N6-(5-Phenylpentan-1-yl)adenine-A New Non-competitive Receptor-Specific Anti-cytokinin.

For the first time, N6-(5-phenylpentan-1-yl)adenine, a synthetic adenine derivative with a receptor-specific anticytokinin effect, was obtained. This compound exhibits a pronounced anticytokinin effect, reducing cytokinin-induced expression of the GUS reporter gene when interacting with the cytokinin receptor CRE1/AHK4 of the model plant Arabidopsis thaliana. This effect manifests itself much weaker with the related AHK2 receptor and is not observed at all with the AHK3 receptor. We showed that N6-(5-phenylpentan-1-yl)adenine does not bind to the ligand-binding sites of the Arabidopsis cytokinin receptors, which does not allow it to be classified as a true cytokinin antagonist. Despite the currently unknown mechanism of action, this compound may find its use as a component of plant growth regulators. Like true anticytokinins, it enhances root growth of Arabidopsis seedlings, apparently suppressing the action of endogenous cytokinins on the "root" receptor CRE1/AHK4.

Synthesis of Fluorine-Containing Analogues of Purine Deoxynucleosides: Optimization of Enzymatic Transglycosylation Conditions.

In this work, a comparative analysis of the conditions of transglycosylation reactions catalyzed by E. coli nucleoside phosphorylases was carried out, and the optimal conditions for the formation of various nucleosides were determined. Under the optimized conditions of transglycosylation reaction, fluorine-containing derivatives of N6-benzyl-2'-deoxyadenosine, potential inhibitors of replication of enteroviruses in a cell, were obtained starting from the corresponding ribonucleosides.

Antiviral and Antimicrobial Nucleoside Derivatives: Structural Features and Mechanisms of Action.

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.

[Antiviral and Antimicrobial Nucleoside Derivatives: Structural Features and Mechanisms of Action].

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 compound, 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.

Comparative Analysis of the Biosynthesis of Isoprenoid and Aromatic Cytokinins.

To compare the biosynthesis pathways of aromatic and isoprenoid cytokinins, a series of nucleoside derivatives of natural cytokinins was synthesized and their cytokinin activity was determined in a test system based on the model plant Arabidopsis thaliana. Cytokinin nucleosides are known to lack the hormonal activity until cleaving the ribose moiety at the position 9. Our experiments have shown that both ribo- and 5'-deoxyribo derivatives of N6-isopentenyladenine were able to turn into active cytokinins in planta exhibiting cytokinin activity. By contrast, 5'-deoxy nucleosides of aromatic cytokinins did not show similar activity. Since 5'-deoxy nucleosides cannot phosphorylate in vivo, the direct pathway of active cytokinin formation by cleavage of nucleotides is blocked here. The detected activity in 5'-deoxy nucleosides of isoprenoid cytokinins and the lack of the activity in 5'-deoxy nucleosides of aromatic cytokinins indicates the difference in the biosynthesis of these compounds.

[The selective toxic effect of dialdehyde derivatives of the pyrimidine nucleosides on human tumor cells].

The impact of a number of synthetic nucleoside derivatives on the growth and survival of cultured human ovarian tumor cells (line SKOV-3) and normal human lung fibroblasts was investigated. It was shown that the dialdehyde derivatives of uridine, 1-ß-D-eritrofuranozyl uracil and 3'-O-ß-D-ribofuranosyl-2'-deoxythymidine, in contrast to their unoxidized counterparts, exert marked toxic effect on SKOV-3 cells. Cultured human fibroblasts were less susceptible to the damaging effect of the dialdehyde nucleosides. The dialdehyde derivative of 1-ß-D-eritrofuranozyl uracil demonstrated greatest differences in the cytotoxic effect on these cultures: inhibition of tumor SKOV-3 cells growth on 50% or more was achieved at the concentrations of this compound ten times lower than in the case of normal fibroblasts.