Dokl Biochem Biophys
December 2023
For the first time, N-(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.
View Article and Find Full Text PDFNucleoside reverse transcriptase inhibitors are the first class of drugs to be approved by the FDA for the suppression of HIV-1 and are widely used for this purpose in combination with drugs of other classes. Despite the progress in HIV-1 treatment, there is still the need to develop novel efficient antivirals. Here the efficiency of HIV-1 inhibition by a set of original 5-substituted uridine nucleosides was studied.
View Article and Find Full Text PDFAdenosine and its analogues play an important role as bioregulators of metabolic processes in animal cells, affecting a variety of metabolic functions by acting through the purinergic signaling system. Synthesis and structure-activity relationship for some known purine nucleosides bearing chiral substituents are considered in this work. These compounds represent a promising potential as drug prototypes for targeted therapy of cancer, metabolic dysfunctions, and neuronal disorders due to their enhanced selectivity to receptors of the purinergic signaling system.
View Article and Find Full Text PDFThe use of cancer chemotherapy sensitizers is a promising approach to induce the effect of clinically used anticancer treatments. One of the interesting targets is Tyrosyl-DNA Phosphodiesterase 1 (Tdp1), a DNA-repair enzyme, that may prevent the action of clinical Topoisomerase 1 (Top1) inhibitors, such as topotecan (Tpc). Tdp1 eliminates covalent Top1-DNA (Top1c) complexes that appear under the action of topotecan and determines the cytotoxic effect of this drug.
View Article and Find Full Text PDFCytokinins, classical phytohormones, affect all stages of plant ontogenesis, but their application in agriculture is limited because of the lack of appropriate ligands, including those specific for individual cytokinin receptors. In this work, a series of chiral -benzyladenine derivatives were studied as potential cytokinins or anticytokinins. All compounds contained a methyl group at the α-carbon atom of the benzyl moiety, making them - or -enantiomers.
View Article and Find Full Text PDFIn 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 N-benzyl-2'-deoxyadenosine, potential inhibitors of replication of enteroviruses in a cell, were obtained starting from the corresponding ribonucleosides.
View Article and Find Full Text PDFInhibition of human DNA repair enzyme tyrosyl-DNA phosphodiesterase 1 (Tdp1) by different chiral lipophilic nucleoside derivatives was studied. New Tdp1 inhibitors were found in the series of the studied compounds with IC = 2.7-6.
View Article and Find Full Text PDFOne of the promising approaches in the development of nucleoside prodrugs is to use the nucleoside analogs containing lipophilic biodegradable residues, which are cleaved to biologically active forms after metabolic transformations in the cell. The introduction of such fragments makes it possible to reduce the general toxicity of the drug candidate and increase its stability in the cell. In order to study the influence of biodegradable lipophilic groups on antiviral activity and cytotoxicity, in this work we synthesized N-benzyl-2',3',5'-tri-O-nicotinoyl adenosine and N-(3-fluorobenzyl)-2',3',5'-tri-O-nicotinoyl adenosine, derivatives of N-benzyladenosine (BAR) and N-(3-fluorobenzyl)adenosine (FBAR), which had previously shown prominent antiviral activity against human enterovirus EV-A71 but appeared to be cytotoxic.
View Article and Find Full Text PDFA comparative analysis of the transglycosylation conditions catalyzed by nucleoside phosphorylases, leading to the formation of 2'-deoxynucleosides, was performed. We demonstrated that maximal yields of 2'-deoxynucleosides, especially modified, can be achieved under small excess of glycosyl-donor (7-methyl-2'-deoxyguanosine, thymidine) and a 4-fold lack of phosphate. A phosphate concentration less than equimolar one allows using only a slight excess of the carbohydrate residue donor nucleoside to increase the reaction's output.
View Article and Find Full Text PDFA simple and efficient method for the preparation of α-D-ribose 1-phosphate and 2-deoxy-α-D-ribose 1-phosphate, key intermediates in nucleoside metabolism and important starting compounds for the enzymatic synthesis of various modified nucleosides, has been proposed. It consists in near-irreversible enzymatic phosphorolysis of readily prepared hydroiodide salts of 7-methylguanosine and 7-methyl-2'-deoxyguanosine, respectively, in the presence of purine nucleoside phosphorylase. α-D-Ribose 1-phosphate and 2-deoxy-α-D-ribose 1-phosphate are obtained in near quantitative yields (by HPLC analysis) and 74%-94% yields after their isolation and purification.
View Article and Find Full Text PDFThe 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.
View Article and Find Full Text PDFThe 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.
View Article and Find Full Text PDFCoronaviruses (CoVs) belong to a large family of zoonotic supercapsid viruses, including about 40 species of RNA-containing viruses with several strains capable of causing damage to the lungs and respiratory tract. The severe acute respiratory syndrome coronavirus (SARS-CoV) was responsible for the worldwide SARS outbreak in 2003. The rapid global spread of SARS-CoV-2 has been the cause of significant health concerns and thousands of deaths in 2019-2020 and outlined the need for novel antivirals.
View Article and Find Full Text PDFInhibition of DNA repair enzymes tyrosyl-DNA phosphodiesterase 1 and poly(ADP-ribose)polymerases 1 and 2 in the presence of pyrimidine nucleoside derivatives was studied here. New effective Tdp1 inhibitors were found in a series of nucleoside derivatives possessing 2',3',5'-tri--benzoyl-d-ribofuranose and 5-substituted uracil moieties and have half-maximal inhibitory concentrations (IC) in the lower micromolar and submicromolar range. 2',3',5'-Tri--benzoyl-5-iodouridine manifested the strongest inhibitory effect on Tdp1 (IC = 0.
View Article and Find Full Text PDFThe biosynthesis of aromatic cytokinins , unlike isoprenoid cytokinins, is still unknown. To compare the final steps of biosynthesis pathways of aromatic and isoprenoid cytokinins, we synthesized a series of nucleoside derivatives of natural cytokinins starting from acyl-protected ribofuranosyl-, 2'-deoxyribofuranosyl- and 5'-deoxyribofuranosyladenine derivatives using stereoselective alkylation with further deblocking. Their cytokinin activity was determined in two bioassays based on model plants and .
View Article and Find Full Text PDFDokl Biochem Biophys
September 2019
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 N-isopentenyladenine were able to turn into active cytokinins in planta exhibiting cytokinin activity.
View Article and Find Full Text PDFBiochim Biophys Acta Proteins Proteom
January 2020
Enzymatic transglycosylation, a transfer of the carbohydrate moiety from one heterocyclic base to another, is catalyzed by nucleoside phosphorylases (NPs) and is being actively developed and applied for the synthesis of biologically important nucleosides. Here, we report an efficient one-step synthesis of 5-substitited pyrimidine ribonucleosides starting from 7-methylguanosine hydroiodide in the presence of nucleoside phosphorylases (NPs).
View Article and Find Full Text PDFCurr Protoc Nucleic Acid Chem
September 2019
In this article, the earlier reported procedure for the synthesis of 2'-O-β-D-ribofuranosyl nucleosides was extended to the synthesis of 2'-O-α-D-ribofuranosyl adenosine, a monomeric unit of poly(ADP-ribose). It consists in condensation of a small excess of 1-O-acetyl-2,3,5-tri-O-benzoyl-α,β-D-arabinofuranose activated with tin tetrachloride with 3',5'-O-tetra-isopropyldisiloxane-1,3-diyl-ribonucleosides in 1,2-dichloroethane. The following debenzoylation and silylation of arabinofuranosyl residue and inversion of configuration at C-2'' atom of arabinofuranosyl residue and final removal of silyl protective groups gave 2'-O-α-D-ribofuranosyl adenosine in overall 13% to 21% yield.
View Article and Find Full Text PDFOur understanding of how, and the extent to which, phytopathogens reconfigure host metabolic pathways to enhance virulence is remarkably limited. Here we investigate the dynamics of the natural disaccharide nucleoside, 3'-O-β-D-ribofuranosyladenosine, in leaves of Arabidopsis thaliana infected with virulent Pseudomonas syringae pv. tomato strain DC3000.
View Article and Find Full Text PDFCurr Protoc Nucleic Acid Chem
December 2018
This unit describes an effective method for the preparation of natural cytokinins and their synthetic derivatives based on enzymatic cleavage of the N-glycosidic bond of N -substituted adenosine or O -substituted inosine derivatives in the presence of purine nucleoside phosphorylase (PNP) and Na HAsO . The arsenolysis reaction is irreversible due to the hydrolysis of the resulting α-D-ribose-1-arsenate. As a result, the desired products are formed in near-quantitative yields, as indicated by high-performance liquid chromatography (HPLC) analysis, and can easily be isolated.
View Article and Find Full Text PDFA new class of tyrosyl-DNA phosphodiesterase 1 (TDP1) inhibitors based on disaccharide nucleosides was identified. TDP1 plays an essential role in the resistance of cancer cells to currently used antitumour drugs based on Top1 inhibitors such as topotecan and irinotecan. The most effective inhibitors investigated in this study have IC values (half-maximal inhibitory concentration) in 0.
View Article and Find Full Text PDFCurr Protoc Nucleic Acid Chem
March 2018
This unit describes preparation of N -substituted adenosines (cytokinin nucleosides), a unique class of compounds with a wide spectrum of biological activities. Regioselective alkylation of N -acetyl-2',3',5'-tri-O-acetyladenosine with alkyl halides under basic conditions or alcohols under Mitsunobu conditions followed by deprotection are the methods of choice for the preparation of the cytokinin nucleosides. The attractive feature of this strategy is the possibility of using a broad library of commercially available alkyl halides and alcohols under mild reaction conditions.
View Article and Find Full Text PDFRecently, we demonstrated that the natural cytokinin nucleosides ⁶-isopentenyladenosine () and ⁶-benzyladenosine () exert a potent and selective antiviral effect on the replication of human enterovirus 71. In order to further characterize the antiviral profile of this class of compounds, we generated a series of fluorinated derivatives of and evaluated their activity on the replication of human enterovirus 71 in a cytopathic effect (CPE) reduction assay. The monofluorination of the -phenyl group changed the selectivity index (SI) slightly because of the concomitant high cell toxicity.
View Article and Find Full Text PDFDesign and development of nucleoside analogs is an established strategy in the antiviral drug discovery field. Nevertheless, for many viruses the coverage of structure-activity relationships (SAR) in the nucleoside chemical space is not sufficient. Here we present the nucleoside SAR exploration for tick-borne encephalitis virus (TBEV), a member of Flavivirus genus.
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