Synthesis and Evaluation of Novel Oligodeoxynucleotides Containing 3′-C-(3-Benzoyloxypropyl)thymidine and Bicyclo Nucleoside Derivatives

Abstract

The stereoselective synthesis of 3′-C-Allyluridine derivative 2 has been accomplished. This nucleoside was used as a key synthon for the synthesis of oligodeoxynucleotides containing 3′-C-(3-benzoyloxypropyl)thymidine (X) or bicyclo nucleoside (Y+Z) monomers. Preliminary thermal experiments are reported.     

Synthesis and Evaluation of Oligodeoxynucleotides Containing 3′-C-Aminomethyl-and 3′-C-Amethylthymidine

Abstract

3′-C-Aminomethyl- and 3′-C-methylthymidine were synthesized and incorporated into oligodeoxynucleotides. Hybridization and enzyme stability of the modified oligonucleotides containing the 3′-C-branched thymidines are discussed.     

Synthesis and Hybridization Properties of Oligodeoxynucleotides Containing 3′-Deoxy-3′-C-methyleneuridine

Abstract

3′-Deoxy-3′-C-methyleneuridine nucleoside 1 ¹ has been incorporated into oligodeoxynucleotides. Relative to the unmodified references, oligomers containing nucleoside 1 displayed reduced binding affinities towards complementary DNA and RNA with a tendency towards RNA-selective hybridization.     

Synthesis of Oligodeoxynucleotides Containing 4′-C-Aminoalkyl-thymidines and Their Thermal Stability and Nuclease-Resistance Properties

Abstract

To find the nuclease-resistant oligodeoxynucleotides (ODNs) with natural phosphodiester linkages, we designed and synthesized ODNs containing 4′-C-aminoalkylthymidines (1–4). We found that the ODNs containing 1, 2, 3 or 4 were more resistant to nucleolytic hydrolysis by both snake venom phosphodiesterase (a 3′-exonuclease) and DNase I (an endonuclease) than unmodified ODNs.     

Synthesis and Characterization of Oligodeoxynucleotides Containing 5′,8-Cyclopurine-2′-Deoxyribonucleosides

Abstract

Oligodeoxynucleotides containing the two 5′R and 5′S diastereoisomers of 5′,8-cyclo-2′-deoxyadenosine (CyclodAdo) and 5′,8-cyclo-2′-deoxyguanosine (CyclodGuo) have been synthesized using the phosphoramidite chemistry. The structural assignment and a few biochemical features of these modified DNA fragments are reported.     

Hoogsteen-Duplex DNA: Synthesis and Base Pairing of Oligodeoxynucleotides Containing 1-Deaza-2′-deoxyadenosine

Abstract

Solid-phase synthesis of oligonucleotides containing 1-deazaadenine was carried out employing phosphonate and phosphoramidite chemistry. Hoogsteen base pairing was established for the duplex d(c¹A₂₀)·d(T₂₀).     

Synthesis and Antiviral Evaluation of Novel 4′-Trifluoromethylated 5′-Deoxyapiosyl Nucleoside Phosphonic Acids

On the basis of the discovery that the threosyl nucleoside phosphonate PMDTA is a potent anti-HIV compound, we synthesized several 4′-trifluoromethyl-5′-deoxyapiosyl nucleoside phosphonic acids and evaluated their anti-HIV activity. An efficient synthetic route was optimized, starting from an α-trifluoromethyl-α,β-unsaturated ester. Glycosylation of the purine nucleosidic bases with a glycosyl donor yielded modified nucleoside intermediates, which were then phosphonated and hydrolyzed to provide the targeted nucleoside analogs. Once synthesized, the anti-HIV and cytotoxic activities of each analog were evaluated. None of the analogs showed significant anti-HIV activity at concentrations up to 100 μM.     

Evaluation of Oligonucleotides Containing Two Novel 2′-O-Methyl Modified Nucleotide Monomers: A 3′-C-Allyl and a 2′-O-3′-C-Linked Bicyclic Derivative

Abstract

The two ribo-configured nucleosides 1-(3-C-allyl-2–0-methyl-β-D-ribo-pentofuranosyl)thymine 3 and (1S,5R,6R,8R)-5-hydroxy-6-(hydroxymethyl)-1-methoxy-8-(thymin-1-yl)-2,7-dioxabicyclo[3.3.0]octane 6 have been transformed into their corresponding phosphoramidites, 5 and 8 respectively, and used as building blocks for the synthesis of modified oligonucleotides. The oligonucleotides were shown to hybridize with decreased binding affinity towards complementary single stranded DNA and RNA.     

Synthesis and Biological Evaluation of (3′S)-3′-Deoxy-3′-Fluoro-3′-C-Ethynylcytidine

The novel pyrimidine nucleoside, (3 ′S)-3 ′-deoxy-3 ′-fluoro-3 ′-C-ethynylcytidine (1) was synthesized from cytidine in seven steps. The key step in the synthesis was the introduction of the tertiary fluorine at the 3 ′-position. Compound 1 was evaluated in vitro against several RNA viruses.     

Conformationally Locked Nucleosides. Synthesis of Oligodeoxynucleotides Containing 3′-Amino-3′-deoxy-3′-N,5′(R)-C-ethylenethymidine

Abstract

3′-Amino-3′-deoxy-5′-O-(4,4′-dimethoxytrityl)-3′-N,5′(R)-C-ethylenethymidine (6) was synthesized starting from 3′-azido-3′-deoxythymidine. Condensation of 6 with 5′-O-(H-phosphonyl)thymidine and 5′-O-(p-nitrophenoxycarbonyl)thymidine derivatives gave dinucleotide and dinucleoside derivatives, respectively, which were incorporated into oligodeoxynucleotides (ODNs). Tm data of the modified ODNs are also presented.     

Synthesis and Biological Evaluation of 4′-C-Methyl Nucleosides

Abstract

A series of 2′-deoxy, 2′,3′-unsaturdted and 2′,3′-dideoxynucleoside analogues, which have an additional methyl group at the 4′-position, have been synthesized. When evaluated for their inhibitory activity against HIV in MT-4 cell, 2′-deoxy-4′-C-methyl nucleosides exhibited potent activity.

     

Synthesis and Evaluation of Antiviral Activity of 3′-C-Cyano-3′-Deoxynucleosides

Abstract

A series of 3′-C-cyano-3′-deoxy and 3′-C-cyano-2′,3′-dideoxy-nucleoside analogues of thymidine, uridine, cytidine and adenosine have been prepared. Their antiviral activity was assessed in various assay systems and while none of the compounas proved specifically active against human immunodeficiency virus, some compounds had marked activity against other viruses.     

Synthesis and Anti-HIV Evaluation of 3′-Triazolo Nucleosides

A series of hitherto unknown 3′-α-[1,2,3]-substituted triazolo-2′,3′-dideoxypyrimidine nucleoside analogues of the anti-HIV 3′-azido-3′-deoxythymidine (AZT) were synthesized through catalyzed alkyne-azide 1,3-dipolar cycloaddition (Huisgen reaction). Those 3′-[1,2,3]-triazolo analogues bearing an azido alkyl chain were evaluated for their anti-HIV activity against HIV-1 in primary human lymphocytes as well as for their cytotoxicity in different cells. None of them inhibit HIV replication (EC₅₀ > 20 μM); two of them were converted to their triphosphate form to evaluate their HIV-RT inhibition.     

Stereocontrolled Facile Synthesis and Biological Evaluation of (3′S) and (3′R)-3′-Amino (and Azido)-3′-Deoxy Pyranonucleosides

This article describes the synthesis of (3 ′S) and (3 ′R)-3 ′-amino-3 ′-deoxy pyranonucleosides and their precursors (3 ′S) and (3 ′R)-3 ′-azido-3 ′-deoxy pyranonucleosides. Azidation of 1,2:5,6-di-O-isopropylidene-3-O-toluenesulfonyl-α-D-allofuranose followed by hydrolysis and subsequent acetylation afforded 3-azido-3-deoxy-1,2,4,6-tetra-O-acetyl-D-glucopyranose, which upon coupling with the proper silylated bases, deacetylation, and catalytic hydrogenation, obtained the target 3 ′-amino-3 ′-deoxy-β-D-glucopyranonucleosides. The desired 1-(3 ′-amino-3 ′-deoxy-β-D-allopyranosyl)5-fluorouracil was readily prepared from the suitable imidazylate sugar after azidation followed by a protection/deprotection sequence and reduction of the unprotected azido precursor. No antiviral activity was observed for the novel nucleosides. Moderate cytostatic activity was recorded for the 5-fluorouracil derivatives.     

3′-Deoxy-3′-C-trifluoromethyl Nucleosides: Synthesis and Antiviral Evaluation

Abstract

2′,3′-Dideoxy-3′-C-trifluoromethylthymidine 9a and -uridine 9b and 3′-C-trifluoromethyl-d4T 11 were prepared in a few steps from 3′-deoxy-3′-C-trifluoromethyl-D-ribose, which synthesis was recently reported. The biological assessment of these nucleoside analogues did not reveal interesting antiviral properties against HIV-1, HSV-1, CMV, Vaccine, and Cox B4.     

Synthesis and Properties of Oligoribonucleotide Analogues Having Amide (3″-CH2-CO-NH-5′) Internucleoside Linkages

Abstract

Amide linked ribonucleoside dimer 5 was prepared and converted into selectively protected H-phosphonate building block 9. Oligoribonucleotide duplexes having amide linkages at selected sites were synthesized and their stability was studied by UV melting experiments.     

Synthesis and Biological Evaluation of Novel 1′‐Branched and Spironucleoside Analogues

Novel anomeric spironucleosides and 1′‐cyano‐2′,3′‐didehydro‐2′,3′‐dideoxyuridine, a structural analogue of known anti‐HIV agents, were prepared by nucleophilic addition of organolithium reagents to 1′‐cyano‐2′‐deoxy‐ and 1′‐cyano‐2′‐deoxy‐2′β‐bromo‐uridine derivatives, respectively. The yield and distribution of products depended on the reaction conditions, which were studied in detail. Although none of the compounds exhibited antiviral activity, two compounds displayed cytostatic activity against both murine leukemia and human T‐lymphocyte cells.     

Synthesis and Antiviral Evaluation of Novel 5′-Norcarboacyclic Phosphonic Acid Nucleosides

This article describes a very simple route for synthesizing a novel 5′-norcarboacyclic nucleotides. The condensation of the mesylates 17 and 18 with the natural nucleosidic bases (A,U,T,C) under standard nucleophilic substitution (K₂CO₃, 18-Crown-6, DMF) and deprotection afforded the target nucleotide analogues 27–34. In addition, these compounds were evaluated for their antiviral properties against various viruses.     

Synthesis of New Homo and Heterodimers of 2′,3′-Dideoxyinosine (ddi) Using Ester Linkages

Abstract

A series of new homo and heterodimers of ddI has been synthesized. A glutarate diester spacer was used to covalently couple ddI onto ddI, AZT or d4T.     

Synthesis of a Novel Aldehyde: 4-O-Methyl-5-formylmethyl- 2′-deoxyuridine

Abstract

The synthesis of the blocked nucleoside 3′,5′-di-O-p-toluoyl-4-O-methyl-5-formylmethyl-2′-deoxyuridine (19) was accomplishied in eleven steps from gamma-butyrolactone. This aldehyde, which should facilitate the synthesis of nucleosides containing ¹⁸F, was converted to the corresponding blocked dithianyl nucleoside (21), and also to 5-(2,2-difluoroethyl)-substituted derivatives of 2′-deoxyuridine and 2′-deoxycytidine.