How does Europe PMC derive its citations network? Protein Interactions. Protein Families. Nucleotide Sequences. Functional Genomics Experiments. Protein Structures. Gene Ontology GO Terms. Data Citations. They were reported synthesis of novel racemic conformationally locked nucleosides with bicyclo[2. Two methodologies were employed for introduction of the chloropurine moiety to the scaffold: i the Mitsunobu reaction of the chloropurine nucleobase with appropriate alcohols and ii a built-up strategy from appropriate amines. These compounds could be considered as the 6-chloropurines substituted at position 9 with different substituted bicyclic scaffolds bicyclo[2.
These bicyclo systems norbornene or norbornane , like the oxabicyclo[2. All compounds were evaluated for antiviral activity against Coxsackie virus B3, as shown in Table 1. Most analogues showed activity in the low micromolar range with minimal cytotoxicity to the cell line used in this study.
Studies on the mode of action of the most promising compounds are in progress. Quadrelli and coworkers synthesized the isoxazoline-based carbocyclic nucleosides and by the linear construction of the desired purine and pyrimidine bases on the regioisomeric aminols Scheme 1. The complex course of 1,3-dipolar cycloaddition between benzonitrile oxide and the cyclohexadiene adduct of nitrosocarbonyl benzene afford regioisomeric mixtures of exo and endo cycloadducts. The exo cycloadducts of are suitable starting materials for isoxazoline-cyclohexane nucleoside synthesis.
Detachment of the benzoyl group and reductive cleavage of the N—O bond provided the stereodefined aminols , which were used for the linear construction of purine nucleosides by well-established synthetic protocols. Substitution with 5-amino-4,6-dichloropyrimidine and subsequent condensation with orthoformates afford the chloropurines and . These were further derivatized by replacement of the chlorine with amines and alkoxides to give suitable samples for antiviral tests in very good yields.
The same group was synthesized isoxazoline-carbocyclic nucleosides hav- ing a hydroxymethylene side chain, and a variety of analogues was attained starting from the stereodefined heterocyclic aminol , which are readily avail- able through exo selective 1,3-dipolar cycloadditions of benzonitrile oxide to 2-azanorbornenes and elaboration of the cycloadducts Scheme 1.
The stereodefined heterocyclic aminols afford the carbocyclic skeleton for the linear construction of the purine rings. Functionalization of the chloropurines —  with a variety of amines extended the synthetic potential of this strategy, allowing for a fine-tuning of their biological and antiviral activity as well as comparison with the corresponding nor-nucleosides. Biological evaluation of the newly obtained compounds — is in progress.
The first ones have the base moiety directly attached to the ring, whereas the other ones have a spacer between the base and the ring Figure 1. Chu and coworkers accomplished the first asymmetric synthesis of d- and l-cyclopropyl nucleosides, which belong to the first category Scheme 1. The requisite cyclopropyl ring was installed by Simmons-Smith cyclopropanation following oxidation, Curtius rearrangement and deprotection protocol to yield cyclopropyl amine The target d-nucleosides were obtained by a linear methodology.
Unfortunately, no significant biological activity was exhibited by synthesized nucleosides. On the other hand, in the second category, several biologically interesting nucleosides were discovered. Ashton et al. Tsuji and coworkers explored extensive SAR of carbocyclic nucleosides bearing a methylene spacer between the base and car- bocyclic ring [,]. Furthermore, this nucleoside was 8- to fold more potent than acyclovir and penciclovir against VZV, and the selectivity index of nucleoside was also high.
As an extension of the research, a series of 5-substituted uracil derivatives were prepared, and some of the target nucleosides exhibited potent anti-VZV activity Scheme 1. Particularly, 5-bromovinyl nucleoside was about fold more potent than acyclovir and had good oral bioavailability in rats The enantiomeric syntheses of compounds and were accomplished using chiral cyclo- propane lactone as starting material.
Zemlicka and coworkers described another type of interesting carbocyclic nucleosides, in which the spacer between the base and the ring is an unsatu- rated double bond [,]. Compounds, such as and Figure 1. The pair of enantiomers and was synthesized through enzymatic as well as chemical resolutions Schemes 1. Further modifications of the spacer generated spiropentane nucleoside Scheme 1. R -Methylenecyclopropylcarbinol was converted in few steps to reagents , which were used for alkylation-elimination of adenine and Scheme 1.
Nucleosides, Nucleotides and Oligonucleotides Conference GRC
It is not cytotoxic, and its efficacy is somewhat lower than that of ganciclovir. Preparation of carbocyclic analogs of the natural counterparts was first reported by Honjo . In addition, the d-enantiomer of C -OXT-G , lobucavir, LBV could be phosphorylated to its triphosphate by viral TK as well as protein kinase  and exhibited broad-spectrum antiviral activity against HBV and herpes viruses .
However, the clinical studies were suspended due to oncogenicity in rodents. Further modifications based on the structure of C -OXTs generated series of interesting four-membered carbocyclic nucleosides. Novel spiro-carbocyclic nucleosides and have been prepared by Chu and coworkers via enzymatic resolution Scheme 1. Reagents and conditions: a P. The NMR conformational studies suggested that the nucleosides antiviral activity was correlated with their predominant conformation Figure 1.
Virus input was 20 plaque-forming units PFU. The values are means of two independent determinations. It is well known that opposite enantiomers can display dif- ferent pharmacological and toxicological properties. Hence, Alibs and coworkers report an enantiodivergent approach to d- and lhydroxycyclohexenyl nucleo- sides — , starting from the common intermediate , which bears a hydrobenzoin moiety as the chiral auxiliary Schemes 1.
They Scheme 1. Unfortunately, none of the compounds was found anti-HIV active. Particularly, the discovery of aba- cavir and entecavir as clinically effective antiviral agents prompted the studies of various carbocyclic nucleosides. Although the synthesis of carbocyclic nucle- osides has advanced dramatically, more efficient and practical methods are still in demand for the preparation of biologically active compounds as well as chi- ral key intermediates. In the future, novel biologically interesting carbocyclic nucleosides will likely be continuously discovered to improve the existing list of chemotherapeutic agents.
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Tetrahedron Letters, 29 , — An enanti- oconvergent route to carbocyclic nucleosides — -aristeromycin and — -neplanocin a via the asymmetric Diels—Alder reaction. Journal of the Chemical Society, Perkin Transactions 1 , , — Boyer, S. Carbocyclic nucleoside analogs. Concise enan- tioselective synthesis of functionalized cyclopentanes and formal total synthesis of aristeromycin. The Journal of Organic Chemistry, 62 , — Brown, B. A novel, one-pot ring expansion of cyclobu- tanones.
Syntheses of carbovir and aristeromycin. The Journal of Organic Chemistry, 65 , — Deardorff, D. Conversion of allylic alcohols into allylic nitromethyl compounds via a palladium-catalyzed solvolysis: An enantioselective synthesis of an advanced carbocyclic nucleoside precursor. The Journal of Organic Chemistry, 61 , — Palladium-catalyzed enantioselective synthesis of carbanucleosides. Asymmetric alkylation of nitroalkanes Ange- wandte Chemie, 39 , — Borcherding, D. Synthesis of analogs of neplanocin A: Utilization of optically active dihydroxycyclopentenones derived from carbohydrates.
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Recent Advances in Nucleosides: Chemistry and Chemotherapy
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