Oligonucleotides Containing Acyclic Nucleoside Analogues with Carbamate Internucleoside Linkages

Abstract

Synthesis of 2′-deoxy-2′,3′-secothymidine t and its dimer t?t, where the two 2′-deoxy-2′,3′-secothymidine t units are connected via a carbamate, ?=3′-NH-CO-O-5′, internucleoside linkage has been achieved. These building blocks were protected in the 5′-position, converted into their phosphoramidites, or attached onto CPG, and then used for “chimeric oligonucleotide” synthesis.     

Studies on Disaccharide Nucleoside Synthesis. Mechanism of the Formation of Trisaccharide Purine Nucleosides

Abstract

The unexpected formation of trisaccharide nucleosides during synthesis of purine 5′-O-β-D-ribofuranosylnucleosides in the presence of Lewis acids was observed.     

Synthesis and Hybridization Studies of Oligonucleotide Sequences with Modified Fluorescent Nucleoside Analogs

Abstract

Two complementary oligodeoxynucleotide hexamers CATGAA and TTCATG and a pentamer with a fluorescent nucleoside analog viz. 9-N-(2′-deoxy-β-D-ribofuranosyl) carbazole (C*) incorporated into it, TTC*ATG were synthesized and characterised by spectroscopic and chromatographic studies. The comparative fluorescent studies of the two nucleoside analogs viz. 9-N-(2′-deoxy-β-D-ribofuranosyl) acridone and its carbazole analog (C*) have been carried out under different experimental conditions. The effect on fluorescence by incorporation of (C*) into the sequence and its subsequent hybridization with the complementary sequence have been studied.     

Synthesis of Some Nucleoside Cyclic Ethylene Phosphothionates

Abstract

This communication describes the synthesis of 5′-deoxy-5′-chloro-3′-(2-thio-1,3,2-dioxaphosphorinanyl)thymidine, N⁴,2′,3′-triacetyl-5′-(2-thio-1,3,2-dioxaphosphorinanyl)-1-β-D-arabinosyl-cytosine and N⁴-acetyl-5′-(2-thio-1,3,2-dioxaphosphorinanyl)-1-β-D-arabinosylcytosine.     

Isolation and Characterization of Diastereomeric 2′-Oeoxy-ribonucleoside-3′-phosphoramidites

Abstract

The commonly used four 2′-deoxyribonucleoside-3′-(0-5-cyanoethyl, N-diisopropyl)-phosphoramidites have been separated into the two diastereomers by chromatographical means. The ¹H-NMR spectra of the two components show characteristic differences, which were utilized to assign the absolute configurations of the P(III)-centers.     

Aminolysis of 2′-Deoxyinosine Aryl Ethers: Nucleoside Model Studies for the Synthesis of Functionally Tethered Oligonucleotides

Abstract

Several O⁶-aryl-2′-deoxyinosines were synthesized and found to undergo conversion to N⁶-substituted-2′-deoxyadenosines upon treatment with aqueous amines. The kinetics for reaction of these nucleosides with various amines suggests that O⁶-phenyl- and O⁶-(p-nitrophenyl)-2′-deoxyinosine are suitable “convertible nucleoside” precursors for the site-specific introduction of functionally tethered 2′-deoxyadenosines into DNA.     

A Short High Yielding Synthesis of the Potent Anti-VZV Carbocyclic Nucleoside Analogue Carba-BVDU

Abstract

A short high yielding synthesis of the potent anti-varicella-zoster virus (VZV) carbocyclic nucleoside analogue carba-BVDU 1 starting from aminodiol 2 is described. Reaction of 2 with acyl carbamate 3 and subsequent ring closure under acidic conditions afforded 5-ethyl-2′-deoxy-4′a-carbauridine 5. In situ acetylation of 5 afforded 3′,5′-di-O-acetyl-5-ethyl-2′-deoxy-4′a-carbauridine 6 in 78% overall yield from 2. Radical bromination of 6 with either bromine or NBS and subsequent treatment with triethylamine gave an efficient conversion to 3′,5′-di-O-acetyl-5-(E)-(2-bromovinyl)-2′-deoxy-4′a-carbauridine 7. Deacetylation of 7 afforded 1 in an overall 45–53% yield from 2.     

Nucleoside H-Phosphonates. XI. A Convenient Method for the Preparation of Nucleoside H-Phosphonates

Abstract

A simple synthetic method for the preparation of nucleoside 3′-H-phosphonates, consisting of reaction of suitably protected nucleosides with phosphonic acid in the presence of a condensing agent, has been developed.     

Synthesis of Triazole Nucleoside Derivatives

Abstract

5′-O-Mesyl-2′,3′-O-isopropylidene ribonucleosides (4 and 12) were converted to their 5′-substituted nucleosides in good yields by reacted with NaN₃ or KI. 2′,3′-O-Isopropylidene ribonucleosides (3 and 11) were prepared in good yields from ribonucleosides 1 and 2 with a reaction mixture of acetone and triethyl orthoformate instead of using acetone diethyl acetal. Compound 1 or 2 was treated with 2-acetoxyisobutyryl halide (Cl or Br) to give 1-[2-O-acetyl-3-halo-3-deoxy-5-O-(2,5,5-trimethyl-1,3-dioxolan-4-on-2-yl)-β-D-xylofuranosyl]-1,2,4-triazole-3-carboxamide (19, 22, and 23) in high yields. Instead of using 2-acetoxyisobutyryl bromide, the mixture of 2-acetoxyisobutyryl chloride and NaBr was employed in the synthesis of 22 and 23. Treatment of 19 with an activated Zn/Cu couple and deprotection gave 2′,3′-anhydro nucleoside (21), and treatment of 22 and 23 with an activated Zn/Cu couple and a little of HOAc and deprotection gave corresponding 2′,3′-unsaturated triazole nucleosides (24 and 25), respectively. The biological activity of the compounds (7 ～ 10, 15 ～ 18, and 24) was examined in human liver cancer cells (A-549), lung cancer cells (BEL-7402), and Flu-A cells.

Synthesis of Triazole Nucleoside Derivatives

All authors

Zicheng Li, Shuhua Chen, Ning Jiang & Gang Cui

https://doi.org/10.1081/NCN-120022032

Published online:

07 February 2007

Compound 1.     

10.

Chromatography and Characterization of Phenylglycidyl Ether Nucleoside Adducts     

E. G. Van den Eeckhout  E. L. Esmans  J. Claereboudt  J. Coene  M. Claeys 《Nucleosides, nucleotides & nucleic acids》2013,32(3):463-465

Abstract

The HPLC separation and structure elucidation (UV, NMR, MS) of the nucleoside adducts formed between 2′—deoxyadenosine, thymidine, 2′—deoxycytidine and 2′—deoxyguanosine with phenylglycidyl ether is described.     

11.

Regioselective 2′/3′-O-Allylation of Pyrimidine Ribonucleosides Using Phase Transfer Catalysis     

Vidhya Gopalakrishnan  Vaijayanti Kumar  K. N. Ganesh 《Nucleosides, nucleotides & nucleic acids》2013,32(6):1263-1273

Abstract

A short and convenient procedure for regiospecific O-allylation of uridine is reported by employing dibutyltin oxide as a mild base in conjunction with a phase transfer catalyst tetrabutylammonium bromide. The resulting isomeric 2′/3′-O-allyl uridines were separated after conversion into their corresponding 5′-O-DMT derivatives. The 2′-O-allyluridine 3 was then transformed into 2′-O-allylcytidine 7 and both were individually converted into the corresponding β-cyanoethyl phosphoramidite monomers (9 and 10) and a phosphodiester monomer 11, required for oligonucleotide assembly. The utility of 11 is demonstrated by synthesis and characterization of a 2′-O-allyl ribodinucleotide UpU.     

12.

Synthesis of Oligodeoxyribonucleotide Analogues by Use of Deoxyribonucleoside-3′-yl O-bis(1,1,1,3,3,3-Hexafluoro-2-Propyl) Phosphites as New Key Intermediates     

Hideo Hosaka  Yoshikazu Suzuki  Hiroyuki Nakamura  Hidenori Funakoshi  Hideki Nakashima  Naoki Yamamoto 《Nucleosides, nucleotides & nucleic acids》2013,32(2-4):669-678

Abstract

The deoxyribonucleoside-3′-yl O-bis(1,1,1,3,3,3-hexafluoro-2-propyl) phosphite units (3) could be converted into the O-nucleosidyl phosphonate, O-2-cyanoethyl O-nucleosidyl phosphonate, and O-1,1,1,3,3,3-hexafluoro-2-propyl O-nucleosidyl phosphonothioate. Compound 3a was activated by methylimidazole to give the dithymidylate derivatives (8). The appropriately protected nucleosidyl phosphonates (3) were applied to the synthesis of oligodeoxyribonucleotides used as antisense oligonucleotides.     

13.

DNA-Triesters - The Synthesis and Absolute Configuration Assignments at P-Stereogenic Centres     

Piotr Guga  Maria Koziołkiewicz  Andrzej Okruszek  Bogdan Uznański  Wojciech J. Stec 《Nucleosides, nucleotides & nucleic acids》2013,32(1-2):111-119

Abstract

Decadeoxyribonucleotide GGGAATTCCC and nine diastereomeric pairs of its mono-O-ethyl ester analogues were synthesized via phosphoramidite approach using the combination of 5′-DMT-base protected (except T) nucleoside 3′-(2-cyanoethyl N,N-diisopropyl phosphoramidites) and 3′-(0-ethyl N,N-diisopropyl phosphoramidites). Under conditions of release from solid support and removal of base-protecting groups (25% NH₄OH, 25°C, 48 h) 2-cyanoethyl groups were removed while O-ethyl phosphate triester functions were practically intact. Isolation of products and separation of diastereomers were performed by means of RP-HPLC. Absolute configuration at P-stereogenic centres was established via degradation of decamers into corresponding dinucleoside O-ethyl phosphates and stereochemical correlation with dinucleoside phosphorothioates of known configuration at phosphorus. Decadeoxyribonucleotide mono-O-ethyl esters were used for mapping the contact points between DNA and Eco RI endonuclease - the restriction enzyme which recognizes canonical sequence. GAATTC and cleaves unmodified DNA strands giving G and p AATTC.     

14.

Facile Synthesis of 8, 2′-S-Cyclopurine Nucleoside     

Keiko Tekenaka  Tadakazu Tsuji  Masako Muraoka 《Nucleosides, nucleotides & nucleic acids》2013,32(5):869-874

Abstract

This paper describes the synthesis of 8,2 -anhydro-8-mercapto-9-(β-D-arabinofuranosyl)purine (8,2′-S-cyclopurinenucleoside, 1) via the shorter route from 3′,5′-di-O-acectyl-8,2′-S-cycloadenosine (6) and by direct reductive deamination with n- pentyl nitrite in tetrahydrofuran (THF) and deacetylation. The preparation of 8,2′-S-cycloadenosine (2) was achieved in good yield by the cyclization of the protected 8-mercaptoadenosine with triphenylphosphine and diethyl azodicarboxylate (DEAD) in THF at room temperature, under Mitsunobu reaction conditions.     

15.

Nucleosides,LVIII1 Synthesis of Base - Modified Oligonucleotides Containing 6- and 7-Aryl Lumazines     

Yuris Maurinsh  Wolfgang Pfleiderer 《Nucleosides, nucleotides & nucleic acids》2013,32(1-3):431-443

Abstract

6-Phenyl-, 7-phenyl-, 6-(4-biphenyl)- 7-(4-biphenyl)lumazine N-1-2-deoxy-β-D-ribofuranosides were synthesized, then converted into the corresponding 5′-O-dimethoxytrityl-3′-O-(β-cyanoethyl, N,N-diisopropyl)phosphoramidites and incorporated into different positions of self-complementary oligonucleotides. The influence of modifications on the melting temparature of the resulting duplexes was studied.

     

16.

A Zero-Length Diazirine Photoactive Nucleoside     

《Nucleosides, nucleotides & nucleic acids》2013,32(5-8):715-717

Abstract

The scheme of synthesis which allows to obtain 5-(3H-diazirin-3-yl)-2′-deoxyuridine as the zero-length photoactive nucleoside is described.     

17.

Conformational Studies on Nucleosides with Furanose Ring Modifications. 1.     

Shashidhar N. Rao 《Nucleosides, nucleotides & nucleic acids》2013,32(4):791-814

Abstract

Conformational energy calculations have been presented on adenine and thymine nucleosides in which the furanose ring is replaced by 2′,3′-dideoxy-2′,3′-didehydrofuran using molecular mechanics and conformational analysis. Conformational energies have been evaluated using the MM2 and AMBER94 force field parameters at two different dielectric constants. The results are presented in terms of isoenergy contours in the conformational space of the glycosidic (χ) and C4′-C5′ (γ) bonds torsions. In general, the χ-γ interrelationships exhibit similarities with the corresponding plots for unmodified nucleosides and nucleotides, reported previously. Consistency of the calculated preferred conformations with the X-ray data is sensitive to the force field employed.     

18.

Biosynthesis of the Naturally Occurring Nucleoside Antibiotics from Adenosine     

Robert J. Suhadolnik  Jeffery C. Hanvey  Somchai Pornbanlualap  Joseph M. Wu  Kamal N. Tiwari  Anna K. Hebbler 《Nucleosides, nucleotides & nucleic acids》2013,32(5-6):983-986

Abstract

9-β-D-Arabinofuranosyladenine (ara-A, l), first isolated from the culture filtrates of StreDtomyces antibioticus, has a broad spectrum of activity against DNA viruses in cell culture and is successfully used in therapy of herpes simplex encephalitis, neonatal herpes, herpes zoster and chronic myelogenous leukemia¹. 2′-Chlorodeoxycoformycin (2′CldCF, 2), 2′-amino-Zt-deoxyadenosine (3) and nucleocidin (4) have been isolated from the culture medium of Fctinomadura and S. clavus, respectively.     

19.

Studies on Aryl H-Phosphonates. Synthesis of Nucleoside N-Alkylphosphonamidates     

Anna Sobkowska  Michał Sobkowski  Jacek Stawidacuteski  Adam Kraszewski 《Nucleosides, nucleotides & nucleic acids》2013,32(3-5):703-706

Abstract

The aminolysis of aryl nucleoside H-phosphonate diesters with various amines was studied. The new simple and efficient method of synthesis of nucleoside phosphonamidates is described.     

20.

Highly Stereoselective Synthesis and Biological Properties of Nucleoside Analogues Bearing a Spiro Inserted Oxirane Ring     

Jean M. J. Tronchet  Imre Kovacs  Michel Seman  Pierre Dilda  Erik De Clercq  Jan Balzarini 《Nucleosides, nucleotides & nucleic acids》2013,32(4):775-794

Abstract

Starting from 2′,5′-di-O-TBDMS-3′-ketouridine 1 or its thymine analogue 2, both xylo (3–10) and ribo (20) epimers of a series of 3″-substituted 3′-spironucleosides have been obtained in good yields and with a total stereoselectivity. Most new compounds were moderately cytotoxic with in some cases slightly selective antiproliferative activities. None of these compounds was active against HIV, but some other antiviral activities against HSV-2, CMV, EBV, or VZV, in the micromolar range, were noted in specific cases.     

Chromatography and Characterization of Phenylglycidyl Ether Nucleoside Adducts

Abstract

The HPLC separation and structure elucidation (UV, NMR, MS) of the nucleoside adducts formed between 2′—deoxyadenosine, thymidine, 2′—deoxycytidine and 2′—deoxyguanosine with phenylglycidyl ether is described.     

Regioselective 2′/3′-O-Allylation of Pyrimidine Ribonucleosides Using Phase Transfer Catalysis

Abstract

A short and convenient procedure for regiospecific O-allylation of uridine is reported by employing dibutyltin oxide as a mild base in conjunction with a phase transfer catalyst tetrabutylammonium bromide. The resulting isomeric 2′/3′-O-allyl uridines were separated after conversion into their corresponding 5′-O-DMT derivatives. The 2′-O-allyluridine 3 was then transformed into 2′-O-allylcytidine 7 and both were individually converted into the corresponding β-cyanoethyl phosphoramidite monomers (9 and 10) and a phosphodiester monomer 11, required for oligonucleotide assembly. The utility of 11 is demonstrated by synthesis and characterization of a 2′-O-allyl ribodinucleotide UpU.     

Synthesis of Oligodeoxyribonucleotide Analogues by Use of Deoxyribonucleoside-3′-yl O-bis(1,1,1,3,3,3-Hexafluoro-2-Propyl) Phosphites as New Key Intermediates

Abstract

The deoxyribonucleoside-3′-yl O-bis(1,1,1,3,3,3-hexafluoro-2-propyl) phosphite units (3) could be converted into the O-nucleosidyl phosphonate, O-2-cyanoethyl O-nucleosidyl phosphonate, and O-1,1,1,3,3,3-hexafluoro-2-propyl O-nucleosidyl phosphonothioate. Compound 3a was activated by methylimidazole to give the dithymidylate derivatives (8). The appropriately protected nucleosidyl phosphonates (3) were applied to the synthesis of oligodeoxyribonucleotides used as antisense oligonucleotides.     

DNA-Triesters - The Synthesis and Absolute Configuration Assignments at P-Stereogenic Centres

Abstract

Decadeoxyribonucleotide GGGAATTCCC and nine diastereomeric pairs of its mono-O-ethyl ester analogues were synthesized via phosphoramidite approach using the combination of 5′-DMT-base protected (except T) nucleoside 3′-(2-cyanoethyl N,N-diisopropyl phosphoramidites) and 3′-(0-ethyl N,N-diisopropyl phosphoramidites). Under conditions of release from solid support and removal of base-protecting groups (25% NH₄OH, 25°C, 48 h) 2-cyanoethyl groups were removed while O-ethyl phosphate triester functions were practically intact. Isolation of products and separation of diastereomers were performed by means of RP-HPLC. Absolute configuration at P-stereogenic centres was established via degradation of decamers into corresponding dinucleoside O-ethyl phosphates and stereochemical correlation with dinucleoside phosphorothioates of known configuration at phosphorus. Decadeoxyribonucleotide mono-O-ethyl esters were used for mapping the contact points between DNA and Eco RI endonuclease - the restriction enzyme which recognizes canonical sequence. GAATTC and cleaves unmodified DNA strands giving G and p AATTC.     

Facile Synthesis of 8, 2′-S-Cyclopurine Nucleoside

Abstract

This paper describes the synthesis of 8,2 -anhydro-8-mercapto-9-(β-D-arabinofuranosyl)purine (8,2′-S-cyclopurinenucleoside, 1) via the shorter route from 3′,5′-di-O-acectyl-8,2′-S-cycloadenosine (6) and by direct reductive deamination with n- pentyl nitrite in tetrahydrofuran (THF) and deacetylation. The preparation of 8,2′-S-cycloadenosine (2) was achieved in good yield by the cyclization of the protected 8-mercaptoadenosine with triphenylphosphine and diethyl azodicarboxylate (DEAD) in THF at room temperature, under Mitsunobu reaction conditions.     

Nucleosides,LVIII1 Synthesis of Base - Modified Oligonucleotides Containing 6- and 7-Aryl Lumazines

Abstract

6-Phenyl-, 7-phenyl-, 6-(4-biphenyl)- 7-(4-biphenyl)lumazine N-1-2-deoxy-β-D-ribofuranosides were synthesized, then converted into the corresponding 5′-O-dimethoxytrityl-3′-O-(β-cyanoethyl, N,N-diisopropyl)phosphoramidites and incorporated into different positions of self-complementary oligonucleotides. The influence of modifications on the melting temparature of the resulting duplexes was studied.

     

A Zero-Length Diazirine Photoactive Nucleoside

Abstract

The scheme of synthesis which allows to obtain 5-(3H-diazirin-3-yl)-2′-deoxyuridine as the zero-length photoactive nucleoside is described.     

Conformational Studies on Nucleosides with Furanose Ring Modifications. 1.

Abstract

Conformational energy calculations have been presented on adenine and thymine nucleosides in which the furanose ring is replaced by 2′,3′-dideoxy-2′,3′-didehydrofuran using molecular mechanics and conformational analysis. Conformational energies have been evaluated using the MM2 and AMBER94 force field parameters at two different dielectric constants. The results are presented in terms of isoenergy contours in the conformational space of the glycosidic (χ) and C4′-C5′ (γ) bonds torsions. In general, the χ-γ interrelationships exhibit similarities with the corresponding plots for unmodified nucleosides and nucleotides, reported previously. Consistency of the calculated preferred conformations with the X-ray data is sensitive to the force field employed.     

Biosynthesis of the Naturally Occurring Nucleoside Antibiotics from Adenosine

Abstract

9-β-D-Arabinofuranosyladenine (ara-A, l), first isolated from the culture filtrates of StreDtomyces antibioticus, has a broad spectrum of activity against DNA viruses in cell culture and is successfully used in therapy of herpes simplex encephalitis, neonatal herpes, herpes zoster and chronic myelogenous leukemia¹. 2′-Chlorodeoxycoformycin (2′CldCF, 2), 2′-amino-Zt-deoxyadenosine (3) and nucleocidin (4) have been isolated from the culture medium of Fctinomadura and S. clavus, respectively.     

Studies on Aryl H-Phosphonates. Synthesis of Nucleoside N-Alkylphosphonamidates

Abstract

The aminolysis of aryl nucleoside H-phosphonate diesters with various amines was studied. The new simple and efficient method of synthesis of nucleoside phosphonamidates is described.     

Highly Stereoselective Synthesis and Biological Properties of Nucleoside Analogues Bearing a Spiro Inserted Oxirane Ring

Abstract

Starting from 2′,5′-di-O-TBDMS-3′-ketouridine 1 or its thymine analogue 2, both xylo (3–10) and ribo (20) epimers of a series of 3″-substituted 3′-spironucleosides have been obtained in good yields and with a total stereoselectivity. Most new compounds were moderately cytotoxic with in some cases slightly selective antiproliferative activities. None of these compounds was active against HIV, but some other antiviral activities against HSV-2, CMV, EBV, or VZV, in the micromolar range, were noted in specific cases.