Studies on the Synthesis of S 5′,6-Methano-5′-Thiourldines

Abstract

Two approaches to the synthesis of the title compounds are described. In the first route, a reactive 5-oxo-6-methylene pyrimidine intermediate that is generated by treating the bis-acetylated or bis-benzoylated nucleosides 10 and 11 with sodium hydroxide undergoes intramolecular attack by the 5′-thiol group to afford the 5-hydroxy cyclonucleoside 12. In the second and higher yielding approach, the S_5′,6-methano linkage is established by an internal allylic displacement reaction that occurs when the 5-bromo-6-methyl nucleoside 24 is treated with base. The conformational properties of S_5′,6-methano-5′-thiouridine (3) and certain long-range spin-spin couplings observed in the NMR spectra of the intermediate nucleosides are discussed.     

Photochemical Synthesis of 6-Aryluridines1)

Abstract

Synthesis of 6-aryluridines was effected by photochemical arylation of 6-iodo-2′,3′-O-isopropylidene-5′-O-methoxymethyluridine.     

Steric Effect of a Bulky Substituent At 5′-Position on the Regioselectivity of 2′ vs. 3′-O-Methylation of N6- Cyclohexyladenosine

Abstract

Steric effect of a trityl or substituted trityl group at 5′-OH of N⁶-cyclohexyladenosine on the regioselective 2′ vs. 3′-O-methylation under phase transfer catalysis conditions was investigated. Compound 4 showed only a modest increase in the selectivity of 2′ over 3′-O-methylation compared to compound 1.     

An Improved Synthesis of N6-(6-Aminohexyl)FAD

Abstract

We report an improved synthesis of N ⁶-(6-aminohexyl)FAD (1) using an efficient one-pot conversion of inosine to the N-trifluoroacetyl protected N ⁶-(6-aminohexyl)adenosine 3. The 5′-O-phosphorylated AMP derivative 4, activated as the imidazolide, was coupled with commercial sodium riboflavin phosphate by using 18-crown-6 in DMF.     

Synthesis of 6-Methyluridine via Palladium-Catalyzed Cross-Coupling Between A 6-Iodouridine Derivative and Tetramethylstannane

Abstract

6-Methyluridine can be synthesized from 5′-O-(tert-butyl-dimethylsilyl)-6-iodo-2′,3′-O-isopropylideneuridine via palladiumcatalyzed cross-coupling with Me₄Sn followed by deprotection. Application of this method for the synthesis of 6-phenyluridine was also carried out.     

Metabolism of O6-Propyl and N6-Propyl-carbovir in CEM Cells

Abstract

The metabolism of O⁶-propyl-carbovir and N⁶-propyl-carbovir, two selective inhibitors of HIV replication, has been evaluated in CEM cells. Both compounds were phosphorylated in intact cells to carbovir-5′-triphosphate. The metabolism of these two agents was inhibited by deoxycoformycin and mycophenolic acid, but not erythro-9-(2-hydroxy-3-nonyl)adenine. No evidence of the 5′-triphosphate of either compound was detected in CEM cells.     

Introduction of a Benzyl Group onto the 2′-OH of 6-Chloropurine 3′-O-Benzoylriboside

Abstract

A new method to introduce a benzyl group onto the 2′-OH of purine ribonucleoside is described. Thus, 6-chloropurine 3′-O-benzoylriboside and its 5′-O-trityl congener were condensed with benzyl alcohol using the Mitsunobu reaction to give the 2′-O-benzyl derivative. The yields were varied from 4.6 to 62.9% depending on the solvent. The product was converted to adenosine, indicating that the stereochemistry at C-2′ is retained.     

Conformational Analysis of 6-Substituted Uridine Analogues: Crystal Structures of Uridine-6-Thiocarboxamide and 6-Cyanouridine

Abstract

Crystal structure analyses of uridine-6-thiocarboxamide (I) and 6-cyanouridine (II) show that both structures adopt a syn conformation about the glycosyl bond. The conformation of I is similar to that of orotidine (III). The furanose ring conformation of I is C4′-exo, unusual for syn conformers, and is C3′-endo in II. These results have a bearing on the inhibition of orotidylate decarboxylase by the 5′-phosphate of I.     

Nucleophilic Substitution Reactions of 5-Bromo-6-methyluridines

Abstract

The reactions of the 5-bromo-6-methyl-2′,3′-O-isopropylideneuridines 9 and 10 with a number of nucleophiles in hot DMF have been investigated. With acetate ion as the nucleophile, either the 5-acetoxy- (11,12) or the 6-acetoxymethyl- (15) products can be obtained in modest yield depending upon the exact reaction conditions. With nitrogen nucleophiles (aniline or p-methoxybenzylamine) reaction takes place at the 6-methyl carbon, whereas with sulfur nucleophiles (thiophenol, thioacetate) only the 5-substituted products are obtained.     

Synthesis of 3′-Fluoro-3′-deoxy-N6-cyclopentyladenosine

Abstract

Starting from 9-(β-D-xylofuranosyl)-6-chloropurine, the title compound was prepared in four steps. Reaction with cyclopentylamine followed by treatment of the 2′-O,5′-O-ditritylated material with diethylaminosulfur trifluoride (DAST), yielded after deprotection the desired compound.     

Thiocyanation of Tubercidin and Its Derivatization to 6-Propyl-and 6-Cyano Derivatives (Nucleosides and Nucleotides. 411.)

Abstract

Thiocyanation of tubercidin with thiocyanogen chloride gave the 5-thiocyanate, which was converted to the 5-methylthio, 5-methylsulfonyl as well as 6-propyl and 6-cyano derivatives. The 6,5′-O-cyclotubercidins were also prepared.     

Adducts of Mannose 6-Phosphate with 5-Iodo-2′-Deoxyuridine and 2-5A as Potential Antiviral Agents

Abstract

To examine the possibility that the mannose 6-phosphate receptor system might be capitalized upon to facilitate uptake of nucleotides or nucleotides into cell, adducts of mannose 6-phosphate with 5-iodo-2′-deoxyuridine 5′-monophosphate and with adenosine 5′-monophosphate, p5′A2′p5′A and p5′A2′p5′A2′p5′A were prepared and evaluated for their antiviral activities. The adducts with 2′,5′-oligoadenylates possessed no significant antiviral activity. The adduct with 5-iodo-2′-deoxyuridine 5′-monophosphate showed activity that could be fully explained by extracellular cleavage to free 5-iodo-2′-deoxyuridine.     

Irreversible Inhibition of Thymidylate Synthase by Pyridoxine (B6) Analogues

Abstract

Three vitamin B₆ analogues have been synthesized and tested as inhibitors of thymidylate synthase. The compounds are: 4′,5′-dichloro-, 4,5′-dibromo- and 4′, 5′-diiodo-pyridoxine. All three analogues inhibited the enzyme irreversibly. The kinetic data for the chloro- and bromo-analogues showed that a limiting rate of inhibition is approached as the inhibitor concentration is increased, which indicates that a reversible enzyme: inhibitor affinity complex is formed prior to the irreversible reaction. 4′,5′-Dibromo-pyridoxine exhibited a greater binding affinity (lower K_i) for thymidylate synthase than 4′,5′-dichloro-pyridoxine, and it also reacted faster to irreversibly inhibit the enzyme. The presence of the substrate dUMP (10μM) completely protected thymidylate synthase from inhibition. These data suggest that the halogenated vitamin B₆ analogues are active site-directed inhitors of thymidylate synthase, which first bind reversibly to the catalytic site and then react irreversibly with the enzyme.     

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.     

Synthesis and Antiviral Activity of 5-Halovinyl-6-Aza-2′-Deoxyuridines

Abstract

(E)-5-(2-bromovinyl)-6-aza-2′-deoxyuridine and some related analogues have been synthesized and evaluated for antiherpes activity.     

Studies on the Chemistry of 5-Acetoxy-6-(Acetoxymethyl)-Uridines: Synthesis of a New type of 5′-Cyclonucleoside1

Abstract

The 5-acetoxy-6-(acetoxymethy1)-uridine derivative 18 is converted in aqueous sodium hydroxide solution into the imidazole cyclonucleoside 22. Compound 22, in which an oxygen bridge links the sugar and base methano groups, represents a new type of 5′-cyclonucleoside.     

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

Abstract

6-Phenyl, 7-phenyl, 6-(4-biphenyl)-, 7-(4-biphenyl)lumazine N¹-(2′-deoxy-D-ribofuranosides) were synthesized and incorporated in the different positions of self-complementary oligodeoxyribonucleotides, and the influence of modifications on the melting points of duplexes was studied.     

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.

     

Formation of 5- and 6-Aminocytosine Nucleosides and Nucleotides from the Corresponding 5-Bromocytosine Derivatives: Synthesis and Reaction Mechanism

Abstract

An improved method for the synthesis of 5-aminocytidine (3a), 5-amino-2′-deoxycytidine (3b), and their 5′-monophosphates (3c,d) from the corresponding 5-bromo pyrimidines, using liquid ammonia, is described. The respective 6-aminocytosine derivatives (4a,b,c,d), minor products of the amination reaction, were isolated and characterized. A plausible mechanism is proposed to account for the formation of both 5-and 6-substituted products.     

Synthesis of 2′,3′,6′-Trideoxy-β-D-erythro-hexopyranosyl Nucleosides Employing Intramolecular Glycosylation as a Key Step

Abstract

2′,3′-Dideoxy-β-D-erythro-hexopyranosyl pyrimidine nucleosides were synthesized in a stereoselective manner utilizing the intramolecular pyrimidine delivery method. The nucleosides obtained from this reaction were further transformed into its 6′-deoxy derivative, which is a promising synthetic intermediate for amicetin family antibiotics.