Enzymatic transglycosylation – the transfer of the carbohydrate moiety from one heterocyclic base to another – is being actively developed and applied for the synthesis of practically important nucleosides. This reaction is catalyzed by nucleoside phosphorylases (NPs), which are responsible for reversible phosphorolysis of nucleosides to yield the corresponding heterocyclic bases and monosaccharide 1‐phosphates. We found that 7‐methyl‐2′‐deoxyguanosine (7‐Me‐dGuo) is an efficient and novel donor of the 2‐deoxyribose moiety in the enzymatic transglycosylation for the synthesis of purine and pyrimidine 2′‐deoxyribonucleosides in excellent yields. Unlike 7‐methylguanosine, its 2′‐deoxy derivative is dramatically less stable. Fortunately, we have found that 7‐methyl‐2′‐deoxyguanosine hydroiodide may be stored for 24 h in Tris‐HCl buffer (pH 7.5) at room temperature without significant decomposition. In order to optimize the reagent ratio, a series of analytical transglycosylation reactions were conducted at ambient temperature. According to HPLC analysis of the transglycosylation reactions, the product 5‐ethyl‐2′‐deoxyuridine (5‐Et‐dUrd) was obtained in high yield (84–93%) by using a small excess (1.5 and 2.0 equiv.) of 7‐Me‐dGuo over 5‐ethyluracil (5‐Et‐Ura) and 0.5 equiv. of inorganic phosphate. Thymidine is a less effective precursor of α‐d‐2‐deoxyribofuranose 1‐phosphate (dRib‐1p) compared to 7‐Me‐dGuo. We synthesized 2′‐deoxyuridine, 5‐Et‐dUrd, 2′‐deoxyadenosine and 2′‐deoxyinosine on a semi‐preparative scale using the optimized reagent ratio (1.5:1:0.5) in high yields. Unlike other transglycosylation reactions, the synthesis of 2‐chloro‐2′‐deoxyadenosine was performed in a heterogeneous medium because of the poor solubility of the initial 2‐chloro‐6‐aminopurine. Nevertheless, this nucleoside was prepared in good yield. The developed enzymatic procedure for the preparation of 2′‐deoxynucleosides may compete with the known chemical approaches.magnified image
The emergence of new viruses and resistant strains of pathogenic microorganisms has become a powerful stimulus in the search for new drugs. Nucleosides are a promising class of natural compounds, and more than a hundred drugs have already been created based on them, including antiviral, antibacterial and antitumor agents. The review considers the structural and functional features and mechanisms of action of known nucleoside analogs with antiviral, antibacterial or antiprotozoal activity. Particular attention is paid to the mechanisms that determine the antiviral effect of nucleoside analogs containing hydrophobic fragments. Depending on the structure and position of the hydrophobic substituent, such nucleosides can either block the process of penetration of viruses into cells or inhibit the stage of genome replication. The mechanisms of inhibition of viral enzymes by compounds of nucleoside and non-nucleoside nature have been compared. The stages of creation of antiparasitic drugs, which are based on the peculiarities of metabolic transformations of nucleosides in humans body and parasites, have been considered. A new approach to the creation of drugs is described, based on the use of prodrugs of modified nucleosides, which, as a result of metabolic processes, are converted into an effective drug directly in the target organ or tissue. This strategy makes it possible to reduce the general toxicity of the drug to humans and to increase the effectiveness of its action on cells infected by the virus.
In this study, we demonstrate that N(6)-isopentenyladenosine, which essentially is a plant cytokinin-like compound, exerts a potent and selective antiviral effect on the replication of human enterovirus 71 with an EC50 of 1.0 ± 0.2 μM and a selectivity index (SI) of 5.7. The synthesis of analogs with modification of the N(6)-position did not result in a lower EC50 value. However, in particular with the synthesis of N(6)-(5-hexene-2-yne-1-yl)adenosine (EC50 = 4.3 ± 1.5 μM), the selectivity index was significantly increased: because of a reduction in the adverse effect of this compound on the host cells, an SI > 101 could be calculated. With this study, we for the first time provide proof that a compound class that is based on the plant cytokinin skeleton offers an interesting starting point for the development of novel antivirals against mammalian viruses, in the present context in particular against enterovirus 71.
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