soluble salt is isolated as the free acid in an organic solvent by suspension in a water-immiscible organic solvent and a dilute aqueous mineral acid, the crude product is purified if desired, by means of preparative chromatography on a RP phase and subsequently the free acid is converted if desired into any desired salt.
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- Expeditious syntheses of sugar-modified nucleosides and collections thereof exploiting furan-, pyrrole-, and thiophene-based siloxy dienes
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A series of individual sugar-modified pyrimidine nucleosides including enantiomerically enriched 2',3'-dideoxynucleosides 14a-c (α and β anomers of L- and D-series), 2',3'-dideoxy-4'-thionucleosides 21a-c (α and β anomers of L- and D-series), and 2',3'-dideoxy-4'-azanucleosides 28a-c (β anomers of L- and D-series) were synthesized, with uniform chemistry and high stereochemical efficiency, exploiting a triad of versatile heterocyclic siloxy dienes, namely, 2-(tert-butyldimethylsiloxy)furan (TBSOF), 2-(tert- butyldimethylsiloxy)thiophene (TBSOT), and N-(tert-butoxycarbonyl)-2-(tert- butyldimethylsiloxy)pyrrole (TBSOP). The synthetic procedure advantageously used both enantiomers of glyceraldehyde acetonide (D-1 and L-1) as sources of chirality and as synthetic equivalents of the formyl cation. The outlined chemistry also allowed for the rapid assemblage of a 30-member collection of racemic nucleosides (D,L-L) as well as one 15-member ensemble of chiral analogues (L-L), along with some related sublibraries.
- Rassu, Gloria,Zanardi, Franca,Battistini, Lucia,Gaetani, Enrico,Casiraghi, Giovanni
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p. 168 - 180
(2007/10/03)
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- Synergistic antiviral nucleoside combinations
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An antiviral composition comprising in combination an effective antiviral amount of 3'-fluoro-2',3'-dideoxy nucleoside compound I of the formula STR1 wherein B is adenine, thymine, guanine, cytosine, inosine, uracil, 5-ethyluracil, 2,6-diaminopurine; and an effective antiviral amount of 2',3'-dideoxy nucleoside compound II of the formula STR2 wherein X is N3 or H or together with Y forms an additional carbon-carbon bond, Y and Z are independently H, OH or F, and B is adenine, thymine, guanine, cytosine, inosine, uracil, 5-ethyluracil, 2,6-diaminopurine, and a physiologically acceptable carrier.
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- Stereocontrolled synthesis of pyrimidine 2',3'-dideoxy-β-nucleosides by intramolecular glycosylation
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β-2',3'-Dideoxynucleosides and their 3'-azido and 3'-fluoro substituted derivatives were synthesized in a stereocontrolled manner by the dimethyl(methylthio)sulfonium tetrafluoroborate promoted intramolecular glycosylation of phenyl 2,3-dideoxy-5-O-(2-pyrimidyl)-1-thioglycosides followed by hydrolysis or ammonolysis.
- Sujino,Sugimura
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p. 1883 - 1886
(2007/10/02)
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- Novel 6-alkoxypurine 2',3'-dideoxynucleosides as inhibitors of the cytopathic effect of the human immunodeficiency virus
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Twenty-one 6-alkoxypurine 2',3'-dideoxynucleosides were enzymatically synthesized with nucleoside phosphorylases purified from E. coli. Eighteen analogs exhibited anti-HIV-1 activity in MT4 cells. Two analogs, 6- (hexyloxy)- (17) and 6-(heptyloxy)- (18) purine 2',3'-dideoxynucleoside, were as potent as 2',3'-dideoxyinosine (ddI, didanosine, Videx). Although the antiviral activities of 17 and 18 were equivalent, 18 was more cytotoxic. Analogs containing less than four carbons in the 6-alkoxypurine substituent exhibited weak anti-HIV-1 activity. Analogs containing more than seven carbons in the 6-alkoxypurine substituent were too cytotoxic to be effectively evaluated for antiviral activity. Several 6-alkoxypurine 2',3'- dideoxynucleosides were evaluated for substrate activity with calf intestinal adenosine deaminase (ADA). Increasing the carbon chain length of the 6- alkoxypurine substituent decreased the rate of dealkoxylation. The best substrate in this series was 6-methoxypurine 2',3'-dideoxynucleoside (1); however, the rate of dealkoxylation of 100 μM 1 was 0.17% of the rate of deamination of 100 μM 2',3'-dideoxyadenosine. Compound 17, the most potent anti-HIV-1 analog, was not a substrate for ADA. EHNA (erythro-9-(2-hydroxy- 3-nonyl)adenine), a potent inhibitor of ADA, had little effect on the antiviral activities of 17 and ddI. In contrast, coformycin, a potent inhibitor of both ADA and AMP deaminase, dramatically decreased the antiviral activity of 17, but not the antiviral activity of ddI. Thus, AMP deaminase appeared to be involved in the anabolism of 17. The pharmacokinetic profile of 17, the most promising analog in this series, was determined in the rat. At least seventeen metabolites of 17, including ddI, were detected in plasma samples. This analog also had poor oral bioavailability.
- Burns,St. Clair,Frick,Spector,Averett,English,Holmes,Krenitsky,Koszalka
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p. 378 - 384
(2007/10/02)
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- A Highly Stereoselective Synthesis of Anti-HIV 2',3'-Dideoxy- and 2',3'-Didehydro-2',3'-dideoxynucleosides
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A general total synthesic method for the stereocontrolled synthesis of 2',3'-dideoxy- as well as 2',3'-didehydro-2',3'-dideoxynucleosides is presented.Introduction of an α-phenylselenenyl group at the 2-position of 2,3-dideoxyribosyl acetate directs the glycosyl bond formation to give >/=95percent β-isomer.This 2'-phenylselenenyl nucleoside may be converted to either the 2',3'-dideoxynucleoside by treatment with n-Bu3SnH and Et3B at room temperature or to the unsaturated derivative by treatment with H2O2/cat. pyridine.The application of this method to the syntheses of pyrimidines (ddU, ddT, ddC), 6-substituted purines (ddA, ddI, 6-chloro-ddP, N6-Me-ddA), and 2,6-disubstituted purines (2-F-ddA, 6-chloro-2-amino-ddP) as well as selected 2',3'-didehydro-2',3'-dideoxy derivatives is reported.
- Beach, J. Warren,Kim, Hea O.,Jeong, Lak S.,Nampalli, Satyanarayana,Islam, Qamrul,et al.
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p. 3887 - 3894
(2007/10/02)
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- Stereoselective glycosylation of hetercyclic bases
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A method of preparation of 2',3'-dideoxy and 2',3'-dideoxy-2',3'-didehydronucleosides that includes the step of condensing a 1-O-activated-2-(aromatic or aliphatic)-selenenyl-5-O-protected ribose with a protected heterocyclic base in the presence of trimethylsilyl triflate or a Lewis acid to form a β-anomeric nucleoside in high yield.
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- Facile Synthesis of 3'-O-Methylthymidine and 3'-Deoxythymidine and Related Deoxygenated Thymidine Derivative: A New Method for Selective Deoxygenation of Secondary Hydroxy Groups
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This paper deals with convenient synthesis of 3'-O-methylthymidine (2) and 3'-deoxythymidine (3), which involve Ag2O-promoted methylation and Barton-Robins reductive deoxygenation, respectively.New methods for the regioselective 3'- and 5'-deoxygenation of thymidine have also been developed.Namely, compound 3 was synthesized by the 3',5'-O-diacylation of thymidine with phenyl chlorothionoformate (PTCF) followed by the selective 3'-reduction with tributyltin hydride and successive alkaline hydrolysis. 5'-Deoxythymidine (18) was obtained by the 5'-selective acylation of thymidine with PTCF followed by reduction with tributyltin hydride.
- Sekine, Mitsuo,Nakanishi, Takeshi
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p. 924 - 928
(2007/10/02)
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- A Highly Stereoselective Glycosylation of 2-(Phenylselenenyl)-2,3-dideoxyribose Derivative with Thymine: Synthesis of 3'-Deoxy-2',3'-didehydrothymidine and 3'-Deoxythymidine
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A highly stereoselective synthesis of 3'-deoxy-2',3'-didehydrothymidine (D4T) and 3'-deoxythymidine (D2T) was achieved from the condensation of 2-(phenylselenenyl)-2,3-dideoxyribose derivative and silylated thymine in the presence of trimethylsilyl triflate.
- Chu, Chung K.,Babu, J. Ramesh,Beach, J. Warren,Ahn, Soon K.,Huang, Haoqiang,et al.
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p. 1418 - 1420
(2007/10/02)
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- Synthesis and evaluation of a series of 1-(3-alkyl-2,3-dideoxy-alpha,beta-D-erythro-pentofuranosyl)thymines.
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A series of 1-(3-alkyl-2,3-dideoxy-alpha,beta-D-erythro-pentofuranosyl)thymines (3'-alkyl-3'-deoxythymidines) has been prepared from 5-O-(tert-butyldiphenylsilyl)-2,3-dideoxy-D-glycero-pent-2- enono-1,4-lactone ((S)-5-[(tert-butyldiphenylsilyl)oxymethyl]-2(5H)- furanone) by Michael addition of the appropriate organocopper reagent, followed by reduction of the lactone, acetylation of the resulting hemiacetal, and trimethylsilyl triflate-catalyzed coupling with 2,4-di-O-(trimethylsilyl)thymine. The protected nucleosides were desilylated by using tetrabutylammonium fluoride to give anomeric mixtures of the free nucleosides. The unsubstituted 2',3'-dideoxynucleoside analog was similarly prepared from 5-O-(tert-butyldiphenylsilyl)-2,3-dideoxy-D-glycero-pentono- 1,4-lactone ((S)5-[(tert-butyldiphenylsilyl)-oxymethyl]-dihydro-2(3H)-fu r anone).
- Agyei-Aye,Baker
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p. 261 - 275
(2007/10/02)
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- A NOVEL AND EFFICIENT PREPARATION OF 2',3'-DIDEOXYNUCLEOSIDES
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A new reductive cleavage of secondary alcohols via methylthionocarbonates has been developed and applied to the synthesis of 2',3'-dideoxynucleosides.
- Prisbe, Ernest J.,Martin, John C.
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p. 401 - 410
(2007/10/02)
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- Analogs of pyrimidine nucleosides. 16. Racemic 2′,3′-dideoxynucleosides and their derivatives
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The chlorination of 2-halomethyltetrahydrofurans and acyl derivatives of tetrahydrofuryl alcohol wasstudied; mixtures of 2,5- and 2,2-disubstituted tetrahydrofurans are formed as a result of the reaction. 2,4-Bis(trimethylsilyl) derivatives of uracil, 5-substituted uracils, and cytosine are alkylated by the resulting mixtures of α-chloro ethers without separation, and mixtures of cis and transisomers of 1-(5-substituted-2-tetrahydrofuryl) and 1-(2-substituted-2-tetrahydrofuryl) derivatives of uracil, 5-substituted uracils, and cytosine are obtained. The reaction products were identified onthe basis of their PMR spectra.
- Kaulinya,Liepin'sh,Lidak,Zhuk
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